diff --git "a/README.md" "b/README.md" --- "a/README.md" +++ "b/README.md" @@ -11,38 +11,58 @@ model-index: -# baseline +# Overview This model is a fine-tuned version of [output/ms2/led-base/baseline](https://huggingface.co/output/ms2/led-base/baseline) on the allenai/mslr2022 ms2 dataset. It achieves the following results on the evaluation set: - eval_loss: 3.7527 - -- eval_rouge1_recall: [20.28985507246377, 16.363636363636363, 30.0, 14.035087719298245, 45.83333333333333, 32.25806451612903, 28.57142857142857, 12.76595744680851, 12.048192771084338, 47.05882352941176, 9.278350515463918, 23.18840579710145, 14.754098360655737, 18.91891891891892, 39.473684210526315, 15.0, 27.659574468085108, 19.696969696969695, 33.33333333333333, 29.268292682926827, 25.0, 11.458333333333332, 16.49484536082474, 17.24137931034483, 55.55555555555556, 11.11111111111111, 24.0, 9.67741935483871, 17.94871794871795, 10.112359550561797, 21.052631578947366, 12.244897959183673, 9.917355371900827, 31.25, 23.809523809523807, 37.93103448275862, 19.230769230769234, 17.77777777777778, 27.160493827160494, 13.88888888888889, 23.404255319148938, 28.57142857142857, 10.204081632653061, 25.925925925925924, 22.807017543859647, 12.244897959183673, 55.00000000000001, 10.344827586206897, 19.444444444444446, 22.950819672131146, 16.666666666666664, 15.0, 26.666666666666668, 25.71428571428571, 33.33333333333333, 23.61111111111111, 36.666666666666664, 8.280254777070063, 40.0, 9.523809523809524, 56.25, 6.521739130434782, 11.76470588235294, 30.23255813953488, 12.56544502617801, 25.0, 10.0, 20.689655172413794, 19.230769230769234, 9.482758620689655, 24.390243902439025, 29.411764705882355, 10.077519379844961, 30.952380952380953, 13.157894736842104, 7.317073170731707, 19.35483870967742, 38.88888888888889, 8.620689655172415, 23.636363636363637, 30.76923076923077, 15.384615384615385, 16.666666666666664, 29.166666666666668, 32.55813953488372, 12.987012987012985, 25.925925925925924, 5.376344086021505, 15.66265060240964, 17.647058823529413, 9.67741935483871, 37.77777777777778, 11.76470588235294, 26.5625, 21.62162162162162, 19.642857142857142, 24.489795918367346, 17.543859649122805, 48.38709677419355, 34.883720930232556, 20.0, 25.0, 25.925925925925924, 12.5, 9.6045197740113, 16.216216216216218, 14.285714285714285, 8.080808080808081, 17.24137931034483, 8.433734939759036, 35.18518518518518, 16.9811320754717, 37.03703703703704, 22.22222222222222, 11.827956989247312, 31.57894736842105, 10.784313725490197, 5.714285714285714, 21.153846153846153, 18.27956989247312, 23.809523809523807, 18.75, 18.181818181818183, 17.543859649122805, 15.151515151515152, 30.76923076923077, 40.0, 37.03703703703704, 15.0, 39.285714285714285, 32.35294117647059, 8.227848101265822, 12.82051282051282, 17.20430107526882, 21.666666666666668, 11.881188118811881, 13.793103448275861, 20.454545454545457, 20.930232558139537, 0.0, 12.5, 11.818181818181818, 35.483870967741936, 8.421052631578947, 19.444444444444446, 25.0, 12.5, 21.73913043478261, 17.142857142857142, 30.0, 42.30769230769231, 33.33333333333333, 26.785714285714285, 33.33333333333333, 35.0, 17.72151898734177, 8.333333333333332, 12.244897959183673, 35.294117647058826, 27.586206896551722, 6.722689075630252, 20.930232558139537, 31.70731707317073, 17.72151898734177, 50.0, 33.33333333333333, 9.923664122137405, 36.84210526315789, 41.17647058823529, 32.35294117647059, 14.705882352941178, 20.37037037037037, 32.69230769230769, 10.0, 9.090909090909092, 13.953488372093023, 49.35064935064935, 23.809523809523807, 19.166666666666668, 15.625, 31.818181818181817, 40.476190476190474, 16.666666666666664, 9.929078014184398, 14.285714285714285, 13.333333333333334, 26.190476190476193, 28.57142857142857, 28.26086956521739, 7.518796992481203, 41.02564102564102, 13.513513513513514, 11.11111111111111, 28.888888888888886, 27.450980392156865, 24.0, 40.0, 7.909604519774012, 25.0, 27.083333333333332, 16.853932584269664, 14.942528735632186, 15.909090909090908, 50.0, 28.205128205128204, 26.229508196721312, 15.436241610738255, 0.0, 8.0, 19.35483870967742, 14.285714285714285, 29.629629629629626, 27.500000000000004, 25.71428571428571, 35.294117647058826, 15.942028985507244, 35.0, 28.57142857142857, 21.052631578947366, 45.0, 20.0, 14.444444444444443, 25.0, 31.25, 52.63157894736842, 8.0, 23.076923076923077, 38.46153846153847, 25.925925925925924, 8.75, 10.344827586206897, 12.244897959183673, 40.35087719298245, 19.696969696969695, 17.5, 21.59090909090909, 47.05882352941176, 23.404255319148938, 25.71428571428571, 32.5, 11.627906976744185, 24.137931034482758, 43.47826086956522, 32.075471698113205, 22.22222222222222, 22.058823529411764, 27.083333333333332, 19.81132075471698, 30.23255813953488, 60.97560975609756, 13.636363636363635, 58.333333333333336, 24.59016393442623, 27.659574468085108, 14.678899082568808, 28.8135593220339, 35.714285714285715, 31.57894736842105, 21.875, 23.076923076923077, 25.64102564102564, 8.527131782945736, 23.52941176470588, 19.565217391304348, 37.93103448275862, 8.0, 21.666666666666668, 12.903225806451612, 9.75609756097561, 57.14285714285714, 31.03448275862069, 15.686274509803921, 47.61904761904761, 16.3265306122449, 33.33333333333333, 38.23529411764706, 25.301204819277107, 42.30769230769231, 14.754098360655737, 64.0, 37.5, 14.545454545454545, 16.666666666666664, 36.58536585365854, 15.909090909090908, 28.39506172839506, 22.727272727272727, 10.989010989010989, 27.27272727272727, 14.545454545454545, 27.500000000000004, 20.0, 9.027777777777777, 40.0, 69.23076923076923, 21.21212121212121, 29.411764705882355, 25.0, 33.33333333333333, 33.33333333333333, 14.000000000000002, 9.615384615384617, 21.428571428571427, 34.78260869565217, 5.769230769230769, 20.930232558139537, 9.01639344262295, 40.476190476190474, 32.758620689655174, 8.13953488372093, 8.421052631578947, 18.0327868852459, 27.27272727272727, 19.19191919191919, 10.43956043956044, 32.18390804597701, 20.0, 36.36363636363637, 52.38095238095239, 8.333333333333332, 28.333333333333332, 17.441860465116278, 16.666666666666664, 13.636363636363635, 29.508196721311474, 14.285714285714285, 23.214285714285715, 23.809523809523807, 13.0, 20.37037037037037, 16.39344262295082, 52.63157894736842, 21.153846153846153, 10.344827586206897, 25.0, 24.0, 8.333333333333332, 19.672131147540984, 20.0, 9.696969696969697, 12.121212121212121, 10.714285714285714, 9.70873786407767, 20.0, 25.0, 7.4074074074074066, 14.285714285714285, 9.523809523809524, 8.0, 11.76470588235294, 29.166666666666668, 30.303030303030305, 16.546762589928058, 28.125, 25.0, 15.492957746478872, 27.77777777777778, 42.42424242424242, 29.03225806451613, 28.947368421052634, 21.428571428571427, 8.527131782945736, 66.66666666666666, 18.181818181818183, 42.857142857142854, 12.5, 12.76595744680851, 28.440366972477065, 11.538461538461538, 7.894736842105263, 30.0, 15.625, 38.46153846153847, 66.66666666666666, 27.380952380952383, 13.333333333333334, 7.926829268292683, 8.695652173913043, 31.372549019607842, 34.48275862068966, 26.923076923076923, 32.0, 68.75, 15.384615384615385, 18.421052631578945, 16.27906976744186, 23.684210526315788, 30.303030303030305, 18.867924528301888, 23.91304347826087, 16.666666666666664, 32.55813953488372, 26.31578947368421, 10.44776119402985, 23.333333333333332, 21.0, 51.724137931034484, 12.23021582733813, 11.11111111111111, 34.48275862068966, 11.494252873563218, 26.190476190476193, 24.074074074074073, 24.390243902439025, 22.413793103448278, 10.975609756097562, 8.433734939759036, 12.727272727272727, 18.9873417721519, 11.666666666666666, 21.052631578947366, 41.66666666666667, 9.090909090909092, 36.36363636363637, 17.333333333333336, 8.16326530612245, 20.833333333333336, 17.647058823529413, 21.568627450980394, 13.924050632911392, 19.35483870967742, 12.162162162162163, 28.205128205128204, 17.80821917808219, 9.836065573770492, 41.17647058823529, 11.363636363636363, 12.068965517241379, 15.384615384615385, 40.909090909090914, 22.727272727272727, 21.73913043478261, 10.526315789473683, 14.814814814814813, 18.75, 26.41509433962264, 31.57894736842105, 26.190476190476193, 19.230769230769234, 22.5, 4.891304347826087, 7.6923076923076925, 20.0, 28.57142857142857, 5.714285714285714, 46.42857142857143, 26.31578947368421, 20.0, 21.58273381294964, 38.23529411764706, 18.120805369127517, 20.0, 31.25, 21.27659574468085, 37.77777777777778, 17.391304347826086, 20.3125, 9.30232558139535, 9.45945945945946, 31.25, 13.636363636363635, 8.19672131147541, 3.4482758620689653, 12.0, 13.88888888888889, 57.57575757575758, 29.629629629629626, 22.22222222222222, 1.8867924528301887, 15.789473684210526, 5.681818181818182, 10.638297872340425, 62.5, 15.151515151515152, 21.052631578947366, 14.000000000000002, 32.25806451612903, 21.73913043478261, 21.73913043478261, 18.75, 27.586206896551722, 28.888888888888886, 18.487394957983195, 9.803921568627452, 36.36363636363637, 9.75609756097561, 22.5, 11.538461538461538, 31.818181818181817, 31.818181818181817, 8.88888888888889, 26.47058823529412, 16.417910447761194, 14.084507042253522, 21.568627450980394, 15.66265060240964, 45.45454545454545, 10.476190476190476, 52.94117647058824, 23.076923076923077, 21.153846153846153, 44.44444444444444, 9.63855421686747, 32.926829268292686, 24.46808510638298, 14.285714285714285, 10.526315789473683, 19.230769230769234, 44.44444444444444, 15.463917525773196, 14.37908496732026, 33.33333333333333, 16.901408450704224, 8.695652173913043, 46.15384615384615, 35.13513513513514, 14.285714285714285, 26.08695652173913, 32.25806451612903, 16.666666666666664, 45.0, 11.827956989247312, 45.45454545454545, 16.666666666666664, 22.916666666666664, 22.22222222222222, 23.333333333333332, 5.555555555555555, 11.76470588235294, 43.75, 20.689655172413794, 15.384615384615385, 27.419354838709676, 53.84615384615385, 16.0, 27.659574468085108, 9.67741935483871, 20.0, 21.50537634408602, 10.869565217391305, 28.07017543859649, 10.81081081081081, 14.285714285714285, 30.555555555555557, 52.63157894736842, 17.80821917808219, 12.698412698412698, 23.076923076923077, 17.647058823529413, 36.36363636363637, 4.6875, 30.303030303030305, 9.923664122137405, 19.35483870967742, 18.96551724137931, 36.36363636363637, 20.833333333333336, 13.043478260869565, 38.70967741935484, 13.157894736842104, 13.043478260869565, 44.44444444444444, 60.0, 13.793103448275861, 32.608695652173914, 4.545454545454546, 13.953488372093023, 29.03225806451613, 14.285714285714285, 34.48275862068966, 29.411764705882355, 13.333333333333334, 27.586206896551722, 15.730337078651685, 30.76923076923077, 6.25, 9.333333333333334, 15.555555555555555, 8.771929824561402, 23.52941176470588, 7.547169811320755, 21.62162162162162, 18.9873417721519, 45.45454545454545, 19.047619047619047, 47.82608695652174, 7.5, 17.02127659574468, 5.88235294117647, 16.091954022988507, 40.0, 23.684210526315788, 25.925925925925924, 47.05882352941176, 20.0, 15.254237288135593, 11.11111111111111, 50.0, 5.263157894736842, 21.53846153846154, 41.17647058823529, 22.727272727272727, 34.04255319148936, 30.76923076923077, 16.666666666666664, 47.61904761904761, 25.0, 13.793103448275861, 10.95890410958904, 17.02127659574468, 7.0588235294117645, 35.0, 28.57142857142857, 20.833333333333336, 20.967741935483872, 20.0, 36.36363636363637, 13.48314606741573, 20.0, 14.444444444444443, 50.0, 21.73913043478261, 28.57142857142857, 20.0, 10.81081081081081, 32.55813953488372, 10.15625, 21.951219512195124, 11.03448275862069, 28.40909090909091, 20.77922077922078, 32.25806451612903, 41.66666666666667, 18.421052631578945, 21.428571428571427, 14.893617021276595, 27.77777777777778, 55.00000000000001, 22.58064516129032, 28.57142857142857, 47.82608695652174, 29.72972972972973, 12.280701754385964, 25.0, 25.49019607843137, 27.586206896551722, 8.21917808219178, 48.275862068965516, 27.500000000000004, 9.782608695652174, 14.018691588785046, 14.864864864864865, 44.44444444444444, 36.666666666666664, 76.47058823529412, 13.043478260869565, 12.5, 9.937888198757763, 16.25, 25.0, 7.142857142857142, 28.888888888888886, 29.268292682926827, 34.375, 9.090909090909092, 32.075471698113205, 12.0, 13.793103448275861, 12.82051282051282, 20.0, 10.476190476190476, 10.588235294117647, 7.476635514018691, 17.475728155339805, 27.500000000000004, 24.0, 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32.83582089552239, 12.195121951219512, 16.129032258064516, 25.0, 20.0, 17.142857142857142, 14.285714285714285, 8.333333333333332, 15.068493150684931, 22.857142857142858, 6.086956521739131, 12.82051282051282, 14.117647058823529, 27.27272727272727, 27.586206896551722, 20.37037037037037, 18.91891891891892, 23.376623376623375, 17.142857142857142, 21.73913043478261, 23.170731707317074, 15.217391304347828, 31.428571428571427, 50.0, 18.181818181818183, 26.47058823529412, 32.142857142857146, 42.857142857142854, 33.33333333333333, 13.636363636363635, 11.11111111111111, 27.27272727272727, 18.666666666666668, 16.3265306122449, 30.76923076923077, 21.428571428571427, 25.0, 11.11111111111111, 20.967741935483872, 27.692307692307693, 24.137931034482758, 12.82051282051282, 14.893617021276595, 38.46153846153847, 17.647058823529413, 33.33333333333333, 10.714285714285714, 15.384615384615385, 12.987012987012985, 9.433962264150944, 17.857142857142858, 50.0, 33.33333333333333, 15.09433962264151, 20.0, 6.951871657754011, 34.285714285714285, 11.538461538461538, 13.636363636363635, 25.0, 26.47058823529412, 31.25, 21.21212121212121, 25.0, 37.93103448275862, 31.25, 20.833333333333336, 48.38709677419355, 35.08771929824561, 38.82352941176471, 20.454545454545457, 8.21917808219178, 16.94915254237288, 13.793103448275861, 8.823529411764707, 28.205128205128204, 35.18518518518518, 29.78723404255319, 15.686274509803921, 15.789473684210526, 8.0, 40.74074074074074, 21.25984251968504, 33.33333333333333, 6.41025641025641, 22.950819672131146, 13.333333333333334, 37.142857142857146, 13.043478260869565, 16.666666666666664, 32.142857142857146, 14.666666666666666, 13.953488372093023, 12.82051282051282, 22.22222222222222, 25.0, 57.14285714285714, 27.083333333333332, 23.809523809523807, 24.137931034482758, 17.391304347826086, 40.909090909090914, 23.88059701492537, 22.388059701492537, 17.5, 15.789473684210526, 12.871287128712872, 10.0, 9.655172413793103, 13.445378151260504, 14.772727272727273, 12.5, 14.285714285714285, 19.047619047619047, 22.22222222222222, 40.909090909090914, 9.345794392523365, 39.39393939393939, 34.375, 47.368421052631575, 38.46153846153847, 7.59493670886076, 10.606060606060606, 13.559322033898304, 23.91304347826087, 12.643678160919542, 12.82051282051282, 18.75, 21.875, 15.254237288135593, 9.876543209876543, 7.142857142857142, 11.904761904761903, 22.22222222222222, 12.5, 25.0, 12.0, 15.957446808510639, 7.476635514018691, 27.27272727272727, 42.857142857142854, 17.647058823529413, 20.930232558139537, 18.91891891891892, 20.212765957446805, 31.57894736842105, 14.285714285714285, 25.0, 25.0, 20.833333333333336, 30.303030303030305, 6.790123456790123, 7.746478873239436, 17.543859649122805, 21.73913043478261, 12.280701754385964, 9.090909090909092, 18.867924528301888, 10.416666666666668, 16.27906976744186, 45.45454545454545, 17.307692307692307, 15.66265060240964, 13.793103448275861, 25.333333333333336, 9.574468085106384, 23.52941176470588, 15.384615384615385, 44.827586206896555, 31.03448275862069, 12.903225806451612, 10.526315789473683, 8.0, 47.61904761904761, 26.190476190476193, 16.923076923076923, 12.037037037037036, 28.57142857142857, 20.253164556962027, 12.76595744680851, 19.230769230769234, 22.58064516129032, 25.71428571428571, 33.33333333333333, 19.047619047619047, 25.0, 29.411764705882355, 22.641509433962266, 9.473684210526317, 22.22222222222222, 25.0, 20.37037037037037, 14.84375, 26.47058823529412, 33.33333333333333, 15.384615384615385, 25.454545454545453, 44.11764705882353, 19.047619047619047, 34.61538461538461, 33.33333333333333, 19.047619047619047, 64.70588235294117, 64.0, 19.148936170212767, 20.689655172413794, 15.714285714285714, 15.384615384615385, 34.61538461538461, 22.5, 10.0, 17.391304347826086, 16.0, 22.22222222222222, 15.18987341772152, 68.75, 33.33333333333333, 50.0, 9.67741935483871, 15.789473684210526, 16.666666666666664, 12.173913043478262, 63.1578947368421, 24.59016393442623] -- eval_rouge1_fmeasure: 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22.58064516129032, 40.0, 23.076923076923077, 50.0, 31.818181818181817, 50.0, 30.434782608695656, 50.0, 50.0, 28.57142857142857, 61.53846153846154, 8.695652173913043, 40.909090909090914, 69.23076923076923, 38.88888888888889, 52.0, 13.636363636363635, 47.61904761904761, 38.095238095238095, 39.285714285714285, 21.052631578947366, 17.02127659574468, 16.0, 21.428571428571427, 7.142857142857142, 23.333333333333332, 18.96551724137931, 26.47058823529412] -- eval_rougeL_recall: [13.043478260869565, 12.727272727272727, 20.0, 14.035087719298245, 29.166666666666668, 16.129032258064516, 21.428571428571427, 10.638297872340425, 12.048192771084338, 41.17647058823529, 5.154639175257731, 18.84057971014493, 9.836065573770492, 13.513513513513514, 31.57894736842105, 10.0, 23.404255319148938, 16.666666666666664, 33.33333333333333, 17.073170731707318, 20.833333333333336, 9.375, 9.278350515463918, 15.517241379310345, 44.44444444444444, 10.1010101010101, 16.0, 6.451612903225806, 12.82051282051282, 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16.666666666666664, 20.833333333333336, 52.38095238095239, 18.75, 19.047619047619047, 17.24137931034483, 17.391304347826086, 31.818181818181817, 19.402985074626866, 19.402985074626866, 15.0, 11.403508771929824, 9.900990099009901, 10.0, 8.275862068965518, 7.563025210084033, 7.954545454545454, 9.375, 9.523809523809524, 19.047619047619047, 16.666666666666664, 36.36363636363637, 6.5420560747663545, 36.36363636363637, 21.875, 36.84210526315789, 30.76923076923077, 6.329113924050633, 10.606060606060606, 10.16949152542373, 19.565217391304348, 10.344827586206897, 8.974358974358974, 15.625, 18.75, 13.559322033898304, 6.172839506172839, 7.142857142857142, 11.904761904761903, 11.11111111111111, 12.5, 25.0, 12.0, 10.638297872340425, 5.607476635514018, 20.454545454545457, 35.714285714285715, 9.411764705882353, 11.627906976744185, 10.81081081081081, 9.574468085106384, 31.57894736842105, 8.16326530612245, 25.0, 14.0625, 20.833333333333336, 24.242424242424242, 6.790123456790123, 5.633802816901409, 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11.428571428571429, 15.384615384615385, 34.61538461538461, 22.5, 7.777777777777778, 11.304347826086957, 12.0, 13.071895424836603, 10.126582278481013, 68.75, 22.22222222222222, 30.76923076923077, 6.451612903225806, 7.894736842105263, 11.11111111111111, 6.086956521739131, 57.89473684210527, 14.754098360655737] -- eval_rougeL_fmeasure: [19.354838709677416, 17.94871794871795, 21.05263157894737, 22.857142857142858, 26.415094339622648, 20.0, 27.27272727272727, 14.92537313432836, 20.408163265306122, 38.88888888888889, 8.547008547008547, 27.956989247311824, 16.000000000000004, 17.24137931034483, 33.80281690140845, 13.186813186813188, 35.483870967741936, 27.499999999999996, 45.714285714285715, 21.538461538461544, 17.54385964912281, 15.65217391304348, 15.65217391304348, 22.78481012658228, 44.44444444444444, 17.54385964912281, 17.77777777777778, 11.320754716981131, 17.241379310344826, 13.861386138613863, 26.666666666666668, 15.254237288135592, 10.071942446043165, 19.672131147540988, 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20.689655172413794, 32.35294117647059] -- eval_rougeLsum_recall: [18.84057971014493, 12.727272727272727, 20.0, 14.035087719298245, 41.66666666666667, 22.58064516129032, 21.428571428571427, 10.638297872340425, 10.843373493975903, 41.17647058823529, 7.216494845360824, 21.73913043478261, 11.475409836065573, 16.216216216216218, 31.57894736842105, 15.0, 25.53191489361702, 19.696969696969695, 33.33333333333333, 19.51219512195122, 20.833333333333336, 10.416666666666668, 14.432989690721648, 13.793103448275861, 44.44444444444444, 11.11111111111111, 16.0, 9.67741935483871, 12.82051282051282, 8.98876404494382, 21.052631578947366, 10.204081632653061, 8.264462809917356, 28.125, 16.666666666666664, 31.03448275862069, 19.230769230769234, 13.333333333333334, 25.925925925925924, 13.88888888888889, 23.404255319148938, 23.809523809523807, 8.16326530612245, 22.22222222222222, 20.175438596491226, 12.244897959183673, 35.0, 10.344827586206897, 16.666666666666664, 19.672131147540984, 16.666666666666664, 10.0, 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5.263157894736842, 15.254237288135593, 12.345679012345679, 13.636363636363635, 26.31578947368421, 3.225806451612903, 21.27659574468085, 17.647058823529413, 23.728813559322035, 27.027027027027028, 17.391304347826086, 16.0, 21.428571428571427, 16.666666666666664, 11.11111111111111, 14.705882352941178, 13.636363636363635, 39.39393939393939, 35.0, 10.465116279069768, 9.333333333333334, 45.45454545454545, 31.818181818181817, 7.6923076923076925, 16.27906976744186, 12.0, 21.73913043478261, 10.0, 7.6923076923076925, 15.66265060240964, 13.846153846153847, 7.207207207207207, 6.25, 20.833333333333336, 11.627906976744185, 18.333333333333332, 10.144927536231885, 17.857142857142858, 0.0, 36.58536585365854, 11.578947368421053, 11.023622047244094, 11.11111111111111, 15.09433962264151, 40.0, 21.27659574468085, 10.465116279069768, 12.5, 16.666666666666664, 9.375, 15.909090909090908, 16.0, 21.951219512195124, 8.823529411764707, 17.391304347826086, 52.94117647058824, 17.857142857142858, 17.24137931034483, 9.45273631840796, 15.841584158415841, 6.122448979591836, 13.953488372093023, 15.476190476190476, 27.77777777777778, 13.043478260869565, 25.71428571428571, 22.857142857142858, 7.8431372549019605, 27.419354838709676, 17.142857142857142, 20.0, 58.333333333333336, 7.547169811320755, 8.24742268041237, 27.27272727272727, 12.396694214876034, 7.0588235294117645, 15.384615384615385, 25.0, 23.333333333333332, 10.76923076923077, 24.0, 3.937007874015748, 14.814814814814813, 20.754716981132077, 11.650485436893204, 20.0, 14.666666666666666, 6.8493150684931505, 31.57894736842105, 4.45859872611465, 26.41509433962264, 30.76923076923077, 16.666666666666664, 15.686274509803921, 22.22222222222222, 33.33333333333333, 7.5, 13.043478260869565, 12.82051282051282, 6.6350710900473935, 5.88235294117647, 10.869565217391305, 21.311475409836063, 22.641509433962266, 7.894736842105263, 8.411214953271028, 9.30232558139535, 11.904761904761903, 8.860759493670885, 28.35820895522388, 8.536585365853659, 13.978494623655912, 22.916666666666664, 15.384615384615385, 17.142857142857142, 11.904761904761903, 5.952380952380952, 13.698630136986301, 20.0, 4.3478260869565215, 12.82051282051282, 10.588235294117647, 21.21212121212121, 20.689655172413794, 20.37037037037037, 16.216216216216218, 22.07792207792208, 17.142857142857142, 17.391304347826086, 21.951219512195124, 10.869565217391305, 28.57142857142857, 32.142857142857146, 18.181818181818183, 20.588235294117645, 25.0, 28.57142857142857, 30.0, 13.636363636363635, 6.944444444444445, 22.727272727272727, 17.333333333333336, 12.244897959183673, 19.230769230769234, 14.285714285714285, 22.22222222222222, 11.11111111111111, 20.967741935483872, 20.0, 20.689655172413794, 11.538461538461538, 13.829787234042554, 38.46153846153847, 17.647058823529413, 33.33333333333333, 7.142857142857142, 12.82051282051282, 12.987012987012985, 8.49056603773585, 14.285714285714285, 35.714285714285715, 28.57142857142857, 11.320754716981133, 20.0, 6.417112299465241, 31.428571428571427, 11.538461538461538, 9.090909090909092, 17.105263157894736, 23.52941176470588, 18.75, 9.090909090909092, 25.0, 27.586206896551722, 25.0, 20.833333333333336, 35.483870967741936, 24.561403508771928, 32.94117647058823, 20.454545454545457, 6.8493150684931505, 11.864406779661017, 13.793103448275861, 6.862745098039216, 25.64102564102564, 31.48148148148148, 23.404255319148938, 15.686274509803921, 15.789473684210526, 4.0, 25.925925925925924, 21.25984251968504, 27.27272727272727, 5.128205128205128, 21.311475409836063, 12.0, 22.857142857142858, 9.782608695652174, 13.88888888888889, 25.0, 14.666666666666666, 13.953488372093023, 7.6923076923076925, 16.666666666666664, 20.833333333333336, 52.38095238095239, 22.916666666666664, 19.047619047619047, 17.24137931034483, 17.391304347826086, 36.36363636363637, 22.388059701492537, 20.8955223880597, 17.5, 14.035087719298245, 10.891089108910892, 10.0, 8.96551724137931, 11.76470588235294, 9.090909090909092, 11.458333333333332, 9.523809523809524, 19.047619047619047, 16.666666666666664, 36.36363636363637, 8.411214953271028, 33.33333333333333, 32.8125, 42.10526315789473, 30.76923076923077, 7.59493670886076, 10.606060606060606, 10.16949152542373, 21.73913043478261, 10.344827586206897, 12.82051282051282, 18.75, 15.625, 15.254237288135593, 9.876543209876543, 7.142857142857142, 11.904761904761903, 11.11111111111111, 12.5, 25.0, 10.666666666666668, 11.702127659574469, 6.5420560747663545, 22.727272727272727, 28.57142857142857, 12.941176470588237, 11.627906976744185, 16.216216216216218, 18.085106382978726, 31.57894736842105, 13.60544217687075, 25.0, 21.875, 20.833333333333336, 24.242424242424242, 6.172839506172839, 6.338028169014084, 15.789473684210526, 21.73913043478261, 12.280701754385964, 9.090909090909092, 16.9811320754717, 10.416666666666668, 11.627906976744185, 36.36363636363637, 16.346153846153847, 13.855421686746988, 12.068965517241379, 20.0, 8.51063829787234, 19.607843137254903, 9.615384615384617, 44.827586206896555, 27.586206896551722, 12.903225806451612, 10.526315789473683, 8.0, 23.809523809523807, 16.666666666666664, 16.923076923076923, 10.185185185185185, 28.57142857142857, 15.18987341772152, 10.638297872340425, 11.538461538461538, 22.58064516129032, 25.71428571428571, 23.809523809523807, 15.873015873015872, 25.0, 29.411764705882355, 20.754716981132077, 8.421052631578947, 22.22222222222222, 21.428571428571427, 12.962962962962962, 14.0625, 23.52941176470588, 23.809523809523807, 14.102564102564102, 20.0, 38.23529411764706, 14.285714285714285, 26.923076923076923, 25.925925925925924, 16.666666666666664, 41.17647058823529, 60.0, 19.148936170212767, 20.689655172413794, 14.285714285714285, 15.384615384615385, 34.61538461538461, 22.5, 10.0, 14.782608695652174, 12.0, 18.954248366013072, 11.39240506329114, 68.75, 33.33333333333333, 38.46153846153847, 8.064516129032258, 10.526315789473683, 11.11111111111111, 10.434782608695652, 63.1578947368421, 18.0327868852459] -- eval_rougeLsum_fmeasure: 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1954, 1955, 1956, 1957, 1958, 1959, 1960, 1961, 1962, 1963, 1964, 1965, 1966, 1967, 1968, 1969, 1970, 1971, 1972, 1973, 1974, 1975, 1976, 1977, 1978, 1979, 1980, 1981, 1982, 1983, 1984, 1985, 1986, 1987, 1988, 1989, 1990, 1991, 1992, 1993, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020] -- eval_perturbation: None -- eval_perturbed_frac: None -- eval_sampling_strategy: random -- eval_perturbed_seed: None - eval_seed: 42 - eval_model_name_or_path: output/ms2/led-base/baseline - eval_doc_sep_token: -- eval_inputs: ["Necrotizing enterocolitis ( NEC ) is one of the most serious gastrointestinal emergencies in very low birth weight ( VLBW ) preterm neonates, affecting 7 - 14 % of these neonates. Due to the seriousness of the disease, prevention of NEC is the most important goal. Quantitative Real-Time PCR Assays To Identify and Quantify Fecal Bifidobacterium Species in Infants Receiving a Prebiotic Infant Formula ABSTRACT A healthy intestinal microbiota is considered to be important for priming of the infants'mucosal and systemic immunity. Breast-fed infants typically have an intestinal microbiota dominated by different Bifidobacterium species. It has been described that allergic infants have different levels of specific Bifidobacterium species than healthy infants. For the accurate quantification of Bifidobacterium adolescentis, Bifidobacterium angulatum, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium dentium, Bifidobacterium infantis, and Bifidobacterium longum in fecal sample s, duplex 5′ nuclease assays were developed. The assays, targeting rRNA gene intergenic spacer regions, were vali date d and compared with conventional PCR and fluorescent in situ hybridization methods. The 5′ nuclease assays were subsequently used to determine the relative amounts of different Bifidobacterium species in fecal sample s from infants receiving a st and ard formula or a st and ard formula supplemented with galacto- and fructo-oligosaccharides ( OSF ). A breast-fed group was studied in parallel as a reference. The results showed a significant increase in the total amount of fecal bifidobacteria ( 54.8 % ± 9.8 % to 73.4 % ± 4.0 % ) in infants receiving the prebiotic formula ( OSF ), with a diversity of Bifidobacterium species similar to breast-fed infants. The intestinal microbiota of infants who received a st and ard formula seems to resemble a more adult-like distribution of bifidobacteria and contains relatively more B. catenulatum and B. adolescentis ( 2.71 % ± 1.92 % and 8.11 % ± 4.12 %, respectively, versus 0.15 % ± 0.11 % and 1.38 % ± 0.98 % for the OSF group ). In conclusion, the specific prebiotic infant formula used induces a fecal microbiota that closely resembles the microbiota of breast-fed infants also at the level of the different Bifidobacterium species The effect of enteral supplementation of a prebiotic mixture of non-human milk galacto-, fructo- and acidic oligosaccharides on intestinal permeability in preterm infants. Preterm infants have an impaired gut barrier function. We aim ed to determine the effects of enteral supplementation of a prebiotic mixture consisting of neutral oligosaccharides ( short-chain galacto-oligosaccharides (SCGOS)/long-chain fructo-oligosaccharides ( LCFOS ) ) and acidic oligosaccharides ( AOS ) on intestinal permeability of preterm infants as measured by the sugar absorption test in the first week of life. Furthermore, we determined host- and treatment-related factors associated with intestinal permeability. In a r and omised controlled trial, preterm infants with a gestational age < 32 weeks and /or birth weight ( BW ) < 1500 g received enteral supplementation of SCGOS/LCFOS/AOS or placebo ( maltodextrin ) between days 3 and 30 of life. Intestinal permeability, reflected by the urinary lactulose/mannitol ( L/M ) ratio after oral ingestion of lactulose and mannitol, was assessed at three time points : before the start of the study ( t = 0 ), at day 4 ( t = 1 ) and at day 7 ( t = 2 ) of life. Data were analysed by generalised estimating equations. In total, 113 infants were included. Baseline patient and nutritional characteristics were not different between the SCGOS/LCFOS/AOS ( n 55 ) and the placebo groups ( n 58 ). SCGOS/LCFOS/AOS had no effect on the L/M ratio between t = 0 and t = 2. In both the groups, the L/M ratio decreased from t = 0 to t = 2 ( P < 0·001 ). Low BW increased the L/M ratio ( P = 0·002 ). Exclusive breast milk feeding and mixed breast milk/formula feeding during the first week of life decreased the L/M ratio ( P < 0·001 and P < 0·05, respectively ). In conclusion, enteral supplementation of a prebiotic mixture does not enhance the postnatal decrease in intestinal permeability in preterm infants in the first week of life Effects of galactooligosaccharide and long-chain fructooligosaccharide supplementation during pregnancy on maternal and neonatal microbiota and immunity--a randomized, double-blind, placebo-controlled study. BACKGROUND Galactooligosaccharides ( GOS ) and long-chain fructooligosaccharides ( lcFOS ) proliferate bifidobacteria in infant gut microbiota. However, it is not known how GOS and FOS influence the microbiota of pregnant women and whether a potential prebiotic effect is transferred to the offspring. OBJECTIVES We aim ed to test how supplementation with GOS and lcFOS ( GOS/lcFOS ) in the last trimester of pregnancy affects maternal and neonatal gut microbiota. Variables of fetal immunity were assessed as a secondary outcome. DESIGN In a r and omized, double-blind, placebo-controlled pilot study, 48 pregnant women were supplemented 3 times/d with 3 g GOS/lcFOS ( at a ratio of 9:1 ) or maltodextrin ( placebo ) from week 25 of gestation until delivery. Percentages of bifidobacteria and lactobacilli within total bacterial counts were detected by fluorescent in situ hybridization and quantitative polymerase chain reaction in maternal and neonatal ( days 5, 20, and approximately 182 ) stool sample s. Variables of fetal immunity were assessed in cord blood by using flow cytometry and cytokine multiplex-array analysis. RESULTS The proportions of bifidobacteria in the maternal gut were significantly higher in the supplemented group than in the placebo group ( 21.0 % and 12.4 %, respectively ; P = 0.026 ) ; the proportion of lactobacilli did not differ between the groups. In neonates, bifidobacteria and lactobacilli percentages, diversity and similarity indexes, and fetal immune parameters did not differ significantly between the 2 groups. Mother-neonate similarity indexes of bifidobacteria decreased over time. CONCLUSIONS GOS/lcFOS supplementation has a bifidogenic effect on maternal gut microbiota that is not transferred to neonates. The increased maternal bifidobacteria did not affect fetal immunity as measured by a comprehensive examination of cord blood immunity variables The capacity of nondigestible carbohydrates to stimulate fecal bifidobacteria in healthy humans: a double-blind, randomized, placebo-controlled, parallel-group, dose-response relation study. BACKGROUND Nondigestible carbohydrates ( NDCHs ) are fermented in the colon, where they can selectively promote the growth of bifidobacteria. OBJECTIVE Our aim was to determine the bifidogenic potential of different NDCHs used in human diets. DESIGN Two hundred healthy volunteers participated in this double-blind study. During phase 1 ( screening ), 64 volunteers were r and omly assigned to 8 groups of 8 subjects each ; for 7 d, they ingested 10 g/d of 1 of the 7 NDCHs tested or of the placebo. During phase 2 ( dose-response study ), 136 volunteers were r and omly assigned to 4 groups of 32 subjects who received 2.5, 5.0, 7.5, or 10 g/d, respectively ( 8 subjects/dose ), of one of the NDCHs that were proven to be bifidogenic during phase 1 and a fifth group of 8 subjects ( control subjects ) who received the placebo. Stools were recovered before and after NDCH consumption. RESULTS In phase 1, 4 NDCHs were found to be bifidogenic : short-chain fructooligosaccharides ( P=0.008 ), soybean oligosaccharides ( P=0.006 ), galactooligosaccharides ( P < 0.0001 ), and type III resistant starch ( P=0.02 ) ; lactulose, long-chain inulin, and isomaltooligosaccharides were not bifidogenic. In phase 2, the effects of 7-d treatment on bifidobacteria concentrations were found to differ significantly among the 4 NDCHs ( P=0.009 for time x treatment interaction ). However, no significant differences were found among doses, and there was no significant dose x time interaction. A low baseline bifidobacteria count was significantly associated with the bifidogenic response to treatment ( P < 0.001 ). CONCLUSION This study showed the different bifidogenic properties among the substrates and underlined the importance of taking into account the baseline bifidobacteria counts when evaluating the effect of the treatment Neutral and acidic oligosaccharides in preterm infants: a randomized, double-blind, placebo-controlled trial. BACKGROUND Serious infectious morbidity is high in preterm infants. Enteral supplementation of prebiotics may reduce the incidence of serious infections, especially infections related to the gastrointestinal tract. OBJECTIVE The objective was to determine the effect of enteral supplementation of a prebiotic mixture consisting of neutral oligosaccharides ( (SC)GOS/(LC)FOS ) and acidic oligosaccharides ( AOS ) on serious infectious morbidity in preterm infants. DESIGN In a r and omized controlled trial, preterm infants ( gestational age < 32 wk and /or birth weight < 1500 g ) received enteral supplementation of 80 % (SC)GOS/(LC)FOS and 20 % AOS ( 1.5 g. kg(-1 ). d(-1 ) ) or placebo ( maltodextrin ) between days 3 and 30 of life. Serious infectious morbidity was defined as a culture positive for sepsis, meningitis, pyelonephritis, or pneumonia. The analysis was performed by intention-to-treat and per- protocol, defined as > or = 50 % supplementation dose during the study period. RESULTS In total, 113 preterm infants were included. Baseline and nutritional characteristics were not different between groups. In the intention-to-treat analysis, the incidence of > or = 1 serious infection, > or = 1 serious endogenous infection, or > or = 2 serious infectious episodes was not significantly different in the (SC)GOS/(LC)FOS/AOS-supplemented and placebo groups. In the per- protocol analysis, there was a trend toward a lower incidence of > or = 1 serious endogenous infection and > or = 2 serious infectious episodes in the (SC)GOS/(LC)FOS/AOS-supplemented group than in the placebo group ( P = 0.09 and P = 0.07, respectively ). CONCLUSIONS Enteral supplementation of (SC)GOS/(LC)FOS/AOS does not significantly reduce the risk of serious infectious morbidity in preterm infants. However, there was a trend toward a lower incidence of serious infectious morbidity, especially for infections with endogenous bacteria. This finding suggests a possible beneficial effect that should be evaluated in a larger study. This trial was registered at is rct n.org as IS RCT N16211826 Motilin and gastrin secretion and lipid profile in preterm neonates following prebiotics supplementation: a double-blind randomized controlled study. BACKGROUND Gut hormones play an important role in the adaptation of the immature neonatal gut, and their secretion may be modulated by prebiotics. Furthermore, prebiotics are well known for their hypolipidemic potentials. We tested the hypothesis that prebiotics could alter motilin and gastrin secretion and reduce lipids in healthy preterms. METHODS A total of 167 newborns were r and omized to either a prebiotics enriched formula containing dietary oligosaccharides ( short-chain galacto-oligo-saccharides/long-chain fructo-oligo-saccharides [ scGOS/lcFOS ] ), at a concentration of 0.8 g/100 ml, or a common preterm formula. Day 1 and 16 basal motilin, gastrin concentrations, and lipids were evaluated together with growth parameters, gastric residue, bowel habits, and feeding tolerance. Adverse events including necrotizing enterocolitis ( NEC ) and septicemia were also recorded. RESULTS Mean motilin increase and day 16 mean values were greater for the intervention, compared with the control group ( P =.001, P =.005, respectively ), while gastrin remained high in both groups. Mean cholesterol and low density lipoprotein ( LDL ) increase were significantly greater in the control, compared with the intervention ( P =.037, and P =.001 ) group. Day 16 LDL levels were significantly higher in the control group. Mean weight was increased in the control group, while gastric residue was less and stool frequency was increased in the intervention group. NEC and septicemia were not statistically different between groups. CONCLUSION A prebiotics enriched formula result ed in significant surge of motilin relating to reduced gastric residue, compared with a common preterm formula. Mean cholesterol change was lower, while LDL was not increased in the prebiotics group, compared with the control group Dosage-Related Bifidogenic Effects of Galacto- and Fructooligosaccharides in Formula-Fed Term Infants Background Human milk oligosaccharides have been shown to stimulate selectively the growth of Bifidobacteria and Lactobacilli in the intestine. In this study, the bifidogenic effect of an experimental prebiotic oligosaccharide mixture consisting of low-molecular-weight galactooligosaccharides and high-molecular-weight fructooligosaccharides was analyzed in 90 term infants. Methods Two test formulas were supplemented with either 0.4 g/dL or with 0.8 g/dL oligosaccharides. In the control formula, maltodextrin was used as placebo. At study day 1 and study day 28, the fecal species, colony forming units ( cfu ) and pH were measured and stool characteristics, growth, and side effects were recorded. Results At study day 1, the median number of Bifidobacteria did not differ among the groups ( 0.4 g/dL group, mean [ interquartile range ] 8.5 [ 1.9 ] cfu/g ; 0.8 g/dL group, 7.7 [ 6.1 ] cfu/g ; and the placebo group, 8.8 [ 6.1 ] cfu/g ) ( figures in square brackets are interquartile range ). At the end of the 28-day feeding period, the number of Bifidobacteria was significantly increased for both groups receiving supplemented formulas ( the 0.4 g/dL group, 9.3 [ 4.9 ] cfu/g ; the 0.8 g/dL group, 9.7 [ 0.8 ] cfu/g ) versus the placebo group ( 7.2 [ 4.9 ] cfu/g, P < 0.001 ). This effect was dose dependent ( 0.4 g/dL versus 0.8 g/dL, P < 0.01 ). The number of Lactobacilli also increased significantly in both groups fed the supplemented formulas ( versus placebo, P < 0.001 ), but there was no statistically significant difference between the group fed formula with 0.4 g/dL oligosaccharides and the group fed formula with 0.8 g/dL oligosaccharides. The dosage of supplement significantly influenced the change in fecal pH ( P < 0.05 ) ( placebo, pH 5.5–6.1 ; 0.4 g/dL formula, pH 5.48–5.44 ; 0.8 g/dL formula, pH 5.54–5.19 ). Slight changes in the stool frequency result ed in a significant difference between the placebo group and the group fed the 0.8 g/dL formula at day 28 ( P < 0.01 ). Supplementation had a significant dose-dependent influence on stool consistency ( 0.8 g/dL versus placebo, P < 0.0001 ; 0.8 g/dL versus 0.4 g/dL, P < 0.01 ). Supplementation had no influence on the incidence of side effects ( crying, regurgitation, vomiting ) or growth. Conclusions These data indicate that supplementation of a term infant's formula with a mixture of galacto- and fructooligosaccharides has Very-low-birth-weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, May 1991 through December 1992. OBJECTIVES Our goals were to determine the mortality risk for infants weighing 501 to 1500 gm according to gestational age, birth weight, and gender and to document birth weight-related changes in mortality and morbidity over a 5-year time period. STUDY DESIGN In this observational study perinatal data were prospect ively collected by the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from May 1991 through December 1992 and compared with the corresponding data from 1987 through 1990. St and ard definitions were used to record sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death. RESULTS The 1991 and 1992 cohort included 4279 in-born infants. Among their mothers 10 % were < 18 years old ; 55 % were black, 31 % were white, and 11 % were Hispanic ; 14 % had received no prenatal care ; and 20 % had received antenatal corticosteroids. Multiple gestations accounted for 20 % of the births. Fifty percent of the infants were delivered by cesarean section. During 1991 and 1992 the overall survival for infants weighing 501 to 1500 gm at birth was 81 %, compared with 74 % in 1987 and 1988. Survival at birth weight 501 to 750 gm was 44 % ; it was 81 % at 751 to 1000 gm, 92 % at 1001 to 1250 gm, and 95 % between 1251 and 1500 gm. Female infants had a significantly greater chance of surviving than male infants at similar birth weights and gestational ages. At any given gestational age, smaller infants were less likely to survive. Survival in all birth weight categories increased between 1987 and 1992, without accompanying increases in medical morbidity. Major morbidity increased with decreasing birth weight and included late-onset septicemia 22 %, chronic lung disease ( oxygen dependence at 36 weeks'corrected age ) 18 %, severe intraventricular hemorrhage ( grade s III and IV ) 11 %, and necrotizing enterocolitis 5 %. Twelve percent of all infants were treated with corticosteroids for chronic lung disease, including 36 % of infants who were oxygen dependent at age 28 days. The mean length of hospital stay was 69 days for survivors and 18 days for infants who died. CONCLUSIONS Mortality for infants between 501 and 1500 gm at birth has declined over the past 5 years. There are interactions between birth weight, gestational age, gender, and survival rate. This increase in survival was not accompanied by an increase in medical morbidity A Specific Prebiotic Mixture Added to Starting Infant Formula Has Long-Lasting Bifidogenic Effects123 There is some evidence that early colonization of the intestine affects the composition of the intestinal microbiota after weaning. In the present study, the effect of prebiotics administered from the first day of life on fecal counts of bifidobacteria and lactobacilli were studied during and after the administration of the prebiotics. In this double-blind, r and omized, placebo-controlled, explorative study, 20 newborns of hepatitis C virus-infected mothers who decided not to breast feed due to their concerns regarding their plasma viral load were r and omly assigned to either a formula with 8 g/L of a specific prebiotic mixture ( short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides, ratio 9:1 ) or a formula containing the same amount of maltodextrin ( placebo ). Clinical examination including anthropometric measurements, microbiological analysis of fecal sample s, and blood leukocyte population analysis were performed at birth and 3, 6, and 12 mo age. At the age of 12 mo, hepatitis B vaccine-specific IgG serum titers ( Hepatitis B virus surface antibodies ) were also measured. Prebiotic supplementation result ed in more fecal bifidobacteria ( P < 0.0001 ) and lactobacilli ( P = 0.0044 ) compared with the placebo group. These differences between the groups were maintained during the second half of the first year without any prebiotic supplementation. There was no influence of the different diets on anthropometric data or the measured immunological variables. The data from this small explorative study indicate that early colonization of the intestine might have long-lasting effects on the composition of the intestinal microbiota Supplementation of a bovine milk formula with an oligosaccharide mixture increases counts of faecal bifidobacteria in preterm infants Background : The establishment of a balanced intestinal microflora which may protect against infection is desirable for the preterm infant. Objective : To investigate the effect of a preterm formula milk supplement consisting of oligosaccharides in similar proportions to human milk on the faecal flora and stool characteristics of preterm infants. Study design : To resemble the effect of human milk, an oligosaccharide mixture consisting of 90 % galacto-oligosaccharides and 10 % fructo-oligosaccharides was used to supplement a st and ard preterm formula at a concentration of 10 g/l. This supplemented formula was studied in 15 preterm infants, and the results were compared with those found in 15 infants fed a formula supplemented with maltodextrin as placebo. A group fed fortified mother's milk was investigated as a reference group ( n = 12 ). On four days during a 28 day feeding period ( 1, 7, 14, and 28 ), the faecal flora was investigated, and stool characteristics, growth, and possible side effects were recorded. Results : During the study period, the number of bifidobacteria in the group fed the oligosaccharide supplemented formula increased to the upper range of bifidobacteria counts in the reference group. The difference between the supplemented and non-supplemented groups was highly significant ( p = 0.0008 ). The stool characteristics were also influenced by the supplement : the stool frequency after 28 days was significantly lower in the control group than in the oligosaccharide supplemented group ( p = 0.0079 ) and the reference group ( p < 0.0001 ). Over the study period, the stool consistency in the control group became harder, but remained fairly stable in the other two groups. There was no effect of the different diets on the incidence of side effects ( crying, regurgitation, vomiting ) or on weight gain or length gain. Conclusion : Supplementing preterm formula with a mixture of galacto- and fructo-oligosaccharides at a concentration of 10 g/l stimulates the growth of bifidobacteria in the intestine and results in stool characteristics similar to those found in preterm infants fed human milk. Therefore prebiotic mixtures such as the one studied may help to improve intestinal tolerance to enteral feeding in preterm infants Prebiotic Effect Of Fructo-Oligosaccharide Supplemented Term Infant Formula at Two Concentrations Compared with Unsupplemented Formula and Human Milk Background : Human milk components, including oligosaccharides, affect the gastrointestinal flora of infants. Previous studies in adults have demonstrated that fructo-oligosaccharides increase potentially beneficial fecal bacteria, including bifidobacteria. The purpose of this study was to determine the prebiotic effect of infant formula supplemented with fructo-oligosaccharides. Methods : Healthy term infants 2 to 6 weeks of age were enrolled in a 5-week, prospect i ve, r and omized, crossover, single-site study with a nonr and omized human milk comparator group. Washout weeks preceded and followed a week of feeding with fructo-oligosaccharide-supplemented formula ( 1.5 or 3.0 g/L ). Stool specimens were quantitatively cultured weekly for bacteroides, lactobacilli, bifidobacteria, clostridia and enterococci and were tested for Clostridium difficile toxin. Results : Seventy-two of 87 infants completed the trial ; 58 were formula fed and 14 were human milk fed. Mean counts of bifidobacteria and lactobacilli were similar in all groups at entry and no group experienced a significant change in counts with fructo-oligosaccharide supplementation. After 7 days of fructo-oligosaccharide supplementation the bifidobacteria counts were greater in the 1.5 g/L fructo-oligosaccharide formula group than in the human milk fed or 3.0 g/L fructo-oligosaccharide formula groups. Formula-fed infants had higher counts of enterococci and bacteroides before fructo-oligosaccharide supplementation, and these counts did not change after supplementation. Clostridium counts increased 7 days after supplementation in the 1.5 g/L fructo-oligosaccharide formula group ( P = 0.0356 ). No human milk fed infants had C. difficile toxin in stools. Fructo-oligosaccharide ( 3.0 g/L ) supplementation result ed in more frequent and significantly softer stools. Conclusions : Infant formula supplemented with 1.5 or 3.0 g/L fructo-oligosaccharides was safe but had minimal effect on fecal flora and C. difficile toxin The Effect of Neutral Oligosaccharides on Reducing the Incidence of Necrotizing Enterocolitis in Preterm infants: A Randomized Clinical Trial Background : Necrotizing enterocolitis ( NEC ) is one of the most destructive diseases associated with conditions of neonatal prematurity. Supplementation with enteral prebiotics may reduce the incidence of NEC, especially in infants who fed exclusively with breast-milk. Therefore, we compared the efficacy and safety of enteral supplementation of a prebiotic mixture ( short chain galacto-oligosaccharides/long chain fructo-oligosaccharides [ SCGOS/LCFOS ] ) versus no intervention on incidence of NEC in preterm infants. Methods : In a single-center r and omized control trial 75 preterm infants ( birth weight [ BW ] ≤1500 g, gestational age ≤34 weeks and were not fed with formula ) on 30 ml/kg/day volume of breast-milk were r and omly allocated to have enteral supplementation with a prebiotic mixture ( SCGOS/LCFOS ; 9:1 ) or not receive any prebiotic. The incidence of suspected NEC, feeding intolerance, time to full enteral feeds, duration of hospitalization were investigated. Results : Differences in demographic characteristics were not statistically important. SCGOS/LCFOS mixture significantly reduced the incidence of suspected NEC, ( 1 [ 4.0 % ] vs. 11 [ 22.0 % ] ; hazard ratio : 0.49 [ 95 % confidence interval : 0.29 - 0.84 ] ; P = 0.002 ), and time to full enteral feeds ( 11 [ 7 - 21 ] vs. 14 [ 8 - 36 ] days ; P - 0.02 ]. Also duration of hospitalization was meaningfully shorter in the prebiotic group ( 16 [ 9 - 45 ] vs. 25 [ 11 - 80 ] ; P - 0.004 ]. Prebiotic oligosaccharides were well tolerated by very low BW ( VLBW ) infants. Conclusions : Enteral supplementation with prebiotic significantly reduced the incidence of NEC in VLBW infants who were fed exclusively breast-milk. This finding suggests that it might have been the complete removal of formula which caused a synergistic effect between nonhuman neutral oligosaccharides ( prebiotic ) and human oligosaccharides The effect of a fructo-oligosaccharide supplemented formula on gut flora of preterm infants. AIM The intestinal flora of breast-fed infants is generally dominated by bifidobacteria which have beneficial properties. Their presence is due to various components of breast milk, including prebiotic substances. This prospect i ve double-blind study compared the numbers of bifidobacteria in the stool flora of bottle-fed preterm infants r and omized to receive for 14 days either a formula with prebiotic fructo-oligosaccharides at a concentration of 0.4 g/dL or the same formula with maltodextrin as a placebo. METHODS Within 0 - 14 days after birth, 56 healthy bottle-fed infants were enrolled to receive either the prebiotic or placebo. Faecal sample s were taken at inclusion day and at study day 7. The number of bifidobacteria in the stools, stool characteristics and somatic growth were recorded during the study. RESULTS In the group fed fructo-oligosaccharides, both the numbers of bifidobacteria in the stools and the proportion of infants colonized with them were significantly higher as compared to the placebo group ( p=0.032 and p=0.030 respectively ). There was also a higher number of bacteroids in the fructo-oligosaccharide group as compared to the placebo ( p=0.029 ). At the same time, reduction was noted in the numbers of Escherichia coli and enterococci. ( p=0.029, and p=0.025, respectively ). Supplementation had also significant influence on stool frequency per day ( p=0.0080 ). CONCLUSION An infant formula containing a small quantity of prebiotic oligosaccharides is well accepted and leads to rapid growth of bifidobacteria in the gut of bottle-fed preterm infants while decreasing the numbers of pathogenic microorganisms Conditions of Bifidobacterial Colonization in Preterm Infants: A Prospective Analysis Background : Premature birth results in a delayed and abnormal qualitative pattern of gut colonization. This abnormal pattern is thought to affect intestinal development and contribute to a higher risk of gastrointestinal infectious diseases such as neonatal necrotizing enterocolitis ( NEC ). In particular, bifidobacteria are thought to play a major role. We therefore studied bifidobacterial colonization in preterm infants during the first month of life. Patients and Methods : Fecal sample s were prospect ively analyzed in 52 infants born at a gestational age ranging from 30 to 35 weeks fed with a preterm formula alone and, in 18, with their mother's milk. Fecal sample s were collected twice per week during the hospital stay. Bifidobacterial colonization was analyzed with culture and a molecular method. Results : Bifidobacterial colonization occurred in 18 infants at a median age of 11 days, always greater than the corrected mean gestational age of 35.4 weeks ( SD, 0.9 ) and greater than 34 weeks for 16 of 18. Colonization by bifidobacteria was affected by neither birthweight nor mode of delivery nor antibiotics given to the mother or infant. In contrast, birth gestational age had a significant impact on colonization by bifidobacteria ( P < 0.05 ), which always occurred in children born at a birth gestational age greater than 32.9 weeks ( P < 0.05 ). Conclusions : Birth gestational age seems to act as a major determinant of bifidobacterial colonization in the premature infant, suggesting the role of gut maturation, a finding that should probably be taken into account in manipulations of the gut flora aim ed at reducing NEC Human milk oligosaccharides are associated with protection against diarrhea in breast-fed infants. OBJECTIVE To determine the association between maternal milk levels of 2-linked fucosylated oligosaccharide and prevention of diarrhea as a result of Campylobacter, caliciviruses, and diarrhea of all causes in breast-fed infants. STUDY DESIGN Data and banked sample s were analyzed from 93 breast-feeding mother-infant pairs who were prospect ively studied during 1988 - 1991 from birth to 2 years with infant feeding and diarrhea data collected weekly ; diarrhea was diagnosed by a study physician. Milk sample s obtained 1 to 5 weeks postpartum were analyzed for oligosaccharide content. Data were analyzed by Poisson regression. RESULTS Total 2-linked fucosyloligosaccharide in maternal milk ranged from 0.8 to 20.8 mmol/L ( 50%-92 % of milk oligosaccharide ). Moderate-to-severe diarrhea of all causes ( n=77 cases ) occurred less often ( P=.001 ) in infants whose milk contained high levels of total 2-linked fucosyloligosaccharide as a percent of milk oligosaccharide. Campylobacter diarrhea ( n=31 cases ) occurred less often ( P=.004 ) in infants whose mother's milk contained high levels of 2'-FL, a specific 2-linked fucosyloligosaccharide, and calicivirus diarrhea ( n=16 cases ) occurred less often ( P=.012 ) in infants whose mother's milk contained high levels of lacto-N-difucohexaose ( LDFH-I ), another 2-linked fucosyloligosaccharide. CONCLUSION This study provides novel evidence suggesting that human milk oligosaccharides are clinical ly relevant to protection against infant diarrhea A Randomized, Double-Blind, Controlled Trial of the Effect of Prebiotic Oligosaccharides on Enteral Tolerance in Preterm Infants (ISRCTN77444690) Breast milk prebiotic oligosaccharides are believed to promote enteral tolerance. Many mothers delivering preterm are unable to provide sufficient milk. We conducted a multicenter, r and omized, controlled trial comparing preterm formula containing 0.8 g/100 mL short-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides in a 9:1 ratio and an otherwise identical formula, using formula only to augment insufficient maternal milk volume. Infants were r and omized within 24 h of birth. The primary outcome ( PO ) was time to establish a total milk intake of 150 mL/kg/d PO and the principal secondary outcome ( PSO ) was proportion of time between birth and 28 d/discharge that a total milk intake of ≥150 mL/kg/d was tolerated. Other secondary outcomes included growth, fecal characteristics, gastrointestinal signs, necrotizing enterocolitis, and bloodstream infection. Outcomes were compared adjusted for prespecified covariates. We recruited 160 infants appropriately grown for GA <33 wk. There were no significant differences in PO or PSOs. After covariate adjustment, we showed significant benefit from trial formula in PSO with increasing infant immaturity ( 2.9 % improved tolerance for a baby born at 28-wk gestation and 9.9 % at 26-wk gestation ; p < 0.001 ) but decreased or no benefit in babies > 31-wk gestation. Prebiotic supplementation appears safe and may benefit enteral tolerance in the most immature infants Prebiotic oligosaccharides reduce stool viscosity and accelerate gastrointestinal transport in preterm infants. AIM To investigate whether a mixture of prebiotic non-digestible oligosaccharides ( GosFos ; referring to galacto- and fructo-oligosaccharides ) would improve feeding tolerance in preterm infants on full enteral formula feeding. We hypothesized that GosFos would : ( 1 ) reduce stool viscosity and ( 2 ) accelerate gastrointestinal transport. METHODS In a placebo-controlled double-blind trial 20 preterm infants on full enteral nutrition ( gestational age 27 ( 24 - 31 ) weeks, postnatal age 42 ( 11 - 84 ) days, and weight at study entry 1570 ( 1080 - 2300 ) g were r and omly allocated to have their feedings supplemented with either GosFos ( 1 g/100 mL ) or placebo for 14 days. Stool viscosity was measured by high-pressure capillary rheometry. Gastrointestinal transport time was assessed as the time from feeding carmine red to its appearance in the diaper. The hypotheses were tested as a priori ordered hypotheses. Data are shown as median ( range ). RESULTS Birth weight, gestational age, postnatal age, and weight at study entry did not differ between groups. GosFos significantly reduced both stool viscosity, as measured by extrusion force ( 32 ( 2 - 67 ) versus 158 ( 24 - 314 ) N ), and gastrointestinal transit time ( 12 ( 4 - 33 ) versus 26 ( 5 - 52 ) h ). No adverse effects were observed. CONCLUSION Formula supplementation with GosFos reduced stool viscosity and accelerated gastrointestinal transport. Further trials are required to investigate whether GosFos facilitates enteral feeding advancement and early enteral nutrition thereby eventually reducing the incidence of catheter-related nosocomial infections and improving long-term outcome Randomized Double-Blind Study of the Nutritional Efficacy and Bifidogenicity of a New Infant Formula Containing Partially Hydrolyzed Protein, a High &bgr;-Palmitic Acid Level, and Nondigestible Oligosaccharides Objectives The aim of this study was to evaluate the nutritional efficacy and bifidogenic characteristics of a new infant formula containing partially hydrolyzed whey protein, modified vegetable oil with a high & bgr;-palmitic acid content, prebiotic oligosaccharides, and starch. Methods In a double-blind study, healthy formula-fed term infants aged younger than 2 weeks were r and omized to receive either the new infant formula ( NF ) or a st and ard formula ( SF ) until the age of 12 weeks. Anthropometric measurements were taken at enrollment, 6 weeks, and 12 weeks. In a sub sample of infants, blood sample s were taken at 6 weeks and stool sample s were taken at enrollment and 6 weeks. Blood sample s were analyzed for biochemical measures of protein status and amino acids, and stools were analyzed for total bacteria and bifidobacteria. Mothers completed a feeding diary and question naire at 6 and 10 weeks. Results One hundred fifty-four infants were enrolled in the study ; 102 completed the trial. The growth of infants in both formula groups was in line with published growth curves. During the first 6 weeks, NF girls gained more weight and head circumference than the SF girls. These velocity differences were not maintained throughout the 12-week study period. The NF stools had a higher proportion of bifidobacteria at 6 weeks compared with the SF stools, and they were softer. There were no clinical ly significant differences in the blood biochemical and amino acid values between groups. Both formulas were well tolerated by the infants. Conclusions When compared with a st and ard infant formula, the new formula supported satisfactory growth, led to higher counts of bifidobacteria in the feces, produced blood bio-chemical values typical of formula-fed infants, and was well tolerated The effect of a prebiotic supplemented formula on growth and stool microbiology of term infants. BACKGROUND The intestinal flora of breast-fed infants is generally dominated by bifidobacteria which have beneficial properties. Their presence is due to various compounds of breast milk including prebiotic substances. AIM This prospect i ve, double blind, study compared the growth, acceptability and the proportion of bifidobacteria and clostridia in the stool flora of bottle-fed infants r and omized to receive a formula with a specific mixture of 0.4 g/100 ml prebiotic galacto- and long-chain fructooligosaccharides or the same formula without added prebiotics. METHODS Within 0 - 14 days after birth at term, healthy bottle-fed infants were enrolled to receive either a prebiotic formula or a st and ard formula. At recruitment anthropometric measurements were done. These were repeated at the age of 6 and 12 weeks. Stool sample s were taken at inclusion and at the age of 6 weeks. The number of bifidobacteria and clostridia was determined by fluorescent in situ hybridization. RESULTS There was good tolerance of the prebiotic formula. Somatic growth was similar in the two groups. Stool frequency was significantly higher in the prebiotic group ( P=0.031 ). Infants in the prebiotic group had also softer stools as compared to the control group ( P=0.026 ). Baseline values of microorganisms at study entry were similar. The percentage of faecal clostridia at the completion of the study was significantly lower in the prebiotic group ( P=0.042 ), while the proportion of faecal bifidobacteria was higher in the prebiotic group as compared to the control group. However this difference did not reach statistical significance ( P=0.262 ). The percentage of E. coli was lower in the prebiotic group but again this did not reach statistical significance ( P=0.312 ). CONCLUSION An infant formula containing prebiotic oligosaccharides is well tolerated, leads to normal somatic growth and suppresses the numbers of clostridia in the faeces with a trend for higher percentage of stool bifidobacteria and lower percentage of E. coli Prebiotics Improve Gastric Motility and Gastric Electrical Activity in Preterm Newborns The aim of this double-blind, r and omized, placebo-controlled study was to evaluate the effect of a prebiotic mixture on gastric motility in preterm newborns. After a feeding period of 15 days, gastric electrical activity was measured by electrogastrography, and the gastric emptying time was studied by ultrasound technique. No difference was seen in the daily increase of body weight, and no adverse events have been reported. The percentage of time in which propagation was detected in the electrogastrography signal was twice in newborns receiving formula with prebiotics with respect to placebo, and the gastric half-emptying time was 30 % faster in the prebiotic group than the placebo group. Prebiotic oligosaccharides can modulate the electrical activity and the gastric emptying and may improve the intestinal tolerance of enteral feeding in preterm infants Term Infants Fed Formula Supplemented With Selected Blends of Prebiotics Grow Normally and Have Soft Stools Similar to Those Reported for Breast-fed Infants Objectives : The present study was design ed to evaluate the effect of 2 different combinations of prebiotic ingredients, polydextrose ( PDX ), galactooligosaccharides ( GOS ), and lactulose ( LOS ), at 2 different intake levels on the overall growth and tolerance in healthy term infants up to 120 days of age. Patients and Methods : Healthy, formula-fed, term infants ( n = 226 ) were r and omly assigned to 1 of 3 study formula groups : control group ( n = 76 ), PG4 group ( control formula supplemented with 4 g/L of a prebiotic blend, n = 74 ), or PGL8 group ( control formula supplemented with 8 g/L of a prebiotic blend, n = 76 ). Anthropometric measurements were taken at 14, 30, 60, 90, and 120 days of age, and 24-hour dietary recall and 24-hour tolerance recall were recorded at 30, 60, 90, and 120 days of age. Adverse events were recorded throughout the study. Results : There were no statistically significant differences among the 3 formula groups for weight growth rate or length growth rate at any time point. Significant differences in stool consistency were detected among the 3 formula groups at 30, 60, and 90 days of age ( P < 0.001, P = 0.025, P = 0.004, respectively ), with the supplemented formula groups having looser stools than the control group. The PGL8 group had significantly higher stool frequency compared with the control and PG4 groups at 30 days of age ( P = 0.021 and P = 0.017, respectively ), but all of the groups were similar at 60, 90, and 120 days of age. A statistical difference was detected among the formula groups in 3 categories of adverse events : diarrhea ( control vs PG4, 4 % vs 18 %, P = 0.008 ), eczema ( PG4 vs control, 18 % vs 7 %, P = 0.046 ; PG4 vs PGL8, 18 % vs 4 %, P = 0.008 ), and irritability ( control vs PGL8, 4 % vs 16 %, P = 0.027 ). Conclusions : Infants fed formula supplemented with a prebiotic mixture achieved normal growth and stool characteristics more similar to those of breast-fed infants in comparison with infants fed an unsupplemented formula. A pediatrician needs to consider the risk of possible intolerance against the benefits of prebiotics The effects of lactulose supplementation to enteral feedings in premature infants: a pilot study. OBJECTIVE To assess the safety and prebiotic effects of lactulose in preterm infants. STUDY DESIGN This was a prospect i ve, double-blinded, placebo-controlled, single-center study in 23- to 34-weeks premature infants. The study group received 1 % lactulose, and control infants received 1 % dextrose in all feeds ( human milk or formula ). RESULTS Twenty-eight infants participated ( 15 lactulose, 13 placebo ). Small doses of lactulose appeared to be safe and did not cause diarrhea. Premature infants on lactulose had more Lactobacilli-positive stool cultures that appeared earlier with larger number of colonies. The lactulose group tended to have less intolerance to enteral feedings, to reach full oral feeds earlier, and to be discharged home earlier. They also tended to have fewer episodes of late-onset sepsis, lower Bell stage necrotizing enterocolitis, and their nutritional laboratory indices were better, especially calcium and total protein. CONCLUSIONS This pilot study supports the safety of supplementing preterm infants'feeds with low doses of lactulose. It also demonstrated trends that may suggest positive prebiotic effects", 'BACKGROUND Several clinical trials have investigated the impact of glucomannan on plasma lipids, body weight, fasting blood glucose ( FBG ), and blood pressure ( BP ), but have yielded conflicting results and had only modest sample sizes. OBJECTIVE The objective was to perform a meta- analysis of r and omized controlled trials of glucomannan to better characterize its impact on plasma lipids, FBG, body weight, and BP. Effect of short-term ingestion of konjac glucomannan on serum cholesterol in healthy men. The effects of the soluble fiber konjac glucomannan ( GM ) on serum cholesterol concentrations were investigated in 63 healthy men in a double-blind crossover, placebo-controlled study. After a 2-wk baseline period, the subjects were given 3.9 g GM or placebo daily for 4 wk. After a washout period of 2 wk, crossover took place, followed by another 4 wk of treatment. The subjects were encouraged not to change their ordinary diets or general lifestyle during the investigation. GM fibers reduced total cholesterol ( TC ) concentrations by 10 % ( P < 0.0001 ), low-density-lipoprotein cholesterol ( LDL-C ) concentrations by 7.2 % ( P < 0.007 ), triglycerides by 23 % ( P < 0.03 ), and systolic blood pressure by 2.5 % ( P < 0.02 ). High-density-lipoprotein cholesterol ( HDL-C ) and the ratio of LDL-C to HDL-C did not change significantly. No change in diastolic blood pressure or body weight was observed. No adverse effects were observed. The results of this study show that GM is an effective cholesterol-lowering dietary adjunct Experiences with three different fiber supplements in weight reduction. BACKGROUND Fiber supplements added to a caloric diet have additional effects on weight reduction in overweight subjects. The aim of this study was to compare the effect of various commercial fiber supplements ( glucomannan, guar gum and alginate ) on weight reduction in healthy overweight subjects. MATERIAL / METHODS One hundred and seventy six men and women were included to receive either active fiber substance or placebo in r and omized placebo-controlled studies. The fiber supplements consisted of the viscous fibers glucomannan ( Chrombalance ), glucomannan and guar gum ( Appe-Trim ) and glucomannan, guar gum and alginat ( Glucosahl ). RESULTS All fiber supplements plus a balanced 1200 kcal diet induced significantly weight reduction more than placebo and diet alone, during a five week observation period. However, there were no significant differences between the different fibers in their ability to induce weight reduction, which was approximately 0.8 kg/week ( 3.8 + /- 0.9, 4.4 + /- 2.0, 4.1 + /- 0.6 in the Chrombalance, Appe-Trim and Glucosahl group, respectively ). CONCLUSIONS Glucomannan induced body weight reduction in healthy overweight subjects, whereas the addition of guar gum and alginate did not seem to cause additional loss of weight Childhood obesity treatment: double blinded trial on dietary fibres (glucomannan) versus placebo. Dietary fibres are frequently used for the treatment of paediatric obesity. The aim of this clinical trial is to evaluate the efficacy of glucomannan in the child obesity management. This experimental design was double blinded with a block r and omisation, alpha = 0.05, beta = 0.2 and delta = 50 %. The study involved 60 children under 15 years of age ( mean age 11.2 years, mean overweight 46 % ), 30 of them under glucomannan treatment ( 1 g twice a day for two months ) and 30 under placebo and the same schedule. The drug and the placebo were indistinguishable both for the family and the physician. During the two months study period the children followed a normocaloric diet evaluated every two weeks by a dietetic record book. At the beginning of the study the drug and the placebo groups were comparable in regards to anthropometric data. At the end, the mean overweight of the drug group was decreased from 49.5 % to 41 % and that of the placebo group from 43.9 % to 41.7 %. Both decreases were significant ( p < 0.01 ), but no significant difference was observed between the drug and the placebo groups. The only significant difference concerned the lipid metabolism. The children under glucomannan treatment manifested a significant decrease of alpha-lipoprotein and an increase of pre-beta-lipoprotein and triglycerides ; the children under placebo manifested only a decrease of triglycerides and apo beta-lipoprotein. We suggest that this metabolic alteration may derive from a primary decrease of alpha-lipoprotein, most likely because of an inadequate water intake. ( ABSTRACT TRUNCATED AT 250 WORDS Effects of a carbohydrate-restricted diet with and without supplemental soluble fiber on plasma low-density lipoprotein cholesterol and other clinical markers of cardiovascular risk. Carbohydrate-restricted diets ( CRDs ) promote weight loss, reductions in plasma triacylglycerol ( TAG ) levels, and increases in high-density lipoprotein cholesterol ( HDL-C ) levels but may cause undesirable low-density lipoprotein cholesterol ( LDL-C ) responses in some people. The objective of the present study was to determine the effect of adding soluble fiber to a CRD on plasma LDL-C and other traditionally measured markers of cardiovascular disease. Using a parallel-arm, double-blind, placebo-controlled design, 30 overweight and obese men ( body mass index, 25 - 35 kg/m(2 ) ) were r and omly assigned to supplement a CRD with soluble fiber ( Konjac-mannan, 3g/d ) ( n = 15 ) or placebo ( n = 15 ). Plasma lipids, anthropometrics, body composition, blood pressure, and nutrient intake were evaluated at baseline and at 6 and 12 weeks. Compliance was excellent as assessed by 7-day weighed dietary records and ketonuria. Both groups experienced decreases in ( P <.01 ) body weight, percent body fat, systolic blood pressure, waist circumference, and plasma glucose levels. After 12 weeks, HDL-C and TAG improved significantly in the fiber ( 10 % and -34 % ) and placebo ( 14 %, -43 % ) groups. LDL-C decreased by 17.6 % ( P <.01 ) at week 6 and 14.1 % ( P <.01 ) at week 12 in the fiber group. Conversely, LDL-C reductions were significant in the placebo group only after 12 weeks ( -6.0 %, P <.05 ). We conclude that although clearly effective at lowering LDL-C, adding soluble fiber to a CRD during active and significant weight loss provides no additional benefits to the diet alone. Furthermore, a CRD led to clinical ly important positive alterations in cardiovascular disease risk factors Effect of dietary supplementation with glucomannan on plasma total cholesterol and low density lipoprotein cholesterol in hypercholesterolemic children. AIM This paper evaluates the effect of the adjunct of the hydrosoluble fiber glucomannan to a Step-One-Diet in 40 plasma hypercholesterolemic children, during a r and omized controlled trial, to reduce plasma cholesterol. METHODS All the subjects recruited underwent an 8-week run in diet period ; a Step-One-Diet was prescribed. After that, they were r and omly allocated to one of two groups : Step-One-Diet only ( control ), and Step-One-Diet plus glucomannan in gelatine capsules. After another 8 weeks of treatment, the results were compared within and between the two groups. RESULTS Glucomannan treated group showed decreased values in plasma total cholesterol ( TC ) and low density lipoprotein cholesterol ( LDL-C ) vs. control group after 8 weeks of treatment. The percentage decrease showed a statistically significant difference between sex groups. Decreases were observed in favor of female vs. male children in TC ( 24 % vs. 9 % ) and LDL-C ( 30 % vs. 9 % ). CONCLUSIONS These results suggest that glucomannan may represent a rationale adjunct to diet therapy in primary prevention in high risk hypercholesterolemic children [The use of highly purified glucomannan-based fibers in childhood obesity]. To evaluate the effectiveness of highly purified glucomannan in childhood obesity a study has been carried out in 23 obese children ( 12 boys and 11 girls, aged 5.2 - 15.8 years ), with excess weight of 51 + /- 16 %, treated with 2 - 3 caps twice a day of glucomannan fibres ( DICOMAN 5:2 - 3 gr/die ), and in 30 obese children ( aged 5 - 18 years ) with excess weight of 51 + /- 10 %, studied as controls. After a three-days food recall, a balanced diet with adequate caloric intake was provided to all obese children. In all patients before and 2 - 4 months after the auxological data ( weight, height, weight excess ) and laboratory data ( serum levels of cholesterol, HDL, triglycerides, glucose, fructosamine, glycosylated hemoglobin, RBC, WBC, hemoglobin, iron, calcium, Cu and Zn ) have been determined. Excess weight and triglycerides levels were significantly decreased in treated obese patients than in obese controls 4 months after the beginning of the study. A decrease of cholesterol levels was also observed in treated obese patients, but not in controls, whereas serum iron, calcium, copper and zinc persisted unchanged. No important side-effects were observed in treated patients. On the basis of our results highly purified glucomannan fibres may be employed with effectiveness in obese and dyslipidemic children together with diet Effect of plant sterols and glucomannan on lipids in individuals with and without type II diabetes Objective : The purpose of this study was to determine whether supplements of plant sterols and /or glucomannan improve lipid profile and cholesterol bio synthesis in mildly hypercholesterolemic type II diabetic and non-diabetic subjects and to compare the response of these two subject groups to the treatments. Design : A r and omized, crossover study consisting of four phases of 21 days, with each phase separated by a 28-day washout. Setting : The Mary Emily Clinical Nutrition Research Unit of McGill University. Subjects : Eighteen non-diabetic individuals and 16 type II diabetic individuals aged 38–74 years. Interventions : Subjects were supplemented with plant sterols ( 1.8 g/day ), glucomannan ( 10 g/day ), a combination of glucomannan and plant sterols, and a placebo, provided in the form of bars. Results : Overall plasma cholesterol concentrations were lowered ( P<0.05 ) after combination treatment ( 4.72±0.20 mmol/l ) compared to control ( 5.47±0.18 mmol/l ). Plasma low-density lipoprotein ( LDL ) cholesterol concentrations were decreased ( P<0.05 ) after glucomannan ( 3.16±0.14 mmol/l ) and combination treatments ( 2.95±0.16 mmol/l ) compared to control ( 3.60±0.16 mmol/l ). The results of lipid profiles did not differ between subject groups. Overall plasma lathosterol concentrations, an index of cholesterol bio synthesis, were lowered ( P<0.05 ) after the combination treatment compared to the plant sterol treatment. Conclusions : The results suggest that glucomannan and a combination of glucomannan and plant sterols substantially improves plasma LDL cholesterol concentrations. Sponsorship : Forbes Medi-Tech Inc., Vancouver, British Columbia, Canada Konjac Supplement Alleviated Hypercholesterolemia and Hyperglycemia in Type 2 Diabetic Subjects—A Randomized Double-Blind Trial Objectives : The present study was design ed to evaluate effects of konjac glucomannan ( KGM ) supplement ( 3.6 g/day ) for 28 days on blood lipid and glucose levels in hyperlipidemic type 2 diabetic patients and the possible mechanism for the reductions in blood lipid levels. Methods : Twenty-two diabetic subjects ( age 64.2 + 8.4 years, BMI 25.5 + 3.2 kg/m2 ) with elevated blood cholesterol levels ( fasting glucose between 6.7–14.4 mmol/L ), but currently not taking lipid-lowering medication, were recruited to participate in a two 28-day period, r and omized, double-blind, crossover clinical trial. Fasting blood sample s drawn on the initial and final days of each period were determined for plasma lipids and glucose levels. Feces collected at the end of each experimental period were analyzed for neutral sterol and bile acid contents. Results : Compared with placebo, KGM effectively reduced plasma cholesterol ( 11.1 %, p = 0.0001, adjusted α = 0.006 ), LDL-cholesterol ( 20.7 %, p = 0.0004, adjusted α = 0.006 ), total/HDL cholesterol ratio ( 15.6 %, p = 0.0005, adjusted α = 0.007 ), ApoB ( 12.9 %, p = 0.0001, adjusted α = 0.006 ) and fasting glucose ( 23.2 %, p = 0.002, adjusted α = 0.008 ). Plasma triglyceride, HDL-cholesterol, LDL/HDL cholesterol, postpr and ial glucose and body weight were not significant after adjustment by the Bonferroni-Hochberg procedure. Fecal neutral sterol and bile acid concentrations were increased by 18.0 % ( p = 0.004 ) and 75.4 % ( p < 0.001 ), respectively, with KGM supplement. Conclusions : The KGM supplement improved blood lipid levels by enhancing fecal excretion of neutral sterol and bile acid and alleviated the elevated glucose levels in diabetic subjects. KGM could be an adjunct for the treatment of hyperlipidemic diabetic subjects Effect of glucomannan on obese patients: a clinical study. An eight-week double-blind trial was conducted to test purified glucomannan fiber as a food supplement in 20 obese subjects. Glucomannan fiber ( from konjac root ) or placebo was given in 1-g doses ( two 500 mg capsules ) with 8 oz water, 1 h prior to each of three meals per d. Subjects were instructed not to change their eating or exercise patterns. Results showed a significant mean weight loss ( 5.5 lbs ) using glucomannan over an eight-week period. Serum cholesterol and low-density lipoprotein cholesterol were significantly reduced ( 21.7 and 15.0 mg/dl respectively ) in the glucomannan treated group. No adverse reactions to glucomannan were reported Glycemic and lipid responses to glucomannan in Thais with type 2 diabetes mellitus. OBJECTIVE To evaluate the benefits of glucomannan supplement on glycemic and lipid controls in type 2 diabetic patients. MATERIAL AND METHOD A single-blind, placebo-controlled, crossover trial with two treatments separated by a 2-week washout period was performed in 10 men and 10 women with type 2 diabetes mellitus. Two separated protocol s of experiments were sequentially followed. Initially, purified glucomannan ( 1 g ) or placebo was ingested 30 min before 75-g glucose load to evaluate their effects on glucose absorption and insulin secretion in oral glucose tolerance test ( OGTT ). Later, the glycemic and lipid changes after 4-week intervention with 3 g/day glucomannan comparing to the placebo were determined. The st and ard OGTT was performed before and after ending of each intervention. RESULTS Glucomannan taken before performing the OGTT can lower the rise of blood glucose and insulin from 1 to 2 hour in comparison with the placebo, though a statistically significance of insulin was not achieved. Long-term glucomannan supplement significantly reduced the 120-min glucose area under the curve of OGTT. Glucomannan also decreased the rise of low-density lipoprotein cholesterol ( LDL-C ). Reductions of HOMA-insulin resistance index and body mass index were detected in glucomannan-treated group though the former was shown only in females. No within- and between-group differences of insulin, fructosamine, and other lipids were observed in glucomannan- nor placebo- treated groups. CONCLUSION In type 2 diabetes, pre-pr and ial glucomannan ingestion attenuated a rise of blood glucose without significantly affecting insulin levels. Long-term supplement of glucomannan to the regular diabetic regimen lessened post challenge glucose AUC and impeded the rise of LDL-C. Supplement of glucomannan may be beneficial to the glycemic and lipid controls in type 2 diabetes mellitus [Chronic use of glucomannan in the dietary treatment of severe obesity]. Two groups of 25 severely obese patients underwent 3 months of hypocaloric diet therapy either alone or associated with a glucomannan-based fibrous diet supplement ( approx. 4 g/die in 3 doses ). The comparative analysis of the results obtained in both groups showed that the diet + glucomannan group had a more significant weight loss in relation to the fatty mass alone, an overall improvement in lipid status and carbohydrate tolerance, and a greater adherence to the diet in the absence of any relevant side effects. Due to the marked ability to satiate patients and the positive metabolic effects, glucomannan diet supplements have been found to be particularly efficacious and well tolerated even in the long-term treatment of severe obesity', 'PURPOSE The goal of this meta- analysis was to determine the clinical utility of acute mountain sickness ( AMS ) history to predict future incidents of AMS. Autonomic cardiovascular regulation in subjects with acute mountain sickness. The aims of this study were 1 ) to evaluate whether subjects suffering from acute mountain sickness ( AMS ) during exposure to high altitude have signs of autonomic dysfunction and 2 ) to verify whether autonomic variables at low altitude may identify subjects who are prone to develop AMS. Forty-one mountaineers were studied at 4,559-m altitude. AMS was diagnosed using the Lake Louise score, and autonomic cardiovascular function was explored using spectral analysis of R-R interval and blood pressure ( BP ) variability on 10-min resting recordings. Seventeen subjects ( 41 % ) had AMS. Subjects with AMS were older than those without AMS ( P < 0.01 ). At high altitude, the low-frequency ( LF ) component of systolic BP variability ( LF(SBP ) ) was higher ( P = 0.02 ) and the LF component of R-R variability in normalized units ( LF(RR)NU ) was lower ( P = 0.001 ) in subjects with AMS. After 3 mo, 21 subjects ( 43 % with AMS ) repeated the evaluation at low altitude at rest and in response to a hypoxic gas mixture. LF(RR)NU was similar in the two groups at baseline and during hypoxia at low altitude but increased only in subjects without AMS at high altitude ( P < 0.001 ) and did not change between low and high altitude in subjects with AMS. Conversely, LF(SBP ) increased significantly during short-term hypoxia only in subjects with AMS, who also had higher resting BP ( P < 0.05 ) than those without AMS. Autonomic cardiovascular dysfunction accompanies AMS. Marked LF(SBP ) response to short-term hypoxia identifies AMS-prone subjects, supporting the potential role of an exaggerated individual chemoreflex vasoconstrictive response to hypoxia in the genesis of AMS Reproducibility of Acute Mountain Sickness in Children and Adults: A Prospective Study OBJECTIVE : Although a history of previous acute mountain sickness ( AMS ) is commonly used for providing advice and recommending its prophylaxis during subsequent exposure, the intraindividual reproducibility of AMS during repeated high-altitude exposure has never been examined in a prospect i ve controlled study. METHODS : In 27 nonacclimatized children and 29 adults, AMS was assessed during the first 48 hours after rapid ascent to 3450 m on 2 consecutive occasions 9 to 12 months apart. RESULTS : During the first exposure, 18 adults ( 62 % ) and 6 children ( 22 % ) suffered from AMS ; during the second exposure, 14 adults ( 48 % ) and 4 children ( 15 % ) suffered from this problem ( adults versus children, P ≤.01 ). Most importantly, the intraindividual reproducibility of AMS was very different ( P <.001 ) between children and adults. None of the 6 children having suffered from AMS during the first exposure suffered from AMS during the second exposure, but 4 children with no AMS during the first exposure did experience this problem during the second exposure. In contrast, 14 of the 18 adults who suffered from AMS on the first occasion also presented with this problem during the second exposure, and no new case developed in those who had not experienced AMS on the first occasion. CONCLUSIONS : In adults, a history of AMS is highly predictable of the disease on subsequent exposure, whereas in children it has no predictive value. A history of AMS should not prompt practitioners to advise against reexposure to high altitude or to prescribe drugs for its prophylaxis in children Vascular endothelial growth factor and acute mountain sickness Study Objective : Despite causing significant morbidity throughout the mountainous regions of the world, the pathophysiology of acute mountain sickness ( AMS ) remains poorly understood. This study aims to improve the underst and ing of altitude illness by determining if vascular endothelial growth factor ( VEGF ) plays a role in the development of AMS. The purpose of this study was to determine if elevated plasma VEGF correlates with increased symptoms of AMS at high altitude. Patients and Methods : This is a prospect i ve study of a cohort of healthy climbers on Denali ( Mount McKinley ) in Alaska at 14, 200 feet. Baseline demographics, medications, rates of ascent, and AMS scores were recorded. Pulse oximetry measurements and venous blood sample s were obtained. Comparisons were made between mountaineers with and without AMS. Results : Seventy-two climbers were approached for participation in the study ; 21 ( 29 % ) refused. Of the 51 climbers participating in the study, 14 subjects ( 27.5 % ) had symptoms of AMS and 37 subjects ( 72.5 % ) were free of symptoms of AMS. Plasma VEGF levels were 79.14 pg/dl ( SD : 121.44 ) and 57.57pg/dl ( SD : 102.71 ) in the AMS and non-AMS groups, respectively. These results were nonsignificant. Similarly, comparison of sex, age, rate of ascent, pulse oximetry values, or history of altitude illness did not reveal significant differences between the AMS and non-AMS groups. Conclusion : This study does not provide evidence in support of the theory that plasma VEGF correlates with symptoms of AMS A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis. Forty-seven climbers participated in a double-blind, r and omized trial comparing acetazolamide 250 mg, dexamethasone 4 mg, and placebo every eight hours as prophylaxis for acute mountain sickness during rapid, active ascent of Mount Rainier ( elevation 4,392 m ). Forty-two subjects ( 89.4 percent ) achieved the summit in an average of 34.5 hours after leaving sea level. At the summit or high point attained above base camp, the group taking dexamethasone reported less headache, tiredness, dizziness, nausea, clumsiness, and a greater sense of feeling refreshed ( p less than or equal to 0.05 ). In addition, they reported fewer problems of runny nose and feeling cold, symptoms unrelated to acute mountain sickness. The acetazolamide group differed significantly ( p less than or equal to 0.05 ) from other groups at low elevations ( 1,300 to 1,600 m ), in that they experienced more feelings of nausea and tiredness, and they were less refreshed. These drug side effects probably obscured the previously established prophylactic effects of acetazolamide for acute mountain sickness. Separate analysis of an acetazolamide subgroup that did not experience side effects at low elevations revealed a prophylactic effect of acetazolamide similar in magnitude to the dexamethasone effect but lacking the euphoric effects of dexamethasone. This study demonstrates that prophylaxis with dexamethasone can reduce the symptoms associated with acute mountain sickness during active ascent and that acetazolamide can cause side effects that may limit its effectiveness as prophylaxis against the disease', 'The purpose of the current study was to clarify the role of the quadriceps tendon ( QT ) autograft for primary ACL reconstruction. Thus, a Bayesian network meta- analysis comparing patients undergoing a primary ACL reconstruction with QT versus patellar tendon ( PT ) and hamstring tendon ( HT ) autografts was conducted. Early post-operative morbidity following anterior cruciate ligament reconstruction: patellar tendon versus hamstring graft Abstract. This study documented postoperative morbidity during the first 4 months following anterior cruciate ligament ( ACL ) reconstruction using either patellar tendon or hamstring tendon autograft. Sixty-five patients undergoing primary arthroscopically assisted single-incision ACL reconstruction were r and omized to have a central third bone patellar tendon bone autograft ( PT ) or a doubled semitendinosus/doubled gracilis autograft ( HS ). Postoperatively patients undertook a st and ard\'accelerated\'rehabilitation protocol. Patients were review ed after 2 weeks, 8 weeks, and 4 months. At each review the location and severity of general knee pain and the presence and severity of anterior knee pain ( AKP ) were recorded as were the presence and size of an effusion as well as the active and passive flexion and passive extension deficits compared to the contralateral limb. Pain on kneeling, KT-1000 measured side to side difference in anterior tibial displacement, isokinetic assessment of quadriceps and hamstring peak torque deficits, IKDC score and Cincinnati sports activity level were also recorded after 4 months. After 2 weeks more patients in the PT group complained of AKP and reported that the pain was more severe. After 8 weeks there was no significant difference between the groups for any variable. After 4 months the severity of general pain experienced and the incidence of pain on kneeling were greater in the PT group. The PT group also demonstrated a significantly greater quadriceps peak torque deficit at 240 ° /s. IKDC scores were higher in the HS group, but Cincinnati sports activity scores were higher in the PT group. Although we observed a lower morbidity in the HS group, primarily related to pain, the severity of pain in both groups was relatively low and, in light of the higher mean sports activity level observed in the PT group at 4 months the clinical impact of the difference may not be significant A 10-year comparison of anterior cruciate ligament reconstructions with hamstring tendon and patellar tendon autograft: a controlled, prospective trial. BACKGROUND There are no controlled, prospect i ve studies comparing the 10-year outcomes of anterior cruciate ligament ( ACL ) reconstruction using patellar tendon ( PT ) and 4-str and hamstring tendon ( HT ) autografts. HYPOTHESIS Comparable results are possible with HT and PT autografts. STUDY DESIGN Cohort study ; Level of evidence, 2. METHODS One hundred eighty ACL-deficient knees that met inclusion criteria underwent ACL reconstruction ( 90 HT autograft, 90 PT autograft ) by one surgeon and were treated with an accelerated rehabilitation program. All knees were observed in a prospect i ve fashion with subjective, objective, and radiographic evaluation at 2, 5, 7, and 10-year intervals. RESULTS At 10 years, there were no differences in graft rupture rates ( 7/90 PT vs. 12/90 HT, P =.24 ). There were 20 contralateral ACL ruptures in the PT group, compared with 9 in the HT group ( P =.02 ). In all patients, graft rupture was associated with instrumented laxity > 2 mm at 2 years ( P =.001 ). Normal or near-normal function of the knee was reported in 97 % of patients in both groups. In the PT group, harvest-site symptoms ( P =.001 ) and kneeling pain ( P =.01 ) were more common than in the HT group. More patients reported pain with strenuous activities in PT knees than in HT knees ( P =.05 ). Radiographic osteoarthritis was more common in PT knees than the HT-reconstructed knees ( P =.04 ). The difference, however, was composed of patients with mild osteoarthritis. Other predictors of radiographic osteoarthritis were < 90 % single-legged hop test at 1 year and the need for further knee surgery. An " ideal " outcome, defined as an overall International Knee Documentation Committee grade of A or B and a radiographic grade of A at 10 years after ACL reconstruction, was associated with <3 mm of instrumented laxity at 2 years, the absence of additional surgery in the knee, and HT grafts. CONCLUSIONS It is possible to obtain excellent results with both HT and PT autografts. We recommend HT reconstructions to our patients because of decreased harvest-site symptoms and radiographic osteoarthritis Comparison of Kneelax and KT-1000 knee ligament arthrometers. Two commercially available knee ligament arthrometers ( KT-1000 MEDmetric Corporation, San Diego, California and Kneelax MR Systems, Haarlem, The Netherl and s ) were used to measure anterior tibial translation. In this study 91 subjects with no history of knee pathology were tested using both devices. Both normal knees were tested and comparison of recorded anterior translation ( millimeters ) was performed. Absolute numbers at forces of 67N, 89N, 134N, and manual maximum displacements were recorded. Side-to-side differences were calculated and data were compared. There was a significant difference found between the absolute values of each device. The KT-1000 was found to record greater values in millimeters of translation. Although the absolute values were significantly different, the side-to-side differences were not significantly different between devices Comparison of Patellar Tendon and Hamstring Tendon Anterior Cruciate Ligament Reconstruction Background : Numerous studies have compared patellar tendon ( PT ) and hamstring tendon ( HS ) anterior cruciate ligament ( ACL ) reconstructions in the short to midterm, but fewer long-term results have been published. Hypothesis : There will be no difference in functional outcome between ACL reconstruction performed with PT and HS grafts, but PT grafts will have more donor site morbidity. Study Design : R and omized controlled trial ; Level of evidence, 1. Methods : Sixty-five patients undergoing ACL reconstruction were r and omized to receive either a PT graft or a 4-str and HS graft. Early results were reported at 4, 8, 12, 24, and 36 months. Forty-seven patients ( 22 of 31 PT and 25 of 34 HS ) were review ed at a mean of 15.3 years. Results : Four graft ruptures ( 1 PT, 3 HS ) and 6 contralateral ACL injuries ( 4 PT, 2 HS ) occurred in the group that was review ed. There was no statistically significant difference between the groups for any of the variables measured. There was a similar incidence of anterior knee pain and kneeling pain in both groups. The previously observed increased extension deficit in the PT group at 3 years was not present at 15 years, and there was no significant between-group difference in knee laxity. A higher proportion of patients in the PT group were participating in sport on a weekly basis ( 73 % PT, 48 % HS ; P =.05 ). There was no difference in the degree of osteoarthritis between the groups. Conclusion : This r and omized controlled trial showed that HS and PT ACL reconstructions have comparable results at an average 15-year follow-up. Contrary to the study hypothesis, some of the graft differences seen at earlier review were not present at 15 years, and patients with PT grafts were more active in sport participation. Overall, both graft types provided good long-term subjective and objective outcomes Long-term Comparison of Semitendinosus and Gracilis Tendon Versus Patellar Tendon Autografts for Anterior Cruciate Ligament Reconstruction: A 17-Year Follow-up of a Randomized Controlled Trial Background : Short-term and mid-term differences between hamstring and patellar tendon autografts for anterior cruciate ligament ( ACL ) reconstruction are well documented. Systematic review s highlight the lack of long-term results between the two grafts. Hypothesis : Seventeen years after ACL reconstruction, no difference will be found in functional outcome, quality of life, and graft failure between patients with patellar tendon ( PT ) or semitendinosus and gracilis tendon ( STG ) autografts ; however, a significant difference will be seen in the prevalence of osteoarthritis. Study Design : R and omized controlled trial ; Level of evidence, 2. Methods : Sixty-four patients were included in this prospect i ve study ( 32 in each group ). A single surgeon performed primary ACL reconstruction in alternating sequence. Forty-eight patients ( 24 in each group ) were evaluated 17 years after ACL reconstruction : A clinical assessment was made based on the International Knee Documentation Committee ( IKDC ) form, instrumented laxity was measured with KT-1000 arthrometer, and radiography of the operated knee was conducted and assessed for degenerative disease. The Lysholm question naire and the Short Form–36 version 2 question naire were filled out by the patients. Results : At the 17-year follow-up, no statistically significant differences were seen with respect to graft failure ( 2 reruptures in the semitendinosus and gracilis tendon [ STG ] group [ 6.3 % ] and 3 reruptures in the PT group [ 9.4 % ] ) and functional outcome. Increased instrumented laxity ( > 3 mm ) measured with KT-1000 arthrometer was seen in significantly more patients in the STG group ( 8 in the STG group compared with 2 in the PT group ; P =.03 ) with a mean side-to-side difference of 2.17 ± 1.86 mm in the STG group compared with 1.33 ± 1.93 mm in the PT group. A significant difference was found in frequency of knee osteoarthritis (OA)—100 % in the PT group compared with 71 % in the STG group ( P =.004 ). Patients in the PT group tended to have higher grade OA according to the IKDC grading system, with an average grade of 1.46 in the PT group compared with 1 in the STG group ( P =.055 ). The degenerative changes in the PT group were more common in the medial and patellofemoral compartments ( P =.003 and P =.04, respectively ). Conclusion : Both autografts provided good to excellent subjective outcomes. No significant differences were noted in graft failure and clinical instability. However, significantly more patients in the STG group had increased instrumented anteroposterior translation measured with KT-1000 arthrometer, and there was a greater prevalence of knee OA at 17 years after surgery in the PT group Assessment of Differences Between the Modified Cincinnati and International Knee Documentation Committee Patient Outcome Scores Background Functional outcome question naires have become a common part of patient follow-up in the orthopaedic community. The modified Cincinnati Knee Rating System and the International Knee Documentation Committee ( IKDC ) subjective scale were design ed to provide clinicians with information regarding a patient ’s functional and clinical status after knee surgery. Hypothesis The functional outcome data reported on the modified Cincinnati Knee Rating System and the IKDC subjective question naire are equivalent. Study Design Cohort study ( diagnosis ) ; Level of evidence, 2. Methods Between 2000 and 2007, all patients with complex knee disorders seen in our orthopaedic clinic were prospect ively followed and given simultaneously the modified Cincinnati Knee Rating System and the IKDC subjective question naires to report their functional outcomes. The total scores of each instrument were compared at each time of evaluation. As a measure of responsiveness, the st and ardized response means were calculated. A second within-patient analysis was also performed to determine if the results would be different when looked at by the patient. Results There were a total of 130 patients with a total of 444 modified Cincinnati Knee Rating System question naires and 462 IKDC subjective complete question naires included in the study. Overall total scores on both the modified Cincinnati Knee Rating System and the IKDC subjective question naires were equivalent in a population analysis. Overall total scores showed improvement in function over time from preoperative measurement through the 2-year follow-up. The individual patient analysis demonstrated that, for a specific patient, it was possible that up to 34 % of the population would report a total score of more than 10 points difference, depending on the scale selected. Conclusion The modified Cincinnati Knee Rating System and the IKDC subjective rating question naires reported by patient population provide similar results. The practitioner who is not performing a population -based study but following individual patients for recovery will find that the individual question naires may offer different functional limitations. Individual differences were lost in the population means, with the approximate balance of positive and negative score differences masking the individual patient differences Anterior Cruciate Ligament Revision Surgery: Ipsilateral Quadriceps Versus Contralateral Semitendinosus-Gracilis Autografts. PURPOSE To evaluate the subjective outcomes, knee stability, and donor-site morbidity after revision ACL reconstruction using either autologous ipsilateral quadriceps tendon or contralateral semitendinosus-gracilis tendon. METHODS A sample size calculation suggested that we needed 25 patients in each group to detect e quality between both groups. Therefore, we evaluated 30 consecutive patients who underwent an ACL revision surgery with ipsilateral bone-quadriceps tendon grafts and 30 consecutive patients with the contralateral semitendinosus-gracilis grafts between January 2010 and December 2012. Because of follow-up and exclusion criteria, finally 51 patients were evaluated. All patients were followed prospect ively for at least 2 years with KT1000 arthrometer testing and the International Knee Documentation Committee ( IKDC ) objective grading. At the 24-month follow-up, additional clinical scores were evaluated : the Knee Injury Osteoarthritis Outcome Score ( KOOS ), the Lysholm score, assessing pain during kneeling, and anterior knee pain. RESULTS The KT1000 postoperative arthrometer side-to-side difference was 2.0 ± 1.2 mm for the quadriceps group and 3.0 ± 2.9 mm for the semitendinosus-gracilis group. The difference was not statistically significant ( P =.461 ). There was also no difference in the rate of positive pivot-shift tests between groups ( P =.661 ). The Lysholm score was 82.5 ± 18 in the quadriceps group and 73.8 ± 19 in the semitendinosus-gracilis group. The difference was not statistically significant ( P =.060 ). There was also no significant difference in the single KOOS subscores, assessing pain while kneeling and anterior knee pain ( included in the KOOS score ). No rerupture occurred during follow-up. CONCLUSIONS Revision ACL reconstruction using the quadriceps tendon graft showed clinical outcomes similar to those of the contralateral semitendinosus-gracilis graft in terms of knee stability and function. Thus, the bone-quadriceps tendon graft may be a good alternative to the contralateral semitendinosus-gracilis tendon graft for revision ACL reconstruction. LEVEL OF EVIDENCE Level II, prospect i ve comparative study Autologous patellar tendon and quadrupled hamstring grafts in anterior cruciate ligament reconstruction: a prospective randomized multicenter review of different fixation methods ACL reconstruction with bone patellar tendon bone ( BPTB ) grafts has been shown to produce dependable results. Recently, reconstructions with double-looped semitendinosus gracilis ( DLSG ) grafts have become common. The prevailing opinion is that ACL reconstruction with patellar tendon graft produces a more stable knee with more anterior knee pain than DLSG grafts, while the functional results and knee scores are similar. The present study evaluates BPTB grafts fixed with metallic interference screws and DLSG grafts fixed with Bone Mulch Screw on the femur and WasherLoc fixation on the tibia. All else being the same, there is no difference in the outcome between the two grafts and fixation methods. This is a prospect i ve r and omized multicenter study. A total of 115 patients with isolated ACL ruptures were r and omized to either reconstruction with BPTB grafts fixed with metal interference screws ( 58 patients ) or DLSG grafts ( 57 patients ) fixed with Bone Mulch Screws and WasherLoc Screws. Follow-up was at one and two years ; the latter by an independent observer. At two years, one ACL revision had been performed in each group. Eight patients in the DLSG group and one in the BPTB group underwent meniscus surgery in the follow-up period ( P = 0.014 ). Mean Lysholm score at the two year follow-up was 91 ( SD ± 10.3 ) in the DLSG group and also 91 ( SD ± 10.2 ) in the BPTB group. Mean KT-1000 at two years was 1.5 mm in the BPTB group and 1.8 mm in the DLSG group ( n.s. ). At two years, four patients in the BPTB group and three in the DLSG group had a Lachman test grade 2 or 3 ( n.s. ). More patients in the BPTB group had pain at the lower pole of the patella ( P = 0.04 ). Peak flexion torque and total flexion work were lower in the DLSG group at one year ( P = 0.003 and P = 0.000 ) and total flexion work also at two years ( P = 0.05 ). BPTB ACL reconstruction fixed with interference screws and DLSG fixed with Bone Mulch Screws on the femur and WasherLoc Screws on the tibia produce satisfactory and nearly identical outcomes. Among our patients in the DLSG group, flexion strength was lower, and more patients underwent meniscus surgery in the follow-up period. The BPTB group has more anterior knee pain There is no difference between quadriceps- and hamstring tendon autografts in primary anterior cruciate ligament reconstruction: a 2-year patient-reported outcome study Purpose Graft choice for anterior cruciate ligament ( ACL ) reconstruction is crucial, however the optimal graft source remains a topic of controversy. The purpose of this study is to compare subjective and functional patient-reported outcomes ( PRO ) after single-bundle ACL reconstruction using quadriceps tendon ( QT ) or hamstring tendon ( HT ) autografts for single-bundle ACL reconstruction. We hypothesize that there is no difference in patient-reported functional outcomes after ACL reconstruction using either HT- or QT autograft. Methods All data were extracted from a prospect ively collected ACL registry. A total of 80 patients with at least 2-year follow-up were included in this study. A total of 40 patients with primary ACL reconstruction using a QT autograft harvested via a minimally invasive technique were matched by sex, age and pre-injury Tegner and Lysholm score to 40 patients who received HT autografts. Subjective and functional PRO scores including Lysholm score, Tegner activity level and visual analogue scale for pain were obtained at 6, 12 and 24 months after index surgery. Results No significant difference between the QT and the HT group was seen at any follow-up in regard to any of the PRO scores for function or pain. 24 months post-surgery the mean Tegner activity score of the HT group was significantly ( p = 0.04 ) lower compared to the pre-injury status. At final follow-up, 27 patients ( 67.5 % ) in the QT group and 32 patients ( 80.0 % ) in the HT returned to their pre-injury activity level ( n.s. ). A total of 37 patients ( 92.5 % ) of the QT cohort and 35 patients ( 87.5 % ) of the HT cohort reported “ good ” or “ excellent ” results according to the Lysholm score ( n.s. ). “ No pain ” or “ slight pain ” during severe exertion was reported by 33 patients ( 82.5 % ) with QT autograft and 28 patients ( 82.4 % ) with HT autograft ( n.s. ). Conclusion There is no significant difference between PRO 2 years post-operative using either QT or HT autografts. Both QT and HT grafts show acceptable and comparable PRO scores making the QT a reliable graft alternative to HT for primary ACL reconstruction. Level of evidence III Strength recovery after anterior cruciate ligament reconstruction with quadriceps tendon versus hamstring tendon autografts in soccer players: A randomized controlled trial. BACKGROUND The comparison between HT and QT grafts in strength recovery and function after an ACLR is scarce in the literature. METHODS A total of 56 participants were enrolled in this r and omized controlled trial and placed into two groups : HT or QT. The hamstring/quadriceps ( H/Q ) ratio was the primary end-point measured with a Genu-3 dynamometer. Peak torque, functional assessment ( Lysholm knee scoring scale and Cincinnati Knee Rating System ), and anteroposterior laxity ( KT-2000 ™ arthrometer ) were also assessed. An intention-to-treat analysis was performed. RESULTS The results of the H/Q ratio analysis of the participants over time revealed significant differences at 60, 180, and 300 ° /s at three, six, and 12months of follow-up ( 60 ° /s : F=5.3, p=0.005 ; 180 ° /s : F=5.5, p=0.004 ; 300 ° /s : F=5.1, p=0.005 ). Furthermore, they revealed significant differences at 60 ° /s, 180 ° /s, and 300 ° /s in the participants over time for peak torque in the extensor muscle strength at three and six months of follow-up, with higher values in the hamstring tendon group but not at 12months of follow-up. There were no significant differences in functional endpoints or arthrometer assessment s at 24months of follow-up. CONCLUSION An ACLR with a QT graft showed similar functional results with a better isokinetic H/Q ratio compared to an ACLR with the HT at 12months of follow-up in soccer players. This higher H/Q ratio observed with the QT could be an advantage of this graft over the HT for an ACLR A Randomized Clinical Trial Comparing Patellar Tendon, Hamstring Tendon, and Double-Bundle ACL Reconstructions: Patient-Reported and Clinical Outcomes at a Minimal 2-Year Follow-up Objective : To compare 3 anatomically positioned autografts for anterior cruciate ligament ( ACL ) reconstruction, by measuring patient-reported disease-specific quality of life at 2 years postoperatively. Design : Double-blinded, r and omized clinical trial with intraoperative computer-generated treatment allocation. Patients and an independent trained evaluator were blinded. Setting : University-based orthopedic referral practice. Patients : Three hundred thirty patients ( 14 - 50 years ; 183 male patients ) with isolated ACL deficiency were equally r and omized to : ( 1 ) patellar tendon, PT : 28.7 years ( SD = 9.7 ) ; ( 2 ) quadruple-str and ed hamstring tendon, HT : 28.5 years ( SD = 9.9 ) ; and ( 3 ) double bundle using HT, DB : 28.3 years ( SD = 9.8 ) ; 322 patients completed 2-year follow-up. Intervention : Anterior cruciate ligament reconstruction using PT, HT, or DB autografts. Main Outcome Measures : Measured at baseline, 1 and 2 years postoperatively— primary : anterior cruciate ligament quality -of-life scores ; secondary : International Knee Documentation Committee ( IKDC ) scores, KT-1000 arthrometer, pivot shift, range of motion, Tegner activity, Cincinnati Occupational Scale, and single-leg hop. Proportions of correct graft type guesses by the patients and evaluator assessed blinding effectiveness. Results : Baseline characteristics were not different. Anterior cruciate ligament quality -of-life scores increased over time for all groups ( P = 0.001 ) but were not different at 2 years ( P = 0.591 ) : PT = 84.6 ( SD = 16.6, 95 % confidence interval [ CI ] = 81.4 - 87.8 ), HT = 82.5 ( SD = 17.7, 95 % CI = 79.2 - 85.9 ), and DB = 82.4 ( SD = 17.5, 95 % CI = 79.1 - 85.7 ). Two-year KT-1000 side-to-side differences ( PT = 1.86 mm ; HT = 2.97 mm ; DB = 2.65 mm ) were statistically significant between PT – HT ( P = 0.002 ) and PT – DB ( P = 0.044 ). The remaining secondary outcomes were not statistically different. Correct graft type guesses occurred 51 % of the time for patients and 46 % for the evaluator. Conclusions : Two-year disease-specific quality -of-life outcome was not different between the ACL reconstruction techniques. The PT reconstructions had significantly lower side-to-side differences on static stability measures. Patient and evaluator blinding was achieved. Level of Evidence : Level 1 ( Therapeutic Studies ). Clinical Relevance : This high- quality, large, double-blind r and omized clinical trial ( RCT ) addresses the insufficient evidence in the literature comparing PT, single-bundle hamstring, and DB hamstring reconstructions for ACL rupture in adults. In addition to the clinical and functional results, this RCT uniquely reports on the disease-specific, patient-reported quality -of-life outcome at 2 years postoperatively Patellar tendon or semitendinosus tendon autografts for anterior cruciate ligament reconstruction: a prospective, randomized study with a 7-Year follow-up. BACKGROUND The aim of the study was to compare the results after arthroscopic anterior cruciate ligament ( ACL ) reconstruction using central -third bone-patellar tendon-bone ( BTB ) autografts and triple/quadruple semitendinosus ( ST ) autografts. HYPOTHESIS In the long-term, ACL reconstruction using BTB autografts will render more donor-site problems than ST autografts. STUDY DESIGN R and omized controlled trial ; Level of evidence, 1. METHODS A r and omized series of 71 patients ( 22 women and 49 men ) with a unilateral ACL rupture who underwent reconstructive surgery were included in the study. The BTB graft was used in 34 patients ( BTB group ) and the ST-tendon graft was used in 37 patients ( ST group ). The patients were examined a median of 86 months ( range, 68 to 114 months ) after the reconstruction. RESULTS Sixty-eight of 71 patients ( 96 % ) were examined at follow-up. The clinical assessment s at follow-up revealed no significant differences between the BTB group and the ST group in terms of the Lysholm score, Tegner activity level, International Knee Documentation Committee evaluation system, 1-legged hop test, KT-1000 arthrometer laxity measurements, manual Lachman test, and range of motion. A significant improvement was seen in both groups compared with the preoperative values in terms of most clinical assessment s. Donor-site morbidity in the form of knee-walking ability, kneeling ability, and area of disturbed anterior knee sensitivity revealed no significant differences between the groups. CONCLUSION Seven years after ACL reconstruction, the subjective and objective outcomes were similar after using the central -third BTB autograft and triple/quadruple ST autograft. Furthermore, no difference in terms of donor-site morbidity was found between the 2 groups [Hamstring versus quadriceps tendon graft in double-bundle anterior cruciate ligament reconstruction]. PURPOSE OF THE STUDY The aim of this prospect i ve study was to evaluate functional outcomes and knee joint stability after double-bundle anterior cruciate ligament reconstruction using three-tunnel quadriceps tendon-bone graft and four-tunnel hamstring graft ( semi-tendinosus and gracilis muscles ). MATERIAL Group 1 included 20 patients undergoing reconstruction with quadriceps tendon- bone graft group ; 2 comprised of 20 patients treated by hamstring graft. There were 26 men and 14 women, with an average age of 27 ( range, 16 to 44 ) years. The minimum follow-up period was one year. METHODS In group 1 patients, semi-anatomic anterior cruciate ligament reconstruction was performed by a three-tunnel technique ( two tunnels in the femur and one in the tibia ) using quadriceps femoris muscle graft. Group 2 patients were treated by anatomic four-tunnel reconstruction ( two tunnels in the femur and two in the tibia ) with the use of hamstring graft. Functional outcomes were evaluated on the basis of Lysholm and IKDC scores. Antero-posterior stability was measured with aKT-1000 arthrometer and rotational stability was assessed by the pivot-shift test. For statistical evaluation, the level of significance ( p ) was set at < 0.05. RESULTS The final evaluation showed an average Lysholm score of 88.9 ± 12 ( 76 - 100 ) points for group 1, and 87.9 ± 11 ( 62 - 100 ) points for group 2 ; there was no statistically significant difference. The rounded average result of the functional IKDC score after surgery was the same in the two groups ( 80 ± 10 ). The joints treated by the three-tunnel technique had on average better antero-posterior stability, but this was not statistically significant. The pivot-shift phenomenon was not seen in either of the groups. Operative times in both groups were comparable. An intra-operative fracture of the patella occurred in two patients of group 1. DISCUSSION No similar prospect i ve study comparing the outcomes of the methods reported here has been found in the internatio- nal literature. The studies so far published have not included any such comparison or they compared other techniques, such as single- versus double-bundle reconstructions. CONCLUSIONS Based on Lysholm and IKDC score evaluation and antero-posterior and rotational stability assessment, it can be concluded that both the three- and the four-tunnel technique of anterior cruciate ligament reconstruction gave similar results, with no significant differences, at one-year follow-up. However, these are only short-term results and only a long-term follow-up can prove or disprove the validity of this conclusion Anterior cruciate ligament reconstruction: bone-patellar tendon-bone compared with double semitendinosus and gracilis tendon grafts. A prospective, randomized clinical trial. BACKGROUND The choice of graft for anterior cruciate ligament reconstruction is a matter of debate, with patellar and hamstring tendons being the two most popular autologous graft options. The objective of this study was to determine in a prospect i ve, r and omized clinical trial whether two grafts ( bone-patellar tendon-bone or doubled hamstring tendons ) fixed with modern devices affect the two-year minimum clinical and radiographic outcomes of anterior cruciate ligament reconstruction. METHODS One hundred and twenty patients with a chronic unilateral rupture of the anterior cruciate ligament underwent arthroscopically assisted reconstruction with use of either autologous bone-patellar tendon-bone or doubled hamstring tendon grafts, in a strictly alternating manner. Both groups were comparable with regard to demographic data, preoperative activity level, mechanism of injury, interval between the injury and the operation, and the amount of knee laxity present preoperatively. The same well-proven surgical technique and aggressive controlled rehabilitation was used. An independent observer, who was blinded with regard to the involved leg and the type of graft, performed the outcome assessment with use of a visual analog scale, the new International Knee Documentation Committee form, the Knee Injury and Osteoarthritis Outcome Score, the Functional Knee Score for Anterior Knee Pain, and an arthrometric and an isokinetic dynamometric evaluation. Radiographs were also made. RESULTS At the two-year follow-up evaluation, no differences were found in terms of the visual analog score, the Knee Injury and Osteoarthritis Outcome Score, the new International Knee Documentation Committee subjective and objective evaluation scores, the KT-1000 side-to-side laxity measurements, the Functional Knee Score for Anterior Knee Pain, muscle strength recovery, or return to sports activities. In the bone-patellar tendon-bone group, we found a higher prevalence of postoperative kneeling discomfort ( p < 0.01 ) and an increased area of decreased skin sensitivity ( p < 0.001 ). In the hamstring tendon group, we recorded a higher prevalence of femoral tunnel widening ( p < 0.01 ). In this group, a correlation was also found between medial meniscectomy and an increased prevalence of pivot-shift glide ( p = 0.035 ). CONCLUSIONS We believe that, with use of accurate and proven surgical and rehabilitation techniques, both grafts are an equivalent option for anterior cruciate ligament reconstruction Technique of anatomical footprint reconstruction of the ACL with oval tunnels and medial portal aimers Purpose The purpose of this article was to demonstrate an anterior cruciate ligament ( ACL ) reconstruction technique using oval tunnels. Aim of this single bundle technique is to fit the footprint anatomy of the ACL as closely as possible. Technique and patients The presented technique is a single bundle technique using a semitendinosus graft. For femoral tunnel placement, a specific medial portal aim er ( Karl Storz, Tuttlingen, Germany ) is used. Aim ing and drilling of the femoral tunnel are performed via the medial portal. Oval tunnels are created by stepwise dilatation with ovally shaped dilatators. The position of the femoral tunnel is visualized and controlled with the arthroscope via the medial portal. For the tibial tunnel placement, a specific aim er was used as well. With this technique, 24 patients were operated and all intra- and postoperative complications were analyzed prospect ively. The tunnel position was documented postoperatively by CT scan. Results There were no significant intra- and postoperative complications associated with the oval tunnel technique. The postoperative 3D CT scan revealed that all femoral and tibial tunnels were located within the area of the anatomical ACL insertions. Conclusions This article presents an ACL reconstruction technique using oval dilatators and medial portal aim ers to create oval tunnels. These oval tunnels match the insertion site anatomy much closer than round tunnels do. Level of Evidence Level IV, case series Is Quadriceps Tendon Autograft a Better Choice Than Hamstring Autograft for Anterior Cruciate Ligament Reconstruction? A Comparative Study With a Mean Follow-up of 3.6 Years Background : The quadriceps tendon ( QT ) autograft is known as an effective graft for anterior cruciate ligament ( ACL ) reconstruction and shows a similar functional outcome to the bone-patellar tendon-bone ( BPTB ) in r and omized controlled trials, with a lesser incidence of complications. Up until now, only 2 studies have compared QT to hamstring tendon ( HT ) autograft. Hypothesis : The functional outcomes of the QT technique are at least as good as those of the HT technique, with the same morbidity. Study Design : Cohort study ; Level of evidence, 3. Methods : Ninety-five patients underwent isolated ACL reconstruction between January 1 and December 31, 2012. Fifty underwent ACL reconstruction with the QT and 45 with the HT. The same surgical technique, fixation method, and postoperative protocol were used in both groups. The following parameters were evaluated : surgical revisions, functional outcome ( Lysholm, Knee injury and Osteoarthritis Outcome Score [ KOOS ], Tegner, subjective International Knee Documentation Committee ), joint stability ( KT-1000, Lachman, pivot shift ), anterior knee pain ( Shelbourne-Trumper score ), and isokinetic strength. Descriptive statistics are presented for these variables using the Student t test. Results : Eighty-six patients ( 45 QT, 41 HT ) were review ed with a mean follow-up of 3.6 ± 0.4 years ; minimum follow-up was 3 years. There were 4 reoperations in the QT group ( including 1 ACL revision ) and 3 in the HT group ( including 2 ACL revisions ) ( P >.05 ). The Lysholm ( 89 ± 6.9 vs 83.1 ± 5.3 ), KOOS Symptoms ( 90 ± 11.2 vs 81 ± 10.3 ), and KOOS Sport ( 82 ± 11.3 vs 67 ± 12.4 ) scores were significantly better in the QT group than in the HT group. In terms of stability, the mean side-to-side difference was 1.1 ± 0.9 mm for the QT group and 3.1 ± 1.3 mm for the HT group based on KT-1000 measurements ( P <.005 ). The negative Lachman component was higher in the QT group than in the HT group ( 90 % vs 46 %, P <.005 ). There was a trend for the negative pivot-shift component to be higher in the QT group than in the HT group ( 90 % vs 64 %, P =.052 ). The Shelbourne-Trumper score was the same in both groups. There was no difference between groups in terms of isokinetic strength. Conclusion : The use of a QT graft in ACL reconstruction leads to equal or better functional outcomes than does the use of an HT graft, without affecting morbidity Anterior cruciate ligament reconstruction using patellar tendon versus hamstring tendon: a prospective comparative study with 9-year follow-up. PURPOSE To analyze the long-term evaluation of clinical, functional, and magnetic resonance imaging ( MRI ) results after implant-free press-fit anterior cruciate ligament ( ACL ) reconstruction with bone-patella tendon ( BPT ) versus quadrupled hamstring tendon ( HT ) grafts. METHODS Sixty-two ACL-insufficient patients were included in a prospect i ve, r and omized study ( 31 BPT and 31 HT ). Both surgical procedures were performed without any implants by a press-fit technique by the senior author. The femoral tunnel was drilled through the anteromedial portal for anatomic placement. At 8.8 years after reconstruction, 53 patients ( 28 BPT and 25 HT ) were examined by different clinical and functional tests. Bilateral MRI scans were performed and interpreted by an independent radiologist. RESULTS On follow-up, the score on the International Knee Documentation Committee evaluation form was significantly better in the HT group. The clinical examination including range of motion, KT-1000 test ( MEDmetric, San Diego, CA ), and pivot-shift test showed no significant differences. On isokinetic testing, the mean quadriceps strength was close to normal ( 96 % ) in both groups, but the hamstring strength was lower in the HT group ( 100.3%/95.1 % ). Kneeling ( 1.5/1.1, P =.002 ), knee walking ( 1.72/1.14, P =.002 ), and single-leg hop test ( 95.8%/99.1 %, P =.057 ) were better in the HT group. The MRI findings about the mean degree of cartilage lesion ( International Cartilage Repair Society protocol ) of the operated ( 2.1/2.1 ) and nonoperated ( 1.4/1.8 ) knee showed no significant differences. No significant difference was found in the grade of medial or lateral meniscal lesion or the number of patients having meniscal lesions when the operated and nonoperated knees were compared. Tunnel measurements, Caton-Deschamps Index, and the sagittal ACL angle were similar. CONCLUSIONS The implant-free press-fit technique for anterior cruciate ligament reconstruction by use of bone-patellar tendon and hamstring grafts with anatomic graft placement is an innovative technique to preserve the cartilage and meniscal status without significant differences between the operated and nonoperated knees in the long term. Significantly less anterior knee pain was noted in the hamstring group, when testing for kneeling and knee walking. LEVEL OF EVIDENCE Level II, prospect i ve comparative study A Randomized Comparison of Patellar Tendon and Hamstring Tendon Anterior Cruciate Ligament Reconstruction * Background Patellar and hamstring tendon autografts are the most frequently used graft types for anterior cruciate ligament reconstruction, but few direct comparisons of outcomes have been published. Hypothesis There is no difference in outcome between the two types of reconstruction. Study Design Prospect i ve r and omized clinical trial. Methods After isolated anterior cruciate ligament rupture, 65 patients were r and omized to receive either a patellar tendon or a four-str and hamstring tendon graft reconstruction, and results were review ed at 4, 8, 12, 24, and 36 months. Results Pain on kneeling was more common and extension deficits were greater in the patellar tendon group. There were greater quadriceps peak torque deficits in the patellar tendon group at 4 and 8 months but not thereafter. In the hamstring tendon group, active flexion deficits were greater from 8 to 24 months, and KT-1000 arthrometer side-to-side differences in anterior knee laxity at 134 N were greater. Cincinnati knee scores, International Knee Documentation Committee ratings, and rates of return to preinjury activity levels were not significantly different between the two groups. Conclusions Both grafts result ed in satisfactory functional outcomes but with increased morbidity in the patellar tendon group and increased knee laxity and radiographic femoral tunnel widening in the hamstring tendon group Is quadriceps tendon a better graft choice than patellar tendon? a prospective randomized study. PURPOSE The purpose of this r and omized controlled study was to compare knee stability, kneeling pain, harvest site pain, sensitivity loss, and subjective clinical outcome after primary anterior cruciate ligament ( ACL ) reconstruction with either bone-patellar tendon-bone ( BPTB ) or quadriceps tendon-bone ( QTB ) autografts in a noninferiority study design. METHODS From 2005 to 2009, a total of 51 patients were included in the present study. Inclusion criteria were isolated ACL injuries in adults. Twenty-five patients were r and omized to BPTB grafts and 26 to QTB grafts. An independent examiner performed follow-up evaluations 1 and 2 years postoperatively. Anteroposterior knee laxity was measured with a KT-1000 arthrometer ( MEDmetric, San Diego, CA ). Anterior knee pain was assessed clinical ly and by knee-walking ability. Knee Injury and Osteoarthritis Outcome Score ( KOOS ) and subjective International Knee Documentation Committee ( IKDC ) score were used for patient-evaluated outcome. RESULTS Anterior knee laxity was equal between the 2 groups with KT-1000 values of 1.1 ± 1.4 mm and 0.8 ± 1.7 mm st and ard deviation ( SD ) at follow-up in QTB and BPTB groups, respectively ( P =.65 ), whereas positive pivot shift test results were seen less frequently ( 14 % compared with 38 %, respectively ; P =.03 ). Anterior kneeling pain, evaluated by the knee walking ability test, was significantly less in the QTB group, with only 7 % of patients grading knee walking as difficult or impossible compared with 34 % in the BPTB group. At 1 and 2 years\'follow-up, there was no difference between the 2 groups in subjective patient-evaluated outcome. The IKDC score was 75 ± 13 patients and 76 ± 16 SD at 1-year follow-up in QTB and BPTB groups, respectively ( P =.78 ). At 2 years, 12 patients were lost to follow-up, result ing in 18 in the BPTB group and 21 in the QTB group. CONCLUSIONS The use of the QTB graft results in less kneeling pain, graft site pain, and sensitivity loss than seen with BPTB grafts ; however, similar anterior knee stability and subjective outcomes are seen. The results of this study show that QTB is a viable option for ACL reconstruction. LEVEL OF EVIDENCE Level II, r and omized controlled clinical trial Knee laxity after staircase exercise predicts radiographic disease progression in medial compartment knee osteoarthritis. OBJECTIVE To evaluate whether increased laxity of the knee during daily physical activities such as stair climbing is associated with progression of knee joint osteoarthritis ( OA ). METHODS During the years 2001 - 2003, 136 patients with bilateral primary medial compartment knee joint OA were enrolled in this prospect i ve study. Baseline data collected were body mass index ( BMI ), muscle power, radiographic joint space width, mechanical axis on st and ing radiography, and anteroposterior ( AP ) knee laxity before and after physical exercise. After 8 years of followup, 84 patients were reexamined to assess radiographic changes. Radiographic disease progression was defined as progression of > 1 grade on the Kellgren/Lawrence scale. RESULTS AP knee laxity increased significantly after stair climbing. Patients with OA progression and those without progression did not differ significantly in age, sex, baseline quadriceps muscle strength, mechanical axis, joint space width, and AP knee laxity before exercise. The 2 groups of patients did, however, differ significantly in baseline BMI and change in AP knee laxity due to exercise. The risk of progression of knee OA increased 4.15-fold with each millimeter of increase in the change in AP knee laxity due to exercise and 1.24-fold with each point increase in the BMI. CONCLUSION Our results indicate that patients with OA progression have significantly greater changes in knee joint laxity during physical activities and a higher BMI than patients without OA progression. These findings suggest that larger changes in knee laxity during repetitive physical activities and a higher BMI play significant roles in the progression of knee OA Patellar Tendon Versus Hamstring Tendon Autografts for Anterior Cruciate Ligament Reconstruction Background Controversy remains over the most appropriate graft for anterior cruciate ligament reconstruction. Hypothesis There is no significant difference in outcomes after 4-str and hamstring and patellar tendon autograft anterior cruciate ligament reconstructions using similar fixation techniques. Study Design R and omized controlled trial ; Level of evidence, 1. Methods Between August 2000 and May 2003, 64 Keller Army Hospital patients with complete anterior cruciate ligament tears were r and omized to hamstring ( n = 32 ) or patellar tendon ( n = 32 ) autograft anterior cruciate ligament reconstruction. Operative graft fixation and rehabilitative techniques were the same for both groups. Follow-up assessment s included the Single Assessment Numeric Evaluation score, Lysholm score, International Knee Documentation Committee score, and Knee Injury and Osteoarthritis Outcome Score. Postoperative radiographs were analyzed for tunnel location and orientation. Results Eleven women and 53 men were r and omized. Eighty-three percent of the patients ( 53 of 64 ) had follow-up of greater than 2 years, or to the point of graft rupture or removal ( average follow-up, 36 months ). Four hamstring grafts ( 12.5 % ) and three patellar tendon grafts ( 9.4 % ) ( P =.71 ) ruptured. One deep infection in a hamstring graft patient necessitated graft removal. Forty-five of the 56 patients with intact grafts had greater than 2-year follow-up. Patients with patellar tendon grafts had greater Tegner activity scores ( P =.04 ). Single Assessment Numeric Evaluation scores were 88.5 ( 95 % confidence interval : 83.1, 93.8 ) and 90.1 ( 95 % confidence interval : 85.2, 96.1 ) for the hamstring and patellar tendon groups, respectively ( P =.53 ). Lysholm scores were 90.3 ( 95 % confidence interval : 84.4, 96.1 ) and 90.4 ( 95 % confidence interval : 84.5, 96.3 ) for the hamstring and patellar tendon groups, respectively ( P =.97 ). There were no significant differences in knee laxity, kneeling pain, isokinetic peak torque, International Knee Documentation Committee score, or Knee Injury and Osteoarthritis Outcome Scores. Postoperative graft rupture correlated with more horizontal tibial tunnel orientation. Conclusion Hamstring and patellar tendon autografts provide similar objective, subjective, and functional outcomes when assessed at least 2 years after anterior cruciate ligament reconstruction', "OBJECTIVES to determine the effect of drugs with anti-cholinergic properties on relevant health outcomes. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. OBJECTIVES To investigate the effects of darifenacin controlled-release ( CR ) and oxybutynin extended-release ( ER ) on cognitive function ( particularly memory ) in older subjects. METHODS Healthy subjects ( n=150 ) > /=60 years were r and omised to darifenacin, oxybutynin ER or placebo in a multicentre, double-blind, double-dummy, parallel-group, 3-week study. Doses were administered according to US labels : oxybutynin ER 10 mg once daily ( od ), increasing to 15 mg od then 20 mg od by week 3 ; darifenacin 7.5 mg od in weeks 1 and 2, then 15 mg od in week 3. The primary end point was accuracy on the Name-Face Association Test ( delayed recall ) at week 3. RESULTS Results of the Name-Face Association Test at week 3 showed no significant difference between darifenacin and placebo on delayed recall ( mean difference, -0.06, p=0.908 ). In contrast, oxybutynin ER result ed in memory impairment, with significantly lower scores than placebo and darifenacin ( mean differences, -1.30, p=0.011 and -1.24, p=0.022, respectively ) for delayed recall on the Name-Face Association Test at week 3. Additional tests of delayed recall indicated significant memory impairment with oxybutynin ER versus placebo at certain time points, whereas darifenacin was similar to placebo. No between-treatment differences were detected in self-rated memory, demonstrating that subjects were unaware of memory deterioration. CONCLUSIONS While darifenacin had no significant effects on memory versus placebo, oxybutynin ER caused significant memory deterioration ( magnitude of effect comparable to brain aging of 10 years ). The results also demonstrate that subjects may not recognise/report memory deterioration Anti-cholinergic load, health care utilization, and survival in people with advanced cancer: a pilot study. INTRODUCTION Anti-cholinergic medications have been associated with increased risks of cognitive impairment, premature mortality and increased risk of hospitalisation. Anti-cholinergic load associated with medication increases as death approaches in those with advanced cancer, yet little is known about associated adverse outcomes in this setting. METHODS A sub study of 112 participants in a r and omised control trial who had cancer and an Australia modified Karnofsky Performance Scale ( AKPS ) score ( AKPS ) of 60 or above, explored survival and health service utilisation ; with anti-cholinergic load calculated using the Clinician Rated Anti-cholinergic Scale ( modified version ) longitudinally to death. A st and ardised starting point for prospect ively calculating survival was an AKPS of 60 or above. RESULTS Baseline entry to the sub- study was a mean 62 + /- 81 days ( median 37, range 1 - 588 ) days before death ( survival ), with mean of 4.8 ( median 3, SD 4.18, range 1 - 24 ) study assessment s in this time period. Participants spent 22 % of time as an inpatient. There was no significant association between anti-cholinergic score and time spent as an inpatient ( adjusted for survival time ) ( p = 0.94 ) ; or survival time. DISCUSSION No association between anti-cholinergic load and survival or time spent as an inpatient was seen. Future studies need to include cognitively impaired population s where the risks of symptomatic deterioration may be more substantial Cognitive effects of reducing anticholinergic drug burden in a frail elderly population: a randomized controlled trial. BACKGROUND Observational studies report a relationship between anticholinergic drug scale ( ADS ) score and cognitive function. This study investigated whether a reduced ADS score improved cognitive function in a frail elderly population. METHODS This r and omized, controlled, single-blinded trial, recruited long-term residents with an ADS score of greater than or equal to 3 from 22 nursing homes in Norway. The participants were r and omly allocated ( 1:1 ) to intervention or control. The intervention was a pharmacist-initiated reduction of ADS score after multidisciplinary drug review s. Primary end point was Consortium to Establish a Registry for Alzheimer's Disease 10-wordlist test for immediate recall. Secondary end points were Mini-Mental Sate Examination, delayed recall and recognition of words, saliva flow, and serum anticholinergic activity (SAA).The participants were retested after 4 and 8 weeks, and the study groups were compared after adjusting for baseline differences. RESULTS Eighty-seven patients were included. The median ADS score was reduced by 2 units ( p <.0001 ) in the intervention group and remained unchanged in the control group. After 8 weeks, the adjusted mean difference in immediate recall was 0.54 words between the intervention and control group ( 95 % confidence interval [ CI ] : -0.91, 2.05 ; p =.48 ). The study groups did not differ significantly in any of the other cognitive end points, salvia flow, or SAA at either follow-up ( p >.18 ). CONCLUSION Pharmacist-initiated drug changes significantly reduced ADS score but did not improve cognitive function in nursing home residents. Moreover, the drug changes did not reduce SAA or mouth dryness significantly, which might indicate limited applicability of the ADS score to prevent prescription risks in this population Assessment of cognitive function of the elderly population: effects of darifenacin. PURPOSE Overactive bladder is common in the elderly population, which is susceptible to cognitive disorders and drug induced cognitive impairment. Existing overactive bladder treatments may cause adverse events, such as cognitive impairment, due to antagonism of the M1 receptor in the central nervous system. In this study we evaluated the effect of darifenacin, an M3 selective antagonist, on cognitive function in elderly volunteers without clinical dementia. MATERIAL S AND METHODS This double-blind, 3-period crossover study r and omized 129 volunteers 65 years or older with no/mild cognitive impairment to receive 3 of 5 treatments, namely darifenacin controlled release ( 3.75, 7.5 or 15 mg once daily ), darifenacin immediate-release ( 5 mg 3 times daily ) or matching placebo for 14 days. Each treatment period was separated by 7 days of washout. Cognitive function tests were completed at baseline and at treatment end. RESULTS For the primary end points of memory scanning sensitivity, speed of choice reaction time and word recognition sensitivity, there were no statistically significant differences for darifenacin vs placebo. There were no statistically significant differences in secondary variables except memory scanning speed, which increased in all groups relative to baseline, but improvement was greater with placebo than with 3.75 mg darifenacin. Darifenacin treatment was not associated with changes in alertness, contentment or calmness, which are likely to be clinical ly relevant. Darifenacin was well tolerated. CONCLUSIONS : In elderly volunteers 2 weeks of treatment with darifenacin had no effect on cognitive function compared with baseline and it was not significantly different from placebo. This may be related to its M3 receptor selectivity with negligible M1 receptor antagonism Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study Abstract Objective To assess the potential of anticholinergic drugs as a cause of non-degenerative mild cognitive impairment in elderly people. Design Longitudinal cohort study. Setting 63 r and omly selected general practice s in the Montpellier region of southern France. Participants 372 people aged > 60 years without dementia at recruitment. Main outcome measures Anticholinergic burden from drug use, cognitive examination, and neurological assessment. Results 9.2 % of subjects continuously used anticholinergic drugs during the year before cognitive assessment. Compared with non-users, they had poorer performance on reaction time, attention, delayed non-verbal memory, narrative recall, visuospatial construction, and language tasks but not on tasks of reasoning, immediate and delayed recall of wordlists, and implicit memory. Eighty per cent of the continuous users were classified as having mild cognitive impairment compared with 35 % of non-users, and anticholinergic drug use was a strong predictor of mild cognitive impairment ( odds ratio 5.12, P = 0.001 ). No difference was found between users and non-users in risk of developing dementia at follow-up after eight years. Conclusions Elderly people taking anticholinergic drugs had significant deficits in cognitive functioning and were highly likely to be classified as mildly cognitively impaired, although not at increased risk for dementia. Doctors should assess current use of anticholinergic drugs in elderly people with mild cognitive impairment before considering administration of acetylcholinesterase inhibitors Cumulative anticholinergic exposure is associated with poor memory and executive function in older men. OBJECTIVES To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. DESIGN Prospect i ve cohort study. SETTING A Department of Veterans Affairs primary care clinic. PARTICIPANTS Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. MEASUREMENTS The outcomes were measured using the Hopkins Verbal Recall Test ( HVRT ) for short-term memory and the instrumental activity of daily living ( IADL ) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants'primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. RESULTS Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point ( 95 % confidence interval (CI)= 0.05 - 0.58 ) and 0.10-point ( 95 % CI=0.04 - 0.17 ) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory ( 0.29, 95 % CI=0.01 - 0.56 ) and executive function ( 0.08, 95 % CI=0.02 - 0.15 ) after further adjustment for concomitant non-anticholinergic medications. CONCLUSION Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects Delirium in acute stroke: a preliminary study of the role of anticholinergic medications The pathogenesis of delirium in acute stroke is incompletely understood. The use of medications with anticholinergic ( ACH ) activity is associated with an increased frequency of delirium. We hypothesized that the intake of medications with ACH activity is associated with delirium in acute stroke patients. Delirium was assessed using the DSM‐IV‐TR criteria and the Delirium Rating Scale, in a sample of consecutive patients with an acute ( ≤4 days ) cerebral infa rct or intracerebral haemorrhage ( ICH ). We performed a gender and age matched case – control study. Twenty‐two delirious stroke patients ( cases ) and 52 non‐delirious patients ( controls ) were compared concerning the intake of ACH medications ( i ) before stroke, ( ii ) during hospitalization but before the assessment. The variables associated with delirium on bivariate analysis were entered in a stepwise logistic regression analysis. The final regression model ( Nagelkerke R2 = 0.65 ) retained non‐neuroleptics ACH medication during hospitalization ( OR = 24.4 ; 95 % CI = 2.18–250 ), medical complications ( OR = 20.8 ; 95 % CI = 3.46–125 ), ACH medication taken before stroke ( OR = 17.5 ; 95 % CI = 1.00–333.3 ) and ICH ( OR = 16.9 ; 95 % CI = 2.73–100 ) as independent predictors of delirium. This preliminary result indicates that drugs with subtle ACH activity play a role in the pathogeneses of delirium in acute stroke. Medication with ACH activity should be avoided in acute stroke patients Anticholinergic medications in community-dwelling older veterans: prevalence of anticholinergic symptoms, symptom burden, and adverse drug events. BACKGROUND The use of drugs with anticholinergic adverse effects is often deemed inappropriate in elderly ( aged > or = 65 years ) patients, yet studies continue to show extensive use in this population at high risk for adverse drug events ( ADEs ). The burden of drug-related anticholinergic symptoms in community-dwelling elderly patients has not been well described. OBJECTIVE The aim of this study was to assess the prevalence of anticholinergic symptoms, corresponding symptom burden, and anticholinergic-related ADEs in a sample of community-dwelling elderly veterans. METHODS This prospect i ve cohort study was conducted at the primary care clinics at the Veterans Affairs Medical Center ( VAMC ), Iowa City, Iowa. The study sample included r and omly selected patients with intact cognitive function attending the VAMC and prescribed > or = 5 scheduled medications. Data on current prescription and nonprescription drug use were elicited by a trained research assistant and a clinical pharmacist from patient interviews and electronic medical records. The prevalence and severity of 7 anticholinergic symptoms ( dry mouth, constipation, blurred vision, confusion, urinary hesitation, dry eyes, and drowsiness ) were assessed at baseline. The occurrence of ADEs at 12 weeks was compared between patients using anticholinergic drugs and those not using them. RESULTS A total of 532 patients were included ( 97.9 % men ; mean age, 74.3 years ; 27.1 % used at least 1 anticholinergic drug ). Twenty-two anticholinergic drugs ( 16 prescription medications, 6 over-the-counter medications ) were identified. The mean number of anticholinergic symptoms was significantly higher in the group using anticholinergic drugs ( 3.1 vs 2.5 ; P < 0.01 ). However, only 2 symptoms were statistically more prevalent in the group using anticholinergic drugs : dry mouth ( 57.6 % vs 45.6 % ) and constipation ( 42.4 % vs 29.4 % ) ( both, P < 0.01 ). At 12 weeks, only 1 ( 0.8 % ) patient in the group using anticholinergic drugs reported an ADE considered related to an anticholinergic drug. CONCLUSIONS Anticholinergic drug use was common ( 27.1 % ) in these elderly veterans with intact cognitive function. The mean number of anticholinergic symptoms was significantly greater in this group, and the prevalences of dry mouth and constipation were significantly higher in the group using anticholinergic drugs ( all, P < 0.01 ). Anticholinergic-related ADEs were rare ( 0.8 % ). Although anticholinergic drugs should generally be avoided in the elderly, individual risks and benefits for a patient should be considered Association of Anticholinergic Burden with Cognitive and Functional Status in a Cohort of Hospitalized Elderly: Comparison of the Anticholinergic Cognitive Burden Scale and Anticholinergic Risk Scale Background Drugs with anticholinergic effects are associated with adverse events such as delirium and falls as well as cognitive decline and loss of independence. Objective The aim of the study was to evaluate the association between anticholinergic burden and both cognitive and functional status, according to the hypothesis that the cumulative anticholinergic burden, as measured by the Anticholinergic Cognitive Burden ( ACB ) Scale and Anticholinergic Risk Scale ( ARS ), increases the risk of cognitive decline and impairs activities of daily living. Methods This cross-sectional, prospect i ve study ( 3-month telephone follow-up ) was conducted in 66 Italian internal medicine and geriatric wards participating in the Registry of Polytherapies SIMI ( Società Italiana di Medicina Interna ) ( REPOSI ) study during 2010. The sample included 1,380 in patients aged 65 years or older. Cognitive status was rated with the Short Blessed Test ( SBT ) and physical function with the Barthel Index. Each patient ’s anticholinergic burden was evaluated using the ACB and ARS scores. Results The mean SBT score for patients treated with anticholinergic drugs was higher than that for patients receiving no anticholinergic medications as also indicated by the ACB scale, even after adjustment for age, sex, education, stroke and transient ischaemic attack [ 9.2 ( 95 % CI 8.6–9.9 ) vs. 8.5 ( 95 % CI 7.8–9.2 ) ; p = 0.05 ]. There was a dose – response relationship between total ACB score and cognitive impairment. Patients identified by the ARS had more severe cognitive and physical impairment than patients identified by the ACB scale, and the dose – response relationship between this score and ability to perform activities of daily living was clear. No correlation was found with length of hospital stay. Conclusions Drugs with anticholinergic properties identified by the ACB scale and ARS are associated with worse cognitive and functional performance in elderly patients. The ACB scale might permit a rapid identification of drugs potentially associated with cognitive impairment in a dose – response pattern, but the ARS is better at rating activities of daily living Association of Anticholinergic Drugs with Hospitalization and Mortality among Older Cardiovascular Patients Abstract Background : Many potentially inappropriate drugs prescribed to older people have anticholinergic properties as adverse effects and are therefore potentially harmful. These effects typically include constipation, dry mouth, blurred vision, dizziness and slowing of urination. It has been shown that drugs with anticholinergic properties ( DAPs ) are associated with cognitive decline and dementia, may contribute to events such as falls, delirium and impulsive behaviour, are associated with self-reported adverse effects and physical impairment, and may even be associated with mortality. However, studies of the prognostic implication s of DAPs remain scarce. Objective : To evaluate the impact of DAPs on hospitalization and mortality in older patients with stable cardiovascular disease ( CVD ). Methods : This was a prospect i ve study with a mean follow-up of 3.3 years involving two study groups : users ( n = 295 ) and non-users ( n = 105 ) of DAPs. The participants were 400 community-dwelling older people ( aged 75–90 years ) with stable CVD participating in a secondary prevention study of CVD ( DEBATE ) in Helsinki, Finl and. The use of DAPs was estimated using definitions from the previous scientific literature. The Charlson Comorbidity Index ( CCI ) was used to estimate the burden of co-morbidity and the Mini-Mental State Examination test was used to assess cognitive function. The risks in the two study groups for hospital visits, number of days spent in hospital care and mortality were measured from 2000 to the end of 2003. Results : The unadjusted follow-up mortality was 20.7 % and 9.5 % among the users and non-users of DAPs, respectively ( p = 0.010 ). However, the use of DAPs was not a significant predictor of mortality in multivariate analysis after adjustment for age, sex and CCI score ( hazard ratio 1.57 ; 95 % CI 0.78, 3.15 ). The mean ± SD number of hospital days per person-year was higher in the DAP user group ( 14.9± 32.5 ) than in the non-user group ( 5.2± 12.3 ) [ p < 0.001 ]. In a bootstrap-type analysis of covariance adjusted for age, sex and CCI score, the use of DAPs predicted the number of days spent in hospital ( p = 0.011 ). Conclusions : The use of DAPs in older patients with stable CVD was associated with an increased number of hospital days but not with mortality Use of medications with anticholinergic properties and cognitive function in a young-old community sample. OBJECTIVES To examine whether anticholinergic medications have effects on the level of cognitive function or cognitive decline in persons in their early to mid 60s. METHODS A r and omly selected community-based sample of 2058 persons aged 60 - 64 at baseline was interviewed twice over four years. Anticholinergic medication use was determined from self-report medication data using the Anticholinergic Drug Scale. Cognition was assessed with the California Verbal Learning Test I ( one trial ), Digits Backwards, the Symbol Digit Modalities Test, the Mini-Mental State Exam and simple and choice reaction time. Persons meeting criteria for Mild Cognitive Impairment were identified in a clinical sub study. Mixed models adjusting for age, sex, self-rated depression and physical health, and total number of medications were used to analyse the data. RESULTS There was a significant main effect of anticholinergic group averaged across time for the Symbol Digits Modalities Test with poorer performance among anticholinergic medication users. Main effects for the other cognitive tests and mild cognitive impairment were non-significant. No time by anticholinergic group interactions were significant. CONCLUSIONS This study suggests that exposure to anticholinergic medication is associated with lower level of complex attention in the young-old, but not with greater cognitive decline over time. Although the clinical significance of this is not clear, caution should be taken when prescribing medications with anticholinergic effects to older persons Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single doses of solifenacin 10 mg Objectives : To assess the cognitive effects of single doses of solifenacin 10 mg compared with placebo ( primary objective ) and oxybutynin immediate release ( IR ) 10 mg ( secondary objective ) in elderly subjects. Methods : Single-centre, r and omised, double-blind, placebo-controlled study in 12 healthy elderly volunteers, with three crossover periods separated by two 14-day washout periods. Each sequence consisted of a single dose of solifenacin 10 mg in one period, oxybutynin IR 10 mg in another and placebo in another. Aspects of attention, information processing, working memory, episodic memory and self-rated mood and alertness were tested using the vali date d Cognitive Drug Research computerised assessment system. Results : There was no evidence from absolute mean values or changes from baseline to suggest that solifenacin 10 mg impaired cognition or self-ratings of mood and alertness versus placebo. Post-hoc ANCOVA showed no statistically significant cognitive deterioration with solifenacin versus placebo, when measured at a time point closest to the probable Cmax of solifenacin. Oxybutynin was associated with statistically significant impairments in several measures of cognitive function at a time point corresponding with its probable Cmax. Conclusion : In this pilot study, single 10 mg doses of solifenacin did not show any clear propensity to impair cognitive function in a healthy elderly population Associations between drug burden index and falls in older people in residential aged care. OBJECTIVES To evaluate the association between the Drug Burden Index ( DBI ), a measure of a person's total exposure to anticholinergic and sedative medications that includes principles of dose-response and maximal effect and is associated with impaired physical function in community-dwelling older people, and falls in residents of residential aged care facilities ( RACFs ). DESIGN Data were drawn from participants in a r and omized controlled trial that investigated falls and fractures. SETTING RACFs in Sydney, Australia. PARTICIPANTS Study participants ( N=602 ; 70.9 % female ) were recruited from 51 RACFs. Mean age was 85.7 ± 6.4, and mean DBI was 0.60 ± 0.66. MEASUREMENTS Medication history was obtained on each participant. Drugs were classified as anticholinergic or sedative and a DBI was calculated. Falls were measured over a 12-month period. Comorbidity, cognitive impairment ( Mini-Mental State Examination ) and depression ( Geriatric Depression Scale ) were determined. RESULTS There were 998 falls in 330 individuals during a follow-up period of 574.2 person-years, equating to an average rate of 1.74 falls per person-year. The univariate negative binomial regression model for falls showed incidence rate ratios of 1.69 ( 95 % confidence interval (CI)=1.22 - 2.34 ) for low DBI ( < 1 ) and 2.11 ( 95 % CI=1.47 - 3.04 ) for high DBI ( ≥1 ) when compared with those who had a DBI of 0. After adjusting for age, sex, history of falling, cognitive impairment, depression, use of a walking aid, comorbidities, polypharmacy, and incontinence, incident rate ratios of 1.61 ( 95 % CI=1.17 - 2.23 ) for low DBI and 1.90 ( 95 % CI=1.30 - 2.78 ) for high DBI were obtained. CONCLUSION DBI is significantly and independently associated with falls in older people living in RACFs. Interventional studies design ed for this population are needed to determine whether reducing DBI, through dose reduction or cessation of anticholinergic and sedative drugs, can prevent falls Changes in cognitive functioning with risperidone and olanzapine treatment: a large-scale, double-blind, randomized study Objective The effects of risperidone and olanzapine on cognitive functioning in patients with schizophrenia were compared in a r and omized, double-blind trial. Method Three hundred and seventy-seven patients were r and omly assigned to receive 2–6 mg/day of risperidone or 5–20 mg/day of olanzapine for 8 weeks. Cognitive function was assessed with a focused cognitive assessment battery ; in addition, extrapyramidal symptoms were assessed using the extrapyramidal symptom rating scale ( ESRS ), and the positive and negative syndrome scale ( PANSS ) was rated for all patients. Results Treatment with these two atypical antipsychotic medications was associated with improved performance on the Wisconsin card sorting test, the trail-making test, the California verbal learning test, the continuous performance test, and some aspects of verbal fluency and spatial working memory. No differences in the effects of the drugs on any of the cognitive tests were noted. Correcting for the effects of anticholinergic treatment did not alter the magnitude of cognitive effects. Conclusions Atypical antipsychotic treatment is associated with wide-ranging benefits on cognitive functioning. Previous reports of greater benefits of olanzapine over risperidone in a small- sample pilot study were not substantiated. These results are not due in general to changes in clinical symptoms or movement disorders, suggesting a direct effect of atypical antipsychotic medications on cognitive deficits in schizophrenia Association between prescribing of anticholinergic medications and incident delirium: a cohort study. OBJECTIVES To describe the association between anticholinergic medications and incident delirium in hospitalized older adults with cognitive impairment and to test the hypothesis that anticholinergic medications would increase the risk of incident delirium. DESIGN Observational cohort study. SETTING Urban public hospital in Indianapolis, Indiana. PARTICIPANTS One hundred forty-seven participants aged 65 and older with cognitive impairment who screened negative for delirium at the time of admission to a general medical ward. MEASUREMENTS Cognitive function at the time of admission was assessed using the Short Portable Mental Status Question naire ( SPMSQ ). Anticholinergic medication orders between the time of admission and the final delirium assessment were evaluated. Anticholinergic medication orders were identified using the Anticholinergic Cognitive Burden Scale. Delirium was assessed using the Confusion Assessment Method. RESULTS Fifty-seven percent of the cohort received at least one order for possible anticholinergic medications, and 28 % received at least one order for definite anticholinergic medications. The incident rate for delirium was 22 % of the entire cohort. After adjusting for age, sex, race, baseline SPMSQ score, and Charlson Comorbidity Index, the odds ratio ( OR ) for developing delirium in those with orders for possible anticholinergic medications was 0.33 ( 95 % confidence interval ( CI ) = 0.10 - 1.03 ). The OR for developing delirium among those with orders for definite anticholinergic medications was 0.43 ( 95 % CI = 0.11 - 1.63 ). CONCLUSION The results did not support the hypothesis that prescription of anticholinergic medications increases the risk of incident delirium in hospitalized older adults with cognitive impairment. This relationship needs to be established using prospect i ve study design s with medication dispensing data to improve the performance of predictive models of delirium", "BACKGROUND Observational and some experimental data suggest that low intake of vitamin K may be associated with an increased risk of fracture. OBJECTIVE To assess whether oral vitamin K ( phytonadione and menaquinone ) supplementation can reduce bone loss and prevent fractures. Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG) We have recently demonstrated that glucocorticoid ( GC ) suppresses bone formation and enhances bone resorption, with result ant bone loss. This altered bone turnover is not due to the action of parathyroid hormone ( PTH ), but appears to be related to the suppression of osteoprotegerin ( OPG ). As vitamin K2 ( menatetrenone ) has been used for the treatment of osteoporosis, the present study was carried out to evaluate the effect of vitamin K2 on GC-induced bone loss. Twenty patients with chronic glomerulonephritis treated with GC for the first time were chosen for this study. Ten patients received GC alone ( group A ) and the other 10 patients each received 15 mg of vitamin K2 per day in addition to GC ( group B ). Markers of bone metabolism, including serum OPG, osteocalcin ( OC ), bone-specific alkaline phosphatase activity ( BAP ), PTH, tartrate-resistant acid phosphatase ( TRAP ), and bone mineral density ( BMD ), were measured before and during the treatment. OPG was significantly decreased in group A ( P < 0.001 ), while no significant change was seen in group B. TRAP was markedly increased in both groups, more particularly in group A ( P < 0.01 ). PTH was decreased in group A, but was increased in group B. OC was decreased at month 1 but subsequently increased until month 12 in both groups. BAP had decreased at month 3 in group A ( P < 0.05 ), but not in group B. BMD of the lumbar spine was significantly reduced after 6 months ( P < 0.01 ), and 12 months ( P < 0.001 ) of treatment in group A, whereas there was no remarkable change in group B. The present study demonstrated that the inhibition exerted by vitamin K2 of the reduction in OPG induced by GC may, at least in part, play a role in the prevention and treatment of GC-induced bone loss The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. BACKGROUND Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density. METHODS To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we r and omly assigned 1649 postmenopausal women with osteoporosis ( low bone mineral density ) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months. RESULTS New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period ( relative risk, 0.59 ; 95 percent confidence interval, 0.48 to 0.73 ). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck ( P<0.001 for both comparisons ). There were no significant differences between the groups in the incidence of serious adverse events. CONCLUSIONS Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. It has been previously shown that the level of circulating undercarboxylated osteocalcin ( ucOC ) is elevated in elderly women in comparison with young, healthy, premenopausal ones. To underst and the mechanism of the increase in the ucOC in the elderly and to assess its potential consequences on bone fragility, we have measured ucOC in the sera of 195 elderly institutionalized women 70 - 101 yr of age. In 45 women ( 23 % ) serum ucOC was above the upper limit of the normal range for young women. The level of ucOC was negatively correlated with 25OHD ( r = -0.32, P < 0.001 ) even after excluding the effect of age, parathyroid hormone ( PTH ), and creatinine by partial correlation ( r = -0.24, P < 0.002 ). During an 18-mo follow-up, 15 women sustained a hip fracture and their baseline ucOC level was higher ( P < 0.01 ) in women who subsequently sustained hip fracture than in the nonfracture group contrasting with no significant differences for serum calcium, phosphate, alkaline phosphatase, creatinine, PTH, 250HD, and total and carboxylated OC. The risk of hip fracture was increased in women with elevated ucOC ( relative ratio 5.9, 99.9 % Cl 1.5 - 22.7, P < 0.001 ). During 1 yr of calcium/vitamin D2 treatment, ucOC decreased ( P < 0.05 ), especially in those with the initially increased values ( from 2.22 + /- 0.35 to 1.41 + /- 0.29 ng/ml, P < 0.005 ) contrasting with an increase in the placebo group ( P < 0.05 ). In conclusion, the increase in ucOC in the elderly reflects not only some degree of vitamin K deficiency but also their poor vitamin D status, suggesting that vitamin D may be important, either directly or indirectly through its effect on bone turnover, for achieving a normal gamma-carboxylation of OC. The ucOC, but not conventional calcium metabolism parameters, predicts the subsequent risk of hip fracture, suggesting that serum ucOC reflects some changes in bone matrix associated with increased fragility Vitamin K intake and hip fractures in women: a prospective study. BACKGROUND Vitamin K mediates the gamma-carboxylation of glutamyl residues on several bone proteins, notably osteocalcin. High serum concentrations of undercarboxylated osteocalcin and low serum concentrations of vitamin K are associated with lower bone mineral density and increased risk of hip fracture. However, data are limited on the effects of dietary vitamin K. OBJECTIVE We investigated the hypothesis that high intakes of vitamin K are associated with a lower risk of hip fracture in women. DESIGN We conducted a prospect i ve analysis within the Nurses'Health Study cohort. Diet was assessed in 72327 women aged 38 - 63 y with a food-frequency question naire in 1984 ( baseline ). During the subsequent 10 y of follow-up, 270 hip fractures result ing from low or moderate trauma were reported. RESULTS Women in quintiles 2 - 5 of vitamin K intake had a significantly lower age-adjusted relative risk ( RR : 0.70 ; 95 % CI : 0.53, 0.93 ) of hip fracture than women in the lowest quintile ( < 109 microg/d ). Risk did not decrease between quintiles 2 and 5 and risk estimates were not altered when other risk factors for osteoporosis, including calcium and vitamin D intakes, were added to the models. Risk of hip fracture was also inversely associated with lettuce consumption ( RR : 0.55 ; 95 % CI : 0.40, 0.78 ) for one or more servings per day compared with one or fewer servings per week ), the food that contributed the most to dietary vitamin K intakes. CONCLUSIONS Low intakes of vitamin K may increase the risk of hip fracture in women. The data support the suggestion for a re assessment of the vitamin K requirements that are based on bone health and blood coagulation Vitamin K, bone turnover, and bone mass in girls. BACKGROUND Vitamin K has been suggested to have a role in bone metabolism, and low vitamin K intake has been related to low bone density and increased risk of osteoporotic fracture. OBJECTIVE The objective of this study was to determine whether phylloquinone ( vitamin K(1 ) ) intake and biochemical indicators of vitamin K status are related to bone mineral content ( BMC ) and markers of bone formation and bone resorption in girls. DESIGN Vitamin K status [ plasma phylloquinone concentration and percentage of undercarboxylated osteocalcin ( % ucOC ) ] was measured at baseline in a study of 245 healthy girls aged 3 - 16 y. Cross-linked N-telopeptide of type 1 collagen ( NTx ) breakdown, osteocalcin, and bone-specific alkaline phosphatase were measured to reflect bone resorption and formation. BMC of the total body, lumbar spine, and hip and dietary phylloquinone intake were measured annually for 4 y. RESULTS Phylloquinone intake ( median : 45 microg/d ) was not consistently associated with bone turnover markers or BMC. Better vitamin K status ( high plasma phylloquinone and low % ucOC ) was associated with lower bone resorption and formation. Plasma phylloquinone was inversely associated with NTx and osteocalcin concentrations ( P < 0.05 ), and % ucOC was positively associated with NTx and bone-specific alkaline phosphatase concentrations ( P < 0.05 ). Indicators of vitamin K status were not consistently associated with current BMC or gain in BMC over the 4-y study period. CONCLUSIONS Better vitamin K status was associated with decreased bone turnover in healthy girls consuming a typical US diet. R and omized phylloquinone supplementation trials are needed to further underst and the potential benefits of phylloquinone on bone acquisition in growing children Factors Affecting Bone Loss in Female Endurance Athletes Background : Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female athletes. Purpose : To quantify the rate of bone loss in healthy female athletes and investigate the effects of estrogen and vitamin K supplementation on bone loss. Study Design : Prospect i ve cohort study. Methods : We classified 115 female endurance athletes into amenorrheic, eumenorrheic, or estrogen-supplemented groups and r and omized them to receive either placebo or vitamin K1. The bone mineral densities of the subjects'femoral neck and lumbar spine were measured at baseline and after 2 years. Results : Bone mineral density in the lumbar spine remained constant, but bone density in the femoral neck had decreased significantly after 2 years in all three subgroups. The decrease was higher in amenorrheic ( —6.5 % ± 4.0 % ) than in eumenorrheic ( —3.2 % ± 4.1 % ) and estrogen-supplemented athletes ( —3.9 % ± 3.1 % ). Supplementation with vitamin K did not affect the rate of bone loss. Conclusions : The rate of bone loss in all three subgroups of female athletes was unexpectedly high ; neither estrogen nor vitamin K supplementation prevented bone loss. Clinical Relevance : High-intensity training maintained over several years must be regarded in women as a risk factor for osteoporosis, and protocol s for optimal treatment should be developed Menaquinone-4 in breast milk is derived from dietary phylloquinone. The effect of maternal phylloquinone supplementation on vitamin K in breast milk was studied to establish : ( 1 ) if phylloquinone is the source of menaquinone-4 in breast milk ; ( 2 ) the dose-effect relationship between intake and obtainable levels. Four groups of lactating mothers with a full-term healthy infant participated and took oral phylloquinone supplements of 0.0 ( n 8), 0.8 ( n 8), 2.0 ( n 8), and 4.0 ( n 7 ) mg/d for 12d, starting at day 4 post-partum. Milk sample s were collected on days 4, 8, 16, and 19. Blood sample s were collected on days 4 and 16. Vitamin K and vitamin E concentrations, the latter for reason of comparison, were assayed. Phylloquinone and menaquinone-4 were present in all milk sample s : 5.84 ( SD 2.31 ) and 2.98 ( SD 1.51 ) nmol/l ( n 31 ) respectively, in colostrum ( day 4 sample ). A strong correlation between the vitamers was found ( r 0.78, P<0.001 ). Breast-milk phylloquinone levels were raised in a dose-dependent manner : 4-, 12-, and 30-fold on day 16 for the 08, 2.0, and 4.0 mg group respectively. In addition, menaquinone-4 levels were higher : 2.5- ( P<0.05 ) and 7-fold ( P<0.001 ) in the 2.0 and 4.0 mg groups respectively. Plasma of supplemented subjects contained 3-, 5-, and 10-fold higher phylloquinone levels on day 16. Detectable menaquinone-4 was found in ten of thirty-one day 4 plasma sample s. All day 16 plasma sample s of the 4 mg supplemented group contained the vitamin. There was no correlation between the K-vitamers in plasma. Vitamin E and phylloquinone appear to differ in their distribution in breast milk, milk : plasma concentration ratios were < or = 1 and 3 - 5 for vitamin E and phylloquinone respectively. The milk : plasma concentration ratio of menaquinone-4 was > 10. In conclusion, dietary phylloquinone is a source of menaquinone-4 in breast milk. Phylloquinone supplementation to lactating mothers may be of benefit to the newborn infant, since both phylloquinone and menaquinone-4 are raised by supplementation Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures BACKGROUND Previous studies have shown that alendronate can increase bone mineral density ( BMD ) and prevent radiographically defined ( morphometric ) vertebral fractures. The Fracture Intervention Trial aim ed to investigate the effect of alendronate on the risk of morphometric as well as clinical ly evident fractures in postmenopausal women with low bone mass. METHODS Women aged 55 - 81 with low femoral-neck BMD were enrolled in two study groups based on presence or absence of an existing vertebral fracture. Results for women with at least one vertebral fracture at baseline are reported here. 2027 women were r and omly assigned placebo ( 1005 ) or alendronate ( 1022 ) and followed up for 36 months. The dose of alendronate ( initially 5 mg daily ) was increased ( to 10 mg daily ) at 24 months, with maintenance of the double blind. Lateral spine radiography was done at baseline and at 24 and 36 months. New vertebral fractures, the primary endpoint, were defined by morphometry as a decrease of 20 % ( and at least 4 mm ) in at least one vertebral height between the baseline and latest follow-up radiograph. Non-spine clinical fractures were confirmed by radiographic reports. New symptomatic vertebral fractures were based on self-report and confirmed by radiography. FINDINGS Follow-up radiographs were obtained for 1946 women ( 98 % of surviving participants ). 78 ( 8.0 % ) of women in the alendronate group had one or more new morphometric vertebral fractures compared with 145 ( 15.0 % ) in the placebo group ( relative risk 0.53 [ 95 % Cl 0.41 - 0.68 ] ). For clinical ly apparent vertebral fractures, the corresponding numbers were 23 ( 2.3 % ) alendronate and 50 ( 5.0 % ) placebo ( relative hazard 0.45 [ 0.27 - 0.72 ] ). The risk of any clinical fracture, the main secondary endpoint, was lower in the alendronate than in the placebo group ( 139 [ 13.6 % ] vs 183 [ 18.2 % ] ; relative hazard 0.72 [ 0.58 - 0.90 ] ). The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0.49 ( 0.23 - 0.99 ) and 0.52 ( 0.31 - 0.87 ). There was no significant difference between the groups in numbers of adverse experiences, including upper-gastrointestinal disorders. INTERPRETATION We conclude that among women with low bone mass and existing vertebral fractures, alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebral fractures, as well as other clinical fractures Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. PURPOSE To assess the comparative effectiveness of several medications on bone mineral density, biochemical bone markers, and the incidence of vertebral fractures in postmenopausal women with osteoporosis. METHODS A total of 396 postmenopausal women, aged 50 to 75 years, were allocated r and omly to six equal-sized groups : hormone replacement therapy, etidronate, eel calcitonin, alfacalcidol, vitamin K ( menatetrenone ), or control ( no treatment ). Thoracic and lumbar spine radiographs, bone mineral density at the distal radius, and markers of bone turnover were assessed at baseline and every 3 months during the 2-year study. RESULTS Compared with baseline, the 2-year mean changes in bone mineral density were 2.0 % for hormone replacement therapy, -0.5 % for etidronate, 1.6 % for calcitonin, -3.6 % for alfacalcidol, -1.9 % for vitamin K, and -3.3 % for control. Seventeen ( 26 % ) of the 66 control patients developed new vertebral fractures. Compared with controls, the relative risks of vertebral fracture were 0.35 ( 95 % confidence interval [ CI ] : 0.14 to 0.83 ) for hormone replacement therapy, 0.40 ( 95 % CI : 0.17 to 0.92 ) for etidronate, 0.41 ( 95 % CI : 0.17 to 0.93 ) for calcitonin, 0.56 ( 95 % CI : 0.26 to 1.12 ) for alfacalcidol, and 0.44 ( 95 % CI : 0.20 to 0.99 ) for vitamin K. CONCLUSION We observed significant reductions in the incidence of vertebral fractures with hormone replacement therapy, etidronate, and calcitonin, and significant improvements in bone mineral density with hormone replacement therapy and calcitonin Vitamin K1 Supplementation Retards Bone Loss in Postmenopausal Women Between 50 and 60 Years of Age Although several observational studies have demonstrated an association between vitamin K status and bone mineral density ( BMD ) in postmenopausal women, no placebo-controlled intervention trials of the effect of vitamin K1 supplementation on bone loss have been reported thus far. In the trial presented here we have investigated the potential complementary effect of vitamin K1 ( 1 mg/day ) and a mineral + vitamin D supplement ( 8 µg/day ) on postmenopausal bone loss. The design of our study was a r and omized, double-blind, placebo-controlled intervention study ; 181 healthy postmenopausal women between 50 and 60 years old were recruited, 155 of whom completed the study. During the 3-year treatment period, participants received a daily supplement containing either placebo, or calcium, magnesium, zinc, and vitamin D ( MD group ), or the same formulation with additional vitamin K1 ( MDK group ). The main outcome was the change in BMD of the femoral neck and lumbar spine after 3 years, as measured by DXA. The group receiving the supplement containing additional vitamin K1 showed reduced bone loss of the femoral neck : after 3 years the difference between the MDK and the placebo group was 1.7 % ( 95 % Cl : 0.35–3.44 ) and that between the MDK and MD group was 1.3 % ( 95 % Cl : 0.10–3.41 ). No significant differences were observed among the three groups with respect to change of BMD at the site of the lumbar spine. If co-administered with minerals and vitamin D, vitamin K1 may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency. Significant reduction in bone mineral density ( BMD ) occurs in patients with Parkinson's disease ( PD ), correlating with immobilization and with vitamin D deficiency, and increasing the risk of hip fracture, especially in elderly women. As a biological indicator of compromised vitamin K status, an increased serum concentration of undercarboxylated osteocalcin ( Oc ) has been associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women. We evaluated treatment with vitamin K(2 ) ( menatetrenone ; MK-4 ) in maintaining BMD and reducing the incidence of nonvertebral fractures in elderly female patients with PD. In a r and om and prospect i ve study of PD patients, 60 received 45 mg of MK-4 daily for 12 months, and the remaining 60 ( untreated group ) did not. At baseline, patients of both groups showed vitamin D and K(1 ) deficiencies, high serum levels of ionized calcium, and glutaminic residue ( Glu ) Oc, and low levels of parathyroid hormone ( PTH ) and 1,25-dihydroxyvitamin D [ 1,25-(OH)(2)D ], indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1,25-(OH)(2)D and compensatory PTH secretion. BMD in the second metacarpals increased by 0.9 % in the treated group and decreased by 4.3 % in the untreated group ( p < 0.0001 ). Vitamin K(2 ) level increased by 259.8 % in the treated group. Correspondingly, significant decreases in Glu Oc and calcium were observed in the treated group, in association with an increase in both PTH and 1,25-(OH)(2)D. Ten patients sustained fractures ( eight at the hip and two at other sites ) in the untreated group, and one hip fracture occurred among treated patients ( p = 0.0082 ; odds ratio = 11.5 ). The treatment with MK-4 can increase the BMD of vitamin D- and K-deficient bone by increasing vitamin K concentration, and it can also decrease calcium levels through inhibition of bone resorption, result ing in an increase in 1,25-(OH)(2)D concentration Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis Abstract The effect of the combined administration of vitamin D3 and vitamin K2 on bone mineral density ( BMD ) of the lumbar spine was examined in postmenopausal women with osteoporosis. Ninety-two osteoporotic women who were more than 5 years after menopause, aged 55–81 years, were r and omly divided into four administration groups : vitamin D3 ( 1α hydroxyvitamin D3, 0.75 μg/day ) ( D group ; n = 29 ), vitamin K2 ( menatetrenone, 45 mg/day ) ( K group ; n = 22 ), vitamin D3 plus vitamin K2 ( DK group, n = 21 ), and calcium ( calcium lactate, 2 g/day ) ( C group ; n = 20 ). BMD of the lumbar spine ( L2–L4 ) was measured by dual energy X-ray absorptiometry at 0, 1, and 2 years after the treatment started. There were no significant differences in age, body mass index, years since menopause, and initial BMD among the four groups. One-way analysis of variance ( ANOVA ) with repeated measurements showed a significant decrease in BMD in the C group ( P < 0.001 ). Two-way ANOVA with repeated measurements showed a significant increase in BMD in the D and K groups compared with that in the C group ( P < 0.05 and P < 0.001, respectively ), and a significant increase in BMD in the DK group compared with that in the C, D, and K groups ( P < 0.0001, P < 0.05 and P < 0.01, respectively ). These findings indicate that combined administration of vitamin D3 and vitamin K2, compared with calcium administration, appears to be useful in increasing the BMD of the lumbar spine in postmenopausal women with osteoporosis Calcium plus vitamin D supplementation and the risk of fractures. BACKGROUND The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal. METHODS We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative ( WHI ) clinical trial. We r and omly assigned participants to receive 1000 mg of elemental [ corrected ] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers. RESULTS Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group ( P<0.01 ). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture ( 95 percent confidence interval, 0.72 to 1.08 ), 0.90 for clinical spine fracture ( 0.74 to 1.10 ), and 0.96 for total fractures ( 0.91 to 1.02 ). The risk of renal calculi increased with calcium plus vitamin D ( hazard ratio, 1.17 ; 95 percent confidence interval, 1.02 to 1.34 ). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 ( 95 percent confidence interval, 0.52 to 0.97 ). Effects did not vary significantly according to prer and omization serum vitamin D levels. CONCLUSIONS Among healthy postmenopausal women, calcium with vitamin D supplementation result ed in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. ( Clinical Trials.gov number, NCT00000611. ) Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide. The purpose of this study is to evaluate the efficacy of vitamin K2 and 1,25-dihydroxyvitamin D3 [ 1,25-(OH)2D3 ] in preventing bone loss induced by estrogen deficiency during therapy with the GnRH agonist ( GnRH-a ) leuprolide. One hundred ten women ( mean age, 46.2+/-0.5 yr ), receiving leuprolide therapy for estrogen-dependent diseases ( such as endometriosis and uterine leiomyomas ), were r and omly allocated into four groups ( group A, leuprolide only ; group B, leuprolide with vitamin K2 ; group C, leuprolide with 1,25-(OH)2D3 ; and group D, leuprolide with vitamin K2 and 1,25-(OH)2D3 ). Bone mineral density of the lumbar spine was measured by dual-energy x-ray absorptiometry before and after 6 months of treatment. Bone formation and resorption markers were also measured before and after 6 months of treatment. There were no significant differences in the background parameters among the four groups. Bone mineral density was reduced in all four groups, but the percent changes varied slightly, at - 5.25 % ( group A ), -3.72 % ( P < 0.05 vs. group A ) ( group B ), -4.13 % ( group C ), and -3.59 % ( P < 0.01 vs. group A ) ( group D ), respectively. Bone formation markers were significantly increased in all four groups, and the percent changes of bone formation markers were highest in group B. Bone resorption markers also increased significantly in all four groups after treatment of 6 months. Group B tended to have the highest percent changes of bone resorption markers among the four groups, but these increases were not significantly different between any of the groups. Vitamin K2, especially when combined with 1,25-(OH)2D3, can partially prevent bone loss caused by estrogen deficiency. However, because this effect is attributable mainly to the activation of bone formation, it is not sufficient to eliminate bone loss induced by GnRH-a therapy A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy. OBJECTIVES To investigate the effect of vitamin K2 treatment for a year on spinal bone mineral density ( BMD ) in postmenopausal women, comparing with vitamin D3 hormone replacement therapy and to determine the factors which affect the efficacy of vitamin K2 therapy. SUBJECTS AND METHODS Seventy-two postmenopausal women were r and omized into four groups and treated with respective agents. Before the therapy, 6 and 12 months after the treatment, their lumbar spine BMD were measured by dual energy X-ray absorptiometry. The rates of change in BMD ( delta BMD ) were calculated. Correlations of BMD with age, year since menopause and the initial BMD were determined. RESULTS Vitamin K2 suppressed the decrease in spinal BMD as compared with no treatment group. BMD in women treated with vitamin K2 was inversely correlated with their age ( r = -0.54 ; P < 0.05 ). CONCLUSIONS Vitamin K2 therapy may be a useful method for preventing postmenopausal spinal bone mineral loss. In addition, the therapy should be started early in postmenopausal period Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. BACKGROUND Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. METHODS We r and omly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone ( 1 - 34 ) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study ( median duration of observation, 21 months ) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. RESULTS New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups ; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 ( 95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50 ). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group ( relative risk, 0.47 and 0.46, respectively [ 95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861 ). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck ; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects ( occasional nausea and headache ). CONCLUSIONS Treatment of postmenopausal osteoporosis with parathyroid hormone ( 1 - 34 ) decreases the risk of vertebral and nonvertebral fractures ; increases vertebral, femoral, and total-body bone mineral density ; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. We attempted to investigate whether vitamin K2 ( menatetrenone ) treatment effectively prevents the incidence of new fractures in osteoporosis. A total of 241 osteoporotic patients were enrolled in a 24-month r and omized open label study. The control group ( without treatment ; n = 121 ) and the vitamin K2-treated group ( n = 120 ), which received 45 mg/day orally vitamin K2, were followed for lumbar bone mineral density ( LBMD ; measured by dual-energy X-ray absorptiometry [ DXA ] ) and occurrence of new clinical fractures. Serum level of Glu-osteocalcin ( Glu-OC ) and menaquinone-4 levels were measured at the end of the follow-up period. Serum level of OC and urinary excretion of deoxypyridinoline ( DPD ) were measured before and after the treatment. The background data of these two groups were identical. The incidence of clinical fractures during the 2 years of treatment in the control was higher than the vitamin K2-treated group ( chi2 = 10.935 ; p = 0.0273 ). The percentages of change from the initial value of LBMD at 6, 12, and 24 months after the initiation of the study were -1.8 + /- 0.6 %, -2.4 + /- 0.7 %, and -3.3 + /- 0.8 % for the control group, and 1.4 + /- 0.7 %, -0.1 + /- 0.6 %, and -0.5 + /- 1.0 % for the vitamin K2-treated group, respectively. The changes in LBMD at each time point were significantly different between the control and the treated group ( p = 0.0010 for 6 months, p = 0.0153 for 12 months, and p = 0.0339 for 24 months ). The serum levels of Glu-OC at the end of the observation period in the control and the treated group were 3.0 + /- 0.3 ng/ml and 1.6 + /- 0.1 ng/ml, respectively ( p < 0.0001 ), while the serum level of OC measured by the conventional radioimmunoassay ( RIA ) showed a significant rise ( 42.4 + /-6.9 % from the basal value ) in the treated group at 24 months ( 18.2 + /- 6.1 % for the controls;p = 0.0081 ). There was no significant change in urinary DPD excretion in the treated group. These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures, although the vitamin K2-treated group failed to increase in LBMD. Furthermore, vitamin K2 treatment enhances gamma-carboxylation of the OC molecule Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. BACKGROUND Elderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aim ed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures. METHODS In a factorial- design trial, 5292 people aged 70 years or older ( 4481 [ 85 % ] of whom were women ) who were mobile before developing a low-trauma fracture were r and omly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 ( 800 IU per day ) combined with calcium ( 1000 mg per day ), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures. FINDINGS 698 ( 13 % ) of 5292 participants had a new low-trauma fracture, 183 ( 26 % ) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not ( 331 [ 12.6 % ] of 2617 vs 367 [ 13.7 % ] of 2675 ; hazard ratio ( HR ) 0.94 [ 95 % CI 0.81 - 1.09 ] ) ; between participants allocated vitamin D3 and those who were not ( 353 [ 13.3 % ] of 2649 vs 345 [ 13.1 % ] of 2643 ; 1.02 [ 0.88 - 1.19 ] ) ; or between those allocated combination treatment and those assigned placebo ( 165 [ 12.6 % ] of 1306 vs 179 [ 13.4 % ] of 1332 ; HR for interaction term 1.01 [ 0.75 - 1.36 ] ). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 ( 54.5 % ) of 5292 were still taking tablets, 451 ( 8.5 % ) had died, 58 ( 1.1 % ) had withdrawn, and 1897 ( 35.8 % ) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower ( difference : 9.4 % [ 95 % CI 6.6 - 12.2 ] ), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups. INTERPRETATION The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients. Significant reduction in bone mineral density ( BMD ) occurs in stroke patients on the hemiplegic and contralateral sides, correlating with the degree of paralysis and vitamin D and K deficiency due to malnutrition, and increasing the risk of hip fracture. We evaluated the efficacy of vitamin K2 ( menatetrenone : menaquinone-4 ; MK-4 ) in maintaining BMD by comparing serum biochemical indices of bone metabolism between treated and untreated patients. In a r and om and prospect i ve study, of 108 hemiplegic patients following stroke, 54 received 45 mg menatetrenone daily ( MK-4 group, n = 54 ) for 12 months, and the remaining 54 ( untreatment group ) did not. Nine patients excluded from the study. The BMD in the second metacarpals and serum indices of bone metabolism were determined. BMD on the hemiplegic side increased by 4.3 % in the MK-4 group and decreased by 4.7 % in the untreated group ( p < 0.0001 ), while BMD on the intact side decreased by 0.9 % in the MK-4 group and by 2.7 % in the untreated group ( p < 0.0001 ). At baseline, patients of both groups showed vitamin D and K1 deficiencies, high serum levels of ionized calcium, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen ( ICTP ), and low levels of parathyroid hormones ( PTH ) and bone Gla proteins ( BGP ), indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1, 25-dihydroxyvitamin D ( 1, 25-[OH]2D ) and compensatory PTH secretion. Both vitamins K1 and K2 increased by 97.6 % and 666.9 %, respectively, in the MK-4 group. Correspondingly, a significant increase in BGP and decreases in both ICTP and calcium were observed in the MK-4 group, in association with a simultaneous increase in both PTH and 1, 25-[OH]2D. One patient in the untreated group suffered from a hip fracture, compared with none in the MK-4 group. The treatment with MK-4 can increase the BMD of disused and vitamin D- and K-deficient hemiplegic bone by increasing the vitamin K concentration, and it also can decrease calcium levels through inhibition of bone resorption, result ing in an increase in 1, 25-[OH]2D concentration Effect of menatetrenone on bone mineral density and incidence of vertebral fractures in postmenopausal women with osteoporosis: a comparison with the effect of etidronate Abstract. The purpose of the present study was to compare the effects of etidronate and menatetrenone on bone mineral density ( BMD ) and the incidence of vertebral fractures in postmenopausal women with osteoporosis. Seventy-two osteoporotic women, more than 5 years after menopause, 53–78 years of age, were r and omly divided into three administration groups : E group ; intermittent cyclical etidronate ( 200 mg/day, 14 days per 3 months ; n = 25 ) ; M group ; menatetrenone ( 45 mg/day, daily ; n = 23 ) ; and C group ( control ) ; calcium lactate ( 2 g/day, daily ; n = 24 ). Forearm BMD was measured by dual-energy X-ray absorptiometry at 0, 6, 12, 18, and 24 months after the treatment started. There were no significant differences in age, body mass index, years since menopause, and initial BMD among the three groups. One-way analysis of variance ( ANOVA ) with repeated measurements showed a significant decrease in BMD in the C group ( P < 0.0001 ). Two-way ANOVA with repeated measurements showed a significant increase in BMD in the M group compared with that in the C group ( P < 0.0001 ), and a significant increase in BMD in the E group compared with that in the C and M groups ( P < 0.0001 and P < 0.01, respectively ). The indices of new vertebral fractures/1000 patient-years in the E and M groups were significantly higher than that in the C group ( χ2 = 47.7 ; P < 0.0001 and χ2 = 42.4 ; P < 0.0001, respectively ), and did not differ significantly between the E and M groups. The present preliminary study provides evidence to suggest that, despite the lower increase in BMD produced by me-natetrenone, this agent, as well as etidronate, may have the potential to reduce osteoporotic vertebral fractures in postmenopausal women with osteoporosis", "A systematic review of r and omised controlled trials was undertaken to evaluate the effectiveness of workplace interventions to prevent low back pain. Randomized versus historical controls for clinical trials. To compare the use of r and omized controls ( RCTs ) and historical controls ( HCTs ) for clinical trials, we search ed the literature for therapies studied by both methods. We found six therapies for which 50 RCTs and 56 HCTs were reported. Forty-four of 56 HCTs ( 79 percent ) found the therapy better than the control regimen, but only 10 of 50 RCTs ( 20 percent ) agreed. For each therapy, the treated patients in RCTs and HCTs of the same therapy was largely due to differences in outcome for the control groups, with HCT control patients generally doing worse than the RCT control groups. Adjustment of the outcomes of the HCTs for prognostic factors, when possible, did not appreciably change the results. The data suggest that biases in patient selection may irretrievably weight the outcome of HCts in favor of new therapies. RCTs may miss clinical ly important benefits because of inadequate attention to sample size. The predictive value of each might be improved by reconsidering the use of p less than 0.05 as the significance level for all types of clinical trials, and by the use of confidence intervals around estimates of treatment effects Secondary Prevention of Low‐Back Pain: A Clinical Trial A clinical trial, aim ed at secondary prevention of low-back pain, was performed in 142 hospital employees reporting at least three annual episodes of this condition. Participants were r and omly assigned to one of three groups : a calisthenics program ( CAL ) for 3 months with biweekly sessions of flexion exercises, a back school program ( 5 sessions ), and a control group. The effectiveness of the two intervention programs was evaluated over a 1-year period. Baseline preintervention data and evaluation at the end of 3 months of intervention and after an additional 6 months were collected. A monthly surveillance for the whole year showed a mean of 4.5 “ painful months ” in the CAL group versus 7.3 and 7.4 months in the back school and control groups, respectively ( P < 0.0001 ). The superiority of the CAL group was achieved partly because of the significant increase in trunk forward flexion and to initial increment in abdominal muscle strength. The increased trunk flexion was associated with the rate of participation in the CAL sessions. Further research is needed to answer the question of “ intensity versus type of exercise ” by comparing different intervention programs, with similar intensity Effect of Exercise on Sick Leave Due to Low Back Pain: A Randomized, Comparative, Long‐Term Study Study Design. The study was carried out as an open, r and omized, multicenter, parallel‐group study with an observation period of 12 months. Four Norwegian physiotherapy institutes took part. Patients were subsequently followed for 12 months of home exercise on their own, without the supervision of a physiotherapist. Objectives. 1 ) To investigate and compare the effects of two different exercise programs on low back problems in patients after a 1‐year training program under the supervision of a physiotherapist. 2 ) To investigate the effect supervision by, and motivation from, physiotherapists has on training compliance and efficacy. Summary of Background Data. After ordinary physiotherapy treatment for low back problems, patients were r and omly allocated either to a conventional training program design ed by physiotherapists or to a training program using a new Norwegian‐developed training apparatus called the TerapiMaster. The study included 153 patients with low back problems, all of whom had been referred to physiotherapy by their general practitioners. One hundred twenty‐six patients were followed for an additional 12 months when performing home exercise programs on their own. Methods. Monitoring patient satisfaction with the training program, compliance with the program, and absenteeism from work during the training period. Results. Patient satisfaction with both training programs was high, with about 83 % of participating patients completing the study in accordance with the protocol. Mean absenteeism ( SD ) during the preceding year totaled 82.5 days ( 19.8 ) in the conventional training group and 61.6 days ( 14.7 ) in the TerapiMaster group. Significant reductions to 17.2 days ( 6.0 ) and 15.4 days ( 5.3 ) in the two groups, respectively, were recorded during the training period, corresponding to a 75 % to 80 % reduction compared with the preceding 1‐year period. Mean absenteeism showed a further significant decline during the 12‐month period without supervised training. The average values were 9.9 days ( 3.2 ) for conventional training and 9.3 days ( 3.1 ) for the TerapiMaster, respectively. Conclusions. Both exercise programs reduced absenteeism significantly ( 75‐80 % ). No difference in the effects of the two different programs was discernible. Regular follow‐up through encouragement and variation in the training programs appear to be important factors for motivating patients to adhere to regular exercise programs for low back problems. This thesis was corroborated by the 12‐month study of unsupervised exercise Lumbar supports and education for the prevention of low back pain in industry: a randomized controlled trial. CONTEXT Low back pain is a frequent and costly health problem. Prevention of low back pain is important both for the individual patient and from an economic perspective. OBJECTIVE To assess the efficacy of lumbar supports and education in the prevention of low back pain in industry. DESIGN A r and omized controlled trial with a factorial design. SETTING The cargo department of an airline company in the Netherl and s. PARTICIPANTS A total of 312 workers were r and omized, of whom 282 were available for the 6-month follow-up. INTERVENTIONS Subjects were r and omly assigned to 4 groups : ( 1 ) education ( lifting instructions ) and lumbar support, ( 2 ) education, ( 3 ) lumbar support, and ( 4 ) no intervention. Education consisted of 3 group sessions on lifting techniques with a total duration of 5 hours. Lumbar supports were recommended to be used during working hours for 6 months. MAIN OUTCOME MEASURES Low back pain incidence and sick leave because of back pain during the 6-month intervention period. RESULTS Compliance with wearing the lumbar support at least half the time was 43 %. In the 282 subjects for whom data were available, no statistically significant differences in back pain incidence ( 48 [ 36 % ] of 134 with lumbar support vs 51 [ 34 % ] of 148 without, P=.81 ) or in sick leave because of low back pain ( mean, 0.4 days per month with lumbar support vs 0.4 days without, P=.52 ) were found among the intervention groups. In a subgroup of subjects with low back pain at baseline, lumbar supports reduced the number of days with low back pain per month ( median, 1.2 vs 6.5 days per month ; P=.03 ). CONCLUSIONS Overall, lumbar supports or education did not lead to a reduction in low back pain incidence or sick leave. The results of the subgroup analysis need to be confirmed by future research. Based on our results, the use of education or lumbar supports can not be recommended in the prevention of low back pain in industry How study design affects outcomes in comparisons of therapy. I: Medical. We analysed 113 reports published in 1980 in a sample of medical journals to relate features of study design to the magnitude of gains attributed to new therapies over old. Overall we rated 87 per cent of new therapies as improvements over st and ard therapies. The mean gain ( measured by the Mann-Whitney statistic ) was relatively constant across study design s, except for non-r and omized controlled trials with sequential assignment to therapy, which showed a significantly higher likelihood that a patient would do better on the innovation than on st and ard therapy ( p = 0.004 ). R and omized controlled trials that did not use a double-blind design had a higher likelihood of showing a gain for the innovation than did double-blind trials ( p = 0.02 ). Any evaluation of an innovation may include both bias and the true efficacy of the new therapy, therefore we may consider making adjustments for the average bias associated with a study design. When interpreting an evaluation of a new therapy, readers should consider the impact of the following average adjustments to the Mann-Whitney statistic : for trials with non-r and om sequential assignment a decrease of 0.15, for non-double-blind r and omized controlled trials a decrease of 0.11 Effect of a general fitness program on musculoskeletal symptoms, clinical status, physiological capacity, and perceived work environment among home care service personnel The aim of the present controlled study was to evaluate the effect of a general fitness program, performed by an occupational health service, using pre-post assessment for a number of different outcome measures. A total of 160 employees working in the central home care service district of Umeå, Sweden were asked to participate in a program of a 1-year long exercise program. Of the 160 selected, 54 subjects declined to participate and nine subjects were rejected after a medical check up. The remaining 97 subjects participated in a schedule consisting of pre-post medical and physiotherapy examinations, question naires concerning sociodemography, musculoskeletal and general health complaints and work environment, physiological tests of cardiovascular fitness, and of strength and endurance of shoulder flexors and knee extensors, and registration of sick leave. The subjects were r and omly assigned to an exercise ( treatment ) or control group. The exercise group trained twice a week for 1 year using a mixed program including exercises for coordination, strength/endurance, and fitness. The test schedule was repeated for both groups after 1 year. The exercise intervention was associated with positive changes in prevalence and intensity of musculoskeletal and psychosomatic complaints, better physiotherapy status ( less muscle tightness, better neck mobility, and less tender points ), increased shoulder strength and increased coordination in thigh muscles. However, the exercise group reported worse situations post-exercise concerning aspects of their physical and psychosocial work-environment ( i.e., concerning ergonomy, influence, appreciation and communication with work manager ), which might have been due to stress associated with the exercise situation The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials. The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ). The invited participants were experts in the field of quality assessment of RCTs. The initial item pool contained all items from existing criteria lists. Subsequently, we reduced the number of items by using the Delphi consensus technique. Each Delphi round comprised a question naire, an analysis, and a feedback report. The feedback report included staff team decisions made on the basis of the analysis and their justification. A total of 33 international experts agreed to participate, of whom 21 completed all question naires. The initial item pool of 206 items was reduced to 9 items in three Delphi rounds. The final criteria list ( the Delphi list ) was satisfactory to all participants. It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics. This list is not intended to replace, but rather to be used alongside, existing criteria lists A cost-benefit analysis of a California county's back injury prevention program. Back-related injuries have become a major health problem in the workplace, affecting as many as 35 percent of the work force and accounting for about 25 percent of all compensation cl aims. This study evaluates a back injury prevention program among employees in a northern California county in 1989 - 90. Six divisions of the county government were selected for the study because they had the highest prevalence of back pain experienced and the most back-related injuries in recent years. Four of the six divisions were r and omly selected as the intervention group and the remaining two, the control group. Overall, 77 percent or 205 of the targeted employees in the intervention group participated in the study. The intervention group was given an identical health risk assessment ( HRA ) before and after the 1-year back injury prevention program that offered employees a combination of education, training, physical fitness activities, and ergonomic improvement. The control group was neither given the HRA nor offered the program. The back injury and cost data of both the control and intervention groups were collected before and after the 1-year intervention. The results showed a modest overall decline in back pain prevalence rates, but significant improvement in satisfaction and reduction in risky behaviors. Cost-benefit analysis showed the net benefit of introducing back injury prevention program was $ 161,108, and the return on investment is 179 percent. Therefore, the study offers suggestive evidence for the initial benefits of a back injury prevention program and lends support to the widely held belief that health promotion in the workplace can reduce employee health risks, increase healthful behaviors and attitudes, and improve attitudes toward the employer organization. Whether such intervention will continue to reap benefits in future years depends, to a large extent, on a favorable work environment and the maintenance and continuation of positive behavioral changes Comparison of classroom instruction and independent study in body mechanics. This study was design ed to determine which method of instruction in body mechanics results in the higher subsequent use of the techniques taught. Two groups were formed from nursing personnel at a rural general medical-surgical hospital in the southwestern United States. Subjects from the direct care nursing staff were r and omly assigned to one of the two groups. One group attended two hours of classroom instruction in body mechanics, while the other completed an independent study module. Subjects were pre- and posttested using the Work-Related Body Mechanics Evaluation ( Carlton, 1987 ) while performing a st and ardized lifting task in the clinical setting. Using analysis of covariance, no significant differences were found in the posttest scores of the two groups Teaching and Social Support: Effects on Knowledge, Attitudes, and Behaviors to Prevent Low Back Injuries in Industry This study was funded in part by NIH grant AR36308 The authors thank the employees of the United States Postal Service and the American Postal Workers Union ( APWU ), Boston Metro Area Local, and Maith and lers Local 301 for their help and cooperation ; therapists from the Department of Rehabilitation Services, Bngham and Women's Hospital for help in training workers ; and Ms Nancy Tanner for A controlled trial of an educational program to prevent low back injuries. BACKGROUND Low back injuries are common and costly, accounting for 15 to 25 percent of injuries covered by workers'compensation and 30 to 40 percent of the payments made under that program. The high costs of injury, the lack of effective treatment. and the evidence that there are behavioral risk factors have led to widespread use of employee education programs that teach safe lifting and h and ling. The effectiveness of those programs, however, has received little rigorous evaluation. METHODS We evaluated an educational program design ed to prevent low back injury in a r and omized, controlled trial involving about 4000 postal workers. The program, similar to that in wide use in so-called back schools, was taught by experienced physical therapists. Work units of workers and supervisors were trained in a two-session back school ( three hours of training ), followed by three to four reinforcement sessions over the succeeding few years. Injured subjects ( from both the intervention and the control groups ) were r and omized a second time to receive either training or no training after their return to work. RESULTS Physical therapists trained 2534 postal workers and 134 supervisors. Over 5.5 years of follow-up, 360 workers reported low back injuries, for a rate of 21.2 injuries per 1000 worker-years of risk. The median time off from work per injury was 14 days ( range, 0 to 1717 ) ; the median cost was $ 204 ( range, zero to $ 190,380 ). After their return to work, 75 workers were injured again. Our comparison of the intervention and control groups found that the education program did not reduce the rate of low back injury, the median cost per injury, the time off from work per injury, the rate of related musculoskeletal injuries, or the rate of repeated injury after return to work ; only the subjects'knowledge of safe behavior was increased by the training. CONCLUSIONS A large-scale, r and omized, controlled trial of an educational program to prevent work-associated low back injury found no long-term benefits associated with training The secondary prevention of low back pain: a controlled study with follow-up & NA ; The current investigation studied the effectiveness of a secondary prevention program for nurses with back pain who were deemed at risk for developing a chronic problem. A 2 × 3 repeated measures design was employed with 2 groups and 3 assessment periods. The treatment group received an intervention design ed to reduce current problems, but above all to prevent reinjury and minor pains from becoming chronic medical problems, and it included a physical and behavioral therapy package. The control group was placed on a waiting‐list. Results indicated that the treatment group had significantly greater improvements than the control group for pain intensity, anxiety, sleep quality and fatigue ratings, observed pain behavior, activities, mood, and helplessness. These differences were generally maintained at the 6 month follow‐up. In addition, the treatment group broke a trend for increasing amounts of pain‐related absenteeism, while the control group did not. Taken as a whole, the results suggest that a secondary prevention program aim ed at altering life style factors may represent an effective method for dealing with musculoskeletal pain problems The Influence of Prophylactic Orthoses on Abdominal Strength and Low Back Injury in the Workplace This study was design ed to determine the effect of multimodal intervention and the prevention of back injury, and to evaluate the adverse side effects of using a lumbosacral corset in the workplace. Subjects were 90 male warehouse workers r and omly selected from over 800 employees at a grocery distribution center. Subjects were assigned to three groups : true controls, no back school, no brace orthoses ; back school only ; and back school plus wearing a custom molded lumbosacral orthosis. Comparisons of pre-testing and 6-month follow-up posttesting for abdominal strength, cognitive data, work injury incidence and productivity and use of health care services were evaluated. Controls and training-only group showed no changes in strength productivity or lost time. Orthoses and training-group showed no changes in strength productivity or accident rate ; however, they showed substantially less lost time. This study supports the concept of using education and prophylactic bracing to prevent back injury and reduce time loss. It appears that the use of intermittent prophylactic bracing has no adverse affects on abdominal muscle strength and may contribute to decreased lost time from work injuries Primary Prevention of Back Symptoms and Absence from Work: A Prospective Randomized Study Among Hospital Employees The personnel at a geriatric hospital were r and omized into two groups. One group was allowed to exercise during working hours to improve back muscle strength, endurance, and coordination. The other group did not participate in the exercise program and received no further advice or information. After 13 months, the training group had increased back muscle strength. One subject had been absent from work 28 days in the training group whereas 12 subjects had been absent 155 days from work because of low back pain in the control group ( P<0.004 ). The back pain complaints and intensity of back pain in the training group also decreased in a statistically significant way. Every hour spent by the physiotherapist on the training group reduced the work absence among the participants by 1.3 days, result ing in a cost/benefit ratio greater than 10 How study design affects outcomes in comparisons of therapy. II: Surgical. We analysed the results of 221 comparisons of an innovation with a st and ard treatment in surgery published in six leading surgery journals in 1983 to relate features of study design to the magnitude of gain. For each comparison we measured the gain attributed to the innovation over the st and ard therapy by the Mann-Whitney statistic and the difference in proportion of treatment successes. For primary treatments ( aim ed at curing or ameliorating a patient's principal disease ), an average gain of 0.56 was produced by 20 r and omized controlled trials. This was less than the 0.62 average for four non-r and omized controlled trials, 0.63 for 19 externally controlled trials, and 0.57 for 73 record review s ( 0.50 represents a toss-up between innovation and st and ard ). For secondary therapies ( used to prevent or treat complications of therapy ), the average gain was 0.53 for 61 r and omized controlled trials, 0.58 for eleven non-r and omized controlled trials, 0.54 for eight externally controlled trials, and 0.55 for 18 record review s. Readers of studies evaluating new treatments, particularly for primary treatments, may consider adjustment of the gain according to the study type The effects of body mechanics instruction on work performance. Thirty food service workers were r and omly assigned to two groups ; one group received body mechanics instruction while the other did not. The application of the instruction was measured by evaluating the subjects'use of body mechanics on a novel lifting and lowering task and during performance on the job. Results indicated that the group which received instruction performed significantly better on the novel task than the group that received no instruction. However, no significant difference between groups was found in performance in the work environment. The role of the occupational therapist in a work-related safety program is also discussed Effects of an exercise program on sick leave due to back pain. The purpose s of this study were to evaluate the effect of a weekly exercise program on short-term sick leave ( less than 50 days ) attributable to back pain and to determine whether changes in absenteeism were related to changes in cardiovascular fitness. Subjects were r and omly assigned to an exercise group ( n = 58 ) and a control group ( n = 53 ). Sick leave attributable to back pain was determined in the intervention period of 1 1/2 years and a comparable 1 1/2-year period prior to the study. In the exercise group, the number of episodes of back pain and the number of sick-leave days attributable to back pain in the intervention period decreased by over 50 %. Absenteeism attributable to back pain increased in the control group. The decrease in sick leave in the exercise group was not accompanied by any change in cardiovascular fitness. Suggestions for establishing exercise programs are given The effect of body mechanics instruction on work performance among young workers. Thirty young workers ( aged 14 to 19 years ) employed as groundskeepers and custodians were r and omly assigned to two groups ; one group received body mechanics instruction and the other did not. The instruction focused on proper spinal alignment in the work environment. Instruction on low back pain began with one classroom session before the subjects'first day of work and continued during employment with two on-site sessions. The effect of instruction was evaluated through the observation of body mechanics during actual work performance. The results of the study indicate that the group that received instruction performed significantly better than the control group. This paper also discusses the occupational therapist's role in providing job-specific body mechanics instruction in the work environment as a primary method of preventing low back pain", 'Background. A number of studies have computed the minimally important difference ( MID ) for health-related quality of life instruments. To determine whether there is consistency in the magnitude of MID estimates from different instruments. Quality of life and hospital re-admission in patients with chronic obstructive pulmonary disease. BACKGROUND There is some evidence that quality of life ( QOL ) in patients with chronic obstructive pulmonary disease ( COPD ) may predict clinical outcomes and use of re sources. This study examined whether QOL scores could prospect ively predict re-admission for COPD or death within 12 months of an original admission, and whether QOL scores predicted home nebuliser provision. METHODS The study was carried out in all acute medical wards of Aberdeen Royal Infirmary, Woodend and City Hospitals, Aberdeen over 12 months. A total of 377 patients admitted with an exacerbation of COPD were identified in this time, 111 of whom were not included in the study because they refused the interview or died before discharge. The remaining 266 patients completed the St George\'s Respiratory Question naire ( SGRQ ). Information on spirometric parameters, nebuliser provision at discharge, provision of domiciliary oxygen, and re-admission within 12 months was collected from patient notes. RESULTS The mean age of the patients was 68 years and 53 % were men. The mean ( SD ) forced expiratory volume in one second ( FEV1 ) was 38.8 (18.0)% predicted and forced vital capacity ( FVC ) was 58.9 (23.8)% predicted. Higher ( worse ) scores on the SGRQ were significantly related to re-admission for COPD in the next 12 months ( difference = 4.8, 95 % CI 1.6 to 8.0 ). Patients who were re-admitted and died from COPD did not differ in SGRQ scores from those who were re-admitted and survived for more than 12 months. Re-admission was not related to sex, age, or pulmonary function. One hundred and thirty eight patients did not have a home nebuliser before admission. Of these, 14 were provided with a home nebuliser at discharge. Patients provided with nebulisers had significantly worse SGRQ scores and worse FVC. The 41 patients given domiciliary oxygen did not differ in SGRQ or spirometric parameters. Logistic regression analysis of the three SGRQ subscales ( Symptom, Impact and Activity ), adjusting for lung function, age and sex, showed that all three subscales were significantly related to hospital readmission and that Impact scores were related to nebuliser provision. Women did not differ from men in Symptom scores on the SGRQ but differed markedly on the Activity and Impact scales. CONCLUSIONS It is concluded that poor scores on the SGRQ, a QOL scale which measures patient distress and coping, are associated with re-admission for COPD and use of re sources such as nebulisers, independent of physiological measures of disease severity Structured exercise improves physical functioning in women with stages I and II breast cancer: results of a randomized controlled trial. PURPOSE Self-directed and supervised exercise were compared with usual care in a clinical trial design ed to evaluate the effect of structured exercise on physical functioning and other dimensions of health-related quality of life in women with stages I and II breast cancer. PATIENTS AND METHODS One hundred twenty-three women with stages I and II breast cancer completed baseline evaluations of generic and disease- and site-specific health-related quality of life, aerobic capacity, and body weight. Participants were r and omly allocated to one of three intervention groups : usual care ( control group ), self-directed exercise, or supervised exercise. Quality of life, aerobic capacity, and body weight measures were repeated at 26 weeks. The primary outcome was the change in the Short Form-36 physical functioning scale between baseline and 26 weeks. RESULTS Physical functioning in the control group decreased by 4.1 points, whereas it increased by 5.7 points and 2.2 points in the self-directed and supervised exercise groups, respectively ( P =.04 ). Post hoc analysis showed a moderately large ( and clinical ly important ) difference between the self-directed and control groups ( 9.8 points ; P =.01 ) and a more modest difference between the supervised and control groups ( 6.3 points ; P =.09 ). No significant differences between groups were observed for changes in quality of life scores. In a secondary analysis of participants stratified by type of adjuvant therapy, supervised exercise improved aerobic capacity ( + 3.5 mL/kg/min ; P =.01 ) and reduced body weight ( -4.8 kg ; P <.05 ) compared with usual care only in participants not receiving chemotherapy. CONCLUSION Physical exercise can blunt some of the negative side effects of breast cancer treatment, including reduced physical functioning. Self-directed exercise is an effective way to improve physical functioning compared with usual care. In participants not receiving chemotherapy, supervised exercise may increase aerobic capacity and reduce body weight compared with usual care Quality of life in patients with chronic obstructive pulmonary disease improves after rehabilitation at home. We have developed a rehabilitation programme at home and have investigated its effects on quality of life ( QOL ), lung function, and exercise tolerance in patients with chronic obstructive pulmonary disease ( COPD ). We studied 43 patients with severe airflow obstruction : forced expiratory volume in one second ( FEV1 ) 1.3 + /- 0.4 l ( mean + /- SD ), FEV1/inspiratory vital capacity ( IVC ) 37 + /- 7.9 %. After stratification, 28 patients were r and omly allocated in a home rehabilitation programme for 12 weeks. Fifteen patients in a control group received no rehabilitation. The rehabilitation group received physiotherapy by the local physiotherapist, and supervision by a nurse and a general practitioner. Quality of life was assessed by the four dimensions of the Chronic Respiratory Question naire ( CRQ ). We found a highly significant improvement in the rehabilitation group compared to the control group for the dimensions dyspnoea, emotion, and mastery. Lung function showed no changes in the rehabilitation group. The exercise tolerance improved significantly in the rehabilitation group compared to the control group. The improvement in quality of life was not correlated with the improvement in exercise tolerance. Rehabilitation of COPD patients at home may improve quality of life ; this improvement is not correlated with an improvement in lung function and exercise tolerance Randomized comparison of four tools measuring overall quality of life in patients with advanced cancer. PURPOSE We report on a clinical trial developed to compare four different instruments that provide overall quality -of-life ( QOL ) scores, ranging from a simple, one-item instrument to more detailed instruments. Two issues addressed were ( 1 ) Will QOL tools suffer from missing data when used in a community-based cooperative group setting?, and ( 2 ) Are there additional data generated by a more detailed multiitem instrument over that provided by a single-item global QOL question? MATERIAL S AND METHODS A four-arm r and omized trial was design ed to compare four instruments that provide overall QOL scores in patients with advanced colorectal cancer. Patients and physicians completed the single-item Spitzer Uniscale ( UNISCALE ) at baseline and monthly. Patients were r and omly assigned to complete, in addition, either the 22-item Functional Living Index-Cancer ( FLIC ), the five-item Spitzer QOL index ( QLI ), a picture-face scale ( PICT ), or nothing else. RESULTS A total of 128 patients were r and omized. Greater than 90 % complete QOL data were obtained. There was strong correlation, concordance, and criterion-related validity among all four patient-completed tools. The UNISCALE had a greater decrease over time than did the FLIC ( P=.005 ), which suggests a greater sensitivity ; the UNISCALE was similar to the QLI and the PICT in this regard. Physicians provided lower UNISCALE scores than patients. Results supported the hypothesis that QOL is prognostic for survival. CONCLUSION Patients can effectively complete QOL tools in a cooperative group setting with proper education of health care providers and patients. A simple single-item tool ( UNISCALE ) appears to be appropriate to obtain a measure of overall QOL Defining the minimum level of detectable change for the Roland-Morris questionnaire. BACKGROUND AND PURPOSE The Rol and -Morris Question naire ( RMQ ) is a self-administered disability measure in which greater levels of disability are reflected by higher numbers on a 24-point scale. The RMQ has been shown to yield reliable measurements, which are valid for inferring the level of disability, and to be sensitive to change over time for groups of patients with low back pain. Little is known about the usefulness of this instrument in aiding decision making regarding individual patients. The purpose of this study was to determine the minimum level of detectable change when the RMQ is applied to individual patients. SUBJECTS The study sample consisted of 60 out patients with low back pain. METHODS The RMQ was administered at the subjects\'initial visit and again 4 to 6 weeks later. Conditional st and ard errors of measurement ( CSEMs ) were computed for initial and follow-up RMQ scores, and these values were used to estimate the minimum level of detectable change. Results. Minimum levels of detectable change at the 90 % confidence level varied from 4 to 5 RMQ points. CONCLUSION AND DISCUSSION The magnitude of CSEMs is sufficiently small to detect change in patients with initial scores in the central portion of the scale ( 4 - 20 RMQ points ) ; however, the magnitude is too large to detect improvement in patients with scores of less than 4 and deterioration in patients who have scores greater than 20 Short- and long-term effects of outpatient rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. PURPOSE Pulmonary rehabilitation programs are effective in patients with severe chronic obstructive pulmonary disease ( COPD ) in the short term, but their long-term effects are not known. We investigated the short- and long-term effects of a 6-month outpatient rehabilitation program in patients with severe COPD. SUBJECTS AND METHODS One hundred patients were r and omly assigned to receive either an exercise training program that included cycling, walking, and strength training ( n = 50 ) or usual medical care ( n = 50 ). Thirty-four patients in the training group were evaluated after 6 months ( end of training ), and 26 were evaluated after 18 months of follow-up. In the control group, 28 patients were evaluated at 6 months and 23 after 18 months. We measured pulmonary function, 6-minute walking distance, maximal exercise capacity, peripheral and respiratory muscle strength, and quality of life ( on a 20 to 140-point scale ), and estimated the cost-effectiveness of the program. RESULTS At 6 months, the training group showed improvement in 6-minute walking distance [ mean difference ( training - control ) of 52 m ; 95 % confidence interval ( CI ), 15 to 89 m ], maximal work load ( 12 W ; 95 % CI, 6 to 19 W ), maximal oxygen uptake ( 0.26 liters/min ; 95 % CI, 0.07 to 0.45 liters/min ), quadriceps force ( 18 Nm ; 95 % CI, 7 to 29 Nm ), inspiratory muscle force ( 11 cm H(2)O ; 95 % CI, 3 to 20 cm H(2)O ), and quality of life ( 14 points ; 95 % CI, 6 to 21 points ; all P < 0.05 ). At 18 months all these differences persisted ( P < 0.05 ), except for inspiratory muscle strength. For 6-minute walking distance and quality of life, the differences between the training group and controls at 18 months exceeded the minimal clinical ly-important difference. CONCLUSION Among patients who completed the 6-month program, outpatient training result ed in significant and clinical ly relevant changes in 6-minute walking distance, maximal exercise performance, peripheral and respiratory muscle strength, and quality of life. Most of these effects persisted 18 months after starting the program What are minimal important changes for asthma measures in a clinical trial? In this study, the perceptions of asthmatics to change in their disease was associated with observed changes in clinical asthma measures, in order to identify the threshold where changes in clinical asthma measures are perceivable by patients. The study included 281 asthmatic patients, aged 18 - 63 yrs, in a r and omized, placebo-controlled clinical trial of a leukotriene antagonist. Changes were related in : 1 ) asthma symptom scores ; 2 ) inhaled beta-agonist use ; 3 ) forced expiratory volume in one second ( FEV1 ) ; and 4 ) peak expiratory flow ( PEF ) to a global question that queried overall change in asthma since starting the study drug. Additional analyses examined differences in the group reporting minimal improvement by treatment ( active treatment versus placebo ), sex and age groups. The average minimal patient perceivable improvement for each measure was : 1 ) -0.31 points for the symptom score on a scale of 0 - 6 ; 2 ) -0.81 puffs x day(-1 ) for inhaled beta-agonist use ; 3 ) 0.23 L for FEV1 ; and 4 ) 18.79 L x min(-1 ) for PEF. In general placebo-treated patients and older patients, who reported minimal improvement, experienced less mean improvement from baseline than active-treated patients and younger patients, who reported minimal improvement. Determining the minimal patient perceivable improvement value for a measure may be helpful to interpret changes. However, interpretation should be carried out cautiously when reporting a single value as a clinical ly important change Quality of life in patients with endoscopy-negative heartburn: reliability and sensitivity of disease-specific instruments OBJECTIVES : Endoscopy-negative gastroesophageal reflux disease ( GERD ) lacks objective markers of disease severity. Evaluation of therapies for GERD must therefore rely on subjective measures, including patient self-report question naires, to measure the clinical effectiveness of therapeutic interventions. We aim ed to evaluate the previously vali date d Gastrointestinal Symptoms Rating Scale ( GSRS ) and the Quality of Life in Reflux and Dyspepsia ( QOLRAD ) question naires for reliability and responsiveness to change over time. METHODS : Patients ( n = 1143 ) with heartburn, but no esophagitis included in a r and omized clinical trial assessing the effectiveness of active treatment with proton pump inhibitors over 4 wk were evaluated. RESULTS : The test-retest reliability of both question naires over time was good to excellent ( GSRS 0.53–0.69 ; QOLRAD 0.65–0.76 ), as was the responsiveness estimated by st and ardized response means ( GSRS reflux dimension, −1.43 ; QOLRAD 0.81–1.43 ) and effect sizes ( GRSR reflux dimension, −1.74 ; QOLRAD 0.82–1.56 ). The relationship between improvement in the GSRS reflux dimension score and the amount of clinical benefit as estimated by the patients themselves ( based on the Overall Treatment Evaluation ) suggested a minimally clinical relevant change is 0.5 on the seven grade d scales applied. The importance rating indicated that an important change in the GSRS reflux dimension and the QOLRAD dimensions is equivalent to 1.0, and a very important change to 1.5. CONCLUSIONS : The GSRS and QOLRAD are valid question naires that are reliable and sensitive to change. Both question naires should be suitable for use in clinical trials of therapeutic interventions for patients with heartburn Using the standard error of measurement to identify important changes on the Asthma Quality of Life Questionnaire Objectives : To establish a link between the minimal important difference ( MID ) and the st and ard error of measurement ( SEM ) for all responsive dimensions of the Asthma Quality of Life Question naire ( AQLQ ). Methods : Secondary data analysis of baseline and follow-up interview data from 198 out patients with asthma enrolled in a r and omized controlled trial and receiving care at a major urban academic medical center\'s general medicine clinics. Domain statistics for baseline and follow-up interviews were examined for the AQLQ. The baseline SEM values were compared with established AQLQ MID st and ards using weighted κ values. Results : One SEM identified the MID in responsive AQLQ dimensions. Weighted κ values ( 0.88–0.93 ) vali date d excellent agreement between these two criteria. Conclusion : This is the third study to support using one SEM to identify important individual change in health-related quality of life ( HRQoL ) measures. However, refinement of the process for determining a measure\'s clinical ly meaningful differences is still needed to secure a link between the SEM and the identification of relevant HRQoL change over time Long term benefits of rehabilitation at home on quality of life and exercise tolerance in patients with chronic obstructive pulmonary disease. BACKGROUND --Pulmonary rehabilitation has been shown to have short term subjective and objective benefits for patients with chronic obstructive pulmonary disease ( COPD ). However, appropriately controlled studies have not previously been performed, nor have the benefits of different types of continuation programme for rehabilitation been investigated. Both these problems have been addressed in a single study of the long term effects of once monthly physiotherapy versus once weekly physiotherapy at home after a comprehensive home rehabilitation programme on quality of life and exercise tolerance in patients with COPD. METHODS --Thirty six patients with severe airways obstruction ( mean SD ) forced expiratory volume in one second ( FEV1 ) 1.3(0.4 ) 1, FEV1/inspiratory vital capacity ( IVC ) 37.2(7.9)% ) were studied. Twenty three patients followed a rehabilitation programme at home for 18 months consisting of physiotherapy and supervision by a nurse and general practitioner. During the first three months all 23 patients visited the physiotherapist twice a week for a 0.5 hour session. Thereafter, 11 patients ( group A ) received a session of physiotherapy once weekly while 12 patients ( group B ) received a session of physiotherapy once a month. The control group C ( 13 patients ) received no rehabilitation at all. Quality of life was assessed by the Chronic Respiratory Question naire, exercise tolerance by the six minute walking distance, and lung function by FEV1 and IVC. Outcome measures were assessed at baseline and at three, six, 12, and 18 months. RESULTS --Long term improvements in quality of life were found in patients in groups A and B, but not in those in group C compared with baseline, but these only reached significance in group B at all time points. Patients in group B had a higher quality of life than those in group C only at three and 12 months. There was a decrease in both six minute walking distance ( at 12 and 18 months ) and IVC ( at three, 12, and 18 months ) in patients in group C compared with the baseline measurement. Between groups analysis showed no differences for six minute walking distance, FEV1, and IVC. CONCLUSIONS --This study is the first to show that rehabilitation at home for three months followed by once monthly physiotherapy sessions improves quality of life over 18 months. The change in quality of life was not associated with a change in exercise tolerance Linking clinical relevance and statistical significance in evaluating intra-individual changes in health-related quality of life. OBJECTIVE To compare the st and ard error of measurement ( SEM ) with established st and ards for clinical ly relevant intra-individual change in an evaluation of health-related quality of life. DESIGN Secondary analysis of data from a r and omized controlled trial. SUBJECTS Six hundred and five out patients with a history of cardiac problems attending the general medicine clinics of a major academic medical center. MEASURES Baseline and follow-up interviews included a modified version of the Chronic Heart Failure Question naire ( CHQ ) and the SF-36. The SEM values corresponding to established st and ards for minimal clinical ly important differences ( MCIDs ) on the CHQ were determined. Individual change on the SF-36 was explored using the same SEM criterion. RESULTS One-SEM changes in this population corresponded well to the patient-driven MCID st and ards on all CHQ dimensions ( weighted kappas ( 0.87 ; P < 0.001 ). The distributions of out patients who improved, remained stable, or declined ( defined by the one-SEM criterion ) were generally consistent between CHQ dimensions and SF-36 subscales. CONCLUSIONS The use of the SEM to evaluate individual patient change should be explored among other health-related quality of life instruments with established st and ards for clinical ly relevant differences. Only then can it be determined whether the one-SEM criterion can be consistently applied as a proxy for clinical ly meaningful change What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. To assess the impact of disease and treatment on patients with advanced non-small cell lung cancer ( NSCLC ), we set out to determine a clinical ly meaningful change ( CMC ) on the Lung Cancer Subscale ( LCS ) and the Trial Outcome Index ( TOI ) of the Functional Assessment of Cancer Therapy-Lung ( FACT-L ) question naire. We used data from Eastern Cooperative Oncology Group study 5592 ( E5592 ), a r and omized trial comparing three chemotherapeutic regimens in 599 advanced NSCLC patients. Patients completed the FACT-L at baseline ( pretreatment ), 6 weeks, 12 weeks, and 6 months. Comparing across baseline performance status ( 0 vs. 1 ), prior weight loss ( < 5 % vs. > or = 5 % ), and primary disease symptoms ( < or = 1 vs. > 1 ), LCS and TOI score differences ranged from 2.4 to 3.6 and 6.5 to 9.2, respectively ( all Ps <.001 ). Mean improvement in LCS score from baseline to 12 weeks was 2.4 points in patients who had responded to treatment versus 0.0 points in patients who had progressive disease. Twelve-week LCS change scores for patients progressing early were 3.1 points worse than those of patients progressing later ( mean = -1.2 vs.1.9, respectively ). Similarly, the average TOI change score from baseline to 12 weeks was -6.1 for patients who had progressive disease versus -0.8 points for patients who had responded to treatment. Twelve-week TOI change scores for patients progressing early ( mean = -8.1 ) were 5.7 points worse than those of patients progressing later ( mean = -8.1 vs. -2.4, respectively ). Analyses assuming nonr and om missing data result ed in slightly larger differences. Clinical ly relevant change scores were estimated as two to three points for the LCS and five to seven points for the TOI, setting upper limits for minimal CMCs. These values were comparable to suggested distribution-based criteria of a minimally important difference. These results support use of a two to three point change in the LCS and five to six point change on the TOI of the FACT-L as a CMC, and offer practical direction for inclusion of important patient-based endpoints in lung cancer clinical trials Measurement of fatigue. determining minimally important clinical differences. The purpose was to determine the minimally important clinical difference ( MICD ) in fatigue as measured by the Profile of Mood States, Schwartz Cancer Fatigue Scale ( SCFS ), General Fatigue Scale, and a 10-point single-item fatigue measure. The MICD is the smallest amount of change in a symptom ( e.g., fatigue ) measure that signifies an important change in that symptom. Subjects rated the degree of change in their fatigue over 2 days on a Global Rating Scale. 103 patients were enrolled on this multisite prospect i ve repeated measures design. MICD was determined following established procedures at two time points. Statistically significant changes were observed for moderate and large changes in fatigue, but not for small changes. The scales were sensitive to increases in fatigue over time. The MICD, presented as mean change, for each scale and per item on each scale is : POMS = 5.6, per item = 1.1, SCFS = 5.0, per item = 0.8, GFS = 9.7, per item = 1.0, and the single item measure of fatigue was 2.4 points. This information may be useful in interpreting scale scores and planning studies using these measures Interpreting quality-of-life clinical trial data for use in the clinical practice of antihypertensive therapy. The use of quality -of-life indices in therapeutic trials is gaining recognition as important outcome variables for evaluating the total impact of antihypertensive therapy. While the statistical significance of treatment differentials in quality -of-life indices has been well documented, their clinical relevance still remains unclear. The interpretation of clinical trial quality -of-life treatment differentials depends on a clear underst and ing of the normal variability in the index due to changes in day-to-day living and the relationship between the size of the differential and shifts in population responses. Using the results from a large-scale r and omized clinical trial on quality of life and antihypertensive therapy, a rationale for the interpretation of clinical trial results for use by the practicing clinician is presented Quality of life of women with urinary incontinence: further development of the incontinence quality of life instrument (I-QOL) OBJECTIVES To report on the further development of the Incontinence Quality of Life Instrument ( I-QOL ), a self-report quality of life measure specific to urinary incontinence ( UI ), including its measurement model, responsiveness, and effect size. METHODS Incontinent female patients ( 141 with stress, 147 with mixed UI ) completed the I-QOL and comparative measures at screening, pretreatment, and four subsequent follow-up visits during participation in a multicenter, double-blind, placebo-controlled, r and omized trial assessing the efficacy of duloxetine. Psychometric testing followed st and ardized procedures. RESULTS Factor analysis confirmed an overall score and three subscale scores ( avoidance and limiting behaviors, psychosocial impacts, and social embarrassment ). All scores were internally consistent ( alpha = 0.87 to 0.93 ) and reproducible ( ICC = 0.87 to 0.91 ). The pattern of previously reported correlations with the Short-Form 36-item Health Survey and Psychological Well-Being Schedule were confirmed. Responsiveness statistics using changes in the independent measures of stress test pad weight, number of incontinent episodes, and patient global impression of improvement ranged from 0.4 to 0.8. Minimally important changes ranged from 2 % to 5 % in association with these measures and effect sizes. CONCLUSIONS In a clinical trial, the I-QOL proved to be valid, reproducible, and responsive to treatment for UI in women Minimal clinically important rehabilitation effects in patients with osteoarthritis of the lower extremities. OBJECTIVE To estimate minimal clinical ly important differences ( MCID ) of effects measured by the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) in patients with osteoarthritis ( OA ) of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention. METHODS A prospect i ve cohort study assessed patients\'health by the WOMAC at baseline ( entry into the clinic ) and at the 3 month followup, and by a transition question naire asking about the change of " health in general related to the OA joint " during that time period. The WOMAC section score differences between the " equal " group and the " slightly better " and " slightly worse " groups result ed in the MCID for improvement and for worsening. RESULTS In total 192 patients were followed up. The MCID for improvement ranged from 0.80 to 1.01 points on the continuous WOMAC numerical rating scale from 0 to 10, reflecting changes of 17 to 22 % of baseline scores. The MCID for worsening conditions ranged from 0.29 ( 6 % ) to 1.03 points ( 22 % ). In the transition reply subjectively unchanged patients reported a " pessimistic bias " of 0.35 to 0.51 points, except for the stiffness section. Both MCID and pessimistic bias showed regression to the mean and baseline dependency. CONCLUSION The assessment of MCID using the transition method is a heuristic and valid strategy to detect particular rehabilitation effects in patients with OA of the lower extremities with the use of the WOMAC, and it is worth implementing. The size of the MCID and of the systematic bias is comparable to that assessed by other methods and in other therapeutic setting Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities. OBJECTIVE To discuss the concepts of the minimal clinical ly important difference ( MCID ) and the smallest detectable difference ( SDD ) and to examine their relation to required sample sizes for future studies using concrete data of the condition-specific Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and the generic Medical Outcomes Study 36-Item Short Form ( SF-36 ) in patients with osteoarthritis of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention. METHODS SDD and MCID were determined in a prospect i ve study of 122 patients before a comprehensive inpatient rehabilitation intervention and at the 3-month followup. MCID was assessed by the transition method. Required SDD and sample sizes were determined by applying normal approximation and taking into account the calculation of power. RESULTS In the WOMAC sections the SDD and MCID ranged from 0.51 to 1.33 points ( scale 0 to 10 ), and in the SF-36 sections the SDD and MCID ranged from 2.0 to 7.8 points ( scale 0 to 100 ). Both question naires showed 2 moderately responsive sections that led to required sample sizes of 40 to 325 per treatment arm for a clinical study with unpaired data or total for paired followup data. CONCLUSION In rehabilitation intervention, effects larger than 12 % of baseline score ( 6 % of maximal score ) can be attained and detected as MCID by the transition method in both the WOMAC and the SF-36. Effects of this size lead to reasonable sample sizes for future studies lying below n = 300. The same holds true for moderately responsive question naire sections with effect sizes higher than 0.25. When design ing studies, assumed effects below the MCID may be detectable but are clinical ly meaningless Quality of life changes in COPD patients treated with salmeterol. Changes in health-related quality of life ( HRQoL ) were evaluated in patients with chronic obstructive pulmonary disease ( COPD ) following treatment with placebo, salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler. Patients completed the disease-specific St. George\'s Respiratory Question naire ( SGRQ ) and the Medical Outcomes Study Short Form 36 ( SF-36 ) at baseline and after 16 wk of treatment. Data from 283 patients ( 95 patients in the placebo group and 94 in each salmeterol group ) were available for HRQoL analysis. Apart from a small difference in ages, all treatment groups were well matched at baseline in terms of forced expiratory volume in one second ( FEV1 ) and HRQoL scores. Compared with placebo, salmeterol 50 microg twice a day was associated with significant improvements in SGRQ " Total " and " Impacts " scores which exceeded the threshold for a clinical ly significant change. This was not seen with salmeterol 100 microg twice a day. Changes in SGRQ and SF-36 scores correlated. They also showed a weak but significant relationship with FEV1. This study has shown that a modest change in lung function may be associated with clinical ly significant gain in health and well-being in COPD patients', "Many aspects of long-term pharmacological treatments for anxiety disorders ( AnxDs ) are still debated. We undertook an up date d systematic review of long-term pharmacological studies on panic disorder ( PD ), generalized anxiety disorder ( GAD ), and social anxiety disorder ( SAD ). A Randomized, Naturalistic, Parallel-Group Study for the Long-Term Treatment of Panic Disorder With Clonazepam or Paroxetine Abstract This long-term extension of an 8-week r and omized, naturalistic study in patients with panic disorder with or without agoraphobia compared the efficacy and safety of clonazepam ( n = 47 ) and paroxetine ( n = 37 ) over a 3-year total treatment duration. Target doses for all patients were 2 mg/d clonazepam and 40 mg/d paroxetine ( both taken at bedtime ). This study reports data from the long-term period ( 34 months ), following the initial 8-week treatment phase. Thus, total treatment duration was 36 months. Patients with a good primary outcome during acute treatment continued monotherapy with clonazepam or paroxetine, but patients with partial primary treatment success were switched to the combination therapy. At initiation of the long-term study, the mean doses of clonazepam and paroxetine were 1.9 ( SD, 0.30 ) and 38.4 ( SD, 3.74 ) mg/d, respectively. These doses were maintained until month 36 ( clonazepam 1.9 [ SD, 0.29 ] mg/d and paroxetine 38.2 [ SD, 3.87 ] mg/d ). Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression (CGI)–Improvement rating than treatment with paroxetine ( mean difference : CGI-Severity scale −3.48 vs −3.24, respectively, P = 0.02 ; CGI-Improvement scale 1.06 vs 1.11, respectively, P = 0.04 ). Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine ( 28.9 % vs 70.6 %, P < 0.001 ). The efficacy of clonazepam and paroxetine for the treatment of panic disorder was maintained over the long-term course. There was a significant advantage with clonazepam over paroxetine with respect to the frequency and nature of adverse events Modeling the longitudinal latent effect of pregabalin on self-reported changes in sleep disturbances in outpatients with generalized anxiety disorder managed in routine clinical practice Background Anxiety disorders are among the most common psychiatric illnesses, with generalized anxiety disorder ( GAD ) being one of the most common. Sleep disturbances are highly prevalent in GAD patients. While treatment with pregabalin has been found to be associated with significant improvement in GAD-related sleep disturbance across many controlled clinical trials, mediational analysis has suggested that a substantial portion of this effect could be the result of a direct effect of pregabalin. Thus, the objective of this study was to model the longitudinal latent effect of pregabalin or usual care ( UC ) therapies on changes in sleep in out patients with GAD under routine clinical practice. Methods Male and female GAD out patients, aged 18 years or above, from a 6-month prospect i ve noninterventional trial were analyzed. Direct and indirect effects of either pregabalin or UC changes in anxiety symptoms ( assessed with Hamilton Anxiety Scale ) and sleep disturbances ( assessed with Medical Outcomes Study -Sleep Scale [ MOS-S ] ) were estimated by a conditional latent curve model applying structural equation modeling. Results A total of 1,546 pregabalin-naïve patients were analyzed, 984 receiving pregabalin and 562 UC. Both symptoms of anxiety and sleep disturbances were significantly improved in both groups, with higher mean ( 95 % confidence interval ) score reductions in subjects receiving pregabalin : −15.9 ( −15.2 ; −16.6 ) vs −14.5 ( −13.5 ; −15.5 ), P=0.027, in Hamilton Anxiety Scale ; and −29.7 ( −28.1 ; −31.3 ) vs −24.0 ( −21.6 ; −26.4 ), P<0.001, in MOS-S. The conditional latent curve model showed that the pregabalin effect on sleep disturbances was significant ( γ = −3.99, P<0.001 ), after discounting the effect on reduction in anxiety symptoms. A mediation model showed that 70 % of the direct effect of pregabalin on sleep remained after discounting the mediated effect of anxiety improvement. Conclusion A substantial proportion of the incremental improvements in anxiety-related sleep disturbances with pregabalin vs UC were explained by its direct effect, not mediated by improvements in anxiety symptoms Remission of Generalized Anxiety Disorder after 6 Months of Open-Label Treatment with Venlafaxine XR Background : Remission has become one of the leading outcome criteria in clinical trials. Data collected by this research group assessed the rate of remission after 6 months of treatment of generalized anxiety disorder ( GAD ) with venlafaxine XR, to search for predictors of remission and to define how early on in treatment later remission can be predicted. Method : Two hundred sixty-eight patients with a GAD diagnosis enrolled into an open-label 6-month-treatment trial with venlafaxine XR ( 75 - 225 mg/day ). Remission was defined by a Hamilton anxiety scale total score ≤7. Logistic regression approaches were used to find out how early on in treatment later remission could be predicted, as well as to determine predictors of remission. In addition, adverse events were also followed over time. Results : While the total enrolled patient sample ( n = 268 ) had a remission rate of 53 %, 6-month completers ( n = 159 ) had a remission rate of 79 %. The only statistically significant predictor of remission, independent of baseline anxiety and depression levels, was a low Eysenck neuroticism score. The remission status outcome could best be predicted after 8 weeks of treatment when a CGI-I score of 1 or 2 predicted later remission with 78 % accuracy and later nonremission with 91 % accuracy. The incidence of adverse events decreased over the 6-month period, with sexual adverse events decreasing the least. Conclusion : The only significant predictor of remission was a low score on the Eysenck neuroticism scale. The earliest reliable prediction of later remission, based on improvement, could be made after 8 weeks of treatment with 91 % accuracy Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Collaborative Paroxetine Panic Study Investigators. Paroxetine has been shown to be effective in panic disorder in three 10- to 12-week studies. This trial studied the longer term effects of paroxetine in patients with DSM-III-R defined panic disorder. Patients who satisfactorily completed a 12-week, double-blind, placebo-controlled study of paroxetine and clomipramine could choose to continue receiving their r and omized treatment for a further 36 weeks. Efficacy assessment s included the daily panic attack diary, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, the Marks Sheehan Phobia Scale and the Sheehan Disability Scale. In total, 176 patients were included in the intention-to-treat population. The number of full panic attacks decreased in all three groups during the 12-week study, and improvements continued with long-term therapy. Paroxetine was statistically significantly more effective than placebo throughout the long-term study with respect to reduction from baseline of full panic attacks, and at the end of treatment with respect to the proportion of patients who eventually experienced no panic attacks. There were no significant differences between paroxetine and clomipramine. The proportion of patients who withdrew from the study due to adverse effects was greater in the clomipramine group ( 19 % ) than in either the paroxetine group ( 7 % ) or the placebo group ( 9 % ). Paroxetine was significantly more effective than placebo and as effective as ( but better tolerated than ) clomipramine in the long-term treatment of panic disorder. Not only was efficacy maintained, but continued improvement was also seen, indicating the importance of long-term treatment in patients with panic disorder Interaction between polymorphisms in serotonin transporter (SLC6A4) and serotonin receptor 2A (HTR2A) genes predict treatment response to venlafaxine XR in generalized anxiety disorder Variation in genes involved in serotonergic signaling is thought to be associated with antidepressant treatment response in generalized anxiety disorder ( GAD ). We examined a possible interaction between the serotonin transporter gene ( SLC6A4 ) 5-HTTLPR/rs25531 haplotype and the serotonin 2A receptor gene ( HTR2A ) single-nucleotide polymorphism ( SNP ) rs7997012 in antidepressant treatment outcome in GAD. Patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study. Genotypes obtained for the 5-HTTLPR/rs25531 ( La/La, La/S or S/S ) haplotype and rs7997012 SNP ( G or A ) in the European American population ( n=112 ) were used for pharmacogenetic analysis. Our data show that subjects with genotypes La/La+G/G or La/La+G/A ( n=28 ) had significantly lower Hamilton Anxiety Scale ( HAM-A ) scores than those with genotypes La/S+A/A or S/S+A/A ( n=12 ) at 6 months ( HAM-A difference=10.7 ; P<0.0001 ). Single-marker analysis only showed HAM-A differences of 4.3 ( 5-HTTLPR/rs25531 : La/La versus La/S+S/S ) and 4.8 ( rs7997012 : G/G+G/A versus A/A ), showing for the first time a significant gene – gene interaction between these markers Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial The objective of this study was to evaluate the efficacy and tolerability of extended release quetiapine fumarate ( quetiapine XR ) as maintenance monotherapy for patients with generalized anxiety disorder ( GAD ). Time-to-event ( anxiety symptom recurrence ; maximum 52 weeks ) multicenter, r and omized-withdrawal, parallel-group, double-blind, placebo-controlled study of quetiapine XR ( 50–300 mg/day ) following open-label run-in ( 4–8 weeks ) and open-label stabilization ( ≥12 weeks ). Primary variable : time from r and omization to anxiety event. Secondary variables included : Hamilton Anxiety Rating Scale ( HAM-A ) total, HAM-A psychic/somatic anxiety factors, Clinical Global Impression-Severity of Illness ( CGI-S ), and Quality of Life, Enjoyment and Satisfaction Question naire ( Q-LES-Q ) scores ; adverse events ( AE ) reporting. Four hundred and thirty-two patients, stabilized on quetiapine XR, were r and omized to continue quetiapine XR ( N=216 ) or switch to placebo ( N=216 ). Risk of anxiety symptom recurrence was significantly reduced by 81 % for quetiapine XR versus placebo : hazard ratio=0.19 ( 95 % confidence interval 0.12–0.31 ; P<0.001 ). Fewer patients receiving quetiapine XR ( N=22, 10.2 % ) than placebo ( N=84, 38.9 % ) experienced anxiety symptom recurrence. Significant differences were observed between quetiapine XR and placebo in : HAM-A total, psychic/somatic, CGI-S ( all P<0.001 ) and Q-LES-Q ( P<0.05 ) scores. AEs ( > 10 % ) during open-label treatment were dry mouth, sedation, somnolence, dizziness, fatigue, and constipation. During r and omized treatment, the most common AEs for quetiapine XR were headache and nasopharyngitis. Quetiapine XR monotherapy reduced the risk of anxiety symptom recurrence in patients with GAD stabilized on quetiapine XR, with tolerability results consistent with the known profile of quetiapine Genetic polymorphisms in the PACAP and PAC1 receptor genes and treatment response to venlafaxine XR in generalized anxiety disorder The pituitary adenylate cyclase-activating peptide ( PACAP ) and its receptor ( PAC1 ) are involved in stress response and anxiety. Genotypes for PACAP/PAC1 were examined for effects on treatment response to venlafaxine XR in generalized anxiety disorder. The Asp54Gly ( rs2856966 ) variant in the PACAP gene was associated with better treatment outcome 2nd year maintenance and discontinuation of imipramine in panic disorder with agoraphobia. BACKGROUND The results from our 1 year placebo-controlled maintenance/discontinuation study in remitted panic disorder with agoraphobia patients confirmed the significant prophylactic effectiveness of imipramine maintenance treatment but suggested that this may be necessary in only 37 % of the patients who relapse following discontinuation of 6 months acute imipramine treatment. This paper presents pilot data from a second year extension of the above-mentioned study with the aim of exploring the putative protective effects of maintenance imipramine therapy beyond the 1st year. METHOD Eighteen patients from the 30 who survived, in stable remission, the first 12 months of the maintenance/discontinuation study gave written consent to participate in a double-blind 2nd year extension phase with the knowledge that those on placebo will continue on the same condition ( N = 7, PBO-PBO ) and those on imipramine ( N = 11 ) will be rer and omized to 2nd year maintenance ( N = 4, IMI-IMI ) or placebo substitution ( N = 7, IMI-PBO ). The procedures continued unchanged from that of the 1st year of the study and patients were followed with planned assessment s every 2 months over the second 12-month experimental period of the study. RESULTS None of the IMI-IMI patients relapsed, two ( 28.5 % ) of the IMI-PBO patients relapsed, and two ( 28.5 % ) of PBO-PBO patients relapsed. The mean estimated time without relapse was 10 months and 9 months for IMI-PBO and PBO-PBO, respectively. The estimated probability of not relapsing was.64 for IMI-PBO and.60 for PBO-PBO ( Mantel-cox test chi2 =.84, p =.77 ). CONCLUSION These interlocking controlled observations tentatively suggest that a substantial degree of prophylactic efficacy continues and that a substantial need for continued prophylaxis exists beyond the 1st year of maintenance imipramine treatment in panic disorder with agoraphobia patients Rate of improvement during and across three treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined. BACKGROUND Existing literature on panic disorder ( PD ) yields no data regarding the differential rates of improvement during Cognitive Behavioral Therapy ( CBT ), Selective Serotonin Reuptake Inhibitor ( SSRI ) or both combined ( CBT+SSRI ). METHOD Patients were r and omized to CBT, SSRI or CBT+SSRI which each lasted one year including three months of medication taper. Participating patients kept record of the frequency of panic attacks throughout the full year of treatment. Rate of improvement on panic frequency and the relationship between rate of improvement and baseline agoraphobia ( AG ) were examined. RESULTS A significant decline in frequency of panic attacks was observed for each treatment modality. SSRI and CBT+SSRI were associated with a significant faster rate of improvement as compared to CBT. Gains were maintained after tapering medication. For patients with moderate or severe AG, CBT+SSRI was associated with a more rapid improvement on panic frequency as compared to patients receiving either mono-treatment. LIMITATIONS Frequency of panic attacks was not assessed beyond the full year of treatment. Second, only one process variable was used. CONCLUSIONS Patients with PD respond well to each treatment as indicated by a significant decline in panic attacks. CBT is associated with a slower rate of improvement as compared to SSRI and CBT+SSRI. Discontinuation of SSRI treatment does not result in a revival of frequency of panic attacks. Our data suggest that for patients without or with only mild AG, SSRI-only will suffice. For patients with moderate or severe AG, the combined CBT+SSRI treatment is recommended Maintenance drug treatment of panic disorder. I. Results of a prospective, placebo-controlled comparison of alprazolam and imipramine. One hundred six patients diagnosed according to DSM-III as suffering from agoraphobia with panic disorder, panic disorder with limited phobic avoidance, or uncomplicated panic disorder entered an acute 8-week treatment phase. Patients who improved received an additional 6 months'maintenance treatment. Significantly more patients treated with alprazolam than with imipramine hydrochloride or placebo remained in therapy and experienced panic attack and phobia relief during the acute treatment phase. During the maintenance phase, neither tolerance nor daily dose increase was observed. All patients who completed the maintenance phase ( 27 in the alprazolam group, 11 in the imipramine group, and 10 in the placebo group ) were panic free at the end of 8 months of study treatment. Alprazolam therapy was effective and well tolerated at a mean daily dose of 5.7 mg. Imipramine hydrochloride ( 175 mg/d ) also produced significant panic relief but was associated with poor patient acceptance Treatment-related alteration of cortisol predicts change in neuropsychological function during acute treatment of late-life anxiety disorder. OBJECTIVE Older adults with anxiety disorders are burdened by impairment in neurocognition, which may be mediated by elevated circulating cortisol levels. In a r and omized controlled trial of acute serotonin-reuptake inhibitor treatment for late-life anxiety disorder, we examined whether change in salivary cortisol concentrations during treatment predicted improvements in measures of memory and executive function. METHODS We examined 60 adults aged 60 years and older, who took part in a 12-week trial of escitalopram versus placebo for generalized anxiety disorder. All subjects had pre-treatment and post-treatment assessment s that included monitoring of peak and total daily cortisol and a comprehensive neuropsychological evaluation. RESULTS Salivary cortisol changes during treatment showed significant associations with changes in immediate and delayed memory but no association with executive tasks ( measures of working memory and set shifting ). Analyses suggested that a decrease in cortisol due to serotonin-reuptake inhibitor treatment was responsible for the memory changes : memory improvement was seen with cortisol reduction among patients receiving escitalopram but not among patients receiving placebo. CONCLUSION Serotonin-reuptake inhibitor-induced alteration in circulating cortisol during treatment of generalized anxiety disorder predicted changes in immediate and delayed memory. This finding suggests a novel treatment strategy in late-life anxiety disorders : targeting hypothalamic-pituitary- adrenal axis dysfunction to improve memory Pregabalin long-term treatment and assessment of discontinuation in patients with generalized anxiety disorder. Discontinuation effects following cessation of 12 and 24 wk of pregabalin treatment for generalized anxiety disorder ( GAD ) were evaluated in a placebo- and lorazepam-controlled, r and omized, double-blind, multicentre trial conducted in 16 countries. The study design consisted of two 12-wk treatment periods ( periods 1 and 2 ), each followed by a 1-wk taper and two post-discontinuation assessment s, one immediately following the taper and one 1-wk post-taper. Patients were assigned to receive an initially flexible dose of pregabalin 450 - 600 mg/d, pregabalin 150 - 300 mg/d, or lorazepam 3 - 4 mg/d for 6 wk ; responders continued fixed-dose therapy for 6 additional weeks. Patients entering period 2 continued on the same fixed dose or switched to placebo. Discontinuation effects were evaluated with the Physician Withdrawal Checklist ( PWC ) and reported discontinuation-emergent signs and symptoms. Rebound anxiety was measured with the Hamilton Anxiety Rating Scale. GAD symptoms improved with all treatments and improvements were maintained over 12 and 24 wk. Low levels of discontinuation symptoms were evident in all treatment groups. For patients who received active treatment during both periods, mean ( 95 % confidence interval ) increases on the PWC from last visit on active treatment to the second post-discontinuation assessment were : pregabalin 450 - 600 mg/d : 2.8 ( 1.6 - 3.9 ), pregabalin 150 - 300 mg/d : 1.7 ( 0.7 - 2.8 ), lorazepam 3 - 4 mg/d : 2.2 ( 1.0 - 3.5 ). Rates of rebound anxiety were also low at both 12 and 24 wk ( 0 - 6 % ). This suggests that risk of discontinuation symptoms and rebound anxiety are low for pregabalin after 12 and 24 wk of treatment Broadening of Generalized Anxiety Disorders Definition Does not Affect the Response to Psychiatric Care: Findings from the Observational ADAN Study Objective : To eluci date the consequences of broadening DSM-IV criteria for generalized anxiety disorder ( GAD ), we examined prospect ively the evolution of GAD symptoms in two groups of patients ; one group diagnosed according to DSM-IV criteria and the other, according to broader criteria. Method : Multicentre, prospect i ve and observational study conducted on outpatient psychiatric clinics. Patients were selected from October 2007 to January 2009 and diagnosed with GAD according to DSM-IV criteria ( DSM-IV group ) or broader criteria. Broader criteria were considered 1-month of excessive or non-excessive worry and only 2 of the associated symptoms listed on DSM-IV for GAD diagnosis. Socio-demographic data, medical history and functional outcome measures were collected three times during a 6-month period. Results : 3,549 patients were systematic ally recruited ; 1,815 patients in DSM-IV group ( DG ) and 1,264 in broad group ( BG ) ; 453 patients did not fulfil inclusion criteria and were excluded. Most patients ( 87.9 % in DG, 82.0 % in BG ) were currently following pharmacological therapies ( mainly benzodiazepines ) to manage their anxiety symptoms. The changes observed during the study were : 49.0 % and 58.0 %, respectively of patients without anxiety symptoms as per HAM-A scale at the 6 month visit ( p=0.261 ) and 59.7 % and 67.7 %, respectively ( p=0.103 ) of responder rates ( > 50 % reduction of baseline scoring ). Conclusion : Broadening of GAD criteria does not seem to affect psychiatric care results in subjects with GAD, is able to identify the core symptoms of the disease according to the DSM-IV criteria and could lead to an earlier diagnosis Three year naturalistic outcome study of panic disorder patients treated with paroxetine Background This naturalistic open label follow-up study had three objectives :1 ) To observe the course of illness in Panic Disorder patients receiving long-term versus intermediate-term paroxetine treatment2 ) To compare the relapse rates and side-effect profile after long-term paroxetine treatment between patients with Panic Disorder and Panic Disorder with Agoraphobia.3 ) To observe paroxetine's tolerability over a 24 month period. Methods 143 patients with panic disorder ( PD ), with or without agoraphobia, successfully finished a short-term ( ie 12 week ) trial of paroxetine treatment. All patients then continued to receive paroxetine maintenance therapy for a total of 12 months. At the end of this period, 72 of the patients chose to discontinue paroxetine pharmacotherapy and agreed to be monitored throughout a one year discontinuation follow-up phase. The remaining 71 patients continued on paroxetine for an additional 12 months and then were monitored, as in the first group, for another year while medication-free. The primary limitation of our study is that the subgroups of patients receiving 12 versus 24 months of maintenance paroxetine therapy were selected according to individual patient preference and therefore were not assigned in a r and omized manner. Results Only 21 of 143 patients ( 14 % ) relapsed during the one year medication discontinuation follow-up phase. There were no significant differences in relapse rates between the patients who received intermediate-term ( up to 12 months ) paroxetine and those who chose the long-term course ( 24 month paroxetine treatment ). 43 patients ( 30.1 % ) reported sexual dysfunction. The patients exhibited an average weight gain of 5.06 kg. All patients who eventually relapsed demonstrated significantly greater weight increase ( 7.3 kg ) during the treatment phase. Conclusions The extension of paroxetine maintenance treatment from 12 to 24 months did not seem to further decrease the risk of relapse after medication discontinuation. Twenty-four month paroxetine treatment is accompanied by sexual side effects and weight gain similar to those observed in twelve month treatment Time to relapse after 6 and 12 months' treatment of generalized anxiety disorder with venlafaxine extended release. CONTEXT Generalized anxiety disorder ( GAD ) is a chronic disorder in need of reliable data to guide long-term treatment. OBJECTIVES To assess the benefits of 6 and 12 months'treatment of GAD with venlafaxine hydrochloride extended release ( XR ) in patients who improved after 6 months'open-label venlafaxine XR treatment. DESIGN After 6 months'open-label venlafaxine XR treatment, improved patients were r and omized to venlafaxine XR or placebo for 6 months. All venlafaxine XR patients still in the study at 12 months were r and omized to receive venlafaxine XR or placebo, and all placebo patients continued taking placebo for another 6 months. SETTING One urban site ( 5 locations ). PATIENTS Of 268 patients with a diagnosis of GAD entering the open-label venlafaxine XR treatment phase, 158 ( 59.0 % ) completed 6 months, and 136 ( 50.7 % ) entered relapse phase 2 ( 6 - 12 months ). Fifty-nine ( 43.4 % ) of 136 patients entered phase 3 ( 12 - 18 months ). INTERVENTION Six months'open-label treatment with venlafaxine XR, followed by double-blind venlafaxine XR or placebo for 2 relapse phases, each lasting 6 months. MAIN OUTCOME MEASURES Time to relapse while receiving venlafaxine XR or placebo after 6 and after 12 months of treatment. Relapse was strictly defined to safeguard against assigning patients with venlafaxine XR discontinuation symptoms or temporary anxiety increase as relapse. RESULTS For objective 1, relapse rates in phase 2 ( months 6 - 12 ) were 9.8 % on venlafaxine XR and 53.7 % on placebo ( P <.001 ). For objective 2, relapse rates after 12 months on placebo ( 32.4 % ) were lower than after 6 months on venlafaxine XR ( 53.7 % ) ( P <.03 ). CONCLUSIONS Treatment of GAD with an antidepressant should be continued for at least 12 months. Preliminary data demonstrate that improved patients who relapse while off their antianxiety medication after at least 6 months of treatment will again most likely respond to a second course of treatment with the same medication. Trial Registration clinical trials.gov Identifier : NCT00183274 Effects of once-daily extended release quetiapine fumarate on patient-reported outcomes in patients with generalized anxiety disorder Background We evaluated the effects of once-daily extended-release quetiapine fumarate ( quetiapine XR ) on patient-reported outcomes in generalized anxiety disorder ( GAD ). Methods This is a report of a pooled analysis from three acute 8-week, r and omized, placebocontrolled, fixed-dose ( 50, 150, 300 mg/day ) studies and a 52-week maintenance flexible dose ( 50–300 mg/day ) study of quetiapine XR monotherapy in patients with GAD. Quality of Life Enjoyment and Satisfaction Question naire Short Form ( Q-LES-Q-SF ) percent maximum total scores ( items 1–14 ), item 15 ( “ satisfaction with medication ” ), item 16 ( “ overall life satisfaction ” ), and Pittsburgh Sleep Quality Index ( PSQI ) global scores are reported. Sheehan Disability Scale ( SDS ) total scores were also assessed ( maintenance study only ). Results The acute studies showed significant improvements at week 8 in Q-LES-Q-SF percent maximum total score with quetiapine XR 150 mg/day ( P < 0.001 ) and item 16 with quetiapine XR 50 ( P < 0.05 ) and 150 mg/day ( P < 0.001 ) versus placebo ; PSQI global scores significantly improved with quetiapine XR 50, 150, and 300 mg/day versus placebo ( P < 0.001 ). The maintenance study showed significant benefits versus placebo with quetiapine XR 50–300 mg/day in Q-LES-Q-SF percent total score, item 15 and item 16 scores, PSQI global score, and SDS total score. Conclusion Quetiapine XR 150 mg/day ( acute studies ) and 50–300 mg/day ( maintenance study ) improved quality of life, overall functioning, and sleep quality in patients with GAD Personality disorders and time to remission in generalized anxiety disorder, social phobia, and panic disorder. BACKGROUND This investigation assessed the effect of personality disorders ( PersDs ) on time to remission in patients with generalized anxiety disorder, social phobia, or panic disorder. METHODS Selected Axis I and II predictors of time to remission during 5 years of follow-up were assessed in 514 patients with 1 or more of these anxiety disorders who participated in the Harvard/Brown Anxiety Research Program, a multisite, prospect i ve, longitudinal, naturalistic study. RESULTS The presence of a PersD predicted a 30 % lower likelihood of generalized anxiety disorder remission, a 39 % lower likelihood of social phobia remission, and no difference in likelihood of panic disorder remission. More specifically, a lower likelihood of remission from generalized anxiety disorder was predicted by the presence of avoidant PersD ( 34 % lower ) and dependent PersD ( 14 % lower ). The presence of avoidant PersD predicted a 41 % lower likelihood of social phobia remission. The presence of major depressive disorder did not account for these findings. CONCLUSIONS Our findings provide new data on the pernicious effect of PersDs on the course of generalized anxiety disorder and social phobia but not panic disorder, suggesting that PersDs have a differential effect on the outcome of anxiety disorders The Nottingham Study of Neurotic Disorder: predictors of 12-year outcome of dysthymic, panic and generalized anxiety disorder. BACKGROUND Controlled prospect i ve studies of the simultaneous long-term outcome of several mental disorders are rare. This study sought to determine if there were important differences between the outcome of anxiety and depressive disorders after 12 years and to examine their main predictors. METHOD A cohort of 210 people seen in general practice psychiatric clinics with a DSM-III diagnosis of generalized anxiety disorder ( 71 ), panic disorder ( 74 ), or dysthymic disorder ( 65 ), including combined anxiety-depressive disorder ( cothymia ) ( 67 ) was followed up after 12 years. Interview assessment s of symptoms, social functioning and outcome were made, the latter using a new scale, the Neurotic Disorder Outcome Scale. Seventeen baseline predictors were also examined. RESULTS Data were obtained from 201 ( 96 % ) patients, 17 of whom had died. Only 73 ( 36 % ) had no DSM diagnosis at the time of follow-up. Using univariate and stepwise multiple linear regression those with cothymia, personality disorder, recurrent episodes and greater baseline self-rated anxiety and depression ratings had a worse outcome than others ; initial diagnosis did not contribute significantly to outcome and instability of diagnosis over time was much more common than consistency. CONCLUSION Only two out of five people with the common neurotic disorders have a good outcome despite alleged advances in treatment. Those with greater mood symptoms and pre-morbid personality disorder have the least favourable outcome. It is suggested that greater attention be paid to the concurrent treatment of personality disorder and environmental factors rather than symptoms as these may be the real cause of apparent treatment resistance Antipanic Drug Modulation Of 35% CO2 Hyperreactivity and Short-Term Treatment Outcome Carbon dioxide ( CO2 ) inhalation induces acute anxiety and panic attacks in patients with Panic Disorder ( PD ). Anti-panic drugs decrease CO2 reactivity after the first days of treatment ; however, the clinical meaning of this finding has not yet been established. This study investigated the effects of treatment with tricyclic antidepressants and selective serotonin re-uptake inhibitors ( SSRIs ) on CO2 reactivity and compared the relationships between 35 % CO2 hyperreactivity modulation and short-term clinical outcome. One hundred twenty-three patients with PD with or without agoraphobia who were hyperreactive to CO2 were r and omly assigned to treatment groups with imipramine, clomipramine, paroxetine, sertraline, or fluvoxamine. A double-blind, r and omized design was applied. Each patient received the 35 % CO2 challenge on days 0, 7, and 30. The severity of clinical symptomatology was measured on days 0 and 30. Decreased hyperreactivity to 35 % CO2 in all five treatment groups was already evident after the first week. The decrease in CO2 reactivity at the end of treatment was proportional to the degree of clinical improvement. Multiple regression analyses showed that the decrease in CO2 reactivity after the first week was a significant predictor for good clinical outcome after one month. The results of this study confirm evidence that psychoactive drugs effective in the treatment of PD decrease CO2 hyperreactivity. They also suggest that precocious modulation of CO2 reactivity might fairly reliably predict short-term clinical outcome in patients with “ respiratory ” PD The diagnosis and treatment of generalized anxiety disorder. BACKGROUND Generalized anxiety disorder ( GAD ) is a common and serious disease with a lifetime prevalence of 4.3 % to 5.9 %. It is underdiagnosed in primary care. METHODS Recommendations on the treatment of GAD are given on the basis of all available findings from pertinent r and omized trials, retrieved by a selective search of the literature. RESULTS Among psychotherapeutic techniques, various kinds of cognitive behavioral therapy ( CBT ) have been found useful in controlled trials. The drugs of first choice include selective serotonin reuptake inhibitors ( SSRIs ), serotonin-norepinephine reuptake inhibitors ( SNRIs ), and the calcium-channel modulator pregabalin. Tricyclic antidepressants are also effective but have more adverse effects than SSRIs. Although benzodiazepines are effective anxiolytic agents for short-term use, they should not be given over the long term because of the danger of addiction. Buspirone, an azapirone, was found to be effective in a small number of trials, but the findings across trials are inconsistent. The response rate of GAD to CBT in published studies lies between 47 % and 75 %, while its response rate to drug treatment lies between 44 % and 81 %. CONCLUSION The treatment of GAD with CBT and drugs is evidence -based and has a good chance of improving the manifestations of the disorder Agomelatine prevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. OBJECTIVE This study evaluated the efficacy and tolerability of agomelatine in the prevention of relapse in patients with generalized anxiety disorder ( GAD ). METHOD Patients with GAD ( Hamilton Anxiety Rating Scale [ HARS ] ≥ 22, with items 1 and 2 ≥ 2, item 1 + 2 ≥ 5 ; Montgomery-Asberg Depression Rating Scale [ MADRS ] ≤ 16 ; and < 20 % decrease in HARS total score between screening and baseline ) who responded to a 16-week course of agomelatine 25 - 50 mg/d treatment were r and omly assigned to receive continuation treatment with agomelatine ( n = 113 ) or placebo ( n = 114 ) for 26 weeks. The main outcome measure was time to relapse during this maintenance period. The estimated risk of relapse was calculated using the Kaplan-Meier method, and groups were compared using a log-rank test stratified for country. The study was undertaken in 31 clinical centers in Canada, Denmark, Estonia, Finl and, Hungary, and Sweden from November 2007 to September 2009. RESULTS During the 6-month maintenance period, the proportion of patients that relapsed during the double-blind period in the agomelatine group ( 22 patients, 19.5 % ) was lower than in the placebo group ( 35 patients, 30.7 % ). The risk of relapse over time was significantly lower for patients who continued treatment than for those switched to placebo ( P =.046, log-rank test stratified for country ). Agomelatine was also superior to placebo in preventing relapse in the subset of more severe patients with baseline HARS total score ≥ 25 and CGI-S score ≥ 5. The tolerability of agomelatine was good throughout the study, and there were no differences in discontinuation symptoms after withdrawal of agomelatine in comparison to maintenance on agomelatine. CONCLUSIONS The present study extends the positive findings of an earlier short-term study of agomelatine in GAD, demonstrating that agomelatine is effective and well-tolerated in the longer-term treatment of this chronic disorder. TRIAL REGISTRATION www.is rct n.org identifier : IS RCT N38094599 Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study. OBJECTIVE The authors sought to observe the long-term clinical course of anxiety disorders over 12 years and to examine the influence of comorbid psychiatric disorders on recovery from or recurrence of panic disorder, generalized anxiety disorder, and social phobia. METHOD Data were drawn from the Harvard/Brown Anxiety Disorders Research Program, a prospect i ve, naturalistic, longitudinal, multicenter study of adults with a current or past history of anxiety disorders. Probabilities of recovery and recurrence were calculated by using st and ard survival analysis methods. Proportional hazards regression analyses with time-varying covariates were conducted to determine risk ratios for possible comorbid psychiatric predictors of recovery and recurrence. RESULTS Survival analyses revealed an overall chronic course for the majority of the anxiety disorders. Social phobia had the smallest probability of recovery after 12 years of follow-up. Moreover, patients who had prospect ively observed recovery from their intake anxiety disorder had a high probability of recurrence over the follow-up period. The overall clinical course was worsened by several comorbid psychiatric conditions, including major depression and alcohol and other substance use disorders, and by comorbidity of generalized anxiety disorder and panic disorder with agoraphobia. CONCLUSIONS These data depict the anxiety disorders as insidious, with a chronic clinical course, low rates of recovery, and relatively high probabilities of recurrence. The presence of particular comorbid psychiatric disorders significantly lowered the likelihood of recovery from anxiety disorders and increased the likelihood of their recurrence. The findings add to the underst and ing of the nosology and treatment of these disorders Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial To evaluate the efficacy of pregabalin in facilitating taper off chronic benzodiazepines, out patients ( N = 106 ) with a lifetime diagnosis of generalized anxiety disorder ( current diagnosis could be subthreshold ) who had been treated with a benzodiazepine for 8–52 weeks were stabilized for 2–4 weeks on alprazolam in the range of 1–4 mg/day. Patients were then r and omized to 12 weeks of double-blind treatment with either pregabalin 300–600 mg/day or placebo while undergoing a gradual benzodiazepine taper at a rate of 25 % per week, followed by a 6-week benzodiazepine-free phase during which they continued double-blind study treatment. Outcome measures included ability to remain benzodiazepine-free ( primary ) as well as changes in Hamilton Anxiety Rating Scale (HAM)-A and Physician Withdrawal Checklist ( PWC ). At endpoint, a non-significant higher proportion of patients remained benzodiazepine-free receiving pregabalin compared with placebo ( 51.4 % vs 37.0 % ). Treatment with pregabalin was associated with significantly greater endpoint reduction in the HAM-A total score versus placebo ( −2.5 vs + 1.3 ; p < 0.001 ), and lower endpoint mean PWC scores ( 6.5 vs 10.3 ; p = 0.012 ). Thirty patients ( 53 % ) in the pregabalin group and 19 patients ( 37 % ) in the placebo group completed the study, reducing the power to detect a significant difference on the primary outcome. The results on the anxiety and withdrawal severity measures suggest that switching to pregabalin may be a safe and effective method for discontinuing long-term benzodiazepine therapy Long-term efficacy of pregabalin in generalized anxiety disorder A multicenter, r and omized, placebo-controlled, double-blind study was conducted to evaluate the efficacy of pregabalin in preventing relapse of generalized anxiety disorder ( GAD ) after response to short-term treatment. Out patients ( n=624 ) with GAD for ≥1 year received open-label pregabalin ( 450 mg/day ) for 8 weeks and, if a clinical response was observed, were r and omized to receive either pregabalin ( 450 mg/day ; n=168 ) or placebo ( n=170 ) for 24 weeks. The primary efficacy parameter was time to relapse. Among responders to open-label acute treatment with pregabalin, time to relapse of GAD was significantly longer for patients treated with pregabalin compared with placebo ( P<0.0001 ). Fifty per cent of the placebo group had relapsed by day 23, and at study endpoint, 65 % had relapsed. In the pregabalin group, only 42 % had relapsed by study end. Total attrition during double-blind treatment was somewhat higher on pregabalin compared with placebo ( 21.4 vs. 15.3 % ) ; attrition owing to adverse events ( AEs ) was also somewhat higher on pregabalin ( 6.0 vs. 2.4 % ). AEs were relatively low in the double-blind phase ; only three AEs occurred with an incidence of more than 5 % on pregabalin and placebo, respectively : infection ( 14.9 vs. 11.2 % ), headache ( 10.1 vs. 11.2 % ), and somnolence ( 6.0 vs. 0 % ). No safety concerns were identified with long-term treatment. The study indicates that pregabalin is an effective treatment for the prevention of relapse in patients with GAD Predictors of outcome of pharmacological and psychological treatment of late-life panic disorder with agoraphobia. OBJECTIVE This study aims to evaluate the differential predictive values of age, age of onset and duration of illness on paroxetine and cognitive-behavioural therapy ( CBT ) outcome in late-life panic disorder with agoraphobia. METHOD Patients 60 years and older with a confirmed diagnosis of panic disorder with agoraphobia ( n = 49 ) were r and omly assigned to paroxetine ( 40 mg/day ) treatment, individual CBT or a waiting-list control condition. Multiple regression analyses were conducted per treatment arm with post-treatment avoidance behaviour and agoraphobic cognitions as the dependent variables. RESULTS Higher age at onset and shorter duration of illness were predictors of superior outcomes following CBT, although these variables did not influence the treatment effects of paroxetine. CONCLUSIONS In late-life agoraphobic panic disorder, chronological age has no impact on treatment modality outcome. In older patients with a late disease onset or shorter duration of illness, CBT is to be preferred over paroxetine, whereas paroxetine might be the treatment of choice for older people with an early onset and short duration of illness", "This study aim ed to investigate whether atrial fibrillation ( AF ) predicts myocardial infa rct ion ( MI ) or cardiovascular ( CV ) death. AF is a well-established risk factor for thrombotic stroke and all-cause mortality. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial Aim Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation ( AF ). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation. Methods and results Patients r and omized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ( ROCKET-AF ) trial ( n = 14 264 ) were grouped by baseline AF category : paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment ( rivaroxaban or warfarin ). Of 14 062 patients, 11 548 ( 82 % ) had persistent AF and 2514 ( 18 % ) had paroxysmal AF. Patients with persistent AF were marginally older ( 73 vs. 72, P = 0.03 ), less likely female ( 39 vs. 45 %, P < 0.0001 ), and more likely to have previously used vitamin K antagonists ( 64 vs. 56 %, P < 0.0001 ) compared with patients with paroxysmal AF. In patients r and omized to warfarin, time in therapeutic range was similar ( 58 vs. 57 %, P = 0.94 ). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism ( 2.18 vs. 1.73 events per 100-patient-years, P = 0.048 ) and all-cause mortality ( 4.78 vs. 3.52, P = 0.006 ). Rates of major bleeding were similar ( 3.55 vs. 3.31, P = 0.77 ). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment ( rivaroxaban vs. warfarin, Pinteraction = 0.6 ). Conclusion In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF Risk of Early Death and Recurrent Stroke and Effect of Heparin in 3169 Patients With Acute Ischemic Stroke and Atrial Fibrillation in the International Stroke Trial Background and Purpose — We sought to investigate the apparently high risk of early death after an ischemic stroke among patients with atrial fibrillation ( AF ), identify the main factors associated with early death, and assess the effect of treatment with different doses of subcutaneous unfractionated heparin ( UFH ) given within 48 hours. Methods — We studied the occurrence of major clinical events within 14 days among 18 451 patients from the International Stroke Trial, first for all treatment groups combined. Then, among patients with AF, we examined the effects of treatment with subcutaneous UFH started within 48 hours and continued until 14 days after stroke onset. Results — A total of 3169 patients ( 17 % ) had AF. Seven hundred eighty-four patients were allocated to UFH 12 500 IU SC BID, 773 to UFH 5000 IU SC BID, and 1612 to no heparin. Within each of these groups, half of the patients were r and omly assigned to aspirin 300 mg once daily. Compared with patients without AF, patients with AF were more likely to be female ( 56 % versus 45 % ), to be old ( mean age, 78 versus 71 years ), to have an infa rct on prer and omization CT ( 57 % versus 47 % ), and to have impaired consciousness ( 37 % versus 20 % ). The initial ischemic stroke type was more often a large-artery infa rct ( 36 % versus 21 % ). A lacunar stroke syndrome was less common ( 13 % versus 26 % ). Death within 14 days was more common in patients with AF ( 17 % versus 8 % ) and more often attributed to neurological damage from the initial stroke ( 10 % versus 4 % ). The frequency of recurrent ischemic or undefined stroke was not significantly different ( 3.9 % versus 3.3 % ). The proportion of AF patients with further events within 14 days allocated to UFH 12 500 IU ( n=784 ), UFH 5000 IU ( n=773 ), and to no-heparin ( n=1612 ) groups were as follows : ischemic stroke, 2.3 %, 3.4 %, 4.9 % ( P = 0.001 ) ; hemorrhagic stroke, 2.8 %, 1.3 %, 0.4 % ( P < 0.0001 ) ; and any stroke or death, 18.8 %, 19.4 % and 20.7 % ( P = 0.3 ), respectively. No effect of heparin on the proportion of patients dead or dependent at 6 months was apparent. Conclusions — Acute ischemic stroke patients with AF have a higher risk of early death, which can be explained by older age and larger infa rcts but not by a higher risk of early recurrent ischemic stroke, although slightly more patients with AF died from a fatal recurrent stroke of ischemic or unknown type ( 1.3 % versus 0.9 % ). In patients with AF the absolute risk of early recurrent stroke is low, and there is no net advantage to treatment with heparin. These data do not support the widespread use of intensive heparin regimens in the acute phase of ischemic stroke associated with AF Atrial flutter: Clinical risk factors and adverse outcomes in the Framingham Heart Study. BACKGROUND Few epidemiologic cohort studies have evaluated atrial flutter ( flutter ) as an arrhythmia distinct from atrial fibrillation ( AF ). OBJECTIVE The purpose of this study was to examine the clinical correlates of flutter and its associated outcomes to distinguish them from those associated with AF in the Framingham Heart Study. METHODS We review ed and adjudicated electrocardiograms ( ECGs ) previously classified as flutter or AF/flutter and another 100 ECGs r and omly selected from AF cases. We examined the clinical correlates of flutter by matching up to 5 AF and 5 referents to each flutter case using a nested case referent design. We determined the 10-year outcomes associated with flutter with Cox models. RESULTS During mean follow-up of 33.0 ± 12.2 years, 112 participants ( mean age 72 ± 10 years, 30 % women ) developed flutter. In multivariable analyses, smoking ( odds ratio [ OR ] 2.84, 95 % confidence interval [ CI ] 1.54 - 5.23 ), increased PR interval ( OR 1.28 per SD, 95 % CI 1.03 - 1.60 ), myocardial infa rct ion ( OR 2.25, 95 % CI 1.05 - 4.80 ) and heart failure ( OR 5.22, 95 % CI 1.26 - 21.64 ) were associated with incident flutter. In age- and sex-adjusted models, flutter ( vs referents ) was associated with 10-year increased risk of AF ( hazard ratio [ HR ] 5.01, 95 % CI 3.14 - 7.99 ), myocardial infa rct ion ( HR 3.05, 95 % CI 1.42 - 6.59 ), heart failure ( HR 4.14, 95 % CI 1.90 - 8.99 ), stroke ( HR 2.17, 95 % CI 1.13 - 4.17 ), and mortality ( HR 2.00, 95 % CI 1.44 - 2.79 ). CONCLUSION We identified the clinical correlates associated with flutter and observed that flutter was associated with multiple adverse outcomes Causes of Death and Influencing Factors in Patients With Atrial Fibrillation: A Competing-Risk Analysis From the Randomized Evaluation of Long-Term Anticoagulant Therapy Study Background — Atrial fibrillation is associated with increased mortality, but the specific causes of death and their predictors have not been described among patients on effective anticoagulant therapy. Methods and Results — The R and omized Evaluation of Long-Term Anticoagulant Therapy ( RE-LY ) trial r and omized 18 113 patients ( age, 71.5±9 years ; male, 64 % ; CHADS2 score, 2.1±1 ) to receive dabigatran or warfarin. Median follow-up was 2 years, and complete follow-up was achieved in 99.9 % of patients. All deaths were categorized by the investigators using prespecified definitions followed by central adjudication. Overall, 1371 deaths occurred ( annual mortality rate, 3.84 % ; 95 % confidence interval [ CI ], 3.64–4.05 ). Cardiac deaths ( sudden cardiac death and progressive heart failure ) accounted for 37.4 % of all deaths, whereas stroke- and hemorrhage-related deaths represented 9.8 % of the total mortality. An examination of the causes of death according to dabigatran or warfarin showed that dabigatran significantly reduced vascular ( embolism and hemorrhage-related ) mortality ( relative risk, 0.63 ; 95 % CI, 0.45–0.88 ; P=0.007 ), whereas other causes of death were similar between treatments, including cardiac mortality ( relative risk, 0.96 ; 95 % CI, 0.80–1.15 ; P=0.638 ). The two strongest independent predictors of cardiac death in this population were heart failure ( hazard ratio, 3.02 ; 95 % CI, 2.45–3.73 ; P<0.0001 ), and prior myocardial infa rct ion ( hazard ratio, 2.05 ; 95 % CI, 1.61–2.62 ; P<0.0001 ). Conclusions — The majority of deaths are not related to stroke in a contemporary anticoagulated atrial fibrillation population. These results emphasize the need to identify interventions beyond effective anticoagulation to further reduce mortality in atrial fibrillation. Clinical Trial Registration — URL : http://www. clinical trials.gov. Unique identifier : NCT00262600 Myocardial Ischemic Events in Patients With Atrial Fibrillation Treated With Dabigatran or Warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) Trial Background — There is a modest risk of myocardial infa rct ion ( MI ) and myocardial ischemic events in patients with atrial fibrillation. Methods and Results — Data from the RE-LY study ( R and omized Evaluation of Long-Term Anticoagulation Therapy ) were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of dabigatran versus warfarin. MI occurred at annual rates of 0.82 % and 0.81 % with dabigatran 110 or 150 mg BID compared with 0.64 % with warfarin ( hazard ratio [ HR ] 1.29, 95 % confidence interval [ CI ] 0.96–1.75, P=0.09 for dabigatran 110 mg ; HR 1.27, 95 % CI 0.94–1.71, P=0.12 for dabigatran 150 mg ). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16 % per year with dabigatran 110 mg, 3.33 % per year with dabigatran 150 mg, and 3.41 % per year with warfarin ( HR versus warfarin 0.93, 95 % CI 0.80–1.06, P=0.28 for dabigatran 110 mg and HR 0.98, 95 % CI 0.85–1.12, P=0.77 for dabigatran 150 mg ). Events prespecified as “ net clinical benefit ” ( all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death ) occurred at a rate of 7.34 % per year with dabigatran 110 mg, 7.11 % per year with dabigatran 150 mg, and 7.91 % per year with warfarin ( HR 0.92, 95 % CI 0.84–1.01, P=0.09 for dabigatran 110 mg and HR 0.90, 95 % CI 0.82–0.99, P=0.02 for dabigatran 150 mg ). The relative effects of dabigatran versus warfarin on myocardial ischemic events were consistent in patients with or without a baseline history of MI or coronary artery disease. Conclusions — There was a nonsignificant increase in MI with dabigatran compared with warfarin, but other myocardial ischemic events were not increased. Treatment effects of dabigatran were consistent in patients at higher and lower risk of myocardial ischemic events. Clinical Trial Registration — URL : http://www. clinical trials.gov. Unique identifier : NCT 00262600 Aortic plaque in atrial fibrillation: prevalence, predictors, and thromboembolic implications. BACKGROUND AND PURPOSE Thoracic aortic plaque identified by transesophageal echocardiography heightens the risk of stroke associated with atrial fibrillation ( AF ). We sought to identify the prevalence, predictors, and implication s of aortic plaque in patients with nonvalvular AF. METHODS Thoracic aortic plaque was prospect ively sought in 770 persons with AF with the use of transesophageal echocardiography and classified as simple or complex on the basis of thickness > /=4 mm, ulceration, or mobility. Clinical and echocardiographic features of thromboembolism were correlated by multivariate analysis. RESULTS Aortic plaque was detected in 57 % of the cohort, and complex plaque was detected in 25 %. Both were found more frequently in the descending than in the proximal aorta. Potentially etiologic patient characteristics independently associated with complex plaque included advanced age, history of hypertension, diabetes, and past or present tobacco use. Comorbidities associated with aortic plaque were prior thromboembolism, increased pulse pressure, ischemic heart disease, stenosis or sclerosis of the aortic valve, mitral annular calcification ( > 10 % ), elevated serum creatinine concentration, spontaneous echo contrast in the left atrium or appendage, and left atrial appendage thrombus. The prevalence of complex plaque in patients aged < 70 years with < 10 % mitral annular calcification, without ischemic heart disease, or without pulse pressure > /=65 mm Hg was 4 % ( 95 % CI, 1 % to 6 % ). CONCLUSIONS Aortic plaque is prevalent in patients with AF and is associated with atherosclerosis risk factors and with left atrial stasis or thrombosis, which are themselves independent stroke risk factors. Since the predominant location of complex plaque was in the descending aorta, the role of aortic plaque as a source of embolism in AF is uncertain Atrial fibrillation and the risk of myocardial infarction. IMPORTANCE Myocardial infa rct ion ( MI ) is an established risk factor for atrial fibrillation ( AF ). However, the extent to which AF is a risk factor for MI has not been investigated. OBJECTIVE To examine the risk of incident MI associated with AF. DESIGN, SETTING, AND PARTICIPANTS A prospect i ve cohort of 23,928 participants residing in the continental United States and without coronary heart disease at baseline were enrolled from the Reasons for Geographic and Racial Differences in Stroke ( REGARDS ) cohort between 2003 and 2007, with follow-up through December 2009. MAIN OUTCOMES AND MEASURES Expert-adjudicated total MI events ( fatal and nonfatal ). RESULTS Over 6.9 years of follow-up ( median 4.5 years ), 648 incident MI events occurred. In a sociodemographic-adjusted model, AF was associated with about 2-fold increased risk of MI ( hazard ratio [ HR ], 1.96 [ 95 % CI, 1.52 - 2.52 ] ). This association remained significant ( HR, 1.70 [ 95 % CI, 1.26 - 2.30 ] ) after further adjustment for total cholesterol, high-density lipoprotein cholesterol, smoking status, systolic blood pressure, blood pressure-lowering drugs, body mass index, diabetes, warfarin use, aspirin use, statin use, history of stroke and vascular disease, estimated glomerular filtration rate, albumin to creatinine ratio, and C-reactive protein level. In subgroup analysis, the risk of MI associated with AF was significantly higher in women ( HR, 2.16 [ 95 % CI, 1.41 - 3.31 ] ) than in men ( HR, 1.39 [ 95 % CI, 0.91 - 2.10 ] ) and in blacks ( HR, 2.53 [ 95 % CI, 1.67 - 3.86 ] ) than in whites ( HR, 1.26 [ 95 % CI, 0.83 - 1.93 ] ) ; for interactions, P =.03 and P =.02, respectively. On the other h and, there were no significant differences in the risk of MI associated with AF in older ( ≥75 years ) vs younger ( < 75 years ) participants ( HR, 2.00 [ 95 % CI, 1.16 - 3.35 ] and HR, 1.60 [ 95 % CI, 1.11 - 2.30 ], respectively ) ; for interaction, P =.44. CONCLUSIONS AND RELEVANCE AF is independently associated with an increased risk of incident MI, especially in women and blacks. These findings add to the growing concerns of the seriousness of AF as a public health burden : in addition to being a well-known risk factor for stroke, AF is also associated with increased risk of MI Hemodynamic effects of an irregular sequence of ventricular cycle lengths during atrial fibrillation. OBJECTIVES The aim of this study was to determine the independent hemodynamic effects of an irregular sequence of ventricular cycle lengths in patients with atrial fibrillation ( AF ). BACKGROUND Atrial fibrillation may reduce cardiac output by several possible mechanisms, including loss of the atrial contribution to left ventricular filling, valvular regurgitation, increased ventricular rate or irregular RR intervals. This study was design ed to evaluate the effects of an irregular RR interval, independent of the average ventricular rate, on cardiac hemodynamic data during AF. METHODS Sixteen patients with AF were studied invasively. During intrinsically conducted AF ( mean rate 102 + /- 22 beats/ min ), the right ventricular apex electrogram was recorded onto frequency-modulated ( FM ) tape. After atrioventricular node ablation, the right ventricular apex was stimulated in three pacing modes in r and omized sequence : 1 ) VVI at 60 beats/min ; 2 ) VVI at the same average rate as during intrinsically conducted AF ( 102 + /- 22 beats/min ) ; and 3 ) during VVT pacing in which the pacemaker was triggered by playback of the FM tape recording of the right ventricular apex electrogram previously recorded during intrinsically conducted AF ( VVT 102 + /- 22 beats/min ). RESULTS Compared with VVI pacing at the same average rate, an irregular sequence of RR intervals decreased cardiac output ( 4.4 + /- 1.6 vs. 5.2 + /- 2.4 liters/min, p < 0.01 ), increased pulmonary capillary wedge pressure ( 17 + /- 7 vs. 14 + /- 6 mm Hg, p < 0.002 ) and increased right atrial pressure ( 10 + /- 6 vs. 8 + /- 4 mm Hg, p < 0.05 ). CONCLUSIONS An irregular sequence of RR intervals produces adverse hemodynamic consequences that are independent of heart rate Risk of Myocardial Infarction or Vascular Death After First Ischemic Stroke: The Northern Manhattan Study Background and Purpose — In national guidelines, absolute long-term risk of myocardial infa rct ion ( MI ) or coronary death determines target low-density lipoprotein levels, but stroke patients are not explicitly addressed. We determined the absolute 5-year risk of cardiovascular outcomes and their predictors after first ischemic stroke in a multiethnic cohort. Methods — A population -based cohort of first ischemic stroke patients ≥40 years old was prospect ively followed annually for recurrent stroke, MI and cause-specific mortality. Kaplan-Meier 5-year risks for MI or vascular death ( primary outcome ), and other cardiovascular events, were calculated. Univariate and multivariate Cox proportional hazards models were used to calculate hazard ratios and 95 % CI for predictors of cardiovascular outcomes. Results — Mean age ( n=655 ) was 69.7±12.7 years ; 55.4 % of participants were women, and 51.3 % Hispanic. The 5-year risk of MI or vascular death was 17.4 % ( 95 % CI, 14.2 % to 20.6 % ). Independent historical predictors of MI or vascular death were age > 70 years ( hazard ratio 1.62, 1.07 to 2.44 ), history of coronary artery disease ( hazard ratio 1.76, 1.13 to 2.74 ), and atrial fibrillation ( hazard ratio 1.76, 1.05 to 2.94 ). In the lowest risk group, those ≤70 years old without coronary artery disease, 5-year risk of MI or vascular death was 9.7 %. Conclusions — The absolute risk of MI or vascular death after ischemic stroke, even in those without high-risk features, approximates levels used by national organizations to design ate groups of patients at high risk of vascular events. The comparability of levels of absolute risk among stroke and cardiac patients may have treatment implication Predictors of major adverse cardiovascular events; results of population based MELEN study with prospective follow-up. OBJECTIVE In healthy persons, cardiovascular risk is the result of multiple interacting risk associates including demographic, clinical, genetic and environmental factors. Several non-invasive tools such as echocardiography, ultrasonography and electrocardiography as well as new biochemical markers were shown to be applicable to predict cardiovascular events. However, implementation of all of these tools has not been tested before. The aim of the study was to evaluate the independent predictors of major adverse cardiovascular events in a prospect i ve population based study, with the use of bioempedance analysis, echocardiography, ultrasonography and ECG. PATIENTS AND METHODS The baseline measurements were conducted on 2230 participants ( 1427 women, 803 men with a mean age of 49 ± 15 ). The follow-up was done 36 months after the baseline admission via telephone call. Major adverse event was defined as mortality or myocardial infa rct ion or stroke. RESULTS Follow-up data was possible in 1495 participants ( 65 % ). During the follow-up of 36 months ( 4485 patient years ), 42 major adverse events occurred ( 0.03 % ). Among them, 16 were death ( 1 stroke, 2 cancer, 13 cardiac related ), 12 were stroke and 14 were myocardial infa rct ion. Age, body mass index and atrial fibrillation were independent predictors of major adverse events ; AF being the most powerful ( Odds ratio 10.46 ; 95 % confidence interval [ 1.73 - 63.14 ] ; p = 0.010 ). CONCLUSIONS Age, lower body mass index and atrial fibrillation were independent predictors of major cardiovascular events in our cohort Acute myocardial infarction in patients with atrial fibrillation with a CHA2DS2-VASc score of 0 or 1: a nationwide cohort study. BACKGROUND The risk of acute myocardial infa rct ion ( AMI ) in patients with atrial fibrillation ( AF ) with a CHA2DS2-VASc score of 0 ( for men ) or 1 ( for women ) has not been previously investigated. OBJECTIVE The objective of the present study was to compare the risk of AMI in AF and non-AF subjects with a low ( 0 or 1 ) CHA2DS2-VASc score. METHODS By using the National Health Insurance Research Data base in Taiwan, we identified 7254 men with AF ( with a CHA2DS2-VASc score of 0 ) and 4860 women with AF ( with a CHA2DS2-VASc score of 1 ). For each study patient, 1 age-, sex-, and CHA2DS2-VASc score-matched subject without AF was r and omly selected to constitute the control group ( n = 12,114 ). The clinical end point was the occurrence of AMI. RESULTS During a mean follow-up period of 5.7 ± 3.6 years, 258 patients ( 1.1 % ) suffered an AMI, with an annual incidence of 0.29 % and 0.10 % for patients with and without AF. AF was an independent risk factor of AMI, with an adjusted hazard ratio ( HR ) of 2.93 ( 95 % confidence interval 2.21 - 3.87 ; P <.001 ). The risk of AMI was higher in men with AF than in women with AF, with a hazard ratio of 2.24 ( 95 % confidence interval 1.61 - 3.11 ; P <.001 ) after adjustment for age and other comorbidities. CONCLUSION In patients with a CHA2DS2-VASc score of 0 or 1, AF was an independent risk factor of AMI. The risk of AMI was higher in men with AF than in women with AF. Cardiovascular risk prevention should be performed as part of the holistic management of AF to minimize the risks of AMI associated with AF Atrial fibrillation and mortality in an elderly population. Prospect i ve data from Busselton, Western Australia, collected during triennial surveys from 1966 - 81 with follow-up of subjects to 1983, showed that atrial fibrillation ( AF ) was frequent in elderly people and associated with increased mortality. Of 1770 people aged over 60 years, 40 were in atrial fibrillation when first seen and a further 47 developed it during follow-up. Atrial fibrillation was positively associated with angina, history of a myocardial infa rct ion and left bundle branch block. Relative mortality in those with atrial fibrillation compared with those without it, was 1.92 for all causes, 1.82 for death from cardiovascular causes ( excluding stroke ) and 3.78 for deaths from stroke, after adjustment by proportional hazards regression for confounding effects of age, sex, history of a myocardial infa rct ion, an abnormal electrocardiogram, angina, cholesterol level systolic blood pressure and Quetelet's Index ( weight/height2 ). The excess relative mortality declined with increasing age for both women and men. This raised relative mortality remained constant with time from the first detection of AF for all causes and cardiovascular causes but appeared to increase with time from detection for stroke death. The risk of death from stroke was greatest in the younger women. The observed risk of death from stroke in patients with AF suggests that anticoagulant use should be considered in selected patients Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. OBJECTIVE This study undertook to determine if the presence of atrial fibrillation in patients with asymptomatic and symptomatic left ventricular dysfunction was associated with increased mortality and, if so, whether the increase could be attributed to progressive heart failure or arrhythmic death. BACKGROUND Atrial fibrillation is a common condition in heart failure with the potential to impact hemodynamics and progression of left ventricular systolic dysfunction as well as the electrophysiologic substrate for arrhythmias. The available data do not conclusively define the effect of atrial fibrillation on prognosis in heart failure. METHODS A retrospective analysis of the Studies of Left Ventricular Dysfunction Prevention and Treatment Trials was conducted that compared patients with atrial fibrillation to those in sinus rhythm at baseline for the risk of all-cause mortality, progressive pump-failure death and arrhythmic death. RESULTS The patients with atrial fibrillation at baseline, compared to those in sinus rhythm, had greater all-cause mortality ( 34 % vs. 23 %, p < 0.001 ), death attributed to pump-failure ( 16.7 % vs. 9.4 %, p < 0.001 ) and were more likely to reach the composite end point of death or hospitalization for heart failure ( 45 % vs. 33 %, p < 0.001 ), but there was no significant difference between the groups in arrhythmic deaths. After multivariate analysis, atrial fibrillation remained significantly associated with all-cause mortality ( relative risk [ RR ] 1.34, 95 % confidence interval [ CI ] 1.12 to 1.62, p=0.002 ), progressive pump-failure death ( RR 1.42, 95 % CI 1.09 to 1.85, p=0.01 ), the composite end point of death or hospitalization for heart failure ( RR 1.26, 95 % CI 1.03 to 1.42, p=0.02 ), but not arrhythmic death ( RR 1.13 ; 95 % CI 0.75 to 1.71 ; p=0.55 ). CONCLUSIONS The presence of atrial fibrillation in patients with asymptomatic and symptomatic left ventricular systolic dysfunction is associated with an increased risk for all-cause mortality, largely explained by an increased risk for pump-failure death. These data suggest that atrial fibrillation is associated with progression of left ventricular systolic dysfunction Incidence of myocardial infarction and vascular death in elderly patients with atrial fibrillation taking anticoagulants: relation to atherosclerotic risk factors. BACKGROUND Recent findings suggest that patients with atrial fibrillation ( AF ), in addition being at thromboembolic risk, are at risk of myocardial infa rct ion ( MI ). Our aim was to investigate predictors of MI and cardiovascular death in a cohort of patients with AF who were taking anticoagulants. METHODS We prospect ively followed up 1,019 patients with AF for a median of 33.7 months ( 3,223 person-years ). All patients were treated with oral vitamin K antagonists. Primary outcome was a composite end point of cardiovascular events ( CVEs ) including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death. RESULTS The mean age of the patients was 73.2 years, and 43.8 % were women. At follow-up, 111 CVEs ( 3.43%/y ) had occurred : 47 fatal-nonfatal MI/revascularization and 64 cardiovascular deaths. In addition, 31 stroke/transient ischemic attacks ( 0.96%/y ) were recorded. Patients experiencing CVEs were older ( P <.001 ) and had a higher prevalence of metabolic syndrome ( MetS ) ( P =.005 ), heart failure ( P =.001 ), and prior cardiac ( P <.001 ) and cerebrovascular events ( P <.001 ). On a Cox proportional hazard analysis, age ( hazard ratio [ HR ], 1.083 ; 95 % CI, 1.053 - 1.113 ; P <.001 ), smoking ( HR, 2.158 ; 95 % CI, 1.193 - 3.901 ; P =.011 ), history of cerebrovascular ( HR, 1.704 ; 95 % CI, 1.119 - 2.597 ; P =.013 ) and cardiac ( HR, 1.658 ; 95 % CI, 1.105 - 2.489 ; P =.015 ) events, MetS ( HR, 1.663 ; 95 % CI, 1.107 - 2.499 ; P =.014 ), heart failure ( HR, 1.584 ; 95 % CI, 1.021 - 2.456 ; P =.040 ), and male sex ( HR, 1.499 ; 95 % CI, 1.010 - 2.223 ; P =.044 ) predicted CVEs. CONCLUSIONS Patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF. TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01882114 ; URL : www. clinical trials.gov Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. CONTEXT The risks associated with new-onset atrial fibrillation ( AF ) among middle-aged women and population s with a low comorbidity burden are poorly defined. OBJECTIVES To examine the association between incident AF and mortality in initially healthy women and to evaluate the influence of associated cardiovascular comorbidities on risk. DESIGN, SETTING, AND PARTICIPANTS Between 1993 and March 16, 2010, 34,722 women participating in the Women's Health Study underwent prospect i ve follow-up. Participants were 95 % white, older than 45 years ( median, 53 [ interquartile range { IQR }, 49 - 59 ] years ), and free of AF and cardiovascular disease at baseline. Cox proportional hazards models with time-varying covariates were used to determine the risk of events among women with incident AF. Secondary analyses were performed among women with paroxysmal AF. MAIN OUTCOME MEASURES Primary outcomes included all-cause, cardiovascular, and noncardiovascular mortality. Secondary outcomes included stroke, congestive heart failure, and myocardial infa rct ion. RESULTS During a median follow-up of 15.4 ( IQR, 14.7 - 15.8 ) years, 1011 women developed AF. Incidence rates per 1000 person-years among women with and without AF were 10.8 ( 95 % confidence interval [ CI ], 8.1 - 13.5 ) and 3.1 ( 95 % CI, 2.9 - 3.2 ) for all-cause mortality, 4.3 ( 95 % CI, 2.6 - 6.0 ) and 0.57 ( 95 % CI, 0.5 - 0.6 ) for cardiovascular mortality, and 6.5 ( 95 % CI, 4.4 - 8.6 ) and 2.5 ( 95 % CI, 2.4 - 2.6 ) for noncardiovascular mortality, respectively. In multivariable models, hazard ratios ( HRs ) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14 ( 95 % CI, 1.64 - 2.77 ), 4.18 ( 95 % CI, 2.69 - 6.51 ), and 1.66 ( 95 % CI, 1.19 - 2.30 ), respectively. Adjustment for nonfatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components ( all-cause : HR, 1.70 [ 95 % CI, 1.30 - 2.22 ] ; cardiovascular : HR, 2.57 [ 95 % CI, 1.63 - 4.07 ] ; and noncardiovascular : HR, 1.42 [ 95 % CI, 1.02 - 1.98 ] ). Among women with paroxysmal AF ( n = 656 ), the increase in mortality risk was limited to cardiovascular causes ( HR, 2.94 ; 95 % CI, 1.55 - 5.59 ). CONCLUSION Among a group of healthy women, new-onset AF was independently associated with all-cause, cardiovascular, and noncardiovascular mortality, with some of the risk potentially explained by nonfatal cardiovascular events Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis. BACKGROUND Atrial fibrillation ( AF ) is a major risk factor ( RF ) for ischemic stroke. Its prevalence and prognostic impact in patients with atherothrombosis are unclear. METHODS Risk factors, drug usage, and 1-year cardiovascular ( CV ) outcomes ( CV death, myocardial infa rct ion [ MI ], and stroke ) were compared in AF and non-AF patients from the REduction of Atherothrombosis for Continued Health ( REACH ) Registry, an international, prospect i ve cohort of 68,236 stable out patients with established atherothrombosis or > or=3 atherothrombotic RFs. RESULTS Atrial fibrillation and 1-year follow-up data are available for 63,589 patients. The prevalence of AF was, 12.5 %, 13.7 %, 11.5 %, and 6.2 % among coronary artery disease, CV disease, peripheral artery disease, and RF-only patients, respectively. Of the 6,814 patients with AF, 6.7 % experienced CV death, nonfatal MI, or nonfatal stroke within a year. The annual incidence of nonfatal stroke ( 2.4 % vs 1.6 %, P<.0001 ) and unstable angina ( 6.0 % vs 4.0 %, P<.00001 ) was higher, and CV death was more than double ( 3.2 % vs 1.4 %, P<.0001 ), in AF versus non-AF patients. In these patients with or at high risk of atherothrombosis, most patients with AF received antiplatelet agents, but only 53.1 % were treated with oral anticoagulants. Even with high CHADS2 ( congestive heart failure, hypertension, aging, diabetes mellitus, and stroke ) scores, anticoagulant use did not exceed ( 59 % ). The rate of bleeding requiring hospitalization was higher in AF versus non-AF patients ( 1.5 % vs 0.8 %, P<.0001 ), possibly related to the more frequent use of anticoagulants ( 53.1 % vs 7.1 % ). CONCLUSIONS Atrial fibrillation is common in patients with atherothrombosis, associated with more frequent fatal and nonfatal CV outcomes, and underuse of oral anticoagulants Chronic atrial fibrillation--epidemiologic features and 14 year follow-up: a case control study. In a r and omly selected population of 9067 individuals, 32 - 64 years of age in 1967 - 1970, 25 ( 0.28 % ) had chronic atrial fibrillation ( CAF ). Eight had lone atrial fibrillation. In 1984 the cases were compared with an age- and sex-matched control group of 50 and found to have more cerebrovascular accidents ( 6 versus 2 ; P less than 0.05 ), congestive heart failure ( 9 versus 1 ; P less than 0.001 ), and valvular rheumatic heart disease ( 3 versus 0 ) or history consistent with rheumatic fever ( 6 versus 0 ; P less than 0.01 ). The mortality in the CAF group was 60 % higher due to an excess in cardiovascular ( relative risk 6.1 ; P less than 0.05 ) and cerebrovascular ( relative risk 12.2 ; P less than 0.05 ) causes. The prevalence or incidence of ischaemic or hypertensive heart disease or the presence of coronary risk factors did not significantly differ in the two groups. By M-mode echocardiography the left atrial size, left ventricular enddiastolic dimension and left ventricular mass were increased in the CAF patients, while the systolic left ventricular shortening was significantly less. Thus, the prevalence of CAF is low in a r and omly selected population 32 - 64 years of age and CAF is not strongly associated with ischaemic heart disease or hypertension. The CAF patients have an increased risk of dying prematurely particularly from cerebrovascular causes, even in the absence of valve disease The association between atrial fibrillation and sudden cardiac death: the relevance of heart failure. OBJECTIVES The purpose of this study was to evaluate the role of congestive heart failure ( CHF ) in the association between atrial fibrillation ( AF ) and sudden cardiac death ( SCD ). BACKGROUND Recent studies have reported the possibility of an independent association between AF and SCD. We hypothesized that a history of CHF is a significant confounder of this association. METHODS In a prospect i ve case-control analysis from the community ( The Oregon-SUDS [ Sudden Unexpected Death Study ], 2002 to 2012 ), SCD cases ( n = 652 ) with clinical records available ( including electrocardiography and /or echocardiography ) were compared with age- and sex-matched control patients with coronary artery disease. The association between AF and SCD was analyzed using multivariable logistic regression and propensity score matching. RESULTS Cases ( age 67.3 ± 11.7 years, 65 % male ) were more likely than control patients ( age 67.2 ± 11.4 years, 65 % male ) to have a history of AF ( p = 0.0001 ), myocardial infa rct ion ( p = 0.007 ), CHF ( p < 0.0001 ), stroke ( p < 0.0001 ), and diabetes ( p < 0.0001 ). In multivariate analysis without considering CHF, AF was a significant predictor of SCD ( odds ratio [ OR ] : 1.6 ; 95 % confidence interval [ CI ] : 1.2 to 2.0 ; p = 0.002 ). However, in a model that included CHF, the AF-SCD association was no longer significant ( OR : 1.1 ; 95 % CI : 0.8 to 1.5 ; p = 0.45 ), whereas CHF was a significant predictor of SCD ( OR : 3.1 ; 95 % CI : 2.4 to 4.1 ; p < 0.0001 ). Results on the basis of propensity score matching were consistent. CONCLUSIONS Our findings suggest that a history of CHF, including both systolic and diastolic symptomatic dysfunction, may partially explain the AF-SCD association", 'Background Many interventions delivered to improve health may benefit not only direct recipients but also people in close physical or social proximity. Our objective was to review all published literature about the spillover effects of interventions on health outcomes in low-middle income countries and to identify methods used in estimating these effects. Components of the indirect effect in vaccine trials: identification of contagion and infectiousness effects. Vaccination of one person may prevent the infection of another either because the vaccine prevents the first from being infected and from infecting the second, or because, even if the first person is infected, the vaccine may render the infection less infectious. We might refer to the first of these mechanisms as a contagion effect and the second as an infectiousness effect. In the simple setting of a r and omized vaccine trial with households of size two, we use counterfactual theory under interference to provide formal definitions of a contagion effect and an unconditional infectiousness effect. Using ideas analogous to mediation analysis, we show that the indirect effect ( the effect of one person\'s vaccine on another\'s outcome ) can be decomposed into a contagion effect and an unconditional infectiousness effect on the risk difference, risk ratio, odds ratio, and vaccine efficacy scales. We provide identification assumptions for such contagion and unconditional infectiousness effects and describe a simple statistical technique to estimate these effects when they are identified. We also give a sensitivity analysis technique to assess how inferences would change under violations of the identification assumptions. The concepts and results of this paper are illustrated with hypothetical vaccine trial data Herd protection by a bivalent killed whole-cell oral cholera vaccine in the slums of Kolkata, India. BACKGROUND We evaluated the herd protection conferred by an oral cholera vaccine using 2 approaches : cluster design and geographic information system ( GIS ) design. METHODS Residents living in 3933 dwellings ( clusters ) in Kolkata, India, were cluster-r and omized to receive either cholera vaccine or oral placebo. Nonpregnant residents aged≥1 year were invited to participate in the trial. Only the first episode of cholera detected for a subject between 14 and 1095 days after a second dose was considered. In the cluster design, indirect protection was assessed by comparing the incidence of cholera among non participants in vaccine clusters vs those in placebo clusters. In the GIS analysis, herd protection was assessed by evaluating association between vaccine coverage among the population residing within 250 m of the household and the occurrence of cholera in that population. RESULTS Among 107 347 eligible residents, 66 990 received 2 doses of either cholera vaccine or placebo. In the cluster design, the 3-year data showed significant total protection ( 66 % protection, 95 % confidence interval [ CI ], 50%-78 %, P<.01 ) but no evidence of indirect protection. With the GIS approach, the risk of cholera among placebo recipients was inversely related to neighborhood-level vaccine coverage, and the trend was highly significant ( P<.01 ). This relationship held in multivariable models that also controlled for potentially confounding demographic variables ( hazard ratio, 0.94 [ 95 % CI,.90-.98 ] ; P<.01 ). CONCLUSIONS Indirect protection was evident in analyses using the GIS approach but not the cluster design approach, likely owing to considerable transmission of cholera between clusters, which would vitiate herd protection in the cluster analyses. CLINICAL TRIALS REGISTRATION NCT00289224 Community-wide effects of permethrin-treated bed nets on child mortality and malaria morbidity in western Kenya. Spatial analyses of the effect of insecticide (permethrin)-treated bed nets ( ITNs ) on nearby households both with and without ITNs was performed in the context of a large-scale, group-r and omized, controlled mortality trial in Asembo, western Kenya. Results illustrate a protective effect of ITNs on compounds lacking ITNs located within 300 meters of compounds with ITNs for child mortality, moderate anemia, high-density parasitemia, and hemoglobin levels. This community effect on nearby compounds without nets is approximately as strong as the effect observed within villages with ITNs. This implies that in areas with intense malaria transmission with high ITN coverage, the primary effect of insecticide-treated nets is via area-wide effects on the mosquito population and not, as commonly supposed, by simple imposition of a physical barrier protecting individuals from biting. The strength of the community effect depended upon the proportion of nearby compounds with treated nets. To maximize their public health impact, high coverage with treated nets is essential Improving immunisation coverage in rural India: clustered randomised controlled evaluation of immunisation campaigns with and without incentives Objective To assess the efficacy of modest non-financial incentives on immunisation rates in children aged 1 - 3 and to compare it with the effect of only improving the reliability of the supply of services. Design Clustered r and omised controlled study. Setting Rural Rajasthan, India. Participants 1640 children aged 1 - 3 at end point. Interventions 134 villages were r and omised to one of three groups : a once monthly reliable immunisation camp ( intervention A ; 379 children from 30 villages ) ; a once monthly reliable immunisation camp with small incentives ( raw lentils and metal plates for completed immunisation ; intervention B ; 382 children from 30 villages ), or control ( no intervention, 860 children in 74 villages ). Surveys were undertaken in r and omly selected households at baseline and about 18 months after the interventions started ( end point ). Main outcome measures Proportion of children aged 1 - 3 at the end point who were partially or fully immunised. Results Among children aged 1 - 3 in the end point survey, rates of full immunisation were 39 % ( 148/382, 95 % confidence interval 30 % to 47 % ) for intervention B villages ( reliable immunisation with incentives ), 18 % ( 68/379, 11 % to 23 % ) for intervention A villages ( reliable immunisation without incentives ), and 6 % ( 50/860, 3 % to 9 % ) for control villages. The relative risk of complete immunisation for intervention B versus control was 6.7 ( 4.5 to 8.8 ) and for intervention B versus intervention A was 2.2 ( 1.5 to 2.8 ). Children in areas neighbouring intervention B villages were also more likely to be fully immunised than those from areas neighbouring intervention A villages ( 1.9, 1.1 to 2.8 ). The average cost per immunisation was $ 28 ( 1102 rupees, about £ 16 or € 19 ) in intervention A and $ 56 ( 2202 rupees ) in intervention B. Conclusions Improving reliability of services improves immunisation rates, but the effect remains modest. Small incentives have large positive impacts on the uptake of immunisation services in re source poor areas and are more cost effective than purely improving supply. Trial registration IRSCTN87759937 Effect of scaling up women\'s groups on birth outcomes in three rural districts in Bangladesh: a cluster-randomised controlled trial BACKGROUND Two recent trials have shown that women\'s groups can reduce neonatal mortality in poor communities. We assessed the effectiveness of a scaled-up development programme with women\'s groups to address maternal and neonatal care in three rural districts of Bangladesh. METHODS 18 clusters ( with a mean population of 27 953 [ SD 5953 ] ) in three districts were r and omly assigned to either intervention or control ( nine clusters each ) by use of stratified r and omisation. For each district, cluster names were written on pieces of paper, which were folded and placed in a bottle. The first three cluster names drawn from the bottle were allocated to the intervention group and the remaining three to control. All clusters received health services strengthening and basic training of traditional birth attendants. In intervention clusters, a facilitator convened 18 groups every month to support participatory action and learning for women, and to develop and implement strategies to address maternal and neonatal health problems. Women were eligible to participate if they were aged 15 - 49 years, residing in the project area, and had given birth during the study period ( Feb 1, 2005, to Dec 31, 2007 ). Neither study investigators nor participants were masked to treatment assignment. In a population of 229 195 people ( intervention clusters only ), 162 women\'s groups provided coverage of one group per 1414 population. The primary outcome was neonatal mortality rate ( NMR ). Analysis was by intention to treat. This trial is registered as an International St and ard R and omised Controlled Trial, number IS RCT N54792066. FINDINGS We monitored outcomes for 36 113 births ( intervention clusters, n=17 514 ; control clusters, n=18 599 ) in a population of 503 163 over 3 years. From 2005 to 2007, there were 570 neonatal deaths in the intervention clusters and 656 in the control clusters. Cluster-level mean NMR ( adjusted for stratification and clustering ) was 33.9 deaths per 1000 livebirths in the intervention clusters compared with 36.5 per 1000 in the control clusters ( risk ratio 0.93, 95 % CI 0.80 - 1.09 ). INTERPRETATION For participatory women\'s groups to have a significant effect on neonatal mortality in rural Bangladesh, detailed attention to programme design and context ual factors, enhanced population coverage, and increased enrolment of newly pregnant women might be needed. FUNDING Women and Children First, the UK Big Lottery Fund, Saving Newborn Lives, and the UK Department for International Development Impact of pediatric vaccination with pneumococcal conjugate vaccine on the risk of bacteremic pneumococcal pneumonia in adults. Invasive pneumococcal disease in adults may be declining, reflecting a form of herd protection from a new pediatric pneumococcal conjugate vaccine. Our aim was to determine whether vaccination of children protects adults in the same home from bacteremic pneumococcal pneumonia. We conducted a case-control study with 43 participating hospitals across a five-county region in Pennsylvania. Eligible cases were adults with bacteremic pneumococcal pneumonia identified by the microbiology laboratories at participating hospitals. Controls were healthy adults from the region identified through r and om digit dialing. Cases and controls were interviewed by telephone. We analyzed vaccine protection in those adults who reported living in homes with at least one child < or = 6 years of age. From April 2002 through June 2004, there was a significant decline in the proportion of adult pneumococcal bacteremia due to any of the seven serotypes in the conjugate vaccine ( p=0.006 ). Within this time period, 17 % of cases and controls reported living in homes with at least one child < or = 6 years of age. In adjusted analysis, vaccination of the youngest child in the home was associated with an 80 % reduction in the odds of bacteremic pneumococcal pneumonia among adults with children in the home ( OR=0.2, 95 % CI 0.1 - 0.8 ). We conclude that introduction of a pneumococcal conjugate vaccine for children has reduced the population rate of adult pneumococcal bacteremia due to vaccine serotypes and is associated with a reduced risk of bacteremic pneumococcal pneumonia for adults with children in the home Relationship between neighbourhood-level killed oral cholera vaccine coverage and protective efficacy: evidence for herd immunity. OBJECTIVES The effectiveness of vaccines in population s must consider both direct and indirect protection. This study reanalyses data from a large individually r and omized oral cholera vaccine trial that was conducted in rural Bangladesh from 1985 to 1990. A recent analysis of the results of that trial showed that the proportion of people in household clusters who received the vaccine was inversely related to placebo incidence during the first year of surveillance, which was attributed to herd immunity. METHODS In this study we measure the relationship between neighbourhood-level oral cholera vaccine coverage and protective efficacy ( PE ) during a 2 year follow-up period, controlling for known effect modifiers. We link trial data to a household geographic information system to facilitate the neighbourhood-level analysis. Findings Neighbourhood-level PE can be partially explained by vaccine coverage after adjusting for ecological variables. CONCLUSIONS The inverse relationship between vaccine coverage and efficacy illustrates that people living in high-coverage areas may be indirectly protected from cholera because people living around them are vaccinated The association between latrine use and trachoma: a secondary cohort analysis from a randomized clinical trial. Latrine use has been promoted as a component of an integrated strategy for trachoma control. As part of a r and omized trial in Ethiopia, 12 communities received a mass azithromycin distribution followed by a latrine promotion intervention. A r and om sample of children ages 0 - 9 years in each community was monitored longitudinally for ocular chlamydia. After latrine construction ended, those communities with a higher proportion of households using latrines were more likely to experience a reduction in the prevalence of ocular chlamydia. Specifically, for each 10 % increase in latrine use, there was a 2.0 % decrease ( 95 % confidence interval = 0.2 - 3.9 % decrease ) in the community prevalence of ocular chlamydia over the subsequent year ( P = 0.04 ) Effectiveness and spillover of an after-school health promotion program for Hispanic elementary school children. OBJECTIVES We evaluated the effectiveness and spillover of an after-school health education and physical activity program among Hispanic elementary school children. METHODS In fall 2008, students in third through fifth grade s in 6 schools in El Paso, Texas ( n = 901 ), were r and omized to intervention ( n = 292 participants ) or control ( n = 354 ) classrooms ( 4 unknown ). Intervention classrooms also contained a spillover group ( n = 251 ) that did not join the after-school program but that completed measurements and surveys. The intervention was a 12-week culturally tailored after-school program meeting twice a week. Four-month outcomes were body mass index, aerobic capacity, and dietary intentions and knowledge. We calculated intervention exposure as the proportion of after-school participants per classroom. RESULTS Intervention exposure predicted lower body mass index ( P =.045 ), higher aerobic capacity ( P =.012 ), and greater intentions to eat healthy ( P =.046 ) for the classroom at follow-up. Intervention effectiveness increased with increasing proportions of intervention participants in a classroom. Non participants who had classroom contact with program participants experienced health improvements that could reduce their risk of obesity. CONCLUSIONS Spillover of beneficial intervention effects to non participants is a valuable public health benefit and should be part of program impact assessment Effectiveness of an oral cholera vaccine in Zanzibar: findings from a mass vaccination campaign and observational cohort study. BACKGROUND Zanzibar, in east Africa, has been severely and repeatedly affected by cholera since 1978. We assessed the effectiveness of oral cholera vaccination in high-risk population s in the archipelago to estimate the indirect ( herd ) protection conferred by the vaccine and direct vaccine effectiveness. METHODS We offered two doses of a killed whole-cell B-subunit cholera vaccine to individuals aged 2 years and older in six rural and urban sites. To estimate vaccine direct protection, we compared the incidence of cholera between recipients and non-recipients using generalised estimating equations with the log link function while controlling for potential confounding variables. To estimate indirect effects, we used a geographic information systems approach and assessed the association between neighbourhood-level vaccine coverage and the risk for cholera in the non-vaccinated residents of that neighbourhood, after controlling for potential confounding variables. This study is registered with Clinical Trials.gov, number NCT00709410. FINDINGS Of 48,178 individuals eligible to receive the vaccine, 23,921 ( 50 % ) received two doses. Between February, 2009, and May, 2010, there was an outbreak of cholera, enabling us to assess vaccine effectiveness. The vaccine conferred 79 % ( 95 % CI 47 - 92 ) direct protection against cholera in participants who received two doses. Indirect ( herd ) protection was shown by a decrease in the risk for cholera of non-vaccinated residents within a household\'s neighbourhood as the vaccine coverage in that neighbourhood increased. INTERPRETATION Our findings suggest that the oral cholera vaccine offers both direct and indirect ( herd ) protection in a sub-Saharan African setting. Mass oral cholera immunisation campaigns have the potential to provide not only protection for vaccinated individuals but also for the unvaccinated members of the community and should be strongly considered for wider use. Because this is an internationally-licensed vaccine, we could not undertake a r and omised placebo-controlled trial, but the absence of vaccine effectiveness against non-cholera diarrhoea indicates that the noted protection against cholera could not be explained by bias. FUNDING Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, and the South Korean Government Toward Causal Inference With Interference A fundamental assumption usually made in causal inference is that of no interference between individuals ( or units ) ; that is, the potential outcomes of one individual are assumed to be unaffected by the treatment assignment of other individuals. However, in many setting s, this assumption obviously does not hold. For example, in the dependent happenings of infectious diseases, whether one person becomes infected depends on who else in the population is vaccinated. In this article, we consider a population of groups of individuals where interference is possible between individuals within the same group. We propose estim and s for direct, indirect, total, and overall causal effects of treatment strategies in this setting. Relations among the estim and s are established ; for example, the total causal effect is shown to equal the sum of direct and indirect causal effects. Using an experimental design with a two-stage r and omization procedure ( first at the group level, then at the individual level within groups ), unbiased estimators of the proposed estim and s are presented. Variances of the estimators are also developed. The methodology is illustrated in two different setting s where interference is likely : assessing causal effects of housing vouchers and of vaccines Effectiveness of Vi capsular polysaccharide typhoid vaccine among children: a cluster randomized trial in Karachi, Pakistan. BACKGROUND Typhoid fever is endemic in Karachi, with an incidence among children ranging from 170 to 450 per 100,000 child-years. Vaccination strategies are important for prevention, and the Vi capsular polysaccharide ( ViCPS ) vaccine has been shown to be effective in reducing the burden of typhoid fever. METHODS A cluster r and omized trial was conducted in three low socioeconomic urban squatter settlements in Karachi, Pakistan between 2002 and 2007. Sub sample s were followed up for assessment of immune response and adverse events after vaccination. RESULTS The study participants were similar in a wide variety of socio-demographic and economic characteristics at baseline. A total of 27,231 individuals of the total target population of 51,965 in 120 clusters either received a ViCPS vaccine ( 13,238 [ 52 % coverage ] ) or the control Hepatitis A vaccine ( 13,993 [ 53 % ] ). Typhoid fever was diagnosed in 30 ViCPS vaccine recipients and 49 Hepatitis A vaccine recipients with an adjusted total protective effectiveness of 31 % ( 95%CI : -28 %, 63 % ). The adjusted total vaccine protective effectiveness was -38 % ( 95%CI : -192 %, 35 % ) for children aged 2 - 5 years and 57 % ( 95%CI : 6 %, 81 % ) for children 5 - 16 years old. CONCLUSION The ViCPS vaccine did not confer statistically significant protection to children in the study areas, and there was a decline in antibody response 2 years post-vaccination. However, the ViCPS vaccine showed significant total protection in children 5 - 16 years of age, which is consistent with other studies of ViCPS vaccine conducted in India, Nepal, China and South Africa. These findings suggest that ViCPS vaccination of school-aged children will protect the children of urban, typhoid endemic areas against typhoid fever Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Highest attack rates for influenza occur in children. Immunization of schoolchildren with inactivated influenza vaccine in Michigan and Japan was associated with decreased morbidity and mortality, respectively, in older community contacts. An open-labeled, non-r and omized, community-based trial in children with the cold adapted influenza vaccine, trivalent ( CAIV-T ) was initiated to determine the coverage necessary to reduce spread of influenza in the community. Age-specific baseline rates of medically attended acute respiratory illness ( MAARI ) for Scott and White Health Plan ( SWHP ) members at intervention ( Temple and Belton ) and comparison communities ( Waco, Bryan, and College Station ) were obtained in 1997 - 1998. During three subsequent vaccination years, 4298, 5251 and 5150 children received one dose per season of CAIV-T. Vaccinees represented 20 - 25 % of the age-eligible children. Age-specific MAARI rates were compared for SWHP members in the intervention and comparison sites during the influenza outbreaks. Baseline age-specific MAARI rates per 100 persons for the influenza season were comparable between the intervention and comparison communities. In the subsequent three influenza seasons, the age groups 35 - 44, 45 - 54, 55 - 65 and > 64 years experienced reductions in MAARI rates in the intervention communities. In adults > or = 35 years of age, significant reductions in MAARI of 0.08 ( 95 % CI : 0.04, 0.13 ), 0.18 ( 95 % CI : 0.14, 0.22 ) and 0.15 ( 95 % CI : 0.12, 0.19 ), were observed in the influenza seasons for vaccination years 1, 2 and 3, respectively. No consistent reduction in MAARI rates was detected in the younger age groups. Vaccination of approximately 20 - 25 % of children, 1.5 - 18 years of age in the intervention communities result ed in an indirect protection of 8 - 18 % against MAARI in adults > or = 35 years of age Peer effects in learning HIV results. How do neighbors positively or negatively influence individuals living in rural Malawi to learn their HIV results? Using data of location of homes and distance to neighbors, we measure the social network effects of neighbors\'learning their HIV results on individuals own learning. Using the fact that neighbors were r and omly offered monetary incentives of varying amounts to learn their HIV results, we find positive effects of neighbors attending clinics on others living nearby : a 10 percentage point increase of the percentage of neighbors ( approximately 2.4 individuals ) learning their HIV results increases the probability of learning HIV results by 1.1 percentage points. The strongest network effects are among closest neighbors ; we find no effect among religious social networks. We also find a negative interaction between direct cash incentives and peers : the effect of peers doubles among those who were not offered any individual financial incentive to learn their HIV results Distance to health services affects local-level vaccine efficacy for pneumococcal conjugate vaccine (PCV) among rural Filipino children Significance Although pneumococcal conjugate vaccines ( PCVs ) are widely available in industrialized nations, the cost of these vaccines and the strategy of universal vaccination of infants, as endorsed by the World Health Organization, are daunting obstacles to the adoption of these vaccines in developing countries. Using spatial epidemiological methods to examine the spatial variation in vaccine efficacy ( VE ) in an 11-valent PCV trial in Bohol, Philippines, we suggest an alternative strategy to universal vaccination. Our main finding suggests that areas with poor access to healthcare have the highest VE. An alternative vaccination strategy could target vaccination to areas where children are most likely to benefit, rather than focus on nationwide immunization. Pneumococcal conjugate vaccines ( PCVs ) have demonstrated efficacy against childhood pneumococcal disease in several regions globally. We demonstrate how spatial epidemiological analysis of a PCV trial can assist in developing vaccination strategies that target specific geographic sub population s at greater risk for pneumococcal pneumonia. We conducted a secondary analysis of a r and omized, placebo-controlled, double-blind vaccine trial that examined the efficacy of an 11-valent PCV among children less than 2 y of age in Bohol, Philippines. Trial data were linked to the residential location of each participant using a geographic information system. We use spatial interpolation methods to create smoothed surface maps of vaccination rates and local-level vaccine efficacy across the study area. We then measure the relationship between distance to the main study hospital and local-level vaccine efficacy, controlling for ecological factors, using spatial autoregressive models with spatial autoregressive disturbances. We find a significant amount of spatial variation in vaccination rates across the study area. For the primary study endpoint vaccine efficacy increased with distance from the main study hospital from −14 % for children living less than 1.5 km from Bohol Regional Hospital ( BRH ) to 55 % for children living greater than 8.5 km from BRH. Spatial regression models indicated that after adjustment for ecological factors, distance to the main study hospital was positively related to vaccine efficacy, increasing at a rate of 4.5 % per kilometer distance. Because areas with poor access to care have significantly higher VE, targeted vaccination of children in these areas might allow for a more effective implementation of global programs Assessing effects of cholera vaccination in the presence of interference. Interference occurs when the treatment of one person affects the outcome of another. For example, in infectious diseases, whether one individual is vaccinated may affect whether another individual becomes infected or develops disease. Quantifying such indirect ( or spillover ) effects of vaccination could have important public health or policy implication s. In this article we use recently developed inverse-probability weighted ( IPW ) estimators of treatment effects in the presence of interference to analyze an individually-r and omized, placebo-controlled trial of cholera vaccination that targeted 121,982 individuals in Matlab, Bangladesh. Because these IPW estimators have not been employed previously, a simulation study was also conducted to assess the empirical behavior of the estimators in setting s similar to the cholera vaccine trial. Simulation study results demonstrate the IPW estimators can yield unbiased estimates of the direct, indirect, total, and overall effects of vaccination when there is interference provided the untestable no unmeasured confounders assumption holds and the group-level propensity score model is correctly specified. Application of the IPW estimators to the cholera vaccine trial indicates the presence of interference. For example, the IPW estimates suggest on average 5.29 fewer cases of cholera per 1000 person-years ( 95 % confidence interval 2.61, 7.96 ) will occur among unvaccinated individuals within neighborhoods with 60 % vaccine coverage compared to neighborhoods with 32 % coverage. Our analysis also demonstrates how not accounting for interference can render misleading conclusions about the public health utility of vaccination Users identified challenges in applying GRADE to complex interventions and suggested an extension to GRADE. OBJECTIVES To explore user perspectives on applying the Grading of Recommendations Assessment, Development and Evaluation ( GRADE ) to systematic review s of complex interventions. STUDY DESIGN AND SETTING Thirty-three authors of recent ( 2013 onward ) systematic review s were contacted regarding their perspectives on using GRADE from three Cochrane review groups : Cochrane Developmental, Psychosocial, and Learning Problems Group ; Cochrane Public Health Group ; and Cochrane Depression, Anxiety, and Neurosis Group. Framework Analysis was applied to the data to identify the challenges in applying GRADE and suggestions for its extension, that is, adaptation. These two themes were cross-compared between the groups of answers from " simple " vs. " complex " intervention review authors to identify the specific perspectives on using GRADE in review s of complex interventions. RESULTS Specific challenges were identified in applying GRADE to review s of complex interventions. These were related to the assessment of nonr and omized studies and performance bias in GRADE. Authors perceived these challenges to contribute to frequent downgrading of the " best evidence possible " for complex interventions. Meanwhile, GRADE was found to lack an analytic approach to enable adequate evidence synthesis and assessment of intervention implementation elements. CONCLUSION Users suggest that the GRADE guidance be extended to address-specific considerations for complex interventions The Minicommunity Design to Assess Indirect Effects of Vaccination Abstract We propose the minicommunity design to estimate indirect effects of vaccination. Establishing indirect effects of vaccination in unvaccinated sub population s could have important implication s for global vaccine policies. In the minicommunity design, the household or other small transmission unit serves as the cluster in which to estimate indirect effects of vaccination, similar to studies in larger communities to estimate indirect, total, and overall effects. Examples from the literature include studies in small transmission units to estimate indirect effects of pertussis, pneumococcal, influenza, and cholera vaccines. We characterize the minicommunity design by several method ologic considerations, including the assignment mechanism, ascertainment, the role of transmission outside the transmission unit, and the relation of the size of the transmission unit to number of people vaccinated. The minicommunity study for indirect effects is contrasted with studies to estimate vaccine effects on infectiousness and protective effects under conditions of household exposure within small transmission units. The minicommunity design can be easily implemented in individually r and omized studies by enrolling and following-up members of households of the r and omized individuals. The methodology for the minicommunity design for estimating indirect effects of vaccination deserves much future research Indirect Effect of 7-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Carriage in Newborns in Rural Gambia: A Randomised Controlled Trial Background Gambian infants frequently acquire Streptococcus pneumoniae soon after birth. We investigated the indirect effect of 7-valent pneumococcal conjugate vaccine ( PCV-7 ) on pneumococcal acquisition in newborn Gambian babies. Methods Twenty-one villages were r and omised to receive PCV-7 to all subjects ( 11 vaccinated villages ) or to infants aged 2–30 months ( 10 control villages ). Other control villagers received Meningococcal C conjugate vaccine. From 328 babies born during the trial, nasopharyngeal swabs were collected after birth, then weekly until 8 weeks of age when they received their first dose of PCV-7. Pneumococcal carriage and acquisition rates were compared between the study arms and with a baseline study. Results 57.4 % of 2245 swabs were positive for S. pneumoniae. Overall carriage was similar in both arms. In vaccinated villages fewer infants carried pneumococci of vaccine serotypes ( VT ) ( 16.9 % [ 31/184 ] vs. 37.5 % [ 54/144 ], p<0.001 ) and more carried pneumococci of non-vaccine serotypes ( NVT ) ( 80.9 % [ 149/184 ] vs. 75.7 % [ 109/144 ], p = 0.246 ). Infants from vaccinated villages had a significantly lower acquisition rate of VT ( HR 0.39 [ 0.26–0.58 ], p<0.001 ) and increased acquisition of NVT ( HR 1.16 [ 0.87–1.56 ], p = 0.312 ). VT carriage ( 51.6 % vs. 37.5 %, p = 031 in control and 46.1 % vs. 16.8 %, p<0.001 in vaccinated villages ) and acquisition rates ( HR 0.68 [ 0.50–0.92 ], p = 0.013 in control villages and HR 0.31 [ 0.19–0.50 ], p<.001 in vaccinated villages ) were significantly lower in both study arms than in the baseline study. NVT carriage ( 63.2 % vs. 75.7 %, p = 0.037 in control and 67.2 % vs. 75.3 %, p = 0.005 in vaccinated villages ) and acquisition rates ( HR 1.48 [ 1.06–2.06 ], p = 0.022 ) and ( HR 1.52 [ 1.11–2.10 ], p = 0.010 respectively ) were significantly higher. Conclusion PCV-7 significantly reduced carriage of VT pneumococci in unvaccinated infants. This indirect effect likely originated from both the child and adult vaccinated population s. Increased carriage of NVT pneumococci needs ongoing monitoring. Trial Registration IS RCT N Register Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial BACKGROUND Trachoma-control programmes distribute oral azithromycin to treat the ocular strains of chlamydia that cause the disease and to control infection. Theoretically, elimination of infection is feasible if untreated individuals receive an indirect protective effect from living in repeatedly treated communities, which is similar to herd protection in vaccine programmes. We assessed indirect protection against trachoma with mass azithromycin distributions. METHODS In a cluster r and omised trial, 24 subkebeles ( government-defined units ) in Amhara, Ethiopia, were r and omised, with use of a simple r and om sample, to distribution four times per year of single-dose oral azithromycin to children aged 1 - 10 years ( 12 subkebeles, 4764 children ), or to delayed treatment until after the study ( control ; 12 subkebeles, 6014 children ). We compared the prevalence of ocular chlamydial infection in untreated individuals 11 years and older between baseline and 12 months in the treated subkebeles, and at 12 months between the treated and control subkebeles. Health-care and laboratory personnel were blinded to study group. Analysis was intention to treat. The study is registered with clinical trials.gov, number NCT00322972. FINDINGS At 12 months, 637 children aged 1 - 10 years and 561 adults and children aged 11 years and older were analysed in the children-treated group, and 618 and 550, respectively, in the control group. The mean prevalence of infection in children decreased from 48.4 % ( 95 % CI 42.9 - 53.9 ) to 3.6 % ( 0.8 - 6.4 ) after four mass treatments. At 12 months, the mean prevalence of infection in the untreated age group ( > /=11 years ) was 47 % ( 95 % CI 33 - 57 ) less than baseline ( p=0.002 ), and 35 % ( 95 % CI 1 - 57 ) less than that in untreated communities ( p=0.04 ). INTERPRETATION Frequent treatment of children, who are a core group for transmission of trachoma, could eventually eliminate infection from the entire community. Herd protection is offered by repeated mass antibiotic treatments, providing a strategy for elimination of a bacterial disease when an effective vaccine is unavailable. FUNDING National Institutes of Health Vaccine Protection of Bangladeshi Infants and Young Children Against Cholera: Implications for Vaccine Deployment and Person-to-Person Transmission Background : Killed oral cholera vaccines are internationally licensed for older children and adults, but not for infants and young children. We investigated whether mass immunization of older children and adults can confer herd protection to children too young to be vaccinated. Methods : We analyzed the first year of surveillance of an individually r and omized, placebo-controlled trial of killed oral cholera vaccines in 89,596 older Bangladeshi children and adult women. Vaccine herd protection of children less than 2 years of age, who were too young to participate in the trial, was evaluated by determining whether the incidence of cholera during the first year of follow-up of this age group was lower in residential clusters with higher levels of vaccine coverage than in clusters with lower levels of vaccine coverage. Results : Vaccine coverage of the targeted population ranged from 4 % to 65 % in different clusters. The incidence ( cases per 1000 ) of cholera among children less than 2 years of age ranged from 18.9 in clusters in the lowest quintile of vaccine coverage to 8.6 in clusters in the highest quintile ( P = 0.004 for the inverse association between vaccine coverage and risk of cholera ) Vaccine coverage of adult women ( relative risk of cholera = 0.95 for each percent increase in vaccine coverage ; 95 % confidence interval : 0.92–0.99 ; P < 0.01 ), but not of older children, was independently associated with a lower risk of cholera in children less than 2 years of age. Conclusions : Vaccination of older age groups was associated with protection of children too young to be vaccinated. The pronounced herd protection of young children associated with vaccination of adult women suggests that adult women may play a prominent role in the transmission of cholera to young children in this setting Developments in cluster randomized trials and Statistics in Medicine. The design and analysis of cluster r and omized trials has been a recurrent theme in Statistics in Medicine since the early volumes. In celebration of 25 years of Statistics in Medicine, this paper review s recent developments, particularly those that featured in the journal. Issues in design such as sample size calculations, matched paired design s, cohort versus cross-sectional design s, and practical design problems are covered. Developments in analysis include modification of robust methods to cope with small numbers of clusters, generalized estimation equations, population averaged and cluster specific models. Finally, issues on presenting data, some other clustering issues and the general problem of evaluating complex interventions are briefly mentioned CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials. Kenneth Schulz and colleagues describe the latest version, CONSORT 2010, which up date s the reporting guideline based on new method ological evidence and accumulating experience. To encourage dissemination of the CONSORT 2010 Statement, this article is freely accessible on bmj.com and will also be published in the Lancet, Obstetrics and Gynecology, PLoS Medicine, Annals of Internal Medicine, Open Medicine, Journal of Clinical Epidemiology, BMC Medicine, and Trials Population effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable Haemophilus influenzae in Kilifi, Kenya: findings from cross-sectional carriage studies Summary Background The effect of 7-valent pneumococcal conjugate vaccine ( PCV ) in developed countries was enhanced by indirect protection of unvaccinated individuals, mediated by reduced nasopharyngeal carriage of vaccine-serotype pneumococci. The potential indirect protection of 10-valent PCV ( PCV10 ) in a developing country setting is unknown. We sought to estimate the effectiveness of introduction of PCV10 in Kenya against carriage of vaccine serotypes and its effect on other bacteria. Methods PCV10 was introduced into the infant vaccination programme in Kenya in January, 2011, accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years. We did annual cross-sectional carriage studies among an age-stratified, r and om population sample in the 2 years before and 2 years after PCV10 introduction. A nasopharyngeal rayon swab specimen was collected from each participant and was processed in accordance with WHO recommendations. Prevalence ratios of carriage before and after introduction of PCV10 were calculated by log-binomial regression. Findings About 500 individuals were enrolled each year ( total n=2031 ). Among children younger than 5 years, the baseline ( 2009–10 ) carriage prevalence was 34 % for vaccine-serotype Streptococcus pneumoniae, 41 % for non-vaccine-serotype Streptococcus pneumoniae, and 54 % for non-typeable Haemophilus influenzae. After PCV10 introduction ( 2011–12 ), these percentages were 13 %, 57 %, and 40 %, respectively. Adjusted prevalence ratios were 0·36 ( 95 % CI 0·26–0·51 ), 1·37 ( 1·13–1·65 ), and 0·62 ( 0·52–0·75 ), respectively. Among individuals aged 5 years or older, the adjusted prevalence ratios for vaccine-serotype and non-vaccine-serotype S pneumoniae carriage were 0·34 ( 95 % CI 0·18–0·62 ) and 1·13 ( 0·92–1·38 ), respectively. There was no change in prevalence ratio for Staphylococcus aureus ( adjusted prevalence ratio for those < 5 years old 1·02, 95 % CI 0·52–1·99, and for those ≥5 years old 0·90, 0·60–1·35 ). Interpretation After programmatic use of PCV10 in Kilifi, carriage of vaccine serotypes was reduced by two-thirds both in children younger than 5 years and in older individuals. These findings suggest that PCV10 introduction in Africa will have substantial indirect effects on invasive pneumococcal disease. Funding GAVI Alliance and Wellcome Trust Promoting Transparency in Social Science Research Social scientists should adopt higher transparency st and ards to improve the quality and credibility of research. There is growing appreciation for the advantages of experimentation in the social sciences. Policy-relevant cl aims that in the past were backed by theoretical arguments and inconclusive correlations are now being investigated using more credible methods. Changes have been particularly pronounced in development economics, where hundreds of r and omized trials have been carried out over the last decade. When experimentation is difficult or impossible, research ers are using quasi-experimental design s. Governments and advocacy groups display a growing appetite for evidence -based policy-making. In 2005, Mexico established an independent government agency to rigorously evaluate social programs, and in 2012, the U.S. Office of Management and Budget advised federal agencies to present evidence from r and omized program evaluations in budget requests ( 1, 2 )', 'BACKGROUND Information technology-based interventions are increasingly being used to manage health care. However, there is conflicting evidence regarding whether these interventions improve outcomes in people with type 2 diabetes. OBJECTIVE The objective of this study was to conduct a systematic review and meta- analysis of clinical trials, assessing the impact of information technology on changes in the levels of hemoglobin A1c ( HbA1c ) and mapping the interventions with chronic care model ( CCM ) elements. Diabetes intervention in the information age. Sustained improvement in blood glucose control is the only treatment outcome which will reduce or eliminate the long term complications of diabetes mellitus. We have design ed and evaluated an electronic information system which facilitates this task. The system is voice-interactive, physician directed and affords, to remote patients, 24 h access via touch-tone telephone. Accordingly, patients access the system each day to report self-measured blood glucose levels or hypoglycaemic symptoms together with dietary changes, planned exercise, stress, illness or other lifestyle events. In turn they receive immediate advice with respect to medication dosing changes, and other pertinent feedback. Preliminary system beta-testing for safety and efficacy was performed for one year in an open study of 204 patients derived from two independent, health-care environments. Among the two testing centres, over 60,000 telephone cells were received by the computer systems during the start-up year. Safety and efficacy expectations were met. In addition, prevalence of diabetes related crises ( hyperglycaemia or hypoglycaemia ) fell approximately 3-fold. Glycated haemoglobin fell significantly ( 1.0 - 1.3 % ) in patients actively using the system. In control groups of patients not actively using the system, there were no improvements in metabolic control while body weights were stable in all groups. The new system was safe and effective in our h and s and empowered our health professionals to provide improved diabetes care Overcoming Clinical Inertia: A Randomized Clinical Trial of a Telehealth Remote Monitoring Intervention Using Paired Glucose Testing in Adults With Type 2 Diabetes Background Type 2 diabetes mellitus is a worldwide challenge. Practice guidelines promote structured self-monitoring of blood glucose ( SMBG ) for informing health care providers about glycemic control and providing patient feedback to increase knowledge, self-efficacy, and behavior change. Paired glucose testing — pairs of glucose results obtained before and after a meal or physical activity — is a method of structured SMBG. However, frequent access to glucose data to interpret values and recommend actions is challenging. A complete feedback loop— data collection and interpretation combined with feedback to modify treatment — has been associated with improved outcomes, yet there remains limited integration of SMBG feedback in diabetes management. Incorporating telehealth remote monitoring and asynchronous electronic health record ( EHR ) feedback from certified diabetes educators (CDEs)—specialists in glucose pattern management — employ the complete feedback loop to improve outcomes. Objective The purpose of this study was to evaluate a telehealth remote monitoring intervention using paired glucose testing and asynchronous data analysis in adults with type 2 diabetes. The primary aim was change in glycated hemoglobin (A1c)—a measure of overall glucose management — between groups after 6 months. The secondary aims were change in self-reported Summary of Diabetes Self-Care Activities ( SDSCA ), Diabetes Empowerment Scale, and Diabetes Knowledge Test. Methods A 2-group r and omized clinical trial was conducted comparing usual care to telehealth remote monitoring with paired glucose testing and asynchronous virtual visits. Participants were aged 30 - 70 years, not using insulin with A1c levels between 7.5 % and 10.9 % ( 58 - 96 mmol/mol ). The telehealth remote monitoring tablet computer transmitted glucose data and facilitated a complete feedback loop to educate participants, analyze actionable glucose data, and provide feedback. Data from paired glucose testing were analyzed asynchronously using computer-assisted pattern analysis and were shared with patients via the EHR weekly. CDEs called participants monthly to discuss paired glucose testing trends and treatment changes. Separate mixed-effects models were used to analyze data. Results Participants ( N=90 ) were primarily white ( 64 %, 56/87 ), mean age 58 ( SD 11 ) years, mean body mass index 34.1 ( SD 6.7 ) kg/m2, with diabetes for mean 8.2 ( SD 5.4 ) years, and a mean A1c of 8.3 % ( SD 1.1 ; 67 mmol/mol ). Both groups lowered A1c with an estimated average decrease of 0.70 percentage points in usual care group and 1.11 percentage points in the treatment group with a significant difference of 0.41 percentage points at 6 months ( SE 0.08, t159=–2.87, P=.005 ). Change in medication ( SE 0.21, t157=–3.37, P=.009 ) was significantly associated with lower A1c level. The treatment group significantly Web-based care management in patients with poorly controlled diabetes. OBJECTIVE To assess the effects of web-based care management on glucose and blood pressure control over 12 months in patients with poorly controlled diabetes. RESEARCH DESIGN AND METHODS For this study, 104 patients with diabetes and HbA(1c ) ( A1C ) > or = 9.0 % who received their care at a Department of Veterans Affairs medical center were recruited. All participants completed a diabetes education class and were r and omized to continue with their usual care ( n = 52 ) or receive web-based care management ( n = 52 ). The web-based group received a notebook computer, glucose and blood pressure monitoring devices, and access to a care management website. The website provided educational modules, accepted uploads from monitoring devices, and had an internal messaging system for patients to communicate with the care manager. RESULTS Participants receiving web-based care management had lower A1C over 12 months ( P < 0.05 ) when compared with education and usual care. Persistent website users had greater improvement in A1C when compared with intermittent users ( -1.9 vs. -1.2 % ; P = 0.051 ) or education and usual care ( -1.4 % ; P < 0.05 ). A larger number of website data uploads was associated with a larger decline in A1C ( highest tertile -2.1 %, lowest tertile -1.0 % ; P < 0.02 ). Hypertensive participants in the web-based group had a greater reduction in systolic blood pressure ( P < 0.01 ). HDL cholesterol rose and triglycerides fell in the web-based group ( P < 0.05 ). CONCLUSIONS Web-based care management may be a useful adjunct in the care of patients with poorly controlled diabetes The Cholesterol, Hypertension, And Glucose Education (CHANGE) study: results from a randomized controlled trial in African Americans with diabetes. BACKGROUND Cardiovascular disease ( CVD ) and diabetes account for one-third of the mortality difference between African American and white patients. We evaluated the effect of a CVD risk reduction intervention in African Americans with diabetes. METHODS We r and omized 359 African Americans with type 2 diabetes to receive usual care or a nurse telephone intervention. The 12-month intervention provided monthly self-management support and quarterly medication management facilitation. Co primary outcomes were changes in systolic blood pressure ( SBP ), hemoglobin A1c ( HbA1c ), and low-density lipoprotein cholesterol ( LDL-C ) over 12 months. We estimated between-intervention group differences over time using linear mixed-effects models. The secondary outcome was self-reported medication adherence. RESULTS The sample was 72 % female ; 49 % had low health literacy, and 37 % had annual income < $ 10,000. Model-based estimates for mean baseline SBP, HbA1c, and LDL-C were 136.8 mm Hg ( 95 % CI 135.0 - 138.6 ), 8.0 % ( 95 % CI 7.8 - 8.2 ), and 99.1 mg/dL ( 95 % CI 94.7 - 103.5 ), respectively. Intervention patients received 9.9 ( SD 3.0 ) intervention calls on average. Primary providers replied to 76 % of nurse medication management facilitation contacts, 18 % of these result ed in medication changes. There were no between-group differences over time for SBP ( P =.11 ), HbA1c ( P =.66 ), or LDL-C ( P =.79 ). Intervention patients were more likely than those receiving usual care to report improved medication adherence ( odds ratio 4.4, 95 % CI 1.8 - 10.6, P =.0008 ), but adherent patients did not exhibit relative improvement in primary outcomes. CONCLUSIONS This intervention improved self-reported medication adherence but not CVD risk factor control among African Americans with diabetes. Further research is needed to determine how to maximally impact CVD risk factors in African American patients Improving Diabetes Care in Practice OBJECTIVE —The purpose of this study was to determine whether implementation of a multicomponent organizational intervention can produce significant change in diabetes care and outcomes in community primary care practice s. RESEARCH DESIGN AND METHODS —This was a group-r and omized, controlled clinical trial evaluating the practical effectiveness of a multicomponent intervention ( TRANSLATE ) in 24 practice s. The intervention included implementation of an electronic diabetes registry, visit reminders, and patient-specific physician alerts. A site coordinator facilitated previsit planning and a monthly review of performance with a local physician champion. The principle outcomes were the percentage of patients achieving target values for the composite of systolic blood pressure ( SBP ) < 130 mmHg, LDL cholesterol < 100 mg/dl, and A1C < 7.0 % at baseline and 12 months. Six process measures were also followed. RESULTS —Over 24 months, 69,965 visits from 8,405 adult patients with type 2 diabetes were recorded from 238 health care providers in 24 practice s from 17 health systems. Diabetes process measures increased significantly more in intervention than in control practice s, giving net increases as follows : foot examinations 35.0 % ( P < 0.0.001 ) ; annual eye examinations 25.9 % ( P < 0.001 ) ; renal testing 28.5 % ( P < 0.001 ) ; A1C testing 8.1%(P < 0.001 ) ; blood pressure monitoring 3.5 % ( P = 0.05 ) ; and LDL testing 8.6 % ( P < 0.001 ). Mean A1C adjusted for age, sex, and comorbidity decreased significantly in intervention practice s ( P < 0.02 ). At 12 months, intervention practice s had significantly greater improvement in achieving recommended clinical values for SBP, A1C, and LDL than control clinics ( P = 0.002 ). CONCLUSIONS — Introduction of a multicomponent organizational intervention in the primary care setting significantly increases the percentage of type 2 diabetic patients achieving recommended clinical outcomes Impact of MyCareTeam for poorly controlled diabetes mellitus. OBJECTIVE Web-based diabetes management can be used to provide frequent interactions between patients and providers and thus result in improved glycemic control. METHODS In a single-center, prospect i ve feasibility study, 16 poorly controlled patients with either type 1 or 2 diabetes mellitus were enrolled to assess the impact of using MyCareTeam, a web-based diabetes management application, for diabetes management. Patients were asked to transfer their blood glucose data electronically, maintain exercise logs, and communicate with their provider via MyCareTeam. The provider gave clinical interventions to optimize blood glucose control and provided feedback via MyCareTeam. Diabetes, nutrition, and exercise information was also available via MyCareTeam. RESULTS A significant reduction of over 2.22 % points in hemoglobin A1C was seen for the total patient population. Differences between moderate/heavy users ( n = 8) versus light/never users ( n = 8) of MyCareTeam were evaluated for intergroup differences based upon utilization. Moderate/heavy users had a significant 6-month A1C reduction of 3.15 percentage points compared with a reduction of 1.28 percentage points in light/never users. Other secondary end points were improved as well, including systolic blood pressure, diastolic blood pressure, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. However, as expected, body mass index levels increased because of aggressive diabetes management with insulin therapy. CONCLUSIONS These results demonstrate a significant treatment effect from the MyCareTeam application. A larger r and omized control trial is under way at the Boston Veterans Administration Healthcare System. If these results are confirmed as expected, then web-based diabetes management may prove to be the link to achieving target American Diabetes Association glycemic goals in patients with poorly controlled diabetes Improved Glycemic Control Without Hypoglycemia in Elderly Diabetic Patients Using the Ubiquitous Healthcare Service, a New Medical Information System OBJECTIVE To improve quality and efficiency of care for elderly patients with type 2 diabetes, we introduced elderly-friendly strategies to the clinical decision support system (CDSS)-based ubiquitous healthcare ( u-healthcare ) service, which is an individualized health management system using advanced medical information technology. RESEARCH DESIGN AND METHODS We conducted a 6-month r and omized, controlled clinical trial involving 144 patients aged > 60 years. Participants were r and omly assigned to receive routine care ( control, n = 48 ), to the self-monitored blood glucose ( SMBG, n = 47 ) group, or to the u-healthcare group ( n = 49 ). The primary end point was the proportion of patients achieving A1C < 7 % without hypoglycemia at 6 months. U-healthcare system refers to an individualized medical service in which medical instructions are given through the patient ’s mobile phone. Patients receive a glucometer with a public switched telephone network-connected cradle that automatically transfers test results to a hospital-based server. Once the data are transferred to the server, an automated system, the CDSS rule engine, generates and sends patient-specific messages by mobile phone. RESULTS After 6 months of follow-up, the mean A1C level was significantly decreased from 7.8 ± 1.3 % to 7.4 ± 1.0 % ( P < 0.001 ) in the u-healthcare group and from 7.9 ± 1.0 % to 7.7 ± 1.0 % ( P = 0.020 ) in the SMBG group, compared with 7.9 ± 0.8 % to 7.8 ± 1.0 % ( P = 0.274 ) in the control group. The proportion of patients with A1C < 7 % without hypoglycemia was 30.6 % in the u-healthcare group, 23.4 % in the SMBG group ( 23.4 % ), and 14.0 % in the control group ( P < 0.05 ). CONCLUSIONS The CDSS-based u-healthcare service achieved better glycemic control with less hypoglycemia than SMBG and routine care and may provide effective and safe diabetes management in the elderly diabetic patients Biophysiologic outcomes of the Enhancing Adherence in Type 2 Diabetes (ENHANCE) trial. BACKGROUND Behavioral research to improve lifestyle in broadly defined population s of patients with type 2 diabetes is limited. OBJECTIVE We evaluated a behavioral intervention featuring technology-based self-monitoring on biophysiologic outcomes of glycemic control and markers of cardiovascular risk. DESIGN In this single-site, r and omized clinical trial, participants were stratified by good and poor glycemic control ( glycated hemoglobin < 8 % or ≥8 % ) and absence or presence of kidney disease, ( estimated glomerular filtration rate ≥60 or < 60 mL/min ) and r and omized within strata. Measurements were obtained at 0, 3, and 6 months. PARTICIPANTS / SETTING Self-referred, community-dwelling adults with type 2 diabetes mellitus. INTERVENTION The intervention group received Social Cognitive Theory-based counseling paired with technology-based self-monitoring, and results were compared with an attention control group. MAIN OUTCOME MEASURES Glycated hemoglobin, fasting serum glucose, lipid levels, blood pressure, weight, body mass index, and waist circumference were evaluated. STATISTICAL ANALYSES PERFORMED Mean differences within and between r and omization groups were compared over time. Intervention effects over time were estimated using r and om intercept models. RESULTS Two hundred ninety-six subjects were r and omized, 256 ( 86.5 % ) completed 3-month and 246 ( 83.1 % ) completed 6-month assessment s. Glycated hemoglobin was reduced in the intervention group by 0.5 % at 3 months and 0.6 % at 6 months ( P<0.001 for each ), and the control group by 0.3 % ( P<0.001 ) at 3 months and 0.2 % ( P<0.05 ) at 6 months ; but between-group differences were not significant. In those with baseline glycated hemoglobin ≥8 % and estimated glomerular filtration rate ≥60 mL/min, glycated hemoglobin was reduced in the intervention group by 1.5 % at 3 months and 1.8 % at 6 months ( P<0.001 for each ), and the control group by 0.9 % ( P<0.001 ) at 3 months and 0.8 % ( P<0.05 ) at 6 months ; but between-group differences were not significant. In r and om intercept models, the estimated reduction in glycated hemoglobin of 0.29 % was not significant. CONCLUSIONS Two behavioral approaches to improving general lifestyle management in individuals with type 2 diabetes mellitus were effective in improving glycemic control, but no significant between-group differences were observed Web-Based Collaborative Care for Type 2 Diabetes OBJECTIVE —To test Web-based care management of glycemic control using a shared electronic medical record with patients who have type 2 diabetes. RESEARCH DESIGN AND METHODS —We conducted a trial of 83 adults with type 2 diabetes r and omized to receive usual care plus Web-based care management or usual care alone between August 2002 and May 2004. All patients had GHb ≥7.0 %, had Web access from home, and could use a computer with English language –based programs. Intervention patients received 12 months of Web-based care management. The Web-based program included patient access to electronic medical records, secure e-mail with providers, feedback on blood glucose readings, an educational Web site, and an interactive online diary for entering information about exercise, diet, and medication. The primary outcome was change in GHb. RESULTS —GHb levels declined by 0.7 % ( 95 % CI 0.2−1.3 ) on average among intervention patients compared with usual-care patients. Systolic blood pressure, diastolic blood pressure, total cholesterol levels, and use of in-person health care services did not differ between the two groups. CONCLUSIONS —Care management delivered through secure patient Web communications improved glycemic control in type 2 diabetes The Vermont Diabetes Information System: A Cluster Randomized Trial of a Population Based Decision Support System BACKGROUND Optimal care for patients with diabetes is difficult to achieve in clinical practice. OBJECTIVE To evaluate the impact of a registry and decision support system on processes of care, and physiologic control. PARTICIPANTS R and omized trial with clustering at the practice level, involving 7,412 adults with diabetes in 64 primary care practice s in the Northeast. INTERVENTIONS Provider decision support ( reminders for overdue diabetes tests, alerts regarding abnormal results, and quarterly population reports with peer comparisons ) and patient decision support ( reminders and alerts ). MEASUREMENTS AND MAIN RESULTS Process and physiologic outcomes were evaluated in all subjects. Functional status was evaluated in a r and om patient sample via question naire. We used multiple logistic regression to quantify the effect, adjusting for clustering and potential confounders. Intervention subjects were significantly more likely to receive guideline -appropriate testing for cholesterol ( OR = 1.39 ; [ 95%CI 1.07, 1.80 ] P = 0.012 ), creatinine ( OR = 1.40 ; [ 95%CI 1.06, 1.84 ] P = 0.018 ), and proteinuria ( OR = 1.74 ; [ 95%CI 1.13, 1.69 ] P = 0.012 ), but not A1C ( OR = 1.17 ; [ 95 % CI 0.80, 1.72 ] P = 0.43 ). Rates of control of A1C and LDL cholesterol were similar in the two groups. There were no differences in blood pressure, body mass index, or functional status. CONCLUSIONS A chronic disease registry and decision support system based on easily obtainable laboratory data was feasible and acceptable to patients and providers. This system improved the process of laboratory monitoring in primary care, but not physiologic control Combined Task Delegation, Computerized Decision Support, and Feedback Improve Cardiovascular Risk for Type 2 Diabetic Patients OBJECTIVE —The Diabetes Care Protocol combines task delegation ( a practice nurse ), computerized decision support, and feedback every 3 months. We studied the effect of the Diabetes Care Protocol on A1C and cardiovascular risk factors in type 2 diabetic patients in primary care. RESEARCH DESIGN AND METHODS —In a cluster r and omized trial, mean changes in cardiovascular risk factors between the intervention and control groups after 1 year were calculated by generalized linear models. RESULTS —Throughout the Netherl and s, 26 intervention practice s included 1,699 patients and 29 control practice s 1,692 patients. The difference in A1C change was not significant, whereas total cholesterol, LDL cholesterol, and blood pressure improved significantly more in the intervention group. The 10-year coronary heart disease risk estimate of the UK Prospect i ve Diabetes Study improved 1.4 % more in the intervention group. CONCLUSIONS —Delegation of routine diabetes care to a practice nurse combined with computerized decision support and feedback did not improve A1C but reduced cardiovascular risk in type 2 diabetes patients Effects of a Brief Office-Based Intervention to Facilitate Diabetes Dietary Self-Management OBJECTIVE There is a pressing need for brief practical interventions that address diabetes management. Using a r and omized design, we evaluated a medical office-based intervention focused on behavioral issues relevant to dietary self-management. RESEARCH DESIGN AND METHODS There were 206 adult diabetes patients r and omized to usual care or brief intervention, which consisted of touchscreen computer-assisted assessment to provide immediate feedback on key barriers to dietary self-management, and goal setting and problem-solving counseling for patients. Follow-up components to the single session intervention included phone calls and interactive video or videotape instruction as needed. RESULTS Multivariate analyses of covariance revealed that the brief intervention produced greater improvements than usual care on a number of measures of dietary behavior ( e.g., fewer calories from saturated fat, fewer high-fat eating habits and behaviors ) at the 3-month follow-up. There were also significant differences favoring intervention on changes in serum cholesterol levels and patient satisfaction but not on glycosylated hemoglobin. The intervention effects were relatively robust across a variety of patient characteristics, the two participating physicians, and intervention staff members. CONCLUSIONS If the long-term results are equally positive and generalize to other setting, this intervention could provide a prototype for a feasible cost-effective way to integrate patient views and behavioral management into office-based care for diabetes A pragmatic cluster randomised controlled trial of a Diabetes REcall And Management system: the DREAM trial Abstract Background Following the introduction of a computerised diabetes register in part of the northeast of Engl and, care initially improved but then plateaued. We therefore enhanced the existing diabetes register to address these problems. The aim of the trial was to evaluate the effectiveness and efficiency of an area wide\'extended,\'computerised diabetes register incorporating a full structured recall and management system, including individualised patient management prompts to primary care clinicians based on locally-adapted, evidence -based guidelines. Methods The study design was a pragmatic, cluster r and omised controlled trial, with the general practice as the unit of r and omisation. Set in 58 general practice s in three Primary Care Trusts in the northeast of Engl and, the study outcomes were the clinical process and outcome variables held on the diabetes register, patient-reported outcomes, and service and patient costs. The effect of the intervention was estimated using generalised linear models with an appropriate error structure. To allow for the clustering of patients within practice s, population averaged models were estimated using generalized estimating equations. Results Patients in intervention practice s were more likely to have at least one diabetes appointment recorded ( OR 2.00, 95 % CI 1.02, 3.91 ), to have a recording of a foot check ( OR 1.87, 95 % CI 1.09, 3.21 ), have a recording of receiving dietary advice ( OR 2.77, 95 % CI 1.22, 6.29 ), and have a recording of blood pressure ( BP ) ( OR 2.14, 95 % CI 1.06, 4.36 ). There was no difference in mean HbA1c or BP levels, but the mean cholesterol level in patients from intervention practice s was significantly lower ( -0.15 mmol/l, 95 % CI -0.25, -0.06 ). There were no differences in patient-reported outcomes or in patient-reported use of drugs, or uptake of health services. The average cost per patient was not significantly different between the intervention and control groups. Costs incurred in administering the system at the register and in general practice were in addition to these. Conclusion This study has shown benefits from an area-wide, computerised diabetes register incorporating a full structured recall and individualised patient management system. However, these benefits were achieved at a cost. In future, these costs may fall as electronic data exchange becomes a reliable reality. Trial registration : International St and ard R and omised Controlled Trial Number ( IS RCT N ) Register, IS RCT N32042030 An endocrinologist-supported intervention aimed at providers improves diabetes management in a primary care site: improving primary care of African Americans with diabetes (IPCAAD) 7. OBJECTIVE Management of diabetes is frequently suboptimal in primary care setting s, where providers often fail to intensify therapy when glucose levels are high, a problem known as clinical inertia. We asked whether interventions targeting clinical inertia can improve outcomes. RESEARCH DESIGN AND METHODS A controlled trial over a 3-year period was conducted in a municipal hospital primary care clinic in a large academic medical center. We studied all patients ( 4,138 ) with type 2 diabetes who were seen in continuity clinics by 345 internal medicine residents and were r and omized to be control subjects or to receive one of three interventions. Instead of consultative advice, the interventions were hard copy computerized reminders that provided patient-specific recommendations for management at the time of each patient\'s visit, individual face-to-face feedback on performance for 5 min every 2 weeks, or both. RESULTS Over an average patient follow-up of 15 months within the intervention site, improvements in and final HbA1c ( A1C ) with feedback + reminders ( deltaA1C 0.6 %, final A1C 7.46 % ) were significantly better than control ( deltaA1C 0.2 %, final A1C 7.84 %, P < 0.02 ) ; changes were smaller with feedback only and reminders only ( P = NS vs. control ). Trends were similar but not significant with systolic blood pressure ( sBP ) and LDL cholesterol. Multivariable analysis showed that the feedback intervention independently facilitated attainment of American Diabetes Association goals for both A1C and sBP. Over a 2-year period, overall glycemic control improved in the intervention site but did not change in other primary care sites ( final A1C 7.5 vs. 8.2 %, P < 0.001 ). CONCLUSIONS Feedback on performance aim ed at overcoming clinical inertia and given to internal medicine resident primary care providers improves glycemic control. Partnering generalists with diabetes specialists may be important to enhance diabetes management in other primary care setting A controlled trial of web-based diabetes disease management: the MGH diabetes primary care improvement project. OBJECTIVE To test effects of a web-based decision support tool, the diabetes Disease Management Application ( DMA ), developed to improve evidence -based management of type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted a group r and omized controlled trial of 12 intervention and 14 control staff providers and 307 intervention and 291 control patients with type 2 diabetes in a hospital-based internal medicine clinic. Providers were r and omly assigned from May 1998 through April 1999 to have access to the DMA ( intervention ) or not to have access ( control ). The DMA displays interactive patient-specific clinical data, treatment advice, and links to other web-based care re sources. We compared patients in the intervention and control groups for changes in processes and outcomes of care from the year preceding the study through the year of the study by intention-to-treat analysis. RESULTS The DMA was used for 42 % of scheduled patient visits. The number of HbA(1c ) tests obtained per year increased significantly in the intervention group ( + 0.3 tests/year ) compared with the control group ( -0.04 tests/year, P = 0.008 ), as did the number of LDL cholesterol tests ( intervention, + 0.2 tests/year ; control, + 0.01 tests/year ; P = 0.02 ) and the proportions of patients undergoing at least one foot examination per year ( intervention, + 9.8 % ; control, -0.7 % ; P = 0.003 ). Levels of HbA(1c ) decreased by 0.2 in the intervention group and increased by 0.1 in the control group ( P = 0.09 ) ; proportions of patients with LDL cholesterol levels < 130 mg/dl increased by 20.3 % in the intervention group and 10.5 % in the control group ( P = 0.5 ). CONCLUSIONS Web-based patient-specific decision support has the potential to improve evidence -based parameters of diabetes care Impact of automated calls with nurse follow-up on diabetes treatment outcomes in a Department of Veterans Affairs Health Care System: a randomized controlled trial. OBJECTIVE We evaluated automated telephone disease management ( ATDM ) with telephone nurse follow-up as a strategy for improving diabetes treatment processes and outcomes in Department of Veterans Affairs ( VA ) clinics. We also compared the results with those of a prior ATDM trial conducted in a county health care system. RESEARCH DESIGN AND METHODS A total of 272 VA patients with diabetes using hypoglycemic medications were r and omized. During the 1-year study period, intervention patients received biweekly ATDM health assessment and self-care education calls, and a nurse educator followed up with patients based on their ATDM assessment reports. Telephone surveys were used to measure patients\'self-care, symptoms, and satisfaction with care. Outpatient service use was evaluated using electronic data bases and self-reports, and glycemic control was measured by HbA1c and serum glucose testing. RESULTS At 12 months, intervention patients reported more frequent glucose self-monitoring and foot inspections than patients receiving usual care and were more likely to be seen in podiatry and diabetes specialty clinics. Intervention patients also were more likely than control patients to have had a cholesterol test. Among patients with baseline HbA1c levels > or = 8 %, mean end-point values were lower among intervention patients than control patients ( 8.7 vs. 9.2 %, respectively ; P = 0.04 ). Among intervention and control patients with baseline values > or = 9 %, mean end-point values were 9.1 and 10.2 %, respectively ( P = 0.04 ). At follow-up, intervention patients reported fewer symptoms of poor glycemic control than control patients and greater satisfaction with their health care. CONCLUSIONS This intervention improved the quality of VA diabetes care. Intervention effects for most end points replicated findings from the prior county clinic trial, although intervention-control differences in the current study were smaller because of the relatively good self-care and health status among the current study\'s enrollees Research Paper: A Randomized Trial Comparing Telemedicine Case Management with Usual Care in Older, Ethnically Diverse, Medically Underserved Patients with Diabetes Mellitus: 5 Year Results of the IDEATel Study CONTEXT Telemedicine is a promising but largely unproven technology for providing case management services to patients with chronic conditions and lower access to care. OBJECTIVES To examine the effectiveness of a telemedicine intervention to achieve clinical management goals in older, ethnically diverse, medically underserved patients with diabetes. DESIGN, Setting, and Patients A r and omized controlled trial was conducted, comparing telemedicine case management to usual care, with blinded outcome evaluation, in 1,665 Medicare recipients with diabetes, aged > /= 55 years, residing in federally design ated medically underserved areas of New York State. Interventions Home telemedicine unit with nurse case management versus usual care. Main Outcome Measures The primary endpoints assessed over 5 years of follow-up were hemoglobin A1c ( HgbA1c ), low density lipoprotein ( LDL ) cholesterol, and blood pressure levels. RESULTS Intention-to-treat mixed models showed that telemedicine achieved net overall reductions over five years of follow-up in the primary endpoints ( HgbA1c, p = 0.001 ; LDL, p < 0.001 ; systolic and diastolic blood pressure, p = 0.024 ; p < 0.001 ). Estimated differences ( 95 % CI ) in year 5 were 0.29 ( 0.12, 0.46)% for HgbA1c, 3.84 ( -0.08, 7.77 ) mg/dL for LDL cholesterol, and 4.32 ( 1.93, 6.72 ) mm Hg for systolic and 2.64 ( 1.53, 3.74 ) mm Hg for diastolic blood pressure. There were 176 deaths in the intervention group and 169 in the usual care group ( hazard ratio 1.01 [ 0.82, 1.24 ] ). CONCLUSIONS Telemedicine case management result ed in net improvements in HgbA1c, LDL-cholesterol and blood pressure levels over 5 years in medically underserved Medicare beneficiaries. Mortality was not different between the groups, although power was limited. Trial Registration http:// clinical trials.gov Identifier : NCT00271739 The impact of planned care and a diabetes electronic management system on community-based diabetes care: the Mayo Health System Diabetes Translation Project. OBJECTIVE The Mayo Health System Diabetes Translation Project sought to assess models of community-based diabetes care and use of a diabetes electronic management system ( DEMS ). Planned care is a re design ed model of chronic disease care that involves guideline implementation, support of self-management, and use of clinical information systems. RESEARCH DESIGN AND METHODS We studied adult diabetic patients attending three primary care practice sites in Wisconsin and Minnesota. We implemented planned care at all sites and DEMS in the practice of 16 primary care providers. We assessed quality of diabetes care using st and ard indicators for 200 patients r and omly selected from each site at baseline and at 24 months of implementation. We used multivariable analyses to estimate the association between planned care and DEMS and each quality indicator. RESULTS Planned care was associated with improvements in measurement of HbA(1c ) ( odds ratio 7.0 [ 95 % CI 4.2 - 11.6 ] ), HDL cholesterol ( 5.6 [ 4.1 - 7.5 ] ), and microalbuminuria ( 5.3 [ 3.5 - 8.0 ] ), as well as the provision of tobacco advice ( 6.9 [ 4.7 - 10.1 ] ), among other performance measures. DEMS use was associated with improvements in all indicators, including microalbuminuria ( 3.2 [ 1.9 - 5.2 ] ), retinal examination ( 2.4 [ 1.5 - 3.9 ] ), foot examinations ( 2.3 [ 1.2 - 4.4 ] ), and self-management support ( 2.6 [ 1.7 - 3.8 ] ). Although planned care was associated with improvements in metabolic control, we observed no additional metabolic benefit when providers used DEMS. CONCLUSIONS Planned care was associated with improved performance and metabolic outcomes in primary care. DEMS use augmented the impact of planned care on performance outcomes but not on metabolic outcomes. Optimal identification of the best translation of evidence to diabetes practice will require longer follow-up or new care-delivery models The D-Net diabetes self-management program: long-term implementation, outcomes, and generalization results. BACKGROUND A prerequisite to translating research findings into practice is information on consistency of implementation, maintenance of results, and generalization of effects. This follow-up report is one of the few experimental studies to provide such information on Internet-based health education. METHODS We present follow-up data 10 months following r and omization on the " Diabetes Network ( D-Net ) " Internet-based self-management project, a r and omized trial evaluating the incremental effects of adding ( 1 ) tailored self-management training or ( 2 ) peer support components to a basic Internet-based, information-focused comparison intervention. Participants were 320 adult type 2 diabetes patients from participating primary care offices, mean age 59 ( SD = 9.2 ), who were relatively novice Internet users. RESULTS All intervention components were consistently implemented by staff, but participant website usage decreased over time. All conditions were significantly improved from baseline on behavioral, psychosocial, and some biological outcomes ; and there were few differences between conditions. Results were robust across on-line coaches, patient characteristics, and participating clinics. CONCLUSIONS The basic D-Net intervention was implemented well and improvements were observed across a variety of patients, interventionists, and clinics. There were, however, difficulties in maintaining usage over time and additions of tailored self-management and peer support components generally did not significantly improve results Chronic care model and shared care in diabetes: randomized trial of an electronic decision support system. OBJECTIVE To assess the effect of a specialist telemedicine intervention for improving diabetes care using the chronic care model ( CCM ). PARTICIPANTS AND METHODS As part of the CCM, 97 primary care physicians at 6 primary care practice s in Rochester, MN, referred 639 patients to an on-site diabetes educator between July 1, 2001, and December 31, 2003. On first referral, physicians were central ly r and omized to receive a telemedicine intervention ( specialty advice and evidence -based messages regarding medication management for cardiovascular risk ) or no intervention, keeping outcome assessors and data analysts blinded to group assignment. After each subsequent clinical encounter, endocrinologists review ed an abstract from the patient\'s electronic medical record and provided management recommendations and supporting evidence to intervention physicians via e-mail. Control physicians received e-mail with periodic generic information about cardiovascular risk reduction in diabetes. Outcome measures included diabetes care processes ( diabetes test completion ), outcomes ( metabolic and cardiovascular risk factors, estimated coronary artery disease risk ), and patient costs ( payer perspective ). RESULTS During the intervention, 951 ( 70 % ) of the 1361 endocrinology review s detected performance gaps and result ed in a message ; primary care physicians reported using 49 % of messages in patient care. With a mean of 21 months\'follow-up, the intervention, compared with control, did not significantly enhance metabolic outcomes or reduce estimated risk of coronary artery disease ( adjusted mean difference, -1 % ; 95 % confidence interval, -19 % to 17 % ). The intervention group incurred lower costs ( P=.02 ) but not in diabetes-related costs. CONCLUSION Specialty telemedicine did not significantly enhance the value of CCM in primary care The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long‐Term Complications in Insulin‐Dependent Diabetes Mellitus BACKGROUND Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus ( IDDM ). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. METHODS A total of 1441 patients with IDDM--726 with no retinopathy at base line ( the primary -prevention cohort ) and 715 with mild retinopathy ( the secondary -intervention cohort ) were r and omly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. RESULTS In the primary -prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent ( 95 percent confidence interval, 62 to 85 percent ), as compared with conventional therapy. In the secondary -intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent ( 95 percent confidence interval, 39 to 66 percent ) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent ( 95 percent confidence interval, 14 to 67 percent ). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria ( urinary albumin excretion of > or = 40 mg per 24 hours ) by 39 percent ( 95 percent confidence interval, 21 to 52 percent ), that of albuminuria ( urinary albumin excretion of > or = 300 mg per 24 hours ) by 54 percent ( 95 percent confidence interval 19 to 74 percent ), and that of clinical neuropathy by 60 percent ( 95 percent confidence interval, 38 to 74 percent ). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. CONCLUSIONS Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM Individualized electronic decision support and reminders to improve diabetes care in the community: COMPETE II randomized trial Background : Diabetes mellitus is a complex disease with serious complications. Electronic decision support, providing information that is shared and discussed by both patient and physician, encourages timely interventions and may improve the management of this chronic disease. However, it has rarely been tested in community-based primary care. Methods : In this pragmatic r and omized trial, we r and omly assigned adult primary care patients with type 2 diabetes to receive the intervention or usual care. The intervention involved shared access by the primary care provider and the patient to a Web-based, colour-coded diabetes tracker, which provided sequential monitoring values for 13 diabetes risk factors, their respective targets and brief, prioritized messages of advice. The primary outcome measure was a process composite score. Secondary outcomes included clinical composite scores, quality of life, continuity of care and usability. The outcome assessors were blinded to each patient ’s intervention status. Results : We recruited sequentially 46 primary care providers and then 511 of their patients ( mean age 60.7 [ st and ard deviation 12.5 ] years ). Mean follow-up was 5.9 months. The process composite score was significantly better for patients in the intervention group than for control patients ( difference 1.27, 95 % confidence interval [ CI ] 0.79–1.75, p < 0.001 ) ; 61.7 % ( 156/253 ) of patients in the intervention group, compared with 42.6 % ( 110/258 ) of control patients, showed improvement ( difference 19.1 %, p < 0.001 ). The clinical composite score also had significantly more variables with improvement for the intervention group ( 0.59, 95 % CI 0.09–1.10, p = 0.02 ), including significantly greater declines in blood pressure ( −3.95 mm Hg systolic and −2.38 mm Hg diastolic ) and glycated hemoglobin ( −0.2 % ). Patients in the intervention group reported greater satisfaction with their diabetes care. Interpretation : A shared electronic decision-support system to support the primary care of diabetes improved the process of care and some clinical markers of the quality of diabetes care. ( Clinical Trials.gov trial register no. NCT00813085. The effects of a web-based intervention on the physical outcomes associated with diabetes among adults age 60 and older: a randomized trial. BACKGROUND The emergence of the World Wide Web in the last decade has made it feasible for the Internet to be a vehicle for chronic disease management. METHODS A r and omized controlled trial ( n = 62 ) testing the effects of a 6-month web-based intervention plus usual care, compared with usual care alone, among adults 60 years of age and older with diabetes. The outcomes were hemoglobin A1c ( HbA1c ), blood pressure, weight, cholesterol, and high-density lipoprotein ( HDL ) levels. RESULTS A multivariate analysis of covariance controlling for all baseline outcome variables, age, gender, and number of years with diabetes showed significant ( P = 0.001 ) reductions in HbA1c, weight, and cholesterol level and significant improvement in HDL levels in the intervention versus the control group. CONCLUSIONS Findings show a web-based intervention was effective in improving HbA1c, weight, cholesterol, and HDL levels at a 6-month follow-up. Future research is needed to investigate the long-term effectiveness of web-based interventions Use of a Registry-generated Audit, Feedback, and Patient Reminder Intervention in an Internal Medicine Resident Clinic—A Randomized Trial BACKGROUND Disease registries, audit and feedback, and clinical reminders have been reported to improve care processes. OBJECTIVE To assess the effects of a registry-generated audit, feedback, and patient reminder intervention on diabetes care. DESIGN R and omized controlled trial conducted in a resident continuity clinic during the 2003–2004 academic year. PARTICIPANTS Seventy-eight categorical Internal Medicine residents caring for 483 diabetic patients participated. Residents r and omized to the intervention ( n = 39 ) received instruction on diabetes registry use ; quarterly performance audit, feedback, and written reports identifying patients needing care ; and had letters sent quarterly to patients needing hemoglobin A1c or cholesterol testing. Residents r and omized to the control group ( n = 39 ) received usual clinic education. MEASUREMENTS Hemoglobin A1c and lipid monitoring, and the achievement of intermediate clinical outcomes ( hemoglobin A1c < 7.0 %, LDL cholesterol < 100 mg/dL, and blood pressure < 130/85 mmHg ) were assessed. RESULTS Patients cared for by residents in the intervention group had higher adherence to guideline recommendations for hemoglobin A1c testing ( 61.5 % vs 48.1 %, p =.01 ) and LDL testing ( 75.8 % vs 64.1 %, p =.02 ). Intermediate clinical outcomes were not different between groups. CONCLUSIONS Use of a registry-generated audit, feedback, and patient reminder intervention in a resident continuity clinic modestly improved diabetes care processes, but did not influence intermediate clinical outcomes Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study Abstract Objective : To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Design : Prospect i ve observational study. Setting : 23 hospital based clinics in Engl and, Scotl and, and Northern Irel and. Participants : 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether r and omised or not to treatment, were included in analyses of incidence ; of these, 3642 were included in analyses of relative risk. Outcome measures : Primary predefined aggregate clinical outcomes : any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes : myocardial infa rct ion, stroke, amputation ( including death from peripheral vascular disease ), and microvascular disease ( predominantly retinal photo-coagulation ). Single end points : non-fatal heart failure and cataract extraction. Risk reduction associated with a 1 % reduction in up date d mean HbA1c adjusted for possible confounders at diagnosis of diabetes. Results : The incidence of clinical complications was significantly associated with glycaemia. Each 1 % reduction in up date d mean HbA1c was associated with reductions in risk of 21 % for any end point related to diabetes ( 95 % confidence interval 17 % to 24 %, P<0.0001 ), 21 % for deaths related to diabetes ( 15 % to 27 %, P<0.0001 ), 14 % for myocardial infa rct ion ( 8 % to 21 %, P<0.0001 ), and 37 % for microvascular complications ( 33 % to 41 %, P<0.0001 ). No threshold of risk was observed for any end point. Conclusions : In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range ( < 6.0 % )', "IMPORTANCE OF THE FIELD Cobalamin ( vitamin B12 ) deficiency is particularly common in the elderly ( > 15 % ). Management of cobalamin deficiency with cobalamin injections is well codified at present, but new routes of cobalamin administration ( oral and nasal ) are being studied, especially oral cobalamin therapy for food-cobalamin malabsorption. AREAS COVERED IN THIS REVIEW The objective of this review is to evaluate the efficacy of oral cobalamin treatment in elderly patients. Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption. BACKGROUND The st and ard treatment for cobalamin ( vitamin B(12 ) ) deficiency involves regular intramuscular cobalamin injection. It has been suggested that oral cobalamin therapy may be effective for treating patients who have food-cobalamin malabsorption. SUBJECTS AND METHODS We prospect ively studied 10 patients with cobalamin deficiency and well-established food-cobalamin malabsorption who received 3000 microg or 5000 microg of oral crystalline cyanocobalamin once a week for at least 3 months. Complete blood counts and serum cobalamin, homocysteine, and folate levels were determined at baseline and after 3 months of treatment. Patients were reexamined after 6 months. RESULTS After 3 months of treatment, all patients had increased hemoglobin levels ( mean increase, 1.9 g/dL ; 95 % confidence interval : 0.9 to 3.9 g/dL;P < 0.01 compared with baseline ) and decreased erythrocyte cell volume ( mean decrease, 7.8 fL ; 95 % confidence interval : 0.9 to 16.5 fL;P<0.001 ). However, 2 patients had only minor, if any, responses. Serum cobalamin levels were increased in all 8 patients in whom it was measured. CONCLUSION Our findings suggest that moderate doses of crystalline cyanocobalamin given orally may be an effective treatment for food-cobalamin malabsorption Nasal absorption of hydroxocobalamin in healthy elderly adults. AIMS To investigate the nasal absorption of hydroxocobalamin in 10 healthy elderly adults. METHODS In a cross-over study, blood sample s were collected before administration of the drug and after 10, 20, 30, 40, 60, 120, 180 and 240 min. The plasma cobalamin concentration was determined by competitive radioisotope binding technique. RESULTS The maximal plasma cobalamin concentration ( Cmax ) after nasal administration of 750 microg hydroxocobalamin was 1900 + /- 900 pmol l(-1 ) ( mean + /- s.d. ). The maximal plasma cobalamin concentration was reached in 35 + /- 13 min ( t[max ] ). The Cmax after nasal administration of 1500 microg hydroxocobalamin was 3500 + /- 2500 pmol l(-1 ) with a t(max ) of 28 + /- 16 min. Both the AUC(0,240 min ) and AUC(0,00 ) increased significantly with an increase of the dose from 750 microg to 1500 microg ( P = 0.037 and P = 0.028, respectively ). The nasal spray was well tolerated. No signs of irritation or local sensitivity were noted. CONCLUSIONS The nasal absorption of hydroxocobalamin in healthy elderly adults is rapid, high and well tolerated Effective treatment of cobalamin deficiency with oral cobalamin. Because cobalamin deficiency is routinely treated with parenteral cobalamin, we investigated the efficacy of oral therapy. We r and omly assigned 38 newly diagnosed cobalamin deficient patients to receive cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90 or 2 mg orally on a daily basis for 120 days. Therapeutic effectiveness was evaluated by measuring hematologic and neurologic improvement and changes in serum levels of cobalamin ( normal, 200 to 900 pg/mL ) methylmalonic acid ( normal, 73 to 271 nmol/L ), and homocysteine ( normal, 5.1 to 13.9 micromol/L ). Five patients were subsequently found to have folate deficiency, which left 18 evaluable patients in the oral group and 15 in the parenteral group. Correction of hematologic and neurologic abnormalities was prompt and indistinguishable between the 2 groups. The mean pretreatment values for serum cobalamin, methylmalonic acid, and homocysteine were, respectively, 93 pg/mL, 3,850 nmol/L, and 37. 2 micromol/L in the oral group and 95 pg/mL, 3,630 nmol/L, and 40.0 micromol/L in the parenteral therapy group. After 4 months of therapy, the respective mean values were 1,005 pg/mL, 169 nmol/L, and 10.6 micromol/L in the oral group and 325 pg/mL, 265 nmol/L, and 12.2 micromol/L in the parenteral group. The higher serum cobalamin and lower serum methylmalonic acid levels at 4 months posttreatment in the oral group versus the parenteral group were significant, with P <.0005 and P <.05, respectively. In cobalamin deficiency, 2 mg of cyanocobalamin administered orally on a daily basis was as effective as 1 mg administered intramuscularly on a monthly basis and may be superior Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. BACKGROUND Cobalamin ( vitamin B12 ) deficiency, the most common cause of megaloblastic anemia, is treated with intramuscular ( IM ) cobalamin. It has been suggested by some investigators that oral ( p.o. ) cobalamin treatment may be as effective in the treatment of this condition, with the advantages of ease of administration and lower cost. OBJECTIVE This study assessed the effects and cost of p.o. versus i.m. cobalamin treatment in patients with megaloblastic anemia due to cobalamin deficiency. METHODS This was a 90-day, prospect i ve, r and omized, open-label study conducted at the Division of Hematology, Department of Internal Medicine, Adnan Menderes University Research and Practice Hospital ( Aydin, Turkey ). Patients aged > or = 16 years with megaloblastic anemia due to cobalamin deficiency were r and omized to receive 1000-microg cobalamin p.o. once daily for 10 days ( p.o. group ) or 1000-microg cobalamin i.m. once daily for 10 days ( i.m. group ). After 10 days, both treatments were administered once a week for 4 weeks, and after that, once a month for life. Patients were assessed for the presence of reticulocytosis between treatment days 5 and 10 until it was detected. Therapeutic effectiveness was assessed by measuring hematologic parameters on days 0, 10, 30, and 90 and serum vitamin B12 concentration on days 0 and 90. The Mini-Mental State Examination was used before and after the B12 therapy for cognitive function assessment and 125-Hz diapozone was used for vibration threshold testing. Neurologic sensory assessment, including soft-touch and pinprick examinations, was used to identify neuropathy at baseline and study end. Tolerability was assessed using laboratory tests and patient interview. Cost was assessed using the cost of the study drug and of the injection. RESULTS Sixty patients completed the study 26 in the p.o. group ( 16 men, 10 women ; mean [ SD ] age, 60 [ 15 ] years ) and 34 in the i.m. group ( 17 men, 17 women ; mean [ SD ] age, 64 [ 10 ] years ). Reticulocytosis was observed in all patients. In the p.o. group, at days 30 and 90, all hematologic parameters changed significantly versus day 0 ( mean hemoglobin levels increased [ both P<0.001 ] ; mean corpuscular volume decreased [ both P<0.001 ] ; mean white blood cell count increased [ day 30, P<0.01 ; day 90, P<0.001 ] ; and mean platelet count increased [ both P<0.001 ] ). The mean serum vitamin B12 concentration increased significantly from day 0 to 90 ( P<0.001 ). These hematologic parameters and the recovery patterns were similar between the 2 groups. Neurologic findings included sensitive peripheral neuropathy in 9 patients ( 15.0 % ), alteration of cognitive function ( loss of memory, impaired concentration ) in 7 patients ( 11.7 % ), and loss of sense of vibration in 5 patients ( 8.3 % ). Neurologic improvement was detected in 7 of 9 patients ( 77.8 % ) in the p.o. group and 9 of 12 patients ( 75.0 % ) in the i.m. group at day 30. CONCLUSIONS In this study of patients with megaloblastic anemia due to cobalamin deficiency, p.o. cobalamin treatment was as effective as i.m. cobalamin treatment. P.o. treatment also was better tolerated and less expensive compared with IM treatment. However, because of the small sample size and the short term of this study, further long-term studies are needed to determine the efficacy of p.o. cobalamin treatment Oral cobalamin remains medicine's best kept secret. A cross-sectional survey was conducted in order to describe the use of oral cobalamin among geriatricians, hematologists, and general practitioners, and to explore factors related to its use. The study population consisted of all geriatricians ( n = 138 ) and hematologists ( n = 317 ) listed in the Canadian Medical Directory plus a r and om sample of 307 general practitioners. The overall response rate was 40 %. Intramuscular and oral cobalamin was prescribed by 76 and 32 % of the respondents, respectively. Twenty seven percent reported using both oral and intramuscular cobalamin and 6 % reported using only oral cobalamin. Only 25 % of respondents indicated they were aware of a RCT demonstrating the efficacy of oral cobalamin prior to reading a synopsis of the study in the survey. After multivariate adjustment, only the belief that oral cobalamin was effective and certainty about who carried oral preparations remained independently associated with oral cobalamin use. Oral cobalamin has been shown to be an efficacious, cost efficient and safe method of treating cobalamin deficiency. Nonetheless, it is not used by the majority of physicians treating this condition. Strategies to promote the use of oral cobalamin should be directed at educating physicians of its efficacy and providing them with prescribing information on where it can be purchased Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. BACKGROUND Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B(12 ) deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain. METHODS We conducted a r and omized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B(12 ) deficiency in older people with mild vitamin B(12 ) deficiency, defined as a serum vitamin B(12 ) level of 100 to 300 pmol/L ( 135 - 406 pg/mL ) and a methylmalonic acid level of 0.26 mumol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 mug of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B(12 ) deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80 % to 90 % of the estimated maximal reduction in the plasma methylmalonic acid concentration. RESULTS Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 mug was associated with mean reductions in plasma methylmalonic acid concentrations of 16 %, 16 %, 23 %, 33 %, and 33 %, respectively. Daily doses of 647 to 1032 mug of cyanocobalamin were associated with 80 % to 90 % of the estimated maximum reduction in the plasma methylmalonic acid concentration. CONCLUSION The lowest dose of oral cyanocobalamin required to normalize mild vitamin B(12 ) deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 mug daily Efficacy of short-term oral cobalamin therapy for the treatment of cobalamin deficiencies related to food-cobalamin malabsorption: a study of 30 patients. BACKGROUND It has been suggested that oral cobalamin ( vitamin ( B12 ) ) therapy may be an effective therapy for treating cobalamin deficiencies related to food-cobalamin malabsorption. However, the duration of this treatment was not determined. PATIENTS AND METHOD In an open-label, nonplacebo study, we studied 30 patients with established cobalamin deficiency related to food-cobalamin malabsorption, who received between 250 and 1000 microg of oral crystalline cyanocobalamin per day for at least 1 month. ENDPOINTS Blood counts, serum cobalamin and homocysteine levels were determined at baseline and during the first month of treatment. RESULTS During the first month of treatment, 87 % of the patients normalized their serum cobalamin levels ; 100 % increased their serum cobalamin levels ( mean increase, + 167 pg/dl ; P < 0.001 compared with baseline ) ; 100 % had evidence of medullary regeneration ; 100 % corrected their initial macrocytosis ; and 54 % corrected their anemia. All patients had increased hemoglobin levels ( mean increase, + 0.6 g/dl ) and reticulocyte counts ( mean increase, + 35 x 10(6)/l ) and decreased erythrocyte cell volume ( mean decrease, 3 fl ; all P < 0.05 ). CONCLUSION Our findings suggest that crystalline cyanocobalamin, 250 - 1000 microg/day, given orally for 1 month, may be an effective treatment for cobalamin deficiencies not related to pernicious anemia Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients. BACKGROUND & AIMS Patients with previous stomach and terminal ileum resections are often treated with intramuscular vitamin B12 injections. Disadvantages are, on a worldwide scale, the frequent need for medical personnel to administer injections and the sometimes painful way of application. This study was design ed to investigate the feasibility of intranasal hydroxocobalamin suppletion in cobalamin-deficient patients and to assess whether intranasal hydroxocobalamin application could be an alternative for intramuscular injection. METHODS Six patients with plasma cobalamin concentrations of < 200 ng/L were recruited. A dose of 1500 micrograms hydroxocobalamin was applied intranasally at days 0, 14, and 21. Plasma cobalamin concentrations were determined 1 hour after hydroxocobalamin application and on days 0, 7, 21, 28, and 35. RESULTS All patients showed substantial increase of cobalamin concentrations 1 hour after intranasal application. In these 6 patients, there was an eightfold increase of mean baseline cobalamin concentrations. All patients showed a sustained increase of baseline cobalamin concentrations 1 week after prior intranasal application of hydroxocobalamin. No side effects were noted. CONCLUSIONS Intranasal application of hydroxocobalamin in cobalamin-deficient patients results in fast nasal absorption and leads to sustained increase of baseline cobalamin concentrations Hematological response to short-term oral cyanocobalamin therapy for the treatment of cobalamin deficiencies in elderly patients. OBJECTIVES The aim of this trial was to demonstrate the efficacy of one month of oral cobalamin ( vitamin B12 ) therapy in elderly patients with cobalamin deficiency related to food-cobalamin malabsorption ( FCM ). PATIENTS AND METHOD Twenty elderly patients ( mean age : 78+/-17 years ) with established cobalamin deficiency related to FCM were included in an open-label, non-r and omized, non-placebo trial. They were treated with a maximum of 1,000 microgram per day of oral crystalline cyanocobalamin for at least 1 month. Serum cobalamin levels ( primary endpoint ), blood count abnormalities and reticulocytes count ( secondary endpoints ) were determined at baseline and during the first month of treatment. RESULTS 85 % of the patients normalized their serum cobalamin levels with a mean increase of+167 pg/ml ( p<0.001 compared with baseline ). 100 % of the patients corrected their initial macrocytosis and 25 % their anemia ; 100 % of the patients had medullar regeneration with a mean increase of reticulocytes count of 32+/-11.3 x 106/l ( p=0.03 compared with baseline ). CONCLUSIONS Our findings support the view that one month of oral crystalline cyanocobalamin is effective to correct serum vitamin B12 levels and to obtain hematological responses in elderly patients with cobalamin deficiency related to FCM", "BACKGROUND Necrotizing enterocolitis ( NEC ) is the most common emergency involving the gastrointestinal tract occurring in the neonatal period. There have been published reports that suggest that oral immunoglobulins (Ig)A and IgG produce an immunoprotective effect in the gastrointestinal mucosa. OBJECTIVES To determine the effect of oral immunoglobulin on the incidence of necrotizing enterocolitis and other complications in preterm or low birth weight ( or both ) neonates. GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). In the GRADE approach, r and omized trials start as high- quality evidence and observational studies as low- quality evidence, but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias. Well-established limitations of r and omized trials include failure to conceal allocation, failure to blind, loss to follow-up, and failure to appropriately consider the intention-to-treat principle. More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results. Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance. Risk of bias may vary across outcomes ( e.g., loss to follow-up may be far less for all-cause mortality than for quality of life ), a consideration that many systematic review s ignore. In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies. Rather, for any individual outcome, when there are some studies with a high risk, and some with a low risk of bias, they should consider including only the studies with a lower risk of bias Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial BACKGROUND AND OBJECTIVE : Late-onset sepsis frequently complicates prematurity, contributing to morbidity and mortality. Probiotics may reduce mortality and necrotizing enterocolitis ( NEC ) in preterm infants, with unclear effect on late-onset sepsis. This study aim ed to determine the effect of administering a specific combination of probiotics to very preterm infants on culture-proven late-onset sepsis. METHODS : A prospect i ve multicenter, double-blinded, placebo-controlled, r and omized trial compared daily administration of a probiotic combination ( Bifidobacterium infantis, Streptococcus thermophilus, and Bifidobacterium lactis, containing 1 × 109 total organisms ) with placebo ( maltodextrin ) in infants born before 32 completed weeks ’ gestation weighing < 1500 g. The primary outcome was at least 1 episode of definite late-onset sepsis. RESULTS : Between October 2007 and November 2011, 1099 very preterm infants from Australia and New Zeal and were r and omized. Rates of definite late-onset sepsis ( 16.2 % ), NEC of Bell stage 2 or more ( 4.4 % ), and mortality ( 5.1 % ) were low in controls, with high breast milk feeding rates ( 96.9 % ). No significant difference in definite late-onset sepsis or all-cause mortality was found, but this probiotic combination reduced NEC of Bell stage 2 or more ( 2.0 % versus 4.4 % ; relative risk 0.46, 95 % confidence interval 0.23 to 0.93, P =.03 ; number needed to treat 43, 95 % confidence interval 23 to 333 ). CONCLUSIONS : The probiotics B infantis, S thermophilus, and B lactis significantly reduced NEC of Bell stage 2 or more in very preterm infants, but not definite late-onset sepsis or mortality. Treatment with this combination of probiotics appears to be safe Oral gentamicin therapy in the prevention of neonatal necrotizing enterocolitis. A controlled double-blind trial. The value of prophylactic oral gentamicin sulfate therapy in the prevention of necrotizing enterocolitis ( NEC ) was evaluated in a group of 42 high-risk neonates over a four-month period in a r and omized, double-blind controlled trial. Twenty babies in the treatment group received 2.5 mg/kg of gentamicin sulfate every six hours for one week after birth, and 22 babies received dextrose- and -water placebo in an equivalently small volume. None of the 20 gentamicin-treated babies developed NEC. Four of the control babies did. Two of these babies died, and their diagnosis was pathologically confirmed. This difference in the incidence of NEC between the treatment and control group was significant at the.05 level. These results support the prophylactic use of orally given gentamicin for selected babies at high risk for NEC, particularly those born prematurely and those who have a history of perinatal asphyxia or umbilical artery catheterization or both. Continued surveillance for changes in antimicrobial sensitivity patterns is recommended Prevention of Neonatal Necrotizing Enterocolitis Small premature infants are often hypochlorhydric, and frequently their stomachs are colonized by enteric, gram-negative bacteria. We tested a hypothesis that gastric pH affected the colonization of the stomach with enteric bacteria and that this colonization was causally related to the risk or severity of necrotizing enterocolitis. A prospect i ve, double-blind study was conducted that compared a group of infants supplemented with 0.01–0.02 ml of 1 N HCl/ml of milk to a group with a similar supplement of water. Gastric pH, gastric enteric bacteria counts, and the incidence and severity of necrotizing enterocolitis were monitored. The median gastric pH of the HCl-supplemented group was lower ( 3.0 ) than controls ( 4.0 ) throughout the study ( p < 0.001 ). The gastric enteric bacterial colonization rate and the quantitative bacterial counts were strongly correlated with gastric pH over 4 ( p < 0.001 ). Somatic growth rates in infants in the HCl-supplemented group were equal to, or exceeded, those in the control group. There was 1 case of necrotizing entero-colitis among the 34 infants in the HCl-supplemented group and 8 cases among the 34 in the control group ( p = 0.02 ). It appears that acidifying the feedings of small premature infants to a pH low enough to inhibit bacterial proliferation in the stomach significantly lowers the risk of necrotizing enterocolitis Prevention of necrotizing enterocolitis in low-birth-weight infants by IgA-IgG feeding. In a r and omized clinical trial, we evaluated the efficacy of an oral immunoglobulin preparation ( 73 percent IgA and 26 percent IgG ) in reducing the incidence of necrotizing enterocolitis in infants of low birth weight for whom breast milk from their mothers was not available. A total of 434 infants weighing between 800 and 2000 g were eligible for entry in the study. Of these, 255 were withdrawn - 234 during the first week of the study because breast milk from their mothers became available ( 123 in the treatment group and 111 in the control group ), and 21 because of violations of protocol or because breast milk became available after the first week. The duration of follow-up was 28 days. Among the infants for whom breast milk did not become available during the study, there were no cases of necrotizing enterocolitis among the 88 receiving oral IgA-IgG, as compared with six cases among the 91 control infants ( P = 0.0143 ). Of the infants withdrawn from the study, two assigned to the control group had necrotizing enterocolitis. We conclude that the oral administration of IgA-IgG may prevent the development of necrotizing enterocolitis in low-birth-weight infants Mortality of necrotizing enterocolitis expressed by birth weight categories. PURPOSE Low birth weight is the most important risk factor for developing necrotizing enterocolitis ( NEC ). We aim ed to establish birth weight-based benchmarks for in-hospital mortality in neonates with NEC. METHODS Five hundred eleven centers belonging to the Vermont Oxford Network prospect ively evaluated 71,808 neonates with birth weight of 501 to 1500 g between January 2005 and December 2006. The primary outcome variable was in-hospital mortality. RESULTS Birth weight was divided into 4 categories by 250-g increments. The NEC risk ( P <.001 ) and mortality ( P <.001 ) decreased with higher birth weight category. Necrotizing enterocolitis was associated with a significant odds ratio for death for each category ( P <.001 ). Across groups, the odds ratio for NEC mortality increased with higher birth weight category ( category 1 = 1.6 vs category 4 = 9.9 ; P <.001 ). CONCLUSION The in-hospital mortality rate of neonates with NEC remains high and is significantly related to birth weight category. Although the risk and absolute mortality of NEC decrease with higher birth weight, the odds ratios indicate that NEC has a relatively greater impact upon mortality at higher birth weight. These data afford birth weight-based mortality benchmarks that may be useful in assessing single center NEC outcomes and facilitating comparisons between centers Breast milk and neonatal necrotising enterocolitis In a prospect i ve multicentre study on 926 preterm infants formally assigned to their early diet, necrotising enterocolitis developed in 51 ( 5.5 % ). Mortality was 26 % in stringently confirmed cases. In exclusively formula-fed babies confirmed disease was 6 - 10 times more common than in those fed breast milk alone and 3 times more common than in those who received formula plus breast milk. Pasteurised donor milk seemed to be as protective as raw maternal milk. Among babies born at more than 30 weeks'gestation confirmed necrotising enterocolitis was rare in those whose diet included breast milk ; it was 20 times more common in those fed formula only. Other risk factors included very low gestational age, respiratory disease, umbilical artery catheterisation, and polycythaemia. In formula-fed but not breast-milk-fed infants, delayed enteral feeding was associated with a lower frequency of necrotising enterocolitis. With the fall in the use of breast milk in British neonatal units, exclusive formula feeding could account for an estimated 500 extra cases of necrotising enterocolitis each year. About 100 of these infants would die Prevention of necrotizing enterocolitis in neonates at risk by oral administration of monomeric IgG. Necrotizing enterocolitis ( NEC ) represents one of the major causes of morbidity in low-birth-weight ( LBW ) preterm infants. This r and omized clinical trial evaluated the efficacy of an oral immunoglobulin preparation ( containing monomeric IgG in a concentration of 90 % ) in reducing the incidence of NEC in infants of LBW for whom maternal breast milk was not available. One hundred and thirty-two formula-fed newborns with a birth weight less than or equal to 1,500 g or a gestational age less than or equal to 34 weeks were r and omly studied. Five hundred mg of IgG pro die, subdivided into 5 doses, were given orally to the test group of 65 neonates during the first 2 weeks of life. Although the number of infants included in this group is limited, the results of this study are encouraging : during the first 15 days after birth, none of the subjects developed NEC, while 4 cases were confirmed in the untreated control group. It, therefore, seems possible that oral monomeric IgG administration may prevent the development of NEC in LBW infants Necrotizing enterocolitis prophylaxis: oral antibiotics and lyophilized enterobacteria vs oral immunoglobulins We conducted a prospect i ve r and omized trial to compare the efficacy of oral gentamicin versus oral IgA‐IgG for the prophylaxis of necrotizing enterocolitis ( NEC ) ; 200 newborns considered at high risk for NEC were assigned to group A ( oral IgA‐IgG, n= 100 ) or group B ( oral Gentamicin, n= 100 ). NEC was diagnosed in 13 cases in group A and in 1 case in group B between the 3rd and 16th days of life. Surgical treatment was necessary in 3 cases ( 2 in group A ). All infants survived. We conclude that oral gentamicin is more effective than oral IgA‐IgG in the prevention of NEC in infants at high risk Oral Probiotics Reduce the Incidence and Severity of Necrotizing Enterocolitis in Very Low Birth Weight Infants Objective. We evaluated the efficacy of probiotics in reducing the incidence and severity of necrotizing enterocolitis ( NEC ) in very low birth weight ( VLBW ) infants. Patients and Methods. A prospect i ve, masked, r and omized control trial was conducted to evaluate the beneficial effects of probiotics in reducing the incidence and severity of NEC among VLBW ( < 1500 g ) infants. VLBW infants who started to fed enterally and survived beyond the seventh day after birth were eligible for the trial. They were r and omized into 2 groups after parental informed consents were obtained. The infants in the study group were fed with Infloran ( Lactobacillus acidophilus and Bifidobacterium infantis ) with breast milk twice daily until discharged. Infants in the control group were fed with breast milk alone. The clinicians caring for the infants were blinded to the group assignment. The primary outcome was death or NEC ( ≥ stage 2 ). Results. Three hundred sixty-seven infants were enrolled : 180 in the study group and 187 in the control group. The demographic and clinical variables were similar in both groups. The incidence of death or NEC ( ≥ stage 2 ) was significantly lower in the study group ( 9 of 180 vs 24 of 187 ). The incidence of NEC ( ≥ stage 2 ) was also significantly lower in the study when compared with the control group ( 2 of 180 vs 10 of 187 ). There were 6 cases of severe NEC ( Bell stage 3 ) in the control group and none in the study group. None of the positive blood culture grew Lactobacillus or Bifidobacterium species. Conclusion. Infloran as probiotics fed enterally with breast milk reduces the incidence and severity of NEC in VLBW infants Enteral human IgG for prevention of necrotising enterocolitis: a placebo-controlled, randomised trial BACKGROUND Neonatal necrotising enterocolitis is a serious, commonly fatal disease in premature neonates. Although feeding with expressed breast milk and other good nursery practice s are partly protective, preventive measures are needed. Treating neonates enterally with a mixture of human IgA and IgG, prepared from donated blood, has been cl aim ed to protect against necrotising enterocolitis. However, no IgA preparation is available in Australia. Our aim, therefore, was to identify whether or not enteral IgG could prevent the disorder. METHODS We did a multicentre, double-blind, placebo- controlled trial. We r and omly assigned 768 infants to receive human IgG 1200 mg/kg daily, and 761 to receive placebo, for up to 28 days. Treatment began at the same time as enteral feeding. The primary outcome measure was the proportion of infants who developed definite necrotising enterocolitis during the trial, and any deaths that result ed from the disorder in the treatment and placebo groups. Analysis was on an intention-to-treat basis. FINDINGS 43 infants developed definite necrotising enterocolitis in the IgG group, ten of whom died. In the placebo group, 41 infants contracted the disorder and six died ( p=0.47 ). 25 infants on IgG and 36 on placebo had suspect necrotising enterocolitis ( p=0.14 ). INTERPRETATION Supplementation of enteral feeds with human IgG does not reduce necrotising enterocolitis", 'Summary A systematic review was conducted to evaluate evidence concerning the effect of non-drug interventions by healthcare professionals on community-dwelling postmenopausal osteoporotic women. Evidence available indicates that such interventions are effective in improving the quality of life, medication compliance, and calcium intake, but effect on other outcomes is less conclusive. Introduction The purpose of this study is to conduct a systematic review to evaluate evidence concerning the effect of non-drug interventions by healthcare professionals on community-dwelling postmenopausal osteoporotic women. Positive Effects of Physiotherapy on Chronic Pain and Performance in Osteoporosis Abstract : The aim of this placebo-controlled, r and omized, single-masked study was to establish the effects of a 10-week ambulatory exercise programme for osteoporotic patients on pain, use of analgesics, functional status, quality of life, balance and muscle strength. Fifty-three ambulatory postmenopausal women with at least one spinal crush fracture and pains within the last 3 years were r and omized for physiotherapeutic training twice a week for 10 weeks or no training. The training included general training of balance and muscle strength, with stabilization of the lumbar spine. The participants were tested at baseline, week 5 and week 10 with a balance test, muscle strength test and question naires on pain, use of analgesics, functional status and quality of life. Twelve weeks after the supervised training had finished ( week 22 ) they answered the same question naires. The study groups were comparable at baseline. The training group had a significant reduction in use of analgesics ( p= 0.02 ) and pain level ( p= 0.01 ) during the training period. Distribution of functional score improved ; the improvement was reduced at week 22. Quality of life score improved significantly throughout the study ( p= 0.0008 ), even after week 22. Balance improved non-significantly ( p= 0.08 ). Quadriceps muscle strength improved significantly after 5 weeks ( p= 0.04 ). Back extensor muscle strength improved almost significantly ( p= 0.09 ). In conclusion, this training programme for osteoporotic patients improved balance and level of daily function and decreased experience of pain and use of analgesics. Quality of life was improved even beyond the active training period Multidisciplinary patient education in groups increases knowledge on osteoporosis: A randomized controlled trial Introduction : Specific pharmacological treatment reduces the incidence of fractures significantly in patients with osteoporosis. Unfortunately, compliance with such therapy is low in clinical practice and is inversely related to educational level. We hypothesized that patients\'knowledge of osteoporosis may be increased by a group-based multidisciplinary education programme. Methods : Three hundred patients, aged 45—81 years, recently diagnosed with osteoporosis and started on specific treatment, were r and omized to either the " school\'\' or " control\'\' group. Teaching was performed by nurses, physiotherapists, dieticians, and doctors, and design ed to increase the patient\'s empowerment. The patient\'s knowledge of osteoporosis was tested at study entry and at 3 months using a vali date d question naire. Results : At study entry, no differences in age or score ( 22 ( 18—24 ) ( median ( 25—75 percentiles ) ) vs. 22 ( 18—24 ) ) were seen between the school and control groups. The change in knowledge during the study, however, differed significantly between the two groups ( p<0.001 ). In the school group, the increase in knowledge score correlated inversely with the level of education ; that is, the lower the education level, the higher the gain in knowledge during the course ( Rho=-0.25, p<0.01 ). Conclusions : A group-based multidisciplinary education programme significantly increases patients\'knowledge of the disease Effect of community-based nutrition education intervention on calcium intake and bone mass in postmenopausal Vietnamese women. OBJECTIVE To examine the effect of community-based nutrition education intervention on calcium intake and bone mass in Vietnamese postmenopausal women. DESIGN A controlled trial was conducted in two groups as intervention and control. The intervention group was given nutrition education during 18 months to improve calcium intake, while the control subjects had the usual diet. Calcium intake and bone mass were evaluated every 6 months. Bone mass was assessed by speed of sound ( SOS ) at calcaneus, referred to as quantitative ultrasound measurement. Anthropometric indices and serum parathyroid hormone ( PTH ) were determined at baseline and at the end of intervention. SETTING Two rural communes of Hai Duong province located in the Red River Delta in Vietnam. SUBJECTS A total of 140 women aged 55 - 65 years, who were more than 5 years postmenopausal and with low calcium intake ( < 400 mg/d ), were recruited. After 18 months of intervention, 108 women completed the study. RESULTS Calcium intake in the intervention group had increased significantly ( P < 0.01 ) while it had no significant changes in controls. SOS values were not changed significantly in the intervention subjects while it decreased significantly by 0.5 % in the controls ( P < 0.01 ). The intervention led to a decrease in serum PTH by 12 % ( P < 0.01 ). In the controls, there was an increase in serum PTH by 32 % ( P < 0.001 ). CONCLUSION Nutrition education intervention was effective in improving calcium intake and retarding bone loss in the studied subjects Exercise therapy for osteoporosis: results of a randomised controlled trial. OBJECTIVE : To define the effects of therapeutic exercise on bone density and back complaints. METHODS : A r and omised controlled trial with parallel groups was conducted in an outpatient clinic, Medical School, University of Vienna. Ninety two sedentary post-menopausal women with back problems were r and omly allocated to either exercise ( groups 1 and 2 ) or control ( group 3, no exercise, n = 31 ) ; the exercise group was retrospectively subdivided into compliant ( group 1, n = 27 ) and not fully compliant patients ( group 2, n = 34 ). Regular, initially supervised therapeutic exercise aim ed at restoring biomechanical function was performed for four years. Bone density in the forearm was measured by single photon absorptiometry at entry and after four years ; subjective back complaints were documented. RESULTS : A significant decrease in bone density was observed in groups 2 and 3 ; no change was noted in group 1 ; back complaints decreased in group 1 only. CONCLUSIONS : Sedentary postmenopausal women may benefit from regular long term therapeutic exercise in terms of subjective back complaints and slowed loss of bone mass Efficacy of a Self-Management Program for Osteoporotic Subjects Alp A, Kanat E, Yurtkuran M : Efficacy of a self-management program for osteoporotic subjects. Am J Phys Med Rehabil 2007;86:633–640. Objective : This study is based on whether the self-management program choices For Better Bone Health is effective to promote behavioral strategies for improving bone health, life quality, pain perception, physical function, and balance in osteoporotic subjects. Design : In this single-blind, r and omized controlled study, a total of 50 sedentary women with postmenopausal and idiopathic osteoporosis were selected from the out patients of Atatürk Balneotherapy and Rehabilitation Center according to their physical activity level and T scores of dual-energy x-ray absorptiometry as the inclusion criteria. Fifty sedentary women with BMD T scores of −2.5 or lower were r and omized into two groups ( self-management group : group 1 ; and control group : group 2 ) and enrolled in a 6-mo study. Participants attended self-management class once a week for 5 wks. Evaluations were done at baseline, at the end of the fifth week, and at the sixth month. Pain-intensity evaluation by Visual Analogue Scale ( VAS ), life- quality assessment s by SF-36, balance testing by Sensitized Romberg Test ( SRT ), and functional assessment by Timed Sit to St and test ( TSS ) and a simple question naire were the outcome measures. Results : When the groups were compared by change scores and percentages of change, improvements observed in pain intensity by VAS ( P < 0.001 ), SF-36 Physical Function ( P < 0.001 ), SF-36 Physical Role Limitations ( P < 0.001 ), SF-36 Social Function ( P < 0.001 ), SF-36 Mental Health ( P < 0.001 ), SF-36 Vitality ( P < 0.01 ), SF-36 Pain ( P < 0.001 ), SF-36 General Health Perceptions ( P < 0.05 ), SF-36 Emotional Role Limitations ( P < 0.01 ), SRT eyes open ( P < 0.001 ), SRT eyes closed ( P < 0.001 ), and TSS ( P < 0.001 ) were determined to be superior in group 1 at the end of the sixth month. Seventy-four percent of patients in group 1 engaged in regular physical activities, and 92 % of them declared that they understood the purpose and benefits of medications and dietary calcium intake. Fifty-seven percent of them formed personal plans for preventing traumas, whereas 8 % of the subjects in group 2 experienced new falls but no fractures. Conclusion : It is determined that the self-management class led to improvements in functional, balance, and life- quality outcomes and to reductions in pain perception Effects on function and quality of life of postoperative home-based physical therapy for patients with hip fracture. OBJECTIVE To evaluate the effects of a 3-month home-based physical therapy ( PT ) program for patients with hip fracture after surgery. DESIGN R and omized controlled trial. SETTING Home. PARTICIPANTS Twenty-five patients recently discharged from an acute orthopedic department. INTERVENTIONS Patients were r and omized to the home-based PT group ( n=13 ), where they received home-based PT 8 times from discharge to month 3 postdischarge, or to the control group ( n=12 ). The home-based PT program included exercises for muscle strengthening, range of motion ( ROM ), balance, and functional training. Patients in the control group were instructed to practice the exercise program given at bedside before discharge. MAIN OUTCOME MEASURES Patients were evaluated for hip ROM, strength, walking velocity, Harris hip score, and health-related quality of life ( HRQOL ) at the week of discharge and at 1, 3, and 6 months after discharge. RESULTS The baseline characteristics showed no difference between the 2 groups. Harris score of the home-based PT group progressed from 58.6+/-8.5 to 90.1+/-5.4 at month 3, whereas Harris score of the control group progressed from 54.6+/-14.5 to 77.4+/-10.0 ( P<.01 ). Scores of the psychologic domain of HRQOL for the home-based PT group were significantly better at month 1 ( P<.05 ) and month 3 ( P<.01 ) after discharge. Moreover, the physical domain score of the home-based PT group was also significantly better ( P<.05 ) at 3 months after discharge. CONCLUSIONS Home-based PT programs could help patients regain function and HRQOL earlier Community-based exercise program reduces risk factors for falls in 65- to 75-year-old women with osteoporosis: randomized controlled trial. BACKGROUND Exercise programs improve balance, strength and agility in elderly people and thus may prevent falls. However, specific exercise programs that might be widely used in the community and that might be " prescribed " by physicians, especially for patients with osteoporosis, have not been evaluated. We conducted a r and omized controlled trial of such a program design ed specifically for women with osteoporosis. METHODS We identified women 65 to 75 years of age in whom osteoporosis had been diagnosed by dual-energy X-ray absorptiometry in our hospital between 1996 and 2000 and who were not engaged in regular weekly programs of moderate or hard exercise. Women who agreed to participate were r and omly assigned to participate in a twice-weekly exercise class or to not participate in the class. We measured baseline data and, 20 weeks later, changes in static balance ( by dynamic posturography ), dynamic balance ( by a timed figure-eight run ) and knee extension strength ( by dynamometry ). RESULTS Of 93 women who began the trial, 80 completed it. Before adjustment for covariates, the intervention group tended to have greater, although nonsignificant, improvements in static balance ( mean difference 4.8 %, 95 % confidence interval [ CI ] -1.3 % to 11.0 % ), dynamic balance ( mean difference 3.3 %, 95 % CI -1.7 % to 8.4 % ) and knee extension strength ( mean difference 7.8 %, 95 % CI -5.4 % to 21.0 % ). Mean crude changes in the static balance score were -0.85 ( 95 % CI -2.91 to 1.21 ) for the control group and 1.40 ( 95 % CI -0.66 to 3.46 ) for the intervention group. Mean crude changes in figure-eight velocity ( dynamic balance ) were 0.08 ( 95 % CI 0.02 to 0.14 ) m/s for the control group and 0.14 ( 95 % CI 0.08 to 0.20 ) m/s for the intervention group. For knee extension strength, mean changes were -0.58 ( 95 % CI -3.02 to 1.81 ) kg/m for the control group and 1.03 ( 95 % CI -1.31 to 3.34 ) kg/m for the intervention group. After adjustment for age, physical activity and years of estrogen use, the improvement in dynamic balance was 4.9 % greater for the intervention group than for the control group ( p = 0.044 ). After adjustment for physical activity, cognitive status and number of fractures ever, the improvement in knee extension strength was 12.8 % greater for the intervention group than for the control group ( p = 0.047 ). The intervention group also had a 6.3 % greater improvement in static balance after adjustment for rheumatoid arthritis and osteoarthritis, but this difference was not significant ( p = 0.06 ). INTERPRETATION Relative to controls, participants in the exercise program experienced improvements in dynamic balance and strength, both important determinants of risk for falls, particularly in older women with osteoporosis Effects of extended outpatient rehabilitation after hip fracture: a randomized controlled trial. CONTEXT Hip fractures are common in the elderly, and despite st and ard rehabilitation, many patients fail to regain their prefracture ambulatory or functional status. OBJECTIVE To determine whether extended outpatient rehabilitation that includes progressive resistance training improves physical function and reduces disability compared with low-intensity home exercise among physically frail elderly patients with hip fracture. DESIGN, SETTING, AND PATIENTS R and omized controlled trial conducted between August 1998 and May 2003 among 90 community-dwelling women and men aged 65 years or older who had had surgical repair of a proximal femur fracture no more than 16 weeks prior and had completed st and ard physical therapy. INTERVENTION Participants were r and omly assigned to 6 months of either supervised physical therapy and exercise training ( n = 46 ) or home exercise ( control condition ; n = 44 ). MAIN OUTCOME MEASURES Primary outcome measures were total scores on a modified Physical Performance Test ( PPT ), the Functional Status Question naire physical function subscale ( FSQ ), and activities of daily living scales. Secondary outcome measures were st and ardized measures of skeletal muscle strength, gait, balance, quality of life, and body composition. Participants were evaluated at baseline, 3 months, and 6 months. RESULTS Changes over time in the PPT and FSQ scores favored the physical therapy group ( P =.003 and P =.01, respectively ). Mean change ( SD ) in PPT score for physical therapy was + 6.5 ( 5.5 ) points ( 95 % confidence interval [ CI ], 4.6 - 8.3 ), and for the control condition was + 2.5 ( 3.7 ) points ( 95 % CI, 1.4 - 3.6 points ). Mean change ( SD ) in FSQ score for physical therapy was + 5.2 ( 5.4 ) points ( 95 % CI, 3.5 - 6.9 ) and for the control condition was + 2.9 ( 3.8 ) points ( 95 % CI, 1.7 - 4.0 ). Physical therapy also had significantly greater improvements than the control condition in measures of muscle strength, walking speed, balance, and perceived health but not bone mineral density or fat-free mass. CONCLUSION In community-dwelling frail elderly patients with hip fracture, 6 months of extended outpatient rehabilitation that includes progressive resistance training can improve physical function and quality of life and reduce disability compared with low-intensity home exercise Structural Model for Osteoporosis Preventing Behavior in Postmenopausal Women Background : Osteoporosis prevention behaviors ( OPBs ) can prevent and delay bone deterioration ; dual-energy X-ray absorptiometry ( DXA ) scan can identify osteoporosis and provide personal osteoporosis risk information that may promote prevention behaviors. Objectives : This study was design ed to estimate relationships between receiving personal knowledge of bone mineral density ( gained through DXA scan ), general knowledge of osteoporosis, health beliefs, and the two OPBs of calcium intake and weight-bearing exercise in healthy postmenopausal women 50 to 65 years. Methods : In this longitudinal, r and omized clinical trial ( including covariates ), receipt of personal DXA information was manipulated by r and om assignment to the experimental or control group. The remaining antecedent and outcome variable measures were collected by question naire at three time points ( initial [ T1 ; pre-DXA ], 6 months [ T2 ], 12 months [ T3 ] ) and by bone density assessment from 203 women over an 18-month period in 2001 - 2003. Results : The experimental manipulation ( DXA results ) had a direct positive effect ( & bgr ; =.23, p <.05 ) on calcium intake at T2, and indirectly at T3 through T2. Women in the experimental group who were informed they had osteopenia or osteoporosis had a greater T1-T2 change in daily calcium intake than those with normal bone density ( & bgr ; =.23, p <.05 ). However, providing DXA results did not relate to change in exercise. Health beliefs and general osteoporosis knowledge predicted initial calcium and exercise levels ; there was tentative evidence that susceptibility beliefs partially mediate between DXA results and change in calcium intake. Discussion : Personal knowledge of DXA results was related significantly to increases in calcium intake in postmenopausal women, but not to exercise. Directions for further study are discussed What is the impact of osteoporosis education and bone mineral density testing for postmenopausal women in a managed care setting? Objective To assess whether osteoporosis education, with and without bone mineral density ( BMD ) testing, increases the initiation of lifestyle changes and pharmaceutical treatment to prevent osteoporosis. Design A total of 508 women, aged 54–65, from a large managed care organization who were not on osteoporosis prevention therapy participated in an intervention study. Participants were r and omly assigned to either an education class on osteoporosis ( n = 301 ) or education plus BMD ( n = 207 ). A control group of 187 women receiving no intervention were also surveyed to serve as comparison. Group differences and differences based on BMD test result were compared 6 months after education regarding self-reported changes in health behaviors using & khgr;2 tests and logistic regression analyses. Results Of the 508 intervention participants, 455 ( 90 % ) responded to the follow-up survey. Initiation of hormone replacement therapy was reported by 9 %, with 5 % reporting starting alendronate. More than half reported changes in diet, exercise, or calcium intake. Forty-three percent increased their vitamin D intake. There were no significant group differences in behavior except with regard to pharmaceutical therapy ; subjects with education plus BMD were three times more likely than those receiving education only to report starting hormone replacement therapy ( p = 0.004 ). Low BMD scores were associated with increasing vitamin D intake ( p = 0.03 ) and starting medication ( p = 0.001 ). Women in the intervention groups were significantly more likely to report modifying their diet ( p < 0.001 ), calcium ( p < 0.01 ), and vitamin D intake ( p < 0.0001 ) than women in the control group, not exposed to education. Conclusion Education regarding osteoporosis prevention seems to encourage women to make lifestyle changes. The inclusion of BMD testing enhances the likelihood that women will consider pharmaceutical therapy Does an educational leaflet improve self-reported adherence to therapy in osteoporosis? The OPTIMA study Introduction Adherence to treatment in osteoporosis remains poor. The aim of this study was to evaluate the effects of an educational leaflet on adherence to medication and to assess the association between adherence and health-related quality of life ( HRQOL ). Methods A naturalistic, observational, multi-center, prospect i ve study of 12 months ’ follow-up was performed. Consecutive post-menopausal women aged 50 years to 86 years starting treatment with raloxifene according to daily practice were enrolled from 126 primary care offices in Spain. The women were assigned to two study groups. Group A received an educational leaflet with general information about osteoporosis ; group B followed current practice. To assess adherence to medication and HRQOL, the Morisky test and the EuroQoL question naire were administered. A total of 745 post-menopausal women ( group A, n=366 ; group B n=379 ), with a mean age of 62 years, were included. Results Most patients in both study groups showed high adherence to raloxifene at the 3-month visit : 56.3 % vs 62.7 % for groups A and B, respectively ; this proportion at the 12-month visit was 47.4 % ( P=0.15 ) and 52.5 % ( P=0.02 ), respectively. At baseline, “ pain/discomfort ” was the dimension showing the highest percentage of women reporting problems : 86.4 % vs 83.2 % in groups A and B, respectively ( P=0.22 ). HRQOL improved in both groups throughout the study, with an overall mean increment in the EuroQoL visual analog scale ( EQ VAS ) of 9.2 at 12 months ( P<0.01 ). Correlations between adherence and HRQOL were weak. After receiving an educational leaflet, young post-menopausal women suffering osteoporosis did not show improvement in adherence to therapy. HRQOL improved at 12-month follow-up under treatment. Conclusion No consistent correlation between adherence and HRQOL was found Effect of low-intensity back exercise on quality of life and back extensor strength in patients with osteoporosis: a randomized controlled trial Summary R and omized controlled study in 80 postmenopausal women with osteoporosis was conducted to investigate the effect of a home-based, simple, low-intensity exercise. Low-intensity back-strengthening exercise was effective in improving the quality of life and back extensor strength. Introduction and hypothesisBack-strengthening exercise is effective in increasing back extensor strength and decreasing risk of vertebral fractures. We hypothesized that a home-based, simple, low-intensity exercise could enhance back extensor strength and improve the quality of life and /or spinal range of motion in postmenopausal women in a short-term follow-up. Methods Eighty postmenopausal women with osteoporosis were r and omly assigned to a control group ( n = 38 ) or an exercise group ( n = 42 ). Subjects were instructed to lift their upper trunk from a prone position antigravity and maintain the neutral position. Isometric back extensor strength, spinal range of motion, and scores for quality of life were evaluated at baseline and 4 months. Results Back extensor strength significantly increased both in the exercise group ( 26 % ) and in the control group ( 11 % ). Scores for quality of life increased in the exercise group ( 7 % ), whereas it remained unchanged in the control group ( 0 % ). There was a significant difference in quality of life score between the groups ( p = 0.012 ). Conclusions Low-intensity back-strengthening exercise was effective in improving the quality of life and back extensor strength in patients with osteoporosis Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. CONTEXT Persistence with osteoporosis treatment is poor but is important for maximum benefit. OBJECTIVE The objective of the study was to assess the impact of physician reinforcement using bone turnover markers ( BTMs ) on persistence with risedronate treatment. DESIGN AND SETTING This was a 1-yr multinational prospect i ve, open-label, blinded study in 171 osteoporosis centers in 21 countries. PATIENTS A total of 2382 postmenopausal women ( 65 - 80 yr old ) with spine/hip T-score -2.5 or less or T-score -1.0 or less with a low-trauma fracture. INTERVENTION Intervention included calcium 500 mg/d, vitamin D 400 IU/d, and risedronate 5 mg/d for 1 yr. Centers were r and omized to reinforcement ( RE+ ) or no reinforcement ( RE- ). At 13 and 25 wk, reinforcement based on urinary N-telopeptide of type I collagen change from baseline was provided to the RE+ patients using the following response categories : good ( > 30 % decrease ), stable ( -30 % to + 30 % change ), or poor ( > 30 % increase ). MAIN OUTCOME MEASURES Persistence assessed with electronic drug monitors was measured. RESULTS In the overall efficacy population ( n=2302 ), persistence was unexpectedly high and was similar for both groups ( RE-, 77 % ; RE+, 80 % ; P=0.160 ). A significant relationship between the type of message and persistence was observed ( P=0.017 ). Compared with RE-, intervention based on a good BTM response was associated with a significant improvement in persistence [ hazard ratio ( HR ) 0.71 ; 95 % confidence interval ( CI ) 0.53 - 0.95 ]. Persistence was unchanged ( HR 1.02 ; 95 % CI 0.74 - 1.40 ) or lower ( HR 2.22 ; 95 % CI 1.27 - 3.89 ) when reinforcement was based on a stable or poor BTM response, respectively. Reinforcement was associated with a lower incidence of new radiologically determined vertebral fractures ( odds ratio 0.4 ; 95 % CI, 0.2 - 1.0 ). CONCLUSIONS Reinforcement using BTMs influences persistence with treatment in postmenopausal women with osteoporosis, depending on the BTM response observed A multifaceted intervention to improve treatment of osteoporosis in postmenopausal women with wrist fractures: a cluster randomized trial Summary In a cluster r and omized trial, we evaluated the effect of a multifaceted intervention ( directed at both patient and primary care physician ) on the rates of testing and treatment of osteoporosis in postmenopausal women within six months of their wrist fracture. Compared to usual care, women in the intervention practice s were three times more likely to receive bone mineral density testing and prescribed osteoporosis treatments. Introduction Postmenopausal women with wrist fractures are at increased risk of future fragility fractures, yet they frequently do not receive evaluation and treatment for osteoporosis. We set out to evaluate a multifaceted intervention design ed to improve management of osteoporosis in older women with recent wrist fractures. Methods Cluster r and omized trial of 270 women cared for in 119 primary care practice s. We recruited postmenopausal women with an acute wrist fracture from the emergency departments of hospitals in southeastern Ontario, Canada. Family practice s were r and omly assigned to either the intervention or usual care. The intervention consisted of a mailed reminder with a summary of treatment guidelines and letter sent to the primary care physician, in addition to an educational package and letter to the women. The primary outcome was the proportion of women prescribed osteoporosis therapy within 6 months of their fracture. Results The mean age of women was 69(10.9 ) years. The intervention increased the proportion of women started on osteoporosis medications ( 28 % vs. 10 % ) of controls, adjusted OR 3.45, 95 % CI, 1.58–7.56, p = 0.002 ) and the proportion who had a bone mineral density ( BMD ) test ( 53.3 % vs. 26 % ) of controls, OR 3.38, 95 % CI, 1.83–6.26, p < 0.001 ). In addition to the intervention, having a female physician was a predictor of increased testing and treatment rates. Conclusion A multifaceted intervention significantly improved rates of osteoporosis treatment and BMD testing in postmenopausal women with wrist fractures The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. Long-term adherence and persistence with any therapy are very poor ( approximately 50 % ). Adherence to therapy is defined as the percentage of prescribed medication taken, and persistence is defined as continuing to take prescribed medication. We examined whether monitoring by nursing staff could enhance adherence and persistence with antiresorptive therapy and whether presenting information on response to therapy provided additional benefit. In addition we evaluated the impact of monitoring on treatment efficacy. Seventy-five postmenopausal women with osteopenia were r and omized to 1 ) no monitoring, 2 ) nurse-monitoring, or 3 ) marker-monitoring. All subjects were prescribed raloxifene. At 12, 24, and 36 wk, the nursing staff review ed subjects in the monitored ( nurse-monitoring or marker-monitoring ) groups using a predefined protocol. The marker-monitored group were also presented a graph of response to therapy using percentage change in urinary N-telopeptide of type I collagen ( uNTX ), a bone resorption marker, at each visit. Biological response to therapy at 1 yr was determined using the percent change in bone mineral density ( BMD ) and uNTX. Treatment adherence and persistence were assessed using electronic monitoring devices. Survival analysis showed that the monitored group increased cumulative adherence to therapy by 57 % compared with no monitoring ( P = 0.04 ). There was a trend for the monitored group to persist with therapy for 25 % longer compared with no monitoring ( P = 0.07 ). Marker measurements did not improve adherence or persistence to therapy compared with nurse-monitoring alone. Adherence at 1 yr was correlated with percent change in hip ( BMD ) ( r = 0.28 ; P = 0.01 ) and percent change in uNTX ( r = -0.36 ; P = 0.002 ). In conclusion, monitoring of patients increased adherence to therapy by 57 % at 1 yr. Increased adherence to therapy increased the effectiveness of raloxifene therapy determined using surrogate end points Efficacy of home-based exercise for improving quality of life among elderly women with symptomatic osteoporosis-related vertebral fractures This r and omized controlled trial was design ed to investigate the effect of a 6-month home-based exercise program versus control ( usual activities ) on quality of life for postmenopausal women with osteoporosis who had at least one vertebral fracture. Twelve-month assessment s of outcomes were completed to determine if women would continue exercising with minimal supervision and if benefit could be sustained. The home exercise program followed a " lifestyle exercise " approach where participants completed exercises 60 min per day, 3 days a week and could complete exercises in small periods of time throughout the day. Exercise activities included stretching, strength training and aerobics ( i.e. walking ). Participants were assessed at baseline, 6 months, and 12 months using the Osteoporosis Quality of Life Question naire ( OQLQ ), the Sickness Impact Profile ( SIP ), a balance test, and the Timed Up And Go test. Bone mineral density was assessed at baseline and 12 months for both the lumbar spine and femoral neck. Quality of life ( OQLQ ) improved over 6 months in the exercise group compared to the control group in the domains of symptoms ( P=0.003 ), emotion ( P=0.01 ) and leisure ( P=0.03 ). Results from the balance test indicated a greater effect in the exercise group over 12 months ( P<0.05 ). There were no significant differences between groups in measures of Timed Up and Go, SIP at 6 and 12 months, and femoral neck and lumbar spine bone mineral density at 12 months. Home-based exercise with minimal supervision improves quality of life in elderly women with vertebral fractures. Future research is needed to determine if home exercise programs reduce falls and fall-related injuries in the elderly Results of a 10 week community based strength and balance training programme to reduce fall risk factors: a randomised controlled trial in 65–75 year old women with osteoporosis Objective —To test the efficacy of a community based 10 week exercise intervention to reduce fall risk factors in women with osteoporosis. Methods —Static balance was measured by computerised dynamic posturography ( Equitest ), dynamic balance by timed figure of eight run, and knee extension strength by dynamometry. Subjects were r and omised to exercise intervention ( twice weekly Osteofit classes for 10 weeks ) or control groups. Results —The outcome in 79 participants ( 39 exercise, 40 control ) who were available for measurement 10 weeks after baseline measurement is reported. After confounding factors had been controlled for, the exercise group did not make significant gains compared with their control counterparts, although there were consistent trends toward greater improvement in all three primary outcome measures. Relative to the change in control subjects, the exercise group improved by 2.3 % in static balance, 1.9 % in dynamic balance, and 13.9 % in knee extension strength. Conclusions —A 10 week community based physical activity intervention did not significantly reduce fall risk factors in women with osteoporosis. However, trends toward improvement in key independent risk factors for falling suggest that a study with greater power may show that these variables can be improved to a level that reaches statistical significance Effectiveness of a falls-and-fracture nurse coordinator to reduce falls: a randomized, controlled trial of at-risk older adults. OBJECTIVES To assess the effectiveness of a community-based falls- and -fracture nurse coordinator and multifactorial intervention in reducing falls in older people. DESIGN R and omized, controlled trial. SETTING Screening for previous falls in family practice followed by community-based intervention. PARTICIPANTS Three hundred twelve community-living people aged 75 and older who had fallen in the previous year. INTERVENTION Home-based nurse assessment of falls- and -fracture risk factors and home hazards, referral to appropriate community interventions, and strength and balance exercise program. Control group received usual care and social visits. MEASUREMENTS Primary outcome was rate of falls over 12 months. Secondary outcomes were muscle strength and balance, falls efficacy, activities of daily living, self-reported physical activity level, and quality of life ( Medical Outcomes Study 36-item Short Form Question naire ). RESULTS Of the 3,434 older adults screened for falls, 312 ( 9 % ) from 19 family practice s were enrolled and r and omized. The average age was 81+/-5, and 69 % ( 215/312 ) were women. The incidence rate ratio for falls for the intervention group compared with the control group was 0.96 ( 95 % confidence interval=0.70 - 1.34 ). There were no significant differences in secondary outcomes between the two groups. CONCLUSION This nurse-led intervention was not effective in reducing falls in older people who had fallen previously. Implementation and adherence to the fall-prevention measures was dependent on referral to other health professionals working in their usual clinical practice. This may have limited the effectiveness of the interventions Tailored Interventions to Enhance Osteoporosis Prevention in Women PURPOSE The purpose of this pilot study was to determine if tailored nursing interventions based on personal knowledge of bone mineral density from a dual-energy x-ray absorptiometry cause increases in knowledge of osteoporosis, health beliefs, or osteoporosis-prevention behaviors in postmenopausal women 50–65 years of age, 6 months after the intervention. METHOD The design for this pilot study was a two group quasi-experimental design. The treatment group received a tailored intervention ; the control group did not. Outcome data were gathered at 6 months after dual-energy x-ray absorptiometry. The tailored intervention was design ed and given to each woman via telephone using her dual-energy x-ray absorptiometry results and osteoporosis question naire data that addressed her knowledge of osteoporosis and osteoporosis-prevention behaviors of calcium intake, exercise, smoking, and alcohol use. A written mailed copy of the intervention followed the telephone interview. Six months after the intervention, the women were mailed another osteoporosis question naire to determine if the tailored intervention made a difference in the outcome variables. SAMPLE A total 124 women between the ages of 50 and 65 ( 101 control, 23 treatment ) comprised the sample. RESULTS There was no difference in knowledge between groups. On the average, there were significantly more perceived barriers to calcium in the tailored group ( mean = 13.48 ) than in the nontailored group ( mean = 11.55 ) ( t = 2.147 ; df = 122 ; p =.034 ). There were significantly more perceived barriers to exercise in the tailored group ( mean = 14.39 ) than in the nontailored group ( mean = 12.21 ) ( t =.144 ; df = 122 ; p =.034 ). Daily calcium intake increased in both the tailored and the nontailored groups. The tailored intervention increased women\'s daily calcium intake from 614.28 to 1039.10 mg ( t = −2.896 ; df = 22 ; p =.008 ). The nontailored group daily calcium intake increased from 587.91 to 916.30 mg ( t = −3.541 ; df = 100 ; p =.001 ) ; there was no significant difference between the groups. Weight-bearing exercise behaviors decreased from 96.04 minutes to 59.2 minutes in the tailored group but increased slightly in the nontailored group from 81.47 to 87.26 minutes of exercise. CONCLUSION Tailored interventions increased women\'s perceived barriers to calcium and exercise. Both groups increased calcium intake. The mixed findings of increased perception of barriers to calcium and exercise and decreased exercise behaviors indicate the need for further study. This important intervention has implication s for orthopaedic nurses and healthcare professionals involved in health promotion and prevention of osteoporosis Multifaceted intervention to improve diagnosis and treatment of osteoporosis in patients with recent wrist fracture: a randomized controlled trial Background : Older patients who experience a fragility fracture are at high risk of future fractures but are rarely tested or treated for osteoporosis. We developed a multifaceted intervention directed at older patients with wrist fractures ( in the form of telephone-based education ) and their physicians ( in the form of guidelines endorsed by opinion leaders, supported by reminders ) to improve the quality of osteoporosis care. Methods : In a r and omized controlled trial with blinded ascertainment of outcomes, we compared our intervention with usual care ( provision of printed educational material s to patients ). Eligible patients were those older than 50 years of age who had experienced a wrist fracture and were seen in emergency departments and fracture clinics ; we excluded those who were already being treated for osteoporosis. The primary outcome was bisphosphonate treatment within 6 months after the fracture. Secondary outcomes included bone mineral density testing, “ appropriate care ” ( consisting of bone mineral density testing with treatment if bone mass was low ) and quality of life. Results : We screened 795 patients for eligibility and r and omly assigned 272 to the intervention ( 137 patients ) or control ( 135 patients ) group. The median age was 60 years ; 210 ( 77 % ) of the subjects were women, and 130 ( 48 % ) reported a previous fracture as an adult. Six months after the fracture, 30 ( 22 % ) of the intervention patients, as compared with 10 ( 7 % ) of the control patients, were receiving bisphosphonate therapy for osteoporosis ( adjusted relative risk [ RR ] 2.6, 95 % confidence interval [ CI ] 1.3–5.1, p = 0.008 ). Intervention patients were more likely than control patients to undergo bone mineral density testing ( 71/137 [ 52 % ] v. 24/135 [ 18 % ] ; adjusted RR 2.8, 95 % CI 1.9–4.2, p < 0.001 ) and to receive appropriate care ( 52/137 [ 38 % ] v. 15/135 [ 11 % ] ; adjusted RR 3.1, 95 % CI 1.8–5.3, p < 0.001 ). There were no differences between the groups in other outcomes. One patient died, and 4 others experienced recurrent fracture. Interpretation : A multifaceted intervention directed at high-risk patients and their physicians substantially increased rates of testing and treatment for osteoporosis. Nevertheless, more than half of the patients in the intervention group were not receiving appropriate care 6 months after their fracture, which suggests that additional strategies should be explored. ( Clinical Trials.gov trial register no. NCT00152321. A randomized, prospective study of the effects of Tai Chi Chun exercise on bone mineral density in postmenopausal women. OBJECTIVE To evaluate the potential benefits of programmed Tai Chi Chun ( TCC ) exercise on the weight-bearing bones of early postmenopausal women. DESIGN Age-matched and r and omized prospect i ve intervention. SETTING University medical school. PARTICIPANTS One hundred thirty-two healthy postmenopausal women ( mean age, 54.0+/-3.5y ) within 10 years of menopause onset were recruited and r and omized into the TCC exercise group ( n=67 ) or the sedentary control group ( n=65 ). INTERVENTION Supervised TCC exercise was performed by the TCC group for 45 minutes a day, 5 days a week, for 12 months ; control subjects retained a sedentary life style. Main outcome measures Bone mineral density ( BMD ) was measured in the lumbar spine and proximal femur by using dual-energy x-ray absorptiometry and in the distal tibia by using multislice peripheral quantitative computed tomography ( pQCT ). All BMD measurements were repeated after 12 months in both groups. Fracture rate was also documented. RESULTS Baseline measurements showed homogeneity in age, anthropometric variables, and menstruation status between the TCC and control groups. Exactly 81.6 % of the subjects in the TCC group and 83.1 % of subjects in the control group completed the 12-month follow-up study. BMD measurements revealed a general bone loss in both TCC and sedentary control subjects at all measured skeletal sites, but with a reportedly slower rate in the TCC group. A significant 2.6- to 3.6-fold retardation of bone loss ( P<.01 ) was found in both trabecular and cortical compartments of the distal tibia in the TCC group as compared with the controls, as measured by pQCT. A total of 4 fracture cases were documented during follow-up, including 3 subjects in the control group and 1 in the TCC group. CONCLUSIONS This is the first prospect i ve and r and omized study to show that a programmed TCC exercise intervention is beneficial for retarding bone loss in weight-bearing bones in early postmenopausal women. Long-term follow-up is needed to substantiate the role of TCC exercise in the prevention of osteoporosis and its related fracture Use of a case manager to improve osteoporosis treatment after hip fracture: results of a randomized controlled trial. BACKGROUND Patients who survive hip fracture are at high risk of recurrent fractures, but rates of osteoporosis treatment 1 year after sustaining a fracture are less than 10 % to 20 %. We have developed an osteoporosis case manager intervention. The case manager educated patients, arranged bone mineral density tests, provided prescriptions, and communicated with primary care physicians. The intervention was compared with usual care in a r and omized controlled trial. METHODS We recruited from all hospitals that participate in the Capital Health system ( Alberta, Canada ), including patients 50 years or older who had sustained a hip fracture and excluding those who were receiving osteoporosis treatment or who lived in a long-term care facility. Primary outcome was bisphosphonate therapy 6 months after fracture ; secondary outcomes included bone mineral density testing, appropriate care ( bone mineral density testing and treatment if bone mass was low ), and intervention costs. RESULTS We screened 2219 patients and allocated 220, as follows : 110 to the intervention group and 110 to the control group. Median age was 74 years, 60 % were women, and 37 % reported having had previous fractures. Six months after hip fracture, 56 patients in the intervention group ( 51 % ) were receiving bisphosphonate therapy compared with 24 patients in the control group ( 22 % ) ( adjusted odds ratio, 4.7 ; 95 % confidence interval, 2.4 - 8.9 ; P <.001 ). Bone mineral density tests were performed in 88 patients in the intervention group ( 80 % ) vs 32 patients in the control group ( 29 % ) ( P <.001 ). Of the 120 patients who underwent bone mineral density testing, 25 ( 21 % ) had normal bone mass. Patients in the intervention group were more likely to receive appropriate care than were patients in the control group ( 67 % vs 26 % ; P <.001 ). The average intervention cost was $ 50.00 per patient. CONCLUSION For a modest cost, a case manager was able to substantially increase rates of osteoporosis treatment in a vulnerable elderly population at high risk of future fractures', 'Background Much research has been undertaken to establish the important benefits of physical activity in persons with multiple sclerosis ( MS ). There is disagreement regarding the strength of this research, perhaps because the majority of studies on physical activity and its benefits have not undergone initial and systematic feasibility testing. We aim to address the feasibility processes that have been examined within the context of physical activity interventions in MS. A tutorial on pilot studies: the what, why and how Pilot studies for phase III trials - which are comparative r and omized trials design ed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as " feasibility " or " vanguard " studies, they are design ed to assess the safety of treatment or interventions ; to assess recruitment potential ; to assess the feasibility of international collaboration or coordination for multicentre trials ; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including : 1 ) the general reasons for conducting a pilot study ; 2 ) the relationships between pilot studies, proof-of-concept studies, and adaptive design s ; 3 ) the challenges of and misconceptions about pilot studies ; 4 ) the criteria for evaluating the success of a pilot study ; 5 ) frequently asked questions about pilot studies ; 7 ) some ethical aspects related to pilot studies ; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format The distinction between randomized clinical trials (RCTs) and preliminary feasibility and pilot studies: what they are and are not. Feasibility and pilot studies play an important role in the preliminary planning of a proposed full-size r and omized clinical trial ( RCT ). In essence, feasibility studies are used to help develop trial interventions or outcome measures, whereas pilot studies replicate, in miniature, a planned full-size RCT. However, the terms used for these preliminary studies are sometimes considered synonymous, and in practice may overlap considerably or be combined. The important issue is not the distinction between these : the important distinction is between such preliminary studies and a proper RCT. J Orthop Sports Phys Ther 2014;44(8):555–558. Nuts and bolts of conducting feasibility studies. Many factors can affect the successful implementation and validity of intervention studies. A primary purpose of feasibility and pilot studies is to assess the potential for successful implementation of the proposed main intervention studies and to reduce threats to the validity of these studies. This article describes a typology to guide the aims of feasibility and pilot studies design ed to support the development of r and omized controlled trials and provides an example of the studies underlying the development of one rehabilitation trial. The purpose of most feasibility and pilot studies should be to describe information and evidence related to the successful implementation and validity of a planned main trial. Null hypothesis significance testing is not appropriate for these studies unless the sample size is properly powered. The primary tests of the intervention effectiveness hypotheses should occur in the main study, not in the studies that are serving as feasibility or pilot studies Pragmatic exercise intervention in people with mild to moderate multiple sclerosis: a randomised controlled feasibility study. BACKGROUND People with Multiple Sclerosis ( PwMS ) are less physically active than the general population and pragmatic approaches design ed to equip them with the skills and confidence to participate in long-term physical activity are required. OBJECTIVE The objective of this study was to determine the feasibility of a pragmatic exercise intervention in PwMS. METHODS A voluntary sample of 30 PwMS ( male n = 4, female n = 26 ; mean age = 40 years ; range = 24 - 49 years ), with mild to moderate disability ( EDSS ≤ 5.5 ), were recruited from eligible participants attending outpatient clinics. A total of 28 participants were r and omised to a 10 week pragmatic exercise intervention ( 2 × supervised and 1 × home-based session per week ) or usual care. Clinical, functional and quality of life ( MSQoL-54 ) outcomes were assessed at baseline, immediately and 3 months after the intervention. RESULTS Attrition was low ( 2 participants lost to immediate follow-up and 4 participants lost to 3 month follow-up ), with high compliance rates ( > 75 % of all sessions ). The intervention group achieved progression of exercise volume ( 24.3 ± 7.0 to 30.9 ± 5.5 min per session ), intensity ( 60.4 ± 8.8 to 67.7 ± 6.9 % HR max ) and training impulse ( min × average HR = training impulse/load [ arbitrary units ; AU ] ) ( 2600 ± 1105 to 3210 ± 1269AU ) during the intervention, whilst significantly increasing(P = 0.050 ) their physical composite score ( MSQOL-54 ) at 10 weeks and readiness to exercise ( P = 0.003 ) at 3 months compared with usual care. CONCLUSION This pragmatic intervention was feasible for PwMS, but further research is needed to assess its long-term impact on physical activity behaviour Participant recruitment into a randomised controlled trial of exercise therapy for people with multiple sclerosis Background The success of a clinical trial is often dependant on whether recruitment targets can be met in the required time frame. Despite an increase in research into the benefits of exercise in people with multiple sclerosis ( PwMS ), no trial has reported detailed data on effective recruitment strategies for large-scale r and omised controlled trials. The main purpose of this report is to provide a detailed outline of recruitment strategies, rates and estimated costs in the Exercise Intervention for Multiple Sclerosis ( ExIMS ) trial to identify best practice s for future trials involving multiple sclerosis ( MS ) patient recruitment. Methods The ExIMS research ers recruited 120 PwMS to participate in a 12-week exercise intervention. Participants were r and omly allocated to either exercise or usual-care control groups. Participants were sedentary, aged 18–65 years and had Exp and ed Disability Status Scale scores of 1.0–6.5. Recruitment strategies included attendance at MS outpatient clinics, consultant mail-out and trial awareness-raising activities. Results A total of 120 participants were recruited over the course of 34 months. To achieve this target, 369 potentially eligible and interested participants were identified. A total of 60 % of participants were recruited via MS clinics, 29.2 % from consultant mail-outs and 10.8 % through trial awareness. The r and omisation yields were 33.2 %, 31.0 % and 68.4 % for MS clinic, consultant mail-outs and trial awareness strategies, respectively. The main reason for in eligibility was being too active ( 69.2 % ), whilst for eligible participants the most common reason for non-participation was the need to travel to the study site ( 15.8 % ). Recruitment via consultant mail-out was the most cost-effective strategy, with MS clinics being the most time-consuming and most costly. Conclusions To reach recruitment targets in a timely fashion, a variety of methods were employed. Although consultant mail-outs were the most cost-effective recruitment strategy, use of this method alone would not have allowed us to obtain the predetermined number of participants in the required time period, thus leading to costly extensions of the project or failure to reach the number of participants required for sufficient statistical power. Thus, a multifaceted approach to recruitment is recommended for future trials. Trial registration International St and ard R and omised Controlled Trial Registry number : IS RCT N41541516 ; date registered : 5 February 2009 Feasibility study design and methods for Project GEMS: Guidelines for Exercise in Multiple Sclerosis. The Guidelines for Exercise in Multiple Sclerosis ( GEMS ) program is a r and omized controlled trial ( RCT ) examining the feasibility and efficacy of a home-based exercise training program based on recent physical activity guidelines and principles of behavior change for improving symptoms and health-related quality of life ( HRQOL ) in adults with multiple sclerosis ( MS ). The primary aim is to assess program feasibility in the four domains of process ( e.g., recruitment, retention, and adherence ), re sources ( e.g., communication, staff requirements, and monetary costs ), management ( e.g., time and accuracy in data collection /entry, and reporting of adverse events ) and scientific outcomes ( e.g., safety, burden, participant feedback and efficacy/ outcomes ). The trial will recruit individuals with mild-to-moderate MS-related disability across the United States who will be r and omized into intervention or waitlist control conditions. All participants will complete home-based assessment s ( including wearing an accelerometer for 7 days and completion of a question naire booklet ) prior to and upon completion of the 4-month program. Participants in the intervention will receive a 4-month home-based exercise program emphasizing aerobic and resistance training. Participants will be provided with exercise equipment, a DVD, a manual and a log-book. The exercise program will be supplemented with periodic newsletters in the mail highlighting principles of behavior change, and video-chats with an exercise specialist to provide motivation and social accountability. This trial serves to inform development of Phase II and III RCTs which can determine the actual efficacy and effectiveness of home-based exercise based on the MS-specific physical activity guidelines for improving symptoms and HRQOL Defining Feasibility and Pilot Studies in Preparation for Randomised Controlled Trials: Development of a Conceptual Framework We describe a framework for defining pilot and feasibility studies focusing on studies conducted in preparation for a r and omised controlled trial. To develop the framework, we undertook a Delphi survey ; ran an open meeting at a trial methodology conference ; conducted a review of definitions outside the health research context ; consulted experts at an international consensus meeting ; and review ed 27 empirical pilot or feasibility studies. We initially adopted mutually exclusive definitions of pilot and feasibility studies. However, some Delphi survey respondents and the majority of open meeting attendees disagreed with the idea of mutually exclusive definitions. Their viewpoint was supported by definitions outside the health research context, the use of the terms ‘ pilot ’ and ‘ feasibility ’ in the literature, and participants at the international consensus meeting. In our framework, pilot studies are a subset of feasibility studies, rather than the two being mutually exclusive. A feasibility study asks whether something can be done, should we proceed with it, and if so, how. A pilot study asks the same questions but also has a specific design feature : in a pilot study a future study, or part of a future study, is conducted on a smaller scale. We suggest that to facilitate their identification, these studies should be clearly identified using the terms ‘ feasibility ’ or ‘ pilot ’ as appropriate. This should include feasibility studies that are largely qualitative ; we found these difficult to identify in electronic search es because research ers rarely used the term ‘ feasibility ’ in the title or abstract of such studies. Investigators should also report appropriate objectives and methods related to feasibility ; and give clear confirmation that their study is in preparation for a future r and omised controlled trial design ed to assess the effect of an intervention The feasibility and short-term benefits of Blue Prescription: a novel intervention to enable physical activity for people with multiple sclerosis Purpose : Participation in physical activity for people with Multiple sclerosis ( MS ) is important but can be difficult to sustain long-term. Facilitators for long-term adherence include choice over activity and control over level of engagement, coupled with support, advice and encouragement from a physiotherapist. This is the basis of Blue Prescription, a novel physiotherapy approach aim ed at optimising long-term adherence with physical activity. We evaluated the feasibility and short-term benefits of Blue Prescription in people with MS. Methods : Twenty-seven people with MS ( mean age : 51 ± 11 years, with a range of MS type and disability ) were assessed at baseline and immediately post-intervention with the MS Impact Scale, MS Self-efficacy Scale, and European Quality of Life Question naire. Change in outcomes were analysed with Wilcoxon signed ranks tests. Results : All participants, irrespective of level of disability, were able to choose a physical activity and to engage in it. The physical component MS Impact Scale score significantly improved by a median change of 6.5 ( 95 % CI = −10.5 to −2.0 ; p = 0.007 ; effect size = 0.38 ). There were no other significant changes in outcomes. Conclusion : Blue Prescription appears feasible and potentially beneficial, particularly in reducing the negative impacts of MS upon individuals, and thus warrants further evaluation. Implication s for Rehabilitation Facilitators for long-term adherence for disabled people include choice over activity and control over level of engagement, coupled with support, advice and encouragement from a physiotherapist. Blue Prescription is a physiotherapy approach aim ed at optimising long-term adherence with physical activity for people with multiple sclerosis. Blue Prescription appears to reduce the negative impacts of multiple sclerosis upon individuals Feasibility and effects of a group kickboxing program for individuals with multiple sclerosis: a pilot report. BACKGROUND AND PURPOSE Balance and mobility impairments are common in persons with multiple sclerosis ( MS ). The primary purpose of this pilot program was to evaluate the feasibility and the effects of group kickboxing on balance and mobility in individuals with MS. METHODS Four individuals with relapsing-remitting or secondary progressive MS participated in a group kickboxing program two times per week for 8 weeks. Outcome measures included the Berg Balance Scale ( BBS ), Dynamic Gait Index ( DGI ), Timed Up and Go ( TUG ), walking speed and the Activities Specific Balance Confidence Scale ( ABC ). RESULTS Following training, 3 of 4 participants had improvements in BBS performance. All participants demonstrated improvements in the DGI. Changes in the TUG, ABC, and walking speed were more variable. CONCLUSION Group kickboxing appears to be a feasible exercise activity for individuals with MS and may lead to improvement in select measures of balance. Further investigation may be warranted CONSORT 2010 statement: extension to randomised pilot and feasibility trials The Consoli date d St and ards of Reporting Trials ( CONSORT ) statement is a guideline design ed to improve the transparency and quality of the reporting of r and omised controlled trials ( RCTs ). In this article we present an extension to that statement for r and omised pilot and feasibility trials conducted in advance of a future definitive RCT. The checklist applies to any r and omised study in which a future definitive RCT, or part of it, is conducted on a smaller scale, regardless of its design ( eg, cluster, factorial, crossover ) or the terms used by authors to describe the study ( eg, pilot, feasibility, trial, study ). The extension does not directly apply to internal pilot studies built into the design of a main trial, non-r and omised pilot and feasibility studies, or phase II studies, but these studies all have some similarities to r and omised pilot and feasibility studies and so many of the principles might also apply. The development of the extension was motivated by the growing number of studies described as feasibility or pilot studies and by research that has identified weaknesses in their reporting and conduct. We followed recommended good practice to develop the extension, including carrying out a Delphi survey, holding a consensus meeting and research team meetings, and piloting the checklist. The aims and objectives of pilot and feasibility r and omised studies differ from those of other r and omised trials. Consequently, although much of the information to be reported in these trials is similar to those in r and omised controlled trials ( RCTs ) assessing effectiveness and efficacy, there are some key differences in the type of information and in the appropriate interpretation of st and ard CONSORT reporting items. We have retained some of the original CONSORT statement items, but most have been adapted, some removed, and new items added. The new items cover how participants were identified and consent obtained ; if applicable, the prespecified criteria used to judge whether or how to proceed with a future definitive RCT ; if relevant, other important unintended consequences ; implication s for progression from pilot to future definitive RCT, including any proposed amendments ; and ethical approval or approval by a research review committee confirmed with a reference number. This article includes the 26 item checklist, a separate checklist for the abstract, a template for a CONSORT flowchart for these studies, and an explanation of the changes made and supporting examples. We believe that routine use of this proposed extension to the CONSORT statement will result in improvements in the reporting of pilot trials. Editor ’s note : In order to encourage its wide dissemination this article is freely accessible on the BMJ and Pilot and Feasibility Studies journal websites CONSORT 2010 statement: extension to randomised pilot and feasibility trials The Consoli date d St and ards of Reporting Trials ( CONSORT ) statement is a guideline design ed to improve the transparency and quality of the reporting of r and omised controlled trials ( RCTs ). In this article we present an extension to that statement for r and omised pilot and feasibility trials conducted in advance of a future definitive RCT. The checklist applies to any r and omised study in which a future definitive RCT, or part of it, is conducted on a smaller scale, regardless of its design ( eg, cluster, factorial, crossover ) or the terms used by authors to describe the study ( eg, pilot, feasibility, trial, study ). The extension does not directly apply to internal pilot studies built into the design of a main trial, non-r and omised pilot and feasibility studies, or phase II studies, but these studies all have some similarities to r and omised pilot and feasibility studies and so many of the principles might also apply. The development of the extension was motivated by the growing number of studies described as feasibility or pilot studies and by research that has identified weaknesses in their reporting and conduct. We followed recommended good practice to develop the extension, including carrying out a Delphi survey, holding a consensus meeting and research team meetings, and piloting the checklist. The aims and objectives of pilot and feasibility r and omised studies differ from those of other r and omised trials. Consequently, although much of the information to be reported in these trials is similar to those in r and omised controlled trials ( RCTs ) assessing effectiveness and efficacy, there are some key differences in the type of information and in the appropriate interpretation of st and ard CONSORT reporting items. We have retained some of the original CONSORT statement items, but most have been adapted, some removed, and new items added. The new items cover how participants were identified and consent obtained ; if applicable, the prespecified criteria used to judge whether or how to proceed with a future definitive RCT ; if relevant, other important unintended consequences ; implication s for progression from pilot to future definitive RCT, including any proposed amendments ; and ethical approval or approval by a research review committee confirmed with a reference number. This article includes the 26 item checklist, a separate checklist for the abstract, a template for a CONSORT flowchart for these studies, and an explanation of the changes made and supporting examples. We believe that routine use of this proposed extension to the CONSORT statement will result in improvements in the reporting of pilot trials. Editor ’s note : In order to encourage its wide dissemination this article is freely accessible on the BMJ and Pilot and Feasibility Studies journal websites Design and analysis of pilot studies: recommendations for good practice. Pilot studies play an important role in health research, but they can be misused, mistreated and misrepresented. In this paper we focus on pilot studies that are used specifically to plan a r and omized controlled trial ( RCT ). Citing examples from the literature, we provide a method ological framework in which to work, and discuss reasons why a pilot study might be undertaken. A well-conducted pilot study, giving a clear list of aims and objectives within a formal framework will encourage method ological rigour, ensure that the work is scientifically valid and publishable, and will lead to higher quality RCTs. It will also safeguard against pilot studies being conducted simply because of small numbers of available patients A task-oriented circuit training in multiple sclerosis: a feasibility study Background The aim of this study was to evaluate the safety, feasibility and preliminary effects of a high-intensity rehabilitative task-oriented circuit training ( TOCT ) in a sample of multiple sclerosis ( MS ) subjects on walking competency, mobility, fatigue and health-related quality of life ( HRQoL ). Methods 24 MS subjects ( EDSS 4.89 ± 0.54, 17 female and 7 male, 52.58 ± 11.21 years, MS duration 15.21 ± 8.68 years ) have been enrolled and r and omly assigned to 2 treatment groups : ( i ) experimental group received 10 TOCT sessions over 2 weeks ( 2 hours/each session ) followed by a 3 months home exercise program, whereas control group did not receive any specific rehabilitation intervention. A feasibility patient-reported question naire was administered after TOCT. Functional outcome measures were : walking endurance ( Six Minute Walk Test ), gait speed ( 10 Meter Walk Test ), mobility ( Timed Up and Go test ) and balance ( Dynamic Gait Index ). Furthermore, self-reported question naire of motor fatigue ( Fatigue Severity Scale ), walking ability ( Multiple Sclerosis Walking Scale – 12 ) and health-related quality of life ( Multiple Sclerosis Impact Scale – 29 ) were included. Subjects ’ assessment s were delivered at baseline ( T0 ), after TOCT ( T1 ) and 3 months of home-based exercise program ( T2 ). Results After TOCT subjects reported a positive global rating on the received treatment. At 3 months, we found a 58.33 % of adherence to the home-exercise program. After TOCT, walking ability and health-related quality of life were improved ( p < 0.05 ) with minor retention after 3 months. The control group showed no significant changes in any variables. Conclusions This two weeks high-intensity task-oriented circuit class training followed by a three months home-based exercise program seems feasible and safe in MS people with moderate mobility impairments ; moreover it might improve walking abilities. Trial registration Long-term benefits of exercising on quality of life and fatigue in multiple sclerosis patients with mild disability: a pilot study Objective : To determine if exercise benefits patients with multiple sclerosis. Design : R and omized controlled trial. Setting s : Participants exercised at home and also attended exercise classes held in a hospital physiotherapy gym. Subjects : Thirty patients, diagnosed and independently mobile, were recruited in the Dublin area. Intervention : For three months, classes were held twice-weekly and participants exercised independently once-weekly. The control group was monitored monthly and management remained unchanged. Measurements : Measurements were taken at baseline, three and six months. The Modified Fatigue Impact Scale ( MFIS ), Multiple Sclerosis Impact Scale-29 ( MSIS-29 ) and Functional Assessment of Multiple Sclerosis ( FAMS ) were used to measure fatigue and quality of life ( QOL ). Heart rate ( HR ) and the Borg\'s Rating of Perceived Exertion ( RPE ) were recorded during an incremental exercise test. The change from baseline scores between groups was compared using the Mann — Whitney U-test. Results : Twenty-four participants completed the programme ( n = 12 in each group ). Based on the change in scores at three months, the exercise group had significantly greater improvements in exercise capacity ( HR : —14 [ -18.5, -2.5 ] versus 0.5 [ -4, 5.5 ], P= 0.009 ), QOL ( FAMS : 23 [ 9.5, 42.5 ] versus -3.5 [ -16, 5 ], P=0.006 ) and fatigue ( MFIS : -13 [ -20, -3 ] versus 1 [ -4, 4.5 ], P=0.02 ). At six months, the difference in change scores remained significant for FAMS ( 19 [ 14, 31 ] versus -4.5 [ -25, 8 ], P=0.002 ) and MFIS ( -8.5 [ -19.5, -1 ] versus 0.5 [ -2.5, 6.5 ], P=0.02 ) only. Conclusions : A three-month exercise programme improved participants\'exercise capacity, QOL and fatigue, with the improvements in QOL and fatigue lasting beyond the programme Cost effectiveness of a pragmatic exercise intervention (EXIMS) for people with multiple sclerosis: economic evaluation of a randomised controlled trial Background : Exercise is a safe, non-pharmacological adjunctive treatment for people with multiple sclerosis but cost-effective approaches to implementing exercise within health care setting s are needed. Objective : The objective of this paper is to assess the cost effectiveness of a pragmatic exercise intervention in conjunction with usual care compared to usual care only in people with mild to moderate multiple sclerosis. Methods : A cost-utility analysis of a pragmatic r and omised controlled trial over nine months of follow-up was conducted. A total of 120 people with multiple sclerosis were r and omised ( 1:1 ) to the intervention or usual care. Exercising participants received 18 supervised and 18 home exercise sessions over 12 weeks. The primary outcome for the cost utility analysis was the incremental cost per quality -adjusted life year ( QALY ) gained, calculated using utilities measured by the EQ-5D question naire. Results : The incremental cost per QALY of the intervention was £ 10,137 per QALY gained compared to usual care. The probability of being cost effective at a £ 20,000 per QALY threshold was 0.75, rising to 0.78 at a £ 30,000 per QALY threshold. Conclusion : The pragmatic exercise intervention is highly likely to be cost effective at current established thresholds, and there is scope for it to be tailored to particular sub-groups of patients or services to reduce its cost impact Exercise in the community for people with minimal gait impairment due to MS: an assessor-blind randomized controlled trial Background : While there is an increasing body of evidence supporting the efficacy of exercise in people with multiple sclerosis ( MS ), additional information on the effectiveness of combining aerobic and resistance training, and yoga is required. Objectives : This study evaluated the effectiveness of community exercise interventions for people with MS having minimal gait impairment. Methods : A multi-centred, block-r and omised, assessor-blinded, controlled trial was conducted. Participants were r and omised in groups of eight to physiotherapist (PT)-led exercise ( n = 80 ), yoga ( n = 77 ), fitness instructor (FI)-led exercise ( n = 86 ) and they took part in weekly community-based group exercise sessions. Those in the control group were asked not to change of their exercise habits ( n = 71 ). The primary outcome was the Multiple Sclerosis Impact Scale ( MSIS ) 29v2 physical component, measured before and after the 10-week intervention. Secondary outcomes were the MSIS 29v2 psychological component, the Modified Fatigue Impact Scale ( MFIS ) and the 6-Minute Walk Test ( 6MWT ). Results : The group x time interaction approached significance for the MSIS-29v2 physical component ( f = 2.48, p = 0.061 ) and MFIS total ( f = 2.50, p = 0.06 ), and it was significant for the MFIS physical subscale ( f = 4.23, p = 0.006 ). All three exercise interventions led to a statistically significant improvement on the MSIS-29 psychological component and both the MFIS total and physical subscales, which were greater than the control ( p < 0.05 ). Only the PT-led and FI-led interventions significantly improved the MSIS-29 physical and 6MWT to levels greater than the control ( p < 0.05 ). Conclusions : This study provides evidence for the positive effect of exercise on the physical impact of MS and fatigue. The group nature of the classes may have contributed to the positive effects seen on the psychological impact of MS Effect of Aerobic Training on Walking Capacity and Maximal Exercise Tolerance in Patients With Multiple Sclerosis: A Randomized Crossover Controlled Study Background and Purpose Physical deconditioning is involved in the impaired exercise tolerance of patients with multiple sclerosis ( MS ), but data on the effects of aerobic training ( AT ) in this population are scanty. The purpose of this study was to compare the effects of an 8-week AT program on exercise capacity — in terms of walking capacity and maximum exercise tolerance, as well as its effects on fatigue and health-related quality of life — as compared with neurological rehabilitation ( NR ) in subjects with MS. Subjects and Methods Nineteen subjects ( 14 female, 5 male ; mean age [X̄±SD]=41±8 years ) with mild to moderate disability secondary to MS participated in a r and omized crossover controlled study. Eleven subjects ( 8 female, 3 male ; mean age [X̄±SD]=44±6 years ) completed the study. Results After AT, but not NR, the subjects ’ walking distances and speeds during a self-paced walk were significantly improved, as were their maximum work rate, peak oxygen uptake, and oxygen pulse during cardiopulmonary exercise tests. The increases in peak oxygen uptake and maximum work rate, but not in walking capacity, were significantly higher after AT, as compared with after NR. Additionally, the subjects who were most disabled tended to benefit more from AT. There were no differences between AT and NR in effects on fatigue, and the results showed that AT may have partially affected health-related quality of life. Discussion and Conclusion The results suggest that AT is more effective than NR in improving maximum exercise tolerance and walking capacity in people with mild to moderate disability secondary to MS Fall risk and incidence reduction in high risk individuals with multiple sclerosis: a pilot randomized control trial Objective : To determine the feasibility of three fall prevention programs delivered over 12 weeks among individuals with multiple sclerosis : ( A ) a home-based exercise program targeting physiological risk factors ; ( B ) an educational program targeting behavioral risk factors ; and ( C ) a combined exercise- and -education program targeting both factors. Design : R and omized controlled trial. Setting : Home-based training with assessment s at research laboratory. Participants : A total of 103 individuals inquired about the investigation. After screening, 37 individuals with multiple sclerosis who had fallen in the last year and ranged in age from 45–75 years volunteered for the investigation. A total of 34 participants completed post assessment following the 12-week intervention. Intervention : Participants were r and omly assigned into one of four conditions : ( 1 ) wait-list control ( n = 9 ) ; ( 2 ) home-based exercise ( n = 11 ) ; ( 3 ) education ( n = 9 ) ; or ( 4 ) a combined exercise and education ( n = 8) group. Measures : Before and after the 12-week interventions, participants underwent a fall risk assessment as determined by the physiological profile assessment and provided information on their fall prevention behaviors as indexed by the Falls Prevention Strategy Survey. Participants completed falls diaries during the three-months postintervention. Results : A total of 34 participants completed postintervention testing. Procedures and processes were found to be feasible. Overall, fall risk scores were lower in the exercise groups ( 1.15 SD 1.31 ) compared with the non-exercise groups ( 2.04 SD 1.04 ) following the intervention ( p < 0.01 ). There was no group difference in fall prevention behaviors ( p > 0.05 ). Conclusions : Further examination of home-based exercise/education programs for reducing falls in individuals with multiple sclerosis is warranted. A total of 108 participants would be needed in a larger r and omized controlled trial. Clinical Trials.org # Bridging the goal intention–action gap in rehabilitation: a study of if-then implementation intentions in neurorehabilitation Abstract Purpose : To test the feasibility and acceptability of an implementation intention strategy ( if-then plans ) increasingly used in health psychology to bridge the goal intention – action gap in rehabilitation with people with neurological conditions who are experiencing difficulties with mobility. Methods : Twenty people with multiple sclerosis ( MS ) and stroke, r and omised to an experimental and control group, set up to three mobility related goals with a physiotherapist. The experimental group also formulated if-then plans for every goal. Data collection : Focus groups and interviews with participants and therapists ; Patient Activation Measure ( PAM ), 10-m walk test, Rivermead Mobility Index, self-efficacy, subjective health status, quality of life. Results : Qualitative data highlighted one main theme : Rehabilitation in context, encapsulating the usefulness of the if-then strategy in thinking about the patient in the context of complexity, the usefulness of home-based rehabilitation, and the perceived need for a few more sessions. Changes in walking speed were in the expected direction for both groups ; PAM scores improved over 3 months in both groups. Conclusion : If-then plans were feasible and acceptable in bridging the goal intention – action gap in rehabilitation with people with MS and stroke, who are experiencing difficulties with mobility. This approach can now be adapted and trialled further in a definitive study. Implication s for Rehabilitation Goal planning in rehabilitation necessitates specific strategies that help people engage in goal -related tasks. If-then plans aim to support people to deal more effectively with self-regulatory problems that might undermine goal striving and have been found to be effective in health promotion and health behaviour change. This feasibility study with people with a stroke and multiple sclerosis has demonstrated that if-then plans are feasible and acceptable to patients and physiotherapists in supporting goal -directed behaviour Pilot randomized trial of progressive resistance exercise augmented by neuromuscular electrical stimulation for people with multiple sclerosis who use walking aids. OBJECTIVE To investigate the feasibility and preliminary outcomes of a home progressive resistance training ( PRT ) program augmented by neuromuscular electrical stimulation ( NMES ). DESIGN R and omized controlled pilot trial. SETTING Participant homes. PARTICIPANTS People with multiple sclerosis ( MS ) ( N=37 ) who use a walking aid. INTERVENTIONS A 12-week home PRT program or the same program augmented by NMES. MAIN OUTCOME MEASURES Strength using h and -held dynamometry ; repeated sit to st and test ; Berg Balance Scale ; timed Up & Go test ; 12-Item Multiple Sclerosis Walking Scale ; Multiple Sclerosis Impact Scale-29, version 2 ; and Modified Fatigue Impact Scale ( MFIS ). The NMES group also completed a device usability question naire. RESULTS Only change in MFIS score was significantly greater in the NMES group than the PRT group ( P=.012 ). The NMES group improved significantly in quadriceps endurance ( median of change, 8.5 ; P=.043 ), balance ( median of change, 3.5 ; P=.001 ), physical impact of MS ( median of change, -8.3 ; P=.001 ), and impact of fatigue ( median of change, -17 ; P=.001 ). Participants rated the device as highly usable. CONCLUSIONS This pilot study suggests that a home PRT program with NMES is feasible, and the neuromuscular electrical stimulation device is usable by this population. Only reduction in impact of fatigue was greater in the NMES than the PRT group Exercise for multiple sclerosis: a single-blind randomized trial comparing three exercise intensities Background : The most effective exercise dose has yet to be established for multiple sclerosis ( MS ). Objective : The aim of this study was to investigate the effect of different exercise intensities in people with MS. Methods : We completed a r and omized comparator study of three cycling exercise intensities, with blinded assessment, was carried out in Oxford. Sixty-one adults with MS who fulfilled inclusion criteria were r and omized at entry into the study, using a computer-generated list held by an exercise professional, into either : continuous ( at 45 % peak power, n = 20 ), intermittent ( 30 sec on, 30 sec off at 90 % peak power, n = 21 ) or combined ( 10 min intermittent at 90 % peak power then 10 min continuous at 45 % peak power, n = 20 ) exercise for 20 min twice a week for 12 weeks in a leisure facility. Groups were assessed at : baseline, halfway ( 6 weeks ), end intervention ( 12 weeks ) and follow-up ( 24 weeks ). Primary outcome measure was 2 min walk. Results : Fifty-five participants were included in the analysis ( n = continuous 20, intermittent 18, combined 17 ). No differences were found between groups. After 6 weeks, considering all participants, 2 min walk distance increased by 6.96 ± 2.56 m ( 95 % CI : 1.81 to 12.10, effect size ( es ) : 0.25, p < 0.01 ). The continuous group increased by 4.71 ± 4.24 m ( 95 % CI : −3.80 to 13.22, es : 0.06 ), intermittent by 12.94 ± 4.71 m ( 95 % CI : 3.97 to 21.92, es : 0.28 ) and combined by 3.22 ± 4.60 m ( 95 % CI : −6.01 to 12.46, es : 0.04 ). Two minute walk did not significantly change between further assessment s. Between 6 and 12 weeks there was a drop in attendance that seemed to be associated with the intermittent and combined groups ; these groups also had a greater number of adverse events ( leg pain during cycling most common ) and dropouts ( n = continuous 1, intermittent 5, combined 10 ). Considering all participants, 6 weeks of cycling exercise produced benefits in mobility that were maintained with further sessions. Conclusion : While no differences were found between groups, greater benefit may be associated with higher-intensity exercise, but this may be less well tolerated. CONSORT - trial registration number ( IS RCT N89009719 Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial Background : Few high- quality trials have examined the effects of progressive resistance training ( PRT ) on people with multiple sclerosis ( MS ). Objective : To determine the effectiveness of PRT for people with MS, focusing on improving the gait deficits common in this population. Methods : Using a single blind r and omized controlled trial, people with relapsing – remitting MS were r and omly allocated to either a PRT program targeting the lower limb muscles twice a week for 10 weeks ( n = 36 ), or usual care plus an attention and social program conducted once a week for 10 weeks ( n = 35 ). Outcomes were recorded at baseline, week 10 and week 22. Results : Participants attended 92 % of training sessions, with no serious adverse events. At 10 weeks, no differences were detected in walking performance. However, compared with the comparison group PRT demonstrated increased leg press strength ( 16.8 %, SD 4.5 ), increased reverse leg press strength ( 29.8 %, SD 12.7 ), and increased muscle endurance of the reverse leg press ( 38.7 %, SD 32.8 ). Improvements in favor of PRT were also found for physical fatigue ( Mean difference −3.9 units, 95%CI −6.6 to −1.3 ), and the physical health domain of quality of life ( Mean difference 1.5 units, 95%CI 0.1 to 2.9 ). At week 22 almost no between-group differences remained. Conclusion : PRT is a relatively safe intervention that can have short-term effects on reducing physical fatigue, increasing muscle endurance and can lead to small improvements in muscle strength and quality of life in people with relapsing – remitting MS. However, no improvements in walking performance were observed and benefits do not appear to persist if training is completely stopped Randomized controlled pilot study of customized pamphlets to promote physical activity and symptom self-management in women with multiple sclerosis Objective : Investigate the feasibility and potential efficacy of a customized print-based intervention to promote physical activity and symptom self-management in women with multiple sclerosis. Design : A r and omly allocated two-group repeated measures design, with a delayed-treatment contact group serving as the control. Participants were r and omized to receive the intervention immediately ( n = 14 ) or receive it at week 12 ( n = 16 ). Outcome measures were administered at weeks 1, 12, and 24. Setting : Community-based in metropolitan area. Subjects : Thirty women with multiple sclerosis. Intervention : Prescribing a home-exercise program and following up with customized pamphlets, which are matched to participants ’ stage of readiness to change physical activity behavior and physical activity barriers ( e.g. encouraging self-management of symptoms ). Main Measures : Physical Activity and Disability Survey-revised, Godin Leisure-Time Exercise Question naire, SF-12, Symptoms of Multiple Sclerosis Scale, and 6-minute walk test. Results : Intent-to-treat analyses using mixed multivariate analysis of variance ( MANOVA ) were conducted on ( 1 ) physical activity levels and ( 2 ) health and function outcomes. The mixed MANOVAs for physical activity levels and health and function outcomes indicated significant improvements in the immediate group compared with the delayed group ( i.e. condition by time interaction was significant, Wilks ’ λ = 0.59, F2, 27 = 9.31, P = 0.001 and Wilks ’ λ = 0.70, F4, 25 = 2.72, P = 0.052, respectively ). The intervention had moderate to large effect sizes in improving physical activity levels ( d = 0.63 to 0.89 ), perceptions of physical function ( d = 0.63 ), and 6-minute walk test ( d=0.86 ). Conclusion : This pilot study indicates that a customized print-based intervention shows promise in improving physical activity levels and health and function in women with multiple sclerosis Treadmill training for individuals with multiple sclerosis: a pilot randomised trial This pilot study investigated whether 4 weeks of aerobic treadmill training in individuals with multiple sclerosis ( MS ) improved mobility and reduced fatigue. Individuals with MS were recruited to this prospect i ve, r and omised controlled trial. Individuals were assessed at baseline, week 7 and 12 with a 10 metre timed walk, a 2 minute walk, the Rivermead Mobility Index, and the Fatigue Severity Scale. After a pre- assessment familiarisation session and a baseline assessment, individuals were r and omly allocated to an initial intervention or delayed intervention group. Treadmill training consisted of 4 weeks of supervised aerobic exercise delivered weeks 3–6 in the immediate group and 8–11 in the delayed group. Of the initial 19 recruits, 16 individuals completed the study. There was a significant difference in walking endurance between the delayed and immediate groups at baseline ( p<0.05 ). On re assessment in week 7, decreases in 10 metre walk time were found in both groups, which was significant in the immediate group ( p<0.05 ). The 2 minute walk distance significantly increased in both groups ( p<0.05 ). In the training group, reassessed at week 12 after training ceased, there was a return towards baseline scores. No significant changes in fatigue scores were found. This study showed that in individuals with MS, aerobic treadmill training is feasible and well tolerated. Walking speed and endurance increased following training with no increase in reported fatigue. Detraining occurred in the period following training. A larger r and omised clinical trial is warranted Motivational interviewing may improve exercise experience for people with multiple sclerosis: A small randomized trial. People with multiple sclerosis ( MS ) are likely to benefit from regular exercise, but physical inactivity is more common among people with MS than among the general population. This small r and omized study evaluated whether motivational interviewing ( MI ) affects adherence to and personal experience in an exercise program. Inactive people with MS participating in an eight-week exercise program were r and omized to either three brief MI ( n = 7 ) or three health coaching ( n = 6 ) sessions. Session attendance for both conditions was high, and MI fidelity was rigorously and reliably measured using the Motivational Interviewing Treatment Integrity Scales. The feasibility of using this approach was demonstrated with a small sample. Large effects favoring the MI condition were found for physical exertion, affect during exercise, and fatigue, but no effects were found for adherence to the exercise program. Treatment integrity measures of MI were correlated with outcomes in expected directions. Although this study demonstrated the feasibility of this MI approach, the large effect sizes found should be viewed with substantial skepticism and replicated in sufficiently powered studies using objective measures of exercise adherence', "Background Neck and shoulder disorders may be linked to the presence of myofascial trigger points ( MTrPs ). These disorders can significantly impact a person ’s activities of daily living and ability to work. MTrPs can be involved with pain sensitization, contributing to acute or chronic neck and shoulder musculoskeletal disorders. The aim of this review was to synthesis e evidence on the prevalence of active and latent MTrPs in subjects with neck and shoulder disorders. Changes in pain and pressure pain sensitivity after manual treatment of active trigger points in patients with unilateral shoulder impingement: a case series. The aim of this case series was to investigate changes in pain and pressure pain sensitivity after manual treatment of active trigger points ( TrPs ) in the shoulder muscles in individuals with unilateral shoulder impingement. Twelve patients ( 7 men, 5 women, age : 25 ± 9 years ) diagnosed with unilateral shoulder impingement attended 4 sessions for 2 weeks ( 2 sessions/week ). They received TrP pressure release and neuromuscular interventions over each active TrP that was found. The outcome measures were pain during arm elevation ( visual analogue scale, VAS ) and pressure pain thresholds ( PPT ) over levator scapulae, supraspinatus infraspinatus, pectoralis major, and tibialis anterior muscles. Pain was captured pre-intervention and at a 1-month follow-up, whereas PPT were assessed pre- and post-treatment, and at a 1-month follow-up. Patients experienced a significant ( P < 0.001 ) reduction in pain after treatment ( mean ± SD : 1.3 ± 0.5 ) with a large effect size ( d > 1 ). In addition, patients also experienced a significant increase in PPT immediate after the treatment ( P < 0.05 ) and one month after discharge ( P < 0.01 ), with effect sizes ranging from moderate ( d = 0.4 ) to large ( d > 1).A significant negative association ( r(s ) = -0.525 ; P = 0.049 ) between the increase in PPT over the supraspinatus muscle and the decrease in pain was found : the greater the decrease in pain, the greater the increase in PPT. This case series has shown that manual treatment of active muscle TrPs can help to reduce shoulder pain and pressure sensitivity in shoulder impingement. Current findings suggest that active TrPs in the shoulder musculature may contribute directly to shoulder complaint and sensitization in patients with shoulder impingement syndrome, although future r and omized controlled trials are required Test-retest reliability of myofascial trigger point detection in patients with rotator cuff tendonitis Objectives : To investigate the test-retest reliability of the following clinical diagnostic characteristics of myofascial trigger points : taut b and, spot tenderness, jump sign, pain recognition, referred pain and local twitch responses ( LTRs ). Design : Test-retest reliability study. Setting : This study was undertaken in an outpatient physiotherapy department. Subjects : Fifty-eight patients ( 31 males and 27 females ) with rotator cuff tendonitis were recruited into this study. Intervention : Rotator cuff muscles were assessed by an expert for the presence or absence of the main clinical diagnostic characteristics of trigger point assessment. The process was then repeated three days later by the same expert. Main measures : Outcomes included the presence or absence of : a taut b and, spot tenderness, jump sign, pain recognition, referred pain and LTRs. Results : Kappa values between testing situations for the taut b and, spot tenderness, jump sign and pain recognition were 1. Kappa scores for referred pain ranged between 0.79 and 0.88 and for the local twitch response between 0.75 and 1 depending on the muscles under investigation. Conclusions : The presence or absence of the taut b and, spot tenderness, jump sign and pain recognition was highly reliable between sessions. Referred pain and local twitch response reliability varied depending on the muscle being studied Active myofascial trigger points might be more frequent in patients with cervical radiculopathy. BACKGROUND Myofascial trigger points ( MTrPs ) are commonly observed in the neck, parascapular region, and upper back muscles of patients with cervical pathology. AIM To assess the frequency of latent and active myofascial trigger point ( aMTrP ) in the neck and upper back muscles in patients with cervical radiculopathy and healthy subjects. DESIGN Controlled clinical trials. SETTING Out patients and controls. POPULATION Two hundred and forty four patients and 122 controls METHODS The patients clinical ly diagnosed as cervical radiculopathy with positive Spurling's test and confirmed by MRI, were enrolled in this study. All subjects were examined for active and latent MTrP. In patients with cervical radiculopathy, an aMTrP was distinguished from a latent one when the referred pain elicited by exploration of the MTrP is recognized as familiar. RESULTS The patients comprised of 128 female ( 52.5 % ) and 116 male ( 47.5 % ) patients. Mean age was 44.58(20 - 65 years ). In 125 ( 51.2 % ) of patients with cervical radiculopathy were found an aMTrP at least one muscle from upper trapezius, multifidus, splenius capitis, levator scapulae, rhomboid major, minor and deep paraspinal muscles. Number and distribution of MTrPs in patients with 244 cervical radiculopathy and in healthy controls. aMTrPs were detected most common in levator scapula ( 16.3 % ), splenius capitis ( 14.7 % ), rhomboid minor ( 14.3 % ), upper part of trapezius ( 13.5 % ), rhomboid major ( 10.2 % ) and multifidus ( 8.6 % ) muscles. Patients with cervical radiculopathy showed latent MTrP in levator scapula ( 27 % ), splenius capitis ( 16.8 % ), rhomboid minor ( 24.6 % ), upper part of trapezius ( 33.2 % ), rhomboid major ( 9 % ) and multifidus ( 8.2 % ) muscles. There was significant difference in terms of distribution of active and latent MTrPs in patients with cervical radiculopathy ( P=0.019 ). Number of latent MTrPs in upper trapezius muscles in patients with cervical radiculopathy was more than the expected distribution. None of the subjects of control group had aMTrP. However, healthy controls showed latent MTrP in levator scapula ( 33.6 % ), splenius capitis ( 16.4 % ), rhomboid minor ( 21.3 % ), upper part of trapezius ( 40.2 % ), rhomboid major ( 6.5 % ) and multifidus ( 17.2 % ) muscles. There was no significant difference in terms of distribution of latent MTrPs between cervical radiculopathy and control groups ( P=0.249 ). The frequency of aMTrP was found to be significantly higher in CDH with median localization as compared to posterolateral herniations ( P=0.041 ). After conservative treatment for two weeks, number of patients with active MTrP in cervical radiculopathy were decreased about 50 %. CONCLUSION Cervical root compression would be considered as the starting or maintaining factor of aMTrP. CLINICAL REHABILITATION IMPACT The treatment of cervical radiculopathy might be facilitated the improving in aMTrPs located in aforementioned muscles The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting, internal validity ( bias and confounding ) and power, but also for external validity. DESIGN : A pilot version was first developed, based on epidemiological principles, review s, and existing checklists for r and omised studies. Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies. Using different raters, the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ), test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ), criterion validity, and respondent burden. MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version. The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ). Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good. Reliability of the subscales varied from good ( bias ) to poor ( external validity ). The Quality Index correlated highly with an existing, established instrument for assessing r and omised studies ( r 0.90 ). There was little difference between its performance with non-r and omised and with r and omised studies. Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ). CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies. It has also shown that it is possible to produce a checklist that provides a profile of the paper, alerting review ers to its particular method ological strengths and weaknesses. Further work is required to improve the checklist and the training of raters in the assessment of external validity Inclusion of trigger point dry needling in a multimodal physical therapy program for postoperative shoulder pain: a randomized clinical trial. OBJECTIVE The purpose of this study was to evaluate the effects of including 1 session of trigger point dry needling ( TrP-DN ) into a multimodal physiotherapy treatment on pain and function in postoperative shoulder pain. METHODS Twenty patients ( 5 male ; 15 female ; age, 58 ± 12 years ) with postoperative shoulder pain after either open reduction and internal fixation with Proximal Humeral Internal Locking System plate plate or rotator cuff tear repair were r and omly divided into 2 groups : physiotherapy group ( n = 10 ) who received best evidence physical therapy interventions and a physical therapy plus TrP-DN group ( n = 10 ) who received the same intervention plus a single session of TrP-DN targeted at active TrPs. The Constant-Murley score was used to determine pain, activities of daily living, range of motion, and strength, which was captured at baseline and 1 week after by an assessor blinded to group assignment. RESULTS Analysis of variance showed that subjects receiving TrP-DN plus physical therapy exhibited greater improvement in the Constant-Murley total score ( P <.001 ) and also activities of daily living ( P <.001 ) and strength ( P =.019 ) subscales than those receiving physical therapy alone. Between-group effect sizes were large in favor of the TrP-DN group ( 0.97 < SMD < 1.45 ). Both groups experienced similar improvements in pain ( P <.001 ) and range of motion ( P <.001 ). CONCLUSIONS Our results suggest that including a single session of TrP-DN in the first week of a multimodal physical therapy approach may assist with faster increases in function in individuals with postoperative shoulder pain Upper cervical mobility, posture and myofascial trigger points in subjects with episodic migraine: Case-control study. OBJECTIVES To evaluate the association between episodic migraines and the prevalence of myofascial trigger points ( MTrPs ) in the sternocleidomastoid and upper trapezius, forward head posture ( FHP ), neck range of motion ( ROM ) and cervical facet joint stiffness. METHODS 20 physiotherapy students with episodic migraines and 20 age- and sex matched healthy controls were included in this observational case-control study. Demographics and headache status were evaluated through question naires. Active neck ROM, presence of MTrPs, and cervical facet joint mobility were assessed by physical examination. FHP was measured using a lateral digital photograph taken in a sitting position. RESULTS No significant differences were found in neck ROM measurements and FHP between the migraine and control groups. Significant differences were found in the prevalence of cervical facet joints stiffness in Occiput-C1 ( χ(2 ) = 4.444, p = 0.035 ) and C1-C2 ( χ(2 ) = 10.157, p = 0.001 ), but not in other segments. Significant differences were found in the prevalence of active and latent MTrPs between the migraine and control subjects in the right trapezius ( χ(2 ) = 11.649, p = 0.003 ) and right sternocleidomastoid ( χ(2 ) = 8.485, p = 0.014 ). CONCLUSIONS Our findings support the hypothesis that the prevalence of MTrPs in neck muscles and hypomobility in the upper cervical facet joints are associated with migraines High prevalence of shoulder girdle muscles with myofascial trigger points in patients with shoulder pain Background Shoulder pain is reported to be highly prevalent and tends to be recurrent or persistent despite medical treatment. The pathophysiological mechanisms of shoulder pain are poorly understood. Furthermore, there is little evidence supporting the effectiveness of current treatment protocol s. Although myofascial trigger points ( MTrPs ) are rarely mentioned in relation to shoulder pain, they may present an alternative underlying mechanism, which would provide new treatment targets through MTrP inactivation. While previous research has demonstrated that trained physiotherapists can reliably identify MTrPs in patients with shoulder pain, the percentage of patients who actually have MTrPs remains unclear. The aim of this observational study was to assess the prevalence of muscles with MTrPs and the association between MTrPs and the severity of pain and functioning in patients with chronic non-traumatic unilateral shoulder pain. Methods An observational study was conducted. Subjects were recruited from patients participating in a controlled trial study ing the effectiveness of physical therapy on patients with unilateral non-traumatic shoulder pain. Sociodemographic and patient-reported symptom scores, including the Disabilities of the Arm, Shoulder, and H and ( DASH ) Question naire, and Visual Analogue Scales for Pain were compared with other studies. To test for differences in age, gender distribution, and education level between the current study population and the population s from Dutch shoulder studies, the one sample T-test was used. One observer examined all subjects ( n = 72 ) for the presence of MTrPs. Frequency distributions, means, medians, st and ard deviations, and 95 % confidence intervals were calculated for descriptive purpose s. The Spearman's rank-order correlation ( ρ ) was used to test for association between variables. Results MTrPs were identified in all subjects. The median number of muscles with MTrPs per subject was 6 ( active MTrPs ) and 4 ( latent MTrPs ). Active MTrPs were most prevalent in the infraspinatus ( 77 % ) and the upper trapezius muscles ( 58 % ), whereas latent MTrPs were most prevalent in the teres major ( 49 % ) and anterior deltoid muscles ( 38 % ). The number of muscles with active MTrPs was only moderately correlated with the DASH score. Conclusion The prevalence of muscles containing active and latent MTrPs in a sample of patients with chronic non-traumatic shoulder pain was high", 'Background Resistant starch ( RS ) is a starch that can be fermented by the microbial flora within gut lumen. Insulin resistance ( IR ) is a pathophysiological condition related to diabetes and obesity. RS could reduce blood glucose and ameliorate IR in animals, but its effect in human population is controversial. Objective The authors conducted a systematic literature review to evaluate the effect of RS diet supplement on ameliorating IR in patients with T2DM and simple obesity. Resistant starch lowers postprandial glucose and leptin in overweight adults consuming a moderate-to-high-fat diet: a randomized-controlled trial Background High-amylose maize resistant starch type 2 ( HAM-RS2 ) stimulates gut-derived satiety peptides and reduces adiposity in animals. Human studies have not supported these findings despite improvements in glucose homeostasis and insulin sensitivity after HAM-RS2 intake which can lower adiposity-related disease risk. The primary objective of this study was to evaluate the impact of HAM-RS2 consumption on blood glucose homeostasis in overweight, healthy adults. We also examined changes in biomarkers of satiety ( glucagon-like peptide-1 [ GLP-1 ], peptide YY [ PYY ], and leptin ) and body composition determined by anthropometrics and dual-energy x-ray absorptiometry, dietary intake, and subjective satiety measured by a visual analogue scale following HAM-RS2 consumption. Methods Using a r and omized-controlled, parallel-arm, double-blind design, 18 overweight, healthy adults consumed either muffins enriched with 30 g HAM-RS2 ( n = 11 ) or 0 g HAM-RS2 ( control ; n = 7 ) daily for 6 weeks. The HAM-RS2 and control muffins were similar in total calories and available carbohydrate. Results At baseline, total PYY concentrations were significantly higher 120 min following the consumption of study muffins in the HAM-RS2 group than control group ( P = 0.043 ). Within the HAM-RS2 group, the area under the curve ( AUC ) glucose ( P = 0.028 ), AUC leptin ( P = 0.022 ), and postpr and ial 120-min leptin ( P = 0.028 ) decreased independent of changes in body composition or overall energy intake at the end of 6 weeks. Fasting total PYY increased ( P = 0.033 ) in the HAM-RS2 group, but changes in insulin or total GLP-1 were not observed. Mean overall change in subjective satiety score did not correlate with mean AUC biomarker changes suggesting the satiety peptides did not elicit a satiation response or change in overall total caloric intake. The metabolic response from HAM-RS2 occurred despite the habitual intake of a moderate-to-high-fat diet ( mean range 34.5 % to 39.4 % of total calories ). Conclusion Consuming 30 g HAM-RS2 daily for 6 weeks can improve glucose homeostasis, lower leptin concentrations, and increase fasting PYY in healthy overweight adults without impacting body composition and may aid in the prevention of chronic disease. However, between-group differences in biomarkers were not observed and future research is warranted before specific recommendations can be made. Trial registration None [Effects of resistant starch on insulin resistance of type 2 diabetes mellitus patients]. OBJECTIVE To observe the effects of resistant starch ( RS ) on insulin resistance ( IR ) in type 2 diabetes mellitus patients. METHODS All 40 patients with type 2 diabetes mellitus were r and omly divided into two groups : Group A and Group B. Cross- design of two stages ( I, II ) was used during observation. Group A received RS 30 g/d as an intervention group for ahead of 4 weeks ( I stage ), while group B as a control group. Group B was given RS in late 4 weeks ( II stage ), while Group A as served control group. Blood was taken the first day and on the latest day in each stage. Fasting blood glucose ( FBG ), post blood glucose ( PBG ), fructosamine ( FMN ), total cholesterol ( TC ), triglyceridemic ( TG ), insulin sensitive index ( ISI ), and body mass index ( BMI ) were measured, respectively. RESULTS As Compared with the control group, ISI was higher and FBG, PBG, TC, TG, FMN and BMI were significantly lower in intervention group ( P < 0.05 ). CONCLUSION RS should be effective in improving IR of type 2 diabetes mellitus patients Efficacy of increased resistant starch consumption in human type 2 diabetes Resistant starch ( RS ) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes ( T2DM ) are unknown. This study aim ed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postpr and ial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM ( HbA1c 46.6±2 mmol/mol ) consumed, in a r and om order, either 40 g of type 2 RS ( HAM-RS2 ) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations : a two-step euglycemic – hyperinsulinemic clamp combined with an infusion of [ 6,6 - 2H2 ] glucose, a meal tolerance test ( MTT ) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 result ed in significantly lower postpr and ial glucose concentrations ( P=0.045 ) and a trend for greater glucose uptake across the forearm muscle ( P=0.077 ) ; however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid ( NEFA ) concentrations were significantly lower ( P=0.004 ) and NEFA suppression was greater during the clamp with HAM-RS2 ( P=0.001 ). Fasting triglyceride ( TG ) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 ( P=0.039 and P=0.027 respectively ). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption ( P=0.049 ), postpr and ial GLP1 excursions during the MTT were significantly greater ( P=0.009 ). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal h and ling, possibly due to higher postpr and ial GLP1 Increased gut hormones and insulin sensitivity index following a 3-d intervention with a barley kernel-based product: a randomised cross-over study in healthy middle-aged subjects. Certain purified indigestible carbohydrates such as inulin have been shown to stimulate gut-derived hormones involved in glycaemic regulation and appetite regulation, and to counteract systemic inflammation through a gut microbiota-mediated mechanism. Less is known about the properties of indigestible carbohydrates intrinsic to food. The aim of this study was to investigate the possibility to affect release of endogenous gut hormones and ameliorate appetite control and glycaemic control by ingestion of a whole-grain cereal food product rich in NSP and resistant starch in healthy humans. In all, twenty middle-aged subjects were provided with a barley kernel-based bread ( BB ) or a reference white wheat bread during 3 consecutive days, respectively, in a r and omised cross-over design study. At a st and ardised breakfast the following day ( day 4 ), blood was collected for the analysis of blood ( b ) glucose regulation, gastrointestinal hormones, markers of inflammation and markers of colonic fermentation ; 3 d of intervention with BB increased gut hormones in plasma ( p ) the next morning at fasting ( p-glucagon-like peptide-1 ; 56 % ) and postpr and ially ( p-glucagon-like peptide-2 ; 13 % and p-peptide YY ; 18 % ). Breath H₂ excretion and fasting serum ( s ) SCFA concentrations were increased ( 363 and 18 %, respectively ), and b-glucose ( 22 % ) and s-insulin responses ( 17 % ) were decreased after BB intervention. Insulin sensitivity index ( ISI(composite ) ) was also improved ( 25 % ) after BB. In conclusion, 3 d of intervention with BB increased systemic levels of gut hormones involved in appetite regulation, metabolic control and maintenance of gut barrier function, as well as improved markers of glucose homoeostasis in middle-aged subjects, altogether relevant for the prevention of obesity and the metabolic syndrome Resistant dextrin, as a prebiotic, improves insulin resistance and inflammation in women with type 2 diabetes: a randomised controlled clinical trial. Improvement of insulin resistance and inflammation is a basic strategy in the management of type 2 diabetes. There is limited evidence that prebiotics improve insulin resistance and inflammation. However, the ameliorating effect of resistant dextrin, as a prebiotic, on insulin resistance and inflammation in patients with type 2 diabetes has not been investigated so far. Therefore, the present study aim ed to examine the effects of resistant dextrin on insulin resistance and inflammation in type 2 diabetic patients. In a r and omised controlled clinical trial, fifty-five women with type 2 diabetes were assigned to two groups : the intervention group ( n 30 ) and the control group ( n 25 ). The intervention group received a daily supplement of 10 g resistant dextrin and the control group received a similar amount of maltodextrin as placebo for 8 weeks. Fasting plasma glucose ( FPG ), HbA1c, insulin, high-sensitivity C-reactive protein ( hs-CRP ), IL-6, TNF-α, malondialdehyde ( MDA ) and serum endotoxin concentrations were measured before and after the intervention. Data were analysed using SPSS ( version 13 ). Paired and unpaired t tests and ANCOVA were used to compare quantitative variables after the intervention. Patients supplemented with resistant dextrin exhibited a significant decrease in fasting insulin ( 20.1 pmol/l, 22.8 % ), homeostasis model assessment of insulin resistance ( 1.3, 24.9 % ), quantitative insulin sensitivity check index ( 0.2, 7.2 % ), IL-6 ( 1.4 pg/ml, 28.4 % ), TNF-α ( 5.4 pg/ml, 18.8 % ), MDA ( 1.2 nmol/ml, 25.6 % ) and endotoxin ( 6.2 endotoxin units/ml, 17.8 % ) concentrations than those supplemented with maltodextrin ( P < 0.05 ). Decreases in FPG ( 0.05 mmol/l, 0.6 % ), HbA1c ( 0.5 %, 9.6 % ) and hs-CRP ( 2.7 ng/ml, 35.1 % ) concentrations in the resistant dextrin group were not significant when compared with the maltodextrin group. In conclusion, resistant dextrin supplementation can modulate inflammation and improve insulin resistance in women with type 2 diabetes Resistant Starch Bagels Reduce Fasting and Postprandial Insulin in Adults at Risk of Type 2 Diabetes. BACKGROUND Type 2 diabetes ( T2D ) incidence continues to rise. Although increasing dietary fiber intake is an established strategy for improved glycemic control, most adults consume insufficient amounts. Fiber-enhanced functional foods can increase fiber intake, and there is particular interest in resistant starch ( RS ) as a high-fiber ingredient. Studies show that high-amylose maize resistant starch, type 2 ( HAM-RS2 ) improves acute and chronic glycemic responses, but more studies are needed in individuals at high risk of T2D with RS delivered in commonly consumed foods. OBJECTIVE The objective of this study was to examine the chronic effects of consuming bagels high in HAM-RS2 on fasting and postpr and ial glycemic markers in adults at increased risk of T2D. METHODS With the use of a r and omized, double-blind crossover design, 24 men and women with a mean ± SE age of 55.3 ± 1.59 y and body mass index ( in kg/m2 ) of 30.2 ± 0.57 consumed 1 bagel containing 25 g HAM-RS2/d or 1 control wheat bagel/d for 56 d each, separated by a 4-wk washout. Fasting and postpr and ial oral-glucose-tolerance test ( OGTT ) glucose and insulin were measured on study days 1 and 57 of each bagel treatment. RESULTS The RS bagel treatment result ed in significantly lower fasting ( 22.1 %, P = 0.04 ), 2-h ( 23.3 %, P < 0.008 ), and 3-h ( 18.9 %, P = 0.05 ) insulin incremental areas under the curve and fasting insulin resistance ( homeostasis model assessment of insulin resistance ; 23.1 %, P = 0.04 ) than did the control bagel treatment. Fasting and postpr and ial OGTT glucose concentrations did not differ between the RS and control bagel treatments on study days 1 or 57. CONCLUSIONS These data suggest that consumption of a high-HAM-RS2 bagel improves glycemic efficiency by reducing the amount of insulin required to manage postpr and ial glucose while improving fasting insulin sensitivity in adults at increased risk of T2D. This research provides support for a feasible dietary strategy for T2D risk reduction. This trial was registered at clinical trials.gov as NCT02129946 The Therapeutic Potential of Resistant Starch in Modulation of Insulin Resistance, Endotoxemia, Oxidative Stress and Antioxidant Biomarkers in Women with Type 2 Diabetes: A Randomized Controlled Clinical Trial Aims : This trial aims to determine the effects of resistant starch ( RS ) subtype 2 ( RS2 ) on glycemic status, metabolic endotoxemia and markers of oxidative stress. Methods : A r and omized, controlled, parallel-group clinical trial group of 56 females with type 2 diabetes mellitus ( T2DM ) was divided to 2 groups. The intervention group ( n = 28 ) and control group ( n = 28 ) received 10 g/day RS2 or placebo for 8 weeks, respectively. Fasting blood sample s were taken to determine glycemic status, endotoxin, high sensitivity C-reactive protein ( hs-CRP ), malondialdehyde ( MDA ), total antioxidant capacity ( TAC ), antioxidant enzymes concentrations as well as uric acid at baseline and after the intervention. Results : After 8 weeks, RS2 caused a significant decrease in the levels of MDA ( -34.10 % ), glycosylated hemoglobin ( -9.40 % ), insulin ( -29.36 % ), homeostasis model of insulin resistance ( -32.85 % ) and endotoxin ( -25.00 % ), a significant increase in TAC ( 18.10 % ) and glutathione peroxidase ( 11.60 % ) as compared with control. No significant changes were observed in fasting plasma glucose, quantitative insulin sensitivity check index, hs-CRP, superoxide dismutase, catalase and uric acid in the RS2 group as compared with the control group. Conclusion : Supplementation with RS2 may be improved glycemic status, endotoxemia and markers of oxidative stress in patients with T2DM Dietary treatment with rice containing resistant starch improves markers of endothelial function with reduction of postprandial blood glucose and oxidative stress in patients with prediabetes or newly diagnosed type 2 diabetes. OBJECTIVE We aim ed to evaluate whether 4-week of dietary treatment with rice containing resistant starch reduces blood glucose and oxidative stress as well as improves endothelial function. METHODS Patients with impaired fasting glucose ( IFG ), impaired glucose tolerance ( IGT ) or newly diagnosed type 2 diabetes ( n = 90 ) were r and omly assigned to either a group ingesting rice containing 6.51 g resistant starch daily or a control rice group for 4-weeks. We assessed fasting and postpr and ial levels of glucose and insulin, oxidative stress markers and endothelial function using reactive hyperemia peripheral arterial tonometry ( RH-PAT ). RESULTS The diet containing rice with resistant starch reduced fasting insulin and insulin resistance, postpr and ial glucose ( P = 0.010 ) and insulin levels at 30 min, and glucose and insulin areas under the response curve after the st and ard meal. Rice with resistant starch also decreased urinary 8-epi-PGF(2α ) and plasma malondialdehyde ( MDA ) and increased the RH-PAT index ( P < 0.001 ) and total nitric oxide ( NO ). Postpr and ial changes in glucose at 60 and 120 min and areas under the glucose response curve, MDA, RH-PAT, and total NO of the test group differed significantly from those in the control even after adjusting for baseline values. Overall, changes in the RH-PAT index correlated positively with changes in total NO ( r = 0.336, P = 0.003 ) and superoxide dismutase activity ( r = 0.381, P = 0.001 ) and negatively with changes in MDA ( r = -0.358, P = 0.002 ) and 8-epi-PGF(2α ). CONCLUSIONS In patients with IFG, IGT or newly diagnosed type 2 diabetes, 4-weeks of dietary treatment with rice containing resistant starch was associated with improved endothelial function with reduction of postpr and ial glucose and oxidative stress compared with control Prior short-term consumption of resistant starch enhances postprandial insulin sensitivity in healthy subjects Aims /hypothesisDiets rich in insoluble-fibre are linked to a reduced risk of both diabetes and cardiovascular disease ; however, the mechanism of action remains unclear. The aim of this study was to assess whether acute changes in the insoluble-fibre ( resistant starch ) content of the diet would have effects on postpr and ial carbohydrate and lipid h and ling. Methods Ten healthy subjects consumed two identical, low-residue diets on separate occasions for 24 h ( 33 % fat ; < 2 g dietary fibre ). Of the diets one was supplemented with 60 g resistant starch ( Novelose 260 ). On the following morning a fibre-free meal tolerance test ( MTT ) was carried out ( 59 g carbohydrate ; 21 g fat ; 2.1 kJ ) and postpr and ial insulin sensitivity ( SIORAL ) assessed using a minimal model approach. Results Prior resistant starch consumption led to lower postpr and ial plasma glucose ( p=0.037 ) and insulin ( p=0.038 ) with a higher insulin sensitivity(44±7.5 vs 26±3.5 × 10−4 dl kg−1 min−1 per µUml−1 ; p=0.028 ) and C-peptide-to-insulin molar ratio ( 18.7±6.5 vs 9.7±0.69 ; p=0.017 ). There was no effect of resistant starch consumption on plasma triacylglycerol although non-esterified fatty acid and 3-hydroxybutyrate levels were suppressed 5 h after the meal tolerance test. Conclusion Prior acute consumption of a high-dose of resistant starch enhanced carbohydrate h and ling in the postpr and ial period the following day potentially due to the increased rate of colonic fermentation Is there any place for resistant starch, as alimentary prebiotic, for patients with type 2 diabetes? OBJECTIVE The aim of the present study was to determine effects of Resistant Starch ( RS2 ) on metabolic parameters and inflammation in women with type 2 diabetes ( T2DM ). METHODS In this r and omized controlled clinical trial, 60 females with T2DM were divided into intervention ( n = 28 ) and placebo groups ( n = 32 ). They received 10 g/d RS2 or placebo for 8 weeks, respectively. Fasting blood sugar ( FBS ), glycated hemoglobin ( HbA1c ), lipid profile, high-sensitive C-reactive protein ( hs-CRP ), interleukin-6 ( IL-6 ) and tumor necrosis factor-alpha ( TNF-α ) were measured at baseline and at the end of the trial. Paired t test, unpaired t-test and ANCOVA were used to compare the quantitative variables. The data were analyzed using SPSS software version 13.0. RESULTS RS2 decreased HbA1c ( -0.3 %, -3.6 % ), TNF-α ( -3.4 pg/mL, -18.9 % ), triglyceride ( -33.4 mg/dL, -15.4 % ), and it increased HDL-c ( + 9.4 mg/dL, + 24.6 % ) significantly compared with the placebo group ( p < 0.05 ). Changes in FBS, total cholesterol, low-density lipoprotein, hs-CRP and IL-6 were not significant in the RS2 group compared with the control group. RS2 can improve glycemic status, inflammatory markers and lipid profile in women with T2DM. CONCLUSIONS Although findings of the present study indicated positive effects of RS2 on inflammation and metabolic parameters, more studies are needed to confirm efficacy of RS2 as an adjunct therapy in diabetes', 'Animal and human observational studies suggest that iron deficiency impairs physical exercise performance, but findings from r and omized trials on the effects of iron are equivocal. Iron deficiency and anemia are especially common in women of reproductive age ( WRA ). Clear evidence of benefit from iron supplementation would inform clinical and public health guidelines. Therefore, we performed a systematic review and meta- analysis to determine the effect of iron supplementation compared with control on exercise performance in WRA. Iron supplementation improves endurance after training in iron-depleted, nonanemic women. Our objective was to investigate the effects of iron depletion on adaptation to aerobic exercise, assessed by time to complete a 15-km cycle ergometer test. Forty-two iron-depleted ( serum ferritin < 16 microg/l ), nonanemic ( Hb > 12 g/dl ) women ( 18 - 33 yr old ) received 100 mg of ferrous sulfate ( S ) or placebo ( P ) per day for 6 wk in a r and omized, double-blind trial. Subjects trained for 30 min/day, 5 days/wk at 75 - 85 % of maximum heart rate for the final 4 wk of the study. There were no group differences in baseline iron status or in 15-km time. Iron supplementation increased serum ferritin and decreased transferrin receptors in the S compared with the P group. The S and P groups decreased 15-km time and respiratory exchange ratio and increased work rate during the 15-km time trial after training. The decrease in 15-km time was greater in the S than in the P group ( P = 0.04 ) and could be partially attributed to increases in serum ferritin and Hb. These results indicate that iron deficiency without anemia impairs favorable adaptation to aerobic exercise Marginal iron deficiency without anemia impairs aerobic adaptation among previously untrained women. BACKGROUND Iron deficiency without anemia has been shown to reduce both muscle-tissue oxidative capacity and endurance in animals. However, the consequences of iron deficiency in humans remain unclear. OBJECTIVE We investigated the effects of iron supplementation on adaptation to aerobic training among marginally iron-depleted women. We hypothesized that iron supplementation for 6 wk would significantly improve iron status and maximal oxygen uptake ( VO(2)max ) after 4 wk of concurrent aerobic training. DESIGN Forty-one untrained, iron-depleted, nonanemic women were r and omly assigned to receive either 50 mg FeSO(4 ) or a placebo twice daily for 6 wk in a double-blind trial. All subjects trained on cycle ergometers 5 d/wk for 4 wk, beginning on week 3 of the study. RESULTS Six weeks of iron supplementation significantly improved serum ferritin and serum transferrin receptor ( sTfR ) concentrations and transferrin saturation without affecting hemoglobin concentrations or hematocrit. Average VO(2)max and maximal respiratory exchange ratio improved in both the placebo and iron groups after training ; however, the iron group experienced significantly greater improvements in VO(2)max. Both iron-status and fitness outcomes were analyzed after stratifying by baseline sTfR concentration ( > and < or = 8.0 mg/L ), which showed that the previously observed treatment effects were due to iron-status and fitness improvements among subjects with poor baseline iron status. CONCLUSIONS Our findings strongly suggest that iron deficiency without anemia but with elevated sTfR status impairs aerobic adaptation among previously untrained women and that this can be corrected with iron supplementation Tissue iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women. BACKGROUND We previously showed that iron supplementation significantly improves iron status and maximal work capacity in previously untrained, marginally iron-deficient women with a baseline serum transferrin receptor concentration > 8.0 mg/L. However, the effect of transferrin receptor status on adaptation in endurance capacity after aerobic training in these subjects has not been fully explored. OBJECTIVE Our objective was to examine the effect of baseline serum transferrin receptor status on adaptations in endurance capacity. DESIGN Forty-one untrained, iron-depleted, nonanemic women were r and omly assigned to receive either 100 mg FeSO(4 ) or a placebo for 6 wk in a double-blind trial. All subjects trained on cycle ergometers 5 d/wk for the last 4 wk of the study. Endurance capacity was assessed at baseline and after treatment by using a 15-km time trial conducted on a cycle ergometer. RESULTS Significant treatment effects were observed for time to complete the 15-km time trial, work rate, and percentage of maximal oxygen uptake in subjects with a baseline serum transferrin receptor concentration > 8.0 mg/L. No significant treatment effects were observed in subjects with a normal baseline transferrin receptor concentration. CONCLUSIONS Our findings suggest that, in the presence of overt tissue iron deficiency, iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women. This impairment can be corrected with iron supplementation Functional consequences of iron supplementation in iron-deficient female cotton mill workers in Beijing, China. Eighty iron-deficient, nonpregnant female workers were r and omly assigned to ferrous sulphate ( 60 or 120 mg Fe/d ) or placebo treatment for 12 wk. Energy expenditure was estimated during 3 d by heart rate ( HR ) recording. Production efficiency ( PE ) was calculated as the ratio of productivity to energy expenditure. In the iron-treated group mean hemoglobin ( Hb ) increased from 114 to 127 g/L ( P < 0.001 ), mean serum ferritin increased from 9.7 to 30.0 micrograms/L ( P < 0.001 ), and mean free erythrocyte protoporphyrin decreased from 1.01 to 0.49 mumol/L ( P < 0.001 ). Mean HR at work decreased from 95.5 to 91.1 beats/min ( P < 0.001 ), which was inversely correlated with the change in Hb ( r = -0.60, P < 0.001 ). PE increased significantly in the iron-treated group ( P < 0.001 ) and its change paralleled the change in Hb ( r = 0.58, P < 0.001 ). The results show that iron supplementation enabled these women to do the same work at a lower energy cost Iron depletion without anemia and physical performance in young women. Studies in laboratory animals found that iron deficiency without anemia decreased oxidative capacity and increased reliance on carbohydrate as the substrate for energy, thereby causing impaired endurance. The purpose of this cross-sectional study was to investigate the relation between iron deficiency without anemia and physical performance in healthy active women aged 19 - 36 y. Iron-status assessment included determination of hemoglobin, hematocrit, transferrin saturation, and serum ferritin values. Dietary iron intake was assessed by frequency question naires and physical activity level was estimated by frequency question naires and 2-wk records. Fifteen women with normal iron status and 15 women with iron depletion ( serum ferritin < 12 micrograms/L ) were chosen r and omly from a group of 69 nonanemic women and given physical-performance tests, including determinations of maximum oxygen consumption ( VO2max ), ventilatory threshold, and delta-efficiency. There were no significant differences between the two groups in body size, body composition, physical activity level, dietary iron intake, delta-efficiency, or ventilatory threshold. Compared with the iron-depleted group, the iron-sufficient group had significantly higher hemoglobin, transferrin saturation, and serum ferritin values and a significantly greater tendency to use iron supplements. When physical activity level and fat-free mass were controlled for, the iron-depleted group had a significantly lower VO2max. The difference in VO2max was significantly associated with serum ferritin concentration ; hemoglobin value was not a significant confounder. Therefore, reduction of VO2max in nonanemic women with iron depletion was likely caused by factors related to reduced body iron storage but was unrelated to decreased oxygen-transport capacity of the blood Iron supplementation improves progressive fatigue resistance during dynamic knee extensor exercise in iron-depleted, nonanemic women. BACKGROUND Tissue iron depletion may negatively affect endurance performance and muscle fatigability. OBJECTIVE We investigated tissue-level iron depletion and progressive fatigue of the quadriceps during dynamic knee-extension exercise in young women. DESIGN Twenty iron-depleted ( serum ferritin < 20 micro g/L ), nonanemic ( hemoglobin > 110 g/L ) women ( macro x + /- SEM age : 29.1 + /- 1.2 y ) received iron ( iron group ) or placebo ( placebo group ) for 6 wk in a r and omized, double-blind trial ( n = 10 per group ). A protocol integrating 2 - 3-s maximal voluntary static contractions ( MVCs ) with dynamic knee extensions was used to assess fatigue. RESULTS No significant differences between the groups in baseline iron status, MVC at rest, or MVC at the end of the protocol were observed. After treatment, serum iron and transferrin saturation increased significantly in the iron group ( P = 0.02 and P = 0.03, respectively ). Serum transferrin receptor concentrations increased significantly in the placebo group ( P < 0.01 ) but not in the iron group. After treatment, the rate of decrease in MVC was attenuated in the iron group but not in the placebo group ( P = 0.01 ). In the iron group, MVC at the sixth minute of the fatigue protocol and MVC at the end of the protocol were approximately 15 % ( P = 0.04 ) and approximately 27 % higher ( P < 0.01 ), respectively, after treatment. These improvements were not related to changes in iron-status indexes or tissue iron stores, although power was low ( < 0.50 ) to detect these relations. CONCLUSIONS Iron supplementation was associated with a significant improvement in muscle fatigability. Interpretation regarding the direct role of tissue iron status is limited by the study\'s low power to detect relations between tissue iron improvement and decreased muscle fatigue Iron status in exercising women: the effect of oral iron therapy vs increased consumption of muscle foods. Forty-seven previously sedentary women participating in a 12-wk moderate aerobic-exercise program were r and omly assigned to one of four dietary groups : 50-mg/d iron supplement and a low food-iron diet ( 50 FE + EX ), 10-mg/d iron supplement and a low food-iron diet ( 10 FE + EX ), placebo and unrestricted diet ( P + EX ), and meat supplement and high food-iron diet ( M + EX ). A sedentary control group ( n = 13 ) received no dietary interventions. Hematocrit, total iron-binding capacity, and hemoglobin, serum iron, serum ferritin, and serum albumin concentrations were measured every 4 wk. Hemoglobin values decreased at the end of 4 wk in all exercising groups compared with the control group. Iron status in the 50 FE + EX and M + EX groups improved after week 4 as indicated by an increase in serum ferritin, serum iron, and hemoglobin concentrations, and a decline in total iron-binding capacity. Thus, short-term, moderate aerobic exercise result ed in compromised iron status that was offset to varying degrees by ingesting iron or meat supplements. However, meat supplements were more effective in protecting hemoglobin and ferritin status than were iron supplements Clinical evaluation of iron treatment efficiency among non-anemic but iron-deficient female blood donors: a randomized controlled trial Background Iron deficiency without anemia is related to adverse symptoms that can be relieved by supplementation. Since a blood donation can induce such an iron deficiency, we investigated the clinical impact of iron treatment after a blood donation. Methods One week after donation, we r and omly assigned 154 female donors with iron deficiency without anemia, aged below 50 years, to a four-week oral treatment of ferrous sulfate versus a placebo. The main outcome was the change in the level of fatigue before and after the intervention. Aerobic capacity, mood disorder, quality of life, compliance and adverse events were also evaluated. Hemoglobin and ferritin were used as biological markers. Results The effect of the treatment from baseline to four weeks of iron treatment was an increase in hemoglobin and ferritin levels to 5.2 g/L ( P < 0.01 ) and 14.8 ng/mL ( P < 0.01 ), respectively. No significant clinical effect was observed for fatigue ( -0.15 points, 95 % confidence interval -0.9 points to 0.6 points, P = 0.697 ) or for other outcomes. Compliance and interruption for side effects was similar in both groups. Additionally, blood donation did not induce overt symptoms of fatigue in spite of the significant biological changes it produces. Conclusions These data are valuable as they enable us to conclude that donors with iron deficiency without anemia after a blood donation would not clinical ly benefit from iron supplementation. Trial Registration Clinical Trials.gov : Effects of iron repletion on blood volume and performance capacity in young athletes. PURPOSE The purpose of this study was to find out whether iron repletion leads to an increase in red blood cell volume ( RBV ) and performance capacity in iron-deficient nonanemic athletes. METHODS 40 young elite athletes ( 13 - 25 yr ) with low serum ferritin ( < 20 microg. L-1 ) and normal hemoglobin ( males > 13.5 g.dL-1, females > 11.7 g.dL-1 ) were r and omly assigned to 12-wk treatment with either twice a day ferrous iron ( equivalent to 2 x 100 mg elemental iron ) or with placebo using a double blind method. Before and after treatment, hematological measures and parameters of iron status were determined in venous blood. RBV, blood volume ( BV ), and plasma volume ( PV ) were measured by CO rebreathing. For determination of the aerobic and anaerobic capacity ( maximal accumulated oxygen deficit, MAOD ), the athletes performed an incremental as well as a highly intensive treadmill test. RESULTS After 12 wk, ferritin levels were within the normal range in the iron-treated group ( IG ) with a significant ( P < 0.001 ) mean increase by 20 microg. L-1 opposed to a slight nonsignificant decrease in the placebo group ( PG ). RBV did not change significantly in either group nor did any of the hematological measures. However, only in IG there were significant increases in VO2max and in O2 consumption in the MAOD test. MAOD and maximal capillary lactate concentration remained unchanged in both treatment groups. CONCLUSIONS The results indicate that in young elite athletes with low serum ferritin and normal hemoglobin concentration iron supplementation leads to an increase in maximal aerobic performance capacity without an augmentation of RBV Improvement in iron deficiency anemia through therapy with ferric ammonium citrate and vitamin C and the effects of aerobic exercise. In 781 female college students, there were 41 cases of iron deficiency anemia, 209 of latent iron deficiency, 3 of other anemias, and 528 normal cases. Fifty-four volunteers recruited from the iron deficiency anemia and severe latent iron deficiency groups were r and omly divided into 4 study groups. Groups I and III received 500 mg of vitamin C daily, and groups II and IV received ferric ammonium citrate ( FeAC ; equivalent to 6 mg iron ) in addition to vitamin C for 9 weeks. Groups I and II were loaded by aerobic exercise at 50 % VO2 max. Significant differences between groups were noted in serum ferritin ( SF ) in III/IV, hematocrit ( Ht ) in II/III and III/IV, and reticulocytes ( RET ) in I/II, I/IV, and III/IV. Hemoglobin ( Hb ) and other iron-related blood indices tended to normalize in groups II and IV when compared with the pre-values. VO2 max was elevated in groups I and II regardless of iron treatment, but was augmented more in group II than group Effect of iron supplementation on endurance capacity in iron-depleted female runners. The purpose of this investigation was to examine the effects of oral iron supplementation on endurance performance in initially iron-depleted, nonanemic female distance runners. Eighteen iron-depleted ( serum ferritin less than 20 ng.ml-1, hemoglobin greater than or equal to 12 g.dl-1 ) women ( 22 - 39 yr ) performed a VO2max test and an endurance run to exhaustion. Subjects were pair-matched on the basis of endurance time and then r and omly assigned to an iron supplement or a placebo group. Following supplementation, the iron group had a significantly higher ( P = 0.03 ) mean serum ferritin concentration ( 23.4 vs 15.7 ng.ml-1 ) and lower ( P = 0.04 ) mean total iron-binding capacity than the placebo group. Both groups increased their time to exhaustion ( 25.5 % and 22.2 % for the iron and placebo groups, respectively ) but were not significantly different ( P = 0.72 ) from each other. There were also no differences ( P greater than 0.05 ) between the groups with respect to lactate concentrations and physiological measures taken during the two exercise tests. The results of this study suggest that 8 wk of oral iron supplementation improves iron status in iron-depleted female distance runners, but does not enhance endurance capacity Iron repletion decreases maximal exercise lactate concentrations in female athletes with minimal iron-deficiency anemia. We studied the effect of 2 weeks of iron therapy on exercise performance and exercise-induced lactate production in trained women athletes : six control subjects with normal parameters of iron status and nine with mild iron-deficiency anemia defined by low Fe/TIBC, ferritin, and minimally decreased Hgb values. Iron therapy improved the abnormal measures of iron status and low Hgb in the second group to normal. Exercise performance in a progressive work-exercise protocol on a bicycle ergometer to exhaustion was unchanged after iron therapy in both groups ; however, blood lactate levels at maximum exercise in the iron-deficient group decreased significantly from 10.3 + /- 0.6 mmol/L before therapy to 8.42 + /- 0.7 after therapy ( p less than 0.03 ). The control subjects did not significantly alter lactate levels after maximal exercise on iron compared to placebo : 8.3 + /- 0.8 mmol/L vs. 8.5 + /- 0.7. Although there was not a significant difference in maximum exercise performance after iron therapy, these data support animal experiments implying that iron may play a role in oxidative metabolism and that minimal decreases in Hgb may impair arterial oxygen content enough to affect aerobic metabolism. In addition, these findings may have important implication s for competitive women athletes in whom mild iron deficiency may go unnoticed Iron supplementation maintains ventilatory threshold and improves energetic efficiency in iron-deficient nonanemic athletes Objective : To determine the effect of iron supplementation on iron status and endurance capacity. Design : R and omized, double-blind iron supplementation. Setting : University of Missouri-Columbia and surrounding community. Subjects : Twenty iron-deficient ( serum ferritin, sFer<16 μg/l ; serum transferrin receptor, sTfR>8.0 mg/l ; or sTfR/log sFer index > 4.5 ), nonanemic ( hemoglobin, Hb>120 g/l, women ; > 130 g/l, men ) men and women ( 18–41 years ) were recruited via fliers and newspaper advertisements ; 20 of 31 eligible subjects participated. Interventions : A 30 mg measure of elemental iron as ferrous sulfate or placebo daily for 6 weeks. Results : Dietary iron intake and physical activity did not differ between groups before or after supplementation. Iron supplementation significantly increased sFer compared to placebo ( P=0.01 ), but did not affect Hb or hematocrit. Iron supplementation prevented the decline in ventilatory threshold ( VT ) observed in the placebo group from pre- to post-supplementation ( P=0.01 ) ; this effect was greater in individuals with lower sFer before intervention ( P<0.05 ). Changes in sFer from pre- to post-treatment were positively correlated with changes in VT ( P=0.03 ), independent of supplementation. The iron group significantly increased gross energetic efficiency during the submaximal test ( P=0.04 ). Changes in sFer were negatively correlated with changes in average respiratory exchange ratio during the submaximal test ( P<0.05 ). Conclusions : Iron supplementation significantly improves iron status and endurance capacity in iron-deficient, nonanemic trained male and female subjects. Sponsorship : Missouri University Alumni Association, by the Elizabeth Hegarty Foundation and by the Department of Nutritional Sciences Effect of an iron supplement on body iron status and aerobic capacity of young training women Summary Serum iron deficiency has a high incidence in female athletes. We investigated the effects of a daily oral iron supplement, ( 160 mg ) administered during an intensive 7-week physical training programme, on body iron status, and the maximal aerobic capacity ( VO2max ) of 13 women ( group A ) compared to 15 who took a placebo ( group B ). The subjects were 19 years old. Blood sample s were obtained before training began and on days 1, 7, 21 and 42 of training. They were analysed for packed cell volume ( PVC ) and for haemoglobin ( Hb ), 2,3-diphosphoglycerate ( 2,3-DPG ), haptoglobin, iron and ferritin concentrations. TheVO2max was measured on days 0, 21 and 42 of training. Following 21 days of training Hb, PCV and ferritin were significantly higher ( P⩽0.01 ) in group A compared to group B. Over the training period Hb rose by 9.3 % and 2.4 % in groups A and B, respectively. At the end of training 66 % of group B exhibited ferritin concentrations below 10 ng·ml−1, while none of group A had such low values. MeanVO2max of group A had increased by 7.5 % following 21 days of training ( P⩽0.01 ) and by 15.3 % after 42 days. No appreciable increase inVO2max had occurred in group B by day 21 ( significantly lower thanVO2max of group A;P⩽0.05 ), however by day 42 it had increased by 14.3 % ( P⩽0.05 ). In both groups 2,3-DPG·g Hb−1 had increased significantly ( P⩽0.005 ) by day 7 ( 22 % ) and remained at that level for an additional 35 days. We concluded that a daily oral iron supplement given to young women during intensive training improved several haematological variables and their body iron status. This improvement was associated with an increasedVO2max only during the early stages of their training ( day 21 ) compared with the placebo group Response of serum transferrin receptor to iron supplementation in iron-depleted, nonanemic women. Serum transferrin receptor ( sTfR ) concentration has been recognized recently as a reliable indicator of functional iron deficiency, but its response to iron supplementation has not been investigated in marginally iron-deficient women. In this r and omized, double-blinded trial, 37 female subjects aged 19 - 35 y with iron depletion without anemia ( hemoglobin > 120 g/L and serum ferritin < 16 microg/L ) received an iron supplement or placebo for 8 wk. Iron status was measured before treatment, after 4 wk of treatment, and posttreatment ( ie, after 8 wk of treatment ). Iron supplementation of these iron-depleted, nonanemic women result ed in a progressive and significant decrease in sTfR and a significant increase in serum ferritin, and prevented a fall in hemoglobin. The responsiveness of sTfR to iron treatment indicated that sTfR is a sensitive indicator of marginal iron deficiency in iron-depleted, nonanemic women, even when their body iron stores were being replenished Effects of iron repletion on VO2max, endurance, and blood lactate in women. To determine the effects of an 8-wk dietary iron supplementation ( 100 mg.d-1 ) on low plasma ferritin concentration ( < 20 ng.ml-1 ) and endurance, 20 active women ( 19 - 35 yr ) were studied while performing a VO2max test and an endurance test ( 80 % VO2max ) on a cycle ergometer. Subjects were r and omly placed in an iron supplement ( IG ) or a placebo group ( PG ) using a double-blind method. After treatment in the IG, ferritin levels were higher ( 22.5 + /- 3.4 vs 14.3 + /- 2.2 ng.ml-1 ; P < 0.05 ), Hb increased ( 12.8 + /- 0.4 to 14.1 + /- 0.2 g.dl-1 ; P < 0.05 ), and TIBC decreased ( 366.2 + /- 24.8 to 293.8 + /- 14.0 micrograms.dl-1 ; P < 0.05 ). Also after treatment the IG\'s VO2max was significantly greater ( P < 0.05 ) than the PG value and their postendurance blood lactate decreased ( 5.03 + /- 0.44 to 3.85 + /- 0.6 mM.l-1 ; P < 0.05 ). Endurance time to exhaustion increased 38 % ( 37.28 + /- 5.03 to 51.4 + /- 7.45 min ) following iron treatment ; however, this change was not statistically significant. The results suggest that this level of iron supplementation can reverse mild anemia, increase VO2max, and reduce blood lactate concentration after submaximal exercise Iron supplementation and running performance in female cross-country runners. The purpose of this study was to determine the effects of two weeks of high dosage iron supplementation on various blood iron indices and metabolic parameters in non-anemic, iron-depleted competitive female cross-country runners. The subjects were highly trained members of the Colorado State University cross-country team and were completing 40 to 50 miles of training weekly. A pretest, post-test single-blind crossover design was employed. Upon collection of baseline exercise blood and metabolic data, five subjects were r and omly assigned to iron supplementation ( 650 mg ferrous sulfate ; 130 mg elemental iron ) and five subjects to placebo treatment. At two weeks the treatments were reversed. Exercise blood and metabolic data were collected at two-week intervals. Dietary iron intake was assessed using a three-day dietary survey. Dietary analysis revealed deficiencies in vitamin B-6, iron, magnesium, and zinc according to USRDA st and ards. Baseline blood sample s revealed no deficiencies in iron storage or transport proteins. Two weeks of iron supplementation result ed in no significant increases in blood iron indices. Metabolic parameters related to running performance were also unchanged after iron supplementation. High dosage, short-term iron supplementation appears to have no effect on blood or metabolic parameters in iron-depleted but non-anemic female cross-country runners Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children Iron supplementation strategies in the developing world remain controversial because of fears of exacerbating prevalent infectious diseases. Underst and ing the conditions in which iron will be absorbed and incorporated into erythrocytes is therefore important. We studied Gambian children with either postmalarial or nonmalarial anemia, who were given oral iron supplements daily for 30 days. Supplements administered on days 1 and 15 contained the stable iron isotopes 57Fe and 58Fe, respectively, and erythrocyte incorporation was measured in blood sample s drawn 14 days later. We investigated how the iron-regulatory hormone hepcidin and other inflammatory/iron-related indices, all measured on the day of isotope administration, correlated with erythrocyte iron incorporation. In univariate analyses, hepcidin, ferritin, C-reactive protein, and soluble transferrin receptor ( sTfR ) strongly predicted incorporation of 57Fe given on day 1, while hepcidin, ferritin, and sTfR/log ferritin correlated with 58Fe incorporation. In a final multivariate model, the most consistent predictor of erythrocyte isotope incorporation was hepcidin. We conclude that under conditions of competing signals ( anemia, iron deficiency, and infection ), hepcidin powerfully controls use of dietary iron. We suggest that low-cost point-of-care hepcidin assays would aid iron supplementation programs in the developing world Effects of iron supplementation in female athletes with low serum ferritin concentration. Low serum ferritin concentrations are commonly found in female athletes. By study ing the effects of an 8-week iron or placebo supplementation in 31 female athletes ( aged 17 - 31 years ), with an initial serum ferritin concentration less than or equal to 25 micrograms/l and blood hemoglobin 120 g/l, we investigated whether low serum ferritin values hinder aerobic performance. Serum ferritin concentration increased from 14 ( 25th and 75th percentile : 11, 21 ) to 26 ( 18, 36 ) micrograms/l in the iron-supplemented group, but remained at a low 11 ( 9, 17 ) micrograms/l in the placebo group ( group difference after supplementation : p = 0.001 ). Before supplementation, blood hemoglobin concentration was not different in the two groups. After supplementation, however, the concentration in the iron group was 139 ( 135, 144 ) g/l and 128 ( 126, 134 ) g/l in the placebo group ( group difference : p = 0.001 ). Iron supplementation did not affect blood lactate concentration or VO2max during an incremental ergometer test. Hence, aerobic performance was not impaired in nonanemic female athletes with serum ferritin 25 micrograms/l The effect of iron therapy on the exercise capacity of nonanemic iron-deficient adolescent runners. Iron-deficiency anemia impairs exercise capacity, but whether nonanemic iron depletion decreases endurance performance is unclear. In 14 iron-deficient ( serum ferritin level, less than 20 micrograms/L [ less than 20 ng/L])nonanemic runners, hematologic and treadmill running values were followed up during a competitive season. Following a four-week control period, runners were treated for one month in a double-blind protocol with ferrous sulfate ( 975 mg/d ) or placebo. During treatment, the mean ferritin level rose from 8.7 to 26.6 micrograms/L ( 8.7 to 26.6 ng/mL ) in those patients taking iron and fell from 10.6 to 8.6 micrograms/L ( 10.7 to 8.6 ng/mL ) in the placebo group. Treadmill endurance times improved significantly in the iron-treated runners compared with controls. Endurance time declined in all seven controls ( range, 0.07 to 1.30 minutes ), while six of seven iron-treated subjects improved their performance ( range, 0.03 to 1.92 minutes ). No significant differences in maximal or submaximal oxygen consumption, ventilation, or heart rate were observed between the groups except for a 4 % increase in maximum oxygen consumption during placebo treatment. These data indicate that nonanemic iron deficiency impairs exercise performance but does not influence gas exchange or cardiac measures Randomized, double-blind, placebo-controlled trial of iron supplementation in female soldiers during military training: effects on iron status, physical performance, and mood. BACKGROUND Decrements in iron status have been reported in female soldiers during military training. Diminished iron status adversely affects physical and cognitive performance. OBJECTIVE We wanted to determine whether iron supplementation could prevent decrements in iron status and improve measures of physical performance and cognitive status in female soldiers during basic combat training ( BCT ). DESIGN In this 8-wk r and omized, double-blind, placebo-controlled trial, soldier volunteers ( n = 219 ) were provided with capsules containing either 100 mg ferrous sulfate or a placebo. Iron status indicator assays were performed pre- and post-BCT. Two-mile running time was assessed post-BCT ; mood was assessed by using the Profile of Mood States question naire pre- and post-BCT. RESULTS The BCT course affected iron status : red blood cell distribution width and soluble transferrin receptor were elevated ( P < 0.05 ), and serum ferritin was lowered ( P < 0.05 ) post-BCT. Iron supplementation attenuated the decrement in iron status ; group-by-time interactions ( P < 0.01 ) were observed for serum ferritin and soluble transferrin receptor. Iron supplementation result ed in improved ( P < 0.05 ) vigor scores on the Profile of Mood States post-BCT and in faster running time ( P < 0.05 ) in volunteers reporting to BCT with iron deficiency anemia. CONCLUSIONS Iron status is affected by BCT, and iron supplementation attenuates the decrement in indicators of iron status in female soldiers. Furthermore, iron supplementation may prove to be beneficial for mood and physical performance during the training period. Future efforts should identify and treat female soldiers or athletes who begin training regimens with iron deficiency or iron deficiency anemia The effects of hemoglobin supplements on maximal oxygen uptake in females. There was no significant change in the maximal oxygen uptake for either the experimental or the control group from the pre-test to the post-test. Five blood chemistry measures were unable to predict the post-maximal oxygen uptake scores using the procedure of stepwise regression. An examination of the blood chemistry profiles indicated that sports anemia did not occur. The factorial breakdown was unable to produce any significant insight into the changes in hemoglobin concentration and oxygen consumption. Heme-iron supplementation was unable to override the regulatory system of the body and allow the hemoglobin level to become elevated The effects of prelatent/latent iron deficiency on physical work capacity. In order to examine the effects of mild iron deficiency on physical work capacity, 40 prelatent iron-deficient female endurance runners were studied before and after 8 wk of supplementation with either oral iron ( 320 mg ferrous sulfate ) or a matching placebo. Subjects underwent the following physical work capacity tests : the Wingate cycle ergometer test, the anaerobic speed test, the ventilatory threshold, VO2max, and maximal treadmill velocity during the VO2max test. Muscle biopsy sample s pre- and post-treatment were obtained from 17 of the subjects, and these were assayed for citrate synthase and cytoplasmic alpha-glycerophosphate dehydrogenase activity. Subjects were r and omly assigned to one of the treatment groups, and a double-blind method of administration of the supplements was used. The differences in improvement scores between the two groups on the work capacity and enzyme activity variables were statistically nonsignificant ( P greater than 0.05 ). Serum ferritin values rose from a mean of 12.4 + /- 4.5 to 37.7 + /- 19.7 ng.ml-1 for the experimental group and from 12.2 + /- 4.3 to 17.2 + /- 8.9 ng.ml-1 for the controls ( P = 0.0025 ), whereas hemoglobin levels remained fairly constant for both groups ( P = 0.6 ). Eight weeks of iron supplementation to prelatent/latent iron-deficient, physically active females did not significantly enhance work capacity. Within the limitations of this study, the presence of a serum ferritin below 20 ng.ml-1 does not pose a significant h and icap to physical work capacity Worker productivity and the nutritional status of Kenyan road construction laborers. The effects of energy supplementation ( group I received 200 kcal/day and group II received 1000/kcal day ) were examined on road workers in Kenya. Anthropometric, dietary, worker productivity, clinical hematology, and parasitology data were collected from 224 workers of both sexes or, sub sample s of these workers at base-line, midpoint, and final measurement periods. Sixty-seven percent of the work force was less than 85 % of weight for height. Females tended to be better nourished than males. Multiple regression analysis showed that increases in arm circumference and Hb levels were associated with significant productivity gains of about 4 %. At the midpoint, group II males gained 1.10 kg ( p less than 0.0003 ) while group I males showed no change. Weight loss during the latter part of the study result ed in no significant final weight change for males. " Successful " supplementation was weakly associated with a productivity increase for group II workers of 12.5 % ( p less than 0.10 ) Effects of long-term moderate exercise on iron status in young women. The impact of long-term ( 6-month ) moderate exercise on the iron status of previously sedentary women was determined by r and omly assigning 62 college-age women into one of the following four groups : 1 ) 50 mg.d-1 iron supplement, low iron diet ( N = 16 ) ; 2 ) Placebo, free choice diet ( N = 13 ) ; 3 ) Meat supplement to achieve 15 mg.d-1 iron intake ( N = 13 ) ; and 4 ) Control, free choice diet ( N = 20 ). All groups except the Control group exercised 3 d.wk-1 at 60%-75 % of their heart rate reserve. VO2max was measured at baseline and week 24. Blood was sample d at baseline and every 4 wk thereafter for 24 wk to measure iron status and to eluci date the causes for alterations in iron status. Subjects had depleted iron stores throughout the study as indicated by their serum ferritin levels ( < 15 ng.ml-1 ). Serum iron, total iron binding capacity and transferrin saturation were not compromised with exercise. Mean hemoglobin level in the Placebo/Ex group was significantly ( P < 0.05 ) lower than the 50 Fe/Ex and the Meat/Ex groups by week 24. However, changes in serum albumin, haptoglobin, and erythropoietin data from the study can not explain these changes', "CONTEXT AND OBJECTIVE A growing body of literature suggests that mindfulness techniques may be beneficial in fibromyalgia. A recent systematic review and meta- analysis of six trials indicated improvement in depressive symptoms and quality of life, calling for increased rigor and use of st and ardized measures in future trials. The purpose of the study was to examine the relationship between mindfulness [ as measured by the Five Facet Mindfulness Question naire ( FFMQ ) ] and fibromyalgia impact [ as measured by the Revised Fibromyalgia Impact Question naire ( FIQR ) ]. Follow-up of Yoga of Awareness for Fibromyalgia: Results at 3 Months and Replication in the Wait-list Group Objectives : Published preliminary findings from a r and omized-controlled trial suggest that an 8-week Yoga of Awareness intervention may be effective for improving symptoms, functional deficits, and coping abilities in fibromyalgia. The primary aims of this study were to evaluate the same intervention ’s posttreatment effects in a wait-list group and to test the intervention ’s effects at 3-month follow-up in the immediate treatment group. Methods : Unpaired t tests were used to compare data from a per protocol sample of 21 women in the immediate treatment group who had completed treatment and 18 women in the wait-list group who had completed treatment. Within-group paired t tests were performed to compare posttreatment data with 3-month follow-up data in the immediate treatment group. The primary outcome measure was the Fibromyalgia Impact Question naire Revised ( FIQR ). Multilevel r and om-effects models were also used to examine associations between yoga practice rates and outcomes. Results : Posttreatment results in the wait-list group largely mirrored results seen at posttreatment in the immediate treatment group, with the FIQR Total Score improving by 31.9 % across the 2 groups. Follow-up results showed that patients sustained most of their posttreatment gains, with the FIQR Total Score remaining 21.9 % improved at 3 months. Yoga practice rates were good, and more practice was associated with more benefit for a variety of outcomes. Discussion : These findings indicate that the benefits of Yoga of Awareness in fibromyalgia are replicable and can be maintained Self-report Mindfulness as a Mediator of Psychological Well-being in a Stress Reduction Intervention for Cancer Patients—A Randomized Study Background There is increasing recognition of mindfulness and mindfulness training as a way to decrease stress and increase psychological functioning. Purpose The aims of this study were to examine the effects of mindfulness stress reduction training on perceived stress and psychological well-being and to examine if changes in mindfulness mediate intervention effects on these outcomes. Methods Seventy women and one man with a previous cancer diagnosis ( mean age 51.8 years, st and ard deviation = 9.86 ) were r and omized into an intervention group or a wait-list control group. The intervention consisted of an 8-week mindfulness training course. Results Compared to participants in the control group, participants in the mindfulness training group had significantly decreased perceived stress and posttraumatic avoidance symptoms and increased positive states of mind. Those who participated in the intervention reported a significant increase in scores on the five-facet mindfulness question naire ( FFMQ ) when compared to controls. The increase in FFMQ score mediated the effects of the intervention on perceived stress, posttraumatic avoidance symptoms, and positive states of mind. Conclusions This study indicates that the improvements in psychological well-being result ing from mindfulness stress reduction training can potentially be explained by increased levels of mindfulness as measured with the FFMQ. The importance of these findings for future research in the field of mindfulness is discussed Mindfulness Training as an Intervention for Fibromyalgia: Evidence of Postintervention and 3-Year Follow-Up Benefits in Well-Being Background : Mindfulness-based stress reduction ( MBSR ) proposes a systematic program for reduction of suffering associated with a wide range of medical conditions. Studies suggest improvements in general aspects of well-being, including quality of life ( QoL ), coping and positive affect, as well as decreased anxiety and depression. Methods : A quasi-experimental study examined effects of an 8-week MBSR intervention among 58 female patients with fibromyalgia ( mean, 52 ± 8 years ) who underwent MBSR or an active social support procedure. Participants were assigned to groups by date of entry, and 6 subjects dropped out during the study. Self-report measures were vali date d German inventories and included the following scales : visual analog pain, pain perception, coping with pain, a symptom checklist and QoL. Pre- and postintervention measurements were made. Additionally, a 3-year follow-up was carried out on a subgroup of 26 participants. Results : Pre- to postintervention analyses indicated MBSR to provide significantly greater benefits than the control intervention on most dimensions, including visual analog pain, QoL subscales, coping with pain, anxiety, depression and somatic complaints ( Cohen d effect size, 0.40–1.10 ). Three-year follow-up analyses of MBSR participants indicated sustained benefits for these same measures ( effect size, 0.50–0.65 ). Conclusions : Based upon a quasi-r and omized trial and long-term observational follow-up, results indicate mindfulness intervention to be of potential long-term benefit for female fibromyalgia patients Treating fibromyalgia with mindfulness-based stress reduction: Results from a 3-armed randomized controlled trial & NA ; Mindfulness‐based stress reduction ( MBSR ) is a structured 8‐week group program teaching mindfulness meditation and mindful yoga exercises. MBSR aims to help participants develop nonjudgmental awareness of moment‐to‐moment experience. Fibromyalgia is a clinical syndrome with chronic pain, fatigue, and insomnia as major symptoms. Efficacy of MBSR for enhanced well‐being of fibromyalgia patients was investigated in a 3‐armed trial, which was a follow‐up to an earlier quasi‐r and omized investigation. A total of 177 female patients were r and omized to one of the following : ( 1 ) MBSR, ( 2 ) an active control procedure controlling for nonspecific effects of MBSR, or ( 3 ) a wait list. The major outcome was health‐related quality of life ( HRQoL ) 2 months post‐treatment. Secondary outcomes were disorder‐specific quality of life, depression, pain, anxiety, somatic complaints, and a proposed index of mindfulness. Of the patients, 82 % completed the study. There were no significant differences between groups on primary outcome, but patients overall improved in HRQoL at short‐term follow‐up ( P = 0.004 ). Post hoc analyses showed that only MBSR manifested a significant pre‐to‐post‐intervention improvement in HRQoL ( P = 0.02 ). Furthermore, multivariate analysis of secondary measures indicated modest benefits for MBSR patients. MBSR yielded significant pre‐to‐post‐intervention improvements in 6 of 8 secondary outcome variables, the active control in 3, and the wait list in 2. In conclusion, primary outcome analyses did not support the efficacy of MBSR in fibromyalgia, although patients in the MBSR arm appeared to benefit most. Effect sizes were small compared to the earlier, quasi‐r and omized investigation. Several method ological aspects are discussed, e.g., patient burden, treatment preference and motivation, that may provide explanations for differences. In a 3‐armed r and omized controlled trial in female patients suffering from fibromyalgia, patients benefited modestly from a mindfulness‐based stress reduction intervention A cohort-controlled trial of the addition of customized foot orthotics to standard care in fibromyalgia Customized foot orthotics are widely prescribed for patients with chronic, non-specific low back pain and lower limb pain, but there are few trials demonstrating effectiveness, and none for fibromyalgia. A total of 67consecutive patients presenting with chronic, widespread pain, who met the 1990 American College of Rheumatology criteria for fibromyalgia, were included in the study. A total of 32 subjects were prescribed a spinal exercise therapy program along with analgesics. These subjects formed the Control group. A second group, comprised of 35 subjects, received the same therapy, along with customized foot orthotics ( Orthotics group ). All subjects completed the Revised Fibromyalgia Impact Question naire ( FIQR ) at the initiation of the study and at 8 weeks follow-up. The number of subjects using any type of prescription analgesic or other medication for chronic pain at baseline and at 8 weeks was also recorded. A total of 30 subjects in the Control group and 33 in the Orthotics group completed the study. All subjects completed the baseline and 8-week FIQR. The two groups were well matched in terms of age ( 45.3 ± 11.5 years in the Orthotics group vs. 47.2 ± 8.7 years in the cohort Control ), medication use, duration of pain ( 6.5 ± 4.3 years in the Orthotics group vs. 6.2 ± 3.4 years in the cohort Control group ), as well as baseline FIQR scores ( 55.2 ± 11.0 in the Orthotics group vs. 56.3 ± 12.2 in the cohort Control group ). At 8 weeks, the Orthotics group had a greater reduction in the FIQR score than the cohort Control group ( reduction of 9.9 ± 5.9 vs. 4.3 ± 4.4, respectively ), and this was mainly due to changes in the ‘ function ’ domain of the FIQR ( reduction of 19.6 ± 9.4 in the Orthotics group vs. 8.1 ± 4.3 in the cohort Control group ). As part of a complex intervention, in a cohort-controlled trial of primary care patients with fibromyalgia, the addition of custom-made foot orthotics to usual care appears to improve functioning in the short term The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms. OBJECTIVES To examine the effects of a challenge with monosodium glutamate ( MSG ) as compared to placebo on the symptoms of fibromyalgia ( FM ), in participants who initially experienced > 30 % remission of symptoms on an excitotoxin elimination diet. METHODS Fifty-seven FM patients who also had irritable bowel syndrome ( IBS ) were placed on a 4-week diet that excluded dietary additive excitotoxins including MSG and aspartame. Thirty-seven people completed the diet and 84 % of those reported that > 30 % of their symptoms resolved, thus making them eligible to proceed to challenges. Subjects who improved on the diet were then r and omised to a 2-week double-blind placebo-controlled crossover challenge with MSG or placebo for 3 consecutive days each week. The primary outcome measure was total symptom score. Secondary outcome measures included visual analogue pain scales ( VAS for FM and IBS ), an IBS Quality of Life Question naire ( IBS QOL ) and the Fibromyalgia Impact Question naire-Revised ( FIQR ). Repeated measures ANOVA was used to analyse crossover challenge results. RESULTS The MSG challenge, as compared to placebo, result ed in a significant return of symptoms ( total symptom score, p<0.02 ) ; a worsening of fibromyalgia severity as determined by the FIQR ( p<0.03 ) ; decreased quality of life in regards to IBS symptoms ( IBS QOL, p<0.05 ) ; and a non-significant trend toward worsening FM pain based on visual analogue scale ( VAS, p<0.07 ). CONCLUSIONS These findings suggest that dietary glutamate may be contributing to FM symptoms in some patients. Future research on the role of dietary excitotoxins in FM is warranted The efficacy of mindfulness meditation plus Qigong movement therapy in the treatment of fibromyalgia: a randomized controlled trial. OBJECTIVE To test the short and longterm benefits of an 8 week mind-body intervention that combined training in mindfulness meditation with Qigong movement therapy for individuals with fibromyalgia syndrome ( FM ). METHODS A total of 128 individuals with FM were r and omly assigned to the mind-body training program or an education support group that served as the control. Outcome measures were pain, disability ( Fibromyalgia Impact Question naire ), depression, myalgic score ( number and severity of tender points ), 6 minute walk time, and coping strategies, which were assessed at baseline and at 8, 16, and 24 weeks. RESULTS Both groups registered statistically significant improvements across time for the Fibromyalgia Impact Question naire, Total Myalgic Score, Pain, and Depression, and no improvement in the number of feet traversed in the 6 minute walk. However, there was no difference in either the rate or magnitude of these changes between the mind-body training group and the education control group. Salutary changes occurring by the eighth week ( which corresponded to the end of the mind-body and education control group sessions ) were largely maintained by both groups throughout the 6 month followup period. CONCLUSION While both groups showed improvement on a number of outcome variables, there was no evidence that the multimodal mind-body intervention for FM was superior to education and support as a treatment option. Additional r and omized controlled trials are needed before interventions of this kind can be recommended for treatment of FM Clinical and Economic Characteristics of Patients With Fibromyalgia Syndrome Objectives Fibromyalgia syndrome ( FMS ) is a chronic disorder defined by widespread muscle pain and multiple tender points. The objectives of this study were to estimate prevalence of comorbidities, healthcare re sources utilization, and costs associated with FMS. Methods A retrospective cohort study was conducted using data from the Quebec provincial health plans ( RAMQ ) for a r and om sample of patients with diagnoses of FMS and a control cohort of patients without FMS, matched for age and gender. Prevalence of comorbidities was estimated. Healthcare re sources consumed by FMS and non-FMS patients were identified in terms of visits to physicians, physician's interventions, pain-related medications, nonpain-related medications, and hospitalizations. Results A total of 16,010 patients with 2 diagnoses of FMS were identified, and control patients were r and omly selected with a ratio of 1:1. Incidence of most comorbidities was significantly higher in the FMS group and the chronic disease score ( 3.8 vs. 2.8 ; ANOVA P < 0.001 ). The proportion of patients with at least 1 comorbidity was 87.4 % in the FMS group and 60.1 % in the control group ( χ2P<0.001 ). The annual number of visits to physician and physician's interventions was 25.1 for FMS and 14.8 for non-FMS patients. The amount paid by the RAMQ was significantly higher for patients with FMS ( $ 4065 ) compared with patients without FMS ( $ 2766 ) ( ANOVA P<0.001 ). Discussion Results of this analysis of the RAMQ data base illustrate the high prevalence of comorbidities among patients with a diagnosis of FMS and strongly indicate that the economic burden of FMS is substantial Mindfulness meditation alleviates depressive symptoms in women with fibromyalgia: results of a randomized clinical trial. OBJECTIVE Depressive symptoms are common among patients with fibromyalgia, and behavioral intervention has been recommended as a major treatment component for this illness. The objective of this study was to test the effects of the Mindfulness-Based Stress Reduction ( MBSR ) intervention on depressive symptoms in patients with fibromyalgia. METHODS This r and omized controlled trial examined effects of the 8-week MBSR intervention on depressive symptoms in 91 women with fibromyalgia who were r and omly assigned to treatment ( n = 51 ) or a waiting-list control group ( n = 40 ). Eligible patients were at least 18 years old, willing to participate in a weekly group, and able to provide physician verification of a fibromyalgia diagnosis. Of 166 eligible participants who responded to local television news publicizing, 49 did not appear for a scheduled intake, 24 enrolled but did not provide baseline data, and 2 were excluded due to severe mental illness, leaving 91 participants. The sample averaged 48 years of age and had 14.7 years of education. The typical participant was white, married, and employed. Patients r and omly assigned to treatment received MBSR. Eight weekly 2.5-hour sessions were led by a licensed clinical psychologist with mindfulness training. Somatic and cognitive symptoms of depression were assessed using the Beck Depression Inventory administered at baseline, immediately postprogram, and at followup 2 months after the conclusion of the intervention. RESULTS Change in depressive symptoms was assessed using slopes analyses of intervention effects over time. Depressive symptoms improved significantly in treatment versus control participants over the 3 assessment s. CONCLUSION This meditation-based intervention alleviated depressive symptoms among patients with fibromyalgia Mindfulness therapy for somatization disorder and functional somatic syndromes: randomized trial with one-year follow-up. OBJECTIVE To conduct a feasibility and efficacy trial of mindfulness therapy in somatization disorder and functional somatic syndromes such as fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome, defined as bodily distress syndrome ( BDS ). METHODS We r and omized 119 patients to either mindfulness therapy ( mindfulness-based stress reduction and some cognitive behavioral therapy elements for BDS ) or to enhanced treatment as usual ( 2-hour specialist medical care and brief cognitive behavioral therapy for BDS ). The primary outcome measure was change in physical health ( SF-36 Physical Component Summary ) from baseline to 15-month follow-up. RESULTS The study is negative as we could not demonstrate a different development over time for the two groups ( F(3,2674)=1.51, P=.21 ). However, in the mindfulness therapy group, improvement was obtained toward the end of treatment and it remained present at the 15-month follow-up, whereas the enhanced treatment as usual group achieved no significant change until 15-month follow-up. The change scores averaged half a st and ard deviation which amounts to a clinical ly significant change, 29 % changed more than 1 st and ard deviation. Significant between-group differences were observed at treatment cessation. CONCLUSION Mindfulness therapy is a feasible and acceptable treatment. The study showed that mindfulness therapy was comparable to enhanced treatment as usual in improving quality of life and symptoms. Nevertheless, considering the more rapid improvement following mindfulness, mindfulness therapy may be a potentially useful intervention in BDS patients. Clinical ly important changes that seem to be comparable to a CBT treatment approach were obtained. Further research is needed to replicate or even exp and these findings", 'Academic improvement is amongst the most common treatment targets when prescribing stimulants to children with ADHD. Previous review s on stimulant-related academic improvements are inconclusive and focus on task engagement. Recent literature suggests outcome -domain-specific medication effects that are larger for productivity than for accuracy. The aims of this study are quantifying methylpheni date effects on academic productivity and accuracy for math, reading, spelling ; exploring the mediating or moderating effects of symptom improvements, demographic-, design - and disorder-related variables. Mediators of Methylphenidate Effects on Math Performance in Children with Attention-Deficit Hyperactivity Disorder Objective : Stimulant medications, such as methylpheni date ( MPH ), improve the academic performance of children with attention-deficit hyperactivity disorder ( ADHD ). However, the mechanism by which MPH exerts an effect on academic performance is unclear. We examined MPH effects on math performance and investigated possible mediation of MPH effects by changes in time on-task, inhibitory control, selective attention, and reaction time variability. Methods : Children with ADHD aged 7 to 11 years ( N = 93 ) completed a timed math worksheet ( with problems tailored to each individual\'s level of proficiency ) and 2 neuropsychological tasks ( Go/No-Go and Child Attention Network Test ) at baseline, then participated in a 4-week, r and omized, controlled, titration trial of MPH. Children were then r and omly assigned to their optimal MPH dose or placebo for 1 week ( administered double-blind ) and repeated the math and neuropsychological tasks ( posttest ). Baseline and posttest videorecordings of children performing the math task were coded to assess time on-task. Results : Children taking MPH completed 23 more math problems at posttest compared to baseline, whereas the placebo group completed 24 fewer problems on posttest versus baseline, but the effects on math accuracy ( percent correct ) did not differ. Path analyses revealed that only change in time on-task was a significant mediator of MPH\'s improvements in math productivity. Conclusions : MPH-derived math productivity improvements may be explained in part by increased time spent on-task, rather than improvements in neurocognitive parameters, such as inhibitory control, selective attention, or reaction time variability Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. OBJECTIVE Methylpheni date ( MPH ), the most commonly prescribed drug for attention-deficit/hyperactivity disorder ( ADHD ), has a short half-life, which necessitates multiple daily doses. The need for multiple doses produces problems with medication administration during school and after-school hours, and therefore with compliance. Previous long-acting stimulants and preparations have shown effects equivalent to twice-daily dosing of MPH. This study tests the efficacy and duration of action, in natural and laboratory setting s, of an extended-release MPH preparation design ed to last 12 hours and therefore be equivalent to 3-times-daily dosing. METHODS Sixty-eight children with ADHD, 6 to 12 years old, participated in a within-subject, double-blind comparison of placebo, immediate-release ( IR ) MPH 3 times a day ( tid ), and Concerta, a once-daily MPH formulation. Three dosing levels of medication were used : 5 mg IR MPH tid/18 mg Concerta once a day ( qd ) ; 10 mg IR MPH tid/36 mg Concerta qd ; and 15 mg IR MPH tid/54 mg Concerta qd. All children were currently medicated with MPH at enrollment, and each child\'s dose level was based on that child\'s MPH dosing before the study. The doses of Concerta were selected to be comparable to the daily doses of MPH that each child received. To achieve the ascending rate of MPH delivery determined by initial investigations to provide the necessary continuous coverage, Concerta doses were 20 % higher on a daily basis than a comparable tid regimen of IR MPH. Children received each medication condition for 7 days. The investigation was conducted in the context of a background clinical behavioral intervention in both the natural environment and the laboratory setting. Parents received behavioral parent training and teachers were taught to establish a school-home daily report card ( DRC ). A DRC is a list of individual target behaviors that represent a child\'s most salient areas of impairment. Teachers set daily goals for each child\'s impairment targets, and parents provided rewards at home for goal attainment. Each weekday, teachers completed the DRC, and it was used as a dependent measure of individualized medication response. Teachers and parents also completed weekly st and ardized ratings of behavior and treatment effectiveness. To evaluate the time course of medication effects, children spent 12 hours in a laboratory setting on Saturdays and medication effects were measured using procedures and methods adapted from our summer treatment program. Measures of classroom behavior and academic productivity/accuracy were taken in a laboratory classroom setting during which children completed independent math and reading worksheets. Measures of social behavior were taken in structured, small-group board game setting s and unstructured recess setting s. Measures included behavior frequency counts, academic problems completed and accuracy, independent observations, teacher and counselor ratings, and individualized behavioral target goals. Reports of adverse events, sleep quality, and appetite were collected. RESULTS On virtually all measures in all setting s, both drug conditions were significantly different from placebo, and the 2 drugs were not different from each other. In children\'s regular school setting s, both medications improved behavior as measured by teacher ratings and individualized target behaviors ( the DRC ) ; these effects were seen into the evening as measured by parent ratings. In the laboratory setting, effects of Concerta were equivalent to tid MPH and lasted at least through 12 hours after dosing. Concerta was significantly superior to tid MPH on 2 parent rating scores, and when asked, more Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline. Twenty-two children with attention deficit-hyperactivity disorder underwent a double-blind, placebo-controlled, crossover evaluation of the efficacy of st and ard methylpheni date twice a day and comparable doses every morning of a sustained-release preparation of methylpheni date ( SR-20 Ritalin ), a sustained-release form of dextroamphetamine ( Dexedrine Spansule ), and pemoline. The children were participating in a summer treatment program in which they engaged in recreational and classroom activities. Dependent measures include evaluations of social behavior during group recreational activities, classroom performance, and performance on a continuous performance task. Results revealed generally equivalent and beneficial effects of all four medications. Dexedrine Spansule and pemoline tended to produce the most consistent effects and were recommended for 10 of the 15 children who were responders to medication. The continuous performance task results showed that all four medications had an effect within 2 hours of ingestion, and the effects lasted for 9 hours. The implication s of these results for the use of long-acting stimulant medication in children with attention deficit-hyperactivity disorder are discussed A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study). OBJECTIVE The objective of this study was to evaluate differences in the pharmacodynamic ( PD ) profile of 2 second-generation extended-release ( ER ) formulations of methylpheni date ( MPH ) : Meta date CD ( MCD ; methylpheni date HCl, US Pharmacopeia ) extended-release capsules, CII, and Concerta ( CON ; methylpheni date HCl ) extended-release tablets, CII. Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior. Previous studies have shown that the near-equal doses of MCD and CON provide equivalent, total exposure to MPH as measured by area under the plasma concentration time curve, yet their pharmacokinetic ( PK ) plasma concentration versus time profiles are different. We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes : 1 ) an initial bolus dose of immediate-release ( IR ) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing, which for the MCD capsule is delivered by 30 % of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22 % of the total daily dose ; and 2 ) an extended, controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus, which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system. According to this PK/PD model, clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration. METHODS This was a multisite, double-blind, double-dummy, 3-way crossover study of 2 active treatments ( MCD and CON ) and placebo ( PLA ). Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low ( 20 mg of MCD and 18 mg of CON ), medium ( 40 mg of MCD and 36 mg of CON ), or high ( 60 mg of MCD and 54 mg of CON ), and in a r and omized order each of the study treatments was administered once daily in the morning for 1 week. On the seventh day of each treatment week, children attended a laboratory school, where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals. Safety was assessed by patient reports of adverse events, parent ratings on a stimulant side-effects scale, and measurement of vital signs. RESULTS The analyses of variance revealed large, statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures ( deportment, attention, and permanent product ). The interactions of treatment x session were also highly significant for all 3 outcome measures. Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day : 1 ) PLA > MCD approximately CON ( PLA superiority ) immediately after dosing ; 2 ) MCD > CON > PLA during the morning ( MCD superiority ) Effects of OROS Methylphenidate on Academic, Behavioral, and Cognitive Tasks in Children 9 to 12 Years of Age With Attention-Deficit/Hyperactivity Disorder Objective. To assess effects of OROS methylpheni date on cognitive and academic tasks in 9 to 12 year olds with attention-deficit/hyperactivity disorder ( ADHD ). Methods. A double-blind, within-subject, crossover design was used to compare OROS methylpheni date with placebo in a laboratory classroom setting on several cognitive and academic tasks for 68 children who met r and omization criteria. Results. Performance on the following measures was significantly better when children received individually optimized OROS methylpheni date than placebo : math fluency and accuracy measured by the Permanent Product Math Test, ADHD symptoms observed in the laboratory setting, computerized indices of attention and impulsivity as measured by the Test of Variables of Attention ( TOVA ), and visual — spatial working memory ( Finger Windows Backwards ). Study medication was well tolerated ; adverse events were generally consistent with previous reports. Conclusions. OROS methylpheni date improves performance on measures of attention and vigilance, behavior, and working memory in a laboratory school setting in 9 to 12 year olds with ADHD A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. BACKGROUND Previous studies have demonstrated the short-term efficacy of pharmacotherapy and behavior therapy for attention-deficit/hyperactivity disorder ( ADHD ), but no longer-term ( i.e., > 4 months ) investigations have compared these 2 treatments or their combination. METHODS A group of 579 children with ADHD Combined Type, aged 7 to 9.9 years, were assigned to 14 months of medication management ( titration followed by monthly visits ) ; intensive behavioral treatment ( parent, school, and child components, with therapist involvement gradually reduced over time ) ; the two combined ; or st and ard community care ( treatments by community providers ). Outcomes were assessed in multiple domains before and during treatment and at treatment end point ( with the combined treatment and medication management groups continuing medication at all assessment points ). Data were analyzed through intent-to-treat r and om-effects regression procedures. RESULTS All 4 groups showed sizable reductions in symptoms over time, with significant differences among them in degrees of change. For most ADHD symptoms, children in the combined treatment and medication management groups showed significantly greater improvement than those given intensive behavioral treatment and community care. Combined and medication management treatments did not differ significantly on any direct comparisons, but in several instances ( oppositional/aggressive symptoms, internalizing symptoms, teacher-rated social skills, parent-child relations, and reading achievement ) combined treatment proved superior to intensive behavioral treatment and /or community care while medication management did not. Study medication strategies were superior to community care treatments, despite the fact that two thirds of community-treated subjects received medication during the study period. CONCLUSIONS For ADHD symptoms, our carefully crafted medication management was superior to behavioral treatment and to routine community care that included medication. Our combined treatment did not yield significantly greater benefits than medication management for core ADHD symptoms, but may have provided modest advantages for non-ADHD symptom and positive functioning outcomes Reliability and validity of the SKAMP rating scale in a laboratory school setting. In children with attention deficit hyperactivity disorder ( ADHD ), the effects of methylpheni date were investigated in a pharmacodynamic comparison of placebo and the st and ard b.i.d. administration of methylpheni date. In each of these conditions, teachers completed ratings in classroom setting s at times chosen to coincide with expected " peaks " and " troughs " of serum concentrations in the b.i.d. condition. Analyses of variance ( ANOVAs ) revealed the expected differences between the two conditions in the laboratory classroom setting using st and ard rating scales ( Conners and the IOWA Conners ) and a new rating scale ( the SKAMP ), which specifically measures the classroom manifestation of ADHD. The psychometric properties of the SKAMP were evaluated by calculating test-retest reliability and by calculating correlations with the st and ard rating scales to establish concurrent validity Stimulant Medication and Reading Performance The study examined the sustained effects of methylpheni date on reading performance in a sample of 42 boys, ages 8 to 11, with attention deficit-hyperactivity disorder ( ADHD ). Two subgroups were formed based on the presence or absence of co-occurring conduct disorders. Subjects were selected on the basis of their positive response to methylpheni date as determined in a series of original medication trials ( Forness, Cantwell, Swanson, Hanna, & Youpa, 1991 ). For the purpose of this study, subjects were placed on their optimal dose of medication for a 6-week period and then tested on measures of oral reading and reading comprehension equivalent to those used in the original trials, retested after a week without medication ( placebo ), then tested again the following week after return to medication. Only the subgroup with conduct disorders responded, and this response was limited to reading comprehension improvement in only those subjects who also demonstrated improvement in oral reading on original trials. No response differences were found between subjects with or without learning disabilities A dose-response analysis of the effects of methylphenidate on the peer interactions and simulated classroom performance of ADD children with and without conduct problems. To examine the social effects of methylpheni date, groups of 15 attention-deficit disordered boys with ( ADD ) and 15 ADD boys without conduct problems ( ADD/CP ) were paired with normal peers. ADD and ADD/CP children showed a different pattern of responses to methylpheni date. While on task behavior in ADD/CP dyads increased at 0.15 mg/kg doses, increases in ADD dyads were not observed until doses reached 0.50 mg/kg. Although controlling interaction in ADD children decreased at 0.15 mg/kg, the controlling behavior of ADD/CP children did not decline at either dose. Peers of both ADD and ADD/CP children showed reciprocal declines in controlling behavior. In both free play and cooperative task situations, 0.15 mg/kg increased social interaction in ADD boys and decreased social interaction in ADD/CP boys A longitudinal examination of neuropsychological and clinical functioning in boys with attention deficit hyperactivity disorder (ADHD): improvements in executive functioning do not explain clinical improvement. BACKGROUND Attention deficit hyperactivity disorder ( ADHD ) often, but not always, persists into adulthood. Investigations of the associations between clinical and biological markers of persistence can shed light on causal pathways. It has been proposed that compensatory improvements in executive neuropsychological functioning are associated with clinical improvements. This is the first study to test this hypothesis prospect ively. METHOD The clinical and neuropsychological functioning of 17 boys with ADHD ( mean age 10.45 years at time 1 ; 14.65 years at time 2 ) and 17 typically developing ( TYP ) boys ( mean age 10.39 years at time 1 ; 14.47 years at time 2 ) was tested on two occasions, 4 years apart. This was done using a battery of st and ardized neuropsychological tests that included tasks with high and low executive dem and s. RESULTS Clinical improvements were observed over time. Neuropsychological performance improvements were also evident, with ADHD boys developing with a similar pattern to TYP boys, but with a developmental lag. Whilst there was an association between reduced symptoms and superior performance at retest for one task with a high executive dem and ( spatial working memory ), this was not seen with two further high executive dem and tasks [ Stockings of Cambridge and intra-dimensional extra-dimensional ( ID/ED ) set shifting ]. Also, there was no association between change in executive functioning and change in symptoms. Baseline performance on the ID/ED set-shifting task predicted better clinical outcome. Only change in performance on the low executive dem and delayed matching-to- sample task predicted better clinical outcome. CONCLUSIONS These data highlight the importance of longitudinal measurements of cognition, symptoms and treatment response over time in children and adolescents with ADHD Differential Effects of Stimulant Medication on Reading Performance of Boys With Hyperactivity With and Without Conduct Disorder Controversy surrounding stimulant medication, particularly its effects on reading performance, continues to obscure the issue of the use of this drug in classroom situations. The present study emphasized careful differential diagnosis, double-blind and placebo approaches, and curriculum-based dependent measures to address these concerns. Methylpheni date was administered to two groups of boys, ages 8 through 11. The two groups included 27 subjects meeting criteria for attention deficit-hyperactivity disorder but not conduct disorder, known as hyperactive disorder ( HD ), and 28 subjects meeting criteria for both diagnostic categories, known as hyperactive-aggressive ( HA ). Only four subjects in each group met a discrepancy criterion for learning disabilities ( LD ). Methylpheni date was administered to both groups at three levels of dosage, along with baseline and placebo conditions. Dependent measures involved both reading recognition and reading comprehension, equivalent across all conditions. No significant results were found for the group with HD in either reading recognition or comprehension, due largely to unusual placebo reactions. Results were generally in the direction predicted for the group with HA, but only significantly so in reading comprehension, and no dose effect was found on this variable. Implication s for reading as a dependent measure of medication effects are discussed Comparative efficacy of once–a–day extended–release methylphenidate, two–times–daily immediate–release methylphenidate, and placebo in a laboratory school setting Abstract Background Given the dosing limitations of methylpheni date short – acting preparations in treating ADHD, galenics with longer release of the substance were developed mainly to avoid drug intake during school hours. Objectives This investigation was conducted to assess the efficacy and the duration of action of a new extended-release formulation of methylpheni date ( Medikinet ® retard ) as a once – daily treatment for children with attention – deficit hyperactivity disorder ( ADHD ). Method This was a r and omized, double – blind, crossover multicentre study with three treatment conditions : once – daily extended – release methylpheni date, twice – daily immediate – release methylpheni date and placebo given to 79 children ( 8–14 years old ) with ADHD. Daily assessment s in an analogue classroom setting included blind ratings of attention and deportment and a performance measure ( math test ) obtained 5 times over an 8–hour period. Secondary measures included an ADHD rating scale, based on DSMIV/ ICD–10 separately rated for the morning and the afternoon. Results Both active treatment conditions displayed significant time course effects and were superior to placebo in improving all efficacy measures. Once a day extended – release methylpheni date was not different from the same dose of twice daily immediate – release methylpheni date. Conclusions These data provide support for the benefit of this novel, once-daily methylpheni date preparation in the treatment of ADHD. The longer duration of action of Medikinet Retard has the potential to simplify psychostimulant treatment, thus reducing dose diversion and eliminating the need for in – school administration The Effects of Methylphenidate on Word Decoding Accuracy in Boys With Attention-Deficit/Hyperactivity Disorder The investigation aim ed to delineate the immediate effect of methylpheni date on decoding in the comorbid condition of attention-deficit/hyperactivity disorder and reading disorder. Boys with attention-deficit/hyperactivity and reading disorders ( n = 25 ) between the ages of 7.9 and 11.7 years, with at least average intelligence and verbal processing abilities participated in a double-blind, acute, r and omized, placebo-controlled crossover trial with a single dose of methylpheni date 0.3 to 0.4 mg/kg with weekly intervals between testing sessions. The test battery included tasks of attention/control functions and reading domain functions. Paired comparisons and first trial group comparison comparing performance under placebo and under methylpheni date were used. Methylpheni date selectively improved strategy /set shift ( P = 0.004 ) and facilitated improvement both in rapid naming ( P = 0.043 ) and word/nonword accuracy ( P = 0.028/P = 0.035 ). These findings lend support to a possible influence of methylpheni date on cognitive attention functions related to reading skills in the comorbid group Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Two studies were conducted to investigate the relative effects of sustained release methylpheni date ( Ritalin [ SR-20 ] ) and st and ard methylpheni date ( Ritalin, 10 mg, administered twice daily ). In the first study, 13 boys with attention deficit disorder participating in a summer treatment program went through a double-blind, within-subject trial of each form of methylpheni date and placebo. Measures of social and cognitive behavior were gathered in classroom and play setting s. Although group analyses of the data showed that both drugs were effective and there were few differences between them, st and ard methylpheni date was superior to SR-20 on several important measures of disruptive behavior. Furthermore, analyses of individual responsivity showed clearly that most boys responded more positively to st and ard methylpheni date than to SR-20. The second study involved a partially overlapping group of nine boys with attention deficit disorder participating in the same summer treatment program. Also double-blind, within-subject, and placebo controlled, this study tracked the time courses of the two forms of methylpheni date. Both were shown to have similar time courses on the Abbreviated Conners Rating Scale and other measures, but SR-20 had a slower onset than did the st and ard drug form on a continuous performance task. Effects of SR-20 were still evident eight hours after ingestion Short term effects of methylphenidate on the cognitive, learning and academic performance of children with attention deficit disorder in the laboratory and the classroom. Sixteen children meeting diagnostic criteria for Attention Deficit Disorder with Hyperactivity ( ADD-H ) were tested on methylpheni date ( 0.3 mg/kg ) and placebo on cognitive, learning, academic and behavioral measures in a double-blind study. Assessment s were carried out in the laboratory and in the children\'s regular classrooms. Results indicate methylpheni date -induced improvements on a majority of the measures. Drug-induced changes reflected increased output, accuracy and efficiency and improved learning acquisition. There was also evidence of increased effort and self-correcting behaviours. It is argued that review ers have underestimated the potential of stimulants to improve the performance of ADD-H children on academic, learning and cognitive tasks Pharmacokinetics and therapeutic effect of OROS methylphenidate under different breakfast conditions in children with attention-deficit/hyperactivity disorder. OBJECTIVE To examine the pharmacokinetics ( PKs ) and pharmacodynamics ( PDs ) of OROS methylpheni date ( OROS MPH ) dosed once daily ( QD ) versus an early st and ard regimen ( immediate-release [ IR ] MPH dosed three times daily [ TID ] ) under various breakfast conditions. METHODS This single-center, double-blind, double-dummy, r and omized, crossover study of OROS MPH ( NCT00269815 ) in children aged 6 to 12 years with attention-deficit/hyperactivity disorder evaluated the PKs and PDs of MPH given with different breakfast conditions : OROS MPH administered after a high-fat breakfast, after a normal breakfast, or after fasting and IR MPH administered after a normal breakfast or after fasting in the morning and at two subsequent time points during the day. To maximize information, patients were divided into two groups, each receiving three of the five treatments for 1 day in a three-period, r and omized, crossover design. Patients were assigned to 1 of 3 dosage levels ( OROS MPH 18, 36, and 54 mg QD, and an assumed equivalent regimen of IR MPH 5, 10, and 15 mg given TID ) based on their pre study established clinical dose of IR MPH. PD measurements included Combined-Attention and Deportment scores on a rating scale of school behavior ( the Swanson, Kotkin, Agler, M-Flynn, and Pelham ), global assessment s of efficacy, and activity monitor levels during academic seatwork. Serial blood sample s for PK analysis were taken predose, and then every 60 to 90 minutes until 11.5 hours postdose. Vital signs were assessed predose, and then every 1.5 to 2.5 hours until 11.5 hours postdose. RESULTS Of the 32 patients enrolled, 31 completed the study. The PK profiles for MPH after OROS MPH administration were similar under all conditions ( with normal, high-fat breakfast, or fasting ). No bioequivalence tests of OROS MPH and IR MPH under various breakfast conditions were done because there were so few patients in each dose level of treatment. The two IR MPH conditions ( after normal breakfast and fasting ) were not compared. The drug-to-metabolite ratios ( area under the curve ) for all OROS MPH and IR MPH treatments were similar. OROS MPH and IR MPH provided a similar therapeutic effect, irrespective of breakfast conditions, as demonstrated by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Attention and Deportment measures and global assessment s. No serious adverse events, no deaths, and no clinical ly significant changes in vital signs were reported, except for one patient who was discontinued early because of repeated systolic blood pressure elevations on study day 1. CONCLUSIONS The results of this study demonstrate that in children with attention-deficit/hyperactivity disorder, administering OROS MPH with or without food produces similar PK and PD profiles Methylphenidate in Children With ADHD With or Without Learning Disability Objective : To explore treatment response to Osmotic Release Oral System ® ( OROS ) methylpheni date in children with ADHD with and without comorbid learning disability ( LD ). Method : Data were analyzed from two 6-week, double-blind, r and omized, placebo-controlled, crossover studies evaluating individually determined doses of OROS methylpheni date versus placebo in 135 children ( ages 9 to 12 years ) with ADHD with or without an LD in reading, math, or both. The sample was demographically diverse, with 31 % females and more than 40 % minority, predominantly African American and Hispanic. On two laboratory school days, participants received either OROS methylpheni date or placebo and were given a battery of cognitive and behavioral tests. Results : Treatment with OROS methylpheni date led to improvement in ADHD Rating Scale scores for participants with or without comorbid LD. Both groups performed better during treatment with OROS methylpheni date than placebo on measures of cognitive skills ( i.e., Test of Variables of Attention, Finger Windows Backwards ), academically related tasks ( i.e., Dynamic Indicators of Basic Early Literacy Skills, Test of H and writing Skills – Revised, Permanent Product Math Test ), and observed classroom behavior ( i.e., Swanson, Kotkin, Alger, M-Flynn, and Pelham Scale ). Conclusion : In children with ADHD with or without comorbid LD, behavior and performance improved during treatment with OROS methylpheni date Methylphenidate and children with attention deficit disorder. Dose effects on classroom academic and social behavior. The short-term, dose-response effects of methylpheni date hydrochloride were evaluated on academic and social classroom measures in 29 children with attention deficit disorder. In a double-blind, cross-over design with order r and omized, children received a placebo for two weeks and three doses of methylpheni date hydrochloride ( 0.15 mg/kg, 0.3 mg/kg, and 0.6 mg/kg ) for one week each. Dependent measures included the output and accuracy of performance in grade -appropriate reading comprehension workbooks and arithmetic problems, spelling word acquisition, and observations of disruptive and on-task behavior. Beneficial drug effects and linear dose-response curves on all dependent measures were found. The results suggest that beneficial methylpheni date effects on classroom behavior may be accompanied by enhanced academic achievement in some hyperactive children Comparative effects of methylphenidate on ADD girls and ADD boys. The effects of 0.3 mg/kg methylpheni date were compared for 12 ADD boys and 12 ADD girls participating in a summer treatment program for children with behavior and /or learning problems. Previous investigations have suggested that ADD girls may differ from ADD boys in some important respects. No information exists regarding whether the effects of the most common treatment for these children, methylpheni date, has comparable effects on boys and girls. The boys and girls were matched for age and IQ. The results revealed equivalent and beneficial effects of methylpheni date for both boys and girls. Methylpheni date therefore would appear to be as useful a treatment for ADD girls as for ADD boys Time Course of Treatment Effect of OROS® Methylphenidate in Children With ADHD Objective : The authors evaluated the time course of the treatment effect of Osmotic-Release Oral System methylpheni date ( OROS ® MPH ) HCl ( Concerta ®, Raritan, NJ ) CII in children with ADHD. Method : Data were combined from two double-blind, r and omized, placebo-controlled, cross-over, analog classroom studies in children ( 9 - 12 years ) with ADHD. Participants received an individualized dose of placebo or OROS ® MPH on two laboratory school days. Permanent Product Math Test and Swanson, Kotkin, Agler, M-Flynn, and Pelham scores were evaluated 0.5 hr before dosing and 1, 2, 4, 10, 11, and 12.5 hr post dose. Analysis used a repeated- measures mixed model. Results : Treatment effects were present at all postdose assessment points ( p <.0001 for all comparisons, n = 139 ). Adverse events were similar to previous reports for OROS ® MPH. Conclusion : A robust treatment effect occurred with OROS ® MPH ; onset was at 1 hr and persisted for at least 12.5 hr after dosing Childhood hyperactivity and psychostimulants: a review of extended treatment studies. ABSTRACT Clinical trials with a treatment duration of at least 3 months were review ed to determine the effect of psychostimulants on the core symptoms of attention-deficit hyperactivity disorder ( ADHD ) and on its commonly associated features. Eighteen studies were identified : 17 were studies of methylpheni date, 1 was a study of dextroamphetamine, and none involved pemoline or slow-release stimulants. Eleven of these studies were r and omized controlled trials, whereas seven employed quasi-experimental design s without r and omization. The results of r and omized controlled trials showed that psychostimulants provided greater benefit than did the nonr and omized trials, suggesting that the efficacy of extended treatment may have been underestimated because more seriously disturbed children were assigned to medication treatment than to control treatments in nonr and omized trials. Evidence from the more definitive r and omized controlled trials indicates that stimulants are more effective in ameliorating the core behavioral symptoms of ADHD ( restlessness, inattentiveness, impulsiveness ) than placebos, nonpharmacological therapies, or no treatment-at least in 3 - 7-month trials. During extended psychostimulant treatment, few children become symptom-free, clinical effects may diminish with time, and improvement dissipates rapidly upon discontinuation of medication. There is minimal evidence that extended stimulant treatment improves cognitive deficits or associated problems such as conduct disturbance, low self-esteem, poor peer relationships, or academic underachievement. The belief that stimulants do not improve the long-term prognosis of children with ADHD may be based on weakly design ed studies that focus on associated rather than core symptoms. A failure to assign patients of similar clinical severity to different treatment conditions may also have contributed to obscuring the efficacy of extended psychostimulant treatments', "Patients with Turner syndrome have adverse bone and cardiovascular outcomes from chronic estrogen deficiency. Hence, long-term estrogen replacement therapy is the cornerstone treatment. The estimates of its effect and optimal use, however, remain uncertain. We aim ed to summarize the benefits and harms of estrogen replacement therapy on bone, cardiovascular, vasomotor and quality of life outcomes in patients with Turner syndrome. Population-based cohort study of injuries. A population -based cohort study was done to estimate the incidence of different types of injuries and to evaluate certain risk factors in an urban slum ; 4333 slum dwellers in Madras city in India were r and omly selected by cluster sampling, of whom 1.7 per cent were lost during the 12 months of follow up. The cumulative injury incidence for 12 months for all injuries was 127 per 1000 persons ( 95 per cent confidence interval 117 - 137 ) ; for males 137 per 1000 and for females 118 per 1000. Incidence of unintentional injury was 121 per 1000 persons. The incidence for road traffic injury was 16 per 1000 persons, for household injuries 57 per 1000 persons and for injury at place of work 19 per 1000 persons. The relative risk of males to females for traffic injuries was 3.04 and for household injuries was 0.39. The relative risk of traffic injuries among adult males who reported daily alcohol consumption was 2.26. The incidence of injury is high in an urban slum and it is a priority health problem. This study has identified groups of people who are at high risk for injuries and who may need specific protective measures The pilot study. This pilot aims to better underst and the market for childcare in Saudi Arabia – both the supply and dem and sides – and to design a r and omized controlled experiment to test whether access to affordable day care ( in the form of subsidies, for example ) would incentivize Saudi mothers to search actively for employment and to remain employed once they are hired. In addition, the study seeks to underst and the degree to which employment early on in one ’s life impacts employment in later stages. The pilot will provide information on the groups of women the experiment should target, appropriate levels for the childcare subsidy, and the quality and current geographic locations of daycare sites. Expected Impact Determine the effects of facilitating childcare access on Saudi women ’s employment. PRINCIPAL INVESTIGATORS \uf0d8 Boston University Patricia Cortes \uf0d8 Harvard University Claudia Goldin \uf0d8 Swarthmore College Jennifer A longitudinal study of the effect of subcutaneous estrogen replacement on bone in young women with Turner's syndrome. It is desirable that young women with primary ovarian failure achieve normal peak bone mass to reduce the subsequent risk of osteoporosis, and that there are management strategies to replace bone that is already lost. While estrogen ( E2 ) is generally considered to prevent bone loss by suppressing bone resorption, it is now recognized that estrogen also exerts an anabolic effect on the human skeleton. In this study, we tested whether estrogen could increase bone mass in women with primary ovarian failure. We studied the mechanism underlying this by analyzing biochemical markers of bone turnover and iliac crest biopsy specimens obtained before and 3 years after E2 replacement. Twenty-one women with Turner's syndrome, aged 20 - 40 years, were studied. The T scores of bone mineral density at lumbar spine and proximal femur at baseline were -1.4 and -1.1, respectively. Hormone replacement was given as subcutaneous E2 implants ( 50 mg every 6 months ) with oral medroxy progesterone. Serum E2 levels increased incrementally from 87.5 pM at baseline to 323, 506, 647, and 713 pM after 6 months and 1, 2, and 3 years of hormone replacement therapy ( HRT ), respectively. The bone mineral density at the lumbar spine and proximal femur increased after 3 years to T scores of -0.2 and -0.4, respectively. The cancellous bone volume increased significantly from 13.4 % to 18.8 %. There was a decrease in activation frequency, but the active formation period was increased by HRT. There was a significant increase in the wall thickness from 33.4 microm at baseline to 40.9 microm after 3 years of HRT, reflecting an increase in bone formed at individual remodeling units. Although there was an early increase in biochemical markers of bone formation, these declined thereafter. Our results show that estrogen is capable of exerting an anabolic effect in the skeleton of young women with Turner's syndrome and low bone mass Insulin resistance and body composition in Turner syndrome: Effect of sequential change in the route of estrogen administration The aim of the present study was to examine the impact of sequential change in the route of estrogen administration on body composition and insulin resistance in patients with Turner syndrome ( TS ) using cyclical hormone replacement therapy ( HRT ) with conjugated equine estrogens ( CEE ) plus medroxyprogesterone acetate ( MPA ). We carried out a self-controlled study of nine non-obese patients with TS, with an average age of 23 ± 4.9 years. Body mass index ( BMI ), waist-to-hip ratio ( WHR ), fasting glycemia, insulin tolerance ( glucose disappearance constant during an insulin tolerance test, kITT ) and body composition ( dual-energy X-ray absorptiometry ) were studied after 1 year's use of CEE plus MPA and repeated after 1 year's use of 17β-estradiol gel with the same schedule of MPA administration. We did not observe any difference between the oral and percutaneous HRT with regard to BMI, WHR and insulin tolerance ( kITT : 4.9 ± 1.5 vs. 5.3 ± 1.5%/min, p = 0.8 ). During administration of the 17β-estradiol gel a tendency to increased total lean mass ( p = 0.054 ) was observed. We conclude that sequential change in the route of estrogen administration in TS patients using cyclical HRT with CEE and MPA does not affect insulin resistance, although use of percutaneous 17β-estradiol gel seems to exert favorable changes in body composition Health-related quality of life of young adults with Turner syndrome following a long-term randomized controlled trial of recombinant human growth hormone Background There are limited long-term r and omized controlled trials of growth hormone ( GH ) supplementation to adult height and few published reports of the health-related quality of life ( HRQOL ) following treatment. The present follow-up study of young adults from a long-term controlled trial of GH treatment in patients with Turner syndrome ( TS ) yielded data to examine whether GH supplementation result ed in a higher HRQOL ( either due to taller stature or from the knowledge that active treatment and not placebo had been received ) or alternatively a lower HRQOL ( due to medicalization from years of injections ). Methods The original trial r and omized 154 Canadian girls with TS aged 7 - 13 years from 13 centres to receive either long-term GH injections at the pharmacologic dose of 0.3 mg/kg/week or to receive no injections ; estrogen prescription for induction of puberty was st and ardized. Patients were eligible for the follow-up study if they were at least 16 years old at the time of follow-up. The instrument used to study HRQOL was the SF-36, summarized into physical and mental component scales ( PCS and MCS ) ; higher scores indicate better HRQOL. Results Thirty-four of the 48 eligible participants ( 71 % ) consented to participate ; data were missing for one patient. Both groups ( GH and no treatment ) had normal HRQOL at this post-treatment assessment. The GH group had a ( mean ± SD ) PCS score of 56 ± 5 ; the untreated group 58 ± 4 ; mean score for 16 - 24 year old females in the general population 53.5 ± 6.9. The GH group had a mean MCS score of 52 ± 6 ; the untreated group 49 ± 13 ; mean score for 16 - 24 year old females in the general population 49.6 ± 9.8. Secondary analyses showed no relationship between HRQOL and height. Conclusions We found no benefit or adverse effect on HRQOL either from receiving or not receiving growth hormone injections in a long-term r and omized controlled trial, confirming larger observational studies. We suggest that it remains ethically acceptable as well as necessary to maintain a long-term untreated control group to estimate the effects of pharmacological agents to manipulate adult height. Young adult women with TS have normal HRQOL suggesting that they adjust well to their challenges in life. Trial Registration Clinical Trials.gov Identifier NCT00191113 Decreased bone mass despite long-term estrogen replacement therapy in young women with Turner's syndrome and previously normal bone density. OBJECTIVE To determine whether young women with Turner's syndrome who had normal bone mineral density ( BMD ) before the induction of puberty maintain normal BMD in young adulthood. DESIGN Controlled clinical study. SETTING A private hospital clinical research setting. PATIENTS Young women with Turner's syndrome in Tanner stage V of puberty with previously normal BMD. INTERVENTIONS Oral conjugated estrogens and progesterone acetate were administered continuously for a mean ( + /-SD ) of 4.1+/-1.0 years. Bone mineral densities and blood sample s were evaluated. MAIN OUTCOME MEASURE(S ) The BMD of the lumbar spine and the femoral neck was determined during young adulthood. The change in BMD over the previous 6 years also was evaluated. Serum concentrations of the carboxy-terminal propeptide of type 1 collagen and of the carboxy-terminal cross-linked telopeptide of type 1 collagen were measured. RESULT ( S ) The BMD of the lumbar spine was reduced significantly in our patients. There was no change in the BMD of the femoral neck or lumbar spine over a period of 6.1 years. Concentrations of the carboxy-terminal propeptide of type 1 collagen were decreased, whereas concentrations of the carboxy-terminal cross-linked telopeptide of type 1 collagen were increased. CONCLUSION ( S ) Young women with Turner's syndrome do not attain normal peak bone mass even when estrogen replacement therapy is begun in adolescence. Their low BMD seems to be due to decreased bone formation and increased bone resorption A randomized trial of transdermal and oral estrogen therapy in adolescent girls with hypogonadism Background Adolescent females with ovarian failure require estrogen therapy for induction of puberty and other important physiologic effects. Currently, health care providers have varying practice s without evidence -based st and ards, thus investigating potential differences between oral and transdermal preparations is essential. The purpose of this study was to compare the differential effects of treatment with oral conjugated equine estrogen ( OCEE ), oral 17β estradiol ( OBE ), or transdermal 17β estradiol ( TBE ) on biochemical profiles and feminization in girls with ovarian failure. Study design 20 prepubertal adolescent females with ovarian failure, ages 12–18 years, were r and omized to OCEE ( n = 8), OBE ( n = 7 ), or TBE ( n = 5 ) for 24 months. Estrogen replacement was initiated at a low dose ( 0.15 mg OCEE, 0.25 mg OBE, or 0.0125 mg TBE ) and doubled every 6 months to a maximum dose of 0.625 mg/d OCEE, 1 mg/d OBE, or 0.05 mg/d TBE. At 18 months, micronized progesterone was added to induce menstrual cycles. Biochemical markers including sex hormones, inflammatory markers, liver enzymes, coagulation factors, and lipids were obtained at baseline and 6 month intervals. Differences in levels of treatment parameters between the groups were evaluated with one-way analysis of variance ( ANOVA ). The effect of progesterone on biochemical markers was evaluated with the paired t-test. Results Mean ( ±SE ) estradiol levels at maximum estrogen dose ( 18 months ) were higher in the TBE group ( 53 ± 19 pg/mL ) compared to OCEE ( 14 ± 5 pg/mL ) and OBE ( 12 ± 5 pg/mL ) ( p ≤ 0.01 ). The TBE and OBE groups had more effective feminization ( 100 % Tanner 3 breast stage at 18 months ). There were no statistical differences in other biochemical markers between treatment groups at 18 months or after the introduction of progesterone. Conclusions Treatment with transdermal 17β estradiol result ed in higher estradiol levels and more effective feminization compared to oral conjugated equine estrogen but did not result in an otherwise different biochemical profile in this limited number of heterogeneous patients. OBE and TBE provide safe and effective alternatives to OCEE to induce puberty in girls, but larger prospect i ve r and omized trials are required. Trial registration Clinical Trials Identifier : NCT01023178 Comparison of Transdermal and Oral Estrogen Therapy in Girls with Turner's Syndrome Eight girls with Turner's syndrome were given low dose oral ethinyl estradiol or transdermal 17 beta-estradiol in order to compare the effect of the route of administration on selected markers of hepatic metabolism, and various hormonal concentrations. Oral estrogen was given at a dose of 100 ng/kg/day and transdermal estrogen via adhesive skin patch at 0.0125 mg/kg/day. The subjects received one form of estradiol for one month, and after a one month washout period, received the other form. Both oral and transdermal estradiol caused a significant decrease in FSH while only transdermal result ed in a significant decrease in LH. Oral estradiol, though not transdermal estradiol, increased serum high density lipoprotein, thyroxine binding protein and growth hormone binding protein. Urinary growth hormone excretion increased after both forms of therapy, while insulin-like growth factor-I and insulin-like growth factor binding protein-3 remained unchanged. Thus, in girls with Turner's syndrome, estrogen replacement by the transdermal route may have less deleterious effect on hepatic metabolism than oral estrogen Androgen replacement therapy in Turner syndrome: a pilot study. CONTEXT Women with Turner syndrome ( TS ) have reduced levels of and rogens due to ovarian failure. HYPOTHESES Morbidity associated with TS, such as bone fragility, metabolic changes, obesity, neurocognitive profile, and sexual problems may partly relate to and rogen insufficiency and improve on and rogen replacement therapy ( ART ). OBJECTIVES The objective of the study was to determine the effect of and rogens on morbidity in TS. DESIGN Fourteen TS women ( aged 17 - 27 yr ) participated in a r and omized, double-blind, placebo-controlled crossover pilot. The study was conducted in a hospital outpatient clinic between December 2001 and July 2004. INTERVENTION TS patients were on estrogen/progestin replacement therapy. Subjects received oral 1.5 mg methyl testosterone ( ART ) or placebo for 1 yr and the alternative for another year. MAIN OUTCOME MEASURES The study compared body composition as a primary outcome, and physiology, biochemistry, visceral fat, cognition, and quality of life ( QOL ) as secondary outcomes. RESULTS ART as compared with placebo reduced total cholesterol, triglycerides, and high-density lipoprotein cholesterol. It improved bone mineral density, increased lean body mass, and decreased fat mass. ART improved attention, reaction time, and verbal memory and had no effect on executive functions and spatial cognition. Patients reported improved QOL, including general health, coping with stress, and sexual desire. CONCLUSIONS And rogen insufficiency plays a role in TS-impaired body composition, neurocognition, and QOL, and these aspects improve with ART, which was safe and effective when given for 1 yr Choosing an oestrogen replacement therapy in young adult women with Turner syndrome* OBJECTIVE Hormone replacement therapy ( HRT ) is prescribed to most patients with Turner syndrome ( TS ) although its use in adult TS patients has not been scientifically evaluated. The present study was performed to compare the short‐term effects in adult women with Turner syndrome of low‐dose oral conjugated oestrogen ( 0·625 mg, CE ) with relatively high dose ethinyl oestradiol ( 30 µg, EE2 ) ; both combined with an oral progestin Growth hormone and 17 beta-oestradiol treatment of Turner girls--2-year results. Girls with Turner syndrome are mainly characterized by growth retardation and gonadal insufficiency. In order to evaluate the effect of growth hormone ( GH ) and /or low dose 17 beta-oestradiol ( E2 ) on growth and pubertal development, 39 Turner girls with a chronological age ( CA ) of 7.6 - 18.1 years were divided into three groups depending on pretreatment bone age ( BA ). They were treated with either GH 0.1 IE/kg per day ( n = 13, BA 7.1 - 10.2 ), peroral E2 0.01 mg/kg per day ( n = 8, BA 8.5 - 12.7 ) or both ( n = 18, BA 10.5 - 15.3 ). In the 2nd year the E2 group also received GH, while the E2 dose was reduced 30 %. In the 1st year height velocity ( HV ) expressed as st and ard deviation scores ( SDS ) increased in all groups ( mean ) : from -0.4 to 3.3 ( P < 0.01 ) in the GH group, -0.5 to 2.7 ( P < 0.01 ) in the E2 group, and -0.8 to 4.6 ( P < 0.001 ) in the GH+E2 group. A possible synergistic effect from combination therapy was seen, as HV increase was higher in group 3 than groups 1 and 2 ( P < 0.05 ). In the 2nd year HV was unchanged in groups 1 and 2, while a clear decrease was seen in the GH+E2 group ( P < 0.001 ). In the 1st year BA progression in the E2 group was rapid ( 1.9 BA/CA year ) and higher than in the other groups ( P < 0.05 ). In the 2nd year progression slowed down -- particularly in the E2 group ( 0.7 BA/CA year, P = 0.07 ). ( ABSTRACT TRUNCATED AT 250 WORDS Nonoptimal Lipids Commonly Present in Young Adults and Coronary Calcium Later in Life: The CARDIA (Coronary Artery Risk Development in Young Adults) Study BACKGROUND Dyslipidemia causes coronary heart disease in middle-aged and elderly adults, but the consequences of lipid exposure during young adulthood are unclear. OBJECTIVE To assess whether nonoptimal lipid levels during young adulthood cause atherosclerotic changes that persist into middle age. DESIGN Prospect i ve cohort study. SETTING 4 cities in the United States. PARTICIPANTS 3258 participants from the 5115 black and white men and women recruited at age 18 to 30 years in 1985 to 1986 for the CARDIA ( Coronary Artery Risk Development in Young Adults ) study. MEASUREMENTS Low-density lipoprotein ( LDL ) and high-density lipoprotein ( HDL ) cholesterol, triglycerides, and coronary calcium. Time-averaged cumulative exposures to lipids between age 20 and 35 years were estimated by using repeated serum lipid measurements over 20 years in the CARDIA study ; these measurements were then related to coronary calcium scores assessed later in life ( 45 years [ SD, 4 ] ). RESULTS 2824 participants ( 87 % ) had nonoptimal levels of LDL cholesterol ( > or=2.59 mmol/L [ > or=100 mg/dL ] ), HDL cholesterol ( < 1.55 mmol/L [ < 60 mg/dL ] ), or triglycerides ( > or=1.70 mmol/L [ > or=150 mg/dL ] ) during young adulthood. Coronary calcium prevalence 2 decades later was 8 % in participants who maintained optimal LDL levels ( < 1.81 mmol/L [ < 70 mg/dL ] ), and 44 % in participants with LDL cholesterol levels of 4.14 mmol/L ( 160 mg/dL ) or greater ( P < 0.001 ). The association was similar across race and sex and strongly grade d, with odds ratios for coronary calcium of 1.5 ( 95 % CI, 0.7 to 3.3 ) for LDL cholesterol levels of 1.81 to 2.56 mmol/L ( 70 to 99 mg/dL ), 2.4 ( CI, 1.1 to 5.3 ) for levels of 2.59 to 3.34 mmol/L ( 100 to 129 mg/dL ), 3.3 ( CI, 1.3 to 7.8 ) for levels of 3.37 to 4.12 mmol/L ( 130 to 159 mg/dL ), and 5.6 ( CI, 2.0 to 16 ) for levels of 4.14 mmol/L ( 160 mg/dL ) or greater, compared with levels less than 1.81 mmol/L ( < 70 mg/dL ), after adjustment for lipid exposure after age 35 years and other coronary risk factors. Both LDL and HDL cholesterol levels were independently associated with coronary calcium after participants who were receiving lipid-lowering medications or had clinical ly abnormal lipid levels were excluded. LIMITATION Coronary calcium, although a strong predictor of future coronary heart disease, is not a clinical outcome. CONCLUSION Nonoptimal levels of LDL and HDL cholesterol during young adulthood are independently associated with coronary atherosclerosis 2 decades later. PRIMARY FUNDING SOURCE National Heart, Lung, and Blood Institute Estrogen Deficiency in Adolescents and Young Adults: Impact on Bone Mineral Content and Effects of Estrogen Replacement Therapy Because the long-term effects of estrogen replacement in adolescents with ovarian failure and hypothalamic amenorrhea have not been previously studied, we conducted a 2-year study of 35 patients to determine factors contributing to baseline bone density measures ( bone density, bone mineral content, and bone width ) and the response to estrogen therapy. Estrogen-deficient patients were often profoundly osteopenic by single-photon absorptiometry of the radius and dual-photon absorptiometry of the spine, despite estrogen replacement. Variables that were significant predictors of better initial single-photon absorptiometry measurements included increased age, increased body mass index, spontaneous pubertal development, lack of radiation therapy, and lower serum osteocalcin. Patients treated with estrogen/progestin had stable cortical bone mineral content and bone density at the distal one-third of the radius, a slight improvement in bone density at the distal one-tenth of the radius, and an encouraging, but marginal, improvement in the z score ( st and ard deviation from the mean ) of bone mineral content at the distal onetenth. The z scores for cortical bone width and bone density decreased, suggesting a possible relative worsening over time. In untreated estrogen-deficient girls, bone mineral content and bone density decreased ( but not significantly ) ; the z score of cortical bone width showed a significant decrease. Using dual-photon absorptiometry, a history of radiation therapy was found to be a predictor of lower bone density compared with age-matched controls. Estrogen/ progestin therapy did not result in changes in serum levels of lipids and antithrombin HI, weight, or blood pressure. This study suggests that because most adolescent/young adult patients with estrogen deficiency may not achieve normal bone density with current therapy, earlier and more aggressive intervention may be necessary [The effect of primary lack of estrogens and the influence of the age at the beginning of estrogen therapy on bone mineral density in patients with Turner's syndrome]. Lumbar spine bone mineral density ( BMD ) values were measured in women with Turner's syndrome ( TS ) and the influence of primary ovarian failure as well as the age at the start of estroprogestins ( EP ) therapy were considered. EP treatment with 2 mg of estradiol ( E2 ) and BMD monitoring were started in 72 and finally continued for 5 years in 34 patients with TS, aged 12 - 38 years, previously not treated with growth hormone or anabolic steroids. The mean total BMD gain ( deltaBMD ) was 20 % and the most significant increase was observed after the first ( 7.5 % ) and the second ( 6.6 % ) year of the therapy. Before the start and during EP treatment E2 levels were evaluated : they increased from 9.2pg/ml to the values observed in the controls ( C ) but positive correlation with BMD was not observed. Analysis of TS patients in age brackets ( < 15 years, 15 - 20 years, 21 - 25 years, > 25 years ) showed that only in the group that started EP treatment before the age of 15 every year significant deltaBMD was observed. The group that started EP therapy after the age of 20 didn't achieve significant deltaBMD. Patients wit TS had significantly higher levels of bone metabolism markers ( Ntx and BALP ) than the controls and in both groups negative correlation with age was found. On the basis of the results the conclusion was made that in hypoestrogenic women, not exclusively TS, the age when estrogen therapy is started may determine the effects in relation to bone mass. The administered E2 doses may also be important Mortality ratios, life expectancy, and causes of death in patients with Turner's syndrome. In a prospect i ve study of 156 female patients with Turner's syndrome who had survived infancy and been followed up for an average of 17 years there were 15 deaths. The expected mortality was 3.6. Sixteen of the patients had a congenital heart anomaly and five of the deaths occurred in this group. The 10 deaths in the remaining 140 were three times as many as expected. The reduction in life expectation was 12.5 years at age 1 year, 11 years at age 20, and 10 years at age 40. Deaths were due to a broad spectrum of diseases. In the sample as a whole there were eight deaths from diseases of the circulatory system. This number is significantly greater than expected, but four were due to congenital heart disease. When patients with congenital heart disease were omitted from the sample the mortality from circulatory disorders was not significantly increased. Within the category of circulatory disorders there were three deaths from dissection of the aorta, a number which is greatly in excess of the expected. Two of these patients had no previous evidence of heart disease", 'Objective This systematic review aims to identify generic prognostic factors for disability and sick leave in subacute pain patients. Epidemiology of chronic non-malignant pain in Denmark & NA ; A series of health surveys are conducted every sixth to seventh year in Denmark. In the most recent survey of 2000, a national r and om sample ( > 16 years ) was drawn from the Danish Central Personal Register. Out of the original sample 12,333 ( 74 % ) were interviewed and of these 10,066 returned a completed question naire ( SF‐36 ). The present study includes only those who both took part in the interview and the postal question naire. Cancer patients were excluded. Persons suffering from chronic pain ( PG ) were identified through the question ‘ Do you have chronic/long lasting pain lasting 6 months or more ’? An overall chronic pain prevalence of 19 % was found −16 % for men and 21 % for women. Prevalence of chronic pain increased with increasing age. Persons ≥67 years had 3.9 higher odds of suffering from chronic pain than persons in the age group 16–24 years. Compared with married persons, divorced or separated persons had 1.5 higher odds of chronic pain. Odds for chronic pain were 1.9 higher among those with an education of less than 10 years compared with individuals with an education of 13 years or more. During a 14‐day period reporters of chronic pain had an average of 0.8 days ( range 0–10 ) lost due to illness compared with an average of 0.4 days ( range 0–10 ) for the control group ( CG ) ( Odds Ratio ( OR ) ) 2.0 ). Persons with a job which required high physical strain were more likely to report chronic pain compared with those with a sedentary job ( OR 2.2 ). The odds of quitting one\'s job because of ill health were seven times higher among people belonging to the PG. A strong association between chronic pain and poor self‐rated health was also demonstrated. The PG had twice as many contacts with various health professionals compared with the CG, and the health care system was, on average, utilised 25 % more ( overall contacts ) by the PG than by the general population. Among the persons in the PG, 33 % were not satisfied with the examinations carried out in connection with their pain condition and 40 % were not satisfied with the treatment offered. Nearly 130,000 adults, corresponding to 3 % of the Danish population, use opioids on a regular basis. Opioids are used by 12 % of the PG Increasing value and reducing waste in research design, conduct, and analysis Correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies can produce misleading results and waste valuable re sources. Small effects can be difficult to distinguish from bias introduced by study design and analyses. An absence of detailed written protocol s and poor documentation of research is common. Information obtained might not be useful or important, and statistical precision or power is often too low or used in a misleading way. Insufficient consideration might be given to both previous and continuing studies. Arbitrary choice of analyses and an overemphasis on r and om extremes might affect the reported findings. Several problems relate to the research workforce, including failure to involve experienced statisticians and method ologists, failure to train clinical research ers and laboratory scientists in research methods and design, and the involvement of stakeholders with conflicts of interest. Inadequate emphasis is placed on recording of research decisions and on reproducibility of research. Finally, reward systems incentivise quantity more than quality, and novelty more than reliability. We propose potential solutions for these problems, including improvements in protocol s and documentation, consideration of evidence from studies in progress, st and ardisation of research efforts, optimisation and training of an experienced and non-conflicted scientific workforce, and reconsideration of scientific reward systems Do psychological factors predict outcome in both low-back pain and shoulder pain? Background and Objective : Psychological factors are assumed to predict persistent or recurrent musculoskeletal pain. The influence of psychological factors in patients with low-back pain ( LBP ) or shoulder pain was explored to study whether there is similarity regarding the factors that predict persisting pain and disability. Methods : Patients presenting in primary care with a new episode of shoulder pain or non-specific (sub)acute low back pain ( LBP ) were enrolled in a prospect i ve study. In both patient groups, pain catastrophising, distress, somatisation and fear-avoidance beliefs were measured at baseline. Primary outcome measures at 3 months were ( 1 ) persistent symptoms, and ( 2 ) < 30 % reduction in functional disability. Multivariate logistic regression analysis was used to study the associations between psychological factors and outcome. Results : A total of 587 patients with shoulder pain and 171 patients with LBP were enrolled in the study. In patients with shoulder pain, most associations of psychological factors with outcome were weak and not significant. Only in patients with longer symptom duration at baseline ( ⩾3 months ) were higher scores on catastrophising significantly associated with persistent symptoms ( p = 0.04 ). In patients with LBP, psychological factors were more strongly associated with poor outcome, although most associations were not significant. Conclusion : Psychological factors, with the exception of fear-avoidance beliefs, are more strongly associated with persistent pain and disability in patients with LBP than in those with shoulder pain. This seems to indicate that in a primary care population the influence of psychological factors on outcome may vary across patients with different types of pain Independent evaluation of a clinical prediction rule for spinal manipulative therapy: a randomised controlled trial A clinical prediction rule to identify patients most likely to respond to spinal manipulation has been published and widely cited but requires further testing for external validity. We performed a pre-planned secondary analysis of a r and omised controlled trial investigating the efficacy of spinal manipulative therapy in 239 patients presenting to general practice clinics for acute, non-specific, low back pain. Patients were r and omised to receive spinal manipulative therapy or placebo 2 to 3 times per week for up to 4 weeks. All patients received general practitioner care ( advice and paracetamol ). Outcomes were pain and disability measured at 1, 2, 4 and 12 weeks. Status on the clinical prediction rule was measured at baseline. The clinical prediction rule performed no better than chance in identifying patients with acute, non-specific low back pain most likely to respond to spinal manipulative therapy ( pain P = 0.805, disability P = 0.600 ). At 1-week follow-up, the mean difference in effect of spinal manipulative therapy compared to placebo in patients who were rule positive rather than rule negative was 0.3 points less on a 10-point pain scale ( 95 % CI −0.8 to 1.4 ). The clinical prediction rule proposed by Childs et al. did not generalise to patients presenting to primary care with acute low back pain who received a course of spinal manipulative therapy Point-of-care prognosis for common musculoskeletal pain in older adults. IMPORTANCE Many site-specific, multivariable risk models for predicting the outcome of musculoskeletal pain problems have been published. The overlapping content in these models suggests a common set of generic indicators suitable for use in primary care. OBJECTIVE To investigate whether a brief set of generic prognostic indicators can predict the outcome of musculoskeletal pain in older patients presenting to general practitioners. DESIGN, SETTING, AND PARTICIPANTS A prospect i ve observational cohort study conducted from September 1, 2006, through March 31, 2007, of consecutive patients 50 years or older presenting with noninflammatory musculoskeletal pain to 1 of the 5 participating general practice s in the United Kingdom. MAIN OUTCOME MEASURES During consultation, the treating physician assessed and recorded 5 brief generic items ( duration of present pain episode, current pain intensity, pain interference with daily activities, presence of multiple-site pain, and ultrashort depression screen ) and recorded their overall prognostic judgment. The primary outcome was patient-rated improvement, which was measured 6 months after consultation and cross-vali date d with repeated measures up to 3 years. RESULTS A total of 194 ( 48.1 % ) of 403 participants were classified as having an unfavorable outcome at 6 months. Inclusion of 3 generic prognostic indicators ( duration of present pain episode, pain interference with daily activities, and presence of multiple-site pain ) in the prognostic model improved on reliance on physicians\'prognostic judgment alone ( C statistic = 0.72 vs 0.62 ; net reclassification index = 0.136 ; proportion correctly classified = 69 % ). The improvement in prognostic accuracy was attributable to correcting physicians\'tendency toward overoptimistic expectations of outcome. CONCLUSIONS AND RELEVANCE Three easy-to-obtain pieces of information followed by systematic recording of the general practitioners\'prognostic judgment provide a simple generic assessment of prognosis at point of care in older persons presenting with musculoskeletal problems to primary care practice s in the United Kingdom. Such an assessment offers a common foundation for investigating the usefulness of prognostic stratification for guiding management in the consultation across a range of common painful conditions Are prognostic indicators for poor outcome different for acute and chronic low back pain consulters in primary care? & NA ; Few studies have investigated whether prognostic indicators, which contribute to the transition from acute to chronic low back pain ( LBP ), are also those which contribute to continuing persistence of chronic LBP. We compared the contribution of physical, psychological and social indicators to predicting disability after one year between consulters with LBP of less than 3 months duration and more than 3 months duration. Data from two large prospect i ve cohort studies of consecutive patients consulting with LBP in general practice s were merged, providing complete data for 258 cases with acute/subacute LBP and 668 cases with chronic LBP at 12 months follow‐up. There were significant differences between the two LBP groups in baseline characteristics and clinical course of disability, assessed by Rol and Morris Disability Question naire, during the year of follow‐up. Adjusted associations between potential prognostic indicators and disability at 12 months were carried out in the two LBP subgroups. The final multivariable regression models showed that being non‐employed, having widespread pain, a high level of Chronic Pain Grade, and catastrophising were the strongest prognostic indicators for disability at 12 months in both LBP groups. Fear of pain was significantly associated with disability in chronic LBP. Importantly, beyond baseline disability, the effect size of the other prognostic indicators for poor outcome was rather low. These findings must continue to challenge research ers to identify useful early predictors of outcome in persons with disabling back pain, as screening and targeted treatment approaches are dependent upon prognostic indicators with clinical significance Does a patient’s physical activity predict recovery from an episode of acute low back pain? A prospective cohort study Background Advice to remain active and normalisation of activity are commonly prescribed in the management of low back pain ( LBP ). However, no research has assessed whether objective measurements of physical activity predict outcome and recovery in acute low back pain. Method The aims of this study were to assess the predictive relationship between activity and disability at 3 months in a sub-acute LBP population. This prospect i ve cohort study recruited 101 consenting patients with sub-acute LBP ( < 6 weeks ) who completed the Rol and Morris Disability Question naire ( RMDQ ), the Visual Analogue Scale, and resumption of full ‘ normal ’ activity question ( Y/N ), at baseline and 3 months. Physical activity was measured for 7 days at both baseline and at 3 months with an RT3 accelerometer and a recall question naire. Results Observed and self-reported measures of physical activity at baseline and change in activity from baseline to 3 months were not independent predictors of RMDQ ( p > 0.05 ) or RMDQ change ( p > 0.05 ) over 3 months. A self-report of a return to full ‘ normal ’ activities was significantly associated with greater RMDQ change score at 3 months ( p < 0.001 ). Paired t-tests found no significant change in activity levels measured with the RT3 ( p = 0.57 ) or the recall question naire ( p = 0.38 ) from baseline to 3 months. Conclusions These results question the predictive role of physical activity in LBP recovery, and the assumption that activity levels change as LBP symptoms resolve. The importance of a patient ’s perception of activity limitation in recovery from acute LBP was also highlighted. Trial registration Clinical Trial Registration Number, Psychosocial Variables in Patients With (Sub)Acute Low Back Pain: An Inception Cohort in Primary Care Physical Therapy in the Netherlands Study Design. A prospect i ve cohort study of patients with episodes of acute or subacute low back pain, seeking physical therapy in primary care, with follow-up at weeks 2, 4, 8, and 12. Objectives. To evaluate the association between psychosocial factors and the transition from acute or subacute low back pain to chronicity. Summary of Background Data. Psychosocial factors have long been thought to be associated with chronic pain only. Recent prospect i ve studies, however, suggest that these factors may also be important in acute or subacute low back pain. Methods. Demographic, psychosocial, and psychological baseline data were collected and analyzed from a sample of 66 acute or subacute patients with low back pain in order to predict the 3-month outcome. Results. After 3 months, response rate was 85 % ( 56 patients ). Forty-five percent rated their current status as “ not recovered. ” Twelve percent reported work absenteeism. Using multiple regression analyses, baseline scores on the Acute Low Back Pain Screening Question naire, Pain Coping Inventory, Fear-Avoidance Beliefs Question naire, and Tampa Scale for Kinesiophobia were not significantly associated with nonrecovery at 3 months. The only significant predictor at baseline was the subscale pain of the ALBPSQ, correctly classifying 80 % of the patients. The relative risk for not being recovered was 3.72 ( 95 % confidence interval, 1.63–8.52 ) for the subjects with high scores on the subscale for pain. Pain scores and scores on psychosocial variables at 12 weeks were not associated. Conclusions. The study strongly revealed pain-related items to be essential factors in the development of chronicity and long-term disability in primary care physical therapy. Health status at 8 weeks seems crucial in developing chronicity A longitudinal study on the predictive validity of the fear–avoidance model in low back pain & NA ; Recently, fear – avoidance models have been quite influential in underst and ing the transition from acute to chronic low back pain ( LBP ). Not only has pain‐related fear been found to be associated with disability and increased pain severity, but also treatment focused at reducing pain‐related fear has shown to successfully reduce disability levels. In spite of these developments, there is still a lack in well‐ design ed prospect i ve studies examining the role of pain‐related fear in acute back pain. The aim of the current study was to prospect ively test the assumption that pain‐related fear in acute stages successfully predicts future disability. Subjects were primary care acute LBP patients consulting because of a new episode of LBP ( ≤3 weeks ). They completed question naires on background variables, fear – avoidance model variables and LBP outcome ( Grade d Chronic Pain Scale, GCPS ) at baseline, 3, 6, and 12 months follow‐up and at the end of the study. Two‐hundred and twenty‐two acute LBP patients were included, of whom 174 provided full follow‐up information ( 78.4 % ). A backward ordinal regression analysis showed previous LBP history and pain intensity to be the most important predictors of end of study GCPS. Of the fear – avoidance model variables, only negative affect added to this model. Our results do not really support the longitudinal validity of the fear – avoidance model, but they do feed the discussion on the role of pain‐related fear in early stages of LBP Fear of Movement/(Re)Injury Predicting Chronic Disabling Low Back Pain: A Prospective Inception Cohort Study Study Design. Prospect i ve inception cohort study. Objective. To investigate prospect ively whether pain-related fear predicts future perceived disability and participation in patients with acute low back pain ( LBP ). Summary of Background Data. There are indications that fear of movement/(re)injury, as measured by the Tampa Scale for Kinesiophobia, is present early in an episode of LBP, and that it might be a predictor of future perceived disability and participation. Methods. A cohort of 555 patients with acute LBP included by general practitioners and physical therapists in primary care setting s was followed for 6 months. Results. Results indicate that baseline fear of movement/(re)injury was predictive of future perceived disability and, to a lesser extent ( and together with duration and radiation ), of participation. Conclusions. The results suggest that interventions aim ed at reducing pain-related fear in the acute stage of LBP might prevent restrictions of activity and participation because of pain, and might be a way of preventing the transition from acute to chronic LBP Clinical course and prognostic factors in acute neck pain: an inception cohort study in general practice. OBJECTIVE To describe the natural course of patients with acute neck pain presenting in general practice and to identify prognostic factors for recovery and sick leave. DESIGN We conducted a prospect i ve cohort study with a 1-year follow-up in general practice. Question naires were collected at baseline and after 6, 12, 26, and 52 weeks. Days of sick leave were dichotomized into two groups : below and above 7 days of sick leave. Logistic regression was used to identify prognostic factors for recovery and sick leave. PATIENTS Consecutive patients with nonspecific neck pain lasting no longer than 6 weeks were invited to participate. RESULTS One hundred eighty-seven patients were included and 138 ( 74 % ) provided follow-up data. After 1 year, 76 % of the patients stated to be fully recovered or much improved, although 47 % reported to have ongoing neck pain. Almost half of the patients on sick leave at baseline returned to work within 7 days. Multivariate analysis showed that the highest association with recovery was the advice of the general practitioner ( GP ) " to wait and see " ( odds ratio [ OR ] 6.7, 95 % confidence interval [ CI ] 1.6 - 31.8 ). For sick leave, referral by the GP, for physical therapy or to a medical specialist, showed the highest association ( OR 2.8, 95 % CI 1.0 - 8.4 ). CONCLUSION Acute neck pain had a good prognosis for the majority of patients, but still a relatively high proportion of patients reported neck pain after 1-year follow-up. The advice given by the GP " to wait and see " was associated with recovery, and " referral " was associated with prolonged sick leave A randomized controlled trial comparing manipulation with mobilization for recent onset neck pain. UNLABELLED A r and omized controlled trial comparing manipulation with mobilization for recent onset neck pain. OBJECTIVE To determine whether neck manipulation is more effective for neck pain than mobilization. DESIGN R and omized controlled trial with blind assessment of outcome. SETTING Primary care physiotherapy, chiropractic, and osteopathy clinics in Sydney, Australia. PARTICIPANTS Patients ( N=182 ) with nonspecific neck pain less than 3 months in duration and deemed suitable for treatment with manipulation by the treating practitioner. INTERVENTIONS Participants were r and omly assigned to receive treatment with neck manipulation ( n=91 ) or mobilization ( n=91 ). Patients in both groups received 4 treatments over 2 weeks. MAIN OUTCOME MEASURE The number of days taken to recover from the episode of neck pain. RESULTS The median number of days to recovery of pain was 47 in the manipulation group and 43 in the mobilization group. Participants treated with neck manipulation did not experience more rapid recovery than those treated with neck mobilization ( hazard ratio=.98 ; 95 % confidence interval,.66 - 1.46 ). CONCLUSIONS Neck manipulation is not appreciably more effective than mobilization. The use of neck manipulation therefore can not be justified on the basis of superior effectiveness People seeking treatment for a new episode of neck pain typically have rapid improvement in symptoms: an observational study. QUESTION What is the clinical course of a new episode of non-specific neck pain in people who are treated with multimodal physical therapies in a primary care setting? DESIGN Observational study with 3-month follow-up, run in conjunction with a r and omised trial. PARTICIPANTS 181 adults who consulted a physiotherapist or chiropractor for a new episode of nonspecific neck pain. OUTCOME MEASURES Time to recover from the episode of neck pain, time to recover normal activity, and pain and neck-related disability at three months. Clinical and demographic characteristics were investigated as potential predictors of recovery. RESULTS Within 3 months, 53 % of participants reported complete recovery from the episode of neck pain. On a scale from 0 ( none ) to 10 ( worst ), pain improved from 6.1 ( SD 2.0 ) at baseline to 2.5 ( SD 2.1 ) at 2 weeks and to 1.5 ( SD 1.8 ) at 3 months. On a scale from 0 ( none ) to 50 ( worst ), disability improved from 15.5 ( SD 7.4 ) at baseline to 5.4 ( SD 6.4 ) at 3 months. Faster recovery was independently associated with better self-rated general health, shorter duration of symptoms, being a smoker, and absence of concomitant upper back pain or headache. Higher disability at 3 months was independently associated with higher disability at baseline, concomitant upper or lower back pain, older age, and previous sick leave for neck pain. CONCLUSION People who seek physical treatments for a new episode of neck pain in this primary care setting typically have high pain scores that improve rapidly after commencing treatment. Although almost half of those who seek treatment do not recover completely within three months, residual pain and disability in this group is relatively low. Physiotherapists should reassure people with a new episode of neck pain that rapid improvement in symptoms is common, modifying this advice where applicable based on risk factors The role of fear-avoidance beliefs in acute low back pain: relationships with current and future disability and work status & NA ; Fear‐avoidance beliefs have been identified as an important psychosocial variable in patients with chronic disability doe to low back pain. The importance of fear‐avoidance beliefs for individuals with acute low back pain has not been explored. Seventy‐eight subjects with work‐related low back pain of less than 3 weeks\'duration were studied. Measurements of pain intensity, physical impairment, disability, nonorganic signs and symptoms, and depression were taken at the initial evaluation. Fear‐avoidance beliefs were measured with the work and physical activity subscales of the Fear‐avoidance Beliefs Question naire. Disability and work status were re‐assessed after 4 weeks of physical therapy. Patterns of correlation between fear‐avoidance beliefs and other concurrently‐measured variables were similar to those reported in patients with chronic low back pain. Fear‐avoidance beliefs did not explain a significant amount of the variability in initial disability levels after controlling for pain intensity and physical impairment. Fear‐avoidance beliefs about work were significant predictors of 4‐week disability and work status even after controlling for initial levels of pain intensity, physical impairment, and disability, and the type of therapy received. Fear‐avoidance beliefs are present in patients with acute low back pain, and may be an important factor in explaining the transition from acute to chronic conditions. Screening for fear‐avoidance beliefs may be useful for identifying patients at risk of prolonged disability and work absence Prognostic occupational factors for persistent low back pain in primary care Purpose To reduce the socio-economic burden of persistent low back pain ( LBP ), factors influencing the progression of acute/subacute LBP to the persistent state must be identified at an early stage. Methods Prospect i ve inception cohort study of patients attending a health practitioner for their first episode of acute/subacute or recurrent LBP. Patients were assessed at baseline addressing occupational, psychological, biomedical and demographic/lifestyle factors and followed up over 6 months. Multivariate logistic regression analysis was performed separately for the variables groups of the four different domains, controlling for age, gender and body mass index. The overall predictive value was calculated for the full regression models of the different domains. Finally, all significant variables from the different domains were combined into a final predictor model. Results The final four-predictor model predicted 51 % of variance of persistent LBP and included ‘ resigned attitude towards the job ’ ( OR 1.73 ; 95 % CI 1.16–2.59 ), ‘ social support at work ’ ( OR 0.54 ; 95 % CI 0.32–0.90 ), ‘ functional limitation ’ ( OR 1.05 ; 95 % CI 1.01–1.10 ) and ‘ duration of LBP ’ ( OR 1.04 ; 95 % CI 1.02–1.06 ). The accuracy of the model was 83 %, with 92 % of non-persistent and 67 % of persistent LBP patients correctly identified. Conclusions In this study of patients with acute/subacute LBP, ‘ resigned attitude towards the job ’ increased the likelihood of persistent LBP at 6 month. Addressing this factor with workplace interventions has the potential to modify the outcome. In patients experiencing ‘ social support at work ’, the development of persistent LBP was less likely and might therefore be considered as potential re source for prevention of persistent LBP The Natural History of Headache: Predictors of Onset and Recovery The objective of this study was to determine predictors of onset of new headache episodes and recovery from headache over one year. A population -based cohort study was conducted, comprising a baseline postal survey to a r and om sample of adults aged ≥18 years, with follow-up survey after 1 year. Risk factor data at baseline were compared with headache status at follow-up in two groups : ( i ) those free of recent headache at baseline and ( ii ) those with a recent headache at baseline. In respondents free of recent headache at baseline, previous headache [ risk ratio ( RR ) 4.15 ], the presence of other pain at baseline ( RR 1.43 ), severe sleep problems ( RR 1.67 ) and drinking caffeine ( RR 1.99 ) increased the risk of a new headache episode during the follow-up year. In respondents with recent headache at baseline, less severe headaches at baseline predicted recovery during the follow-up year, as did the absence of anxiety [ recovery ratio ( ReR ) 2.84 ] and of sleep problems ( ReR 2.77 ). Risks for increased headache-related disability reflected those for onset of a new episode and these risks increased in strength for large increases in disability. Sleep problems and caffeine consumption increase the risk of developing headache and thus provide targets for prevention. Low levels of anxiety, sleep problems and the absence of other pain improve the likelihood of recovering and remaining free from headache Predictors of return to work in patients sick listed for sub-acute low back pain: a 12-month follow-up study. OBJECTIVE To investigate whether personal and work-related factors, physical performance and back-specific question naires predict return to work. A prospect i ve study identifying prognostic factors for return to work. SUBJECTS Ninety-three patients sick-listed for 8 - 12 weeks for non-specific sub-acute low back pain included in a r and omized controlled trial. METHODS Patients were examined with regard to demographic variables, a battery of back-specific question naires and physical tests before entering a r and omized controlled trial. A stepwise backward Cox regression model was established to identify the most powerful predictors. RESULTS During follow-up 78.5 % of the patients have returned to full-time work. Fear-avoidance beliefs for work ( relative risk ( RR ) for 1 SD change 0.49 ; 95 % confidence interval ( CI ) 0.38 - 0.64 ), disability ( RR 1.39, 95 % CI 1.02 - 1.88 ) and cardiovascular fitness ( RR 1.42, 95 % CI 1.12 - 1.79 ) were identified as the best predictors for return to work. The prevalence of correct predictions was 69.3 %. CONCLUSION The predictors identified in the present study may reflect personal risk factors in a patient who gets acute low back pain. On the other h and, they may support that fear of pain and injury may be more disabling than pain itself, and that deconditioning is a result of altered behaviour reflecting attitudes towards low back pain in society, and information and advice given in primary healthcare Outcome Determinants of Subacute Low Back Pain Study Design. Descriptive prognostic study. Objectives. To identify outcome determinants of subacute low back pain. Summary of Background Data. The factors predicting recovery from prolonged back pain among working adults are largely unknown. Material s and Methods. One hundred sixty-four employed patients with subacute ( duration of pain 4–12 weeks ) daily low back pain were recruited from primary health care to a r and omized study. Data on potential predictive factors were collected before r and omization. In multiple regressions using repeated measures analysis, the treatment received was adjusted when determining the impact of the predictive factors. Dependent outcome variables used were pain, perceived functional disability, generic health-related quality of life, satisfaction with care, days on sick leave, use of health care, and costs of health care consumption measured, at 3-, 6-, and 12-month follow-ups. Results. Age and intensity of pain at baseline predicted most of the outcomes. The perceived risk of not recovering was a stronger determinant of outcome than gender, education, or self-rated health status ( which did not have any predictive value ) or body mass index, expectations of treatment effect, satisfaction with work, or the presence of radicular symptoms below the knee ( only slight predictive value ). The only factors predicting the duration of sick leave were the duration of sick leave at baseline and the type of occupation. Conclusion. Age and intensity of pain are the strongest predictors of outcome. Accumulation of days on sick leave is predicted by the duration of sick leave at entry and the type of work, but not by pain, perceived disability, or satisfaction with work A Clinical Prediction Rule To Identify Patients with Low Back Pain Most Likely To Benefit from Spinal Manipulation: A Validation Study Context In this r and omized, controlled trial, spinal manipulation plus exercise produced outcomes for low back pain similar to those produced by exercise alone. Yet, some patients did respond to spinal manipulation, and it would be helpful for doctors to be able to identify such patients. Contribution Patients were most likely to benefit from spinal manipulation if they met 4 of 5 of the following criteria : symptom duration less than 16 days, no symptoms distal to knee, score less than 19 on a fear-avoidance measure, at least 1 hypomobile lumbar segment, and at least 1 hip with more than 35 degrees of internal rotation. Implication s Clinicians may be able to use these criteria to identify patients with low back pain who are good c and i date s for spinal manipulation. The Editors Next to the common cold, low back pain is the most common reason that individuals visit a physician\'s office ( 1 ). Billions of dollars in medical expenditures and lost labor costs for this condition are incurred each year ( 2, 3 ). Attempts to identify effective interventions for individuals with low back pain have been largely unsuccessful ( 4 ). In particular, conflicting evidence exists about the effectiveness of spinal manipulation ; some r and omized trials have shown a benefit, while other trials have not ( 5 - 7 ). These conflicting conclusions are reflected in the various recommendations in national clinical practice guidelines, with some recommending manipulation and others not ( 8). The variety of conclusions in trials of manipulation may be attributable to the failure of research ers to adequately consider the importance of classification. Using broad inclusion criteria results in a heterogeneous sample that may include many patients for whom no benefit is expected, thus masking the intervention\'s true value ( 9, 10 ). Consequently, developing methods for matching patients with low back pain to treatments that are most likely to benefit them has become an important research priority ( 11 ). Clinical prediction rules are tools design ed to assist clinicians in decision making when caring for patients ( 12 ). Several clinical prediction rules have been developed and vali date d to improve clinical decision making for the use of imaging in patients with ankle, knee, cervical spine, or minor head injuries ( 13 - 16 ). Few studies have attempted to develop rules that establish prognosis on the basis of outcome from a specific intervention, such as spinal manipulation. Recently, Flynn and colleagues ( 17 ) developed a clinical prediction rule for identifying patients with low back pain who are likely to benefit from manipulation. They examined a series of patients with low back pain who received a manipulation intervention. Five factors formed the most parsimonious set of predictors for identifying patients who achieved at least 50 % improvement in disability within 1 week with a maximum of 2 manipulation interventions ( Table 1 ) ( 17 ). The positive likelihood ratio among patients who met at least 4 of 5 of the criteria was 24.4 ( 95 % CI, 4.6 to 139.4 ). Table 1. Five Criteria in the Spinal Manipulation Clinical Prediction Rule Clinical prediction rules must be vali date d in separate population s before being recommended for widespread implementation ( 18 ). A clinical prediction rule for identifying which patients with low back pain are most likely to respond to manipulation could improve clinical efficiency and re source utilization. Thus, we aim ed to vali date the spinal manipulation clinical prediction rule in a multicenter trial. Methods We considered consecutive patients with a primary symptom of low back pain who were referred to physical therapy for participation. We used 14 physical therapists at 8 clinics in various U.S. regions and setting s ( 2 academic medical centers and smaller outpatient practice setting s ). Most participating sites were health care facilities within the U.S. Air Force. Each site\'s Screening to Identify Patients at Risk: Profiles of Psychological Risk Factors for Early Intervention There is a serious need to provide effective early interventions that prevent the development of persistent pain and disability. Identifying patients at risk for this development is an important step. Our aim was to explore whether distinct subgroups of individuals with similar response patterns on a screening question naire exist. Moreover, the objective was to then relate these groups to future outcomes, for example, sick leave as an impetus for developing tailored interventions that might better prevent chronic problems. A total of 363 patients seeking primary care for acute or subacute spinal pain completed the Örebro Musculoskeletal Pain Screening Question naire and were then followed to determine outcome. Cluster analysis was used to identify subgroups. Validity was tested using 3 methods including the split-half technique. The subgroups were compared prospect ively on outcome measures obtained 1 year later. Using pain intensity, fear-avoidance beliefs, function, and mood, we found 4 distinct profiles : Fear-Avoidant, Distressed Fear-Avoidant, Low Risk, and Low Risk-Depressed Mood. These 4 subgroups were also robust in all 3 of the validity procedures. The 4 subgroups were clearly related to outcome. Although the low risk profiles had virtually no one developing long-term sick leave, the Fear-Avoidant profile had 35 % and the Distressed Fear-Avoidant profile 62 % developing long-term sick leave. Our results suggest that fear-avoidance and distress are important factors in the development of pain-related disability and may serve as a key for early identification. Providing interventions specific to the factors isolated in the profiles should enhance the prevention of persistent pain and disability', "OBJECTIVES Musculoskeletal disorders affect a high percentage of dentists, dental hygienists and therapists. Static and awkward working postures are considered as major risk factors. Proper seat selection and use of magnification loupes are promoted for their ergonomic benefits. The aim of this review was to evaluate the existing empirical evidence on the effect of the above interventions on ( i ) correction of poor posture and ( ii ) reduction in musculoskeletal pain. Effect of magnification loupes on dental hygiene student posture. The chair-side work posture of dental hygienists has long been a concern because of health-related problems potentially caused or exacerbated by poor posture. The purpose of this study was to investigate if using magnification loupes improved dental hygiene students'posture during provision of treatment. The treatment chosen was h and -scaling, and the effect of the timing of introduction of the loupes to students was also examined. Thirty-five novice dental hygiene students took part in the study. Each student was assessed providing dental hygiene care with and without loupes, thus controlling for innate differences in natural posture. Students were r and omized into two groups. Group one used loupes in the first session and did not use them for the second session. Group two reversed this sequence. At the end of each session, all students were videotaped while performing scaling procedures. Their posture was assessed using an adapted version of Branson et al.'s Posture Assessment Instrument ( PAI ). Four raters assessed students at three time periods for nine posture components on the PAI. A paired t-test compared scores with and without loupes for each student. Scores showed a significant improvement in posture when using loupes ( p<0.0001 ), and these improvements were significantly more pronounced for students starting loupes immediately on entering the program compared with students who delayed until the second session ( p<0.1 ). These results suggest a significant postural benefit is realized by requiring students to master the use of magnification loupes as early as possible within the curriculum Rayyan—a web and mobile app for systematic reviews Background Synthesis of multiple r and omized controlled trials ( RCTs ) in a systematic review can summarize the effects of individual outcomes and provide numerical answers about the effectiveness of interventions. Filtering of search es is time consuming, and no single method fulfills the principal requirements of speed with accuracy. Automation of systematic review s is driven by a necessity to expedite the availability of current best evidence for policy and clinical decision-making. We developed Rayyan ( http://rayyan.qcri.org ), a free web and mobile app, that helps expedite the initial screening of abstract s and titles using a process of semi-automation while incorporating a high level of usability. For the beta testing phase, we used two published Cochrane review s in which included studies had been selected manually. Their search es, with 1030 records and 273 records, were uploaded to Rayyan. Different features of Rayyan were tested using these two review s. We also conducted a survey of Rayyan ’s users and collected feedback through a built-in feature. Results Pilot testing of Rayyan focused on usability, accuracy against manual methods, and the added value of the prediction feature. The “ taster ” review ( 273 records ) allowed a quick overview of Rayyan for early comments on usability. The second review ( 1030 records ) required several iterations to identify the previously identified 11 trials. The “ suggestions ” and “ hints, ” based on the “ prediction model, ” appeared as testing progressed beyond five included studies. Post rollout user experiences and a reflexive response by the developers enabled real-time modifications and improvements. The survey respondents reported 40 % average time savings when using Rayyan compared to others tools, with 34 % of the respondents reporting more than 50 % time savings. In addition, around 75 % of the respondents mentioned that screening and labeling studies as well as collaborating on review s to be the two most important features of Rayyan. As of November 2016, Rayyan users exceed 2000 from over 60 countries conducting hundreds of review s totaling more than 1.6 M citations. Feedback from users, obtained mostly through the app web site and a recent survey, has highlighted the ease in exploration of search es, the time saved, and simplicity in sharing and comparing include-exclude decisions. The strongest features of the app, identified and reported in user feedback, were its ability to help in screening and collaboration as well as the time savings it affords to users. Conclusions Rayyan is responsive and intuitive in use with significant potential to lighten the load of review ers Evaluation of ergonomic factors and postures that cause muscle pains in dentistry students’ bodies Background Work-related musculoskeletal disorders commonly experienced by dental professionals are one of the main occupational health problem affecting their health and well-being. This study was conducted to evaluate ergonomic factors and profession-related postures and also investigate relationship between demographic factors and work condition with pain in dental students. Material and Methods 60 freshman and sophomore dentistry students were r and omly chosen as the subjects of control group, and 60 of 5th and 6th-year students were selected as the members of exposure group. Data related to the subjects such as sex, doing exercise, severity of musculoskeletal pain were obtained through question naire. Students ’ postures were directly observed while treating patients and they were scored by REBA method. Data were analyzed by SPSS software using Man-Whitney, Kruskal-Wallis, Spearman and Kendall correlation tests. Results 80.8 % of the subjects were not aware of the correct ergonomic postures for dental procedures. Severity of musculoskeletal pain in the exposure group ( 15.9± 4.2 ) was significantly higher than the control group ( 10.5 ±3.2 ), ( p < 0.001 ). Risk of the most subjects ( 84 % ) was at the medium level. Students who were more involved in clinical activities experienced more muscular pains. Conclusions The musculoskeletal disorders are probable prolonged in working hours in static positions, incorrect work postures, implying more force and even tools and instruments. Therefore, students who are aware of ergonomic principals of their own profession would be able to maintain their health through activities and lifelong. Key words : Posture, dentistry, students, musculoskeletal pain Are neck flexion, neck rotation, and sitting at work risk factors for neck pain? Results of a prospective cohort study OBJECTIVE To study the relation between neck pain and work related neck flexion, neck rotation, and sitting. METHODS A prospect i ve cohort study was performed with a follow up of 3 years among 1334 workers from 34 companies. Work related physical load was assessed by analysing objective ly measured exposure data ( video recordings ) of neck flexion, neck rotation, and sitting posture. Neck pain was assessed by a question naire. Adjustments were made for various physical factors that were related or not related to work, psychosocial factors, and individual characteristics. RESULTS A significant positive relation was found between the percentage of the working time in a sitting position and neck pain, implying an increased risk of neck pain for workers who were sitting for more than 95 % of the working time ( crude relative risk ( RR ) 2.01, 95 % confidence interval ( 95 % CI ) 1.04 to 3.88 ; adjusted RR 2.34, 95 % CI 1.05 to 5.21 ). A trend for a positive relation between neck flexion and neck pain was found, suggesting an increased risk of neck pain for people working with the neck at a minimum of 20 ° of flexion for more than 70 % of the working time ( crude RR 2.01, 95 % CI 0.98 to 4.11 ; adjusted RR 1.63, 95 % CI 0.70 to 3.82 ). No clear relation was found between neck rotation and neck pain. CONCLUSION Sitting at work for more than 95 % of the working time seems to be a risk factor for neck pain and there is a trend for a positive relation between neck flexion and neck pain. No clear relation was found between neck rotation and neck pain Working postures of dentists and dental hygienists. A joint study was conducted by a manufacturer of dental stools in the Midwest of the United States and Marquette University to measure the occupational postures of dentists and dental hygienists. The postures of 10 dentists and 10 dental hygienists were assessed using work sampling and video techniques. Postural data of the neck, shoulders and lower back were recorded from video and categorized into 30-degree intervals : o ( neutral posture of respective joint ), 30, 60 and 90 degrees. Each subject's postures were observed while they were treating patients during a four-hour period, during which 100 observations of postures were recorded at r and om times. Compared to st and ing, dentists and dental hygienists were seated 78 percent and 66 percent of the time, respectively. Dentists and dental hygienists flexed their trunk at least 30 degrees more than 50 percent of the time. They flexed their neck at least 30 degrees 85 percent of the time during the four-hour duration, and their shoulders were elevated to the side of their trunk ( abducted ) at least 30 degrees more half of the time. The postures of the trunk, shoulders, and neck were primarily static. This data base of postures can be used by dental professionals and ergonomists to assess the risk dentists and dental hygienists are exposed to musculoskeletal disorders, such as low back pain or shoulder tenosynovitis, from deviated joint postures. They could use these data to select dental furniture or dental devices that promote good body posture, i.e., reduce the magnitude and duration of deviated joint postures, which, in theory, would decrease the risk of musculoskeletal disorders The effect of magnification loupes on the performance of preclinical dental students. OBJECTIVE optical magnifying devices such as magnification loupes are increasingly used in clinical practice and educational setting s. However, scientific evidence to vali date their benefits is limited. This study assessed the effect of dental magnification loupes on psychomotor skill acquisition during a pre clinical operative dentistry course. METHOD AND MATERIAL S the performance of first-year dental students was assessed during an Advanced Simulation Course ( AS ) using virtual reality-based technology ( VRBT ) training. The test group consisted of 116 dental students using magnification loupes ( + MAG ), while students not using them ( -MAG, n = 116 ) served as the control. The following parameters were evaluated : number of successfully passing preparation procedures per course rotation, amount of time per tooth preparation, number of times students needed computer assistance and evaluation, and amount of time spent in the computer assistance and evaluation mode per procedure. Data were collected on each student through VRBT during the preparation procedure and stored on a closed network server computer. Unpaired t tests were used to analyze mean differences between the groups. In addition, student acceptance of magnification loupes was measured and evaluated through survey interpretation. RESULTS + MAG students completed more preparations, worked faster per procedure, and used the computer-assisted evaluation less frequently and for shorter periods, therefore displaying greater overall performance. The survey revealed a high degree of student acceptance of using magnification. CONCLUSION dental magnification loupes significantly enhanced student performance during pre clinical dental education and were considered an effective adjunct by the students who used them Assessment of dental student posture in two seating conditions using RULA methodology – a pilot study Objectives To assess dental students'posture on two different seats in order to determine if one seat predisposes to a difference in working posture. Design A between-subject experimental design was selected. Setting The study was undertaken at the University of Birmingham School of Dentistry in 2006. Subjects ( material s ) and methods Sixty second year dental students at the University of Birmingham who were attending their fi rst classes in the phantom head laboratory were r and omly selected and allocated to two different seats ( 30 Bambach Saddle Seats and 30 conventional seats ). Students were trained in the use of the seats. After ten weeks, the students were observed, photographs were taken by the research er and these were assessed using Rapid Upper Limb Assessment ( RULA ). Main outcome measures The posture of the students was assessed using the RULA. Each student was given a risk score. A Mann Whitney test was used for statistical analysis. Results The results indicated that the students using the conventional seat recorded signifi cantly higher risk scores ( p < 0.05 ) when compared with the students using Bambach Saddle Seat, suggesting an improvement in posture when using the Bambach Saddle Seat. Conclusion RULA has identifi ed that dental students using a Bambach Saddle Seat were able to maintain an acceptable working posture during simulated dental treatment and this seating may reduce the development of work-related musculoskeletal disorders Assessment of study quality for systematic reviews: a comparison of the Cochrane Collaboration Risk of Bias Tool and the Effective Public Health Practice Project Quality Assessment Tool: methodological research. BACKGROUND The Cochrane Collaboration is strongly encouraging the use of a newly developed tool, the Cochrane Collaboration Risk of Bias Tool ( CCRBT ), for all review groups. However, the psychometric properties of this tool to date have yet to be described. Thus, the objective of this study was to add information about psychometric properties of the CCRBT including inter-rater reliability and concurrent validity, in comparison with the Effective Public Health Practice Project Quality Assessment Tool ( EPHPP ). METHODS Both tools were used to assess the method ological quality of 20 r and omized controlled trials included in our systematic review of the effectiveness of knowledge translation interventions to improve the management of cancer pain. Each study assessment was completed independently by two review ers using each tool. We analysed the inter-rater reliability of each tool's individual domains, as well as final grade assigned to each study. RESULTS The EPHPP had fair inter-rater agreement for individual domains and excellent agreement for the final grade. In contrast, the CCRBT had slight inter-rater agreement for individual domains and fair inter-rater agreement for final grade. Of interest, no agreement between the two tools was evident in their final grade assigned to each study. Although both tools were developed to assess'quality of the evidence ', they appear to measure different constructs. CONCLUSIONS Both tools performed quite differently when evaluating the risk of bias or method ological quality of studies in knowledge translation interventions for cancer pain. The newly introduced CCRBT assigned these studies a higher risk of bias. Its psychometric properties need to be more thoroughly vali date d, in a range of research fields, to underst and fully how to interpret results from its application Effect of magnification lenses on student operator posture. A distinct body of literature supports the association between clinical postures of the dental practitioner and work-related musculoskeletal disorders ( WRMD ). Several aids or devices have been tested to improve clinical posture in the interest of decreasing WRMD. The use of magnification lenses while performing dental procedures may increase the quality of work and decrease the likelihood of musculoskeletal problems. To date, only anecdotal and personal opinions had existed regarding the benefits of using magnification lenses, and no empirical evidence had authenticated the contention that use of magnification lenses exerts a positive change in operator posture. The objective of this study was to assess the effect magnification lenses had on the posture of dental hygiene students. Using a r and omized crossover design, research ers videotaped nineteen senior dental hygiene students performing an intra-oral procedure with and without the use of magnification lenses. The tapes were then evaluated by a panel of five dental hygiene educators calibrated in the use of Branson's Posture Assessment Instrument ( PAI ). Results of a paired t-test indicate that the posture of the students while wearing magnification lenses was more acceptable ( p=.019 ) than when wearing traditional safety glasses. Results of this study indicate a quantifiable change in acceptability of posture for clinicians wearing magnification lenses and suggest that the use of such lenses in dental education may be warranted Work-related musculoskeletal disorders among Brazilian dental students. The aim of this analytical cross-sectional study was to evaluate the presence of work-related musculoskeletal disorders ( WMSD ) among dental students in two Brazilian dental schools. The sample included 227 r and omized subjects from fifth to ninth semesters who were developing clinical activities. Each student signed an informed consent form. A self-reporting question naire was used to obtain data on the practice of physical exercise, the presence of pain during or soon after treating patients, and the adoption of preventive measures related to clinical activities. Results were analyzed using the Statistical Package for Social Sciences 13.0. The chi(2 ) test was used to identify associations between variables. The presence of pain during or after clinical work was reported by 173 participants ( 76.2 percent ). Statistically significant differences were found between gender and the occurrence of pain. Pain was present during clinical activities ( p=0.006 ) and imposed limitations on the work routine ( p=0.011 ). Among those who practice d physical exercise, eighty-eight ( 74.6 percent ) reported pain. The high percentage of pain reported by dental students suggests the value of review ing work conditions in dental practice s in order to minimize the exposure of all workers to WMSD", "OBJECTIVE The main objective of this study was to systematic ally review all the scientific studies that analyse the effectiveness of mud pack therapy on patients diagnosed with knee OA. Both serum receptors of tumor necrosis factor are influenced by mud pack treatment in osteoarthrotic patients. Several authors have demonstrated the pivotal role of proinflammatory cytokines in inducing progressive cartilage degradation and secondary inflammation of the synovial membrane in osteoarthritis ( OA ). It has recently been established that tumor necrosis factor (TNF)-alpha plays a well-defined role in the pathophysiology of inflammatory joint diseases and that binding to circulating soluble TNF-alpha receptors can inactivate it. We investigated the influence of mud pack treatment, which is able to diminish TNF-alpha serum values, on specific TNF receptor ( sTNF-R ) levels. Thirty-six patients with OA were enrolled and r and omized into two groups. Group A underwent mud pack treatment and group B underwent thermal bath treatment. A group of 20 healthy untreated subjects was used as a control. Blood sample s were collected at baseline and after treatment, and assays of sTNF-R55 and sTNF-R75 were performed in both groups. We found small changes in sTNF-Rs serum values but these were not statistically significant. sTNF-R55 serum values decreased by 0.4 % after the therapy in group A, while in group B the decrease was -17.7 %. sTNF-R75 was reduced by -21.17 % in group A and by -10.6 % in group B. In conclusion, through its thermic and ant/inflammatory activity mud pack treatment shows complex interaction with the most common factors of inflammatory and cartilage degradation. Our results suggest that the thermic component of this natural treatment is mainly involved in modulating inflammatory reaction and cartilage damage through binding of the circulating TNF, which controls the activation of the cells responsible for the production of proinflammatory cytokines Comparison of a generic and a disease specific quality of life scale to assess a comprehensive spa therapy program for knee osteoarthritis. OBJECTIVES To compare the differences or correlation between the results obtained from a generic and a disease-specific instrument for the study group and to assess the short-term effects of spa therapy on quality of life of patients with knee osteoarthritis. PATIENTS AND METHODS Fifty patients with knee osteoarthritis were r and omly recruited. They underwent a comprehensive spa therapy program for 21 days. Forty-six patients completed the study. The results were evaluated with Medical Outcomes Study 36-Item Short Form-36 ( SF-36 ) and Arthritis Impact Measurement Scale 2 ( AIMS 2 ). RESULTS Statistically significant improvement was observed in all subscales of SF-36. All subscales of AIMS 2 improved too, but only half of them were significant. Correlation between matching subscales of each test was also significant, except physical activity. CONCLUSION Comprehensive spa therapy seems to increase the quality of life of patients with knee osteoarthritis for short term A study on the efficacy of treatment with mud packs and baths with Sillene mineral water (Chianciano Spa Italy) in patients suffering from knee osteoarthritis Mud-bath therapy plays a primary role in the treatment and prevention of osteoarthritis that has been recognised since antiquity. Numerous studies have demonstrated its clinical benefits and its effects on inflammatory mediators ( interleukins ), the immune system, cenesthesic factors ( endorphins ), and the diencephalic – pituitary – adrenal axis. This study was conducted to assess the efficacy of mud-bath therapy with mineral water from the Sillene Spring at Italy ’s Chianciano Spa in patients with osteoarthritis of the knee. Patients ( n = 61 ) were divided into two groups. Group A underwent three cycles of mud-based spa therapy over a year ’s time, whereas group B did not. Clinical conditions, visual analogue scale pain ratings, and Lequesne indexes of the two groups were compared. We also compared these same parameters in the patients of the two groups that were following the therapy with drugs and in the patients of the group A before and after spa treatment. The percentage of patients with no symptoms or mild symptoms was higher in group A than in group B. Within group A, this percentage was higher after treatment than before spa therapy. Even in the comparison between the patients of the two groups that were following the therapy with drug, the results was that in group A the percentage of patients with no symptoms or mild symptoms was higher than in group B. Statistical analyses based on various tests revealed that almost all these differences were highly significant. No adverse effects were observed in any of the patients in group A. In conclusion, the mud-bath therapy performed at Chianciano Spa with Sillene Spring water remarkably improved the clinical conditions of patients with knee arthritis and significantly reduces the frequency and severity of symptoms and the disability they cause Therapy With Mud Compresses for Knee Osteoarthritis: Comparison of Natural Mud Preparations With Mineral-Depleted Mud Mud pack therapy is an alternative mode of treatment for rheumatic diseases. It is based on the application of heated mud packs to the entire body or to specific areas, such as over joints. The aim of the current study was to evaluate the efficacy of treatment with mud compresses at patients ’ homes for osteoarthritis of the knee. Fifty-eight patients with osteoarthritis of the knee were enrolled in a prospect i ve, double-blinded, controlled study. Forty patients were treated with natural mineral-rich mud compresses and 18 patients were treated with mineral-depleted mud compresses. Mud compresses were applied 5 times each week during 3 weeks for a total of 15 treatments. Patients were assessed at baseline, at completion of the 3-week treatment period, and twice after the conclusion of the treatment period — after 1 month and after 3 months. The main outcome measures were the Lequesne Index of severity of knee osteoarthritis, patient self- assessment of pain, and severity of knee pain on a visual analog scale. A reduction of 20 % or more in the pain scores was considered clinical ly significant. In the group treated with natural mud compresses, a significant reduction in knee pain was observed at all assessment s. Similarly, improvement in the Lequesne Index was seen at the end of therapy and a month after treatment. In the control group, given mineral-depleted mud compresses, no significant change in knee pain was seen at any assessment. Improvement in the Lequesne Index was seen 1 and 3 months after completion of the therapy, but not at the end of therapy. Seventy-two percent of the patients in the treatment group had an improvement of > 20 % in self- assessment of knee pain, compared with 33 % in the control group ( p = 0.005).The data suggest that treatment with mud compresses, but only in their natural form, temporarily relieves pain in patients with osteoarthritis of the knees. We believe that treatment with mud compresses might augment conventional medical therapy in these patients Spa therapy in the treatment of knee osteoarthritis: a large randomised multicentre trial Objective To determine whether spa therapy, plus home exercises and usual medical treatment provides any benefit over exercises and usual treatment, in the management of knee osteoarthritis. Methods Large multicentre r and omised prospect i ve clinical trial of patients with knee osteoarthritis according to the American College of Rheumatology criteria, attending French spa resorts as out patients between June 2006 and April 2007. Zelen r and omisation was used so patients were ignorant of the other group and spa personnel were not told which patients were participating. The main endpoint criteria were patient self-assessed. All patients continued usual treatments and performed daily st and ardised home exercises. The spa therapy group also received 18 days of spa therapy ( massages, showers, mud and pool sessions ). Main Endpoint The number of patients achieving minimal clinical ly important improvement ( MCII ) at 6 months, defined as ≥19.9 mm on the visual analogue pain scale and /or ≥9.1 points in a normalised Western Ontario and McMaster Universities osteoarthritis index function score and no knee surgery. Results The intention to treat analysis included 187 controls and 195 spa therapy patients. At 6 months, 99/195 ( 50.8 % ) spa group patients had MCII and 68/187 ( 36.4 % ) controls ( χ2=8.05 ; df=1 ; p=0.005 ). However, no improvement in quality of life ( Short Form 36 ) or patient acceptable symptom state was observed at 6 months. Conclusion For patients with knee osteoarthritis a 3-week course of spa therapy together with home exercises and usual pharmacological treatments offers benefit after 6 months compared with exercises and usual treatment alone, and is well tolerated. Trial registration number NCT00348777 Efficacy of balneotherapy on pain, function and quality of life in patients with osteoarthritis of the knee The aims of this study were to evaluate whether balneotherapy with mineral sulphate – bicarbonate – calcium water could determine substantial symptomatic improvement, and to detect any changes in the quality of life ( QoL ) of patients with symptomatic knee osteoarthritis ( OA ). This was a prospect i ve r and omized, single blind controlled trial. Sixty out patients with primary bilateral knee OA, according to ACR criteria, were included in the study and r and omized to one of two groups : group I ( 30 patients ) was treated with a daily sulphate – bicarbonate – calcium mineral water bath ; group II ( 30 patients ), the control group, continued their regular outpatient care routine. At baseline, after 15 days and after 12 weeks, patients were evaluated by Visual Analogue Scale ( VAS ) for spontaneous pain, Lequesne and Womac Index for gonarthrosis, SF-36, Arthritis Impact Measurement Scale ( AIMS ) and symptomatic drugs consumption. We observed a significant improvement of all parameters at the end of the cycle of balneotherapy which persisted throughout the follow-up period, whereas in the control group no significant differences were noted. This symptomatic effect was confirmed by the significant reduction of symptomatic drugs consumption. The differences between the two groups were significant for all considered parameters already from the 15th day and persisted during follow-up. Tolerability of balneotherapy seemed to be good, with light and transitory side effects. Our results confirm that the beneficial effects of balneotherapy in patients with knee OA last over time, with positive effects on the painful symptomatology, a significant improvement on functional capacities and QoL. Balneotherapy can represent a useful backup to pharmacological treatment of knee OA or a valid alternative for patients who do not tolerate pharmacological treatments Mud bath therapy influences nitric oxide, myeloperoxidase and glutathione peroxidase serum levels in arthritic patients. Nitric oxide ( NO ) has recently been proposed as an important mediator in inflammatory phases and in loss of cartilage. In inflammatory arthritis NO levels are correlated with disease activity and articular cartilage is able to produce large amounts of NO with the appropriate inducing factors such as cytokines and /or endotoxin. Neutrophils also play an important role in inflammatory reactions and the level of myeloperoxidase, a constituent of neutrophil granules, is related to the intensity of the inflammation. Because there is evidence that suggests that mud packs influence the main cytokines involved in cartilage damage, we tried to determine whether NO and myeloperoxidase are involved in the mechanisms of action of mud bath treatment. We enrolled 37 subjects and r and omly assigned them to two groups : 19 patients underwent mud bath treatment ( group A ) while 18 patients underwent bath treatment alone. Blood sample s were obtained before and after the treatment cycles to assay serum levels of NO, myeloperoxidase ( MPO ) and glutathione (GSH)-peroxidase. The results showed a statistically significant decrease in NO and myeloperoxidase serum values in groups A and B, while GSH-peroxidase was not significantly increase in either of the groups ; no correlation was found between NO, myeloperoxidase and GSH-peroxidase serum values. Mud bath treatment can exert beneficial effects on cartilage homeostasis and inflammatory reactions, influencing NO and decreasing myeloperoxidase serum values. The increase in GSH-peroxidase was not correlated with the reduction of other biochemical markers, suggesting that mud bath treatment has different mechanisms of action Therapeutic effect of spa therapy and short wave therapy in knee osteoarthritis: a randomized, single blind, controlled trial Spa therapy and short wave therapy are two of the most commonly used non-pharmacological approaches for osteoarthritis. The aim of this study was to assess their efficacy in comparison to conventional therapy in patients with osteoarthritis of the knee in a single blind, r and omized, controlled trial. Seventy-four out patients were enrolled ; 30 patients were treated with a combination of daily local mud packs and arsenical ferruginous mineral bath water from the thermal resort of Levico Terme ( Trento, Italy ) for 3 weeks ; 24 patients were treated with short wave therapy for the same period and 20 patients continued regular, routine ambulatory care. Patients were assessed at baseline, upon completion of the 3-week treatment period, and 12 weeks later. Spa therapy and short wave therapy both demonstrated effective symptomatic treatment in osteoarthritis of the knee at the end of the treatment, but only the spa therapy was shown to have efficacy persistent over time. Our study demonstrated the superiority of arsenical ferruginous spa therapy compared to short wave therapy in the treatment of osteoarthritis of the knee, probably in relationship to the specific effects of the minerals in this water [Therapeutic efficacy of peloid plasters in the treatment of osteoarthritis of the peripheral joints and spondylosis]. The objective of the study was to investigate the efficacy and tolerability of the peloid plasters in the group of 20 patients with osteoarthritis of peripheral joints ( 10 patients with gonarthrosis and 10 with omarthrosis ) and 20 patients with spondylosis. This form of the pelotherapy decreased pain in joints after 10 days of the treatment. No allergic or other side effects were observed. Peloid plasters through the analgesic action improve the comfort of life and reduce the use of oral analgesic drugs Mud pack therapy in osteoarthrosis. Changes in serum levels of chondrocyte markers. We have previously shown that thermal mud therapy is able to influence chondrocyte activity of osteoarthrosic patients by modulating the production of serum cytokines, such as interleukin 1, and this was related to the presence of an anti-inflammatory principle in mature thermal mud. Mud therapy influences many biochemical processes of the body, independently of the thermic stimulation alone and the present paper documents specific increases of insulin growth factor 1 and decreases of tumor necrosis factor alpha in serum of osteoarthrosic patients after 12 days of mud pack application The efficacy of balneotherapy and mud-pack therapy in patients with knee osteoarthritis. OBJECTIVES Knee osteoarthritis ( OA ) is a common chronic degenerative disorder. There are various treatment modalities. This study was planned to investigate the efficacy of balneotherapy, mud-pack therapy in patients with knee OA. METHODS A total of 80 patients with knee OA were included. Their ages ranged between 39 - 78. The patients were separated in to three groups. Group I ( n=25 ) received balneotherapy, group II ( n=29 ) received mud-pack therapy and group III ( n=26 ) was hot-pack therapy group. The therapies were applied for 20 min duration, once a day, five times per week and a total of 10 session. Patients were assessed according to pain, functional capacity and quality of life parameters. Pain was assessed by using Visual Analogue Scale ( VAS ) and Western Ontario McMaster Osteoarthritis Index ( WOMAC ) pain scale ( 0 - 4 likert scale ). Functional capacity was assessed by using WOMAC functional capacity and WOMAC global index. Quality of life was evaluated by Nottingham Health Profile ( NHP ) self-administered question naire. Also physician's global assessment and the maximum distance that patient can walk without pain, were evaluated. The assessment parameters were evaluated before and after three months. RESULTS There were statistically significant improvement in VAS and WOMAC pain scores in group I ( p<0.001 ), group II and III ( p<0.05 ). The WOMAC functional and global index also decreased in group I ( p<0.05 ), group II ( p<0.001 ) and hot-pack group ( p<0.05 ). Quality of life results were significantly improved in balneotherapy and mud-pack therapy groups ( p<0.05 ). No difference was observed in hot-pack therapy group ( p>0.05 ). The maximum distance was improved both in group I and II ( p<0.05 ) but not in group III. Also physician's global assessment was found to be improved in all groups ( p<0.05 ). CONCLUSIONS Balneotherapy and mud-pack therapy were effective in treating patients with knee OA Cytokine levels in osteoarthrosis patients undergoing mud bath therapy. Osteoarthritis is an important rheumatic condition characterized by the progressive destruction of cartilage. The pathophysiologic phenomena leading to the pathologic changes in the joint appear to result from biomechanical factors and activation of final common pathways of tissue damage influencing chondrocyte homeostasis and a functional program. Several cytokines and growth factors are reported to be responsible for inflammation and cartilage degradation. Among these, IL-1 and TNF alpha have been suggested as important in promoting cartilage inflammation and tissue destruction, while IGF I has a protective influence on cartilage structure. Chondrocytes and their metabolism have gained interest as targets of drug intervention ; the results of this study confirm that mud bath therapy is also able to influence chondrocyte activities. Our data suggest that mud bath therapy influences cytokines related to osteoarthrosis pathomechanism and maintenance, and encourage further investigations to evaluate possible synergism between pharmacological treatment and mud bath therapy Short- and Long-Term Effects of Spa Therapy in Knee Osteoarthritis Fioravanti A, Iacoponi F, Bellisai B, Cantarini L, Galeazzi M : Short- and long-term effects of spa therapy in knee osteoarthritis. Objective : To assess both the short- and long-term effectiveness of spa therapy in patients with primary knee osteoarthritis in a prospect i ve, r and omized, single-blinded, controlled trial. Design : Eighty out patients were enrolled in this study ; 40 patients were treated with a combination of daily local mud packs and bicarbonate-sulfate mineral bath water from the spa center of Rapolano Terme ( Siena, Italy ) for 2 wks, and 40 patients continued regular, routine ambulatory care. Patients were assessed at baseline time ; after 2 wks ; after 3, 6, and 9 mos after the beginning of the study and were evaluated by Visual Analog Scale for spontaneous pain, Lequesne index, Western Ontario and McMaster Universities Index for gonarthrosis, Arthritis Impact Measurement Scale-1, and symptomatic drug consumption. Results : We observed a significant improvement of all evaluated parameters at the end of the cycle of spa therapy, which persisted throughout the whole of the follow-up period, whereas in the control group no significant differences were noted. This symptomatic effect was confirmed by the significant reduction of symptomatic drug consumption. Tolerability of spa therapy seemed to be good, with light and transitory side effects. Conclusions : The results from our study confirm that the beneficial effects of spa therapy in patients with knee osteoarthritis lasts over time, with positive effects on the painful symptomatology and a significant improvement on functional capacities. Spa therapy can represent a useful backup to pharmacologic treatment of knee osteoarthritis or a valid alternative for patients who do not tolerate pharmacologic treatments", 'Despite the high morbidity and mortality associated with bipolar depression, the optimal treatment for this phase is still a matter of debate. The aim of the current review was to provide up date d evidence about the efficacy and tolerability of anticonvulsants in the treatment of acute bipolar depression. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine ( LTG ) and gabapentin ( GBP ) monotherapy versus placebo ( PLC ). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, r and omized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a st and ardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose ( LTG 500 mg or GBP 4,800 mg ). The primary outcome measure was the Clinical Global Impressions Scale ( CGI ) for Bipolar Illness as supplemented by other st and ard rating instruments. The mean doses at week 6 were 274 + /- 128 mg for LTG and 3,987 + /- 856 mg for GBP. Response rates ( CGI ratings of much or very much improved ) were the following : LTG, 52 % ( 16/31 ) ; GBP, 26 % ( 8/31 ) ; and PLC, 23 % ( 7/31 ) ( Cochran\'s Q = 6.952, df = 2, N = 31, p = 0.031 ). Post hoc Q differences ( df = 1, N = 31 ) were the following : LTG versus GBP ( Qdiff = 5.33, p = 0.011 ) ; LTG versus PLC ( Qdiff = 4.76, p = 0.022 ) ; and GBP versus PLC ( Qdiff = 0.08, p = 0.70 ). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study. OBJECTIVE To determine the efficacy of divalproex ( extended release ) in the treatment of acute nonrefractory bipolar depression. METHOD In a stratified, double-blind, r and omized, placebo-controlled trial, 18 acutely depressed bipolar out patients ( DSM-IV criteria ) received either divalproex monotherapy ( target dose level, 70 - 90 ng/dL ) ( N = 9 ) or placebo ( N = 9 ) for 6 weeks. Patients were recruited between January 2004 and May 2005. Clinical assessment on the Montgomery-Asberg Depression Rating Scale ( MADRS ) determined primary efficacy. RESULTS The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo ( group x time interaction, p =.0078 ). Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo ( p =.003, linear growth curve model ). St and ardized effect size was large ( Cohen d = 0.81 ). MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms. There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group ( r = 0.29, df = 51, p =.03 ), but not in the placebo group ( r = -0.15, df = 35, p =.36 ). CONCLUSIONS Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression, which is consistent with previous small r and omized studies. Some evidence of benefit in the depressive mixed state was observed. Confirmation or refutation with larger r and omized clinical trials is warranted. CLINICAL TRIAL REGISTRATION Clinical Trials.gov identifier NCT00226343 The long-term natural history of the weekly symptomatic status of bipolar I disorder. BACKGROUND To our knowledge, this is the first prospect i ve natural history study of weekly symptomatic status of patients with bipolar I disorder ( BP-I ) during long-term follow-up. METHODS Analyses are based on ongoing prospect i ve follow-up of 146 patients with Research Diagnostic Criteria BP-I, who entered the National Institute of Mental Health ( Bethesda, Md ) Collaborative Depression Study from 1978 through 1981. Weekly affective symptom status ratings were analyzed by polarity and severity, ranging from asymptomatic, to subthreshold levels, to full-blown major depression and mania. Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined. Finally, 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I. RESULTS Patients with BP-I were symptomatically ill 47.3 % of weeks throughout a mean of 12.8 years of follow-up. Depressive symptoms ( 31.9 % of total follow-up weeks ) predominated over manic/hypomanic symptoms ( 8.9 % of weeks ) or cycling/mixed symptoms ( 5.9 % of weeks ). Subsyndromal, minor depressive, and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms ( 29.9 % vs 11.2 % of weeks, respectively ). Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year. Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up, as did comorbid drug-use disorder. CONCLUSIONS The longitudinal weekly symptomatic course of BP-I is chronic. Overall, the symptomatic structure is primarily depressive rather than manic, and subsyndromal and minor affective symptoms predominate. Symptom severity levels fluctuate, often within the same patient over time. Bipolar I disorder is expressed as a dimensional illness featuring the full range ( spectrum ) of affective symptom severity and polarity A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. BACKGROUND Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. METHODS After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were r and omized to lamotrigine ( 100 - 400 mg daily ), lithium ( 0.8 - 1.1 mEq/L ), or placebo as double-blind maintenance treatment for as long as 18 months. RESULTS Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were r and omized to double-blind maintenance treatment ( lamotrigine, 59 patients ; lithium, 46 patients ; and placebo, 70 patients ). Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode ( lamotrigine vs placebo, P =.02 ; lithium vs placebo, P =.006 ). Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P =.02 ). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode ( P =.006 ). The most common adverse event reported for lamotrigine was headache. CONCLUSIONS Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. OBJECTIVE Clinicians have few evidence -based options for the management of treatment-resistant bipolar depression. This study represents the first r and omized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone. METHOD Participants ( N=66 ) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were r and omly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks. RESULTS No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8 %, whereas the recovery rates with inositol and risperidone were 17.4 % and 4.6 %, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone. CONCLUSIONS No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression Influence of sub-syndromal symptoms after remission from manic or mixed episodes. BACKGROUND Sub-syndromal symptoms in bipolar disorder impair functioning and diminish quality of life. AIMS To examine factors associated with time spent with sub-syndromal symptoms and to characterise how these symptoms influence outcomes. METHOD In a double-blind r and omised maintenance trial, patients received either olanzapine or lithium monotherapy for 1 year. Stepwise logistic regression models were used to identify factors that were significant predictors of percentage time spent with sub-syndromal symptoms. The presence of sub-syndromal symptoms during the first 8 weeks was examined as a predictor of subsequent relapse. RESULTS Presence of sub-syndromal depressive symptoms during the first 8 weeks significantly increased the likelihood of depressive relapse ( relative risk 4.67, P<0.001 ). Patients with psychotic features and those with a greater number of previous depressive episodes were more likely to experience sub-syndromal depressive symptoms ( RR=2.51, P<0.001 and RR=2.35, P=0.03 respectively ). CONCLUSIONS These findings help to identify patients at increased risk of affective relapse and suggest that appropriate therapeutic interventions should be considered even when syndromal-level symptoms are absent Carbamazepine in manic-depressive illness: a new treatment. The authors evaluated carbamazepine ( Tegretol ), a drug of choice for treatment of temporal lobe epilepsy, in a double-blind placebo-controlled trial in patients with manic-depressive illness. Seven of 9 manic patients had a partial to marked response ; several also showed relapses when placebo was substituted and improvement when carbamazepine was reinstituted. Five of 13 depressed patients showed significant improvement in depression ratings ; 3 additional patients experienced partial relapse when placebo was substituted. Carbamazepine might also have prophylactic as well as acute efficacy in patients with both phases of manic-depressive illness, including some patients who do not respond to lithium. Therapeutic effects were achieved with 600 - 1600 mg/day at blood levels of 8 - 12 microgram/ml with relatively few side effects. Carbamazepine may prove to be a useful additional treatment for affective illness A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. OBJECTIVE Determine the efficacy and tolerability of olanzapine/fluoxetine combination ( OFC ) for treatment of acute bipolar I depression compared with lamotrigine. METHOD The 7-week, acute phase of a r and omized, double-blind study compared OFC ( 6/25, 6/50, 12/25, or 12/50 mg/day ; N = 205 ) with lamotrigine ( [ LMG ] titrated to 200 mg/day ; N = 205 ) in patients with DSM-IV-diagnosed bipolar I disorder, depressed. The study was conducted from November 2003 to August 2004. RESULTS Completion rates were similar between treatments ( OFC, 66.8 % vs. LMG, 65.4 % ; p =.835 ). OFC-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale ( primary outcome ) ( p =.002, effect size = 0.26 ), Montgomery-Asberg Depression Rating Scale ( MADRS ) ( p =.002, effect size = 0.24 ), and Young Mania Rating Scale total scores ( p =.001, effect size = 0.24 ). Response rates did not significantly differ between groups when defined as > or = 50 % reduction in MADRS score ( OFC, 68.8 % vs. LMG, 59.7 % ; p =.073 ). Time to response was significantly shorter for OFC-treated patients ( median days [ 95 % CI ] = OFC, 17 [ 14 to 22 ] vs. LMG, 23 [ 21 to 34 ] ; p =.010 ). There was a significant difference in incidence of " suicidal and self-injurious behavior " adverse events ( OFC, 0.5 % vs. LMG, 3.4 % ; p =.037 ). Somnolence, increased appetite, dry mouth, sedation, weight gain, and tremor occurred more frequently ( p <.05 ) in OFC-treated patients than lamotrigine-treated patients. Weight, total cholesterol, and triglyceride levels were significantly elevated in OFC-treated patients compared with lamotrigine-treated patients ( all p < or =.001 ). CONCLUSIONS Patients with acute bipolar I depression had statistically significantly greater improvement in depressive and manic symptoms, more treatment-emergent adverse events, greater weight gain, and some elevated metabolic factors with OFC than lamotrigine. Treatment differences were of modest size Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. OBJECTIVE Antiepileptic drugs ( AEDs ) are commonly employed in the treatment of bipolar disorder. The efficacy and tolerability of topiramate, a novel anticonvulsant, and bupropion SR when added to mood stabilizer therapy were compared under single-blind conditions ( rater-blinded ) in patients meeting DSM-IV criteria for bipolar I/II depression. METHODS A total of 36 out- patients with Hamilton Depression Rating Scale ( HDRS-17 ) scores > or = 16 were r and omized to receive escalating doses of either topiramate ( 50 - 300 mg/day ) or bupropion SR ( 100 - 400 mg/day ) for 8 weeks. Data were analyzed on an intent-to-treat basis using the last observation carried forward method. RESULTS The percentage of patients meeting a priori response criteria ( > or = 50 % decrease from baseline in mean HDRS-17 total score ) was significant for both topiramate ( 56 % ) and bupropion SR ( 59 % ) [ t(17 ) = 2.542, p = 0.04 and t(17 ) = 2.661, p = 0.03, respectively ]. Baseline demographic and clinical parameters were comparable between the two treatment groups. The mean doses of study medication were 176 mg/day ( SD = 102 mg/day ) for the topiramate-treated group and 250 mg/day ( SD = 133 mg/day ) for the bupropion SR-treated group. A significant and comparable reduction in depressive symptoms was observed from baseline to endpoint following topiramate and bupropion SR treatment, according to a > or = 50 % reduction in the HDRS-17. Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups ( p = 0.001 ), however, differences between the topiramate-treated group and the bupropion SR-treated group were not significant [ t(36 ) = 1.754, p = 0.097 ]. Both topiramate and bupropion SR were generally well tolerated. Thirteen patients discontinued the study : 2 because of lack of efficacy, 1 due to withdrawal of consent and 10 following side-effects ( six in the topiramate and four in the bupropion SR-treated group ). There were no cases of affective switch in either arm. Weight loss was experienced by patients in both groups ( mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8 kg in topiramate ) [ t(17 ) = 2.325, p = 0.061 and t(17 ) = 2.481, p = 0.043, respectively ]. CONCLUSIONS These preliminary data suggest that adjunctive topiramate may reduce depressive symptom severity in acute bipolar depression. The antidepressant efficacy of this compound requires confirmation via double- Adjunctive herbal medicine with carbamazepine for bipolar disorders: A double-blind, randomized, placebo-controlled study. Chinese herbal medicines possess the therapeutic potential for mood disorders. This double-blind, r and omized, placebo-controlled study was design ed to evaluate the efficacy and side effects of the herbal medicine called Free and Easy W and erer Plus ( FEWP ) as an adjunct to carbamazepine ( CBZ ) in patients with bipolar disorders. One hundred and twenty-four bipolar depressed and 111 manic patients were r and omized to treatment with CBZ alone, CBZ plus FEWP, or equivalent placebo for 12 weeks. CBZ was initiated at 300mg/day and FEWP was given at a fixed dose of 36g/day. Efficacy measures included the Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, Young Mania Rating Scale, Bech-Rafaelsen Mania Scale, and Clinical Global Impression-Severity ( CGI-S ). CBZ monotherapy produced significantly greater improvement on manic measures at week 2 through endpoint and CGI-S of depression at endpoint compared to placebo. CBZ monotherapy also yielded significantly higher clinical response rates than placebo on bipolar depression ( 63.8 % vs. 34.8 %, p=0.044 ) and mania ( 87.8 % vs. 57.1 %, p=0.012 ). Compared to CBZ monotherapy, adjunctive FEWP with CBZ result ed in significantly better outcomes on the three measures of depression at week 4 and week 8 and significantly greater clinical response rate in depressed subjects ( 84.8 % vs. 63.8 %, p=0.032 ), but failed to produce significantly greater improvement on manic measures and the response rate in manic subjects. There was a lesser incidence of dizziness and fatigue in the combination therapy compared to CBZ monotherapy. These results suggest that adjunctive FEWP has additive beneficial effects in bipolar patients, particularly for those in depressive phase A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. BACKGROUND This is the first prospect i ve longitudinal study, to our knowledge, of the natural history of the weekly symptomatic status of bipolar II disorder ( BP-II ). METHODS Weekly affective symptom status ratings for 86 patients with BP-II were based on interviews conducted at 6- or 12-month intervals during a mean of 13.4 years of prospect i ve follow-up. Percentage of weeks at each symptom severity level and the number of shifts in symptom status and polarity were examined. Predictors of chronicity for BP-II were evaluated using new chronicity measures. Chronicity was also analyzed in relation to the percentage of follow-up weeks with different types of somatic treatment. RESULTS Patients with BP-II were symptomatic 53.9 % of all follow-up weeks : depressive symptoms ( 50.3 % of weeks ) dominated the course over hypomanic ( 1.3 % of weeks ) and cycling/mixed ( 2.3 % of weeks ) symptoms. Subsyndromal, minor depressive, and hypomanic symptoms combined were 3 times more common than major depressive symptoms. Longer intake episodes, a family history of affective disorders, and poor previous social functioning predicted greater chronicity. Prescribed somatic treatment did not correlate significantly with symptom chronicity. Patients with BP-II of brief ( 2 - 6 days ) vs longer ( > or = 7 days ) hypomanias were not significantly different on any measure. CONCLUSIONS The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms. Symptom severity fluctuates frequently within the same patient over time, involving primarily symptoms of minor and subsyndromal severity. Longitudinally, BP-II is expressed as a dimensional illness involving the full severity range of depressive and hypomanic symptoms. Hypomania of long or short duration in BP-II seems to be part of the same disease process A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. BACKGROUND Long-term outcomes are often poor in patients with bipolar disorder despite treatment ; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. METHODS A r and omized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode ( n = 372 ) were r and omized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before r and omization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. RESULTS The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. CONCLUSIONS The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures Levetiracetam in the management of bipolar depression: a randomized, double-blind, placebo-controlled trial. OBJECTIVE To study the efficacy of adjunctive levetiracetam therapy compared with placebo in the treatment of subjects with depression with bipolar disorder. METHOD This double-blind, placebo-controlled clinical trial r and omly assigned out patients with bipolar disorder type I and type II who were experiencing a major depressive episode ( Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version criteria ) to treatment with either placebo or adjunctive levetiracetam ( up to 2,500 mg/d flexibly dosed ) for 6 weeks. The subjects were recruited from October 2005 to June 2008. The primary efficacy measure was mean change from baseline to week 6 in the Hamilton Depression Rating Scale ( 21-item ). Secondary efficacy assessment s included the Montgomery-Åsberg Depression Rating Scale, the Beck Depression Inventory, the Clinical Global Impressions-Bipolar Version scale, the Hamilton Anxiety Rating Scale, and the Young Mania Rating Scale. RESULTS Of 42 subjects r and omly assigned to placebo or drug, 32 received at least 1 postbaseline assessment and thus were included in the analysis. The mean ( SD ) levetiracetam daily dose at endpoint evaluation was 1,132 ( 425 ) mg/d. There was no significant difference in the mean change from baseline to week 6 in the Hamilton Depression Rating Scale scores for levetiracetam compared with placebo. There were no significant differences in any of the secondary outcome measures. CONCLUSIONS Levetiracetam adjunctive therapy was not superior to placebo in the short-term treatment of subjects with depression with bipolar disorder in the population studied. TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00566150 Number needed to treat analyses of drugs used for maintenance treatment of bipolar disorder Rationale Due to the episodic and chronic nature of bipolar disorder ( BD ), maintenance therapy represents a critical part of treatment ; however, there is a paucity of studies comparing effectiveness of available long-term treatments. Objective The aim of this study is to determine and compare the efficacy of pharmacological treatments for maintenance treatment of BD by means of the number needed to treat ( NNT ). Methods The efficacy of drugs used for maintenance treatment of BD, as emerging from the results of r and omized controlled trials, was assessed using the size effect measure of NNT. PubMed search es were conducted on English- language articles published until May 2010 using the search terms “ bipolar disorder, ” “ mania, ” “ mixed episode, ” or “ bipolar depression, ” cross-referenced with trial characteristic search phrases and generic names of medications. The search was supplemented by manually review ing reference lists from identified publications. Results In 15 studies, aripiprazole, olanzapine, quetiapine, risperidone long-acting injection, lithium, lamotrigine, and divalproex proved effectiveness in terms of NNTs ( ≥10 % advantage over placebo ) for prevention of relapse into any mood episode. Quetiapine, lithium, risperidone long-acting injection, aripiprazole, and olanzapine are effective in manic recurrence prevention. Lamotrigine, quetiapine, and lithium present significant NNTs for prevention of depressive relapses. Conclusions All of the pharmacological agents assessed were effective in the prevention of any kind of mood episode ; however, different efficacy profiles were found for prevention of manic and /or depressive relapses. The comparison of NNT values of the available agents may represent a useful tool in clinical setting s, in order to facilitate implementation of long-term pharmacological interventions in patients with BD Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). OBJECTIVE Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence. METHOD The authors examined prospect i ve data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression. RESULTS Of 1,469 participants symptomatic at study entry, 858 ( 58.4 % ) subsequently achieved recovery. During up to 2 years of follow-up, 416 ( 48.5 % ) of these individuals experienced recurrences, with more than twice as many developing depressive episodes ( 298, 34.7 % ) as those who developed manic, hypomanic, or mixed episodes ( 118, 13.8 % ). The time until 25 % of the individuals experienced a depressive episode was 21.4 weeks and until 25 % experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence. CONCLUSIONS Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence Maintenance Efficacy of Divalproex in the Prevention of Bipolar Depression Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A r and omized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were r and omized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of pre study illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness Antidepressant effects of carbamazepine. Thirty-five depressed patients diagnosed by DSM-III criteria participated in a double-blind study of the acute antidepressant effects of the anticonvulsant carbamazepine, at average doses of 971 mg/day, achieving mean + /- SD blood levels of 9.3 + /- 1.9 micrograms/ml ( range, 3 - 12.5 micrograms/ml ). Twenty patients ( 57 % ) showed at least mild improvement, and 12 showed more substantial improvement. Possible clinical predictors of antidepressant response to carbamazepine are discussed. These preliminary data suggest that carbamazepine has some acute antidepressant efficacy in addition to the growing evidence that it has acute antimanic and longer-term prophylactic efficacy in both phases of manic-depressive illness Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: a double-blind, randomized, placebo-controlled trial. OBJECTIVE To conduct an exploratory evaluation of the acute efficacy of extended-release divalproex sodium compared to placebo in patients with bipolar I or II depression. METHOD Out patients aged 18 - 70 years with mood stabilizer-naive bipolar I or II disorder experiencing a major depressive episode ( DSM-IV ) were r and omly assigned to 6 weeks of divalproex sodium monotherapy or placebo. The primary outcome measure was mean change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale ( MADRS ) total score. Secondary outcomes included rates of response and remission, changes in the Clinical Global Impressions-Bipolar ( CGI-BP ) Severity of Illness scores, and changes in anxiety symptoms as measured by the Hamilton Anxiety Rating Scale. The study was conducted between 2003 and 2007. RESULTS Fifty-four subjects with bipolar I ( n = 20 ) or bipolar II ( n = 34 ) disorder were r and omly assigned to divalproex or placebo ; 67 % ( 36 of 54 ) met DSM-IV criteria for rapid cycling. Divalproex treatment produced statistically significant improvement in MADRS scores compared with placebo from week 3 onward. The proportions of patients meeting response criteria were 38.5 % ( 10 of 26 ) in the divalproex group versus 10.7 % ( 3 of 28 ) for the placebo group ( P =.017 ). The proportions of patients meeting remission criteria were 23.1 % ( 6 of 26 ) for divalproex versus 10.7 % ( 3 of 28 ) for placebo ( P =.208 ). Subgroup analysis revealed no separation between divalproex and placebo for those with bipolar II diagnoses. Nausea, increased appetite, diarrhea, dry mouth, and cramps were the most common side effects. CONCLUSIONS These data suggest that divalproex sodium is efficacious and reasonably well tolerated in the acute treatment of mood stabilizer-naive patients with bipolar depression, particularly for those with rapid-cycling type I presentations, and that confirmatory large-scale studies are indicated. TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00194116 Divalproex in the treatment of bipolar depression: a placebo-controlled study. BACKGROUND The treatment of bipolar disorder in the depressed phase is complicated by a tendency for conventional antidepressant drugs to worsen the course of the illness by precipitating a manic episode or increasing cycle frequency. Thus, the potential antidepressant efficacy of mood stabilizers, such as divalproex, which is an effective treatment for the manic phase of bipolar disorder, is of considerable interest. METHODS The clinical efficacy of divalproex ( valproate, Depakote ) was tested in an 8-week, double-blind, placebo-controlled, r and omized clinical trial in 25 out patients with bipolar I depression. The primary outcome measure was the 17-item Hamilton Rating Scale for Depression, and secondary measures included the Hamilton Rating Scale for Anxiety, the Clinician Administered Rating Scale for Mania, and the Clinical Global Impression scale. RESULTS Using repeated measures ANOVA with last observation carried forward, divalproex was more effective than placebo in improving symptoms of depression ( p = 0.0002 ) and symptoms of anxiety ( p = 0.0001 ) than placebo. LIMITATIONS The sample size was small, and most patients were male. CONCLUSIONS These pilot results indicate that divalproex is effective in reducing the symptoms of depression and anxiety in bipolar I, depressed phase. These positive results support the need to perform a larger, multisite study of divalproex treatment for bipolar depression A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. BACKGROUND More treatment options for bipolar depression are needed. Currently available antidepressants may increase the risk of mania and rapid cycling, and mood stabilizers appear to be less effective in treating depression than mania. Preliminary data suggest that lamotrigine, an established antiepileptic drug, may be effective for both the depression and mania associated with bipolar disorder. This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression. METHODS Out patients with bipolar I disorder experiencing a major depressive episode ( DSM-IV, N = 195 ) received lamotrigine ( 50 or 200 mg/day ) or placebo as monotherapy for 7 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression ( HAM-D ), the Montgomery-Asberg Depression Rating Scale ( MADRS ), Mania Rating Scale, and the Clinical Global Impressions scale for Severity ( CGI-S ) and Improvement ( CGI-I ) were completed at each weekly visit. RESULTS Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures. The proportions of patients exhibiting a response on CGI-I were 51 %, 41 %, and 26 % for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups, respectively. Adverse events and other safety results were similar across treatment groups, except for a higher rate of headache in the lamotrigine groups. CONCLUSION Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design. OBJECTIVE In two previous manuscripts, we described the efficacy of lamotrigine versus placebo as add-on to lithium ( followed by the addition of paroxetine in nonresponders ) in the short-term treatment of bipolar depression. In this paper we describe the long-term ( 68 weeks ) outcome of that study. METHODS A total of 124 bipolar depressed patients receiving lithium were r and omized to addition of lamotrigine or placebo. After eight weeks, paroxetine was added to nonresponders for another eight weeks. Responders continued medication and were followed for up to 68 weeks or until a relapse or recurrence of a depressive or manic episode. RESULTS After eight weeks, the addition of lamotrigine to lithium was significantly more efficacious than addition of placebo, while after addition of paroxetine in nonresponders both groups further improved with no significant difference between groups at week 16. During follow-up the efficacy of lamotrigine was maintained : time to relapse or recurrence was longer for the lamotrigine group [ median time 10.0 months ( confidence interval : 1.1 - 18.8 ) ] versus the placebo group [ 3.5 months ( confidence interval : 0.7 - 7.0 ) ]. CONCLUSION In patients with bipolar depression, despite continued use of lithium, addition of lamotrigine revealed a continued benefit compared to placebo throughout the entire study A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. BACKGROUND The anticonvulsant lamotrigine was previously shown to be effective for bipolar depression. This study assessed the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of mood episodes in bipolar disorder. METHOD During an 8- to 16-week open-label phase, lamotrigine ( titrated to 200 mg/day ) was added to current therapy for currently or recently depressed DSM-IV-defined bipolar I out patients ( N = 966 ) and concomitant drugs were gradually withdrawn. Patients stabilized on open-label treatment ( N = 463 ) were then r and omly assigned to lamotrigine ( 50, 200, or 400 mg/day ; N = 221 ), lithium ( 0.8 - 1.1 mEq/L ; N = 121 ), or placebo ( N = 121 ) monotherapy for up to 18 months. The primary outcome measure was time from r and omization to intervention ( addition of pharmacotherapy ) for any mood episode ( depressive, manic, hypomanic, or mixed ). Data were gathered from September 1997 to August 2001. RESULTS Time to intervention for any mood episode was statistically superior ( p =.029 ) for both lamotrigine and lithium compared with placebo-median survival times were 200, 170, and 93 days, respectively. Intervention for depression was more frequent than for mania by a factor of nearly 3:1. Lamotrigine was statistically superior to placebo at prolonging the time to intervention for a depressive episode ( p =.047 ). The proportions of patients who were intervention-free for depression at 1 year were lamotrigine 57 %, lithium 46 %, and placebo 45 %. Lithium was statistically superior to placebo at prolonging the time to intervention for a manic or hypomanic episode ( p =.026 ). The proportions of patients who were intervention-free for mania at 1 year were lamotrigine 77 %, lithium 86 %, and placebo 72 %. Headache was the most frequent adverse event for all 3 treatment groups. CONCLUSION Lamotrigine and lithium were superior to placebo for the prevention of mood episodes in bipolar I patients, with lamotrigine predominantly effective against depression and lithium predominantly effective against mania Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. OBJECTIVE Lamotrigine is one of the pharmacologic options for the treatment of bipolar depression but has only been studied as monotherapy. This study compared the acute effects of lamotrigine and placebo as add-on therapy to ongoing treatment with lithium in patients with bipolar depression. METHOD Out patients ( N = 124 ) aged 18 years and older with a DSM-IV bipolar I or II disorder and a major depressive episode ( Montgomery-Asberg Depression Rating Scale [ MADRS ] score > or = 18 and Clinical Global Impressions-Bipolar Version [ CGI-BP ] severity of depression score > or = 4 ) while receiving lithium treatment ( 0.6 - 1.2 mmol/L ) were r and omly assigned to 8 weeks of double-blind treatment with lamotrigine ( titrated to 200 mg/d ) or placebo. The primary outcome measure was mean change from baseline in total score on the MADRS at week 8. Secondary outcome measures were response ( defined as a reduction of > or = 50 % on the MADRS and /or change of depression score on the CGI-BP of " much improved " or " very much improved " compared to baseline ) and switch to mania or hypomania ( defined as a CGI-BP severity of mania score of at least mildly ill at any visit ). Patients were included in the study between August 2002 ( Spain started in October 2003 ) and May 2005. RESULTS Endpoint mean change from baseline MADRS total score was -15.38 ( SE = 1.32 ) points for lamotrigine and -11.03 ( SE = 1.36 ) points for placebo ( t = -2.29, df = 104, p =.024 ). Significantly more patients responded to lamotrigine than to placebo on the MADRS ( 51.6 % vs. 31.7 %, p =.030 ), but not on the CGI-BP change of depression ( 64.1 % vs. 49.2 %, p =.105 ). Switch to mania or hypomania occurred in 5 patients ( 7.8 % ) receiving lamotrigine and 2 patients ( 3.3 % ) receiving placebo ( p =.441 ). CONCLUSION Lamotrigine was found effective and safe as add-on treatment to lithium in the acute treatment of bipolar depression. TRIAL REGISTRATION clinical trials.gov Identifier : NCT00224510 Randomized, double-blind pilot trial comparing lamotrigine versus citalopram for the treatment of bipolar depression. BACKGROUND Uncertainty exists regarding the best approach for treating bipolar depression among patients already receiving a first-line mood stabilizer. The aim of this pilot study was to compare adding a second mood stabilizer or an antidepressant at this treatment decision point. METHODS Twelve-week, r and omized, double-blind pilot trial comparing the addition of lamotrigine or citalopram for bipolar depressed patients on mood stabilizer medication. Change in depressive symptoms and risk of switch were examined. RESULTS Twenty subjects were r and omized. Each treatment group experienced a significant mean reduction in total MADRS scores ( citalopram Delta - 14.2, p=0.002 ; lamotrigine Delta - 13.3, p= 0.001 ), and there was no significant difference between treatment groups ( p=0.78 ). Total response rates increased from 31.6 % at week 6 to 52.6 % at week 12. One out of ten patients in each group experienced a switch to hypomania. LIMITATIONS Small sample size. Lack of a placebo arm. CONCLUSIONS Results of this small trial suggest that both lamotrigine and citalopram appear to be reasonable choices as add-on acute treatment for bipolar depression, with response rates continuing to rise considerably past 6 weeks of treatment Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. BACKGROUND Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression. OBJECTIVE To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. DESIGN Double-blind, 8-week, r and omized controlled trial. SETTING Eighty-four sites ( inpatient and outpatient ) in 13 countries. Patients A total of 833 r and omized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale ( MADRS ) score of at least 20. Intervention Patients were r and omly assigned to receive placebo ( n = 377 ) ; olanzapine, 5 to 20 mg/d ( n = 370 ) ; or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d ( n = 86 ). MAIN OUTCOME MEASURE Changes in MADRS total scores using mixed-effects model repeated- measures analyses. RESULTS During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group ( P<.001 for all ). The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8. At week 8, MADRS total scores were lower than at baseline by 11.9, 15.0, and 18.5 points in the placebo, olanzapine, and olanzapine-fluoxetine groups, respectively. Remission criteria were met by 24.5 % ( 87/355 ) of the placebo group, 32.8 % ( 115/351 ) of the olanzapine group, and 48.8 % ( 40/82 ) of the olanzapine-fluoxetine group. Treatment-emergent mania ( Young Mania Rating Scale score < 15 at baseline and > or = 15 subsequently ) did not differ among groups ( placebo, 6.7 % [ 23/345 ] ; olanzapine, 5.7 % [ 19/335 ] ; and olanzapine-fluoxetine, 6.4 % [ 5/78 ] ). Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea. CONCLUSIONS Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms', 'Context Nonalcoholic fatty liver disease ( NAFLD ) is a highly prevalent and underdiagnosed comorbidity of many chronic diseases that is associated with altered intestinal bacterial communities. This association has prompted research into alternative treatments aim ed at modulating intestinal microbiota. Given the novelty of these treatments, scarce evidence regarding their effectiveness in clinical population s exists. Objective This meta- analysis sought to systemically review and quantitatively synthesize evidence on prebiotic, probiotic, and synbiotic therapies for patients with NAFLD in r and omized controlled trials. Effects of Cassia tora fiber supplement on serum lipids in Korean diabetic patients. Cassia tora fiber supplement consisting of 2 g of soluble fiber extracted from Cassia semen ( C. tora L. ), 200 mg of alpha-tocopherol, 500 mg of ascorbic acid, and 300 mg of maltodextrin was formulated in a pack, and given to 15 type II diabetic subjects ( seven men and eight women 57.1 + /- 2.9 years old ) with instructions to take two packs per day for 2 months. Placebo contained maltodextrin only with a little brown caramel color. Lifestyle factors and dietary intakes of the subjects were not altered during the 2-month period. Serum total cholesterol was moderately ( P <.1 ) decreased in the C. tora group compared with the age- and gender-matched placebo group, as was the ratio of apolipoprotein B to apolipoprotein A1 ( P <.1 ). Levels of serum triglycerides and low-density lipoprotein-cholesterol tended to decrease more in the C. tora-supplemented group than in the placebo group. Serum alpha-tocopherol was increased ( P <.01 ) but lipid peroxides were not significantly lower in the C. tora group. Fasting blood glucose, hemoglobin A1c, blood urea nitrogen, creatinine, and activities of serum aspartate aminotransferase and alanine aminotransferase were not changed by the fiber supplement. We concluded that C. tora supplements can help improve serum lipid status in type II diabetic subjects without serious adverse effects Effect of Daily Consumption of Probiotic Yoghurt on Serum Levels of Calcium, Iron and Liver Enzymes in Pregnant Women Background : To reach fetal appropriate growth during the third trimester, the requirements for dietary calcium and iron intakes during the pregnancy increases. This study was carried out to determine the effects of daily consumption of probiotic yoghurt on serum calcium and iron levels and liver enzymes among Iranian healthy pregnant women. Methods : In this controlled clinical trial, 70 primigravida pregnant women carrying singleton pregnancy at their third trimester were participated. Participants were r and omly divided into two groups of consuming 200 g/d of conventional ( n = 33 ) or probiotic yogurts ( n = 37 ) for 9 weeks. The probiotic yogurt contained Lactobacillus acidophilus and Bifidobacterium lactis with a total of min 1 × 107 CFU. To measure serum calcium, iron, aspartate aminotransferase ( AST ) and alanine aminotransferase ( ALT ) levels, blood sample s were drawn in a fasting state at baseline and after 9 weeks intervention. Results : Consumption of probiotic yogurt result ed in maintaining serum calcium levels compared with the conventional yogurt ( P = 0.01 ). Within-group differences in the conventional yogurt group revealed a significant reduction of serum calcium levels ( −1.7 mg/dL, P < 0.0001 ). No significant differences were found between the two yogurts in terms of their effects on serum iron, AST and ALT levels. Conclusions : Consumption of probiotic yogurt among pregnant women result ed in maintaining serum calcium levels compared with the conventional yogurt ; however, it could not affect serum iron, ALT and AST levels Supplementation with probiotics modifies gut flora and attenuates liver fat accumulation in rat nonalcoholic fatty liver disease model This study aim ed to evaluate the relationship between gut probiotic flora and nonalcoholic fatty liver disease in a diet-induced rat model, and to compare the effects of two different probiotic strains on nonalcoholic fatty liver disease. Forty male Sprague-Dawley rats were r and omized into 4 groups for 12 weeks : control ( st and ard rat chow ), model ( fat-rich diet ), Lactobacillus ( fat-rich diet plus Lactobacillus acidophilus ), and Bifidobacterium ( fat-rich diet plus Bifidobacterium longum ) groups. Probiotics were provided to rats in drinking water ( 1010/ml ). Gut bifidobacteria and lactobacilli were obviously lower at weeks 8 and 10, respectively, in the model group compared with the control group. Supplementation with Bifidobacterium significantly attenuated hepatic fat accumulation ( 0.10 ± 0.03 g/g liver tissue ) compared with the model group ( 0.16 ± 0.03 g/g liver tissue ). However, there was no improvement in intestinal permeability in either the Lactobacillus or the Bifidobacterium group compared with the model group. In all 40 rats, the hepatic total lipid content was negatively correlated with gut Lactobacillus ( r = −0.623, p = 0.004 ) and Bifidobacterium ( r = −0.591, p = 0.008 ). Oral supplementation with probiotics attenuates hepatic fat accumulation. Further, Bifidobacterium longum is superior in terms of attenuating liver fat accumulation than is Lactobacillus acidophilus Effect of microbial cell preparation on renal profile and liver function among type 2 diabetics: a randomized controlled trial Background The beneficial effect of probiotics on renal profile and liver function has been reported among patients with chronic kidney disease and fatty liver respectively. However, its effect on renal profile and liver function among type 2 diabetic individuals has not been fully understood. To investigate the effect of microbial cell preparation on renal profile and liver function tests among type 2 diabetic individuals. Methods A r and omized, double-blind, parallel-group, controlled clinical trial was conducted on a total of 136 type 2 diabetics age 30 - 70 years old in a teaching hospital in Kuala Lumpur, Malaysia. Subjects were r and omly assigned to receive microbial cell preparation ( N = 68 ) or a placebo ( N = 68 ) for 12 weeks. The outcomes measured at baseline, week 6, and week 12 and included changes in renal profile ( Sodium, Potassium, Urea, Creatinine, Glomerular Filtration Rate ), and liver function tests ( Albumin, Total Protein, Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase ). Intention to treat ( ITT ) analysis was performed on all the recruited subjects, while per protocol ( PP ) analysis was conducted on those who completed the trial with good compliance. Result The urea levels significantly declined in the probiotic group. Serum urea levels reduced from 4.26 mmol/L to 4.04 mmol/L in Probiotic Group while it increased in Placebo Group from 4.03 mmol/L to 4.24 mmol/L. These changes were significant between groups in ITT analysis ( p = 0.018 ). Other parameters did not change significantly between groups. Conclusion 12 weeks supplementation with daily dosage of 6 × 1010 Colony Forming Units of multi-strain microbial cell preparation significantly improved urea levels. Trial registration ( Clinical trials : # NCT01752803 Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. BACKGROUND Nonalcoholic fatty liver disease ( NAFLD ) is the most common chronic liver disease in the world. Oral administration of synbiotic has been proposed as an effective treatment of NAFLD because of its modulating effect on the gut flora, which can influence the gut-liver axis. OBJECTIVE The objective was to evaluate the effects of supplementation with synbiotic on hepatic fibrosis, liver enzymes, and inflammatory markers in patients with NAFLD. DESIGN In a r and omized, double-blind, placebo-controlled clinical trial conducted as a pilot study, 52 patients with NAFLD were supplemented twice daily for 28 wk with either a synbiotic or a placebo capsule. Both groups were advised to follow an energy-balanced diet and physical activity recommendations. RESULTS At the end of the study, the alanine aminotransferase ( ALT ) concentration decreased in both groups ; this reduction was significantly greater in the synbiotic group. At the end of the study, the following significant differences [ means ( 95 % CIs ) ] were seen between the synbiotic and placebo groups, respectively : ALT [ -25.1 ( -26.2, -24 ) compared with -7.29 ( -9.5, -5.1 ) IU/L ; P < 0.001 ], aspartate aminotransferase [ -31.33 ( -32.1, -30.5 ) compared with -7.94 ( -11.1, -4.8 ) IU/L ; P < 0.001 ], γ-glutamyltransferase [ -15.08 ( -15.5, -14.7 ) compared with -5.21 ( -6.6, -3.9 ) IU/L ; P < 0.001 ], high-sensitivity C-reactive protein [ -2.3 ( -3, -1.5 ) compared with -1.04 ( -1.5, -0.6 ) mmol/L ; P < 0.05 ], tumor necrosis factor-α [ -1.4 ( -1.7, -1.1 ) compared with -0.59 ( -0.8, -0.3 ) mmol/L ; P < 0.001 ], total nuclear factor κ-B p65 [ -0.016 ( -0.022, -0.011 ) compared with 0.001 ( -0.004, -0.007 ) mmol/L ; P < 0.001 ], and fibrosis score as determined by transient elastography [ - 2.98 ( -3.6, -2.37 ) compared with -0.77 ( -1.32, -0.22 ) kPa ; P < 0.001 ]. CONCLUSIONS Synbiotic supplementation in addition to lifestyle The effect of enriched chicory inulin on liver enzymes, calcium homeostasis and hematological parameters in patients with type 2 diabetes mellitus: A randomized placebo-controlled trial. BACKGROUND S AND AIMS Type 2 diabetic mellitus ( T2DM ) as one of the main causes of morbidity and mortality is associated with immune system disturbances and metabolic abnormalities. In the current study we aim ed to evaluate the effects of enriched chicory inulin supplementation on liver enzymes, serum calcium and phosphorous concentrations and hematological parameters in patients with T2DM. METHODS Forty-six diabetic females patients were r and omly allocated into intervention ( n=27 ) and control ( n=22 ) groups. Subjects in the intervention group received a daily dose of 10 g of chicory and subjects in control group received a placebo for two months. Anthropometric variables, glucose homeostasis, hematological parameters and metabolic indices including serum alanine aminotransfersae ( ALT ), aspartate aminotransferase ( AST ), alkaline phosphatase ( ALP ), calcium and phosphorous as well as creatinine concentrations, glomerular filtration rate ( GFR ) and blood pressure were assessed at the beginning and end of the trial. RESULTS Significant reductions in fasting serum glucose ( FSG ), Hb A1C, AST and ALP concentrations were observed in chicory-treated group. Systolic and diastolic blood pressures were also reduced in chicory-treated group. Serum calcium significantly increased after chicory supplementation but no change in placebo treated group has been occurred ( P=0.014 ). Supplementation with enriched chicory for two months significantly reduced hematocrit and mean corpuscular volume ( MCV ) values ( P<0.05 ). Changes in serum insulin, creatinine and GFR were not significant. CONCLUSION The present study showed beneficial effects of oligofructose-enriched chicory on the improvement of the glucose and calcium homeostasis, liver function tests, blood pressure and reduction in hematologic risk factors of diabetes in female patients with T2DM. Further studies in both genders are needed to generalize these findings to total population Effects of symbiotic and vitamin E supplementation on blood pressure, nitric oxide and inflammatory factors in non-alcoholic fatty liver disease Non-alcoholic fatty liver disease ( NAFLD ) has been suggested to be well correlated with altered blood pressure. This study was conducted to determine the effects of symbiotic and vitamin E supplementation on blood pressure and inflammatory indices of patients with NAFLD. This r and omized, double-blind, placebo-controlled trial was performed among 60 NAFLD patients aged 25 to 64 years old. Participants were r and omly divided into four groups to receive a 400 IU alpha-tocopherol and 2 × 108 CFU/g symbiotic supplement for 8 weeks. The anthropometric parameters, systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ), serum malondialdehyde ( MDA ), nitric oxide ( NO ) and tumor necrosis factor α ( TNFα ) were assessed at baseline and after 8 weeks of intervention. After 8 weeks of intervention, combined symbiotic and alpha-tocopherol, symbiotic and alpha-tocopherol alone administration, compared with the placebo, result ed in significant decreases in SBP ( -17.07±2.1, -16.07±3.56, -1.73±2.25 and -1.55±3.01 mmHg, P=0.01 ), serum MDA ( -1.19±0.5, -0.12±0.65, 0.14 ± 0.64 and 0.16±0.34 nmol/mL, P<0.001 ), serum TNFα ( -15.62±13.93, -9.24±7.12, -11.44 ± 15.47 and 3.01±1.71 pg/ml, P<0.001 ) concentrations. A significant decrease in serum AST ( -11.36±4.52, -7.43±8.58, -5.93±6.61 and 2.5±5.75 μmol/L, P < 0.001 ), ALT ( -12.79±3.65, -3.66±6.81, -6.54±7.66 and 4.16±3.43 μmol/L, P < 0.001 ) and ALP ( -26.8±11.1, -4.56±9.22, -14.48±12.22 and 5.19±2.64 μmol/L, P < 0.001 ) was seen. Variations in DBP and serum NO concentration were not significant. Alpha-tocopherol and symbiotic supplementation among patients with NAFLD result ed in decreased SBP, serum MDA, TNFα levels and enzymes liver ; however, they did not affect DBP and serum NO concentration Beneficial Effect of Synbiotic Supplementation on Hepatic Steatosis and Anthropometric Parameters, But Not on Gut Permeability in a Population with Nonalcoholic Steatohepatitis Nonalcoholic fatty liver disease is the most prevalent chronic liver disease in Western countries ; it can progress to nonalcoholic steatohepatitis ( NASH ), cirrhosis and hepatocarcinoma. The importance of gut-liver-adipose tissue axis has become evident and treatments targeting gut microbiota may improve inflammatory and metabolic parameters in NASH patients. In a r and omized, controlled clinical trial, involving 50 biopsy-proven NASH patients, we investigated the effects of synbiotic supplementation on metabolic parameters, hepatic steatosis, intestinal permeability, small intestinal bacterial overgrowth ( SIBO ) and lipopolysaccharide ( LPS ) serum levels. Patients were separated into two groups receiving Lactobacillus reuteri with guar gum and inulin for three months and healthy balanced nutritional counseling versus nutritional counseling alone. Before and after the intervention we assessed steatosis by magnetic resonance imaging, intestinal permeability by lactulose/mannitol urinary excretion and SIBO by glucose breath testing. NASH patients presented high gut permeability, but low prevalence of SIBO. After the intervention, only the synbiotic group presented a reduction in steatosis, lost weight, diminished BMI and waist circumference measurement. Synbiotic did not improve intestinal permeability or LPS levels. We concluded that synbiotic supplementation associated with nutritional counseling seems superior to nutritional counseling alone for NASH treatment as it attenuates steatosis and may help to achieve weight loss Effects of Synbiotic Food Consumption on Serum Minerals, Liver Enzymes, and Blood Pressure in Patients with Type 2 Diabetes: A Double-blind Randomized Cross-over Controlled Clinical Trial Background : This research was to examine the effects of synbiotic intake on minerals, liver enzymes, and blood pressure in patients with type 2 diabetes ( T2D ). Methods : This r and omized, cross-over clinical trial was performed among 62 diabetic patients. Persons were r and omly assigned to intake either a synbiotic ( n = 62 ) or a control food ( n = 62 ) for 6 weeks. A 3-week washout period was applied following which persons were crossed over to the alternate intervention arm for an additional 6 weeks. The synbiotic was consisted of Lactobacillus sporogenes ( 1 × 107 CFU ), 0.04 g inulin ( HPX ) as prebiotic. Persons were asked to consume the synbiotic and control foods 27 g a day. Blood pressure was measured, and blood sample s were taken at baseline and after 6-week intervention to assess calcium, magnesium, iron, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin. Results : The consumption of a synbiotic food, compared to the control food, result ed in a significant rise of calcium ( 0.66 vs. −0.14 mg/dL, P = 0.03 ) and iron ( 5.06 vs. −9.98 mg/dL, P = 0.03 ). The decrease of total bilirubin ( 0.08 vs. −0.04 mg/dL ; P = 0.009 ) was also seen in the synbiotic group compared with the control group. Conclusions : Overall, synbiotic in T2D patients had beneficial effects on calcium, iron, and total bilirubin concentrations Effects of xylooligosaccharides in type 2 diabetes mellitus. The purpose of this study was to evaluate the effect of xylooligosaccharide ( XOS ) on the blood sugar, lipids and oxidative status in type 2 diabetes mellitus ( DM ). A total of 26 outpatient subjects of Taichung Veterans General Hospital, Taiwan, with HbA1c levels between 7.0 and 10.0 % and triglyceride < 400 mg/dL were enrolled in the present study. Subjects were supplemented with 4 g/d XOS ( n=12 ) or a placebo ( n=14 ) for 8 wk in a r and omized double-blind clinical design. The results showed that the anthropometric values and nutrient intakes did not change during the experimental period. XOS supplementation not only reduced the glucose, HbA1c and fructosamine concentrations, but also decreased the levels of total cholesterol, low density lipoprotein ( LDL ) cholesterol, oxidized low density lipoprotein ( ox-LDL ) and apolipoprotein B. The activity of catalase of the erythrocyte sample decreased in the XOS group, but not the activities of superoxide dismutase and glutathione peroxidase. In conclusion, the dietary supplementation with XOS for 8 wk was effective in improving the blood sugar and lipids in type 2 diabetes, indicating that XOS-containing diets might be beneficial to DM subjects The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Flaws in the design, conduct, analysis, and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Altered Fecal Microbiota Correlates with Liver Biochemistry in Nonobese Patients with Non-alcoholic Fatty Liver Disease Increasing evidence suggests a role of intestinal dysbiosis in obesity and non-alcoholic fatty liver disease ( NAFLD ). But it remains unknown in nonobese NAFLD. This prospect i ve, cross-sectional study sought to characterize differences in fecal microbiota between nonobese adult individuals with and without NAFLD and their potential association with metabolic markers of disease progression. A total of 126 nonobese subjects were enrolled : 43 NAFLD and 83 healthy controls ( HC ). The microbial community was profiled by denaturing gradient gel electrophoresis and examined by 454 pyrosequencing of the 16S ribosomal RNA V3 region. Lower diversity and a phylum-level change in the fecal microbiome were found in NAFLD. Compared with HC, patients had 20 % more phylum Bacteroidetes ( p = 0.005 ) and 24 % less Firmicutes ( p = 0.002 ). Within Firmicutes, four families and their 8 genera, which were short-chain fatty acids-producing and 7α-dehydroxylating bacteria, were significantly decreased. Moreover, Gram-negative ( G− ) bacteria were prevalent in NAFLD ( p = 0.008 ). Furthermore, a significant correlation with metabolic markers was revealed for disturbed microbiota in NAFLD. This novel study indicated that intestinal dysbiosis was associated with nonobese NAFLD and might increase the risk of NAFLD progression Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. BACKGROUND Probiotics have profound effect on nonalcoholic steatohepatitis ( NASH ) in animal models. We aim ed to test the hypothesis that probiotics treatment was superior to usual care in reducing liver fat in NASH patients. MATERIAL AND METHODS Patients with histology-proven NASH were r and omized to receive probiotics ( n = 10 ) or usual care ( n = 10 ) for 6 months. The Lepicol probiotic formula contained Lactobacillus plantarum, Lactobacillus deslbrueckii, Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacterium bifidum. The primary endpoint was change in intrahepatic triglyceride content ( IHTG ), as measured by proton-magnetic resonance spectroscopy, from baseline to month 6. Secondary endpoints included changes in liver biochemistry and metabolic profile. RESULTS IHTG decreased from 22.6 ± 8.2 % to 14.9 ± 7.0 % in the probiotic group ( P = 0.034 ) but remained static in the usual care group ( 16.9 ± 6.1 % to 16.0 ± 6.6 % ; P = 0.55 ). Six subjects in the probiotic group had IHTG reduced by more than 30 % from baseline, compared to 2 subjects in the usual care group ( P = 0.17 ). The probiotic group also had greater reduction in serum aspartate aminotransferase level ( P = 0.008 ). On the other h and, the use of probiotics was not associated with changes in body mass index, waist circumference, glucose and lipid levels. CONCLUSIONS Probiotics treatment may reduce liver fat and AST level in NASH patients. The therapeutic potential of probiotics in NASH should be tested in larger studies The Effect of Chlorella vulgaris Supplementation on Liver En-zymes, Serum Glucose and Lipid Profile in Patients with Non-Alcoholic Fatty Liver Disease. BACKGROUND Non-alcoholic fatty liver disease ( NAFLD ) is becoming a public health problem worldwide and using microalgae is a new approach on its treatment. The aim of this study was to investigate the effect of Chlorella vulgaris supplementation on liver enzymes, serum glucose and lipid profile in patients with NAFLD. METHODS This double-blind r and omized placebo-controlled clinical trial was conducted on 60 NAFLD patients from specialized clinics of Tabriz University of Medical Sciences from December 2011 to July 2012. The subjects were r and omly allocated into 2 groups : 1 ) " intervention " ( n=30 ) received 400 mg/day vitamin E plus four 300 mg tablets of Chlorella vulgaris and, 2 ) " placebo " ( n=30 ) received 400 mg/day vitamin E and four placebo tablets per day for 8 weeks. Weight, liver enzymes and metabolic factors were assessed in fasting serum and dietary data was collected at baseline and end of the study. RESULTS Weight, liver enzymes, fasting blood sugar ( FBS ) and lipid profile decreased significantly in both groups ( P<0.05 ). The differences in weight, ALP and FBS between the two groups were statistically significant ( P=0.01, P=0.04 and P=0.02, respectively ). CONCLUSION C. vulgaris seems to improve FBS and lipid profile and therefore could be considered as an effective complementary treatment in NAFLD Oat Prevents Obesity and Abdominal Fat Distribution, and Improves Liver Function in Humans Obesity is associated with a great diversity of diseases including non-alcoholic fatty liver disease. Our recent report suggested that oat, rich in beta-glucan, had a metabolic-regulating and liver-protecting effect in an animal model. In this study, we performed a clinical trial to further confirm the effect of oat. Subjects with BMI ≧27 and aged 18–65, were r and omly divided into a control ( n = 18 ) and an oat-treated ( n = 16 ) group, taking a placebo or beta glucan-containing oat cereal, respectively, for 12 weeks. Our data showed that consumption of oat reduced body weight, BMI, body fat and the waist-to-hip ratio. Profiles of hepatic function, including AST, but especially ALT, were useful re sources to help in the evaluation of the liver, since both showed decrements in patients with oat consumption. Nevertheless, anatomic changes were still not observed by ultrasonic image analysis. Ingestion of oat was well tolerated and there was no adverse effect during the trial. In conclusion, consumption of oat reduced obesity, abdominal fat, and improved lipid profiles and liver functions. Taken as a daily supplement, oat could act as an adjuvant therapy for metabolic disorders Fecal Microbiota Transplantation: From Clostridium difficile to Inflammatory Bowel Disease. Fecal microbiota transplantation ( FMT ) has evolved from a case report in the medical literature to the basis of major innovations in the treatment of Clostridium difficile infection ( CDI ) and, potentially, inflammatory bowel disease ( IBD ). In the clinical setting, FMT was noted to significantly lower the risk of recurrent CDI, likely by increasing microbial diversity and altering the metabolic environment in the intestinal tract of recipients. In parallel, advances in the ability to quantify and characterize microbial communities in fecal sample s led to the association of IBD with a state of intestinal dysbiosis. Consequently, a number of case series and r and omized, controlled trials have evaluated FMT in treating active ulcerative colitis or Crohn\'s disease. Unlike in CDI, the efficacy of FMT in the treatment of IBD appears to be influenced by a number of factors, including donor microbial profiles, inflammatory burden, and the microbial diversity of the recipient. The therapeutic potential of the microbiome has led to a number of biotechnology and pharmaceutical companies isolating specific strains from healthy stool for use as targeted therapies for IBD in clinical trials. Ongoing studies are likely to determine the missing link between the efficacy of FMT and its impact on microbial communities and mucosal inflammation Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. The effects of chronic alcohol consumption on the bowel flora and the potential therapeutic role of probiotics in alcohol-induced liver injury have not previously been evaluated. In this study, 66 adult Russian males admitted to a psychiatric hospital with a diagnosis of alcoholic psychosis were enrolled in a prospect i ve, r and omized, clinical trial to study the effects of alcohol and probiotics on the bowel flora and alcohol-induced liver injury. Patients were r and omized to receive 5 days of Bifidobacterium bifidum and Lactobacillus plantarum 8PA3 versus st and ard therapy alone ( abstinence plus vitamins ). Stool cultures and liver enzymes were performed at baseline and again after therapy. Results were compared between groups and with 24 healthy, matched controls who did not consume alcohol. Compared to healthy controls, alcoholic patients had significantly reduced numbers of bifidobacteria ( 6.3 vs. 7.5 log colony-forming unit [CFU]/g ), lactobacilli ( 3.15 vs. 4.59 log CFU/g ), and enterococci ( 4.43 vs. 5.5 log CFU/g ). The mean baseline alanine aminotransferase ( ALT ), aspartate aminotransferase ( AST ), and gamma-glutamyl transpeptidase ( GGT ) activities were significantly elevated in the alcoholic group compared to the healthy control group ( AST : 104.1 vs. 29.15 U/L ; ALT : 50.49 vs. 22.96 U/L ; GGT 161.5 vs. 51.88 U/L ), indicating that these patients did have mild alcohol-induced liver injury. After 5 days of probiotic therapy, alcoholic patients had significantly increased numbers of both bifidobacteria ( 7.9 vs. 6.81 log CFU/g ) and lactobacilli ( 4.2 vs. 3.2 log CFU/g ) compared to the st and ard therapy arm. Despite similar values at study initiation, patients treated with probiotics had significantly lower AST and ALT activity at the end of treatment than those treated with st and ard therapy alone ( AST : 54.67 vs. 76.43 U/L ; ALT 36.69 vs. 51.26 U/L ). In a subgroup of 26 subjects with well-characterized mild alcoholic hepatitis ( defined as AST and ALT greater than 30 U/L with AST-to-ALT ratio greater than one ), probiotic therapy was associated with a significant end of treatment reduction in ALT, AST, GGT, lactate dehydrogenase, and total bilirubin. In this subgroup, there was a significant end of treatment mean ALT reduction in the probiotic arm versus the st and ard therapy arm. In conclusion, patients with alcohol-induced liver injury have altered bowel flora compared to Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. OBJECTIVE The present pilot trial was carried out to evaluate the effects of an acute treatment with a mixture containing 500 million of Lactobacillus bulgaricus and Streptococcus thermophilus per day in patients with non alcoholic fatty liver disease ( NAFLD ). RESEARCH METHODS A sample of 30 patients with NAFLD ( diagnosed by liver biopsy ) was enrolled and 28 patients were analyzed in a double blind r and omized clinical trial. Patients were r and omized to one of the following treatments during 3 months : group I, treated with one tablet per day with 500 million of Lactobacillus bulgaricus and Streptococcus thermophilus and group II, treated with one placebo tablet ( 120 mg of starch ). RESULTS In group I, alanine amino transferase ( ALT : 67.7 + /- 25.1 vs. 60.4 + /- 30.4 UI/L ; p < 0.05 ), aspartate aminotransferase activity ( AST : 41.3 + /- 15.5 vs. 35.6 + /- 10.4 UI/L ; p < 0.05 ) and gammaglutamine transferase levels ( gammaGT : 118.2 + /- 63.1 vs. 107.7 + /- 60.8 UI/L ; p < 0.05 ) decreased. In group II, all liver function parameters remained unchanged ( ALT : 60.7 + /- 32.1 vs. 64.8 + /- 35.5 UI/L ; p < 0.05 ), aspartate aminotransferase activity ( AST : 31.7 + /- 13.1 vs. 36.4 + /- 13.8 UI/L ; ns ) and gammaglutamine transferase levels ( gammaGT : 82.1 + /- 55.1 vs. 83.6 + /- 65.3 UI/L ; ns ). Anthropometric parameters and cardiovascular risk factors remained unchanged after treatment in both groups. CONCLUSION A tablet of 500 million of Lactobacillus bulgaricus and Streptococcus thermophilus, with a r and omized clinical design, improved liver aminotransferases levels in patients with NAFLD The Effect of Symbiotic Supplementation on Liver Enzymes, C-reactive Protein and Ultrasound Findings in Patients with Non-alcoholic Fatty Liver Disease: A Clinical Trial Background : Regarding to the growing prevalence of nonalcoholic fatty liver disease ( NAFLD ), concentrating on various strategies to its prevention and management seems necessary. The aim of this study was to determine the effects of symbiotic on C-reactive protein ( CRP ), liver enzymes, and ultrasound findings in patients with NAFLD. Methods : Eighty NAFLD patients were enrolled in this r and omized, double-blind, placebo-controlled clinical trial. Participants received symbiotic in form of a 500 mg capsule ( containing seven species of probiotic bacteria and fructooligosaccharides ) or a placebo capsule daily for 8 weeks. Ultrasound grading, CRP, and liver enzymes were evaluated at the baseline and the end of the study. Results : In the symbiotic group, ultrasound grade decreased significantly compared to baseline ( P < 0.005 ) but symbiotic supplementation was not associated with changes in alanine aminotransferase ( ALT ) and aspartate transaminase ( AST ) levels. In the placebo group, there was no significant change in steatosis grade whereas ALT and AST levels were significantly increased ( P = 0.002, P = 0.02, respectively ). CRP values remained static in either group. Conclusions : Symbiotic supplementation improved steatosis in NAFLD patients and might be useful in the management of NAFLD or protective against its progression [Non alcoholic fatty liver disease: treatment with soluble fibres]. The pilot study evaluated the efficiency of oral soluble fibers to treat patients with nonalcoholic fatty liver disease. Twelve patients received 10 g/day of soluble fibers during 3 months. After the treatment 100 % of patients presented reduction in body mass index, waist circumference and insulin resistance index. In 66.7 % of the patients were observed reduction of the cholesterol levels and 75 % presented normal liver enzymes ( AST, ALT, and GGT ). The present study suggests that oral soluble fibers may be useful to control risk factors and liver enzymes in patients with nonalcoholic fatty liver disease. However, future studies with histological controls are considered necessary Effects of Probiotics on Nonalcoholic Fatty Liver Disease in Obese Children and Adolescents Objectives : This study aims to evaluate the effects of some probiotics on sonographic and biochemical nonalcoholic fatty liver disease ( NAFLD ). Methods : This r and omized triple-blind trial was conducted among 64 obese children with sonographic NAFLD. They were r and omly allocated to receive probiotic capsule ( containing Lactobacillus acidophilus ATCC B3208, 3 × 109 colony forming units [ CFU ] ; Bifidobacterium lactis DSMZ 32269, 6 × 109 CFU ; Bifidobacterium bifidum ATCC SD6576, 2 × 109 CFU ; Lactobacillus rhamnosus DSMZ 21690, 2 × 109 CFU ) or placebo for 12 weeks. Results : After intervention, in the probiotic group the mean levels of alanine aminotransferase decreased from 32.8 ( 19.6 ) to 23.1 ( 9.9 ) U/L ( P = 0.02 ) and mean aspartate aminotransferase decreased from 32.2 ( 15.7 ) to 24.3 ( 7.7 ) U/L ( P = 0.02 ). Likewise the mean cholesterol, low-density lipoprotein-C, and triglycerides as well as waist circumference decreased in the intervention group, without significant change in weight, body mass index, and body mass index z score. After the trial, normal liver sonography was reported in 17 ( 53.1 % ) and 5 ( 16.5 % ) of patients in the intervention and placebo groups, respectively. Conclusions : The present findings suggest that a course of the abovementioned probiotic compound can be effective in improving pediatric NAFLD Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non‐alcoholic steatohepatitis Gut microbiota modifiers may have beneficial effects of non‐alcoholic fatty liver disease ( NAFLD ) but r and omised controlled trials ( RCT ) are lacking in children Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy Background Hepatic encephalopathy ( HE ) is a reversible neuropsychiatric syndrome in patients with liver disease. It was suggested that Bifidobacterium+fructo-oligosaccharides ( FOS ) may decrease blood and brain ammonia levels. Aim The study was conducted to compare the efficacy of Bifidobacterium+FOS and lactulose in patients with HE. Methods One hundred and twenty-five patients ( 35 hepatitis B virus infected, 70 hepatitis C virus infected and 20 cryptogenetic cirrhosis ) were enrolled in the study. Patients were r and omized either to a treatment for 60 days with Bifidobacterium and FOS ( group A ) or into-group receiving lactulose ( group B ) in double-blind. Results After 30 days of the study period, the Bifidobacterium+FOS-treated patients compared with lactulose-treated patients showed a significant decrease of Trail Making Test B ( TMT B ) ( P<0.005 ), and a significant increase of Symbol Digit Modalities Test ( P<0.001 ) and Block Design Test ( P<0.001 ). After 60 days of the study period, the Bifidobacterium+FOS-treated patients compared with lactulose-treated patients showed a significant decrease of NH4 fasting HE1 ( P<0.001 ), TMT A ( P<0.05 ), TMT B ( P<0.001 ), and a significant increase of Symbol Digit Modalities Test ( P<0.001 ) and Block Design Test ( P<0.001 ). Conclusion The treatment with Bifidobacterium+FOS is an alternative to the use of lactulose in patients with cirrhosis, for its usefulness in reducing blood ammonia levels and improvement of psychometric tests Effects of traditional homemade koumiss on some hematological and biochemical characteristics in sedentary men exposed to exercise Abstract We evaluated the effects of koumiss on some hematological and biochemical characteristics of persons who exercise. Eighteen sedentary males were assigned to three equal groups : koumiss ( K ), koumiss + exercise ( KE ) and exercise alone ( E ). Leukocytes ( WBC ), differential leucocyte count, erythrocytes ( RBC ), hemoglobin ( HGB ), hematocrit ( HCT ), platelet ( PLT ), glucose, total cholesterol, triglycerides, high density lipoprotein ( HDL ), aspartate aminotransferase ( AST ) and alanine aminotransferase ( ALT ) were assessed In blood sample s. By the end of the study, triglycerides ( TG ) and cholesterol levels tended to decrease in all groups, but the decrease was significant only at day 15 for the KE group. HDL tended to be increased in all groups at day 15, but the increase was significant only in the KE group. We found that koumiss had beneficial effects on some hematological and biochemical characteristics Probiotics reduce the inflammatory response induced by a high-fat diet in the liver of young rats. Nonalcoholic fatty liver disease ( NAFLD ) is the most common form of chronic liver disease in the pediatric population. Preliminary evidence suggests a potential therapeutic utility of probiotics for this condition. Here, we tested the potential effect of the probiotic VSL#3 ( a multistrain preparation composed of Streptococcus thermophilus and several species of Lactobacillus and Bifidobacteria ) on oxidative and inflammatory damage induced by a high-fat diet in the liver of young rats. At weaning, young male Sprague-Dawley rats were r and omly divided into 3 groups ( n = 6 ) fed a st and ard, nonpurified diet ( Std ; 5.5 % of energy from fat ) or a high-fat liquid diet ( HFD ; 71 % of energy from fat ). One of the HFD groups received by gavage VSL#3 ( 13 x 10(9 ) bacteria x kg(-1 ) x d(-1 ) ). After 4 wk, the HFD rats had greater body weight gain, fat mass, serum aminotransferase, and liver weight than rats fed the Std diet. The HFD induced liver lipid peroxidation, tumor necrosis factor ( TNFalpha ) production, protein S-nitrosylation, inducible nitric oxide synthase ( iNOS ), cyclooxygenase (COX)-2 expression, and metalloproteinase ( MMP ) activity. Moreover, in the HFD group, PPARalpha expression was less than in rats fed the Std diet. In rats fed the HFD diet and treated with VSL#3, liver TNFalpha levels, MMP-2 and MMP-9 activities, and expression of iNOS and COX-2 were significantly lower than in the HFD group. In VSL#3-treated rats, PPARalpha expression was greater than in the HFD group. A modulation of the nuclear factor-kappaB pathway by VSL#3 was also demonstrated. Our data suggest that VSL#3 administration could limit oxidative and inflammatory liver damage in patients with NAFLD', 'Purpose Our aim was to assess the efficacy of metformin for weight loss in overweight and obese people through a systematic review and network meta- analysis and to identify the most suitable dosage and intervention period for using metformin in adolescents and adults. The Effects of Metformin on Body Mass Index and Glucose Tolerance in Obese Adolescents With Fasting Hyperinsulinemia and a Family History of Type 2 Diabetes Objectives. The prevalence of type 2 diabetes in American adolescents has increased markedly during the past generation. Although the factors that contribute to the development of type 2 diabetes are complex and not wholly eluci date d, the triad of severe obesity, hyperinsulinemia, and a family history of type 2 diabetes places a child at an increased risk for development of the disease. Current approaches to the prevention of type 2 diabetes, including dietary counseling and exercise, have had limited success. We reasoned that drugs that increase glucose tolerance in diabetic patients might prove useful in preventing the progression to glucose intolerance in high-risk patients. To that end, we conducted a double-blind, placebo-controlled study of the effects of metformin on body mass index ( BMI ), serum leptin, glucose tolerance, and serum lipids in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Methods. The study population consisted of 29 white and black adolescents aged 12 to 19 years. All had BMI s exceeding 30 kg/m2. Criteria for enrollment included : 1 ) a fasting insulin concentration exceeding 15 μU/mL ; and 2 ) at least 1 first- or second-degree relative with type 2 diabetes. All patients had fasting plasma glucose concentrations < 110 mg% and hemoglobin A1c concentrations ≤6.0 %. All had normal linear growth and sexual development for age, with no marked hirsutism, severe acne, or menstrual irregularities characteristic of polycystic ovary syndrome. Eight participants had acanthosis nigricans. After baseline laboratory studies including a rapidly sample d intravenous glucose tolerance test, patients were r and omized to receive metformin ( 500 mg twice daily ) or a placebo for a total of 6 months. The effects of metformin on BMI st and ard deviation score, serum leptin, glucose tolerance, and serum lipids were analyzed. The study was double-blinded and included no specific dietary restrictions. Results. Metformin caused a decline of 0.12 st and ard deviation in BMI in study participants ( −1.3 % from baseline ), and a 5.5 % reduction in serum leptin in girls. In contrast, BMI and serum leptin rose 0.23 st and ard deviation ( 2.3 % ) and 16.2 %, respectively, in the placebo group during the treatment period. Metformin caused a progressive decline in fasting blood glucose ( from a mean of 84.9 to 75.1 mg% ) and a reduction in fasting insulin levels ( from 31.3 to 19.3 μU/mL ). In contrast, fasting glucose levels in the placebo group rose slightly from 77.2 to 82.3 mg%, and fasting insulin levels did not change. Insulin sensitivity, as assessed by the ratio of fasting insulin to glucose concentrations and the quantitative insulin sensitivity check index ( 1/[log fasting insulin + Enhancing treatment of obesity by using a distracting mini-meal: a new approach to an old problem OBJECTIVE The management of obesity, apart from exercise, mainly involves a calorie restriction regimen. A pharmaceutical treatment is often used to improve patient compliance and diet effectiveness, although several side-effects have previously been described. To improve patient compliance and diet effectiveness without incurring unpleasant side-effects, we evaluated whether a distracting mini-meal can physiologically decrease the absorption of fats and carbohydrates. DESIGN Two minutes before each of the three meals consumed daily, 32 obese patients were treated with a distracting mini-meal, 32 with metformin, and 32 with placebo. At baseline and after 1, 3, and 6 months of treatment, body weight, body mass index, waist circumference, fasting/post-pr and ial insulinaemia and glycaemia, homeostasis model assessment -index, triacylglycerols, and total cholesterol were evaluated. RESULTS All patients showed good compliance. With the exception of post-pr and ial glycaemia, a significant reduction in all parameters was documented in every group, albeit the greater variation was observed in patients treated with a distracting mini-meal or metformin. No one showed noteworthy side-effects. CONCLUSIONS Our study focuses on a distracting mini-meal that could become a useful tool in enhancing weight loss. The beneficial effect of a distracting meal on insulin resistance, glucose, and lipid metabolism suggest its possible use to prevent or mitigate obesity-related disorders Metformin-based treatment for obesity-related hypertension: a randomized, double-blind, placebo-controlled trial Objectives : Obesity and hypertension are associated with an adverse metabolic profile and systemic low- grade inflammation. Metformin reduces weight and inflammation in patients with diabetes, but it is unclear whether it has beneficial effects in patients without diabetes. The objective was to explore whether metformin-based treatment could benefit obesity-related hypertension without diabetes. Methods : A r and omized, double-blind, placebo-controlled factorial trial was conducted in 360 obese hypertensive patients without diabetes in Chongqing, China. After a 1–2-week run-in period, patients were r and omly assigned to metformin ( 500 mg once per day ) or placebo, as well as to an antihypertensive medication. Change in blood pressure, obesity measurements and metabolic profile were assessed at 24 weeks. Results : The 180 participants r and omized to metformin and 180 r and omized to placebo were similar at baseline. At 24 weeks, metformin compared with placebo did not have significant effects on blood pressure, blood glucose, high-density or low-density lipoprotein cholesterol, but it did reduce total serum cholesterol ( 0.27mmol/l, P = 0.038 ). Metformin also significantly reduced weight ( −0.7 kg, P = 0.006 ), BMI ( −0.2 kg/m2, P = 0.024 ), waist circumference ( −0.9 cm, P = 0.008 ), and both subcutaneous ( −6.1 cm2, P = 0.043 ) and visceral adiposity ( −5.4 cm2, P = 0.028 ) as measured by computed tomography, and lowered serum high-sensitivity C-reactive protein levels ( −0.6 mg/dl, P < 0.001 ). There was no significant difference in adverse events ( P = 0.785 ). Conclusions : Metformin has no effect on blood pressure and blood glucose levels, but it does reduce total cholesterol, abdominal obesity and C-reactive protein levels in obese hypertensive patients without diabetes Metformin in combination with structured lifestyle intervention improved body mass index in obese adolescents, but did not improve insulin resistance This study assessed the efficacy of adding metformin to a structured lifestyle intervention in reducing BMI in obese adolescents with insulin resistance. Obese adolescents ( 25 ) aged 10–16 years with a body mass index ( BMI ) > 95th percentile and insulin resistance ( Homeostasis Model Assessment —HOMA ) > 3.0 were assessed in a community clinic. A structured lifestyle intervention comprising nutritional and exercise education and motivational support in both individual and group sessions was delivered over 6 months. Subjects were r and omized to lifestyle intervention alone or with metformin ( 1500 g daily ). The primary outcome measures were a change in BMI and modification of metabolic risk factors, including insulin resistance, plasma lipids and adipocytokines. Eleven adolescents receiving lifestyle and metformin intervention and 14 receiving lifestyle alone completed the study. BMI decreased by 1.8 kg/m2 with lifestyle and metformin but did not change with lifestyle alone. HOMA was significantly decreased in the lifestyle intervention group, but not following metformin, while the adiponectin/leptin ratio improved significantly in both groups. Dyslipidemic profiles improved most significantly with metformin. We conclude that metformin in combination with a 6-month structured lifestyle intervention is effective in reducing BMI in obese adolescents but did not improve insulin resistance. Lifestyle intervention, with or without metformin, improved metabolic risk factors such as plasma lipids and adipocytokines Long term cardiovascular effects of oral antidiabetic agents in non-diabetic patients with insulin resistance: double blind, prospective, randomised study Objective : To study the long term cardiovascular effects of oral antidiabetic agents in non-diabetic patients with insulin resistance. Patients : 181 African American subjects with insulin resistance and normal glucose tolerance test were r and omised to receive glipizide 5 mg/day ( n = 25 ), metformin 500 mg/day ( n = 59 ), or placebo ( n = 97 ) for 24 months. Insulin sensitivity, glucose tolerance, lipid profile, left ventricular mass ( echocardiography ), aortic distensibility ( echocardiography, blood pressure ), aortic pulse wave velocity ( PWV, carotid to femoral artery, Doppler ) were measured at baseline and at 12 and 24 months after r and omisation. Results : A significant increase in PWV was observed in both glipizide ( mean ( SEM ) change at 24 months 2.8 ( 2.7 ) m/s, p = 0.012 ) and metformin ( 2.2 ( 0.7 ) m/s, p = 0.01 ) groups during the follow up period. In contrast, PWV remained unchanged in the placebo group. The increase in PWV in the treatment groups was significant compared with placebo ( analysis of variance p < 0.05 ). Other cardiovascular or metabolic variables did not change significantly compared with placebo during follow up. Conclusions : The observed increase in PWV is consistent with a decrease in the elastic properties of the aorta. The use of oral antidiabetic agents for the prevention of cardiovascular complications in non-diabetic African Americans with insulin resistance needs to be critically evaluated Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome ( PCOS ). Dietary-induced weight loss and the administration of insulin-lowering drugs, such as metformin, are usually followed by improved hyper and rogenism and related clinical abnormalities. This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight, fat distribution, the glucose-insulin system, and hormones in a group of 20 obese PCOS women [ body mass index ( BMI ) > 28 kg/m2 ] with the abdominal phenotype ( waist to hip ratio > 0.80 ), and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS. At baseline, we measured sex hormone, sex hormone-binding globulin ( SHBG ), and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography ( CT ) at the L4-L5 level, to measure sc adipose tissue area ( SAT ) and visceral adipose tissue area. All women were then given a low-calorie diet ( 1,200 - 1,400 kcal/day ) alone for one month, after which anthropometric parameters and CT scan were newly measured. While continuing dietary treatment, PCOS women and obese controls were subsequently placed, in a r and om order, on metformin ( 850 mg/os, twice daily ) ( 12 and 8, respectively ) or placebo ( 8 and 12, respectively ), according to a double-blind design, for the following 6 months. Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment. During the treatment period, 3 women of the control group ( all treated with placebo ) were excluded because of noncompliance ; and 2 PCOS women, both treated with metformin, were also excluded because they became pregnant. Therefore, the women cohort available for final statistical analysis included 18 PCOS ( 10 treated with metformin and 8 with placebo ) and 17 control women ( 8 treated with metformin and 9 with placebo ). The treatment was well tolerated. In the PCOS group, metformin therapy improved hirsutism and menstrual cycles significantly more than placebo. Baseline anthropometric and CT parameters were similar in all groups. Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups, without any significant effect on CT scan parameters. In both PCOS and control women, however, metformin treatment reduced body weight and BMI significantly more than placebo. Changes in the waist-to-hip ratio values were similar in PCOS women and controls, regardless of pharmacological treatment. Metformin treatment significantly decreased SAT values in both PCOS and control Combination of direct and indirect evidence in mixed treatment comparisons. Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials, to data structures that include, for example, A vs B, B vs C, and A vs C trials. There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments, by including both\'direct\'and\'indirect\'comparisons. The other is to facilitate simultaneous inference regarding all treatments, in order for example to select the best treatment. In this paper, we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS. These are multivariate r and om effects models that allow for variation in true treatment effects across trials. We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models. We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution. These models are applied to an illustrative data set and posterior parameter distributions are compared. We discuss model critique and model selection, illustrating the role of Bayesian deviance analysis, and node-based model criticism. The assumptions underlying the MTC models and their parameterization are also discussed Effects of Metformin on Body Weight and Body Composition in Obese Insulin-Resistant Children OBJECTIVE Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant. RESEARCH DESIGN AND METHODS This study was a r and omized double-blind placebo-controlled trial consisting of 100 severely obese ( mean BMI 34.6 ± 6.6 kg/m2 ) insulin-resistant children aged 6–12 years, r and omized to 1,000 mg metformin ( n = 53 ) or placebo ( n = 47 ) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program. RESULTS Eighty-five percent completed the 6-month r and omized phase. Children prescribed metformin had significantly greater decreases in BMI ( difference −1.09 kg/m2, CI −1.87 to −0.31, P = 0.006 ), body weight ( difference −3.38 kg, CI −5.2 to −1.57, P < 0.001 ), BMI Z score ( difference between metformin and placebo groups −0.07, CI −0.12 to −0.01, P = 0.02 ), and fat mass ( difference −1.40 kg, CI −2.74 to −0.06, P = 0.04 ). Fasting plasma glucose ( P = 0.007 ) and homeostasis model assessment ( HOMA ) insulin resistance index ( P = 0.006 ) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17 %. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score ; those treated continuously with metformin did not significantly change BMI Z score further. CONCLUSIONS Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program Metformin treatment leads to an increase in basal, but not insulin-stimulated, glucose disposal in obese patients with impaired glucose tolerance. AIMS This study was initiated to test the hypothesis that metformin treatment leads to enhanced glucose disposal at ambient insulin concentrations. METHODS Nineteen obese patients with impaired glucose tolerance ( IGT ) were treated with either metformin or placebo in a r and omized, double-blind, placebo-controlled, cross-over study. Insulin secretion and insulin resistance were quantified using the homeostasis model assessment ( HOMA ) and insulin-stimulated glucose disposal were measured by determining the steady-state plasma glucose ( SSPG ). RESULTS The average benefit of metformin was 0.6 mmol/l for glucose ( 95 % confidence interval ( CI ) 0.2 - 0.9 P = 0.002 ), 2.8 pmol/l for insulin ( 95 % CI 0.2 - 5.4, P = 0.019 ). Insulin resistance, as quantified by HOMA, was improved by 1.1 ( 95 % CI 0.2 - 2.0, P = 0.004 ), without any change in insulin secretion. Basal and insulin-stimulated glucose oxidation were comparable in the placebo and metformin-treated groups at the end of each treatment period, as was the SSPG concentration. However, both systolic and diastolic blood pressures fell significantly following metformin administration as compared to treatment with placebo. CONCLUSIONS These results indicate that metformin administration to patients with IGT is associated with enhanced glucose disposal at baseline insulin concentrations and a fall in blood pressure. In contrast, neither glucose oxidation nor glucose disposal were increased in association with metformin treatment under conditions of physiological hyperinsulinaemia Treatment with metformin of non-diabetic men with hypertension, hypertriglyceridaemia and central fat distribution: the BIGPRO 1.2 trial. BACKGROUND In the BIGPRO 1 trial, one year of treatment with metformin in non-diabetic obese subjects with a central fat distribution had no significant effect on fasting plasma triglyceride concentration or on blood pressure despite a decrease in weight, fasting plasma insulin and glucose concentrations. To re-evaluate the effect of metformin on fasting triglyceride concentration and on blood pressure, the BIGPRO 1.2 trial included non-diabetic men ( n=168 ) with a fasting plasma triglyceride concentration > or = 1.7 and < or = 6.5 mmol/l, high blood pressure ( systolic > or = 140 and < or = 180 and /or diastolic > or = 90 and < or = 105 mmHg, or treatment for hypertension ) and a waist-to-hip ratio > or = 0.95. METHODS A r and omised double-blind trial comparing metformin treatment ( 850 mg bid ) with placebo. RESULTS Metformin had no significant effect either on blood pressure or plasma triglyceride concentration. In comparison with the placebo group, fasting plasma insulin ( p<0.04 ), total cholesterol ( p<0.05 ) and Apo B ( p<0.008 ) concentrations decreased more in the metformin group in the BIGPRO 1. 2 trial, confirming most of the previous results of the BIGPRO 1 trial. Tissue plasminogen activator antigen concentration decreased significantly ( p<0.01 ) only in the metformin group, but this was not significantly different from the placebo group ( p<0.12 ) ; further, there were no significant differences in the change in plasminogen activator inhibitor 1. CONCLUSIONS The consistency of the two BIGPRO trials supports the conclusion that metformin affects several cardiovascular risk factors favourably in non-diabetic subjects with a central fat distribution Metformin and placebo therapy both improve weight management and fasting insulin in obese insulin-resistant adolescents: a prospective, placebo-controlled, randomized study. OBJECTIVE To study whether metformin reduces obesity, homeostasis model assessment for insulin resistance index ( HOMA-IR ), and the metabolic syndrome ( MtS ) in obese European adolescents in addition to previous unsuccessful lifestyle intervention. DESIGN AND METHODS After 6 months of multiprofessional lifestyle intervention, 70 out of 86 adolescents without improvement in body mass index ( BMI ) and HOMA-IR were r and omized into either the placebo ( n=34 ) or the metformin group ( 2 × 500 mg/day, n=36 ) in addition to ongoing lifestyle intervention for another 6 months. RESULTS Age was 13.8 years, BMI was 33.1 kg/m(2 ), 65 % were female, and 89 % were Caucasians. During lifestyle intervention alone, BMI and HOMA-IR deteriorated significantly. In the subsequent medication period, HOMA-IR and fasting insulin improved similarly in the placebo and metformin groups ( HOMA-IR decreased 73 vs 54 % respectively in metformin versus placebo ; P=0.048 ), but BMI remained unchanged. The insulin sensitivity index, however, only improved in the metformin group. High fasting insulin is correlated with a subsequent BMI increase irrespective of the medication. MtS remained unchanged. CONCLUSIONS Obese European adolescents\'insulin sensitivity improved without weight change during placebo or metformin intervention in addition to lifestyle intervention. Most differences did not reach statistical significance, probably due to improved compliance with lifestyle intervention as a placebo effect. In addition, the metformin dose may be too low A randomized, triple masked, placebo-controlled clinical trial for controlling childhood obesity Background The efficacy of pharmacological treatment in controlling childhood obesity is controversial. We aim ed to compare the effects of three types of drug regimens and placebo on generalized and abdominal obesity among obese children and adolescents who did not succeed to lose weight 3 months after lifestyle modification ( diet and exercise ). Methods This triple-masked r and omized clinical trial was conducted among 180 participants aged 10–16 years. They were assigned r and omly to 4 groups of equal number to receive metformin, fluoxetine, a combination of the two drugs, or placebo. The trial lasted for 12 weeks and participants were followed up for an additional 12-week period. Results Overall, 91.1 % ( n=164 ) of the enrolled participants completed the trial. After the 12-week trial, the body mass index decreased significantly in all groups receiving medications [ approximately −1.2 ( 0.2 ) kg/m2, P<0.05 ]. This decrease was not significant in the placebo group. Waist circumference decreased significantly in the groups receiving metformin [ −2.1 ( 0.4 ) cm, P=0.03 ) ] as well as in the group receiving a combination therapy of metformin and fluoxetine [ −2.5 ( 0.4 ) cm, P=0.01 ) ]. In the 24-week follow-up study, these anthropometric indexes were lower than the baseline in the group that had received a combination therapy of metformin and fluoxetine. No serious drug side-effects were reported. Conclusions A limited period of such treatment may help weight control, and might be used to encourage those children who have been refractory to weight loss for continuing the non-pharmacological programs. Our findings should be confirmed in future studies with a longer follow-up period Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. OBJECTIVE To evaluate the effects of metformin on glucagon-like peptide 1 ( GLP-1 ) and leptin levels. RESEARCH DESIGN AND METHODS A total of 10 obese nondiabetic male patients were studied before and after a 14-day treatment with 2,550 mg/day metformin and were compared with 10 untreated obese control subjects. On days 0 and 15, leptin and GLP-1(7 - 36)amide/(7 - 37 ) levels were assessed before and after an oral glucose load during a euglycemic hyperinsulinemic clamp to avoid the interference of variations of insulinemia and glycemia on GLP-1 and leptin secretion. The effects of metformin on GLP-1(7 - 36)amide degradation in human plasma and in a buffer solution containing dipeptidyl peptidase IV ( DPP-IV ) were also studied. RESULTS Leptin levels were not affected by the oral glucose load, and they were not modified after metformin treatment. Metformin induced a significant ( P < 0.05 ) increase of GLP-1(7 - 36)amide/(7 - 37 ) at 30 and 60 min after the oral glucose load ( 63.8 + /- 29.0 vs. 50.3 + /- 15.6 pmol/l and 75.8 + /- 35.4 vs. 46.9 + /- 20.0 pmol/l, respectively ), without affecting baseline GLP-1 levels. No variations of GLP-1 levels were observed in the control group. In pooled human plasma, metformin ( 0.1 - 0.5 microg/ml ) significantly inhibited degradation of GLP-1(7 - 36)amide after a 30-min incubation at 37 degrees C ; similar results were obtained in a buffer solution containing DPP-IV. CONCLUSIONS Metformin significantly increases GLP-1 levels after an oral glucose load in obese nondiabetic subjects ; this effect could be due to an inhibition of GLP-1 degradation Effect of metformin on patients with impaired glucose tolerance. AIMS To evaluate the effect of metformin on glucose metabolism, insulin sensitivity and rate of conversion diabetes in people with impaired glucose tolerance ( IGT ). METHODS Seventy subjects with IGT were r and omized under double-blind conditions to receive either placebo ( n = 37 ) or metformin ( n = 33 ) at a dosage of 250 mg three times daily for a duration of 12 months. Glycaemic control, plasma insulin and other biochemical indexes were assessed before and after 3, 6 and 12 months. RESULT At 12 months the conversion rate to diabetes was 16.2 % in the placebo group compared to 3.0 % for the metformin group ( P = 0.011 ). Of subjects treated with metformin for 12 months, 84.9 % became normoglycaemic compared to 51.4 % of those receiving the placebo. Significant improvements in fasting glucose, glucose tolerance and insulin sensitivity were found at 12 months and at intermediate clinic assessment s. CONCLUSIONS Metformin can improve glucose metabolism in IGT patients and may be a treatment option in their management of IGT subjects Metformin use in children with obesity and normal glucose tolerance – effects on cardiovascular markers and intrahepatic fat Abstract Objective : To determine if metformin improves markers of inflammation, thrombosis, and intrahepatic fat contents in children with uncomplicated obesity. Methods : Obese children with normal glucose tolerance but elevated highly sensitive C-reactive protein ( hsCRP ) and /or fibrinogen concentrations ( > 2 st and ard deviations ) were r and omized to structured diet/exercise or diet/exercise and metformin for 6 months. Blood sample s, dual energy X-ray absorptiometry data, and liver magnetic resonance images were obtained. Results : Forty-two of 66 recruited children ( 7–18 years ) completed 6 months. Weight loss was modest but more pronounced in the metformin group ( –4.9±1.0 kg ) than in the diet/exercise group ( –1.7±1.1 kg, p<0.03 ), whereas hsCRP and fibrinogen decreased more in the diet/exercise pubertal group. Baseline intrahepatic fat was high but decreased only in the diet/exercise ( not metformin ) pubertal group. Conclusions : Six months of metformin therapy improved weight loss and reduced abdominal adiposity, but did not enhance the beneficial effect of diet and exercise on markers related to inflammation, thrombosis, or hepatic fat in obese children with normal glucose tolerance Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. The presence of fatty liver per ultrasound and liver-associated enzymes were measured in a select cohort of youth with both obesity and insulin resistance, and the effect of metformin on these parameters evaluated. Fifty obese, multiethnic, insulin-resistant adolescents ( mean age 15.1 yr, mean body mass index 39.8 kg/m2 ) were r and omized to receive lifestyle recommendations plus either twice per day doses of 850 mg of metformin or placebo. Fasting and post-glucose challenge biochemistries and liver ultrasounds were compared at baseline and 6 months. The prevalence of fatty liver was 74 %, elevated alanine aminotransferase ( ALT ) 14 %, aspartate aminotransferase ( AST ) 14 %, and gamma-glutamyl transferase ( GGT ) 17 %. Fatty liver was mild in 23 %, moderate in 31 %, and severe in 46 %. Fatty liver was more common in male and Hispanic subjects and elevated ALT more common in Hispanic subjects. Subjects with fatty liver appeared more insulin resistant ( higher fasting insulin and triglycerides, lower high-density lipoprotein cholesterol ) and had higher ALT and AST. At 6 months, mean ALT, GGT, and fasting insulin improved significantly in all subjects. Fatty liver prevalence ( p < 0.04 ), severity ( p < 0.04 ), and fasting insulin ( p < 0.025 ) improved significantly with metformin compared to placebo. Non-alcoholic fatty liver disease ( NAFLD ) occurs with a high prevalence and severity in obese, insulin-resistant adolescents. While metformin plus lifestyle intervention appears promising, defining NAFLD therapies capable of preventing fibrosis and cirrhosis requires further study The effects of metformin on inflammatory mediators in obese adolescents with insulin resistance: controlled randomized clinical trial Abstract Objective : To compare serum concentrations of inflammatory cytokines, interleukin 6 ( IL-6 ), high-sensitivity C-reactive protein ( hs-CRP ), adiponectin, and tumor necrosis factor α ( TNFα ), before and after 3 months treatment with metformin in obese adolescents with insulin resistance ( IR ). Design and subjects : This was a r and omized, double-blinded, clinical trial of two groups of obese adolescents with IR, aged 9–18 years : a placebo group ( n=14 ) and a metformin group ( n=12 ) who received 500 mg metformin every 12 h for 3 months. Anthropometric and biochemical ( metabolic and inflammatory cytokines ) assessment s were compared at the beginning and end of treatment. Results : After 3 months of treatment, body mass index ( kg/m2 ) was reduced in both groups : placebo group ( 32.82±6.37–32.10±6.52 ; p=0.011 ) and metformin group ( 33.44±5.82–32.71±5.77 ; p=0.015 ). Serum fasting insulin concentrations ( pmol/L ) increased in the placebo group ( 189.45±112.64–266.06±167.79 ; p=0.01 ) and showed a slight decrease in the metformin group ( 256.82±113.89–229.25±86.53 ; p=0.64 ). Adiponectin concentrations ( μg/mL ) decreased in the placebo group ( 13.17±7.31–5.65±6.69 ; p=0.02 ), while these remained stable in the metformin group ( 8.57±3.98–7.86±6.23 ; p=0.64 ). In the metformin group, significant reductions were found in the variances of serum TNFα concentrations ( p=0.006 ; Levene test ). Conclusion : These results suggest that treating obese adolescents with IR using metformin for 3 months is an option for patients without response to traditional lifestyle change because metformin improves inflammatory activity, which is an etiological factor in cardiovascular disease development GRADE guidelines: 3. Rating the quality of evidence. This article introduces the approach of GRADE to rating quality of evidence. GRADE specifies four categories-high, moderate, low, and very low-that are applied to a body of evidence, not to individual studies. In the context of a systematic review, quality reflects our confidence that the estimates of the effect are correct. In the context of recommendations, quality reflects our confidence that the effect estimates are adequate to support a particular recommendation. R and omized trials begin as high- quality evidence, observational studies as low quality. " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision, inconsistency, indirectness of study results, and publication bias. In addition, several factors can increase our confidence in an estimate of effect. GRADE provides a systematic approach for considering and reporting each of these factors. GRADE separates the process of assessing quality of evidence from the process of making recommendations. Judgments about the strength of a recommendation depend on more than just the quality of evidence Metformin for overweight women at midlife: a double-blind, randomized, controlled trial Abstract Aim This study was undertaken to determine whether metformin would ameliorate insulin resistance, reduce weight and waist circumference and improve lipids in obese, but not morbidly obese, euglycemic women. Methods Obese women ( body mass index ( BMI ) ≥ 30 and < 40 kg/m2 and /or waist circumference > 88 cm ), aged 35–65 were r and omized ( 1:1 ) to metformin 850 mg or identical placebo, twice daily for 26 weeks. The primary outcome was the change in insulin resistance determined by the homeostasis model of assessment ( HOMA-IR ). Secondary outcomes included fasting insulin, glucose, weight, waist circumference and BMI. Results Of the 125 women screened, 117 enrolled and 100 women, mean age 53 years, were included in the primary intention-to-treat analysis. Metformin result ed in statistically significant between-group difference in the change in HOMA-IR ( change in median − 0.04 vs. placebo + 0.1, p = 0.018 ) and BMI ( mean change − 1.00 kg/m2 ; 95 % confidence interval ( CI ) 1.37 to − 0.62 vs. placebo mean change 0.00 ; 95 % CI − 0.29 to 0.28, p < 0.001 ). Statistically significant reductions in HbA1c ( p = 0.008 ) and fasting insulin ( p = 0.03 ) and a borderline decrease in high density lipoprotein cholesterol ( p = 0.07 ) were also observed for metformin, compared with placebo. No effects were seen for waist circumference, fasting glucose or other lipids. Conclusion Treatment of euglycemic, obese, middle-aged women with metformin 1700 mg per day reduced insulin resistance and weight compared with placebo. Further studies are needed to determine whether the use of metformin will prevent the progression of insulin resistance to type 2 diabetes mellitus in obese women Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial. The objective was to determine the effect of metformin on the concentrations of resistin and other markers of insulin resistance or inflammation ( C-reactive protein, cytokines, body weight, HbA1c, among others ) in minors with glucose intolerance. Patients aged 4 to 17 years with glucose intolerance were studied. They were r and omized to receive 850 mg of either metformin or placebo twice daily for 12 weeks, during which all followed an iso-caloric diet and an exercise program. High sensitivity C-reactive protein, TNF-alpha, IL-6, IL1-beta, resistin, leptin, adiponectin, glucose, insulin, HbA1c, lipid profile and transaminases were measured at the beginning and at the end of the period. Fifty-two patients were included, 11.9±2.6 years old ; 28 ( 12 males/16 females ) received metformin and 24 placebo ( 11 males/13 females ). Baseline characteristics were similar between groups ( except for body mass index, which in the metformin group was slightly higher ). Percentage weight loss was greater in the metformin group ( -5.86 % vs 2.75 %, P<.05 ). At study end, there were statistically significant differences in resistin concentrations, even after adjusting for confounding variables ( F=7.714 ; P<.006 ). Also, metformin was associated with a significant decrease in HOMA-IR index ( P=.032 ) and HbA1c levels ( P=.001 ), but no change was observed in the concentration of other markers of inflammation. Metformin result ed in significant reductions of plasma resistin levels in minors with glucose intolerance. This change is independent of its effects on body weight. In contrast, metformin did not alter the concentration of inflammatory markers Lifestyle intervention improves fitness independent of metformin in obese adolescents. PURPOSE Obesity in adolescence increases the risk for early adult cardiovascular disease. We recently showed that 6 months of diet, exercise, and metformin result ed in reductions in adiposity and that diet/exercise alone reduced proinflammatory factors and intrahepatic fat in pubertal children with uncomplicated obesity. The purpose of the present study was to determine whether changes in cardiorespiratory fitness ( CRF ) after 6 months of structured diet and exercise ( DE ) or DE plus metformin are related to the previously observed changes in adiposity, markers of inflammation, and intrahepatic fat. METHODS Sixteen obese pubertal adolescents between the ages of 10 and 17 were r and omized into a structured lifestyle program consisting of DE or DE plus metformin. Subjects performed aerobic and resistance exercise 3 d·wk⁻¹, 30 min per session. Cycle ergometer maximal oxygen consumption ( V˙O2max ), body composition, blood markers ( glucose, insulin, homeostatic model assessment -insulin resistance, interleukin-6, hsCRP ), and intrahepatic fat were measured at baseline and 6 months. RESULTS In the cohort, as whole-body weight decreased by 4.0 % ( P = 0.009 ), body mass index decreased by 4.9 % ( P = 0.003 ), percent body fat decreased by 8.8 % ( P < 0.001 ), and V˙O2max improved in 10 of 16 subjects. The addition of metformin provided no further effect on body composition, CRF, or inflammatory factors. More favorable changes in adiposity, adiponectin, and a trend toward blood glucose and interleukin-6 concentrations ( P = 0.07 ) were observed in subjects who increased V˙O2max at 6 months ( n = 10 ) compared with no change in these variables in those who did not improve V˙O2max. CONCLUSIONS Metformin did not provide benefits above lifestyle modification for improving CRF in obese adolescents. Improvements in V˙O2max seem to be associated with more favorable metabolic outcomes Metformin in obese children and adolescents: the MOCA trial. CONTEXT Childhood obesity is increasingly associated with type 2 diabetes ( T2D ). Metformin reduces the risk for T2D in adult obese nondiabetic patients, but the evidence in obese children and young people is inconclusive. OBJECTIVE The objective of the study was to assess the effect of metformin on body mass index sd score ( BMI -SDS ), metabolic risk factors, and adipokines. DESIGN This was a prospect i ve, r and omized, double-blind, placebo-controlled trial. SETTING The study was conducted at six pediatric endocrine centers in the United Kingdom. PARTICIPANTS One hundred fifty-one obese children and young people with hyperinsulinemia and /or impaired fasting glucose or impaired glucose tolerance ( metformin : 74, placebo : 77 ). The study was comprised of 67.5 % females, 65.6 % postpubertal individuals, and 23.8 % British Asian or Afro-Caribbean participants. The age range was 8 - 18 yr, the mean age was 13.7 ( SD 2.3 ) yr, and the mean BMI -SDS was + 3.4 ( SD 0.5 ). INTERVENTIONS The intervention included metformin 1 g in the morning and 500 mg in the evening vs. placebo for 6 months. MAIN OUTCOME MEASURE The main outcome measure was a reduction in BMI -SDS at 6 months. Secondary outcomes included insulin and glucose levels from oral glucose tolerance tests, alanine aminotransferase ( ALT ), and adiponectin to leptin ratio ( ALR ) at 3 and 6 months. RESULTS Metformin was associated with a significant reduction in BMI -SDS compared with placebo at 6 months [ mean difference -0.1 SD ( 95 % confidence interval -0.18 to -0.02 ), P = 0.02 ]. Significant improvements at 3 months were found in the metformin group : fasting glucose, -0.16 mmol/liter ( -0.31 to -0.00 ), P = 0.047 ; ALT, 19 % ( 5 - 36 % ), P = 0.008 ; and ALR, 32 % ( 4 - 67 % ), P = 0.02. CONCLUSIONS Metformin therapy has a beneficial treatment effect over placebo for BMI -SDS, fasting glucose, ALT, and ALR ratio at 3 months, with changes in BMI -SDS sustained at 6 months Efficacy and Safety of Linagliptin Co-Administered with Low-Dose Metformin Once Daily Versus High-Dose Metformin Twice Daily in Treatment-Naïve Patients with Type 2 Diabetes: a Double-Blind Randomized Trial Introduction The aim of this study was to investigate the efficacy and safety of linagliptin + low-dose ( LD ) metformin once daily versus high-dose ( HD ) metformin twice daily in treatment-naïve patients with type 2 diabetes. Methods Patients ( n = 689 ) were r and omized ( 1:1 ) to double-blind treatment with linagliptin 5 mg + LD metformin ( 1000 mg ) or HD metformin ( 2000 mg ) for 14 weeks. Metformin was initiated at 500 mg/day and up-titrated within 2 weeks ; the dose then remained unchanged. The primary endpoint was change in glycated hemoglobin ( HbA1c ) from baseline to Week 14 in patients who tolerated a daily metformin dose of ≥1000 mg after 2 weeks. Results At Week 14, HbA1c changed from a mean baseline of 8.0 % ( 64 mmol/mol ) by −0.99 % ( −11 mmol/mol ) for linagliptin + LD metformin, and −0.98 % ( −11 mmol/mol ) for HD metformin [ treatment difference −0.01 % ( 95 % confidence interval −0.13, 0.12 ) ( 0 mmol/mol ), P = 0.8924 ]. The proportion of patients who achieved HbA1c < 7.0 % ( 53 mmol/mol ) without occurrence of moderate or severe gastrointestinal ( GI ) events ( including abdominal pain, nausea, vomiting, diarrhea, and decreased appetite ) was the same in both groups ( 51.3 % for both ). Although the occurrence of moderate or severe GI events was similar, the linagliptin + LD metformin group had fewer mild GI events ( 18.5 % versus 24.3 % ). The incidence of hypoglycemia was low in both groups. Conclusion Linagliptin + LD metformin combination showed similar efficacy and safety to HD metformin. This combination may be an alternative treatment option in patients who may have difficulty tolerating metformin doses > 1000 mg/day. Funding Boehringer Ingelheim Reliability of the PEDro scale for rating quality of randomized controlled trials. BACKGROUND AND PURPOSE Assessment of the quality of r and omized controlled trials ( RCTs ) is common practice in systematic review s. However, the reliability of data obtained with most quality assessment scales has not been established. This report describes 2 studies design ed to investigate the reliability of data obtained with the Physiotherapy Evidence Data base ( PEDro ) scale developed to rate the quality of RCTs evaluating physical therapist interventions. METHOD In the first study, 11 raters independently rated 25 RCTs r and omly selected from the PEDro data base. In the second study, 2 raters rated 120 RCTs r and omly selected from the PEDro data base, and disagreements were resolved by a third rater ; this generated a set of individual rater and consensus ratings. The process was repeated by independent raters to create a second set of individual and consensus ratings. Reliability of ratings of PEDro scale items was calculated using multirater kappas, and reliability of the total ( summed ) score was calculated using intraclass correlation coefficients ( ICC [ 1,1 ] ). RESULTS The kappa value for each of the 11 items ranged from.36 to.80 for individual assessors and from.50 to.79 for consensus ratings generated by groups of 2 or 3 raters. The ICC for the total score was.56 ( 95 % confidence interval=.47-.65 ) for ratings by individuals, and the ICC for consensus ratings was.68 ( 95 % confidence interval=.57-.76 ). DISCUSSION AND CONCLUSION The reliability of ratings of PEDro scale items varied from " fair " to " substantial, " and the reliability of the total PEDro score was " fair " to " good. The effect of comprehensive lifestyle intervention or metformin on obesity in young women. BACKGROUND AND AIM Young women are at high risk of weight gain but few weight management interventions have been investigated in this group. This study aim ed to determine the effect of metformin on body weight, body composition, metabolic risk factors and reproductive hormone levels in overweight or obese young women compared to placebo and comprehensive lifestyle intervention. METHODS AND RESULTS 203 overweight or obese young women ( BMI 33.2+/-0.3 kg/m², age 28+/-0.3 years ) were r and omised to 1500 mg/day metformin ( M ) plus general lifestyle advice, placebo ( P ) plus general lifestyle advice or comprehensive lifestyle intervention including structured diet, exercise and behavioural therapy ( L ) for 12-weeks. At 12-weeks, linear mixed models found that L group had greater weight loss ( -4.2+/-0.4 kg ) compared to M ( -1.0+/-0.4 kg ) and P groups ( -0.2+/-0.3 kg ) ( P < 0.0001 ). Weight loss between M and P groups were not significantly different. Attrition rate was 48 % for L, 34 % for M and 29 % for P ( P = 0.08 ). Intention-to-treat analysis showed that 10 % ( 8/79 ) of the subjects in P group had gained weight ( > 3 % ), compared to 3 % ( 2/65 ) from M group and none ( 0/59 ) from L group ( P < 0.001 ). The L group had the greatest decrease in waist circumference ( -5.2+/-0.7 cm ) and fat mass ( -5.4+/-0.7 kg ) compared to the other groups ( P < 0.05 ). No significant time-by-group effects were seen in plasma lipids, SHBG, testosterone, blood pressure, serum folate, serum ferritin and serum vitamin B12. CONCLUSION Lifestyle intervention was more effective in reducing body weight and improving body composition compared to metformin among healthy overweight or obese young women', "INTRODUCTION Fall risk screening tools are frequently used as a part of falls prevention programs in hospitals. Design -related bias in evaluations of tool predictive accuracy could lead to overoptimistic results, which would then contribute to program failure in practice. Use of the 'STRATIFY' falls risk assessment in patients recovering from acute stroke. OBJECTIVES To investigate the predictive validity and reliability of the STRATIFY falls risk assessment tool as applied to patients recovering from acute stroke. DESIGN Prospect i ve cohort study. SETTING Six stroke rehabilitation units in the North of Engl and. SUBJECTS All patients with a diagnosis of acute stroke admitted to the participating stroke units during a 6-month study period. ASSESSMENT on admission, falls risk ( STRATIFY ), disability ( Barthel index ), mobility ( Rivermead mobility index ), cognitive impairment ( abbreviated mental test score ) and visual neglect ( Albert's test ) were assessed. Then, STRATIFY was completed weekly and within 48 h of anticipated discharge. Consenting patients were contacted at 3 months after discharge to determine falls. OUTCOME MEASURES Occurrence of a fall within 28 days of the baseline STRATIFY ( in-patient study ), falls in the first 3 months after discharge ( post-discharge study ) and falls during stroke unit stay ( reliability study ). RESULTS From 387 patients admitted to the participating units during the study period, 225 contributed to the 28 day in-patient study, and 234 were followed up at 3 months after discharge. STRATIFY performed poorly in predicting falls in the first 28 days ( sensitivity 11.3 % and specificity 89.5 % ) and after discharge ( sensitivity 16.3 % and specificity 86.4 % ). Agreement was'fair'between baseline and discharge scores ( kappa = 0.263 ) and'good'between the pre-hospital discharge score and that obtained in the week preceding discharge ( kappa = 0.639 ). CONCLUSION STRATIFY performed poorly as a predictor of falls in a heterogeneous population of stroke patients. There is a need for a disease-specific rather than a generic falls risk assessment tool Effectiveness of targeted falls prevention programme in subacute hospital setting: randomised controlled trial Abstract Objective To assess the effectiveness of a targeted, multiple intervention falls prevention programme in reducing falls and injuries related to falls in a subacute hospital. Design R and omised controlled trial of a targeted multiple intervention programme implemented in addition to usual care compared with usual care alone. Setting Three subacute wards in a metropolitan hospital specialising in rehabilitation and care of elderly patients. Participants 626 men and women aged 38 to 99 years ( average 80 years ) were recruited from consecutive admissions to subacute hospital wards. Intervention Falls risk alert card with information brochure, exercise programme, education programme, and hip protectors. Main outcome measures Incidence rate of falls, injuries related to falls, and proportion of participants who experienced one or more falls during their stay in hospital. Results Participants in the intervention group ( n = 310 ) experienced 30 % fewer falls than participants in the control group ( n = 316 ). This difference was significant ( Peto log rank test P = 0.045 ) and was most obvious after 45 days of observation. In the intervention group there was a trend for a reduction in the proportion of participants who experienced falls ( relative risk 0.78, 95 % confidence interval 0.56 to 1.06 ) and 28 % fewer falls result ed in injury ( log rank test P = 0.20 ). Conclusions A targeted multiple intervention falls prevention programme reduces the incidence of falls in the subacute hospital setting Internal validation of predictive models: efficiency of some procedures for logistic regression analysis. The performance of a predictive model is overestimated when simply determined on the sample of subjects that was used to construct the model. Several internal validation methods are available that aim to provide a more accurate estimate of model performance in new subjects. We evaluated several variants of split- sample, cross-validation and bootstrapping methods with a logistic regression model that included eight predictors for 30-day mortality after an acute myocardial infa rct ion. R and om sample s with a size between n = 572 and n = 9165 were drawn from a large data set ( GUSTO-I ; n = 40,830 ; 2851 deaths ) to reflect modeling in data sets with between 5 and 80 events per variable. Independent performance was determined on the remaining subjects. Performance measures included discriminative ability, calibration and overall accuracy. We found that split- sample analyses gave overly pessimistic estimates of performance, with large variability. Cross-validation on 10 % of the sample had low bias and low variability, but was not suitable for all performance measures. Internal validity could best be estimated with bootstrapping, which provided stable estimates with low bias. We conclude that split- sample validation is inefficient, and recommend bootstrapping for estimation of internal validity of a predictive logistic regression model Further validation of the Elderly Mobility Scale for measurement of mobility of hospitalized elderly people Objective : To further assess the validity and inter-rater reliability of the Elderly Mobility Scale ( EMS ). Also whether the scale reflects elderly people's perceptions regarding their mobility, and whether it can predict discharge destination, or likelihood of falling. Design : Question naire-based study completed on admission and weekly after this on all patients referred to physiotherapy for mobility problems over the course of one month. Setting : Care of the elderly wards in the Bristol General Hospital. Subjects : Sixty-six patients ( ages 66 - 69 years, 66 % female ) were included in the validity study. Nineteen patients ( ages 71 - 95 years, 47 % female ) were included in the inter-rater reliability study. Interventions : EMS, Barthel and patients'perceptions of mobility were tested with routine physiotherapy treatment carried out as necessary. Main outcome measures : Concurrent validity was assessed by correlating EMS scores with Barthel scores using Spearman's test. Inter-rater reliability was also tested using a Spearman's correlation. EMS scores of patients were also evaluated in conjunction with whether or not they fell and their destination on discharge. Results : A significant correlation between EMS and Barthel scores indicated concurrent validity. Inter-rater reliability was demonstrated on 19 patients with a significant correlation between scores. No predictive validity could be ascribed to EMS in terms of discharge destination or likelihood of falling. Results do indicate a possible predictive validity of the functional reach component of the EMS regarding the risk of future falls. Conclusions : The EMS was found to be a valid scale with good inter-rater reliability that could be readily applied during daily clinical work. However, it was found to have no predictive validity in terms of falling or discharge destination A randomized trial of identification bracelets to prevent falls among patients in a rehabilitation hospital. This purpose of this study was to determine whether an identification bracelet is effective in preventing falls among high-risk patients who are undergoing in-patient physical rehabilitation. A stratified, r and omized, balanced controlled clinical trial was conducted ; participants were blinded as to the outcome and the study hypothesis. All patients having one or more risk factors that predisposed them to falls were r and omized to receive either a blue identification bracelet or no bracelet. The identification bracelet was intended to increase patients'vigilance about falling. Two risk strata were specified. The high risk stratum consisted of patients with stroke or ataxia, urinary incontinence, or a history of falls. The low risk stratum comprised patients older than 80 years and those on one or more medications that had been identified as contributing to an individual's risk of falling. This report presents the effect of the identification bracelet only among persons in the high-risk stratum. Over 1 year, 65 high-risk subjects were r and omized to receive the blue identification bracelet and 69 high-risk subjects were controls. In the intervention group, 27 persons ( 41 % ) fell at least once, whereas in the control group 21 persons ( 30 % ) fell at least once yielding a hazard ratio of 1.3 ( 95 % confidence interval : 0.8 to 2.4 ). These results suggest that the identification system was of no benefit in preventing falls among high-risk persons Prediction of falls using a risk assessment tool in the acute care setting Background The British STRATIFY tool was previously developed to predict falls in hospital. Although the tool has several strengths, certain limitations exist which may not allow generalizability to a Canadian setting. Thus, we tested the STRATIFY tool with some modification and re-weighting of items in Canadian hospitals. Methods This was a prospect i ve validation cohort study in four acute care medical units of two teaching hospitals in Hamilton, Ontario. In total, 620 patients over the age of 65 years admitted during a 6-month period. Five patient characteristics found to be risk factors for falls in the British STRATIFY study were tested for predictive validity. The characteristics included history of falls, mental impairment, visual impairment, toileting, and dependency in transfers and mobility. Multivariate logistic regression was used to obtain optimal weights for the construction of a risk score. A receiver-operating characteristic curve was generated to show sensitivities and specificities for predicting falls based on different threshold scores for considering patients at high risk. Results Inter-rater reliability for the weighted risk score indicated very good agreement ( inter-class correlation coefficient = 0.78 ). History of falls, mental impairment, toileting difficulties, and dependency in transfer / mobility significantly predicted fallers. In the multivariate model, mental status was a significant predictor ( P < 0.001 ) while history of falls and transfer / mobility difficulties approached significance ( P = 0.089 and P = 0.077 respectively ). The logistic regression model led to weights for a risk score on a 30-point scale. A risk score of 9 or more gave a sensitivity of 91 % and specificity of 60 % for predicting who would fall. Conclusion Good predictive validity for identifying fallers was achieved in a Canadian setting using a simple-to-obtain risk score that can easily be incorporated into practice Development and evaluation of evidence based risk assessment tool (STRATIFY) to predict which elderly inpatients will fall: case-control and cohort studies Abstract Objectives : To identify clinical characteristics of elderly in patients that predict their chance of falling ( phase 1 ) and to use these characteristics to derive a risk assessment tool and to evaluate its power in predicting falls ( phases 2 and 3 ). Design : Phase 1 : a prospect i ve case-control study. Phases 2 and 3 : prospect i ve evaluations of the derived risk assessment tool in predicting falls in two cohorts. Setting : Elderly care units of St Thomas's Hospital ( phase 1 and 2 ) and Kent and Canterbury Hospital ( phase 3 ). Subjects : Elderly hospital in patients ( aged \ue42165 years ) : 116 cases and 116 controls in phase 1, 217 patients in phase 2, and 331 in phase 3. Main outcome measures : 21 separate clinical characteristics were assessed in phase 1, including the abbreviated mental test score, modified Barthel index, a transfer and mobility score obtained by combining the transfer and mobility sections of the Barthel index, and several nursing judgments. Results : In phase 1 five factors were independently associated with a higher risk of falls : fall as a presenting complaint ( odds ratio 4.64 ( 95 % confidence interval 2.59 to 8.33 ) ; a transfer and mobility score of 3 or 4 ( 2.10 ( 1.22 to 3.61 ) ) ; and primary nurses'judgment that a patient was agitated ( 20.9 ( 9.62 to 45.62 ) ), needed frequent toileting ( 2.48 ( 1.08 to 5.70 ) ), and was visually impaired ( 3.56 ( 1.26 to 10.05 ) ). A risk assessment score ( range 0 - 5 ) was derived by scoring one point for each of these five factors. In phases 2 and 3 a risk assessment score > 2 was used to define high risk : the sensitivity and specificity of the score to predict falls during the following week was 93 % and 88 % respectively in phase 2 and 92 % and 68 % respectively in phase 3. Conclusion : This simple risk assessment tool predicted with clinical ly useful sensitivity and specificity a high percentage of falls among elderly hospital in patients Predicting which patient will fall again... and again. In order to compare the characteristics, preventive interventions and outcomes of single and multiple fallers, a retrospective cross-sectional study was conducted in a 680-bed acute-care hospital in Western Australia. Fifty patients falling more than once ( multiple fallers ) were r and omly selected from all patients reported to have fallen between 1 July 1989 and 31 December 1989, and age-sex matched with 50 patients falling once in the trial period ( single fallers ). In total, 382 in- patients were reported to have sustained 578 falls in the 6-month trial period. Fifty-two per cent of these falls involved multiple fallers. An analysis of the 100 single and multiple fallers showed that single fallers were more likely to have fallen from their bed ; be discharged home from hospital ; and be clinical ly deteriorating at the time of the fall. Multiple fallers were more likely to be transferred to a long-term nursing facility after discharge from hospital ; suffer blindness/poor vision ; be se date d post fall ; be ordered to be restrained following a fall ; and be hospitalized for longer periods. There was also a tendency for multiple fallers to repeat the type and location of the fall on successive falls. Stepwise logistic regression showed that falling from the bed on the first fall predicted remaining a single faller. Being ordered to be restrained following the first fall and hospitalized for longer periods predicted the patient would fall repeatedly. Further analytical research incorporating an exp and ed number of independent variables is needed to allow confident assertions of causality. To test the effectiveness of preventive measures, a prospect i ve longitudinal study is required Use of initial risk assessment and recording as the main nursing intervention in identifying risk of falls. The consequences of falls among hospital patients are a great problem, for the patient, the family and society, and cost billions of dollars. In Sweden, almost one-third of all hip fractures occur in the hospital population. Despite this, very few prevention strategies have been developed and tested. In this study, a risk assessment and recording programme in relation to the risk of falling among patients in a geriatric department at a Swedish hospital was implemented. The records of all patients admitted to a geriatric unit during one year, and a stratified r and om sample of patient records, constituting the control group from the year before, were review ed. No recording of assessment s regarding the patients'risk of falling, and no preventive nursing interventions, were found in the records of the control group. The study group, however, increased the recording of risk assessment to 96 %. Only implemented nursing interventions were found in the patients'records, despite the fact that Swedish law makes it obligatory for the registered nurse to record both the planning and implementation of nursing care. In the study group there were explicit descriptions of problems of concern for nursing regarding the patients'risk of falling in less than one-third of the records, the nursing care plans were rare, and the evaluations were not satisfactory. Nursing interventions consisted mostly of information or education, promotion of patient participation, and structuring of the environment. There was no agreement on any st and ard-care plan. Recording of falls was found more often in the study group than in the control group ( probably due to more careful recording ), but the proportion of injuries in relation to falls was higher in the control group. The results of this study may be used as a baseline for developing a nursing strategy and documentation relating to falls Using targeted risk factor reduction to prevent falls in older in-patients: a randomised controlled trial. BACKGROUND falls and related injuries are known to be a significant problem for older people. There is evidence that identifying and addressing individual risk factors can reduce the incidence of falls in the community but no evidence of the effectiveness of targeted risk factor reduction methods applied to hospital in- patients. OBJECTIVE to test the efficacy of a targeted risk factor reduction core care plan in reducing risk of falling while in hospital. DESIGN a group ( ward ) r and omised trial. SETTING elderly care wards and associated community units of a district general hospital in the North of Engl and. SUBJECTS all elderly patients who received care in eight wards and community units during a 12-month study period. METHODS matched pairs of wards were r and omly allocated to intervention or control groups. In the intervention wards, staff used a pre-printed care plan for patients identified as at risk of falling and introduced appropriate remedial measures. Numbers of falls in each group were then compared. RESULTS after introduction of the care plan there was a significant reduction in the relative risk of recorded falls on intervention wards ( relative risk 0.79, 95 % CI 0.65 - 0.95 ) but not on control wards ( RR 1.12, 95 % CI 0.96 - 1.31 ). The difference in change between the intervention wards and control wards was highly significant ( RR 0.71, 95 % CI 0.55 - 0.90, P = 0.006 ). There was no significant reduction in the incidence of falls-related injuries. CONCLUSION the use of a core care plan targeting risk factor reduction in older hospital in- patients was associated with a reduction in the relative risk of recorded falls Falls prevention: the efficacy of a bed alarm system in an acute-care setting. The present study examined the clinical efficacy of a bed alarm system in reducing falls from bed on a geriatric evaluation and treatment unit. A nine-month case-controlled study was design ed, in which 70 patients ( 60 women, 10 men ; mean age 84 years, range 67 - 97 years ) at increased risk for bed falls were r and omly assigned to either an experimental or a control group. Subjects in the experimental group ( n = 35 ) received a bed alarm system and those in the control group ( n = 35 ) did not. Outcome measures included bed falls, performance of the bed alarm system, and staff attitudes toward the use of the system. Although results failed to demonstrate a statistical difference in bed falls between the experimental ( n = 1 ) and control ( n = 4 ) groups ( p = 1.00 ), there was a clinical trend toward reduced falls in the experimental group. The system functioned properly, activating an alarm in all instances when patients were transferring from bed, and with the exception of one case, nurses could respond in a timely fashion to assist patients and prevent bed falls. The system did not produce any adverse effects in patients, nor did the device interfere with the rendering of medical care. The system was well accepted by patients, families, and nurses. These data suggest that bed alarm systems are beneficial in guarding against bed falls and are an acceptable method of preventing falls A new instrument for targeting falls prevention interventions was accurate and clinically applicable in a hospital setting. BACKGROUND AND OBJECTIVE To describe the diagnostic accuracy and practical application of the Peter James Centre Falls Risk Assessment Tool ( PJC-FRAT ), a multidisciplinary falls risk screening and intervention deployment instrument. METHODS In phase 1, the accuracy of the PJC-FRAT was prospect ively compared to a gold st and ard ( the STRATIFY ) on a cohort of subacute hospital patients ( n = 122 ). In phase 2, the PJC-FRAT was temporally reassessed using a subsequent cohort ( n = 316 ), with results compared to those of phase 1. Primary outcomes were falls ( events ), fallers ( patients who fell ), and hospital completion rates of the PJC-FRAT. RESULTS In phase 1, PJC-FRAT accuracy of identifying fallers showed sensitivity of 73 % ( bootstrap 95 % confidence interval CI = 55, 90 ) and specificity of 75 % ( 95 % CI = 66, 83 ), compared with the STRATIFY ( cutoff > or = 2/5 ) sensitivity of 77 % ( 95 % CI = 59, 92 ) and specificity of 51 % ( 95 % CI = 41, 61 ). This difference was not significant. In phase 2, accuracy of nursing staff using the PJC-FRAT was lower. PJC-FRAT completion rates varied among disciplines over both phases : nurses and physiotherapists, > or = 90 % ; occupational therapists, > or = 82 % ; and medical officers, > or = 57 %. CONCLUSION The PJC-FRAT was practical and relatively accurate as a predictor of falls and a deployment instrument for falls prevention interventions, although continued staff education may be necessary to maintain its accuracy Fall risk assessment: a prospective investigation of nurses' clinical judgement and risk assessment tools in predicting patient falls. A prospect i ve cohort study was used to determine the reliability and validity of two fall risk assessment tools and nurses'clinical judgement in predicting patient falls. The study wards comprised two aged care and rehabilitation wards within a 570 bed acute care tertiary teaching hospital in Western Australia. Instrument testing included test-retest reliability and calculations of sensitivity, specificity, positive predictive value, negative predictive value and accuracy. The test retest reliability of all methods was good. In this setting, the three methods of assessing fall risk showed good sensitivity but poor specificity. Also, all methods had limited accuracy, and overall, exhibited an inability to adequately discriminate between patient population s at risk of falling and those not at risk of falling. Consequently, neither nurses'clinical judgement nor the fall risk assessment tools could be recommended for assessing fall risk in this clinical setting Using the Downton index to predict those prone to falls in stroke rehabilitation. BACKGROUND AND PURPOSE Falls are a major complication in inpatient stroke rehabilitation. An important issue in preventive strategies is the early identification of those at risk. This study aim ed at assessing the fall-prediction accuracy of an easily administered fall risk index in stroke rehabilitation. METHODS A consecutive series of 135 patients admitted to a geriatric stroke rehabilitation unit was studied. A score on the Downton fall risk index was obtained from the admission assessment data and used as a predictive indicator of the risk of falls. The patients'falls were prospect ively recorded during their rehabilitation stay. The correlation between falls and the predicted risk was assessed by means of survival analysis and a multiple regression analysis, adjusting for the time of observation. RESULTS The risk of falls as a function of the time observed was significantly greater among those predicted to be at high risk ( index score > or = 3 ) than among the others ( P =.009, log-rank test ; odds ratio, 2.9 ). Furthermore, the number of falls during rehabilitation stay was moderately correlated ( R =.57 ) with the fall risk index sum when adjusted as for the time of observation. The sensitivity of the fall prediction as to outcome was 91 %, whereas the specificity was limited to 27 %. CONCLUSIONS A moderately high correlation was found between the predicted and the observed risk of falls in stroke rehabilitation when the Downton fall risk index was used. However, a low specificity rate limits the accuracy of the prediction Hospital falls: development of a predictive model for clinical practice. A retrospective case-control study related to falls was conducted at an 1,120-bed acute care tertiary hospital. The case ( fall ) sample consisted of 102 falls and 236 control ( nonfall ) charts during a 1-month period. An instrument developed by Hendrich ( 1988 ) was modified for use in the study. Demographic data and risk factors were recorded. Descriptive statistics included risk factor percentages for each sample and the corresponding univariate relative risks. Logistic regression was used to develop a multivariate risk factor model with seven risk factors. The significant risk factors were recent history of falls, depression, altered elimination patterns, dizziness or vertigo, primary cancer diagnosis, confusion, and altered mobility. The adjusted relative risks were converted to risk points to be used to assess a patient's level of fall risk. Within the data set, a sensitivity of 77 % ( 79 of 102 ) and specificity of 72 % ( 169 of 236 ) were calculated. The model was cross-vali date d in a 1987 data set with a sensitivity of 83 % ( 59 of 71 ) and specificity of 66 % ( 106 of 161 ) Validation of the Hendrich II Fall Risk Model: a large concurrent case/control study of hospitalized patients. This large case/control study of fall and non-fall patients, in an acute care tertiary facility, was design ed to concurrently test the Hendrich Fall Risk Model. Cases and controls ( 355/780 ) were r and omly enrolled and assessed for more than 600 risk factors ( intrinsic/extrinsic ). St and ardized instruments were used for key physical attributes as well as clinician assessment s. A risk factor model was developed through stepwise logistic regression. Two-way interactions among the risk factors were tested for significance. The best fitting model included 2 Log L chi square statistic as well as sensitivity and specificity values retrospectively. The result of the study is an easy to use vali date d Hendrich Fall Risk Model with eight assessment parameters for high-risk fall identification tested in acute care environments Evaluation of the STRATIFY falls prediction tool on a geriatric unit. Accurate prediction of fall-prone hospitalized older adults may be integral to reducing falls. The STRATIFY, a simple 5-point falls prediction tool, was prospect ively vali date d on a Geriatric Assessment and Rehabilitation Unit as a one-time initial predictor of patients likely to fall. Sensitivity and specificity were lower than in the original British study. Introducing risk assessment s vali date d elsewhere on a patient care unit or on a hospital-wide scale requires caution Falls prevention revisited: a call for a new approach. BACKGROUND Patient falls constitute a major threat to health services'ability to provide care. Previous studies confirm that nurses can identify patients at risk and that a preventative programme can reduce the rate of falls but few studies have been evaluated over time. AIMS AND OBJECTIVES A study was undertaken to test a Falls Prevention Programme in an acute medical area that was re-evaluated 5 years later to determine if the effects were sustainable. DESIGN The design included two groups of patients admitted before and after the programme. Variables such as staffing, equipment, environment and routines were controlled. However, because of ethical approval constraints, some variables such as age, mental status, mobility and gender were not. METHODS The programme included a risk assessment tool, a choice of interventions, a graphic that alerted others to'at risk patients'and simple patient and staff education. Data were collected using incident forms and a formula was used to calculate a rate of falls. A non-paired t-test compared rates and anova examined the relationship of age, gender, mobility and mental status on the incidence of falls. Control graphs determined the stability of the process. RESULTS The falls rate was significantly reduced. Control graphs demonstrate that the process achieved greater control with less variation. In the next 5 years the falls rate increased to preprogramme levels and control graphs demonstrated that the process was no longer controlled. Compliance with the programme had deteriorated. CONCLUSIONS The practice review considered skill mix, patient activity and acuity but provided no definitive answers to explain non-compliance. The implication s to nursing are discussed. RELEVANCE TO CLINICAL PRACTICE Clinicians are called to conduct more rigorous research into falls prevention but it may be more useful to direct research towards examining nursing work and increasing nurse autonomy in falls prevention A comparative study of the use of four fall risk assessment tools on acute medical wards. OBJECTIVES To compare the effectiveness of four falls risk assessment tools ( STRATIFY, Downton, Tullamore, and Tinetti ) by using them simultaneously in the same environment. DESIGN Prospect i ve, open, observational study. SETTING Two acute medical wards admitting predominantly older patients. PARTICIPANTS One hundred thirty-five patients, 86 female, mean age+/-st and ard deviation 83.8+/-8.01 ( range 56 - 100 ). MEASUREMENTS A single clinician prospect ively completed the four falls risk assessment tools. The extent of completion and time to complete each tool was recorded. Patients were followed until discharge, noting the occurrence of falls. The sensitivity, specificity, negative predictive accuracy, positive predictive accuracy, and total predictive accuracy were calculated. RESULTS The number of patients that the STRATIFY correctly identified ( n=90 ) was significantly higher than the Downton ( n=46 ; P<.001 ), Tullamore ( n=66 ; P=.005 ), or Tinetti ( n=52 ; P<.001 ) tools, but the STRATIFY had the poorest sensitivity ( 68.2 % ). The STRATIFY was also the only tool that could be fully completed in all patients ( n=135 ), compared with the Downton ( n=130 ; P=.06 ), Tullamore ( n=130 ; P=.06 ), and Tinetti ( n=17 ; P<.001 ). The time required to complete the STRATIFY tool ( average 3.85 minutes ) was significantly less than for the Downton ( 6.34 minutes ; P<.001 ), Tinetti ( 7.4 minutes ; P<.001 ), and Tullamore ( 6.25 minutes ; P<.001 ). The Kaplan-Meier test showed that the STRATIFY ( log rank P=.001 ) and Tullamore tools ( log rank P<.001 ) were effective at predicting falls over the first week of admission. The Downton ( log rank P=.46 ) and Tinetti tools ( log rank P=.41 ) did not demonstrate this characteristic. CONCLUSION Significant differences were identified in the performance and complexity between the four risk assessment tools studied. The STRATIFY tool was the shortest and easiest to complete and had the highest predictive value but the lowest sensitivity Factors associated with falling in elderly hospital patients. Forty-four patients aged 65 years and over who fell whilst in an acute hospital and 44 patients who did not fall during their hospital stay underwent structured medical examinations to identify factors associated with falling. The control subjects were matched for age ( + /- 3 years ), sex, patient type, and primary diagnosis. The examination was based on established assessment s of posture, balance and gait, the musculoskeletal system, vision, cardiovascular status, and neurological function. Bivariate analyses revealed seven assessment measures that were significantly associated with falls : cognitive impairment, particularly impaired orientation ; evidence of previous cerebrovascular accident ; incoordination as measured clinical ly ; inability to perform the'Get-up- and -go'test, especially an inability to turn around after a 5-metre walk, and the use of psycho-active medications. Of these variables, impaired orientation, psycho-active drug use, evidence of stroke, and impaired performance in the'Get-up- and -go'test were included in a stepwise logistic regression which correctly classified 80 % of the patients into faller and non-faller groups. Falling was also related to the number of these identified risk factors. These findings suggest that a simple screening protocol, taking about 5 min to complete, can assist in the identification of patients at risk of falls whilst in hospital", "BACKGROUND The use of cementless acetabular components in total hip arthroplasty has gained popularity over the past decade. Most total hip arthroplasties being performed in North America currently use cementless acetabular components. The objective of this systematic review and meta- analysis was to compare the survivorship and revision rate of cemented and cementless acetabular components utilized in total hip arthroplasty. A comparison of polyethylene wear rates between cemented and cementless cups. A prospective, randomised trial. We selected r and omly a consecutive series of 162 patients requiring hip replacement to receive either a cementless, hemispherical, modular, titanium acetabular cup or a cemented, all-polyethylene cup. These replacements were performed by two surgeons in four general hospitals. The same surgical technique was used and a 26 mm metal-head femoral component was used in every case. After exclusions, 115 hips were studied for differences in rates of wear and osteolysis. The mean clinical follow-up was eight years and the mean radiological follow-up, 6.5 years. The cementless cups wore at a mean rate of 0.15 mm per year and the cemented cups at 0.07 mm per year. This difference was significant ( p < 0.0001 ). Our findings in this mid-term study suggest that cementless cups wear more than cemented cups Long-term survivorship of the Charnley Elite Plus femoral component in young patients. We studied prospect ively the long-term results of the Charnley Elite-Plus femoral stem in 184 consecutive young patients ( 194 hips ). There were 130 men and 54 women with a mean age of 49.1 years ( 21 to 60 ). The predominant diagnosis was osteonecrosis of the femoral head ( 63.6 %, 117 patients ). Clinical and radiological evaluation was undertaken at each follow-up. The mean follow-up was 11.2 years ( 10 to 12 ). The mean pre-operative Harris hip score was 43.4 ( 12 to 49 ) which improved to 91 ( 59 to 100 ) at the final follow-up. The survival of the femoral stem at 12 years was 99 % with revision as the end-point. The mean annual linear wear of the polyethylene liner was 0.17 mm ( 0.13 to 0.22 ). The prevalence of acetabular osteolysis was 10.8 % ( 21 hips ) and osteolysis of the calcar femorale 12.9 % ( 25 hips ). A third-generation cementing technique, accurate alignment of the stem and the use of a 22 mm zirconia head were important factors in the prevention of aseptic loosening of the Elite Plus femoral stem in these high-risk young patients The Porous Coated Anatomic Total Hip Replacement: A Ten to Fourteen-Year Follow-up Study of a Cementless Total Hip Arthroplasty Background : We previously reported our two and five‐year results of arthroplasty with the Porous Coated Anatomic total hip prosthesis. We now report on the performance of this prosthesis at ten to fourteen years. Methods : The results of 311 total hip replacements in which a Porous Coated Anatomic prosthesis was inserted without cement in 279 patients were analyzed prospect ively. The average age of the patients at the time of the replacement was sixty-one years ( range, twenty to eighty‐one years ). Sixty‐four patients ( seventy-six hips ) died postoperatively. Forty‐five patients ( forty‐seven hips ) were lost to follow‐up, and four were excluded because of their medical condition. One hundred and sixty‐eight patients ( 187 hips ) were followed for ten to fourteen years ( average, twelve years ). Seventeen of those patients ( seventeen hips ) had a revision. Results : The overall survival rate ( with any revision as the end point ) was 90.0 % ± 5.4 % at fourteen years, with an average Harris hip score of 85 ± 14 points. The prevalence of thigh pain was 36 % ( fifty-six of 157 ) in the late period ( more than ten years postoperatively ). Radiographs showed stable fixation, with bone ingrowth, of 83 % ( 130 ) of the 156 acetabular components and 88 % ( 137 ) of the 156 femoral components at the latest follow‐up evaluation. Men had a significantly higher rate of femoral osteolysis than did women ( p < 0.001 ). The rates of acetabular and femoral osteolysis associated with 32‐mm femoral heads ( 49 % [ twenty-three ] of forty-seven and 70 % [ thirty-three ] of forty-seven, respectively ) were significantly higher ( p < 0.01 ) than those associated with 26‐mm heads ( 26 % [ twenty-eight ] of 109 and 30 % [ thirty-three ] of 109, respectively ). Despite this, revision ( removal or exchange of components ) was not directly related to head size ; instead, it was related to polyethylene thickness. Conclusions : There have been persistent problems with the Porous Coated Anatomic hip system, including thigh pain and an increasing prevalence of osteolysis with time. Revision because of aseptic loosening was related more to the thickness of the polyethylene liner than to the size of the femoral head. Femoral heads with a 32-mm diameter did not increase the risk for revision provided that an adequate thickness of polyethylene had been used No differences in outcomes between cemented and uncemented acetabular components after 12–14 years: results from a randomized controlled trial comparing Duraloc with Charnley cups Background Even though there are multiple studies documenting the outcome of the Charnley low-friction arthroplasty as well as abundant studies on uncemented arthroplasties, there is a dearth of comparative studies of the uncemented acetabular component and a cemented component. In this study we aim ed to document the long-term clinical and radiographic outcome as well as component survival in a r and omized controlled trial. Material s and methods Two hundred fifteen patients ( 240 hips ) were r and omly allocated to receive a cemented Charnley cup or uncemented Duraloc 1200 cup. All patients received cemented Charnley stems and were evaluated clinical ly and radiographically after 6 months, and 2, 5, and 10 years. Results Harris Hip Scores improved from 48.3 [ 95 % confidence interval ( CI ) 45.0–51.6 ] to 90.2 [ 95 % CI 87.9–92.6 ] in the Charnley group and from 49.3 [ 95 % CI 86.9–91.3 ] in the Duraloc group at 6 months. After 10 years, the Charnley group ’s Harris Hip Score was 89.8 [ 95 % confidence interval ( CI ) 87.0–92.6 ], and the Duraloc group ’s score was 87.3 ( 95 % CI 84.1–90.6 ). In the radiographic analysis after 10 years, there was no statistical difference in the prevalence of radiographic signs of loosening. Nine cups were revised in the Charnley group, and five cups were removed in the Duraloc group. The difference was not statistically significant. There was no statistical difference between the cups when aseptic loosening was the end-point, nor in survival analyses. Conclusions There is no statistically significant difference in clinical or radiological outcome between the Charnley cup and the Duraloc after 10 years, and no difference in implant survival after 12–14 years. The uncemented Duraloc cup is as good as the cemented Charnley cup after 10 years Results of Porous-Coated Anatomic Total Hip Arthroplasty without Cement at Fifteen Years: A Concise Follow-up of a Previous Report* Abstract : The purpose of this study was to up date the results of a prospect i ve series of primary cementless total hip arthroplasties after a minimum of fifteen years of follow-up. It is one of the first studies of cementless total hip arthroplasties followed for a minimum of fifteen years. One hundred consecutive Porous Coated Anatomic ( PCA ) total hip replacements were implanted between October 1983 and January 1986. Fifty-five patients ( sixty-four hips ) that were alive at a minimum of fifteen years postoperatively are the focus of the present study. At this time of follow-up, at an average of 15.6 years ( range, fifteen to seventeen years ) after the total hip arthroplasty, 17 % ( seventeen hips ) of the entire cohort and 23 % ( fifteen hips ) of the living cohort had undergone revision because of loosening of the acetabular component or osteolysis. Seven percent ( seven hips ) of the entire cohort and 6 % ( four hips ) of the living cohort had undergone revision for loosening of the femoral component or osteolysis. Only four femoral stems had been revised for isolated loosening ( without osteolysis).The PCA femoral component proved to be durable at a minimum of fifteen years postoperatively, while the acetabular component was less durable. Level of Evidence : Therapeutic study, Level IV ( case series [ no, or historical, control group ] ). See Instructions to Authors for a complete description of levels of evidence Long-term clinical and radiological results of the Lord total hip prosthesis. A prospective study. We enrolled 98 patients ( 107 hips ) with a mean age of 47 years ( SD 8.6 ) into a prospect i ve study of the Madreporic Lord THR ; 34 hips had primary and 73 secondary osteoarthritis. After ten years, the survival rate using revision as the endpoint for failure was 70 % ( + /-9 ) for the cup and 98 % ( + /-0.3 ) for the stem. The combined clinical and radiological survival rates were 46 % ( + /-11 ) and 81 % ( + /-10 ), respectively. Osteoporosis due to stress-shielding was observed in the proximal femur. Hips with radiologically dense bone postoperatively showed the most pronounced bone loss. We recommend continued radiological follow-up of patients with this type of implant to allow revision to be performed before there is severe bony destruction of the pelvis The results of the titanium-coated RM acetabular component at 20 years: a long-term follow-up of an uncemented primary total hip replacement. In a prospect i ve study, 93 unselected consecutive uncemented hip arthroplasties were performed in 80 patients using the titanium-coated RM acetabular component and the CLS femoral component. The mean age of the patients at operation was 52 years ( 28 to 81 ). None were lost to follow-up. In the 23 patients who had died ( 26 hips ) only one acetabular component had been revised. In the 57 living patients ( 67 hips ), 13 such revisions had been performed. Of the 14 revisions, seven were for osteolysis, five for loosening and two for infection. Survival analysis of this implant showed a total probability of survival of 83 % ( 95 % confidence interval 73 to 90 ), with all revisions as the endpoint, and a probability of 94 % ( 95 % confidence interval 87 to 98 ) with revision for aseptic loosening as the endpoint, indicating reliable long-term fixation of the titanium-coated RM acetabular component Results of Charnley total hip arthroplasty at a minimum of thirty years. A concise follow-up of a previous report. The purpose of the current study was to up date the results of a prospect i ve, single-surgeon series of primary Charnley total hip arthroplasties performed with cement. This investigation is one of the first studies in which hips treated with total hip arthroplasty with cement were followed for a minimum of thirty years. Twenty-seven patients ( thirty-four [ 10.3 % ] of the hips in the initial study group ) were alive at a minimum of thirty years postoperatively. These patients served as the focus of the present study. Revision because of aseptic loosening of the acetabular component was performed in 7.3 % ( twenty-three ) of the hips from the original study group ( excluding those revised because of infection or dislocation ) and 26 % ( eight ) of the hips in the living cohort. Revision because of aseptic loosening of the femoral component was performed in 3.2 % ( ten ) of the hips from the original study group ( excluding those revised because of infection or dislocation ) and 10 % ( three ) of the hips in the living patients. Since the twenty-five-year review, three hips were revised ( one because of acetabular loosening, one because of femoral loosening, and one because of instability ). This end- result study demonstrated the remarkable durability of cemented Charnley total hip replacements over a span of three decades, with 88 % of the original prostheses intact at the time of the final follow-up or at the patient's death Comparison of total hip replacement with and without cement in patients younger than 50 years of age: the results at 18 years. There have been comparatively few studies of the incidence of osteolysis and the survival of hybrid and cementless total hip replacements ( THRs ) in patients younger than 50 years of age. We prospect ively review ed 78 patients ( 109 hips ) with a hybrid THR having a mean age of 43.4 years ( 21 to 50 ) and 79 patients ( 110 hips ) with a cementless THR with a mean age of 46.8 years ( 21 to 49 ). The patients were evaluated clinical ly using the Harris hip score, the Western Ontario and McMaster Universities ( WOMAC ) osteoarthritis score and the University of California, Los Angeles ( UCLA ) activity score. Radiographs and CT scans were assessed for loosening and osteolysis. The mean follow-up was for 18.4 years ( 16 to 19 ) in both groups. The mean post-operative Harris hip scores ( 91 points versus 90 points ), the mean WOMAC scores ( 11 points versus 13 points ) and UCLA activity scores ( 6.9 points versus 7.1 points ) were similar in both groups. The revision rates of the acetabular component ( 13 % versus 16 % ) and the femoral component ( 3 % versus 4 % ), and the survival of the acetabular component ( 87 % versus 84 % ) and the femoral component ( 97 % versus 96 % ) were similar in both groups. Although the long-term fixation of the acetabular metallic shell and the cemented and cementless femoral components was outst and ing, wear and peri-acetabular osteolysis constitute the major challenges of THR in young patients Inferior Survival of Hydroxyapatite versus Titanium-coated Cups at 15 Years Hydroxyapatite ( HA ) particles have long been suspected to disintegrate from implant surfaces, become entrapped in joint spaces of orthopaedic bearing couples, and start a cascade leading to progressive polyethylene ( PE ) wear, increased osteolysis, and aseptic loosening. We compared cup revision at 15 years ’ followup in a r and omized group of patients with 26 cementless THA components with titanium ( Ti ) versus first-generation HA coating. We also assessed radiographic PE wear and osteolysis to the 12-year followup or end point revision at a minimum of 5 years ( mean, 10.9 years ; range, 5–12.6 years ). Two Ti-coated cups ( 17 % ) and eight HA-coated cups ( 57 % ) were revised at 15 years ’ followup. Femoral head penetration rate was 0.46 mm/year ( st and ard deviation, 0.26 ) with the HA-coated cups ( n = 12 ) and 0.38 mm/year ( st and ard deviation, 0.14 ) with the Ti-coated cups ( n = 10 ) ; we observed a wide variance of linear wear with the HA-coated cups. We also observed a positive association between high wear rate and revision, and between a high volume of osteolysis and revision. Our findings suggest inferior survival of medium-thickness spray-dried HA-coated cups with individual cases of excessive PE wear and premature cup failure. These findings apply to first-generation modular cups and may not apply to other cup design s and new HA-coating technologies. Level of Evidence : Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence What Works Best, a Cemented or Cementless Primary Total Hip Arthroplasty?: Minimum 17-year Followup of a Randomized Controlled Trial Background Total hip arthroplasty ( THA ) has been associated with high survival rates, but debate remains concerning the best fixation mode of THA. Questions / purpose sWe conducted a r and omized controlled trial ( RCT ) with 250 patients with a mean age of 64 years between October 1987 and January 1992 to compare the results of cementless and cemented fixation. Patients and Methods Patients were evaluated for revision of either of the components. One hundred twenty-seven patients had died ( 51 % ) and 12 ( 4.8 % ) were lost to followup. The minimum 17-year followup data ( mean, 20 years ; range, 17–21 years ) for 52 patients of the cementless group and 41 patients of the cemented group were available for evaluation. Results Kaplan-Meier survivorship analysis at 20 years revealed lower survival rates of cemented compared with cementless THA. The cementless tapered stem was associated with a survivorship of 99 %. Age younger than 65 years and male gender were predictors of revision surgery. Conclusions The efficacy of future RCTs can be enhanced by r and omizing patients in specific patient cohorts stratified to age and gender in multicenter RCTs. Including only younger patients might improve the efficacy of a future RCT with smaller sample sizes being required. A minimum 10-year followup should be anticipated, but this can be expected to be longer if the difference in level of quality between the compared implants is smaller. Level of Evidence Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence Effects of mechanical compression of a fibrous tissue interface on bone with or without high-density polyethylene particles in a rabbit model of prosthetic loosening. BACKGROUND The mechanisms leading to aseptic loosening of a total hip replacement are not fully understood. A fibrous tissue interface can be present around the implant. Hypothetically, component micromovements can compress this interface and cause increased fluid pressure according to biphasic models. We tested the hypothesis that compression of a fibrous membrane with or without the presence of high-density polyethylene particles leads to bone degradation. METHODS A titanium implant was inserted in forty-five rabbit tibiae, and, after osseous integration was achieved, a fibrous tissue interface was generated. The animals were r and omized to undergo a sham operation, treatment with compression of the fibrous membrane, treatment with high-density polyethylene particles, or treatment with both compression and particles. Morphometric analysis of the surrounding bone was performed on cryostat sections after Giemsa staining and staining of tartrate-resistant acid phosphatase activity. RESULTS Forty specimens were available for analysis ; five tibiae with an infection were excluded. After nine weeks, the controls showed vital bone, whereas the specimens treated with compression showed necrosis of bone and replacement of bone by cartilage in a discontinuous layer ( p < 0.05 for both ) but not fibrous tissue. Treatment with high-density polyethylene particles caused replacement of bone by fibrous tissue ( p < 0.05 ) but not necrosis or cartilage formation. Compression combined with the presence of high-density polyethylene particles caused bone necrosis and loss of bone with replacement by cartilage and fibrous tissue ( p < 0.05 ). CONCLUSIONS In this in vivo study in rabbits, fibrous membrane compression led to bone necrosis and cartilage formation, possibly because of fluid pressure or fluid flow, whereas the presence of high-density polyethylene particles led to the loss of bone with replacement of bone by fibrous tissue. Cartilage formation may be a protective response to fluid pressure and /or fluid flow. Fibrous membrane compression may play an important role in the early stages of loosening of a total hip replacement Matched-pair analysis of cemented and cementless acetabular reconstruction in primary total hip arthroplasty. In a matched-pair study of primary total hip arthroplasty, 45 all-polyethylene cemented acetabular components were compared with 45 cementless, hemispheric, titanium acetabular components. At 9 to 12 years, 1 of the cemented acetabular components was revised for aseptic loosening, and 14 ( 31 % ) were radiographically loose. Nine ( 20 % ) cemented acetabular components had pelvic osteolysis. In the cementless acetabular component group, 2 well-fixed components were revised. No components were radiographically loose, and 3 ( 7 % ) had pelvic osteolysis. Thirty-eight ( 97 % ) of the patients in each group were satisfied with the surgery. The clinical results of the cemented and cementless components were excellent. The cementless components had less loosening ( P <.001 ) than the cemented components Long term results of the Corin C-Fit uncemented total hip arthroplasty in young patients Introduction We conducted a prospect i ve study to evaluate the long-term results after Corin C-Fit uncemented total hip arthroplasty in young patients with hydroxyapatite or porous coated components. Material s and methods We prospect ively followed 36 patients ( 38 hips ) who had Corin C-Fit uncemented total hip arthroplasties by eight experienced consultant surgeons at two centres. The acetabular and femoral components were hydroxyapatite or porous coated. Results The overall 10-year survival rate for the Corin C-Fit arthroplasty was 43 %. The 10-year survivorship for the femoral implant was 56 % and for the acetabular component 59 %. Conclusion The evidence presented in this study suggests that the Corin C-Fit uncemented total hip arthroplasty has one of the highest mid- and long-term failure rates for both femoral and acetabular components in the literature. We believe this implant should not be used and patients who have had this form of total hip arthroplasty should be kept under regular review", 'BACKGROUND Fibromyalgia is characterized by chronic widespread pain, tenderness at muscle and tendon insertions point when digital pressure is applied, sleep disorders, chronic fatigue, depressive episodes, anxiety, and other functional somatic syndromes. OBJECTIVE The aim of this study was to determine whether balneotherapy with mineral waters and mineral-water containing mud is effective in the management of fibromyalgia. Both serum receptors of tumor necrosis factor are influenced by mud pack treatment in osteoarthrotic patients. Several authors have demonstrated the pivotal role of proinflammatory cytokines in inducing progressive cartilage degradation and secondary inflammation of the synovial membrane in osteoarthritis ( OA ). It has recently been established that tumor necrosis factor (TNF)-alpha plays a well-defined role in the pathophysiology of inflammatory joint diseases and that binding to circulating soluble TNF-alpha receptors can inactivate it. We investigated the influence of mud pack treatment, which is able to diminish TNF-alpha serum values, on specific TNF receptor ( sTNF-R ) levels. Thirty-six patients with OA were enrolled and r and omized into two groups. Group A underwent mud pack treatment and group B underwent thermal bath treatment. A group of 20 healthy untreated subjects was used as a control. Blood sample s were collected at baseline and after treatment, and assays of sTNF-R55 and sTNF-R75 were performed in both groups. We found small changes in sTNF-Rs serum values but these were not statistically significant. sTNF-R55 serum values decreased by 0.4 % after the therapy in group A, while in group B the decrease was -17.7 %. sTNF-R75 was reduced by -21.17 % in group A and by -10.6 % in group B. In conclusion, through its thermic and ant/inflammatory activity mud pack treatment shows complex interaction with the most common factors of inflammatory and cartilage degradation. Our results suggest that the thermic component of this natural treatment is mainly involved in modulating inflammatory reaction and cartilage damage through binding of the circulating TNF, which controls the activation of the cells responsible for the production of proinflammatory cytokines Balneotherapy in fibromyalgia: a single blind randomized controlled clinical study We aim ed to evaluate the effectiveness of balneotherapy in fibromyalgia management. Fifty women with fibromyalgia under pharmacological treatment were r and omly assigned to either the balneotherapy ( 25 ) or the control ( 25 ) group. Four patients from the balneotherapy group and one patient from the control group left the study after r and omization. The patients in the balneotherapy group ( 21 ) had 2 thermomineral water baths daily for 2 weeks in Tuzla Spa Center. The patients in the control group ( 24 ) continued to have their medical treatment and routine daily life. An investigator who was blinded to the study arms assessed the patients. All patients were assessed four times ; at the beginning of the study, at the end of the 2nd week, the 1st month, and the 3rd month after balneotherapy. Outcome measures of the study were pain intensity, Fibromyalgia Impact Question naire ( FIQ ), Beck Depression Inventory ( BDI ), patient ’s global assessment, investigator ’s global assessment, SF-36 scores, and tender point count. Balneotherapy was found to be superior at the end of the cure period in terms of pain intensity, FIQ, Beck Depression Inventory, patient ’s global assessment, investigator ’s global assessment scores, and tender point count as compared to the control group. The superiority of balneotherapy lasted up to the end of the 3rd month, except for the Beck Depression Inventory score and the investigator ’s global assessment score. Significant improvements were observed in PF, GH, and MH subscales of SF-36 during the study period in the balneotherapy group ; however, no such improvement was observed in the control group. Balneotherapy was superior only in VT subscale at the end of therapy and at the end of the third month after the therapy as compared to the controls. It was concluded that balneotherapy provides beneficial effects in patients with fibromyalgia Effects of balneotherapy on serum IL-1, PGE2 and LTB4 levels in fibromyalgia patients The purpose of this study was to investigate the clinical effects of balneotherapy in the treatment of Fibromyalgia Syndrome ( FMS ) and to determine if balneotherapy influences serum levels of inflammation markers, IL-1, PGE2 and LTB4. 24 primary fibromyalgia female patients diagnosed according to American College of Rheumatology criteria were included to the study. Their ages ranged between 33 and 55 years. FMS patients were r and omly assigned in two groups as, group 1 ( n = 12 ) and group 2 ( n = 12 ). Group 1 received 20-min bathing, once in a day for five days per week. Patients participated in the study for 3 weeks ( total of 15 sessions ) in Denizli. Group 2 did not receive balneotherapy. FMS patients were evaluated by tenderness measurements ( tender point count and algometry ), Visual Analogue Scale, Beck ’s Depression Index, Fibromyalgia Impact Question naire. Ten healthy women recruited group three as the controls. Serum PGE2, LTB4 and IL1-α levels were measured in all three groups. The biochemical measurements and clinical assessment s were performed before and at the end of general period of therapy. Statistically significant alterations in algometric score, Visual Analogue score, Beck ’s Depression Index and PGE2 levels ( P < 0.001 ), numbers of tender points ( P < 0.01 ) and Fibromyalgia Impact Question naire score ( P < 0.05 ) were found after the balneotherapy between group 1 and 2. Mean PGE2 level of FMS patients were higher compared to healthy control group ( P < 0.0001 ) and decreased after the treatment period, only in group 1 ( P < 0.05 ). As in the group 2 and 3, detectable IL-1 and LTB4 measurements were insufficient, statistical analysis was performed, only in group 1. After balneotherapy IL-1 and LTB4 significantly decreased in group 1 ( P < 0.05 ). In conclusion, balneotherapy is an effective choice of treatment in patients with FMS relieving the clinical symptoms, and possibly influencing the inflammatory mediators The effect of combined therapy (ultrasound and interferential current) on pain and sleep in fibromyalgia Multidisciplinary treatment has proven to be the best therapeutic option to fibromyalgia ( FM ) and physiotherapy has an important role in this approach. Considering the controversial results of electrotherapy in this condition, the aim of this study was to assess the effects of combined therapy with pulsed ultrasound and interferential current ( CTPI ) on pain and sleep in FM. Seventeen patients fulfilling FM criteria were divided into two groups, CTPI and SHAM, and su bmi tted to pain and sleep evaluations. Pain was evaluated by body map ( BM ) of the painful areas ; quantification of pain intensity by visual analog scale ( VAS ) ; tender point ( TP ) count and tenderness threshold ( TT ). Sleep was assessed by inventory and polysomnography ( PSG ). After 12 sessions of CTPI or SHAM procedure, patients were evaluated by the same initial protocol. After treatment, CTPI group showed, before and after sleep, subjective improvement of pain in terms of number ( BM ) and intensity ( VAS ) of painful areas ( P<0.001, both ) ; as well as objective improvement, with decrease in TP count and increase in TT ( P<0.001, both ). Subjective sleep improvements observed after CTPI treatment included decrease in morning fatigue and in non‐refreshing sleep complaint ( P<0.001, both ). Objective ly, PSG in this group showed decrease in sleep latency ( P<0.001 ) and in the percentage of stage 1 ( P<0.001 ), increase in the percentage of slow wave sleep ( P<0.001 ) and in sleep cycle count ( P<0.001 ). Decrease in arousal index ( P<0.001 ), number of sleep stage changes ( P<0.05 ) and wake time after sleep onset ( P<0.05 ), were also observed and no difference regarding pain or sleep parameters were verified after SHAM procedure. This study shows that CTPI can be an effective therapeutic approach for pain and sleep manifestations in FM Function of the hypothalamic adrenal axis in patients with fibromyalgia syndrome undergoing mud-pack treatment. Fibromyalgia ( FM ) is a nonarticular rheumatological syndrome associated with diverse clinical and psychological features. One of the major complaints in FM is reduced pain tolerance, especially in tender points ( TP ) for which patients derive significant benefit from nonsteroidal antiinflammatory drugs or corticosteroids. Patients with FM also have altered reactivity of the hypothalamic pituitary adrenal ( HPA ) axis where the predominant feature is reduced containment of the stress response system through diminished adrenocortical output and feedback resistance. Our results show that mud packs together with antidepressant treatment are able to influence the HPA axis, stimulating increased levels of adrenocorticotropic hormone, cortisol and beta-endorphin serum levels. The discharge of corticoids in the blood and the increase in beta-endorphin serum levels are followed by a reduction in pain symptoms, which is closely related to an improvement in disability, depression and quality of life. It seems that the synergic association between a pharmacological treatment ( trazodone ) and mud packs acts by helping the physiological responses to achieve homeostasis and to rebalance the stress response system. To clarify and optimize the effectiveness of this synergic association, studies involving a larger number of FM patients and a different pharmacological treatment are needed Investigation of the effects of pool-based exercise on fibromyalgia syndrome Objective The aim of this study was to compare pool-based exercise and balneotherapy in fibromyalgia syndrome ( FMS ) patients. Methods Fifty female patients diagnosed with FMS according to the American College of Rheumatism ( ACR ) criteria were r and omly assigned to two groups : group 1 ( n=25 ) with pool-based exercise, and in group 2 ( n=25 ) balneotherapy was applied in the same pool without any exercise for 35 min three times a week for 12 weeks. In both groups, pre- ( week 0 ) and post-treatment ( weeks 12 and 24 ) evaluation was performed by one of the authors, who was blind to the patient group. Evaluation parameters included pain, morning stiffness, sleep, tender points, global evaluation by the patient and the physician, fibromyalgia impact question naire, chair test, and Beck depression inventory. Statistical analysis was done on data collected from three evaluation stages. Results Twenty-four exercise and 22 balneotherapy patients completed the study. Pretreatment ( week 0 ) measurements did not show any difference between the groups. In group 1, statistically significant improvement was observed in all parameters ( P<0.01 ) except for the chair test at both weeks 12 and 24. In group 2, week 12 measurements showed significant improvement in all parameters ( P<0.01 ) except for the chair test and Beck depression inventory. Week 24 evaluation results in group 2 showed significant improvements in pain and fatigue according to visual analogue scale ( VAS ), 5-point scale, number of tender points, algometric and myalgic scores, and patient and physician global evaluation ( P<0.01 and P<0.05, respectively ), while improvements were nonsignificant in morning stiffness, sleep, fibromyalgia impact question naire ( FIQ ), chair test, and Beck depression inventory parameters in this group. Comparison of the two groups based on the post-treatment ( weeks 12 and 24 ) percent changes and difference scores relative to pretreatment ( week 0 ) values failed to show a significant difference between the groups for any parameter except Beck depression inventory ( P<0.01 ). Conclusion The results of our study showed that pool-based exercise had a longer-lasting effect on some of the FMS symptoms, but statistical analysis failed to show a significant superiority of pool-based exercise over balneotherapy without exercise. While we believe that exercise is a gold st and ard in FMS treatment, we also suggest in light of our results that balneotherapy is among the valid treatment options in FMS, and further research regarding the type and duration of the exercise programs is necessary Phytothermotherapy: a possible complementary therapy for fibromyalgia patients. OBJECTIVE It is a traditional practice in the Alpine region of Trentino and Alto Adige ( Italy ) to use phytothermotherapeutic treatment with fermenting grass ( " hay baths " ) for rheumatic diseases. However, despite its long history and popularity, a clinical validation of the efficacy and tolerability of the treatment has yet to be found in current literature. Fibromyalgia syndrome ( FMS ) is characterised by generalised musculoskeletal pain, high tender point counts, sleep disturbance, fatigue, headaches, irritable bowel syndrome, frequent psychological distress and depressed mood. There is no st and ard therapy regime for FMS and the variety of medical treatments used have given limited benefits. The aim of this study was to assess the efficacy and tolerability of a cycle of phytothermotherapy through a single-blind, controlled, r and omised trial, in patients with primary FMS. METHODS Fifty-six patients with primary FMS according to the ACR criteria were r and omly allocated to two groups : 30 were su bmi tted to phytothermotherapy at the thermal resort of Garniga Terme ( Trento, Italy ) and the other 26 were considered as controls. All patients were evaluated by FIQ, Tender Points Count, HAQ and AIMS 1 at baseline, after 10 days, then after 12 and 24 weeks. RESULTS Patients su bmi tted to phytothermotherapy showed visible and significant improvement of all evaluation parameters at the end of the treatment, which persisted during the follow-up period. No significant difference was found in the control group. Regarding the tolerability, none of the patients presented side effects. CONCLUSIONS Our results suggest the efficacy and the tolerability of phytothermotherapy in patients with primary FMS Effects of mud-bath treatment on fibromyalgia patients: a randomized clinical trial The efficacy of balneotherapy in fibromyalgia syndrome ( FS ) has been well demonstrated, while controlled studies using mud packs are lacking. We performed a r and omized clinical trial to evaluate the effects and the tolerability of mud-bath treatment in FS patients, who are poor responders to pharmacological therapy. Eighty patients with primary FS, according to ACR criteria, were r and omly allocated to two groups : 40 were su bmi tted to a cycle of 12 mud packs and thermal baths, and 40 were considered as controls. At baseline, after thermal treatment and after 16 weeks, patients were evaluated by FIQ, tender points count, VAS for “ minor ” symptoms, AIMS 1 and HAQ. Control patients were assessed at the same time periods. A significant improvement of all evaluation parameters after mud-bath therapy and after 16 weeks was observed. Mud packs were well tolerated and no drop-outs were recorded. Our results suggest the efficacy and the tolerability of mud-bath treatment in primary FS Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. OBJECTIVE To measure, and seek clinical correlates with, levels of substance P ( SP ) in the cerebrospinal fluid ( CSF ) of fibromyalgia syndrome ( FMS ) patients. METHODS CSF from 32 FMS patients and 30 normal control subjects was tested for SP by radioimmunoassay. Clinical measures included tender point examination and st and ardized question naires. RESULTS CSF SP levels were 3-fold higher in FMS patients than in normal controls ( P < 0.001 ), but they correlated only weakly with tenderness found on examination. CONCLUSION SP is significantly elevated in FMS CSF, but other abnormalities must exist in FMS to more fully explain the symptoms Responsiveness of fibromyalgia clinical trial outcome measures. OBJECTIVE To assess the responsiveness of the Fibromyalgia Impact Question naire ( FIQ ), patient ratings of pain intensity, number of tender points, and total tender point pain intensity score to perceived changes in clinical status in patients with fibromyalgia ( FM ). METHODS Using data from a r and omized placebo controlled study evaluating efficacy of magnetic therapy in patients with FM, the ability of primary outcomes to detect clinical ly meaningful changes over a 6 month period was assessed by : ( 1 ) degree of association between outcome change scores and patient global ratings of symptom change ( Spearman rank-order correlations ) ; ( 2 ) ability of these scores to discriminate among groups of patients whose perceived health status had changed to varying degrees ( ANOVA ) ; ( 3 ) ability of these scores, individually and jointly, to discriminate between patients who had reported improvement and those who did not ( logistic regression ) ; ( 4 ) effect size, st and ardized response mean, and Guyatt\'s statistic were calculated to quantify responsiveness. RESULTS Correlations showed the outcome measures were moderately responsive to perceived symptomatic change. For FIQ, pain intensity ratings and number of tender points, differences in change scores between globally improved and unchanged groups and between globally improved and worsened groups were significant ; for total tender point pain intensity, the globally improved differed from worsened group. FIQ outperformed the other measures in discriminating between patients who reported improvement from those who did not. Summary statistics were consistent with discriminatory analyses, indicating the measures were sensitive to improvement, but relatively unresponsive to decline. CONCLUSION The FIQ was the most responsive measure to perceived clinical improvement and we recommend its inclusion as a primary endpoint in FM clinical trials SPA therapy in fibromyalgia: a randomised controlled clinic study Objective : The aim of the present study is to evaluate the effectiveness of spa therapy in the management of fibromyalgia. Methods : Thirty women with fibromyalgia were r and omly assigned to either a spa therapy group or a control group. The spa therapy group ( n = 16 ) had spa treatment for 2 weeks in addition to their medical treatment. The control group ( n = 14 ) continued to have their medical treatment and /or daily exercises. An investigator who was blinded for the intervention assessed all the patients for 9 months. Improvements in Fibromyalgia Impact Question naire ( FIQ ), pain and number of tender points were primary outcomes. Secondary outcome measures were improvement in sleep disturbance, fatigue, gastrointestinal symptoms, anxiety, Beck Depression Inventory and patient ’s global evaluation. Results : the spa group was found to be superior to the control group at the end of intervention in terms of FIQ, pain, tender point count, fatigue and patients ’ global assessment. This superiority remained for 6 months in FIQ, 1 month in pain and tender point count. Conclusion : It was concluded that the addition of spa therapy to medical therapy has both short- and long-term beneficial effects in female patients with fibromyalgia Cytokine levels in osteoarthrosis patients undergoing mud bath therapy. Osteoarthritis is an important rheumatic condition characterized by the progressive destruction of cartilage. The pathophysiologic phenomena leading to the pathologic changes in the joint appear to result from biomechanical factors and activation of final common pathways of tissue damage influencing chondrocyte homeostasis and a functional program. Several cytokines and growth factors are reported to be responsible for inflammation and cartilage degradation. Among these, IL-1 and TNF alpha have been suggested as important in promoting cartilage inflammation and tissue destruction, while IGF I has a protective influence on cartilage structure. Chondrocytes and their metabolism have gained interest as targets of drug intervention ; the results of this study confirm that mud bath therapy is also able to influence chondrocyte activities. Our data suggest that mud bath therapy influences cytokines related to osteoarthrosis pathomechanism and maintenance, and encourage further investigations to evaluate possible synergism between pharmacological treatment and mud bath therapy The effects of balneotherapy on fibromyalgia patients Abstract. Fibromyalgia syndrome ( FMS ) is a very common rheumatological diagnosis. There are various treatment modalities. This study was planned to investigate the effects of balneotherapy in the treatment of FMS. A total of 42 primary fibromyalgia patients diagnosed according to American College of Rheumatology criteria were included in the study. Their ages ranged between 30 and 55 years. Patients were r and omly assigned to two groups. None of them had had a cardiovascular disease before. Group 1 ( n=22 ) received 20-min bathing, once a day and five times per week. Patients participated in the study for 3 weeks ( total of 15 sessions ). Group 2 ( n=20 ) was accepted as the control group. Patients were evaluated by the number of tender points, Visual Analogue Scale for pain, Beck\'s Depression Index for depression, and Fibromyalgia Impact Question naire for functional capacity. Measurements were assessed initially, after the therapy, and at the end of the 6th month. In group 1, there were statistically significant differences in numbers of tender points, Visual Analogue scores, Beck\'s Depression Index, and Fibromyalgia Impact Question naire scores after the therapy program ( P<0.001 ). Also, 6 months later in group 1, there was still an improvement in the number of tender points ( P<0.001 ), Visual Analogue scores, and Fibromyalgia Impact Question naire ( P<0.005 ). But there was not a statistical difference in Beck\'s Depression Index scores compared to the control group ( P>0.05 ). Patients with FMS mostly complain about pain, anxiety, and the difficulty in daily living activities. This study shows that balneotherapy is effective and may be an alternative method in treating fibromyalgia patients', "In low- and middle-income countries ( LMICs ), naturally occurring social networks may be particularly vital to health outcomes as extended webs of social ties often are the principal source of various re sources. Longitudinal analysis of large social networks: Estimating the effect of health traits on changes in friendship ties We develop novel mixed effects models to examine the role of health traits on the status of peoples'close friendship nominations in the Framingham Heart Study. The health traits considered are both mutable ( body mass index ( BMI ), smoking, blood pressure, body proportion, muscularity, and depression ) and, for comparison, basically immutable ( height, birth order, personality type, only child, and h and edness ) ; and the traits have varying degrees of observability. We test the hypotheses that existing ties ( i.e. close friendship nominations ) are more likely to dissolve between people with dissimilar ( mutable and observable ) health traits whereas new ties are more likely to form between those with similar ( mutable and observable ) traits while controlling for persons'age, gender, geographic separation, and education. The mixed effects models contain r and om effects for both the nominator ( ego ) and nominated ( alter ) persons in a tie to account for the fact that people were involved in multiple relationships and contributed observations at multiple exams. Results for BMI support the hypotheses that people of similar BMI are less likely to dissolve existing ties and more likely to form ties, while smoker to non-smoker ties were the least likely to dissolve and smoker to smoker ties were the most likely to form. We also vali date d previously known findings regarding homophily on age and gender, and found evidence that homophily also depends upon geographic separation. Copyright © 2011 John Wiley & Sons, Dynamic social networks promote cooperation in experiments with humans Human population s are both highly cooperative and highly organized. Human interactions are not r and om but rather are structured in social networks. Importantly, ties in these networks often are dynamic, changing in response to the behavior of one's social partners. This dynamic structure permits an important form of conditional action that has been explored theoretically but has received little empirical attention : People can respond to the cooperation and defection of those around them by making or breaking network links. Here, we present experimental evidence of the power of using strategic link formation and dissolution, and the network modification it entails, to stabilize cooperation in sizable groups. Our experiments explore large-scale cooperation, where subjects ’ cooperative actions are equally beneficial to all those with whom they interact. Consistent with previous research, we find that cooperation decays over time when social networks are shuffled r and omly every round or are fixed across all rounds. We also find that, when networks are dynamic but are up date d only infrequently, cooperation again fails. However, when subjects can up date their network connections frequently, we see a qualitatively different outcome : Cooperation is maintained at a high level through network rewiring. Subjects preferentially break links with defectors and form new links with cooperators, creating an incentive to cooperate and leading to substantial changes in network structure. Our experiments confirm the predictions of a set of evolutionary game theoretic models and demonstrate the important role that dynamic social networks can play in supporting large-scale human cooperation Cooperative behavior cascades in human social networks Theoretical models suggest that social networks influence the evolution of cooperation, but to date there have been few experimental studies. Observational data suggest that a wide variety of behaviors may spread in human social networks, but subjects in such studies can choose to befriend people with similar behaviors, posing difficulty for causal inference. Here, we exploit a seminal set of laboratory experiments that originally showed that voluntary costly punishment can help sustain cooperation. In these experiments, subjects were r and omly assigned to a sequence of different groups to play a series of single-shot public goods games with strangers ; this feature allowed us to draw networks of interactions to explore how cooperative and uncooperative behaviors spread from person to person to person. We show that, in both an ordinary public goods game and in a public goods game with punishment, focal individuals are influenced by fellow group members ’ contribution behavior in future interactions with other individuals who were not a party to the initial interaction. Furthermore, this influence persists for multiple periods and spreads up to three degrees of separation ( from person to person to person to person ). The results suggest that each additional contribution a subject makes to the public good in the first period is tripled over the course of the experiment by other subjects who are directly or indirectly influenced to contribute more as a consequence. These results show experimentally that cooperative behavior cascades in human social networks Food-Sharing Networks in Lamalera, Indonesia Exponential r and om graph modeling ( ERGM ) is used here to test hypotheses derived from human behavioral ecology about the adaptive nature of human food sharing. Respondents in all ( n = 317 ) households in the fishing and sea-hunting village of Lamalera, Indonesia, were asked to name those households to whom they had more frequently given ( and from whom they had more frequently received ) food during the preceding sea-hunting season. The responses were used to construct a social network of between-household food-sharing relationships in the village. The results show that kinship, proximity, and reciprocal sharing all strongly increase the probability of giving food to a household. The effects of kinship and distance are relatively independent of each other, although reciprocity is more common among residentially and genealogically close households. The results show support for reciprocal altruism as a motivation for food sharing, while kinship and distance appear to be important partner-choice criteria Emergence and Robustness of a Community Discussion Network on Mercury Contamination and Health in the Brazilian Amazon Information exchanges, debates, and negotiations through community social networks are essential to ensure the sustainability of the development process initiated in participatory research. The authors analyze the structural properties and robustness of a discussion network about mercury issues in a community in the Brazilian Amazon involved in a participatory research aim ed at reducing exposure to the pollutant. Most of the villagers are connected in a large network and are separated from other individuals by few intermediaries. The structure of the discussion network displays resilience to the r and om elimination of villagers but shows vulnerability to the removal of one villager who has been a long-term collaborator of the project. Although the network exhibits a structure likely to favor an efficient flow of information, results show that specific actions should be taken to stimulate the emergence of a pool of opinion leaders and increase the redundancy of discussion channels Social networks and infant feeding in Oaxaca, Mexico. The health benefits of delaying the introduction of complementary foods to infants'diets are widely known. Many studies have shown that mothers with the support of close social network members are more compliant with medical recommendations for infant feeding. In our study, we examine the effects of a broader spectrum of network members ( 40 people ) on mothers'infant feeding decisions. The survey was conducted in Oaxaca, Mexico as part of a follow-up to a nationwide Mexican Social Security Institute survey of infant health. Sixty mothers were interviewed from a stratified r and om sample of the original respondents. Multivariate tests were used to compare the efficacy of network-level variables for predicting the introduction of 36 foods into infants'diets, when compared with respondent-level variables. The study yields four findings. First, network-level variables were better predictors of the timing of food introduction than socio-demographic variables. Second, mothers with more indigenous networks delayed the introduction of some grains ( oatmeal, cereal, noodle soup, rice ) and processed pork products ( sausage and ham ) to the infant's diet longer than mothers with less indigenous networks. Third, mothers who had stronger ties to their networks delayed the introduction of rice and processed pork products ( sausage and ham ) to the infant's diet longer than mothers who had weaker ties to their networks. Fourth, mothers who heeded the advice of distant network members introduced some grains ( rice and cereal ) earlier than mothers who did not heed the advice of distant network members Food-Sharing Networks in Lamalera, Indonesia: Status, Sharing, and Signaling. Costly signaling has been proposed as a possible mechanism to explain food sharing in foraging population s. This sharing-as-signaling hypothesis predicts an association between sharing and status. Using exponential r and om graph modeling ( ERGM ), this prediction is tested on a social network of between-household food-sharing relationships in the fishing and sea-hunting village of Lamalera, Indonesia. Previous analyses ( Nolin 2010 ) have shown that most sharing in Lamalera is consistent with reciprocal altruism. The question addressed here is whether any additional variation may be explained as sharing-as-signaling by high-status households. The results show that high-status households both give and receive more than other households, a pattern more consistent with reciprocal altruism than costly signaling. However, once the propensity to reciprocate and household productivity are controlled, households of men holding leadership positions show greater odds of unreciprocated giving when compared to households of non-leaders. This pattern of excessive giving by leaders is consistent with the sharing-as-signaling hypothesis. Wealthy households show the opposite pattern, giving less and receiving more than other households. These households may reciprocate in a currency other than food or their wealth may attract favor-seeking behavior from others. Overall, status covariates explain little variation in the sharing network as a whole, and much of the sharing observed by high-status households is best explained by the same factors that explain sharing by other households. This pattern suggests that multiple mechanisms may operate simultaneously to promote sharing in Lamalera and that signaling may motivate some sharing by some individuals even within sharing regimes primarily maintained by other mechanisms Raising the Level of Analysis of Food-Borne Outbreaks: Food-Sharing Networks in Rural Coastal Ecuador Objectives : Consuming contaminated food is a well-documented individual-level risk factor for diarrheal disease. The sharing of food also influences the distribution of diarrheal disease risk through a community and region. Underst and ing this social process at a population level is therefore an important dimension of risk not captured by st and ard individual-level analyses. We examined social networks related to food-sharing in rural villages at 2 scales : within a village, examining whether connections within these networks clustered or were uniformly spread ; and among villages, looking at whether food-sharing networks differed according to the village's remoteness from a population center. Methods : We surveyed 2129 individuals aged 13 years and older in 2003–2004, within a representative ( block-r and omized ) sample of 21 rural villages in Esmeraldas province, northern coastal Ecuador. We calculated degree ( number of social contacts ) for a social network defined by sharing food. Results : Networks of households sharing food differ according to remoteness from a metropolitan center. On average, residents living in “ far villages ” had 2 more social contacts than those in “ close villages, ” and 12 more years of residence in their village. Estimates of transmissibility ( a measure of outbreak potential ) based on network structure varied as much as 2-fold across these villages. Conclusions : Food-sharing practice s link particular households in rural villages and have implication s for the spread of food-borne pathogens. The food-sharing networks in remote rural villages are heterogeneous and clustered, consistent with contemporary theories about disease transmitters. Network-based measures may offer tools for predicting patterns of disease outbreaks, as well as guidance for interventions A 61-million-person experiment in social influence and political mobilization Human behaviour is thought to spread through face-to-face social networks, but it is difficult to identify social influence effects in observational studies, and it is unknown whether online social networks operate in the same way–. Here we report results from a r and omized controlled trial of political mobilization messages delivered to 61 million Facebook users during the 2010 US congressional elections. The results show that the messages directly influenced political self-expression, information seeking and real-world voting behaviour of millions of people. Furthermore, the messages not only influenced the users who received them but also the users ’ friends, and friends of friends. The effect of social transmission on real-world voting was greater than the direct effect of the messages themselves, and nearly all the transmission occurred between ‘ close friends ’ who were more likely to have a face-to-face relationship. These results suggest that strong ties are instrumental for spreading both online and real-world behaviour in human social networks", 'Purpose - We performed a systematic review and meta-analyses to evaluate the early and long-term migration patterns of tibial components of TKR of all known RSA studies. Postoperative clodronate decreases prosthetic migration: 4–year follow-up of a randomized radiostereometric study of 50 total knee patients Background We have previously reported that 6 months of oral treatment with clodronate reduced the migration of the NexGen total knee prosthesis during the first postoperative year, as measured by radiostereometry ( RSA ). We now report the 4-year results. Methods This was a double-blind r and omized study, using RSA with maximal total point motion ( MTPM ). Results With analysis according to the “ intention to treat ” principle, the only remaining difference between the groups at 4 years was reduced rotation around the transverse axis ( a secondary variable ) in the clodronate group. However, 3 patients ( all clodronate ) did not take any tablet after surgery. If they are excluded, there was an almost statistically significant difference between the groups at 4 years regarding MTPM from baseline, with the clodronate group showing 25 % less migration. From 1 to 4 years, there was no difference in migration rate by MTPM, but there was a continuous increase in rotation around the transverse axis in the controls, which differed from the clodronate group. There were no cases of aseptic loosening. 2 patients had migration of more than 1.3 mm from baseline to 4 years ; neither of them had taken clodronate. The others had migration of less than 0.9 mm. Interpretation Because migration was clearly reduced by clodronate during the first postoperative year, and there was still a difference at 4 years when analyzed per protocol, it appears likely that this treatment can diminish the risk of loosening. The difference in the number of outliers also points in this direction, and may be more relevant than mean migration values Fixation of high-flexion total knee prostheses: five-year follow-up results of a four-arm randomized controlled clinical and roentgen stereophotogrammetric analysis study. BACKGROUND High-flexion total knee arthroplasty was introduced to meet the dem and s of daily activity requiring increased knee flexion. However, concerns have been raised regarding the fixation of high-flexion total knee arthroplasty components and increased rates of loosening have been reported. To date, migration, and thus fixation, of high-flexion total knee arthroplasty components has not been analyzed and the preferential bearing type ( mobile or fixed ) is unknown. METHODS Of eighty-six consecutive eligible patients, seventy-four patients ( seventy-eight knees ) scheduled for total knee arthroplasty were r and omized to one of four Legacy Posterior Stabilized ( LPS ) total knee prosthesis design s : ( 1 ) LPS-Flex mobile, ( 2 ) LPS-Flex fixed, ( 3 ) LPS mobile, and ( 4 ) LPS fixed. The primary outcome was component migration measured with use of Roentgen stereophotogrammetric analysis, and secondary outcomes were postoperative knee flexion and extension and Knee Society Score. Patients were evaluated postoperatively at six, twelve, twenty-six, and fifty-two weeks and annually thereafter. At the five-year follow-up, eight patients had died and two patients were lost to follow-up. Seventy-seven tibial and forty-two femoral components were suitable for migration measurements. RESULTS The overall five-year migration of the seventy-seven tibial components was not significantly different among the four total knee prosthesis design s ( compared with the LPS fixed design, the range of overall mean differences for the other three design s was 0.02 to 0.25 mm ) and migration was comparable at the two and five-year follow-up. Migration stabilized in all but three components ( two LPS-Flex mobile and one LPS fixed ) ; one of these components has already been revised and was aseptically loose. The overall five-year migration of the forty-two femoral components was comparable among the four design s ( compared with the LPS fixed design, the range of overall mean differences for the other three design s was 0.01 to 0.18 mm ) and was similar at two and five years postoperatively. One femoral component ( LPS-Flex mobile ) migrated excessively. In patients who had a mean postoperative flexion of ≥ 125 ° or a maximum flexion of ≥ 135 ° during the one to five-year follow-up period, migration of high-flexion components was comparable with that of conventional components and indicative of appropriate fixation. Postoperative flexion, extension, Knee Society Score, and Knee Society Score function were comparable during the five-year follow-up period and at the two and five-year follow-up. CONCLUSIONS The LPS- Hydroxyapatite-Enhanced Tibial Prosthetic Fixation Sixty-two knees ( 60 patients ) were r and omized to four noncemented groups. In Groups 1, 3, and 4, the bone cuts were made with a cooled saw blade. In Group 1, 15 patients were operated on with the porous coated Osteonic 7000 tibial component. In Group 2, 15 patients were operated on with the same tibial component as in Group 1 but with the use of a st and ard saw blade. In Group 3, 16 patients were operated on with the hydroxyapatite-coated Osteonic tibial component, and in Group 4, 16 patients were operated on with the hydroxyapatite Duracon tibial component. All patients were followed up clinical ly and with roentgenstereometric analysis. There were no differences among the groups regarding clinical outcome. One knee was revised ( Group 2 ) after 1 year because of loosening of the tibial component. The maximum migration at 1 year was 1.7 mm in Group 1, 1.9 mm in Group 2, 1.3 mm in Group 3, and 1 mm in Group 4. At the 2-year followup, the migrations were 1.8 mm, 1.5 mm, 1.4 mm, and 1 mm in Groups 1, 2, 3, and 4, respectively. The inducible displacement that occurred at 1 year was 0.6 mm in Group 1, 0.5 mm in Group 2, 0.4 mm in Group 3, and 0.4 mm in Group 4. The hydroxyapatite coating had a strong positive effect on the tibial component fixation. No prosthesis in the hydroxyapatite groups showed continuous migration Similar early migration when comparing CR and PS in Triathlon™ TKA: A prospective randomised RSA trial. OBJECTIVES The objective of this study was to compare the early migration of the cruciate retaining and posterior stabilising versions of the recently introduced Triathlon ™ total knee system, with a view to predicting long term fixation performance. METHODS Sixty patients were prospect ively r and omised to receive either Triathlon ™ posterior stabilised cemented knee prosthesis or Triathlon ™ cruciate retaining cemented knee prosthesis. Tibial component migration was measured by radiostereometric analysis postoperatively and at three months, one year and two years. Clinical outcome was measured by the American Knee Society Score and Knee Osteoarthritis and Injury Outcome Score. RESULTS There were no differences in rotation around the three coordinal axes or in the maximum total point motion ( MTPM ) during the two year follow-up. The posterior stabilised prosthesis had more posterior-anterior translation at three months and one year and more caudal-cranial translation at one year and two years. There were no differences in functional outcome between the groups. CONCLUSION The tibial tray of the Triathlon ™ cemented knee prosthesis showed similar early stability. LEVEL OF EVIDENCE Level I. ARTICLE SUMMARY Article focus : This was a prospect i ve r and omised trial aim ing to compare the single radius posterior stabilised ( PS ) Triathlon ™ total knee arthroplasty ( TKA ) to the cruciate retaining Triathlon ™ TKA system with regard to fixation. Strengths and limitations of this study : Strength of this study was that it is a r and omised prospect i ve trial using an objective measuring tool. The sample size of 25 - 30 patients was reportedly sufficient for the screening of implants using RSA [ 1 ]. TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT00436982 The effect of Palamed® G bone cement on early migration of tibial components in total knee arthroplasty Abstract Objective : Migration of the tibial component in total knee arthroplasty ( TKA ) is subject of many studies using roentgen stereophotogrammetric analysis ( RSA ). In previous studies of cemented and uncemented tibial components, high migration values were found. Improvements in cementing technique, prosthetic design and pre-coating techniques reduced these values as shown in more recent studies. Material and subjects : A total of 35 patients were initially included in the study and operated on between 12/1999 and 10/2000. All patients received a NexGen ® TKA cemented into the proximal tibia using Palamed ® G bone cement. The implants and the tibial metaphysis were marked with st and ard tantalum markers. Radiostereometric analysis was performed post-operatively and after 3, 6 and 12 months using a st and ard digital radiostereometric analysis. Functional parameters were assessed using the Knee Society Score ( KSS ) clinical rating system. Results : There were no complications and failures within the first year. After 1 year radiostereometric measurements of the translational parameters along and the rotational parameters around the x-, y- and z-axis revealed : X-Trans –0.19 mm, Y-Trans + 0.02 mm, Z-Trans + 0.08 mm, X-Rot + 0.26 °, Y-Rot –0.35 °, Z-Rot + 0.09 °. The maximum total point motion was + 0.96 mm and the mean maximum subsidence was –0.23 mm. Except for anterior-posterior, medio-lateral stability and extension leg all endpoints of the KSS clinical rating system showed a significant improvement. Conclusions : After 12 months, the use of Palamed ® G bone cement in total knee arthroplasty was demonstrated to be safe. Both the clinical and radiostereometric results were good and comparable to the results reported in other RSA studies in cemented total knee arthroplasty Differences in long-term fixation between mobile-bearing and fixed-bearing knee prostheses at ten to 12 years\' follow-up: a single-blinded randomised controlled radiostereometric trial. This single-blinded r and omised controlled trial investigated whether one design of mobile-bearing ( MB ) total knee replacement ( TKR ) has any advantage over a fixed-bearing ( FB ) design on long-term fixation as measured by radiostereometry. The amount of wear underneath the mobile bearing was also evaluated. A series of 42 knees was r and omised to MB or FB tibial components with appropriate polyethylene inserts and followed for between ten and 12 years, or until the death of the patient. The polyethylene in the MB group was superior in that it was gamma-irradiated in inert gas and was calcium-stearate free ; the polyethylene in the FB group was gamma-irradiated in air and contained calcium stearate. In theory this should be advantageous to the wear rate of the MB group. At final follow-up the overall mean migration was 0.75 mm ( SD 0.76 ) in the MB group and 0.66 mm ( SD 0.4 ) in the FB group, with the FB group demonstrating more posterior tilt and the MB group more internal rotation. In the FB group there was one revision for aseptic loosening, but none in the MB group. There were no significant differences in clinical or radiological scores. For the MB group, the mean linear wear rate on the under-surface was 0.026 mm/year ( SD 0.014 ). This was significantly smaller than the wear rate of 0.11 mm/year ( SD 0.06 ) in the MB between femur and polyethylene ( p < 0.001 ). Nevertheless, even in a best-case setting the mobile bearings of this TKR design had no apparent advantage in terms of fixation over the FB knee prosthesis at ten to 12 years. The wear underneath the mobile bearing was small and is unlikely to be clinical ly relevant Cemented tibial component fixation performs better than cementless fixation Background The question whether the tibial component of a total knee arthroplasty should be fixed to bone with or without bone cement has not yet been definitely answered. We studied movements between the tibial component and bone by radiostereometry ( RSA ) in total knee replacement ( TKR ) for 3 different types of fixation : cemented fixation ( C-F ), uncemented porous fixation ( UC-F ) and uncemented porous hydroxyapatite fixation ( UCHA-F ). Patients 116 patients with osteoarthrosis, who had 146 TKRs, were included in 2 r and omized series. The first series included 86 unilateral TKRs stratified into 1 of the 3 types of fixation. The second series included 30 patients who had simultaneous bilateral TKR surgery, and who were stratified into 3 subgroups of pairwise comparisons of the 3 types of fixation. Results After 5 years 2 knees had been revised, neither of which were due to loosening. 1 UCHA-F knee in the unilateral series showed a large and continuous migration and a poor clinical result, and is a pending failure. The C-F knees rotated and migrated less than UC-F and UCHA-F knees over 5 years. UCHA-F migrated less than UC-F after 1 year. Interpretation Cementing of the tibial component offers more stable bone-implant contact for 5 years compared to uncemented fixation. When using uncemented components, however, there is evidence that augmenting a porous surface with hydroxyapatite may mean less motion between implant and bone after the initial postoperative year Celecoxib does not appear to affect prosthesis fixation in total knee replacement Background and purpose After joint replacement, a repair process starts at the interface between bone and cement. If this process is disturbed, the prosthesis may never become rigidly fixed to the bone, leading to migration— and with time, loosening. Cox-2 inhibitors are widely used as postoperative analgesics, and have adverse effects on bone healing. This could tamper prosthesis fixation. We investigated whether celecoxib, a selective Cox-2 inhibitor, increases prosthesis migration in total knee replacement ( TKR ). Methods 50 patients were r and omized to either placebo or celecoxib treatment, 200 mg twice daily, for 3 weeks after TKR ( NexGen ; Zimmer ). Maximum total point motion ( MTPM ) of the tibial component was measured after 2 years using radiostereometric analysis ( RSA ). In addition, range of motion, pain, and, subjective outcome were evaluated. Results No differences in prosthesis migration, pain scores, range of motion, and subjective outcome were found after 2 years. Confidence intervals were narrow. Interpretation It is unlikely that Celecoxib increases the risk of loosening, and it may be used safely in conjunction with TKR The beneficial effect of hydroxyapatite lasts Background and purpose In contrast to early migration, the long-term migration of hydroxyapatite- ( HA- ) coated tibial components in TKA has been scantily reported. This r and omized controlled trial investigated the long-term migration measured by radiostereometric analysis ( RSA ) of HA-coated, uncoated, and cemented tibial components in TKA. Patients and methods 68 knees were r and omized to HA-coated ( n = 24 ), uncoated ( n = 20 ), and cemented ( n = 24 ) components. All knees were prospect ively followed for 11–16 years, or until death or revision. RSA was used to evaluate migration at yearly intervals. Clinical and radiographic evaluation was according to the Knee Society system. A generalized linear mixed model ( GLMM, adjusted for age, sex, diagnosis, revisions, and BMI ) was used to take into account the repeated-measurement design. Results The present study involved 742 RSA analyses. The mean migration at 10 years was 1.66 mm for HA, 2.25 mm for uncoated and 0.79 mm for the cemented group ( p < 0.001 ). The reduction of migration by HA as compared to uncoated components was most pronounced for subsidence and external rotation. 3 tibial components were revised for aseptic loosening ( 2 uncoated and 1 cemented ), 3 for septic loosening ( 2 uncoated and 1 cemented ), and 1 for instability ( HA-coated ). 2 of these cases were revised for secondary loosening after a period of stability : 1 case of osteolysis and 1 case of late infection. There were no statistically significant differences between the fixation groups regarding clinical or radiographic scores. Interpretation HA reduces migration of uncemented tibial components. This beneficial effect lasts for more than 10 years. Cemented components showed the lowest migration. Longitudinal follow-up of TKA with RSA allows early detection of secondary loosening Local peroperative treatment with a bisphosphonate improves the fixation of total knee prostheses: A randomized, double-blind radiostereometric study of 50 patients Background Postoperative migration of a joint prosthesis is related to the risk of late loosening. We have previously reported that oral treatment with clodronate reduced migration of the cemented NexGen total knee prosthesis during the first postoperative year, as measured by radiostereometry ( RSA ). Oral bisphosphonate treatment is sometimes unpleasant, and local treatment will enable higher local concentrations. We now report the results of local peroperative treatment with another bisphosphonate, ib and ronate, with the same prosthesis. Methods This is a double-blind, r and omized study of 50 patients using RSA with maximal total point motion ( MTPM ) as primary effect variable. 1 mg ib and ronate ( 1 mL ) or 1 mL saline was applied to the tibial bone surface 1 min before cementation. RSA examination was done on the first postoperative day, and at 6, 12, and 24 months. Results One ib and ronate-treated patient died of unrelated causes, and 1 control patient refused to come for follow-up, leaving 24 patients in each group for analysis. There were no cases of aseptic loosening. By repeated measures ANOVA, migration ( MTPM ) was reduced by local application of ib and ronate ( p = 0.006 ). The effect was most pronounced at 6 months, with a reduction from 0.45 to 0.32 mm ( 95 % CI for reduction : 0.04–0.21 mm ). At 12 months, the migration from the postoperative examination was reduced from 0.47 to 0.36 mm ( 95 % CI for reduction : 0.02–0.20 mm ). At 24 months, the reduction was from 0.47 to 0.40 mm ( 95 % CI : -0.01–0.16 mm ). Interpretation This is the first study to show improvement of prosthesis fixation by local pharmacological treatment in humans. The treatment appears to be safe, cheap, and easy to perform. However, the improvement in postoperative stability was not greater than with systemic clodronate treatment Inferior performance of Boneloc bone cement in total knee arthroplasty: a prospective randomized study comparing Boneloc with Palacos using radiostereometry (RSA) in 19 patients. We compared Boneloc bone cement with conventional cement ( Palacos ) in fixating the tibial component during 2 - 5 years in 19 patients with gonarthrosis undergoing total knee arthroplasty in a prospect i ve r and omized study. Boneloc displayed significantly larger migration, subsidence and lift-off than Palacos. The difference was identifiable already within 3 months postoperatively, but became significant at 12 months. In the Boneloc group, all components showed subsidence of the posterior part and lift-off of the anterior part of the tibial component, whereas in the Palacos group, the locations of subsidence and lift-off were evenly distributed about the edge of the implant. At 5 years, both Boneloc knees so far investigated were clinical failures with high migration rates. We conclude that, even in total knee arthroplasty, there is a substantial risk that Boneloc leads to inferior clinical results, but later than in hip replacements Hydroxyapatite coating versus cemented fixation of the tibial component in total knee arthroplasty: prospective randomized comparison of hydroxyapatite-coated and cemented tibial components with 5-year follow-up using radiostereometry. Fifty-three consecutive patients ( 57 knees ; mean age, 69 years ) entered a prospect i ve r and omized study to compare the fixation of hydroxyapatite (HA)-coated ( 29 knees ) with cemented ( 28 knees ) tibial components in the Tricon II total knee arthroplasty. The quality of the fixation during 5 years postoperatively was evaluated with radiostereometric analysis ( RSA ). Three HA-coated implants were revised : 2 owing to infection, and 1 owing to early delamination of the coating and clinical loosening. Eight patients ( 9 knees ) died, 1 patient sustained a stroke, and 1 patient refused investigations after 1 year. In the 40 patients ( 19 HA-coated, 21 cemented ) remaining at 5 years, the magnitude of the micromotion between the HA-coated and cemented groups did not differ. The HA-coated implants displayed most of the migration within the initial 3 months then stabilized, whereas the cemented implants showed an initially lower, but over time continuously increasing migration. Between 1 and 2 years, 4 of 24 HA-coated and 10 of 23 cemented implants migrated > 0.2 mm and were categorized unstable, which has been shown to have a prognostic value as regards future aseptic loosening. Progressive radiolucent lines developed in 2 cemented knees, which both were categorized unstable. If HA-coated implants can sustain the forces that threaten the fixation in the early period after implantation, a strong and enduring fixation may be obtained Migration of a cemented fixed-bearing, polished titanium tibial baseplate (Genesis II) at ten years : a radiostereometric analysis. AIMS The purpose of the present study was to examine the long-term fixation of a cemented fixed-bearing polished titanium tibial baseplate ( Genesis ll ). PATIENTS AND METHODS Patients enrolled in a previous two-year prospect i ve trial ( n = 35 ) were recalled at ten years. Available patients ( n = 15 ) underwent radiostereometric analysis ( RSA ) imaging in a supine position using a conventional RSA protocol. Migration of the tibial component in all planes was compared between initial and ten-year follow-up. Outcome scores including the Knee Society Score, Western Ontario and McMaster Universities Arthritis Index, 12-item Short Form Health Survey, Forgotten Joint Score, and University of California, Los Angeles Activity Score were recorded. RESULTS At ten years, the mean migration of the tibial component was less than 0.1 mm and 0.1 ° in all planes relative to the post-operative RSA exam. Maximum total point movement increased with time ( p = 0.002 ) from 0.23 mm ( sd 0.18 ) at six weeks to 0.42 mm ( sd 0.20 ) at ten years. CONCLUSION The low level of tibial baseplate migration found in the present study correlates to the low rate of revision for this implant as reported in individual studies and in joint replacement registries. TAKE HOME MESSAGE Overall, the implant was found to be well fixed at ten years, supporting its continued clinical use and the predictive power of RSA for determining long-term fixation of implants. Cite this article : Bone Joint J 2016;98-B:616 - 21 Proximally cemented versus uncemented Freeman-Samuelson knee arthroplasty. A prospective randomised study. We studied the effect of a layer of cement placed under the tibial component of Freeman-Samuelson total knee prostheses with a metal back and an 80 mm intramedullary stem, using roentgen stereophotogrammetry to measure the migration of the tibial component during one year in 13 uncemented and 16 cemented knees. The addition of cement produced a significant reduction in migration at one year, from a mean of 1.5 mm to one of 0.5 mm ( p less than 0.01 ), including a significant reduction in pure subsidence. One year postoperatively the clinical results were similar between the groups, but, at three years, one uncemented knee had required revision Survival of knee arthroplasties. A nation-wide multicentre investigation of 8000 cases. A prospect i ve nation-wide study of knee arthroplasty has been under way in Sweden since October 1975. By the end of 1983, 4505 arthroplasties for osteoarthritis and 3495 for rheumatoid arthritis had been recorded and review ed one, three and six years after the operation. Using actuarial methods, the probability of the prosthesis remaining in situ after six years was calculated. In osteoarthritis this probability ranged from 65 % for hinged prostheses to 90 % for medial compartment prostheses. Two- and three-compartment prostheses produced intermediate results with 87 % survival. In rheumatoid arthritis the probability varied from 72 % for medial compartment prostheses to 90 % for two- and three-compartment prostheses. The main reason for failure was loosening of the components, the second most common was infection. The probability of revision for infection by six years was 2 % in osteoarthritis and 3 % in rheumatoid arthritis. Most revisions were to a three-compartment prosthesis. Knee fusion at primary revision was required in 2 % of the cases at six years Effect of a cooled saw blade on prosthesis fixation. Randomized radiostereometry of 33 knee cases. Tibial migration in 33 cementless total knee replacements, which were performed with a cooled saw blade vs. a conventional blade, was studied in a r and omized prospect i ve study using roentgen stereophotogrammetric analysis ( radiostereometry ). All cases were clinical ly successful after 2 years and inducible displacement was smaller in the group operated with the cooled saw blade. This group also had a tendency towards less continuous migration Early Inducible Displacement of Tibial Components in Total Knee Prostheses Inserted with and without Cement. A Randomized Study with Roentgen Stereophotogrammetric Analysis* The fixation of tibial components r and omized to insertion with or without cement in twenty-six knees was examined for inducible displacement at six weeks and one year postoperatively with use of roentgen stereophotogrammetric analysis. Furthermore, migration was studied during the first two postoperative years. Inducible displacement was found in all knees at both the six-week and the one-year follow-up examination, but no differences were detected with respect to the type of fixation ( p > 0.05 ). All tibial components migrated for as long as one year postoperatively, after which most stabilized. No difference was found between the groups with respect to migration during the first two years postoperatively ( p > 0.05 ), with the exception of subsidence of the component, which was found to be 0.0 ± 0.1 millimeter ( mean and st and ard error of the mean ) for the components inserted with cement and 0.5 ± 0.1 millimeter for the components inserted without cement ( p < 0.01 ). Migration after one year was the same for both groups. We found a relationship between inducible displacement at six weeks and at one year as well as one between inducible displacement and migration at one year. To our knowledge, the present study is the first in which the micromotion of an interference-fit prosthesis was found to be similar to that of a device inserted with cement. The results of the present study emphasize the importance of the initial prosthetic fixation Fixation of the tibial component using CMW-1 or Palacos bone cement with gentamicin: Similar outcome in a randomized radiostereometric study of 51 total knee arthroplasties We studied CMW-1 bone cement with gentamicin in the laboratory and in a r and omized clinical study. Palacos bone cement containing gentamicin was used as the control. In the pre clinical evaluation, the CMW cement had slightly less mechanical strength. In the clinical study, 51 patients ( 51 knees ) operated on with total knee arthroplasty were studied for 2 years. We used radiostereometric analysis to measure migration of the tibial components, r and omized to fixation with either of the two types of cement. The extent and pattern of migration were similar in both groups, and we found no differences in the number, size and extent of radiolucent lines or clinical outcome. No complications occurred. Our findings suggest a need for more studies of CMW-1 bone cement containing gentamicin in a larger cohort of patients Mobile Bearings Do Not Improve Fixation in Cemented Total Knee Arthroplasty Mobile bearings were introduced to improve wear and knee kinematics. By uncoupling the forces generated at the articulation from the implant-bone interface this would, theoretically, also improve the fixation of the implant to bone. We did this study to evaluate whether mobile bearings improve the fixation of the tibial component to bone. Fifty-two consecutive knees in 47 patients ( average age, 72 years ; range, 62 - 84 years ) with primary osteoarthrosis were r and omized into two groups to receive a cemented total knee arthroplasty with either a fixed-bearing or mobile-bearing tibial component. The quality of fixation was analyzed with radiostereometric analysis for up to 2 years. Mobile bearings did not improve fixation. Both magnitudes and directions of component rotations were similar, and the number of implants with continuous migration was almost identical. Both implant types had a combination of subsidence and lift-off, but where the mobile bearing implants displayed more of subsidence, the fixed bearing knees showed more lift-off. It might be that the somewhat stiffer cobalt-chromium baseplate or the different joint conformity used in the mobile-bearing knees counteracts any potential effects of the mobile bearing. Level of Evidence : Therapeutic Level I. See the Guidelines for Authors for a complete description of levels of evidence Increased varus-valgus tilting of screw-fixated knee prostheses. Stereoradiographic study of uncemented versus cemented tibial components. Twenty-six women and three men ( 34 knees ) with osteoarthrosis were operated with the Miller-Galante I ( Zimmer, Warsaw, IN ) knee prosthesis. The patients were r and omized to either cemented or uncemented fixation of the tibial component. All patients received a TiVaAl alloy tibial plate with four pegs and titanium fiber-mesh undersurface. In the uncemented knees four screws were added. The fixation of the tibial component was determined by roentgen stereophotogrammetric analysis during the first 2 postoperative years. Rotations of the entire tibial component were recorded, as well as proximal or distal translation of various parts of the prosthetic edge corresponding to subsidence and lift-off. The uncemented components displayed almost all rotation and translation during the first 6 weeks, whereas the cemented ones displayed a more gradually increasing migration during the 2 years. Tibial component rotation about the sagittal axis was significantly increased in the uncemented knees throughout the investigation period. This corresponded to increased subsidence medially or laterally in the uncemented knees, whereas lift-off was equal in the two groups. Thin ( 8.5 mm ) uncemented tibial components displayed more subsidence than the thicker ones at the medial or lateral edge 3 months after surgery The effect of tourniquet use on fixation quality in cemented total knee arthroplasty a prospective randomized clinical controlled RSA trial. BACKGROUND A concern that arises with any change in technique is whether it affects the long-term implant stability. The objective of this study was to evaluate the early migration, measured by radiostereometric analysis ( RSA ), and the functional outcome of the Triathlon ™ cemented knee prosthesis, operated on with or without a tourniquet. During the last decades RSA has emerged as a way to assess prosthetic fixation and long time prognosis. The method has been used extensively in both hip and knee arthroplasty. METHOD This was a single centre prospect i ve study including 60 patients r and omized into two groups operated on either with or without tourniquet. RSA investigation was done within 2 - 3 days postoperatively after full weight bearing, and then at 3 months, 1 year and 2 years postoperatively. RESULTS There were no differences between the groups regarding the translation along or rotation around the three coordinal axes, or in maximum total point motion ( MTPM ). At 2 years the mean MTPM ( SD ) was 0.71 mm ( 0.64 ) for the tourniquet-group and 0.53 mm ( 0.21 ) for the non-tourniquet-group. CONCLUSIONS The tibial tray of the Triathlon ™ cemented knee prosthesis showed similar early stability whether operated on with or without tourniquet. LEVEL OF EVIDENCE Level I. ARTICLE SUMMARY Article focus : A safety study for total knee replacement operated on with or without perioperative tourniquet regarding the prosthetic fixation. Strengths and limitations : Strength of this study is that it is a r and omized prospect i ve trial using an objective measuring tool. The sample size of 25 - 30 patients is reportedly sufficient for the screening of implants using RSA ( 1 - 3 ). TRIAL REGISTRATION Clinical trials NCT01604382, Ethics Committee approval D-nr : 144/20085 Ceramic coating improves tibial component fixation in total knee arthroplasty. Forty uncemented total knee arthroplasties ( 36 patients ) were r and omly allocated to a Miller-Galante II prosthesis with or without hydroxyapatite/tricalcium phosphate ( HA/TCP ) coating on the titanium fiber mesh on the undersurface of the tibial component. The patients were followed for 2 years with repeated radiostereometric examinations. After 2 years, the HA/TCP tibial components displayed smaller anterior-posterior tilt and less subsidence. The mean value of maximal total point motion was small : 0.5 mm in both groups. At 24 months, there were more radiolucent lines under the tibial tray and around the stem in the uncoated group, but the clinical results did not differ. HA/TCP coating on the undersurface of the tibial component improved the stability and seemed to improve the quality of the interface between the tibial component and the bone The stability of three different cementless tibial components. A randomized radiostereometric study in 45 knee arthroplasty patients. We conducted a prospect i ve, r and omized study of 45 patients to evaluate 3 different uncemented tibial component design s in total knee arthroplasty. The stability of the components was assessed by radiostereometry ( RSA ), both as migration during 2 years and as inducible displacement at 2 years. The PCA resurfacing, the Tricon stem and the Tricon-M prosthesis groups showed a similar level of migration at 2 years, about 1.4 mm. In response to externally applied rotatory forces, the Tricon groups rotated more than the PCA group, interpreted as a consequence of the more conforming articular surface in the Tricon design. The series was divided into one group of continuously migrating prostheses with a poor prognosis ( unstable, one third ) and another group of prostheses in which migration stopped after 1 year ( stable, two thirds ). With this classification, no differences between the prostheses design groups were revealed. However, the unstable group showed a larger inducible displacement by provocation, an association hitherto not established VersaBond bone cement prospective randomized study of the clinical properties of a new bone cement in total knee replacement. VersaBond is a newly developed bone cement. To investigate its clinical performance, VersaBond was compared to Palacos R in a prospect i ve r and omized study in total knee replacement. Fifty-nine patients ( 61 knees ) undergoing total knee replacement were r and omized to either VersaBond or Palacos R bone cement and followed for 24 months using radiostereometric analysis ( RSA ). Up to 2 years there were no significant differences in clinical performance between the two cements. The mean/median values for implant migration were very similar for the two bone cements, as were the dispersion, and distribution of outliers. Also the proportion " stable " and " continuously migrating " implants was similar between the two cements. The result of this study indicates that VersaBond bone cement will perform at least equally as well as Palacos R in total knee replacement as regards as aseptic loosening Absence of a Tourniquet Does Not Affect Fixation of Cemented TKA: A Randomized RSA Study of 70 Patients. We aim ed to determine whether not using a tourniquet in cemented TKA would affect migration of the tibial component measured by radiosterometric analysis ( RSA ). Seventy patients were r and omized into a tourniquet group and a non-tourniquet group and using model-based RSA, the migration of the tibial component was analyzed. Primary and secondary outcome measures were maximum total point motion ( MTPM ) and translations and rotations. Follow-up period was 2 years. The tibial component was well fixated in both groups and no significant difference in migration between the two groups was detected ( P=0.632 ). Mean MTPM ( SD ) was 0.47 mm ( 0.16 ) in the tourniquet group and 0.45 mm ( 0.21 ) in the non-tourniquet group. Absence of tourniquet indicates that stable fixation of the tibial component can be achieved in cemented TKA', 'INTRODUCTION The treatment strategy for appendiceal mass is controversial, ranging from operation or image-guided drainage to conservative treatment with or without antibiotics. The aim of this study was to assess the various treatment modalities with respect to complications and treatment failure. Resource utilization and outcomes from percutaneous drainage and interval appendectomy for perforated appendicitis with abscess. OBJECTIVE Given the perceived technical dem and s of laparoscopic appendectomy and the expected postoperative morbidity in patients with a well-defined abscess, initial percutaneous drainage has become an attractive option in this patient population. This strategy allows for a laparoscopic appendectomy to be performed in an elective manner at the convenience of the surgeon. However, the medical burden on the patient and on the quality of patient outcomes has not been described in the literature. Therefore, we audited our experience with initial percutaneous drainage followed by laparoscopic interval appendectomy to evaluate the need for a prospect i ve trial. METHODS After institutional review board approval, a retrospective chart review was performed on all children who presented with perforated appendicitis and a well-defined abscess and were treated by initial percutaneous aspiration/drainage followed by interval appendectomy between January 2000 and September 2006. Continuous variables are listed with st and ard deviation. RESULTS There were 52 patients with a mean age of 9.0 + /- 3.9 years and weight of 34.4 + /- 18.8 kg. The mean duration of symptoms at presentation was 8.4 + /- 7.6 days. Percutaneous aspiration only was performed in 2 patients. The mean volume of fluid on initial aspiration/drain placement was 76.3 + /- 81.1 mL. The mean time to appendectomy was 61.9 + /- 25.2 days. The laparoscopic approach was used in 49 patients ( 94.2 % ), of which one was converted to an open operation. The mean length of hospitalization after interval appendectomy was 1.4 + /- 1.4 days. A recurrent abscess developed in 17.3 % of the patients. Six patients ( 11.5 % ) required another drainage procedure. The mean total charge to the patients was $ 40,414.02. There were 4 significant drain complications ( ileal perforation, colon perforation, bladder perforation, and buttock/thigh necrotizing abscess ). The child with the ileal perforation after drain placement is the only patient who failed initial nonoperative therapy. CONCLUSIONS The use of initial percutaneous aspiration/drainage of periappendiceal abscess followed by interval appendectomy is an effective approach. However, this management poses complication risks and uses considerable re sources. Therefore, this strategy should be compared with early operation in a prospect i ve trial Evaluation of early surgical management of complicated appendicitis by appendicular mass. AIM This prospect i ve study was done to evaluate the feasibility and safety of immediate appendicectomy in the presence of appendicular mass. METHODS A prospect i ve, nonr and omized study was conducted over 46 consecutive patients ( mean age : 24 ± 8.76 years ) presenting with an appendicular mass over a 4-year period. They were subjected for immediate appendicectomy within 24 h of admission. RESULTS The appendix was identified and removed in all 46 patients at operation. Peri-appendiceal abscesses were present in 25 % ( 11 of 46 ). There was difficulty with adhesolysis and localization of the appendix in 10%(4 ) of patients. Superficial wound infection had occurred in 8(17 % ) while deep wound infection had occurred in 9%(4 ) patients. The mean hospital stay was 3 ± 0.25 day. No major complications had occurred. CONCLUSIONS Early surgical intervention in patients with an appendicular mass is feasible, safe and avoids the consequences of the misdiagnosis and mistreatment of other surgical pathologies Long-Term Outcome of Mesocolic and Pelvic Diverticular Abscesses of the Left Colon: A Prospective Study of 73 Cases PURPOSE The aim of of this study was to evaluate prospect ively the long-term outcome of mesocolic and pelvic diverticular abscesses of the left colon. METHODS Between October 1986 and October 1997, a total of 465 patients urgently admitted to our hospital with a suspected diagnosis of acute left-sided colonic diverticulitis had a CT scan. Of 76 patients ( 17 percent ) who had an associated mesocolic or pelvic abscess, 3 were lost to follow-up. The remaining 73 patients ( 45 with a mesocolic abscess and 28 with a pelvic abscess ) were followed for a median of 43 months. RESULTS of the 45 patients with a mesocolic abscess, 7 ( 15 percent ) required surgery during their first hospitalization versus 11 ( 39 percent ) of the 28 patients with a pelvic abscess ( P = 0.04 ). At the end of follow-up, 22 ( 58 percent ) of the 38 patients with a mesocolic abscess who had successful conservative treatment during their first hospitalization did not need surgical treatment vs. 8 ( 47 percent ) of the 17 who had a pelvic abscess. Altogether, 51 percent of the patients with a mesocolic abscess had surgical treatment versus 71 percent of those with a pelvic abscess ( P = 0.09 ). CONCLUSIONS Considering the poor outcome of pelvic abscess associated with acute left-sided colonic diverticulitis, percutaneous drainage followed by secondary colectomy seems justified. Mesocolic abscess by itself is not an absolute indication for colectomy Prospective evaluation of nonsurgical versus surgical management of appendiceal mass. PURPOSE Prospect i ve evaluation was undertaken of surgical findings, complications, morbidity, and hospital stay between initial nonsurgical management versus early surgical intervention of an appendicular mass. METHODS A prospect i ve, nonr and omized study was conducted of 82 consecutive patients ( mean age, 6.9 + /- 3.3 years ) presenting with an appendicular mass over a 5-year period. They were categorized as group 1, 58.5 % ( 48 of 82 ) nonsurgically managed and an interval appendectomy performed at a mean period of 8.6 + /- 4.6 weeks and group 2, 41.5 % ( 34 of 82 ) appendectomy at presentation. RESULTS An appendix was identified in all 82 patients in both groups at operation. In-group 1, recurrent episodes of abdominal pain necessitated interval appendectomy in 39.6 % ( 19 of 48 ) patients at a mean 4.3 + /- 0.8 versus 11.5 + /- 3.7 weeks in 60.4 % ( 29 of 48 ) who underwent scheduled interval appendectomy. Periappendiceal abscesses present at interval appendectomy in group 1 was ( 38 of 48 ) 79.2 % versus 100 % ( 34 of 34 ) at appendectomy in group 2. Adhesions at interval appendectomy in group 1 was 81.3 % ( 39 of 48 ) versus 100 % ( 34 of 34 ) at appendectomy in group 2. In-group 1, superficial wound infection was observed in 0 versus 4 wound infections in group 2. Overall morbidity rate between group 1 and group 2 was statistically significant ( P <.05 ). Total mean hospital stay in group 1 was 13.2 + /- 1.5 versus 4.8 + /- 0.4 days in group 2. Of the 48-interval appendectomy specimens, 37 of 48 ( 77 % ) appendices had a patent lumen, and 11 of 48 ( 23 % ) showed fibrosis and obliteration of appendicular lumen. There was no correlation ( r = 0.22 ) between the histopathologic findings and the interval between abscess treatment and interval appendectomy. CONCLUSIONS Early surgical intervention was beneficial over nonoperative management in this cohort of patients. Interval appendectomy is recommended after nonsurgical management of an appendicular mass Conservative approach versus urgent appendectomy in surgical management of acute appendicitis with abscess or phlegmon. BACKGROUND Surgical management of acute appendicitis with appendiceal abscess or phlegmon remains controversial. We studied the results of initial conservative treatment ( antibiotics and percutaneous drainage if necessary, with or without interval appendectomy ) compared with immediate surgery. METHODS We undertook an observational, retrospective cohort study of patients with a clinical and radiological diagnosis of acute appendicitis with an abscess or phlegmon, treated in our hospital between January 1997 and March 2009. Patients younger than 14, with severe sepsis or with diffuse peritonitis were excluded. A study group of 15 patients with acute appendicitis complicated with an abscess or phlegmon underwent conservative treatment. A control group was composed of the other patients, who all underwent urgent appendectomy, matched for age and later r and omized 1:1. The infectious risk stratification was established with the National Nosocomial Infections Surveillance System ( NNIS ) index. Dependent variables were hospital stay and surgical site infection. Analysis was with SPSS, with p < 0.05 considered significant. RESULTS Interval appendectomy was performed in 7 study group patients. Surgical site infection episodes were more frequent in the control group ( 6 vs. 0, p < 0.001 ). A greater percentage of high risk patients ( NNIS ≥ 2 ) was identified in the control group ( 80 vs. 28.7 %, p < 0.03 ), mostly related with contaminated or dirty procedures in this group ( p < 0.001 ). No significant difference between groups was found in hospital stay. CONCLUSION Initial conservative treatment should be considered the best therapeutic choice for acute appendicitis with abscess or phlegmon Influence of Risk Factors on the Safety of Ileocolic Anastomosis in Crohn’s Disease Surgery BACKGROUND : Ileocecal resection is the most commonly performed operation in patients with Crohn ’s disease. Anastomotic-associated complications, with their associated morbidity, are the most feared risks of surgery. OBJECTIVE : This study aim ed to assess the influence of a variety of putative risk factors in a homogenous group of patients undergoing first or subsequent surgery for Crohn ’s disease to quantify the cumulative risk for anastomotic-associated complications. DESIGN AND PATIENTS : All patients undergoing ileocecal or ileocolic resections for Crohn ’s disease from 2000 to 2010 were studied with the use of a prospect i ve data base. Demographics, operative details, possible risk factors, and anastomotic-associated complications were recorded. Patients having strictureplasties, multiple resections, or subtotal colonic resections were excluded from analysis. Statistical analysis was by univariate analysis ( Mann-Whitney U test ) and binary logistic regression. OUTCOMES : An anastomotic-associated complication was defined as a proven anastomotic leak, postoperative fistulation, or intra-abdominal abscess formation. RESULTS : Two hundred seven patients ( 109 female ) with a median age of 35 years ( range, 13 - 75 years ) were identified. One hundred seventy-three underwent primary anastomosis, 94 as an emergency procedure. Fifty-three had laparoscopic ( 5 converted ) procedures. Nineteen of 173 anastomotic complication events ( 11 % ) were recorded. Steroid usage ( OR 2.67, 95 % CI 1.0 - 7.2 ) and the presence of preoperative abscess formation ( OR 3.4, 95 % CI 1.2 - 9.8 ) were identified as independent predictors of anastomotic-associated complications. In the absence of both steroids and intra-abdominal abscess, the risk of anastomotic complications was 6 %, which increased to 14 % if either risk factor was present. When both risk factors were present, complication rates reached 40 %. CONCLUSION : Steroid usage and preoperative abscess were associated with higher rates of anastomotic complications following ileocolic resection for Cohn ’s disease. When both risk factors are present, it is best to avoid primary anastomosis Comparison of therapeutic effectiveness of percutaneous drainage with antibiotics versus antibiotics alone in the treatment of periappendiceal abscess Background The present study was design ed to compare the therapeutic effectiveness of percutaneous drainage with antibiotics versus antibiotics alone in the treatment of appendicitis complicated by periappendiceal abscess. Methods In a prospect i ve study, 50 patients with acute appendicitis complicated by periappendiceal abscess ≥ 3 cm in size were r and omly assigned to two groups. The first group received treatment with ultrasound guided-percutaneous drainage and i.v. antibiotics ( ampicillin, cefuroxime, and metronidazole ), and the other group received antibiotics only. Patient ’s baseline characteristics, duration of hospital stay, and treatment outcome and complications were analyzed. Results Appendectomy was avoided in 16/25 patients in the drainage group and 2/25 patients in the non-drainage group during follow-up with RR of 0.39 ( 95 % CI = 0.22–0.62 ; p < 0.05 ). One patient in the drainage group and 8 patients in the non-drainage group underwent surgery in the first month after the beginning of treatment. Eight patients in the drainage group and 15 in the non-drainage group underwent interval appendectomy. There was no statistically significant difference between the two groups regarding patient demographics, abscess size, and pretreatment clinical symptoms. Hospital stay up to the subsidence of clinical and sonographic signs was significantly shorter ( p < 0.001 ) in the drainage group, with a mean difference of 6.4 days ( 95 % CI = 5.0–7.9 ; p < 0.05 ). Conclusions Percutaneous drainage with antibiotics is a safe and effective way of treating acute perforated appendicitis. The recurrence rate for these patients is relatively low, and very often interval appendectomy is not required. For patients with periappendiceal abscess ≥ 3 cm in diameter, antibiotic therapy alone is insufficient and the recurrence rate is high Appendiceal mass: conservative therapy followed by interval laparoscopic appendectomy. BACKGROUND Current therapy of patients with appendiceal abscess or phlegmon is in evolution. Controversial areas include initial conservative therapy, drainage of periappendiceal abscesses, and the role of interval appendectomy. OBJECTIVE To evaluate the safety and efficacy of conservative therapy and of interval laparoscopic appendectomy ( ILA ). PATIENTS AND METHODS Patients with signs and symptoms of acute appendicitis and a palpable right lower quadrant mass were included. Abscess/phlegmon was documented with ultrasound or computerized tomography. After initial therapy with antibiotics, patients were discharged to home. ILA was performed 6 to 12 weeks later. RESULTS Twelve patients were included. Four patients had phlegmonous appendicitis and eight had an abscess, but only four had percutaneous drainage. All patients improved without surgical exploration and were subjected to ILA. ILA was successful in 11 of 12 patients ; a median hospital postoperative stay of 1 day was required, and no perioperative morbidity was encountered. All patients returned to routine activities within 2 weeks of surgery. CONCLUSIONS 1 ) Initial conservative management of patients with appendiceal abscess/phlegmon is prudent, safe, and effective. 2 ) Interval laparoscopic appendectomy can be performed safely and effectively Is early laparoscopic appendectomy feasible in children with acute appendicitis presenting with an appendiceal mass? A prospective study. BACKGROUND The management of an appendiceal mass remains controversial with 2 schools of thought ; early surgical intervention vs nonoperative management with or without interval appendectomy. The aim is to determine the role and safety of early laparoscopic appendectomy ( LA ) in children with acute appendicitis presenting with an appendiceal mass. METHODS This is a prospect i ve study of 88 consecutive pediatric patients who underwent attempted LA for suspected acute appendicitis at KK Women\'s and Children\'s Hospital, Singapore, between May and October 2003. RESULTS A total of 88 patients with a mean age of 10 + /- 3 years ( range, 3 - 16 years ) underwent LA for an appendiceal mass ( n = 22 ), simple appendicitis ( n = 36 ), other complicated ( gangrenous or perforated ) appendicitis ( n = 23 ), and a normal appendix ( n = 7 ). There were 7 conversions to open appendicectomy, 3 of which occurred in patients with an appendiceal mass. There were no perioperative or postoperative mortalities. Morbidity occurred in only one patient who underwent LA for perforated appendicitis. He had prolonged sepsis that resolved after 2 weeks of intravenous antibiotics. None of the patients with an appendiceal mass developed complications. Patients who underwent early LA for an appendiceal mass had a statistically significant ( P <.05 ) longer operating time ( median, 103 minutes ; interquartile range, 90 - 151 minutes, vs median, 87 minutes ; interquartile range, 71 - 112 minutes ), prolonged time to ambulation ( median, 2.0 days ; interquartile range, 2 - 2.5 days, vs median, 1.0 days ; interquartile, 1 - 2 days ), increased time to resumption of diet ( median, 4 days ; interquartile, 3 - 5 days, vs median, 2 days ; interquartile, 2 - 3 days ), and longer postoperative stay ( median, 6.0 days ; interquartile, 5.5 - 6.5 days, vs median, 4.0 days ; interquartile, 3 - 5.5 days ) compared with patients presenting with appendicitis without mass formation. However, there was no statistical difference in these parameters when LA for an appendiceal mass was compared with LA for other complicated appendicitis ( perforated and gangrenous ). CONCLUSION Although early LA for an appendiceal mass is a technically dem and ing procedure, it can be performed safely in children with minimal morbidity and mortality. In an era where patients\'dem and for " key-hole " surgery is rising, early LA is a safe and viable option in the management of children with an appendiceal mass. It also offers the advantage of avoiding misdiagnoses and the need for a second hospitalization Is a long delay necessary before appendectomy after appendiceal mass formation? A preliminary report. The st and ard treatment for an appendiceal mass is conservative therapy followed by appendectomy after 6 to 10 weeks. With the advent of antibiotics design ed to prevent the growth of anaerobes, early appendectomy can now be carried out without complication. The authors studied 56 patients with appendiceal mass formation, 26 ( group A ) treated conventionally and 30 ( group B ) treated by early appendectomy. In group B, the infection rate was 17 %, the mean operating time was 38.7 minutes, the mean hospital stay was 15 days and there was an early return to work. The corresponding parameters for group A were an infection rate of 8 %, a mean operating time of 35.2 minutes, a hospital stay of 19.1 days and a late return to work. Furthermore, 15 % of the patients in group A had a recurrent acute episode during the waiting period. Overall, early appendectomy appears to be a safe and cost-effective treatment for appendiceal mass formation Initial laparoscopic appendectomy versus initial nonoperative management and interval appendectomy for perforated appendicitis with abscess: a prospective, randomized trial. INTRODUCTION Perforated appendicitis is a common condition in children, which, in a small number of patients, may be complicated by a well-formed abscess. Initial nonoperative management with percutaneous drainage/aspiration of the abscess followed by intravenous antibiotics usually allows for an uneventful interval appendectomy. Although this strategy has become well accepted, there are no published data comparing initial nonoperative management ( drainage/interval appendectomy ) to appendectomy upon presentation with an abscess. Therefore, we conducted a r and omized trial comparing these 2 management strategies. METHODS After internal review board approval ( # 06 11 - 164 ), children who presented with a well-defined abdominal abscess by computed tomographic imaging were r and omized on admission to laparoscopic appendectomy or intravenous antibiotics with percutaneous drainage of the abscess ( when possible ), followed by interval laparoscopic appendectomy approximately 10 weeks later. This was a pilot study with a sample size of 40, which was based on our recent volume of patients presenting with appendicitis and abscess. RESULTS On presentation, there were no differences between the 2 groups regarding age, weight, body mass index, sex distribution, temperature, leukocyte count, number of abscesses, or greatest 2-dimensional area of abscess in the axial view. Regarding outcomes, there were no differences in length of total hospitalization, recurrent abscess rates, or overall charges. There was a trend toward a longer operating time in patients undergoing initial appendectomy ( 61 minutes versus 42 minutes mean, P =.06 ). CONCLUSIONS Although initial laparoscopic appendectomy trends toward a requiring longer operative time, there seems to be no advantages between these strategies in terms of total hospitalization, recurrent abscess rate, or total charges Treatment of appendiceal mass: prospective, randomized clinical trial. BACKGROUND Appendiceal mass may be treated in several ways. However, no r and omized trial has been conducted to find the best option. OBJECTIVE To compare the three most commonly used methods for treating appendiceal mass. METHODS Over a three-year period, 60 consecutive patients with appendiceal mass were r and omly allocated to three groups : Group A -- initial conservative treatment followed by interval appendectomy six weeks later ; Group B -- appendectomy as soon as appendiceal mass resolved using conservative means ; Group C -- conservative treatment alone. Short-term outcome measures included operative time, operative difficulty, postoperative complications, length of hospital stay, and duration of time away from work. Long-term outcome measures were : number of hospital visits made, presence of severe incisional pain, scar appearance, and patients with recurrent appendicitis. RESULTS Baseline characteristics were comparable in the three groups. In patients in Group A, operative time was less, adhesions were encountered less frequently, the incision had to be extended less often and post-operative complications were fewer, as compared to Group B. Patients in Group C had the shortest hospital stay and duration of work-days lost ; only 2 of 20 patients in this group developed recurrent appendicitis during a follow-up period of 24 - 52 ( median 33.5 ) months. CONCLUSION Of the three treatment modalities compared, conservative treatment without subsequent appendectomy appears to be the best', 'ABSTRACT Introduction : Results of previous clinical trials evaluating the effect of resveratrol supplementation on blood pressure ( BP ) are controversial. Purpose : We aim ed to assess the impact of resveratrol on BP through systematic review of literature and meta- analysis of available r and omized, controlled clinical trials ( RCTs ). Placebo-controlled, randomised clinical trial: high-dose resveratrol treatment for non-alcoholic fatty liver disease ABSTRACT Objective “ The obesity epidemic ” has led to an increase in obesity-related conditions including non-alcoholic fatty liver disease ( NAFLD ), for which effective treatments are in dem and. The polyphenol resveratrol prevents the development of experimental NAFLD through modulation of cellular pathways involved in calorie restriction. We aim ed to test the hypothesis that resveratrol alleviates NAFLD in a r and omised, clinical trial. Material s and methods A total of 28 overweight patients with transaminasemia and histological NAFLD were r and omised 1:1 to placebo or resveratrol 1.5 g daily for 6 months. Twenty-six participants completed the trial and underwent repeated clinical investigation, blood work, MR spectroscopy ; and 19 participants agreed to a repeat liver biopsy. Results Resveratrol treatment was generally not superior to placebo in improving plasma markers of liver injury ( primary outcome : alanine transaminase, p = 0.51 ). Resveratrol-treated patients showed a 3.8 % decrease in liver lipid content ( p = 0.03 ), with no difference between the two treatment arms ( p = 0.38 ) and no improvement of histological features. Resveratrol treatment was not associated with improvements in insulin sensitivity or markers of the metabolic syndrome, except for a transient decrease in systolic BP. Microarray analysis and qRT-PCR revealed no major changes in expression profile. Also, we report a serious adverse event in a patient who developed fever and bicytopenia. Conclusions In this placebo-controlled, high-dose and long-term study, resveratrol treatment had no consistent therapeutic effect in alleviating clinical or histological NAFLD, though there may be a small ameliorating effect on liver function tests and liver fat accumulation Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Resveratrol is a naturally occurring polyphenolic compound. Numerous animal studies have been reported on its wide-ranging beneficial effects in the biological system including diabetes mellitus ( DM ). We hypothesized, therefore, that oral supplementation of resveratrol would improve the glycemic control and the associated risk factors in patients with type 2 diabetes mellitus ( T2DM ). The present clinical study was therefore carried out to test the hypothesis. Sixty-two patients with T2DM were enrolled from Government Headquarters Hospital, Ootacamund, India, in a prospect i ve, open-label, r and omized, controlled trial. Patients were r and omized into control and intervention groups. The control group received only oral hypoglycemic agents, whereas the intervention group received resveratrol ( 250 mg/d ) along with their oral hypoglycemic agents for a period of 3 months. Hemoglobin A(1c ), lipid profile, urea nitrogen, creatinine, and protein were measured at the baseline and at the end of 3 months. The results reveal that supplementation of resveratrol for 3 months significantly improves the mean hemoglobin A(1c ) ( means ± SD, 9.99 ± 1.50 vs 9.65 ± 1.54 ; P <.05 ), systolic blood pressure ( mean ± SD, 139.71 ± 16.10 vs 127.92 ± 15.37 ; P <.05 ), total cholesterol ( mean ± SD, 4.70 ± 0.90 vs 4.33 ± 0.76 ; P <.05 ), and total protein ( mean ± SD, 75.6 ± 4.6 vs 72.3 ± 6.2 ; P <.05 ) in T2DM. No significant changes in body weight and high-density lipoprotein and low-density lipoprotein cholesterols were observed. Oral supplementation of resveratrol is thus found to be effective in improving glycemic control and may possibly provide a potential adjuvant for the treatment and management of diabetes Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus. Resveratrol has been reported to have potent anti-atherosclerotic effects in animal studies. However, there are few interventional studies in human patients with atherosclerogenic diseases. The cardio-ankle vascular index ( CAVI ) reflects arterial stiffness and is a clinical surrogate marker of atherosclerosis. The aim of the present study was to investigate the effect of resveratrol on arterial stiffness assessed by CAVI in patients with type 2 diabetes mellitus (T2DM).In this double-blind, r and omized, placebo-controlled study, 50 patients with T2DM received supplement of a 100 mg resveratrol tablet ( total resveratrol : oligo-stilbene 27.97 mg/100 mg/day ) or placebo daily for 12 weeks. CAVI was assessed at baseline and the end of study. Body weight ( BW ), blood pressure ( BP ), glucose and lipid metabolic parameters, and diacron-reactive oxygen metabolites ( d-ROMs ; an oxidative stress marker ) were also measured. Resveratrol supplementation decreased systolic BP ( -5.5 ± 13.0 mmHg ), d-ROMs ( -25.6 ± 41.8 U.CARR ), and CAVI ( -0.4 ± 0.7 ) significantly ( P < 0.05 ) and decreased BW ( -0.8 ± 2.1 kg, P = 0.083 ) and body mass index ( -0.5 ± 0.8 kg/m2, P = 0.092 ) slightly compared to baseline, while there were no significant changes in the placebo group. Decreases in CAVI and d-ROMs were significantly greater in the resveratrol group than in the placebo group. Multivariate logistic regression analysis identified resveratrol supplementation as an independent predictor for a CAVI decrease of more than 0.5.In conclusion, 12-week resveratrol supplementation may improve arterial stiffness and reduce oxidative stress in patients with T2DM. Resveratrol may be beneficial in preventing the development of atherosclerosis induced by diabetes. However, a large-scale cohort study is required to vali date the present findings Grape Resveratrol Increases Serum Adiponectin and Downregulates Inflammatory Genes in Peripheral Blood Mononuclear Cells: A Triple-Blind, Placebo-Controlled, One-Year Clinical Trial in Patients with Stable Coronary Artery Disease Purpose The grape and wine polyphenol resveratrol exerts cardiovascular benefits but evidence from r and omized human clinical trials is very limited. We investigated dose-depending effects of a resveratrol-containing grape supplement on stable patients with coronary artery disease ( CAD ) treated according to currently accepted guidelines for secondary prevention of cardiovascular disease. Methods In a triple-blind, r and omized, placebo-controlled, one-year follow-up, 3-arm pilot clinical trial, 75 stable-CAD patients received 350 mg/day of placebo, resveratrol-containing grape extract ( grape phenolics plus 8 mg resveratrol ) or conventional grape extract lacking resveratrol during 6 months, and a double dose for the following 6 months. Changes in circulating inflammatory and fibrinolytic biomarkers were analyzed. Moreover, the transcriptional profiling of inflammatory genes in peripheral blood mononuclear cells ( P BMC s ) was explored using microarrays and functional gene expression analysis. Results After 1 year, in contrast to the placebo and conventional grape extract groups, the resveratrol-containing grape extract group showed an increase of the anti-inflammatory serum adiponectin ( 9.6 %, p = 0.01 ) and a decrease of the thrombogenic plasminogen activator inhibitor type 1 ( PAI-1 ) ( −18.6 %, p = 0.05 ). In addition, 6 key inflammation-related transcription factors were predicted to be significantly activated or inhibited, with 27 extracellular-space acting genes involved in inflammation, cell migration and T-cell interaction signals presenting downregulation ( p < 0.05 ) in P BMC s. No adverse effects were detected in relation to the study products. Conclusions Chronic daily consumption of a resveratrol-containing grape nutraceutical could exert cardiovascular benefits in stable-CAD patients treated according to current evidence -based st and ards, by increasing serum adiponectin, preventing PAI-1 increase and inhibiting atherothrombotic signals in P BMC Antihyperglycemic Effects of Short Term Resveratrol Supplementation in Type 2 Diabetic Patients The objective of this study was to examine the effectiveness of resveratrol in lowering blood glucose in the presence of st and ard antidiabetic treatment in patients with type 2 diabetes, in a r and omized placebo-controlled double-blinded parallel clinical trial. A total of 66 subjects with type 2 diabetes were enrolled in this study and r and omly assigned to intervention group which was supplemented with resveratrol at a dose 1 g/day for 45 days and control group which received placebo tablets. Body weight, blood pressure, fasting blood glucose, haemoglobin A1c, insulin, homeostatic assessment s for insulin resistance, triglycerides, total cholesterol, low density lipoprotein, high density lipoprotein, and markers of liver and kidney damage were measured at baseline and after 45 days of resveratrol or placebo supplementation. Resveratrol treatment significantly decreased systolic blood pressure, fasting blood glucose, haemoglobin A1c, insulin, and insulin resistance, while HDL was significantly increased, when compared to their baseline levels. On the other h and, the placebo group had slightly increased fasting glucose and LDL when compared to their baseline levels. Liver and kidney function markers were unchanged in the intervention group. Overall, this study showed that resveratrol supplementation exerted strong antidiabetic effects in patients with type 2 diabetes Resveratrol increases bone mineral density and bone alkaline phosphatase in obese men: a randomized placebo-controlled trial. CONTEXT Metabolic syndrome ( MetS ) is associated with low- grade inflammation, which may harmfully affect bone. Resveratrol ( RSV ) possesses anti-inflammatory properties, and rodent studies suggest bone protective effects. OBJECTIVE This study sought to evaluate effects of RSV treatment on bone in men with MetS. SETTING AND DESIGN The study was conducted at Aarhus University Hospital as a r and omized, double-blinded, placebo-controlled trial assessing changes in bone turnover markers, bone mineral density ( BMD ), and geometry. PARTICIPANTS The study population comprised 74 middle-aged obese men with MetS recruited from the general community, of which 66 completed all visits. Mean age of participants was 49.3 ± 6.3 years and mean body mass index was 33.7 ± 3.6 kg/m(2 ). INTERVENTION Oral treatment with 1.000 mg RSV ( RSV(high ) ), 150 mg RSV ( RSV(low ) ), or placebo daily for 16 weeks. MAIN OUTCOME MEASURE Prespecified primary endpoint was change in bone alkaline phosphatase ( BAP ). RESULTS BAP increased dose dependently with RSV ( R = 0.471, P <.001 ), result ing in a significantly greater increase in BAP in the RSV(high ) group compared with placebo at all time-points ( week 4, 16.4 ± 4.2 %, P <.001 ; week 8, 16.5 ± 4.1 %, P <.001 ; week 16, 15.2 ± 3.7 %, P <.001 ). Lumbar spine trabecular volumetric bone mineral density ( LS vBMD(trab ) ) also increased dose dependently with RSV ( R = 0.268, P =.036 ), with a significant increase of 2.6 ± 1.3 % in the RSV(high ) group compared with placebo ( P =.043 ). In addition, changes in BAP and LS vBMD(trab ) were positively correlated ( R = 0.281, P =.027 ). No consistent changes were detected in bone density at the hip. CONCLUSIONS Our data suggest that high-dose RSV supplementation positively affects bone, primarily by stimulating formation or mineralization. Future studies of longer duration comprising population s at risk of osteoporosis are needed to confirm these results Resveratrol as Add-on Therapy in Subjects With Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial OBJECTIVE To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of st and ard diabetes care. RESEARCH DESIGN AND METHODS Seventeen subjects with well-controlled type 2 diabetes ( T2D ) were treated with placebo and 150 mg/day resveratrol ( resVida ) in a r and omized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique. RESULTS Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol ; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels ( R = −0.68, P = 0.03 ). Intramyocellular lipid content increased in type 2 muscle fibers ( P = 0.03 ), and systolic blood pressure tended to decrease ( P = 0.09 ) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function ( state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005 ). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol ( dihydroresveratrol ) and the metformin dose used by the patients ( R = 0.66, P = 0.005 ), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction. CONCLUSIONS Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. Non-alcoholic fatty liver disease ( NAFLD ) is usually associated with insulin resistance, central obesity, reduced glucose tolerance, type 2 diabetes mellitus and hypertriacylglycerolaemia. The beneficial effects of resveratrol on metabolic disorders have been shown previously. The aim of this study was to evaluate the effects of resveratrol supplementation on cardiovascular risk factors in patients with NAFLD. In this r and omised double-blinded placebo-controlled clinical trial, fifty NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks. Both groups were advised to follow an energy-balanced diet and physical activity recommendations. resveratrol supplementation reduced alanine aminotransferase ( ALT ) and hepatic steatosis significantly more than placebo ( P0·05 ). There were no significant changes in blood pressure, insulin resistance markers and TAG in either group ( P>0·05 ). Our data have shown that 12-week supplementation of 500 mg resveratrol does not have any beneficial effect on anthropometric measurements, insulin resistance markers, lipid profile and blood pressure ; however, it reduced ALT and hepatic steatosis in patients with NAFLD Resveratrol does not benefit patients with nonalcoholic fatty liver disease. BACKGROUND & AIMS Nonalcoholic fatty liver disease ( NAFLD ), characterized by accumulation of hepatic triglycerides ( steatosis ), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. METHODS Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were r and omly assigned to groups given 3000 mg resveratrol ( n = 10 ) or placebo ( n = 10 ) daily for 8 weeks. Outcomes included insulin resistance ( assessed by the euglycemic-hyperinsulinemic clamp ), hepatic steatosis, and abdominal fat distribution ( assessed by magnetic resonance spectroscopy and imaging ). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured ; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. RESULTS Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. CONCLUSIONS Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no : ACTRN12612001135808 Chronic resveratrol consumption improves brachial flow-mediated dilatation in healthy obese adults Background : We have previously demonstrated acute dose-dependent increases of flow-mediated dilatation ( FMD ) in the brachial artery after resveratrol consumption in mildly hypertensive, overweight/obese adults. Resveratrol supplementation has also been shown to increase cerebral blood flow acutely, without affecting cognition. Objectives : To evaluate the effects of chronic resveratrol supplementation on both FMD and cognitive performance. Method : Twenty-eight obese but otherwise healthy adults ( BMI : 33.3 ± 0.6 kg/m2 ) were r and omized to take a single 75 mg capsule of trans-resveratrol ( Resvida ) or placebo daily for 6 weeks each in a double-blind crossover supplementation trial. Blood pressure, arterial compliance, FMD, and performance on the Stroop Color-Word Test were assessed at the end of each 6-week intervention period while fasted and at least 18 h after taking the last daily capsule. An additional capsule of the same supplement was then taken. FMD assessment was repeated 1 h later. Results : Chronic resveratrol supplementation for 6 weeks was well tolerated and result ed in a 23 % increase in FMD compared with placebo ( P = 0.021, paired t-test ). The extent of increase correlated negatively with baseline FMD ( r = −0.47, P = 0.01 ). A single dose of resveratrol ( 75 mg ) following chronic resveratrol supplementation result ed in a 35 % greater acute FMD response than the equivalent placebo supplementation. These FMD improvements remained significant after adjusting for baseline FMD. Blood pressure, arterial compliance, and all components of the Stroop Color-Word Test were unaffected by chronic resveratrol supplementation. Conclusion : Daily resveratrol consumption was well tolerated and has the potential to maintain healthy circulatory function in obese adults', 'QUESTIONS In people with Parkinson\'s disease, does home-based prescribed exercise improve balance-related activities and quality of life compared with no intervention? Are the effects of home-based exercise similar to those of equivalent centre-based exercise? Exercise for falls prevention in Parkinson disease Objective : To determine whether falls can be prevented with minimally supervised exercise targeting potentially remediable fall risk factors, i.e., poor balance, reduced leg muscle strength, and freezing of gait, in people with Parkinson disease. Methods : Two hundred thirty-one people with Parkinson disease were r and omized into exercise or usual-care control groups. Exercises were practice d for 40 to 60 minutes, 3 times weekly for 6 months. Primary outcomes were fall rates and proportion of fallers during the intervention period. Secondary outcomes were physical ( balance, mobility, freezing of gait, habitual physical activity ), psychological ( fear of falling, affect ), and quality -of-life measures. Results : There was no significant difference between groups in the rate of falls ( incidence rate ratio [ IRR ] = 0.73, 95 % confidence interval [ CI ] 0.45–1.17, p = 0.18 ) or proportion of fallers ( p = 0.45 ). Preplanned subgroup analysis revealed a significant interaction for disease severity ( p < 0.001 ). In the lower disease severity subgroup, there were fewer falls in the exercise group compared with controls ( IRR = 0.31, 95 % CI 0.15–0.62, p < 0.001 ), while in the higher disease severity subgroup, there was a trend toward more falls in the exercise group ( IRR = 1.61, 95 % CI 0.86–3.03, p = 0.13 ). Postintervention, the exercise group scored significantly ( p < 0.05 ) better than controls on the Short Physical Performance Battery, sit-to-st and, fear of falling, affect, and quality of life, after adjusting for baseline performance. Conclusions : An exercise program targeting balance, leg strength, and freezing of gait did not reduce falls but improved physical and psychological health. Falls were reduced in people with milder disease but not in those with more severe Parkinson disease. Classification of evidence : This study provides Class III evidence that for patients with Parkinson disease, a minimally supervised exercise program does not reduce fall risk. This study lacked the precision to exclude a moderate reduction or modest increase in fall risk from exercise. Trial registration : Australian New Zeal and Clinical Trials Registry ( ACTRN12608000303347 ) The PIT: SToPP Trial—A Feasibility Randomised Controlled Trial of Home-Based Physiotherapy for People with Parkinson\'s Disease Using Video-Based Measures to Preserve Assessor Blinding Purpose. To trial four-week\'s physiotherapy targeting chair transfers for people with Parkinson\'s disease ( PwPD ) and explore the feasibility of reliance on remote outcome measurement to preserve blinding. Scope. We recruited 47 PwPD and r and omised 24 to a focused home physiotherapy programme ( exercise, movement strategies, and cueing ) and 23 to a control group. We evaluated transfers ( plus mobility, balance, posture, and quality of life ) before and after treatment and at followup ( weeks 0, 4, 8, and 12 ) from video produced by, and question naires distributed by, treating physiotherapists. Participants fed back via end-of- study question naires. Thirty-five participants ( 74 % ) completed the trial. Excluding dropouts, 20 % of question naire data and 9 % of video data were missing or unusable ; we had to evaluate balance in situ. We noted trends to improvement in transfers, mobility, and balance in the physiotherapy group not noted in the control group. Participant feedback was largely positive and assessor blinding was maintained in every case. Conclusions. Intense, focused physiotherapy at home appears acceptable and likely to bring positive change in those who can participate. Remote outcome measurement was successful ; question naire followup and further training in video production would reduce missing data. We advocate a fully powered trial, design ed to minimise dropouts and preserve assessor blinding, to evaluate this intervention Home-based step training using videogame technology in people with Parkinson’s disease: a single-blinded randomised controlled trial Objectives : To determine whether 12-week home-based exergame step training can improve stepping performance, gait and complementary physical and neuropsychological measures associated with falls in Parkinson ’s disease. Design : A single-blinded r and omised controlled trial. Setting : Community ( experimental intervention ), university laboratory ( outcome measures ). Subjects : Sixty community-dwelling people with Parkinson ’s disease. Interventions : Home-based step training using videogame technology. Main measures : The primary outcomes were the choice stepping reaction time test and Functional Gait Assessment. Secondary outcomes included physical and neuropsychological measures associated with falls in Parkinson ’s disease, number of falls over six months and self-reported mobility and balance. Results : Post intervention, there were no differences between the intervention ( n = 28 ) and control ( n = 25 ) groups in the primary or secondary outcomes except for the Timed Up and Go test, where there was a significant difference in favour of the control group ( P = 0.02 ). Intervention participants reported mobility improvement, whereas control participants reported mobility deterioration — between-group difference on an 11-point scale = 0.9 ( 95 % confidence interval : −1.8 to −0.1, P = 0.03 ). Interaction effects between intervention and disease severity on physical function measures were observed ( P = 0.01 to P = 0.08 ) with seemingly positive effects for the low-severity group and potentially negative effects for the high-severity group. Conclusion : Overall, home-based exergame step training was not effective in improving the outcomes assessed. However, the improved physical function in the lower disease severity intervention participants as well as the self-reported improved mobility in the intervention group suggest home-based exergame step training may have benefits for some people with Parkinson ’s disease Balance training in individuals with Parkinson\'s disease: Therapist-supervised vs. home-based exercise programme. BACKGROUND Poor locomotion and balance in Parkinson\'s disease ( PD ) often diminishes independence. Accordingly, gait is considered one of the most relevant rehabilitation outcomes, and home-based balance exercises might be a viable mode of exercise delivery for individuals with PD. However, research on PD interventions rarely indicate best practice s to deliver exercises. Therefore, this study endeavoured to compare the efficacy of a home-based and therapist-supervised balance programme on gait parameters, dynamic balance, balance confidence and motivation in individuals diagnosed with PD. METHODS An experimental study design, including a cluster r and omized convenience sample, of 40 participants with idiopathic PD ( Hoehn and Yahr stage I-III ; age : 65.0±7.7years ). Participants were divided into a therapist-supervised ( n=24 ) and home-based group ( n=16 ). Groups received either eight weeks of balance training with an exercise therapist or a DVD. Outcome measures include the instrumented Timed-Up- and -Go, Functional Gait Analysis ( FGA ), Activity-specific Balance confidence ( ABC ) scale and Intrinsic Motivation Inventory ( IMI ). RESULTS Both groups improved in stride length ( p<0.05 ). Similar FGA improved by 9 % and 16 % in the therapist-supervised and home-based group, respectively ( p<0.01 ). Only the therapist-supervised group showed improvements in ABC ( p=0.051 ), stride velocity ( p=0.0006 ) and cadence ( p=0.046 ) over the intervention ; the latter two were also better compared to home-based ( p<0.05 ). Furthermore the therapist-supervised group were more motivated ( p=002 ). CONCLUSION The home-based balance programme was effective in improving some aspects of gait, albeit the programme supervised by an exercise therapist included somewhat more benefits after the intervention i.e. stride velocity and cadence in individuals with mild to moderate PD A home program of strength training, movement strategy training and education did not prevent falls in people with Parkinson\'s disease: a randomised trial. QUESTIONS For people with idiopathic Parkinson\'s disease, does a 6-week, comprehensive, home exercise program reduce falls and disability and improve health-related quality of life? Is the program cost-effective? DESIGN R and omised, controlled trial with concealed allocation and assessor blinding. PARTICIPANTS One hundred and thirty-three community-dwelling adults with Parkinson\'s disease. INTERVENTION The experimental group completed a 6-week home program comprising progressive resistance strength training, movement strategy training and falls education. The control group completed 6 weeks of non-specific life skills training. Participants in both groups received weekly therapist-guided sessions for 6 consecutive weeks and a weekly self-directed home program. OUTCOME MEASURES The primary outcome was the rate of falls, documented for the 12-month period immediately after therapy. Secondary outcomes were disability and health-related quality of life, assessed before and after intervention and at a 12-month follow-up. RESULTS A total of 2255 falls were reported by the 12-month follow-up. The proportion of fallers in the experimental and control groups was 61 and 72 %, respectively, which was not statistically significantly different ( RR=0.85, 95 % CI 0.66 to 1.09 ). There was no significant between-group difference in the rate of falls ( incidence rate ratio=1.58, 95 % CI 0.73 to 3.43 ). A survival analysis of participant time to first fall did not show a significant between-group difference ( log-rank test χ2=0.79, p=0.37 ). No significant between-group differences occurred for mobility, disability or quality of life. The mean cost of delivering the experimental intervention was AUD1596. CONCLUSION A home program of strength and movement strategy training and falls education does not prevent falls when applied at the dose used in this study. Arguably, the dosage of therapy was insufficient. Future trials need to explore further therapy content, repetitions and duration, in order to optimise outcomes and cost-effectiveness. [ Morris ME, Taylor NF, Watts JJ, Evans A, Horne M, Kempster P, Danoudis M, McGinley J, Martin C, Menz HB ( 2017 ) A home program of strength training, movement strategy training and education did not prevent falls in people with Parkinson\'s disease : a r and omised trial. Journal of Physiotherapy 63 : 94 - 100 ] Virtual Reality Telerehabilitation for Postural Instability in Parkinson\'s Disease: A Multicenter, Single-Blind, Randomized, Controlled Trial Introduction Telerehabilitation enables patients to access remote rehabilitation services for patient-physiotherapist videoconferencing in their own homes. Home-based virtual reality ( VR ) balance training has been shown to reduce postural instability in patients with Parkinson\'s disease ( PD ). The primary aim was to compare improvements in postural stability after remotely supervised in-home VR balance training and in-clinic sensory integration balance training ( SIBT ). Methods In this multicenter study, 76 PD patients ( modified Hoehn and Yahr stages 2.5–3 ) were r and omly assigned to receive either in-home VR telerehabilitation ( n = 38 ) or in-clinic SIBT ( n = 38 ) in 21 sessions of 50 minutes each, 3 days/week for 7 consecutive weeks. VR telerehabilitation consisted of grade d exergames using the Nintendo Wii Fit system ; SIBT included exercises to improve postural stability. Patients were evaluated before treatment, after treatment, and at 1-month follow-up. Results Analysis revealed significant between-group differences in improvement on the Berg Balance Scale for the VR telerehabilitation group ( p = 0.04 ) and significant Time × Group interactions in the Dynamic Gait Index ( p = 0.04 ) for the in-clinic group. Both groups showed differences in all outcome measures over time, except for fall frequency. Cost comparison yielded between-group differences in treatment and equipment costs. Conclusions VR is a feasible alternative to in-clinic SIBT for reducing postural instability in PD patients having a caregiver Home-based treadmill training for individuals with Parkinson’s disease: a randomized controlled pilot trial Objective : To investigate the feasibility and effectiveness of six weeks of home-based treadmill training in people with mild Parkinson ’s disease. Design : Pilot r and omized controlled trial of a six-week intervention followed by a further six weeks follow-up. Setting : Home-based treadmill training with outcome measures taken at a hospital clinic. Participants : Twenty cognitively intact participants with mild Parkinson ’s disease and gait disturbance. Two participants from the treadmill training group and one from the control group dropped out. Interventions : The treadmill training group undertook a semi-supervised home-based programme of treadmill walking for 20–40 minutes, four times a week for six weeks. The control group received usual care. Main outcome measures : The feasibility of the intervention was assessed by recording exercise adherence and acceptability, exercise intensity, fatigue, muscle soreness and adverse events. The primary outcome measure of efficacy was walking capacity ( 6-minute walk test distance ). Results : Home-based treadmill training was feasible, acceptable and safe with participants completing 78 % ( SD 36 ) of the prescribed training sessions. The treadmill training group did not improve their walking capacity compared to the control group. The treadmill training group showed a greater improvement than the control group in fatigue at post test ( P = 0.04 ) and in quality of life at six weeks follow-up testing ( P = 0.02 ). Conclusions : Semi-supervised home-based treadmill training is a feasible and safe form of exercise for cognitively intact people with mild Parkinson ’s disease. Further investigation regarding the effectiveness of home-based treadmill training is warranted Minimal Detectable Change of the Timed “Up & Go” Test and the Dynamic Gait Index in People With Parkinson Disease Background The minimal detectable change ( MDC ) is the smallest amount of difference in individual scores that represents true change ( beyond r and om measurement error ). The MDCs of the Timed “ Up & Go ” Test ( TUG ) and the Dynamic Gait Index ( DGI ) in people with Parkinson disease ( PD ) are largely unknown, limiting the interpretability of the change scores of both measures. Objective The purpose of this study was to estimate the MDCs of the TUG and the DGI in people with PD. Design This investigation was a prospect i ve cohort study. Methods Seventy-two participants were recruited from special clinics for movement disorders at a university hospital. Their mean age was 67.5 years, and 61 % were men. All participants completed the TUG and the DGI assessment s twice, about 14 days apart. The MDC was calculated from the st and ard error of measurement. The percentage MDC ( MDC% ) was calculated as the MDC divided by the mean of all scores for the sample. Furthermore, the intraclass correlation coefficient was used to examine the reproducibility between testing sessions ( test-retest reliability ). Results The respective MDC and MDC% of the TUG were 3.5 seconds and 29.8, and those of the DGI were 2.9 points and 13.3. The test-retest reliability values for the TUG and the DGI were high ; the intraclass correlation coefficients were.80 and.84, respectively. Limitations The study sample was a convenience sample, and the participants had mild to moderately severe PD. Conclusions The results showed that the TUG and the DGI have generally acceptable r and om measurement error and test-retest reliability. These findings should help clinicians and research ers determine whether a change in an individual patient with PD is a true change Comparison of the effects of a physiotherapist-supervised exercise programme and a self-supervised exercise programme on quality of life in patients with Parkinson’s disease Objectives : To compare the effects of a physiotherapist-supervised exercise programme in an exercise unit and self-supervised home exercise programme on quality of life in patients with Parkinson ’s disease. Design : Assessor-blinded, quasi-r and omized trial ( alternate allocation ). Setting : An outpatient exercise unit ; home setting s. Participants : Thirty patients with idiopathic Parkinson ’s disease, Hoehn & Yahr I — III, stable medication use. Interventions : Patients were included in the physiotherapist-supervised or home group. The exercise programme was performed for 10 weeks, three times/week either under the supervision of a physiotherapist or at home without supervision. Main outcome measures : Parkinson ’s Disease Quality of Life Question naire ( PDQLQ ), Nottingham Health Profile ( NHP ), Unified Parkinson ’s Disease Rating Scale ( UPDRS ), Beck Depression Inventory ( BDI ). Results : Patients in the supervised physiotherapy group improved more than the home exercise group in Parkinson ’s Disease Quality of Life Question naire ( total score, Parkinson ’s symptoms, emotional function ), Nottingham Health Profile total, Unified Parkinson ’s Disease Rating Scale ( all domains ) and Beck Depression Inventory scores. Conclusions : The exercise programme under physiotherapist supervision was found to be more effective at improving activities of daily living, motor, mental, emotional functions and general health quality in patients with Parkinson ’s disease compared with a self-supervised home programme An exercise intervention to prevent falls in Parkinson’s: an economic evaluation Background People with Parkinson ’s ( PwP ) experience frequent and recurrent falls. As these falls may have devastating consequences, there is an urgent need to identify cost-effective interventions with the potential to reduce falls in PwP. The purpose of this economic evaluation is to compare the costs and cost-effectiveness of a targeted exercise programme versus usual care for PwP who were at risk of falling. Methods One hundred and thirty participants were recruited through specialist clinics, primary care and Parkinson ’s support groups and r and omised to either an exercise intervention or usual care. Health and social care utilisation and health-related quality of life ( EQ-5D ) were assessed over the 20 weeks of the study ( ten-week intervention period and ten-week follow up period ), and these data were complete for 93 participants. Incremental cost per quality adjusted life year ( QALY ) was estimated. The uncertainty around costs and QALYs was represented using cost-effectiveness acceptability curves. Results The mean cost of the intervention was £ 76 per participant. Although in direction of favour of exercise intervention, there was no statistically significant differences between groups in total healthcare ( −£128, 95 % CI : -734 to 478 ), combined health and social care costs ( £ -35, 95 % CI : -817 to 746 ) or QALYs ( 0.03, 95 % CI : -0.02 to 0.03 ) at 20 weeks. Nevertheless, exploration of the uncertainty surrounding these estimates suggests there is more than 80 % probability that the exercise intervention is a cost-effective strategy relative to usual care. Conclusion Whilst we found no difference between groups in total healthcare, total social care cost and QALYs, analyses indicate that there is high probability that the exercise intervention is cost-effective compared with usual care. These results require confirmation by larger trial-based economic evaluations and over the longer term The effects of an exercise program on fall risk factors in people with Parkinson\'s disease: a randomized controlled trial. This r and omized controlled trial with blinded assessment aim ed to determine the effect of a 6-month minimally supervised exercise program on fall risk factors in people with Parkinson\'s disease ( PD ). Forty-eight participants with PD who had fallen or were at risk of falling were r and omized into exercise or control groups. The exercise group attended a monthly exercise class and exercised at home three times weekly. The intervention targeted leg muscle strength, balance, and freezing. The primary outcome measure was a PD falls risk score. The exercise group had no major adverse events and showed a greater improvement than the control group in the falls risk score, which was not statistically significant ( between group mean difference = -7 %, 95 % CI -20 to 5, P = 0.26 ). There were statistically significant improvements in the exercise group compared with the control group for two secondary outcomes : Freezing of Gait Question naire ( P = 0.03 ) and timed sit-to-st and ( P = 0.03 ). There were statistically nonsignificant trends toward greater improvements in the exercise group for measures of muscle strength, walking, and fear of falling, but not for the measures of st and ing balance. Further investigation of the impact of exercise on falls in people with PD is warranted Exercise and Motor Training in People with Parkinson\'s Disease: A Systematic Review of Participant Characteristics, Intervention Delivery, Retention Rates, Adherence, and Adverse Events in Clinical Trials There is research evidence that exercise and motor training are beneficial for people with Parkinson\'s disease ( PD ), and clinicians seek to implement optimal programs. This paper summarizes important factors about the nature and reporting of r and omized controlled trials of exercise and /or motor training for people with PD which are likely to influence the translation of research into clinical practice. Search es identified 53 relevant trials with 90 interventions conducted for an average duration of 8.3 ( SD 4.2 ) weeks. Most interventions were fully supervised ( 74 % ) and conducted at a facility ( 79 % ). Retention rates were high with 69 % of interventions retaining ≥85 % of their participants ; however adherence was infrequently reported, and 72 % of trials did not report adverse events. Overall, the labor-intensive nature of most interventions tested in these trials and the sparse reporting of adherence and adverse events are likely to pose difficulties for therapists attempting to balance benefits and costs when selecting protocol s that translate to sustainable clinical practice for people with PD The Effects of Highly Challenging Balance Training in Elderly With Parkinson’s Disease Background. Highly challenging exercises have been suggested to induce neuroplasticity in individuals with Parkinson ’s disease ( PD ) ; however, its effect on clinical outcomes remains largely unknown. Objective. To evaluate the short-term effects of the HiBalance program, a highly challenging balance-training regimen that incorporates both dual-tasking and PD-specific balance components, compared with usual care in elderly with mild to moderate PD. Methods. Participants with PD ( n = 100 ) were r and omized, either to the 10-week HiBalance program ( n = 51 ) or to the control group ( n = 49 ). Participants were evaluated before and after the intervention. The main outcomes were balance performance ( Mini-BESTest ), gait velocity ( during normal and dual-task gait ), and concerns about falling ( Falls Efficacy Scale – International ). Performance of a cognitive task while walking, physical activity level ( average steps per day ), and activities of daily living were secondary outcomes. Results. A total of 91 participants completed the study. After the intervention, the between group comparison showed significantly improved balance and gait performance in the training group. Moreover, although no significant between group difference was observed regarding gait performance during dual-tasking ; the participants in the training group improved their performance of the cognitive task while walking, as compared with the control group. Regarding physical activity levels and activities of daily living, in comparison to the control group, favorable results were found for the training group. No group differences were found for concerns about falling. Conclusions. The HiBalance program significantly benefited balance and gait abilities when compared with usual care and showed promising transfer effects to everyday living. Long-term follow-up assessment s will further explore these effects Effects of home exercises on motor performance in patients with Parkinson\'s disease Objective : To investigate the effect of home exercises on the motor performance of patients with Parkinson\'s disease. Design : A prospect i ve blinded study with allocation of patients into their groups by alternate weeks. Setting : A University Hospital neurology and physiotherapy department. Subjects : Recruited from a movement disorders outpatient clinic of Cerrahpasa School of Medicine diagnosed with Parkinson\'s disease, classified as Hoehn and Yahr Grade s I, II and III. Interventions : Patients who fulfilled the inclusion criteria were recruited to the study. Each patient was evaluated at the end of first and second month after the baseline evaluation. Patients were divided into two groups. Those in the first and third week were put in the exercise group and second and fourth week in the control group. Patients in the exercise group ( n=15 ) were given a schedule of exercises to undertake at home ; the others ( n=15 ) did not receive this instruction. Measures : Ten- and 20-m walking test, first pace length, pace number in 10 m, walking around a chair, Nine Hole Peg Board ( NHPB ) test. Results : Following the home exercise programme, patients in the exercise group showed improvement in walking 10 and 20 m, time elapsed to complete walking around a chair and length of the first pace length, and in the motor performance of both h and s ( p < 0.001 ). Conclusions : A home-based rehabilitation programme for patients with Parkinson\'s disease helped to improve motor performance compared to patients who did not take advantage of a regular, professionally design ed exercise programme Reliability of measurements obtained with the Timed "Up & Go" test in people with Parkinson disease. BACKGROUND AND PURPOSE The Timed " Up & Go " Test ( TUG ) is used to measure the ability of patients to perform sequential locomotor tasks that incorporate walking and turning. This study investigated the retest reliability, interrater reliability, and sensitivity of scores obtained with the TUG in detecting changes in mobility in subjects with idiopathic Parkinson disease ( PD ). SUBJECTS The performance of 12 people with PD was compared with that of 12 age-matched comparison subjects without PD. METHODS The subjects with PD completed 5 trials of the TUG after withdrawal of levodopa for 12 hours ( " off " phase of the medication cycle ) as well as an additional 5 trials 1 hour after levodopa was administered ( " on " phase of the medication cycle ). They were scored on the Modified Webster Scale at both sessions. The comparison subjects also performed 5 TUG trials. All trials were videotaped and timed by 2 experienced raters. The videotape was later rated by 3 experienced clinicians and 3 inexperienced clinicians. RESULTS For the subjects with PD, within-session performance was highly consistent, with correlations ( r ) ranging from.80 to.98 for the " off " phase and from.73 to.99 for the " on " phase. The performance of the comparison subjects across the 5 trials was also highly consistent ( r=.90-.97 ). Comparisons showed differences between trials 1 and 2 on the TUG for both groups. Removal of data for trial 1 ( the practice trial ) further enhanced retest reliability. There was close agreement in TUG scores among raters despite different levels of experience ( intraclass correlation coefficient [3,1]=.87-.99 ). Mean TUG scores were different between the " on " and " off " phases of the levodopa cycle and between subjects with PD and comparison subjects during the " on " phase. CONCLUSION AND DISCUSSION Retest reliability and interrater reliability of the TUG measurements were high, and the measurements reflected changes in performance according to levodopa use. The TUG can also be used to detect differences in performance between people with PD and elderly people without PD Comparison of Reliability, Validity, and Responsiveness of the Mini-BESTest and Berg Balance Scale in Patients With Balance Disorders Background Recently, a new tool for assessing dynamic balance impairments has been presented : the 14-item Mini-BESTest. Objective The aim of this study was to compare the psychometric performance of the Mini-BESTest and the Berg Balance Scale ( BBS ). Design A prospect i ve, single-group, observational design was used in the study. Methods Ninety-three participants ( mean age=66.2 years, SD=13.2 ; 53 women, 40 men ) with balance deficits were recruited. Interrater ( 3 raters ) and test-retest ( 1–3 days ) reliability were calculated using intraclass correlation coefficients ( ICCs ). Responsiveness and minimal important change were assessed ( after 10 sessions of physical therapy ) using both distribution-based and anchor-based methods ( external criterion : the 15-point Global Rating of Change [ GRC ] scale ). Results At baseline, neither floor effects nor ceiling effects were found in either the Mini-BESTest or the BBS. After treatment, the maximum score was found in 12 participants ( 12.9 % ) with BBS and in 2 participants ( 2.1 % ) with Mini-BESTest. Test-retest reliability for total scores was significantly higher for the Mini-BESTest ( ICC=.96 ) than for the BBS ( ICC=.92 ), whereas interrater reliability was similar ( ICC=.98 versus.97, respectively ). The st and ard error of measurement ( SEM ) was 1.26 and the minimum detectable change at the 95 % confidence level ( MDC95 ) was 3.5 points for Mini-BESTest, whereas the SEM was 2.18 and the MDC95 was 6.2 points for the BBS. In receiver operating characteristic curves, the area under the curve was 0.92 for the Mini-BESTest and 0.91 for the BBS. The best minimal important change ( MIC ) was 4 points for the Mini-BESTest and 7 points for the BBS. After treatment, 38 participants evaluated with the Mini-BESTest and only 23 participants evaluated with the BBS ( out of the 40 participants who had a GRC score of ≥3.5 ) showed a score change equal to or greater than the MIC values. Limitations The consecutive sampling method drawn from a single rehabilitation facility and the intrinsic weakness of the GRC for calculating MIC values were limitations of the study. Conclusions The 2 scales behave similarly, but the Mini-BESTest appears to have a lower ceiling effect, slightly higher reliability levels, and greater accuracy in classifying individual patients who show significant improvement in balance function Validating the Berg Balance Scale for patients with Parkinson\'s disease: a key to rehabilitation evaluation. OBJECTIVE To assess the criterion-related validity of the Berg Balance Scale ( BBS ) in subjects with Parkinson\'s disease ( PD ). DESIGN Prospect i ve, correlational analysis between the BBS and accepted measures of PD motor and functional impairment. SETTING The federally funded PD research center, an interdisciplinary center of excellence for people with PD within a Veterans Affairs medical center. PARTICIPANTS Thirty-eight men ( average + /- st and ard deviation, 71.1+/-10.5 y ) with confirmed PD. Their initial diagnosis had been made on average 5.8+/-3.6 years earlier. All could st and or walk unassisted and had mild to moderate disability. Patients who could not ambulate without assistive devices were excluded. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Correlational analyses between the BBS and the Unified Parkinson\'s Disease Rating Scale ( UPDRS ) motor scale, Modified Hoehn and Yahr Staging ( Hoehn and Yahr ) Scale, and the Modified Schwab and Engl and Capacity for Daily Living Scale ( S&E ADL Scale ). RESULTS BBS score showed significant correlations with indicators of motor functioning, stage of disease, and daily living capacity. BBS score was inversely associated with the UPDRS motor score ( -.58, P <.005 ), Hoehn and Yahr Scale staging ( -.45, P <.005 ), and S&E ADL Scale rating (.55, P <.005 ). In all 3 correlations, lower scores on the BBS ( indicating greater balance deficits ) correlated with higher UPDRS scores ( indicating greater motoric or functional impairment ). CONCLUSIONS Results support the criterion-related validity of the BBS. Its utility in other balance conditions of older adults has been established. Rehabilitation interventions have been shown to improve the balance deficits associated with PD. Early referral and periodic re assessment is vital to achieving and maintaining improvements. Our research results agree with other published research in suggesting that the BBS may be used as a screening tool and ongoing assessment tool for patients with PD Reliability of the PEDro scale for rating quality of randomized controlled trials. BACKGROUND AND PURPOSE Assessment of the quality of r and omized controlled trials ( RCTs ) is common practice in systematic review s. However, the reliability of data obtained with most quality assessment scales has not been established. This report describes 2 studies design ed to investigate the reliability of data obtained with the Physiotherapy Evidence Data base ( PEDro ) scale developed to rate the quality of RCTs evaluating physical therapist interventions. METHOD In the first study, 11 raters independently rated 25 RCTs r and omly selected from the PEDro data base. In the second study, 2 raters rated 120 RCTs r and omly selected from the PEDro data base, and disagreements were resolved by a third rater ; this generated a set of individual rater and consensus ratings. The process was repeated by independent raters to create a second set of individual and consensus ratings. Reliability of ratings of PEDro scale items was calculated using multirater kappas, and reliability of the total ( summed ) score was calculated using intraclass correlation coefficients ( ICC [ 1,1 ] ). RESULTS The kappa value for each of the 11 items ranged from.36 to.80 for individual assessors and from.50 to.79 for consensus ratings generated by groups of 2 or 3 raters. The ICC for the total score was.56 ( 95 % confidence interval=.47-.65 ) for ratings by individuals, and the ICC for consensus ratings was.68 ( 95 % confidence interval=.57-.76 ). DISCUSSION AND CONCLUSION The reliability of ratings of PEDro scale items varied from " fair " to " substantial, " and the reliability of the total PEDro score was " fair " to " good. A randomised controlled trial of a home based exercise programme to reduce the risk of falling among people with Parkinson’s disease Objective : To evaluate the effectiveness of a personalised home programme of exercises and strategies for repeat fallers with Parkinson ’s disease ( PD ). Method : Patients with a confirmed diagnosis of idiopathic PD, independently mobile, living at home in the community, experiencing more than one fall in the previous 12 months and with intact gross cognitive function were invited to participate in this r and omised controlled trial. Usual care was compared with a personalised 6 week, home based exercise and strategy programme. The primary outcomes were rates of falling at 8 weeks and 6 months. Whether participants had repeat fallen, nearly fallen or experienced injurious falls were also examined. Functional Reach, the Berg Balance Test, PD Self- assessment Scale and the Euro Quol were rated by a blinded assessor. Results : Participants were r and omised to the exercise ( n = 70 ) and control ( n = 72 ) groups. There was a consistent trend towards lower fall rates in the exercise group at both 8 weeks and 6 months and lower rates of injurious falls needing medical attention at 6 months. Lower rates of repeat near falling were evident for the exercise group at 8 weeks ( p = 0.004 ) and 6 months ( p = 0.007 ). There was a positive effect of exercises at 6 months on Functional Reach ( p = 0.009 ) and quality of life ( p = 0.033 ). No significant differences were found on other secondary outcomes measures. Conclusion : There was a trend towards a reduction in fall events and injurious falls with a positive effect of exercises on near falls and quality of life A Randomized Controlled Trial to Reduce Falls in People With Parkinson’s Disease Background. Falls are common and disabling in people with Parkinson ’s disease ( PD ). There is a need to quantify the effects of movement rehabilitation on falls in PD. Objective. To evaluate 2 physical therapy interventions in reducing falls in PD. Methods. We r and omized 210 people with PD to 3 groups : progressive resistance strength training coupled with falls prevention education, movement strategy training combined with falls prevention education, and life-skills information ( control ). All received 8 weeks of out-patient therapy once per week and a structured home program. The primary end point was the falls rate, recorded prospect ively over a 12 month period, starting from the completion of the intervention. Secondary outcomes were walking speed, disability, and quality of life. Results. A total of 1547 falls were reported for the trial. The falls rate was higher in the control group compared with the groups that received strength training or strategy training. There were 193 falls for the progressive resistance strength training group, 441 for the movement strategy group and 913 for the control group. The strength training group had 84.9 % fewer falls than controls ( incidence rate ratio [ IRR ] = 0.151, 95 % CI 0.071 - 0.322, P <.001 ). The movement strategy training group had 61.5 % fewer falls than controls ( IRR = 0.385, 95 % CI 0.184 - 0.808, P =.012 ). Disability scores improved in the intervention groups following therapy while deteriorating in the control group. Conclusions. Rehabilitation combining falls prevention education with strength training or movement strategy training reduces the rate of falls in people with mild to moderately severe PD and is feasible Cueing training in the home improves gait-related mobility in Parkinson’s disease: the RESCUE trial Objectives : Gait and mobility problems are difficult to treat in people with Parkinson ’s disease. The Rehabilitation in Parkinson ’s Disease : Strategies for Cueing ( RESCUE ) trial investigated the effects of a home physiotherapy programme based on rhythmical cueing on gait and gait-related activity. Methods : A single-blind r and omised crossover trial was set up, including 153 patients with Parkinson ’s disease aged between 41 and 80 years and in Hoehn and Yahr stage II – IV. Subjects allocated to early intervention ( n = 76 ) received a 3-week home cueing programme using a prototype cueing device, followed by 3 weeks without training. Patients allocated to late intervention ( n = 77 ) underwent the same intervention and control period in reverse order. After the initial 6 weeks, both groups had a 6-week follow-up without training. Posture and gait scores ( PG scores ) measured at 3, 6 and 12 weeks by blinded testers were the primary outcome measure. Secondary outcomes included specific measures on gait, freezing and balance, functional activities, quality of life and carer strain. Results : Small but significant improvements were found after intervention of 4.2 % on the PG scores ( p = 0.005 ). Severity of freezing was reduced by 5.5 % in freezers only ( p = 0.007 ). Gait speed ( p = 0.005 ), step length ( p<0.001 ) and timed balance tests ( p = 0.003 ) improved in the full cohort. Other than a greater confidence to carry out functional activities ( Falls Efficacy Scale, p = 0.04 ), no carry-over effects were observed in functional and quality of life domains. Effects of intervention had reduced considerably at 6-week follow-up. Conclusions : Cueing training in the home has specific effects on gait, freezing and balance. The decline in effectiveness of intervention effects underscores the need for permanent cueing devices and follow-up treatment. Cueing training may be a useful therapeutic adjunct to the overall management of gait disturbance in Parkinson ’s disease Effects of Group, Individual, and Home Exercise in Persons With Parkinson Disease: A Randomized Clinical Trial Background and Purpose : Comparative studies of exercise interventions for people with Parkinson disease ( PD ) rarely considered how one should deliver the intervention. The objective of this study was to compare the success of exercise when administered by ( 1 ) home exercise program, ( 2 ) individualized physical therapy, or ( 3 ) a group class. We examined if common comorbidities associated with PD impacted success of each intervention. Methods : Fifty-eight people ( age = 63.9 ± 8 years ) with PD participated. People were r and omized into ( 1 ) home exercise program, ( 2 ) individual physical therapy, or ( 3 ) group class intervention. All arms were st and ardized and based on the Agility Boot Camp exercise program for PD, 3 times per week for 4 weeks. The primary outcome measure was the 7-item Physical Performance Test. Other measures of balance, gait, mobility, quality of life, balance confidence, depressions, apathy, self-efficacy and UPDRS-Motor, and activity of daily living scores were included. Results : Only the individual group significantly improved in the Physical Performance Test. The individual exercise showed the most improvements in functional and balance measures, whereas the group class showed the most improvements in gait. The home exercise program improved the least across all outcomes. Several factors effected success, particularly for the home group. Discussion and Conclusions : An unsupervised, home exercise program is the least effective way to deliver exercise to people with PD, and individual and group exercises have differing benefits. Furthermore, people with PD who also have other comorbidities did better in a program directly supervised by a physical therapist. Video Abstract available for additional insights from the authors ( see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A112 ) An exercise intervention to prevent falls in people with Parkinson\'s disease: a pragmatic randomised controlled trial Objectives To compare the effectiveness of an exercise programme with usual care in people with Parkinson\'s disease ( PD ) who have a history of falls. Design Pragmatic r and omised controlled trial. Setting Recruitment was from three primary and four secondary care organisations, and PD support groups in South West Engl and. The intervention was delivered in community setting s. Participants People with PD, with a history of two or more falls in the previous year, who were able to mobilise independently. Intervention 10 week, physiotherapy led, group delivered strength and balance training programme with supplementary home exercises ( intervention ) or usual care ( control ). Main outcome measure Number of falls during the ( a ) 10 week intervention period and ( b ) the 10 week follow-up period. Results 130 people were recruited and r and omised ( 64 to the intervention ; 66 to usual care ). Seven participants ( 5.4 % ) did not complete the study. The incidence rate ratio for falls was 0.68 ( 95 % CI 0.43 to 1.07, p=0.10 ) during the intervention period and 0.74 ( 95 % CI 0.41 to 1.33, p=0.31 ) during the follow-up period. Statistically significant between group differences were observed in Berg balance, Falls Efficacy Scale-International scores and recreational physical activity levels. Conclusions The study did not demonstrate a statistically significant between group difference in falls although the difference could be considered clinical ly significant. However, a type 2 error can not be ruled out. The findings from this trial add to the evidence base for physiotherapy and exercise in the management of people with PD. Trial registration IS RCT N50793425 A pilot study of a minimally supervised home exercise and walking program for people with Parkinson\'s disease in Jordan. AIM This study aim ed to evaluate the feasibility and cultural considerations of a minimally supervised, home-based exercise program in Jordan. METHODS Quantitative and qualitative approaches were used. Thirty participants were r and omly allocated to either an 8-week intervention group ( n = 16 ), or a st and ard care group ( n = 14 ). The intervention incorporated the home use of an exercise DVD, walking program and initial instructional sessions and weekly phone calls provided by a physiotherapist. Interviews were used to explore feasibility. Unified Parkinson\'s disease rating scale ( UPDRS-III ) ; balance and walking speed were assessed. RESULTS The retention rate was 86.7 % and mean adherence rate was 77 %. Personal and sociocultural barriers of adherence to the exercise program were identified. UPDRS-III at follow-up was lower in the intervention group. CONCLUSION A home exercise program was feasible. Sociocultural barriers specific to Arabic culture may affect the uptake of such an intervention in Parkinson\'s disease in these countries Long-term effects of highly challenging balance training in Parkinson’s disease—a randomized controlled trial Objectives : To determine long-term effects of a highly challenging training program in people with Parkinson ’s disease, as well as describe how initially observed improvements of the program deteriorated over time. Design : Long-term follow-up of previously reported outcomes at 10 weeks of a r and omized controlled trial. Setting : University hospital setting. Participants : One-hundred elderly with mild-to-moderate ( Hoehn and Yahr 2–3 ) Parkinson ’s disease. Interventions : Participants in the training group ( n = 51 ) received 10 weeks ( three times/week ) of balance and gait exercises, incorporating dual-tasks, while the control group ( n = 49 ) received care as usual. Main Outcome Measures : Balance control ( Mini-Balance Evaluation System Test ( Mini-BESTest ) ) and gait velocity. Mixed- design analyses of variance were used to determine potential training effects at 6- and 12-month follow-up, and piecewise regression models predicted the rate of deterioration. Results : Seventy-six participants were included at final follow-up. No significant ( P >.05 ) between-group differences remained at either 6 or 12 months following the intervention. The mean Mini-BESTest scores of the training and control group were 19.9 ( SD 4.4 ) and 18.6 ( SD 4.3 ), respectively, at the 12-month follow-up. Gait speed was 1.2 ( SD 0.2 ) m/s in both groups at 12 months. The training group showed a larger deterioration rate per month in balance performance ( 0.21 point ) and gait velocity ( 0.65 cm/s ) than controls ( P <.05 ). Conclusion : These results suggest that training effects diminish within 6 months after balance training, implying that the program may need to be repeated regularly', 'BACKGROUND Several lines of evidence have indicated the insulin-sensitizing, anti-diabetic and anti-atherosclerotic properties of adiponectin, as well as the inverse association between circulating levels of this adipokine and development of cardiovascular outcomes. Improvement of adiponectin status has been reported as a pleiotropic effect of fibrate therapy, but the findings have not been conclusive. OBJECTIVE To systematic ally review and meta-analyze available evidence from r and omized placebo-controlled trials ( RCTs ) on the impact of fibrate therapy on circulating levels of adiponectin. Restoration of adipose function in obese glucose-tolerant men following pioglitazone treatment is associated with CCAAT enhancer-binding protein β up-regulation. Obese AT ( adipose tissue ) exhibits increased macrophage number. Pro-inflammatory CD16 + peripheral monocyte numbers are also reported to increase with obesity. The present study was undertaken to simultaneously investigate obesity-associated changes in CD16 + monocytes and ATMs ( AT macrophages ). In addition, a pilot r and omized placebo controlled trial using the PPAR ( peroxisome-proliferator-activated receptor ) agonists, pioglitazone and fenofibrate was performed to determine their effects on CD14+/CD16 + monocytes, ATM and cardiometabolic and adipose dysfunction indices. Obese glucose-tolerant men ( n=28 ) were r and omized to placebo, pioglitazone ( 30 mg/day ) and fenofibrate ( 160 mg/day ) for 12 weeks. A blood sample was taken to assess levels of serum inflammatory markers and circulating CD14+/CD16 + monocyte levels via flow cytometry. A subcutaneous AT biopsy was performed to determine adipocyte cell surface and ATM number, the latter was determined via assessment of CD68 expression by IHC ( immunohistochemistry ) and real-time PCR. Subcutaneous AT mRNA expression of CEBPβ ( CCAAT enhancer-binding protein β ), SREBP1c ( sterol-regulatory-element-binding protein 1c ), PPARγ2, IRS-1 ( insulin receptor substrate-1 ), GLUT4 ( glucose transporter type 4 ) and TNFα ( tumour necrosis factor α ) were also assessed. Comparisons were made between obese and lean controls ( n=16 ) at baseline, and pre- and post-PPAR agonist treatment. Obese individuals had significantly increased adipocyte cell surface, percentage CD14+/CD16 + monocyte numbers and ATM number ( all P=0.0001 ). Additionally, serum TNF-α levels were significantly elevated ( P=0.017 ) and adiponectin levels reduced ( total : P=0.0001 ; high : P=0.022 ) with obesity. ATM number and percentage of CD14+/CD16 + monocytes correlated significantly ( P=0.05 ). Pioglitazone improved adiponectin levels significantly ( P=0.0001 ), and result ed in the further significant enlargement of adipocytes ( P=0.05 ), without effect on the percentage CD14+/CD16 + or ATM number. Pioglitazone treatment also significantly increased subcutaneous AT expression of CEBPβ mRNA. The finding that improvements in obesity-associated insulin resistance following pioglitazone were associated with increased adipocyte cell surface and systemic adiponectin levels, supports the central ity of AT to the cardiometabolic derangement underlying the development of T2D ( Type 2 diabetes ) and CVD ( cardiovascular disease ) The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. The insulin-sensitizing effects of thiazolidinediones are thought to be mediated through peroxisome proliferator-activated receptor-gamma, a nuclear receptor that is highly abundant in adipose tissue. It has been reported that adipocytes secrete a variety of proteins, including tumor necrosis factor-alpha, resistin, plasminogen activator inhibitor-1, and adiponectin. Adiponectin is a fat cell-secreted protein that has been reported to increase fat oxidation and improve insulin sensitivity. Our aim was to study the effects of troglitazone on adiponectin levels in lean, obese, and diabetic subjects. Ten diabetic and 17 nondiabetic subjects ( 8 lean, BMI < 27 kg/m(2 ) and 9 obese, BMI > 27 kg/m(2 ) ) participated in the study. All subjects underwent an 80 mU. m(-2 ). min(-1 ) hyperinsulinemic-euglycemic glucose clamp before and after 3 months\'treatment with the thiazolidinedione ( TZD ) troglitazone ( 600 mg/day ). Fasting plasma glucose significantly decreased in the diabetic group after 12 weeks of treatment compared with baseline ( 9.1 + /- 0.9 vs. 11.1 + /- 0.9 mmol/l, P < 0.005 ) but was unchanged in the lean and obese subjects. Fasting insulin for the entire group was significantly lower than baseline ( P = 0.02 ) after treatment. At baseline, glucose disposal rate ( R(d ) ) was lower in the diabetic subjects ( 3.4 + /- 0.5 mg. kg(-1 ). min(-1 ) ) than in the lean ( 12.3 + /- 0.4 ) or obese subjects ( 6.7 + /- 0.7 ) ( P < 0.001 for both ) and was significantly improved in the diabetic and obese groups ( P < 0.05 ) after treatment, and it remained unchanged in the lean subjects. Baseline adiponectin levels were significantly lower in the diabetic than the lean subjects ( 9.0 + /- 1.7 vs. 16.7 + /- 2.7 micro g/ml, P = 0.03 ) and rose uniformly in all subjects ( 12.2 + /- 2.3 vs. 25.7 + /- 2.6 micro g/ml, P < 10(-4 ) ) after treatment, with no significant difference detected among the three groups. During the glucose clamps, adiponectin levels were suppressed below basal levels in all groups ( 10.2 + /- 2.3 vs. 12.2 + /- 2.3 micro g/ml, P < 0.01 ). Adiponectin levels correlated with R(d ) ( r = 0.46, P = 0.016 ) and HDL cholesterol levels ( r = 0.59, P < 0.001 ) and negatively correlated with fasting insulin ( r = -0.39, P = 0.042 ) and plasma triglyceride ( r = -0.61, P < 0.001 ). Our findings show that TZD treatment increased adiponectin levels in all subjects, including normal subjects in which no other effects of TZDs are observed. Insulin also appears to suppress adiponectin levels. We have confirmed these results in normal rats. These findings suggest that adiponectin can be regulated by obesity, diabetes, TZDs, and insulin, and it may play a physiologic role in enhancing insulin sensitivity Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia. OBJECTIVE Improvement in endothelial function is predicted to improve insulin sensitivity, and this may be one mechanism by which fenofibrate decreases the incidence of coronary heart disease. We hypothesize fenofibrate improves endothelial function by enhancing insulin sensitivity. RESEARCH DESIGN AND METHODS We administered placebo or fenofibrate 200 mg daily for 8 weeks to 46 patients with primary hypertriglyceridemia ( 24 had metabolic syndrome ). This study was r and omized, double blind, placebo controlled, and crossover in design. RESULTS Compared with placebo, fenofibrate decreased total cholesterol, non-HDL cholesterol, apolipoprotein B, and triglycerides and increased HDL cholesterol and apolipoprotein A-I ( all P < 0.001 ) while tending to decrease LDL cholesterol ( P = 0.069 ). Fenofibrate significantly improved percent flow-mediated dilator response to hyperemia by 48 + /- 5 % ( P < 0.001 ) and lowered plasma levels of high-sensitivity C-reactive protein ( hsCRP ) relative to baseline measurements from 0.80 to 0.70 mg/l ( P = 0.001 ) and fibrinogen levels by 16 + /- 3 % ( P < 0.001 ). Compared with placebo, fenofibrate therapy significantly increased plasma levels of adiponectin by 14 + /- 5 % ( P = 0.008 ) and increased insulin sensitivity ( assessed by quantitative insulin sensitivity check index [ QUICKI ] ) by 6 + /- 2 % ( P = 0.048 ). There were significant correlations between percent changes in adiponectin levels and percent changes in flow-mediated dilation ( r = 0.401, P = 0.006 ), hsCRP ( r = -0.443, P = 0.002 ), or QUICKI ( r = 0.292, P = 0.049 ). Multivariate regression analysis showed that only changes in adiponectin levels persisted as an independent predictor of changes in flow-mediated dilation ( r = 0.504, P = 0.013 ). Overall, we observed similar results in 24 patients with metabolic syndrome. CONCLUSIONS Fenofibrate therapy significantly improved percent flow-mediated dilator response to hyperemia, reduced inflammation marker levels, increased adiponectin levels, and improved insulin sensitivity in hypertriglyceridemic or metabolic syndrome patients Acute Exercise Increases Adiponectin Levels in Abdominally Obese Men Objective. To examine the effect of acute and short-term ( ~1 week ) aerobic exercise training on plasma adiponectin levels in inactive, abdominally obese men. Material s and Methods. Inactive and abdominally obese men ( n = 38, waist circumference ≥102 cm ) recruited from Kingston, Canada were r and omly allocated to perform three bouts of aerobic treadmill exercise at either low ( 50 % VO2 peak ) or high ( 75 % VO2 peak ) intensity during a 1-week period. Blood sample s were taken before and after the first exercise session and 24–72 hours following the completion of the final exercise session. Results. Adiponectin levels were elevated immediately following an acute bout of exercise at both high and low intensities ( High : 5.79 ± 0.42 versus 5.05 ± 0.41 ug/mL ; Low : 5.24 ± 0.44 versus 4.37 ± 0.44 ug/mL, P < 0.05 ) and remained elevated following 30 minutes of rest. In comparison to baseline, adiponectin levels were also elevated 24–72 hours following the final exercise session ( High : 5.47 ± 0.48 versus 4.88 ± 0.48 ug/mL ; Low : 5.18 ± 0.49 versus 4.47 ± 0.49 ug/mL, P < 0.05 ). Conclusion. Both acute and short-term aerobic exercise result in a significant increase in plasma adiponectin levels in inactive, abdominally obese men independent of intensity Effects of combination lipid therapy in type 2 diabetes mellitus. BACKGROUND We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS We r and omly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infa rct ion, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS The annual rate of the primary outcome was 2.2 % in the fenofibrate group and 2.4 % in the placebo group ( hazard ratio in the fenofibrate group, 0.92 ; 95 % confidence interval [ CI ], 0.79 to 1.08 ; P=0.32 ). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5 % in the fenofibrate group and 1.6 % in the placebo group ( hazard ratio, 0.91 ; 95 % CI, 0.75 to 1.10 ; P=0.33 ). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women ( P=0.01 for interaction ), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol ( P=0.057 for interaction ). CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infa rct ion, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. ( Clinical Trials.gov number, NCT00000620. Combination of niacin and fenofibrate with lifestyle changes improves dyslipidemia and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of "heart positive," a randomized, controlled trial. CONTEXT HIV patients on antiretroviral therapy ( ART ) have a unique dyslipidemia [ elevated triglycerides and non-high-density lipoprotein-cholesterol ( HDL-C ), low HDL-C ] with insulin resistance ( characterized by hypoadiponectinemia ). OBJECTIVE The aim was to test a targeted, comprehensive, additive approach to treating the dyslipidemia. DESIGN AND SETTING We conducted a r and omized, double-blind, placebo-controlled, 24-wk trial of lifestyle modification, fenofibrate, and niacin in multiethnic HIV clinics at an academic center. PARTICIPANTS Hypertriglyceridemic adult patients were stratified on three combinations of ART classes. Subjects retained at the first measurement ( 2 wk ) after entry were included in the analysis ( n = 191 ). INTERVENTIONS Subjects were r and omized into five treatment groups : usual care ( group 1 ) ; low-saturated-fat diet and exercise ( D/E ; group 2 ) ; D/E + fenofibrate ( group 3 ) ; D/E + niacin ( group 4 ) ; or D/E + fenofibrate + niacin ( group 5 ). MAIN OUTCOME MEASURES We measured changes in fasting triglycerides, HDL-C, and non-HDL-C ( primary ), and in insulin sensitivity, glycemia, adiponectin, C-reactive protein, energy expenditure, and body composition ( secondary ). Data were analyzed as a factorial set of treatment combinations using a mixed repeated measures model, last observation carried forward, and complete case approaches ( groups 2 - 5 ), and as an unstructured set of treatments ( groups 1 - 5 ). RESULTS Fenofibrate improved triglycerides ( P = 0.002 ), total cholesterol ( P = 0.02 ), and non-HDL-C ( P = 0.003 ), whereas niacin improved HDL-C ( P = 0.03 ), and both drugs decreased the total cholesterol-to-HDL-C ratio ( P = 0.005 - 0.01 ). The combination of D/E, fenofibrate, and niacin provided maximal benefit, markedly reducing triglycerides ( -52 % compared to usual care ; P = 0.003 ), increasing HDL-C ( + 12 % ; P < 0.001 ), and decreasing non-HDL-C ( -18.5 % ; P = 0.003 ) and total cholesterol-to-HDL-C ratio ( -24.5 % ; P < 0.001 ). Niacin doubled adiponectin levels. CONCLUSIONS A combination of fenofibrate and niacin with low-saturated-fat D/E is effective and safe in increasing HDL-C, decreasing non-HDL-C and hypertriglyceridemia, and ameliorating hypoadiponectinemia in patients with HIV/ART-associated dyslipidemia Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. BACKGROUND Coronary heart disease patients with low high-density lipoprotein cholesterol ( HDL-C ) levels, high triglyceride levels, or both are at an increased risk of cardiovascular events, but the clinical impact of raising HDL-C or decreasing triglycerides remains to be confirmed. METHODS AND RESULTS In a double-blind trial, 3090 patients with a previous myocardial infa rct ion or stable angina, total cholesterol of 180 to 250 mg/dL, HDL-C < or = 45 mg/dL, triglycerides < or = 300 mg/dL, and low-density lipoprotein cholesterol < or = 180 mg/dL were r and omized to receive either 400 mg of bezafibrate per day or a placebo ; they were followed for a mean of 6.2 years. The primary end point was fatal or nonfatal myocardial infa rct ion or sudden death. Bezafibrate increased HDL-C by 18 % and reduced triglycerides by 21 %. The frequency of the primary end point was 13. 6 % on bezafibrate versus 15.0 % on placebo ( P=0.26 ). After 6.2 years, the reduction in the cumulative probability of the primary end point was 7.3 %, ( P=0.24 ). In a post hoc analysis in the subgroup with high baseline triglycerides ( > or = 200 mg/dL ), the reduction in the cumulative probability of the primary end point by bezafibrate was 39.5 % ( P=0.02 ). Total and noncardiac mortality rates were similar, and adverse events and cancer were equally distributed. CONCLUSIONS Bezafibrate was safe and effective in elevating HDL-C levels and lowering triglycerides. An overall trend in a reduction of the incidence of primary end points was observed. The reduction in the primary end point in patients with high baseline triglycerides ( > or = 200 mg/dL ) requires further confirmation Plasma adiponectin levels and risk of myocardial infarction in men. CONTEXT Adiponectin, a recently discovered adipocyte-derived peptide, is involved in the regulation of insulin sensitivity and lipid oxidation and, purportedly, in the development of atherosclerosis and coronary heart disease in humans. OBJECTIVE To assess prospect ively whether plasma adiponectin concentrations are associated with risk of myocardial infa rct ion ( MI ). DESIGN, SETTING, AND PARTICIPANTS Nested case-control study among 18 225 male participants of the Health Professionals Follow-up Study aged 40 to 75 years who were free of diagnosed cardiovascular disease at the time of blood draw ( 1993 - 1995 ). During 6 years of follow-up through January 31, 2000, 266 men subsequently developed nonfatal MI or fatal coronary heart disease. Using risk set sampling, controls were selected in a 2:1 ratio matched for age, date of blood draw, and smoking status ( n = 532 ). MAIN OUTCOME MEASURE Incidence of nonfatal MI and fatal coronary heart disease by adiponectin level. RESULTS After adjustment for matched variables, participants in the highest compared with the lowest quintile of adiponectin levels had a significantly decreased risk of MI ( relative risk [ RR ], 0.39 ; 95 % confidence interval [ CI ], 0.23 - 0.64 ; P for trend <.001 ). Additional adjustment for family history of MI, body mass index, alcohol consumption, physical activity, and history of diabetes and hypertension did not substantively affect this relationship ( RR, 0.41 ; 95 % CI, 0.24 - 0.70 ; P for trend <.001 ). Further adjustment for hemoglobin A1c or C-reactive protein levels also had little impact, but additional adjustment for low- and high-density lipoprotein cholesterol levels modestly attenuated this association ( RR, 0.56 ; 95 % CI, 0.32 - 0.99 ; P for trend =.02 ). CONCLUSIONS High plasma adiponectin concentrations are associated with lower risk of MI in men. This relationship can be only partly explained by differences in blood lipids and is independent of inflammation and glycemic status Influence of PPAR-alpha agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with type 2 diabetes. PPAR-alpha agonists improve insulin sensitivity in rodent models of obesity/insulin resistance, but their effects on insulin sensitivity in humans are less clear. We measured insulin sensitivity by hyperinsulinemic-isoglycemic clamp in 10 obese females with type 2 diabetes before and after three months of treatment with PPAR-alpha agonist fenofibrate and studied the possible role of the changes in endocrine function of adipose tissue in the metabolic effects of fenofibrate. At baseline, body mass index, serum glucose, triglycerides, glycated hemoglobin and atherogenic index were significantly elevated in obese women with type 2 diabetes, while serum HDL cholesterol and adiponectin concentrations were significantly lower than in the control group ( n=10 ). No differences were found in serum resistin levels between obese and control group. Fenofibrate treatment decreased serum triglyceride concentrations, while both blood glucose and glycated hemoglobin increased after three months of fenofibrate administration. Serum adiponectin or resistin concentrations were not significantly affected by fenofibrate treatment. All parameters of insulin sensitivity as measured by hyperinsulinemic-isoglycemic clamp were significantly lower in an obese diabetic group compared to the control group before treatment and were not affected by fenofibrate administration. We conclude that administration of PPAR-alpha agonist fenofibrate for three months did not significantly affect insulin sensitivity or resistin and adiponectin concentrations in obese subjects with type 2 diabetes mellitus. The lack of insulin-sensitizing effects of fenofibrate in humans relative to rodents could be due to a generally lower PPAR-alpha expression in human liver and muscle Significant differential effects of omega-3 fatty acids and fenofibrate in patients with hypertriglyceridemia. BACKGROUND Omega-3 fatty acids and fenofibrate are both used to treat patients with hypertriglyceridemia. However, a head-to-head comparison of the lipoprotein and metabolic effects of these two medicines has not been published. METHODS This was a r and omized, single-blind, placebo-controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Fifty patients in each group were given placebo, omega-3 fatty acids 2 g ( most commonly used dosage in Korean patients ), or fenofibrate 160 mg, respectively daily for 2 months. RESULTS Omega-3 fatty acids therapy decreased triglycerides by 21 % and triglycerides/HDL cholesterol and improved flow-mediated dilation ( P<0.01 ), however, did not significantly change insulin, plasma adiponectin levels, and insulin sensitivity ( determined by QUICKI ) relative to baseline measurements. Fenofibrate therapy decreased total cholesterol, triglycerides by 29 %, and triglycerides/HDL-cholesterol ( all P<0.01 ) and improved flow-mediated dilation when compared with baseline. When compared with placebo and omega-3 fatty acids, fenofibrate therapy decreased non-HDL cholesterol ( P<0.001 ) and triglycerides/HDL cholesterol ( P=0.016 ) while increasing HDL cholesterol ( P<0.001 ) and apolipoprotein AI ( P=0.001 ). Of note, when compared with omega-3 fatty acids, fenofibrate therapy decreased fasting insulin ( P=0.023 ) and increased plasma adiponectin ( P=0.002 ) and insulin sensitivity ( P=0.015 ). CONCLUSIONS Omega-3 fatty acids and fenofibrate therapy promoted similar changes in triglycerides and endothelium-dependent dilation. However, fenofibrate therapy had substantially better effects on lipoprotein and metabolic profiles in patients with hypertriglyceridemia Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate. BACKGROUND Development of insulin resistance ( IR ) may be important in the pathogenesis of both metabolic syndrome and type 2 diabetes mellitus. Few data are available regarding the short-term efficacy of the peroxisome proliferator-activated receptor lig and bezafibrate on IR, and its long-term effect is unknown. The present analysis aim ed to investigate the effect of bezafibrate on IR in patients with coronary artery disease enrolled in the Bezafibrate Infa rct ion Prevention Study. METHODS Metabolic and inflammatory parameters were analyzed from stored frozen plasma sample s obtained from patients who completed a 2-year, r and omized, double-blind, placebo-controlled study. The homeostatic indexes of IR ( HOMA-IRs ) were calculated according to the homeostasis model of assessment. RESULTS Both the patients taking bezafibrate ( n = 1262 ) and those taking placebo ( n = 1242 ) displayed similar baseline characteristics. The HOMA-IRs significantly correlated at baseline and during follow-up with glucose ( r = 0.35 and 0.31, respectively ) and triglycerides ( r = 0.16 and 0.19, respectively ). In a subgroup of 351 patients with diabetes, HOMA-IR at baseline was 88 % higher than in their counterparts with normal glucose levels ( P<.001 ). In the placebo group, during follow-up there was a significant 34.4 % rise in HOMA-IR. In contrast, in the bezafibrate group there was only a nonsignificant 6.6 % change in HOMA-IR. The intergroup differences in percentage changes of HOMA-IR were in favor of bezafibrate ( P<.001 ). CONCLUSIONS In patients with coronary artery disease enrolled in our study, as represented by the placebo group, HOMA-IR increased over time. During the 2 years of the follow-up, bezafibrate significantly attenuated this process Peroxisome Proliferator–Activated Receptor Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in Patients With Coronary Artery Disease Background —Recent studies have shown that type 2 diabetes is preventable by both lifestyle interventions and medications that influence primary glucose metabolism. Whether pharmacological interventions that influence primary lipid metabolism can also delay development of type 2 diabetes is unknown. The goal of this study was to evaluate the effect of the peroxisome proliferator – activated receptor lig and bezafibrate on the progression of impaired fasting glucose phase to type 2 diabetes in patients with coronary artery disease over a 6.2-year follow-up period. Methods and Results —The study sample comprised 303 nondiabetic patients 42 to 74 years of age with a fasting blood glucose level of 110 to 125 mg/dL ( 6.1 to 6.9 mmol/L ). The patients received either 400 mg bezafibrate retard ( 156 patients ) or placebo ( 147 patients ) once a day. No patients were using statins, and use of ACE inhibitors, which also reduce diabetes incidence, was relatively low. During follow-up, development of new-onset diabetes was recorded in 146 patients : in 80 ( 54.4 % ) from the placebo group and 66 ( 42.3 % ) from the bezafibrate group ( P = 0.04 ). The mean time until onset of new diabetes was significantly delayed in patients on bezafibrate compared with patients on placebo : 4.6±2.3 versus 3.8±2.6 years ( P = 0.004 ). Multivariate analysis identified bezafibrate treatment as an independent predictor of reduced risk of new diabetes development ( hazard ratio, 0.70 ; 95 % CI, 0.49 to 0.99 ). Other significant variables associated with future overt type 2 diabetes in patients with impaired fasting glucose were total cholesterol level ( hazard ratio, 1.22 ; 95 % CI 1.0 to 1.51 ) and body mass index ( hazard ratio, 1.10 ; 95 % CI, 1.05 to 1.16 ). Conclusions —Bezafibrate reduces the incidence and delays the onset of type 2 diabetes in patients with impaired fasting glucose. Whether the combination of bezafibrate with other recommended drugs for secondary prevention ( statins and ACE inhibitors ) would be as efficacious as suggested by our results remains to be determined Apolipoprotein B-48 as a determinant of endothelial function in obese subjects with type 2 diabetes mellitus: effect of fenofibrate treatment. OBJECTIVE Elevated triglyceride-rich lipoproteins may contribute to endothelial dysfunction in obese diabetic subjects. We investigated the association between plasma concentrations of chylomicron-related particles and endothelial function, and the corresponding responses to fenofibrate treatment. METHODS Plasma apolipoprotein ( apo ) B-48 and remnant-like particle (RLP)-cholesterol concentrations were measured in 28 obese subjects with T2DM. Flow-mediated endothelium-dependent dilation ( FMD ) and glyceryl-trinitrate mediated dilatation ( GTNMD ) in the brachial artery during reactive hyperaemia were examined by high-resolution ultrasound technique. RESULTS In univariate analysis, plasma apoB-48 and RLP-cholesterol concentrations were inversely associated with brachial artery FMD ( r = -0.425 and -0.423, respectively, P<0.05 ), but not with GTNMD. In regression models including BMI and HOMA score, plasma apoB-48 was an independent predictors ( P<0.05 ) of brachial artery FMD ( β coefficient = -0.384 ). Replacing HOMA-IR score with plasma triglyceride, adiponectin or CRP concentrations did not alter the findings. The subjects were then r and omized to a 12-week treatment period of either 200 mg micronized fenofibrate or matching placebo. Compared with the placebo group, fenofibrate treatment ( 200 mg daily for 12 weeks ) achieved significant increase in FMD ( + 34 % ) and reduction in plasma triglyceride ( -42 % ), apoB-48 ( -52 % ) and RLP-cholesterol ( -51 % ) concentrations. The increase in FMD with fenofibrate was significantly associated with the corresponding decrease in plasma apoB-48 ( r = -0.644, P<0.02 ) concentrations. CONCLUSIONS Our findings demonstrate an association between changes in lipid metabolism and improvement in endothelial function in patients with diabetic dyslipidaemia treated with fenofibrate that may involve the effect of apoB-48 on endothelium-dependent vasodilator function Bezafibrate Retard in Type II Diabetic Patients: Effects on Hemostasis and Glucose Homeostasis A double-blind, placebo-controlled trial assessed the effect of a slow-release formulation of bezafibrate ( Bezalip Mono, 400 mg daily for 3 months ) on lipid profile, glucose homeostasis, platelet function, and plasma fibrinogen concentration in non-insulin-dependent ( type II ) diabetics. Twenty-four patients completed the trial. There was a significant improvement in the cholesterol ( p < 0.02 ), triglyceride ( p < 0.01 ), and nonesterified fatty acid ( p < 0.05 ) concentrations and in the fasting blood glucose ( p < 0.03 ) and glycosylated hemoglobin ( p < 0.01 ) levels of those ( n = 11 ) who received the active preparation but not in those ( n = 13 ) who received placebo. Treatment, but not placebo, also result ed in a significant ( p < 0.01 ) fall in plasma fibrinogen concentration and a trend towards inhibition of platelet aggregation. Bezafibrate was well tolerated ; only one patient ( not included in the analysis of results ) withdrew from the trial possibly because of side effects of the drug. A larger study is needed to establish whether bezafibrate can reduce nonlipid risk factors ( e.g., plasma fibrinogen concentration, glucose intolerance, and hyperinsulinemia ) in normo- and hyperlipidemic subjects Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men. Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk. We conducted a r and omised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist ( fenofibrate ) and a PPAR gamma agonist ( pioglitazone ) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity ( PWV ). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function. Insulin sensitivity improved with pioglitazone treatment ( p=0.001 ) and, in keeping with this, adiponectin increased by 85.2 % ( p<0.001 ). Pro-inflammatory cytokine levels ( TNFalpha, IL-6 and IL-1 beta ) fell with both treatments ( p<0.01 for TNFalpha and IL-1 beta, p<0.001 for IL-6 ). VCAM-1 and ICAM-1 were reduced with both treatments ( p<0.001 for VCAM-1, p<0.05 for ICAM-1 ) and E-selectin improved with pioglitazone treatment ( p=0.05 ). Both treatments result ed in a fall in augmentation index. PWV fell by 17.4 % with fenofibrate treatment ( p<0.001 ) and 16.3 % with pioglitazone treatment ( p<0.001 ). Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. BACKGROUND Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We design ed the Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study to assess the effect of fenofibrate on cardiovascular disease events in these patients. METHODS We did a multinational, r and omised controlled trial with 9795 participants aged 50 - 75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we r and omly assigned patients ( 2131 with previous cardiovascular disease and 7664 without ) with a total-cholesterol concentration of 3.0 - 6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0 - 5.0 mmol/L to micronised fenofibrate 200 mg daily ( n=4895 ) or matching placebo ( n=4900 ). Our primary outcome was coronary events ( coronary heart disease death or non-fatal myocardial infa rct ion ) ; the outcome for prespecified subgroup analyses was total cardiovascular events ( the composite of cardiovascular death, myocardial infa rct ion, stroke, and coronary and carotid revascularisation ). Analysis was by intention to treat. The study was prospect ively registered ( number IS RCT N 64783481 ). FINDINGS Vital status was confirmed on all but 22 patients. Averaged over the 5 years\'study duration, similar proportions in each group discontinued study medication ( 10 % placebo vs 11 % fenofibrate ) and more patients allocated placebo ( 17 % ) than fenofibrate ( 8 % ; p<0.0001 ) commenced other lipid treatments, predominantly statins. 5.9 % ( n=288 ) of patients on placebo and 5.2 % ( n=256 ) of those on fenofibrate had a coronary event ( relative reduction of 11 % ; hazard ratio [ HR ] 0.89, 95 % CI 0.75 - 1.05 ; p=0.16 ). This finding corresponds to a significant 24 % reduction in non-fatal myocardial infa rct ion ( 0.76, 0.62 - 0.94 ; p=0.010 ) and a non-significant increase in coronary heart disease mortality ( 1.19, 0.90 - 1.57 ; p=0.22 ). Total cardiovascular disease events were significantly reduced from 13.9 % to 12.5 % ( 0.89, 0.80 - 0.99 ; p=0.035 ). This finding included a 21 % reduction in coronary revascularisation ( 0.79, 0.68 - 0.93 ; p=0.003 ). Total mortality was 6.6 % in the placebo group and 7.3 % in the fenofibrate group ( p=0.18 ). Fenofibrate was associated with less albuminuria progression ( p=0.002 ), and less retinopathy needing laser treatment ( 5.2%vs 3.6 %, p=0.0003 ). There was a slight increase in pancreatitis ( 0.5%vs 0.8 %, p=0.031 ) and pulmonary embolism ( 0.7%vs 1.1 %, p=0.022 ), but no other significant adverse effects. INTERPRETATION Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infa rct ions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit Effects of fenofibrate therapy on circulating adipocytokines in patients with primary hypertriglyceridemia. BACKGROUND We investigated effects of fenofibrate therapy on endothelial dysfunction and adipocytokine profiles. METHODS A r and omized, single-blind, placebo-controlled, cross-over study was conducted in 53 patients with primary hypertriglyceridemia. We administered placebo or fenofibrate 160 mg daily for 8 weeks. RESULTS When compared with placebo, fenofibrate therapy substantially lowered plasma levels of TNF-α by 6±3 % ( P=0.014 ) and hsCRP from 1.10 to 0.90mg/l ( P=0.004 ). When compared with placebo, fenofibrate therapy increased plasma levels of adiponectin by 17±4 % ( P=0.001 ), insulin sensitivity by 4±1 % ( as assessed by QUICKI, P=0.009 ), and decreased plasma levels of leptin and resistin by 4±7 % ( P=0.022 ) and 10±3 % ( P=0.001 ), respectively. There were correlations between percent changes in QUICKI and percent changes in adiponectin levels ( r=0.279, P=0.043 ) or leptin ( r=-0.280, P=0.042 ). CONCLUSIONS Fenofibrate therapy significantly reduced pro-inflammatory biomarkers and improved adipocytokines levels and insulin sensitivity in hypertriglyceridemic patients', "Importance Vitamin D and calcium supplements are recommended for the prevention of fracture, but previous r and omized clinical trials ( RCTs ) have reported conflicting results, with uncertainty about optimal doses and regimens for supplementation and their overall effectiveness. Objective To assess the risks of fracture associated with differences in concentrations of 25-hydroxyvitamin D ( 25[OH]D ) in observational studies and the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs. Combined Calcium and Vitamin D3 Supplementation in Elderly Women: Confirmation of Reversal of Secondary Hyperparathyroidism and Hip Fracture Risk: The Decalyos II Study Vitamin D insufficiency and low calcium intake contribute to increase parathyroid function and bone fragility in elderly people. Calcium and vitamin D supplements can reverse secondary hyperparathyroidism thus preventing hip fractures, as proved by Decalyos I. Decalyos II is a 2-year, multicenter, r and omized, double-masked, placebo-controlled confirmatory study. The intention-to-treat population consisted of 583 ambulatory institutionalized women ( mean age 85.2 years, SD = 7.1 ) r and omized to the calcium – vitamin D3 fixed combination group ( n= 199 ) ; the calcium plus vitamin D3 separate combination group ( n= 190 ) and the placebo group ( n= 194 ). Fixed and separate combination groups received the same daily amount of calcium ( 1200 mg ) and vitamin D3 ( 800 IU ), which had similar pharmacodynamic effects. Both types of calcium-vitamin D3 regimens increased serum 25-hydroxyvitamin D and decreased serum intact parathyroid hormone to a similar extent, with levels returning within the normal range after 6 months. In a subgroup of 114 patients, femoral neck bone mineral density ( BMD ) decreased in the placebo group ( mean = –2.36 % per year, SD = 4.92 ), while remaining unchanged in women treated with calcium-vitamin D3 ( mean = 0.29 % per year, SD = 8.63 ). The difference between the two groups was 2.65 % ( 95 % CI = –0.44, 5.75 % ) with a trend in favor of the active treatment group. No significant difference between groups was found for changes in distal radius BMD and quantitative ultrasonic parameters at the os calcis. The relative risk ( RR ) of HF in the placebo group compared with the active treatment group was 1.69 ( 95 % CI = 0.96, 3.0 ), which is similar to that found in Decalyos I ( RR = 1.7 ; 95 % CI = 1.0, 2.8 ). Thus, these data are in agreement with those of Decalyos I and indicate that calcium and vitamin D3 in combination reverse senile secondary hyperparathyroidism and reduce both hip bone loss and the risk of hip fracture in elderly institutionalized women The Effects of Vitamin D Supplementation on Physical Function and Quality of Life in Older Patients With Heart Failure: A Randomized Controlled Trial Background —Low 25-hydroxyvitamin D levels, commonly found in older patients with heart failure, may contribute to the chronic inflammation and skeletal myopathy that lead to poor exercise tolerance. We tested whether vitamin D supplementation of patients with heart failure and vitamin D insufficiency can improve physical function and quality of life. Methods and Results —In a r and omized, parallel group, double-blind, placebo-controlled trial, patients with systolic heart failure aged ≥70 years with 25-hydroxyvitamin D levels < 50 nmol/L ( 20 ng/mL ) received 100000 U of oral vitamin D2 or placebo at baseline and 10 weeks. Outcomes measured at baseline, 10 weeks, and 20 weeks were 6-minute walk distance, quality of life ( Minnesota score ), daily activity measured by accelerometry, Functional Limitations Profile, B-type natriuretic peptide, and tumor necrosis factor-&agr;. Participants in the vitamin D group had an increase in their 25-hydroxyvitamin D levels compared with placebo at 10 weeks ( 22.9 versus 2.3 nmol/L [ 9.2 versus 0.9 ng/mL ] ; P<0.001 ) and maintained this increase at 20 weeks. The 6-minute walk did not improve in the treatment group relative to placebo. No significant benefit was seen on timed up and go testing, subjective measures of function, daily activity, or tumor necrosis factor. Quality of life worsened by a small, but significant amount in the treatment group relative to placebo. B-type natriuretic peptide decreased in the treatment group relative to placebo ( −22 versus + 78 pg/mL at 10 weeks ; P=0.04 ). Conclusions —Vitamin D supplementation did not improve functional capacity or quality of life in older patients with heart failure with vitamin D insufficiency. Clinical Trial Registration —www.controlled-trials.com. Identifier : IS RCT N51372896 Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a NOREPOS study. BACKGROUND Despite considerable interest, the relationship between circulating 25-hydroxyvitamin D and the risk of hip fracture is not fully established. OBJECTIVE The objective of the study was to study the association between serum 25-hydroxyvitamin D concentrations [ s-25(OH)D ] and the risk of hip fracture in Norway, a high-latitude country that has some of the highest hip fracture rates worldwide. METHODS A total of 21 774 men and women aged 65 - 79 years attended 4 community-based health studies during 1994 - 2001. Information on subsequent hip fractures was retrieved from electronic hospital discharge registers, with a maximum follow-up of 10.7 years. Using a stratified case-cohort design, s-25(OH)D was determined by HPLC-atmospheric pressure chemical ionization-mass spectrometry in stored serum sample s in hip fracture cases ( n = 1175 ; 307 men, 868 women ) and in gender-stratified r and om sample s ( n = 1438 ). Cox proportional hazards regression adapted for the case-cohort design was performed. RESULTS We observed an inverse association between s-25(OH)D and hip fracture ; those with s-25(OH)D in the lowest quartile ( < 42.2 nmol/L ) had a 38 % [ 95 % confidence interval ( CI ) 9 - 74 % ] increased risk of hip fracture compared with the highest quartile ( ≥67.9 nmol/L ) in a model accounting for age, gender, study center, and body mass index. The association was stronger in men than in women : hazard ratio 1.65 ( 95 % CI 1.04 - 2.61 ) vs hazard ratio 1.25 ( 95 % CI 0.95 - 1.65 ). CONCLUSION In this prospect i ve case-cohort study of hip fractures, the largest ever reported, we found an increased risk of hip fracture in subjects in the lowest compared with the highest quartile of serum 25-hydroxyvitamin D. In accordance with the findings of previous community-based studies, low vitamin D status was a modest risk factor for hip fracture High‐Dose Monthly Vitamin D for Prevention of Acute Respiratory Infection in Older Long‐Term Care Residents: A Randomized Clinical Trial OBJECTIVES To determine the efficacy and safety of high-dose vitamin D supplementation for prevention of acute respiratory infection ( ARI ) in older long-term care residents. DESIGN R and omized controlled trial investigating high-dose vs st and ard-dose vitamin D from 2010 to 2014. SETTING Colorado long-term care facilities. PARTICIPANTS Long-term care residents aged 60 and older ( n = 107 ). INTERVENTION The high-dose group received monthly supplement of vitamin D3 100,000 IU, the st and ard-dose group received a monthly placebo ( for participants taking 400 - 1,000 IU/d as part of usual care ) or a monthly supplement of 12,000 IU of vitamin D3 ( for participants taking < 400 IU/d as part of usual care ). MEASUREMENTS The primary outcome was incidence of ARI during the 12-month intervention. Secondary outcomes were falls and fractures, 25-hydroxyvitamin D levels, hypercalcemia, and kidney stones. RESULTS Participants ( 55 high dose, 52 st and ard dose ) were r and omized and included in the final analysis. The high-dose group had 0.67 ARIs per person-year and the st and ard-dose group had 1.11 ( incidence rate ratio ( IRR ) = 0.60, 95 % confidence interval ( CI ) = 0.38 - 0.94, P =.02 ). Falls were more common in the high-dose group ( 1.47 per person-year vs 0.63 in st and ard-dose group ; IRR = 2.33, 95 % CI = 1.49 - 3.63, P <.001 ). Fractures were uncommon and similar in both groups ( high dose 0.10 vs st and ard dose 0.19 per person-year ; P =.31 ). Mean trough 25-hydroxyvitamin D levels during the trial were 32. ng/mL in the high-dose group and 25.1 ng/mL in the st and ard-dose group. There was no hypercalcemia or kidney stones in either group. CONCLUSION Monthly high-dose vitamin D3 supplementation reduced the incidence of ARI in older long-term care residents but was associated with a higher rate of falls without an increase in fractures Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation Introduction Osteoporotic fractures in older people are a major and increasing public health problem. We examined the effect of vitamin D supplementation on fracture rate in people living in sheltered accommodation. Methods In a pragmatic double blind r and omised controlled trial of 3 years duration, we examined 3,440 people ( 2,624 women and 816 men ) living in residential or care home. We used four-monthly oral supplementation using 100,000 IU vitamin D2 ( ergocalciferol ). As a main outcome measure, we used the incidence of first fracture using an intention to treat analysis. This was a multicentre study in 314 care homes or sheltered accommodation complexes in South Wales, UK. Results The vitamin D and placebo groups had similar baseline characteristics. In intention-to-treat analysis, 205 first fractures occurred in the intervention group during a total of 2,846 person years of follow-up ( 7 fractures per 100 people per year of follow-up ), with 218 first fractures in the control group over 2,860 person years of follow-up. The hazard ratio of 0.95 ( 95 % confidence interval 0.79–1.15 ) for intervention compared to control was not statistically significant. ConclusionS upplementation with four-monthly 100,000 IU of oral vitamin D2 is not sufficient to affect fracture incidence among older people living in institutional care Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care Summary This trial compared the effects of daily treatment with vitamin D or placebo for 1 year on blood tests of vitamin D status. The results demonstrated that daily 4000 IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention. Introduction The aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000 IU ( 100 μg ), 2000 IU ( 50 μg ) or placebo for 1 year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes. Methods This is a r and omized placebo-controlled trial in 305 community-dwelling people aged 65 years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status ( plasma 25-hydroxy-vitamin D [ 25[OH]D ], parathyroid hormone [ PTH ], calcium and alkaline phosphatase ), cardiovascular risk factors and tests of physical function. Results Mean ( SD ) plasma 25(OH)D levels were 50 ( 18 ) nmol/L at baseline and increased to 137 ( 39 ), 102 ( 25 ) and 53 ( 16 ) nmol/L after 12 months in those allocated 4000 IU, 2000 IU or placebo, respectively ( with 88 %, 70 % and 1 % of these groups achieving the pre-specified level of > 90 nmol/L ). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000 IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function. Conclusions After accounting for average 70 % compliance in long-term trials, doses of 4000 IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. UNLABELLED This study of 9605 community-dwelling residents supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in elderly in a northern European region known to be deficient in vitamin D, especially during winter periods. INTRODUCTION We evaluated the effect of two programs for the prevention of osteoporotic fractures leading to acute hospital admission in a population of elderly community-dwelling residents. MATERIAL S AND METHODS This was a factorial, cluster-r and omized, pragmatic, intervention study. We included 9605 community-dwelling residents aged 66 + years. We offered a prevention program of a daily supplement of 1000 mg of elemental calcium as calcium carbonate and 400 IU ( 10 microg ) of vitamin D3 to a total of 4957 participants. Another program with evaluation and suggestions for the improvement of the domestic environment was offered to a total of 5063 participants. Both programs included revision of the resident's current pharmaceutical treatment. We achieved information on osteoporotic fractures in the study population from the Danish Hospital Registration Data base. We defined osteoporotic fractures as low energy fractures of the proximal humerus, distal forearm, vertebral column, pelvis, cervical femur, and intertrochanteric femur. RESULTS Active participation was 50.3 % in the Calcium and Vitamin D Program and 46.4 % in the Environmental and Health Program. We observed a 16 % reduction in fracture incidence rate ( relative risk [ RR ], 0.84 ; CI, 0.72 - 0.98 ; p < 0.025 ) among male and female residents offered the Calcium and Vitamin D Program ( intention-to-prevent analysis ). CONCLUSIONS This study supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in community-dwelling elderly people in a northern European region known to be deficient in vitamin D, especially during winter periods Relationship between the effect of eldecalcitol and serum 25(OH)D level In previous studies, we demonstrated that 12-month treatment with 0.75μg/day eldecalcitol increased bone mineral density in osteoporotic patients regardless of serum 25-hydroxyvitamin D ( 25(OH)D ) level, and in a 3-year r and omized double-blind clinical trial, eldecalcitol significantly reduced the incidences of vertebral and wrist fractures compared to alfacalcidol. However, it remains unclear whether the fracture risk reduction by eldecalcitol is affected by serum 25(OH)D. In the fracture prevention trial, patients with low 25(OH)D level at baseline were supplemented with 400IU/day native vitamin D3. In the current study, patients from that trial were divided according to the tertiles of serum 25(OH)D level at 6 months after treatment initiation. The increases in lumbar and hip BMD by eldecalcitol were significantly higher in all tertiles than those by alfacalcidol. The incidences of vertebral and osteoporotic fractures tended to be lower in each tertile of the eldecalcitol-treated group than in the corresponding tertile of the alfacalcidol-treated group, with the exception of vertebral fractures in the low tertile. We also investigated whether eldecalcitol treatment affected levels of serum 25(OH)D, serum 1,25(OH)2D, and parathyroid hormone in patients without vitamin D supplementation. With eldecalcitol treatment, serum 1,25(OH)2D concentration was reduced by approximately 50 %, whereas serum levels of parathyroid hormone and 25(OH)D were not affected. The major findings of the present study were that eldecalcitol did not affect serum 25(OH)D levels, and that it reduced the incidence of osteoporotic fractures and increased BMD in comparison with alfacalcidol regardless of serum 25(OH)D level within the range of serum 25(OH)D concentrations at or higher than 20ng/mL. Whether eldecalcitol is similarly effective at vitamin D deficient serum 25(OH)D levels remains to be clarified. This article is part of a Special Issue entitled'Vitamin D Workshop' Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial Conflicting data regarding cardiovascular effects of thiazolidinediones ( TZDs ) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation ( TIDE ) trial aim ed to assess the effects of TZDs ( rosiglitazone and pioglitazone ) on cardiovascular outcomes and the effects of vitamin D ( cholecalciferol ) on cancers and mortality. A large multicentre 3 × 2 factorial double-blind placebo-controlled r and omised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥50 years whose HbA1c was 6.5–9.5 % ( 48–80 mmol/mol ) when using two or fewer glucose-lowering drugs were r and omised by a central computer system to placebo ( n = 541 ), rosiglitazone 4–8 mg/day ( n = 399 ) or pioglitazone 30–45 mg/day ( n = 392 ) ; 1,221 participants were r and omised to placebo ( n = 614 ) or vitamin D 1,000 IU/day ( n = 607 ). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infa rct ion, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All r and omised participants were included in the primary analysis. From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants ( 0.9 % ) in the placebo groups and three participants ( 0.4 % ) in the TZD groups ( two allocated to pioglitazone, one to rosiglitazone ). In the vitamin D arm, the primary outcome occurred in three participants ( 0.5 % ) in the placebo group and in two participants ( 0.3 % ) receiving vitamin D. Adverse events were comparable in all groups. Uncertainty persists regarding the clinical ly relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial. Clinical Trials.gov NCT00879970 The study was funded by GlaxoSmithKline Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women. BACKGROUND Ergocalciferol ( vitamin D(2 ) ) supplementation plays a role in fall prevention, but the effect in patients living in the community in sunny climates remains uncertain. We evaluated the effect of ergocalciferol and calcium citrate supplementation compared with calcium alone on the risk of falls in older women at high risk of falling. METHODS A 1-year population -based, double-blind, r and omized controlled trial of 302 community-dwelling ambulant older women aged 70 to 90 years living in Perth, Australia ( latitude, 32 degrees S ), with a serum 25-hydroxyvitamin D concentration of less than 24.0 ng/mL and a history of falling in the previous year. Participants were r and omized to receive ergocalciferol, 1000 IU/d, or identical placebo ( hereinafter, ergocalciferol and control groups, respectively ). Both groups received calcium citrate, 1000 mg/d. Fall data were collected every 6 weeks. RESULTS Ergocalciferol therapy reduced the risk of having at least 1 fall over 1 year after adjustment for baseline height, which was significantly different between the 2 groups ( ergocalciferol group, 53.0 % ; control group, 62.9 % ; odds ratio [ OR ], 0.61 ; 95 % confidence interval [ CI ], 0.37 - 0.99 ). When those who fell were grouped by the season of first fall or the number of falls they had, ergocalciferol treatment reduced the risk of having the first fall in winter and spring ( ergocalciferol group, 25.2 % ; control group, 35.8 % ; OR, 0.55 ; 95 % CI, 0.32 - 0.96 ) but not in summer and autumn, and reduced the risk of having 1 fall ( ergocalciferol group, 21.2 % ; control group, 33.8 % ; OR, 0.50 ; 95 % CI, 0.28 - 0.88 ) but not multiple falls. CONCLUSION Patients with a history of falling and vitamin D insufficiency living in sunny climates benefit from ergocalciferol supplementation in addition to calcium, which is associated with a 19 % reduction in the relative risk of falling, mostly in winter The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Flaws in the design, conduct, analysis, and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women Abstract Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight-section Brocade ( MESE ) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women ( n = 198 ) aged 50 to 75 years were r and omized into Control, Ca, MESE, and MESE + Ca. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE + Ca group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery ( HSS ) scores of both knees, chronic back pain visual analogue scale scores ( VAS ), bone mineral density ( BMD ) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test ( 3′ ) and one-leg Stance ( OLS ). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE + Ca group was better than that in control group. There was 1.9 % and 1.7 %, 2.3 %, and 2.1 % net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE + Ca groups. For the balance capacity, the subjects in MESE and MESE + Ca groups secured much better performance than those in Ca and control group after the treatment for 12 months ( P < 0.001, P < 0.001 ). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial. In a double-blind trial, 327 patients ( 57 men ) over 65 ( mean age 79.5 ) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, meth and ienone 2.5 mg and /or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed : the greatest changes occurred with meth and ienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively ; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant ( P less than 0.001 ) in those receiving vitamin D3 and meth and ienone Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. CONTEXT Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures ; however, adherence to daily supplementation is typically poor. OBJECTIVE To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture. DESIGN, SETTING, AND PARTICIPANTS A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were r and omly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008. INTERVENTION 500,000 IU of cholecalciferol or placebo. MAIN OUTCOME MEASURES Falls and fractures were ascertained using monthly calendars ; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a sub study, 137 r and omly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels. RESULTS Women in the cholecalciferol ( vitamin D ) group had 171 fractures vs 135 in the placebo group ; 837 women in the vitamin D group fell 2892 times ( rate, 83.4 per 100 person-years ) while 769 women in the placebo group fell 2512 times ( rate, 72.7 per 100 person-years ; incidence rate ratio [ RR ], 1.15 ; 95 % confidence interval [ CI ], 1.02 - 1.30 ; P =.03 ). The incidence RR for fracture in the vitamin D group was 1.26 ( 95 % CI, 1.00 - 1.59 ; P =.047 ) vs the placebo group ( rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo ). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months ( test for homogeneity ; P =.02 ). In the sub study, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3 % of the sub study participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing. CONCLUSION Among older community-dwelling women, annual oral administration of high-dose cholecalciferol result ed in an increased risk Hip Fractures and Bone Mineral Density in the Elderly—Importance of Serum 25-Hydroxyvitamin D Background The significance of serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations for hip fracture risk of the elderly is still uncertain. Difficulties reaching both frail and healthy elderly people in r and omized controlled trials or large cohort studies may in part explain discordant findings. We determined hazard ratios for hip fractures of elderly men and women related to serum 25(OH)D, including both the frail and the healthy segment of the elderly population. Methods The AGES-Reykjavik Study is a prospect i ve study of 5764 men and women, age 66–96 years, based on a representative sample of the population of Reykjavik, Icel and. Participation was 71.8 %. Hazard ratios of incident hip fractures and baseline bone mineral density were determined according to serum concentrations of 25(OH)D at baseline. Results Mean follow-up was 5.4 years. Compared with referent values ( 50–75 nmol/L ), hazard ratios for hip fractures were 2.24 ( 95 % CI 1.63, 3.09 ) for serum 25(OH)D < 30 nmol/L, adjusting for age, sex, body mass index, height, smoking, alcohol intake and season, and 2.08 ( 95 % CI 1.51, 2.87 ), adjusting additionally for physical activity. No difference in risk was associated with 30–50 nmol/L or ≥75 nmol/L in either model compared with referent. Analyzing the sexes separately, hazard ratios were 2.61 ( 95 % CI 1.47, 4.64 ) in men and 1.93 ( 95 % CI 1.31, 2.84 ) in women. Values < 30 nmol/L were associated with significantly lower bone mineral density of femoral neck compared with referent, z-scores -0.14 ( 95 % CI −0.27, −0.00 ) in men and −0.11 ( 95 % CI −0.22, −0.01 ) in women. Conclusions Our results lend support to the overarching importance of maintaining serum 25(OH)D above 30 nmol/L for bone health of elderly people while potential benefits of having much higher levels could not be detected Association between plasma 25-hydroxyvitamin D levels and fracture risk: the EPIC-Oxford study. The importance of vitamin D for bone health is well established, but few data exist on the relation between plasma levels of 25-hydroxyvitamin D and risk of fracture. The authors examined this association within the EPIC-Oxford ( European Prospect i ve Investigation into Cancer and Nutrition-Oxford cohort ) study of men and women in the United Kingdom ( 1993 - 1999 ). Five years after recruitment, participants completed a follow-up question naire where fracture incidence was self-reported. Plasma 25-hydroxyvitamin D concentration was measured in 730 incident fracture cases and 1,445 matched controls. There was a clear association between plasma 25-hydroxyvitamin D concentration and month of blood draw, the highest values being during the summer months. Among women, there were significant relations between 25-hydroxyvitamin D levels and age, body mass index, marital status, use of hormone therapy, physical activity, diet group, dietary intake of vitamin D, and alcohol. Similar relations were seen among men, although often they were nonsignificant because of smaller numbers. There was no evidence of an association between plasma 25-hydroxyvitamin D and fracture risk for men or women ; the relative risks associated with a doubling of plasma 25-hydroxyvitamin D were 1.15 ( 95 % confidence interval : 0.82, 1.61 ) and 0.95 ( 95 % confidence interval : 0.80, 1.13 ), respectively. These results were not affected by adjustment for potential confounders and were consistent across a number of subgroups Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial. BACKGROUND The 2009 KDIGO ( Kidney Disease : Improving Global Outcomes ) chronic kidney disease-mineral and bone disorder clinical practice guideline suggests correcting 25-hydroxyvitamin D3 ( 25[OH]D ) levels<30ng/mL in patients treated with maintenance hemodialysis, but does not provide a specific treatment protocol. STUDY DESIGN 2-center, double-blind, r and omized, 13-week, controlled trial followed by a 26-week open-label study. SETTING & PARTICIPANTS 55 adult maintenance hemodialysis patients with 25(OH)D levels<30ng/mL were recruited from June 2008 through October 2009. INTERVENTION Cholecalciferol, 25,000IU, per week orally versus placebo for 13 weeks, then 26 weeks of individualized cholecalciferol prescription based on NKF-KDOQI ( National Kidney Foundation-Kidney Disease Outcomes Quality Initiative ) guidelines. OUTCOMES Primary end point was the percentage of patients with 25(OH)D levels≥30ng/mL at 13 weeks. Secondary outcomes included the percentage of patients with normal calcium, phosphorus, and intact parathyroid hormone ( iPTH ) blood levels. Safety measures included incidence of hypercalcemia and hypervitaminosis D. MEASUREMENTS Blood calcium and phosphate were measured weekly ; iPTH, 25(OH)D, 1,25-dihydroxyvitamin D3 ( 1,25[OH]2D ), and bone turnover markers, trimonthly ; fetuin A and fibroblast growth factor 23 ( FGF-23 ) serum levels and aortic calcification scores were determined at weeks 0 and 39. RESULTS The primary end point significantly increased in the treatment group compared with the placebo group ( 61.5 % vs 7.4 % ; P<0.001 ), as well as 1,25(OH)2D levels ( 22.5 [ IQR, 15 - 26 ] vs 11 [ IQR, 10 - 15]pg/mL ; P<0.001 ) and the proportion of patients achieving the target calcium level ( 76.9 % vs 48.2 % ; P=0.03 ). Incidence of hypercalcemia and phosphate and iPTH levels were similar between groups. The second 26-week study phase did not significantly modify the prevalence of 25(OH)D level≥30ng/mL in patients issued from the placebo group. LIMITATIONS Small size of the study population. CONCLUSIONS Oral weekly administration of 25,000IU of cholecalciferol for 13 weeks is an effective, safe, inexpensive, and manageable way to increase 25(OH)D and 1,25(OH)2D levels in hemodialysis patients. Further evaluation of clinical end points is suggested Multivitamin and mineral supplementation is associated with the reduction of fracture risk and hospitalization rate in Chinese adult males: a randomized controlled study Controversy exists in the literature regarding the efficacy of bone health-related nutrients, especially calcium and vitamin D, in preventing fractures. The aim of our present study was to determine the effect of multivitamin and mineral supplementation on fracture incidence among 3,318 participants from a nutritional intervention trial in Linxian, China. A total of 1,461 men and 1,857 women were enrolled and r and omized to daily supplementation with 26 vitamins and minerals tablet or placebo pills for 6 years, followed by a 16-year post-interventional follow-up. The date s, sites, and causes of the fractures were collected retrospectively via a st and ardized question naire. Cox proportional hazard model was used to estimate hazard ratios and 95 % confidence intervals of fracture incidence in the intervention versus the placebo group. A total of 221 fractures ( 57 in men and 164 in women ) occurred during the entire study period of 21 years and 9 months. In men, the supplement reduced the risk of fracture by 63 % during the trial period, and this protective effect was sustained and statistically significant when analysis included both the trial period and 5- or 10-year post-intervention follow-up ( years 0–11, P = 0.04 ; years 0–16, P = 0.02, respectively ). The protection against fracture was not apparent > 10 years after cessation of the intervention. In women, no significant effect of supplementation on fracture incidence was seen in any of the study periods. These results demonstrate that a 6-year multivitamin and mineral intervention was associated with significant reduction of fracture risk and fracture-related hospitalization in men, but not in women Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial Abstract Objective : To determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community. Design : R and omised double blind controlled trial of 100 000 IU oral vitamin D3 ( cholecalciferol ) supplementation or matching placebo every four months over five years. Setting and participants : 2686 people ( 2037 men and 649 women ) aged 65 - 85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk. Main outcome measures : Fracture incidence and total mortality by cause. Results : After five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites ( hip, wrist or forearm, or vertebrae ). Relative risks in the vitamin D group compared with the placebo group were 0.78 ( 95 % confidence interval 0.61 to 0.99, P=0.04 ) for any first fracture and 0.67 ( 0.48 to 0.93, P=0.02 ) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 ( 0.74 to 1.06, P=0.18 ). Findings were consistent in men and women and in doctors and the general practice population. Conclusion : Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community. What is already known in this topic Vitamin D and calcium supplements are effective in preventing fractures in elderly women Whether isolated vitamin D supplementation prevents fractures is not clear What this paper adds Four monthly oral supplementation with 100 000 IU vitamin D reduces fractures in men and women aged over 65 living in the general community Total fracture incidence was reduced by 22 % and fractures in major osteoporotic sites by 33 A randomized controlled trial of vitamin D dosing strategies after acute hip fracture: No advantage of loading doses over daily supplementation Background There remains uncertainty regarding the appropriate therapeutic management of hip fracture patients. The primary aim of our study was to examine whether large loading doses in addition to daily vitamin D offered any advantage over a simple daily low-dose vitamin D regimen for increasing vitamin D levels. Methods In this r and omized controlled study, patients over age 50 with an acute fragility hip fracture were enrolled from two hospital sites in Ontario, Canada. Participants were r and omized to one of three loading dose groups : placebo ; 50,000 IU vitamin D2 ; or 100,000 IU D2. Following a placebo/loading dose, all patients received a daily tablet of 1,000 IU vitamin D3 for 90 days. Serum 25-hydroxy vitamin D ( 25-OHD ) was measured at baseline, discharge from acute care ( approximately 4-weeks ), and 3-months. Results Sixty-five patients were enrolled in the study ( 44 % male ). An immediate rise in 25-OHD occurred in the 100,000 group, however there were no significant differences in 25-OHD between the placebo, 50,000 and 100,000 loading dose groups after 4-weeks ( 69.3, 84.5, 75.6 nmol/L, p = 0.15 ) and 3-months ( 86.7, 84.2, 73.3 nmol/L, p = 0.09 ), respectively. At the end of the study, approximately 75 % of the placebo and 50,000 groups had reached the target therapeutic range ( 75 nmol/L ), and 44 % of the 100,000 group. Conclusions In correcting vitamin D insufficiency/deficiency in elderly patients with hip fracture, our findings suggest that starting with a lower daily dose of Vitamin D3 achieved similar results as providing an additional large loading dose of Vitamin D2. At the end of the study, all three groups were equally effective in attaining improvement in 25-OHD levels. Given that a daily dose of 1,000 IU vitamin D3 ( with or without a loading dose ) result ed in at least 25 % of patients having suboptimal vitamin D status, patients with acute hip fracture may benefit from a higher daily dose of vitamin D.Trial registration Clinical Trials # Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care Abstract Objective To assess whether supplementation with calcium and cholecaliferol ( vitamin D3 ) reduces the risk of fracture in women with one or more risk factors for fracture of the hip. Design Pragmatic open r and omised controlled trial. Setting Practice nurse led clinics in primary care. Participants 3314 women aged 70 and over with one or more risk factors for hip fracture : any previous fracture, low body weight ( < 58 kg ), smoker, family history of hip fracture, or fair or poor self reported health. Intervention Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only ( control group ). Main outcome measures Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life ( measured with the SF-12 ). Results 69 % of the women who completed the follow-up question naire at 24 months were still taking supplements ( 55 % with inclusion of r and omised participants known to be alive ). After a median follow-up of 25 months ( range 18 to 42 months ), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures ( odds ratio for fracture in supplemented group 1.01, 95 % confidence interval 0.71 to 1.43 ). The odds ratio for hip fracture was 0.75 ( 0.31 to 1.78 ). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups. Conclusion We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration IS RCT N26118436, controlled trials registry An initial loading-dose vitamin D versus placebo after hip fracture surgery: randomized trial Background Improving vitamin D ( 25-OHD ) status may be an important modifiable factor that could reduce disability severity, fall-rates and mortality associated after hip fracture surgery. Providing a loading-dose post-surgery may overcome limitations in adherence to daily supplementation. Method In this r and omized, double-blind, placebo-controlled trial, 218 adults, aged 65-years or older, requiring hip fracture surgery were assigned to receive a single loading-dose of cholecalciferol ( 250,000 IU vitamin-D3, the REVITAHIP - Replenishment of Vitamin D in Hip Fracture strategy ) or placebo, both receiving daily vitamin-D(800 IU ) and calcium ( 500 mg ) for 26-weeks. Outcome measures were 2.4 m gait-velocity, falls, fractures, death ( Week-4 ), 25-OHD levels, quality -of-life measure ( EuroQoL ) and mortality at weeks-2, 4 and 26. Results Mean age of 218 participants was 83.9(7.2 ) years and 77.1 % were women. Baseline mean 25-OHD was 52.7(23.5)nmol/L, with higher levels at Week-2 ( 73 vs 66 nmol/L ; p =.019 ) and Week-4 ( 83 vs 75 nmol/L ; p =.030 ) in the Active-group, but not at Week-26. At week-4, there were no differences in 2.4 m gait-velocity ( 0.42 m/s vs 0.39 m/s, p =.490 ), fractures ( 2.7 % vs 2.8 %, p =.964 ) but Active participants reported less falls ( 6.3 % vs 21.1 %, χ2 = 4.327 ; p = 0.024 ), with no significant reduction in deaths at week-4 ( 1 vs 3, p = 0.295 ), higher percentage reporting ‘ no pain or discomfort ’ ( 96.4 % vs 88.8 %, p = 0.037 ), and trended for higher EuroQoL-scores ( p = 0.092 ) at week-26. One case of hypercalcemia at week-2 normalised by week-4. Conclusion Among older people after hip fracture surgery, the REVITAHIP strategy is a safe and low cost method of improving vitamin-D levels, reducing falls and pain levels. Trial registration The protocol for this study is registered with the Australian New Zeal and Clinical Trials Registry ANZCTRN ACTRN12610000392066 ( Date of registration : 14/05/2010 ) Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. UNLABELLED Dietary supplementation with vitamin K(1 ), with vitamin D(3 ) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius. INTRODUCTION The putative beneficial role of high dietary vitamin K(1 ) ( phylloquinone ) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or = 60 years of age. MATERIAL S AND METHODS Healthy, nonosteoporotic women ( n = 244 ) were r and omized to receive either ( 1 ) placebo, ( 2 ) 200 microg/day vitamin K(1 ), ( 3 ) 10 microg ( 400 IU ) vitamin D(3 ) plus 1000 mg calcium/day, or ( 4 ) combined vitamins K(1 ) and D(3 ) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables. RESULTS Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1 ) increased by 157 % ( p < 0.001 ), the percentage of undercarboxylated osteocalcin ( % GluOC ) decreased by 51 % ( p < 0.001 ), serum 25-hydroxyvitamin D [ 25(OH)D ] increased by 17 % ( p < 0.001 ), and PTH decreased by 11 % ( p = 0.049 ). CONCLUSIONS These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1 ) together with supplements of calcium plus moderate vitamin D(3 ) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial Importance Evidence suggests that low vitamin D status may increase the risk of cancer. Objective To determine if dietary supplementation with vitamin D3 and calcium reduces the risk of cancer among older women. Design, Setting, and Participants A 4-year, double-blind, placebo-controlled, population -based r and omized clinical trial in 31 rural counties ( June 24, 2009, to August 26, 2015—the final date of follow-up ). A total of 2303 healthy postmenopausal women 55 years or older were r and omized, 1156 to the treatment group and 1147 to the placebo group. Duration of treatment was 4 years. Interventions The treatment group ( vitamin D3 + calcium group ) received 2000 IU/d of vitamin D3 and 1500 mg/d of calcium ; the placebo group received identical placebos. Main Outcomes and Measures The primary outcome was the incidence of all-type cancer ( excluding nonmelanoma skin cancers ), which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. Results Among 2303 r and omized women ( mean age, 65.2 years [ SD, 7.0 ] ; mean baseline serum 25-hydroxyvitamin D level, 32.8 ng/mL [ SD, 10.5 ] ), 2064 ( 90 % ) completed the study. At year 1, serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D3 + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was confirmed in 109 participants, 45 ( 3.89 % ) in the vitamin D3 + calcium group and 64 ( 5.58 % ) in the placebo group ( difference, 1.69 % [ 95 % CI, −0.06 % to 3.46 % ] ; P =.06 ). Kaplan-Meier incidence over 4 years was 0.042 ( 95 % CI, 0.032 to 0.056 ) in the vitamin D3 + calcium group and 0.060 ( 95 % CI, 0.048 to 0.076 ) in the placebo group ; P =.06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 ( 95 % CI, 0.47 to 1.02 ). Adverse events potentially related to the study included renal calculi ( 16 participants in the vitamin D3 + calcium group and 10 in the placebo group ), and elevated serum calcium levels ( 6 in the vitamin D3 + calcium group and 2 in the placebo group ). Conclusions and Relevance Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention. Trial Registration clinical trials Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial. BACKGROUND Care of elderly patients after hip fracture is not well established. METHODS We enrolled 173 patients with acute hip fracture who were 65 years or older ( 79.2 % women ; mean age, 84 years ; 77.4 % living at home ). Using a factorial design, we r and omly allocated patients to extended physiotherapy ( PT ) ( supervised 60 min/d during acute care plus an unsupervised home program ) vs st and ard PT ( supervised 30 min/d during acute care plus no home program ; single-blinded ), and to cholecalciferol therapy, 2000 vs 800 IU/d ( double-blinded ). Primary outcome was rate of falls ; secondary outcome was rate of hospital readmissions during the 12-month follow-up. All analyses included 173 individuals and used multivariate Poisson regression analyses. RESULTS At baseline, 50.9 % of participants had 25-hydroxyvitamin D levels of less than 12 ng/mL and 97.7 % of less than 30 ng/mL. We documented 212 falls and 74 hospital readmissions. Because this was a factorial design trial, all analyses tested the main effect of each treatment while controlling for the other in 173 participants. Extended vs st and ard PT reduced the rate of falls by 25 % ( 95 % confidence interval [ CI ], -44 % to -1 % ). Cholecalciferol treatment, 2000 vs 800 IU/d, did not reduce falls ( 28 % ; 95 % CI, -4 % to 68 % ), but reduced the rate of hospital readmissions by 39 % ( 95 % CI, -62 % to -1 % ). CONCLUSIONS Extended PT was successful in reducing falls but not hospital readmissions, whereas cholecalciferol treatment, 2000 IU/d, was successful in reducing hospital readmission but not falls. Thus, the 2 strategies may be useful together because they address 2 different and important complications after hip fracture", "OBJECTIVE To up date the evidence on the effectiveness of lumbar supports, education and exercise in the primary prevention of low back pain at the workplace. Secondary Prevention of Low‐Back Pain: A Clinical Trial A clinical trial, aim ed at secondary prevention of low-back pain, was performed in 142 hospital employees reporting at least three annual episodes of this condition. Participants were r and omly assigned to one of three groups : a calisthenics program ( CAL ) for 3 months with biweekly sessions of flexion exercises, a back school program ( 5 sessions ), and a control group. The effectiveness of the two intervention programs was evaluated over a 1-year period. Baseline preintervention data and evaluation at the end of 3 months of intervention and after an additional 6 months were collected. A monthly surveillance for the whole year showed a mean of 4.5 “ painful months ” in the CAL group versus 7.3 and 7.4 months in the back school and control groups, respectively ( P < 0.0001 ). The superiority of the CAL group was achieved partly because of the significant increase in trunk forward flexion and to initial increment in abdominal muscle strength. The increased trunk flexion was associated with the rate of participation in the CAL sessions. Further research is needed to answer the question of “ intensity versus type of exercise ” by comparing different intervention programs, with similar intensity No significant differences between intervention programmes on neck, shoulder and low back pain: a prospective randomized study among home-care personnel. The effects of two different prevention programmes on : ( 1 ) reported neck, shoulder and back pain, ( 2 ) perceived physical exertion at work and perceived work-related psychosocial factors, were evaluated by question naires after 12 and 18 months. Female nursing aides and assistant nurses ( n = 282 ) working in the home-care services, were r and omly assigned to one of three groups for : ( 1 ) individually design ed physical training programme, ( 2 ) work-place stress management, ( 3 ) control group. Results revealed no significant differences between the three groups. However, improvements in low back pain were registered within both intervention groups for up to 18 months. Perceived physical exertion at work was reduced in the physical training group. Improvements in neck and shoulder pain did not differ within the three groups. Dissatisfaction with work-related, psychosocial factors was generally increased in all groups. As the aetiology of neck, shoulder and back disorders is multifactorial, a combination of the two intervention programmes might be preferable and should be further studied Lumbar supports and education for the prevention of low back pain in industry: a randomized controlled trial. CONTEXT Low back pain is a frequent and costly health problem. Prevention of low back pain is important both for the individual patient and from an economic perspective. OBJECTIVE To assess the efficacy of lumbar supports and education in the prevention of low back pain in industry. DESIGN A r and omized controlled trial with a factorial design. SETTING The cargo department of an airline company in the Netherl and s. PARTICIPANTS A total of 312 workers were r and omized, of whom 282 were available for the 6-month follow-up. INTERVENTIONS Subjects were r and omly assigned to 4 groups : ( 1 ) education ( lifting instructions ) and lumbar support, ( 2 ) education, ( 3 ) lumbar support, and ( 4 ) no intervention. Education consisted of 3 group sessions on lifting techniques with a total duration of 5 hours. Lumbar supports were recommended to be used during working hours for 6 months. MAIN OUTCOME MEASURES Low back pain incidence and sick leave because of back pain during the 6-month intervention period. RESULTS Compliance with wearing the lumbar support at least half the time was 43 %. In the 282 subjects for whom data were available, no statistically significant differences in back pain incidence ( 48 [ 36 % ] of 134 with lumbar support vs 51 [ 34 % ] of 148 without, P=.81 ) or in sick leave because of low back pain ( mean, 0.4 days per month with lumbar support vs 0.4 days without, P=.52 ) were found among the intervention groups. In a subgroup of subjects with low back pain at baseline, lumbar supports reduced the number of days with low back pain per month ( median, 1.2 vs 6.5 days per month ; P=.03 ). CONCLUSIONS Overall, lumbar supports or education did not lead to a reduction in low back pain incidence or sick leave. The results of the subgroup analysis need to be confirmed by future research. Based on our results, the use of education or lumbar supports can not be recommended in the prevention of low back pain in industry Lumbar supports for prevention and treatment of low back pain: a systematic review within the framework of the Cochrane Back Review Group. STUDY DESIGN A systematic review of r and omized and nonr and omized controlled trials. SUMMARY OF BACKGROUND DATA Lumbar supports are used in the treatment of low back pain, but also to prevent the onset ( primary prevention ) or recurrences of a low back pain episode ( secondary prevention ). OBJECTIVES To assess the effects of lumbar sup-ports for prevention and treatment of nonspecific low back pain. METHODS The Medline, Cinahl, and Current Contents data bases ; the Cochrane Controlled Trials Register up to September 1999 ; and the Embase data base up to September 1998 were all search ed. References of identified trials and systematic review s were review ed and the Science Citation Index used to identify additional trials. Method ologic quality assessment and data extraction were performed by two review ers independently. A quantitative analysis was performed in which the strength of evidence was classified as strong, moderate, limited or conflicting, and no evidence. RESULTS Five r and omized and two nonr and omized preventive trials and six r and omized therapeutic trials were included in the review. Only 4 of the 13 studies were of high quality. There was moderate evidence that lumbar supports are not effective for primary prevention. No evidence was found on the effectiveness of lumbar supports for secondary prevention. The systematic review of therapeutic trials showed that there is limited evidence that lumbar supports are more effective than no treatment, whereas it is still unclear whether lumbar supports are more effective than other interventions for treatment of low back pain. CONCLUSIONS There continues to be a need for high quality r and omized trials on the effectiveness of lumbar supports. One of the most essential issues to tackle in these future trials seems to be the realization of adequate compliance Teaching and Social Support: Effects on Knowledge, Attitudes, and Behaviors to Prevent Low Back Injuries in Industry This study was funded in part by NIH grant AR36308 The authors thank the employees of the United States Postal Service and the American Postal Workers Union ( APWU ), Boston Metro Area Local, and Maith and lers Local 301 for their help and cooperation ; therapists from the Department of Rehabilitation Services, Bngham and Women's Hospital for help in training workers ; and Ms Nancy Tanner for A controlled trial of an educational program to prevent low back injuries. BACKGROUND Low back injuries are common and costly, accounting for 15 to 25 percent of injuries covered by workers'compensation and 30 to 40 percent of the payments made under that program. The high costs of injury, the lack of effective treatment. and the evidence that there are behavioral risk factors have led to widespread use of employee education programs that teach safe lifting and h and ling. The effectiveness of those programs, however, has received little rigorous evaluation. METHODS We evaluated an educational program design ed to prevent low back injury in a r and omized, controlled trial involving about 4000 postal workers. The program, similar to that in wide use in so-called back schools, was taught by experienced physical therapists. Work units of workers and supervisors were trained in a two-session back school ( three hours of training ), followed by three to four reinforcement sessions over the succeeding few years. Injured subjects ( from both the intervention and the control groups ) were r and omized a second time to receive either training or no training after their return to work. RESULTS Physical therapists trained 2534 postal workers and 134 supervisors. Over 5.5 years of follow-up, 360 workers reported low back injuries, for a rate of 21.2 injuries per 1000 worker-years of risk. The median time off from work per injury was 14 days ( range, 0 to 1717 ) ; the median cost was $ 204 ( range, zero to $ 190,380 ). After their return to work, 75 workers were injured again. Our comparison of the intervention and control groups found that the education program did not reduce the rate of low back injury, the median cost per injury, the time off from work per injury, the rate of related musculoskeletal injuries, or the rate of repeated injury after return to work ; only the subjects'knowledge of safe behavior was increased by the training. CONCLUSIONS A large-scale, r and omized, controlled trial of an educational program to prevent work-associated low back injury found no long-term benefits associated with training The Influence of Prophylactic Orthoses on Abdominal Strength and Low Back Injury in the Workplace This study was design ed to determine the effect of multimodal intervention and the prevention of back injury, and to evaluate the adverse side effects of using a lumbosacral corset in the workplace. Subjects were 90 male warehouse workers r and omly selected from over 800 employees at a grocery distribution center. Subjects were assigned to three groups : true controls, no back school, no brace orthoses ; back school only ; and back school plus wearing a custom molded lumbosacral orthosis. Comparisons of pre-testing and 6-month follow-up posttesting for abdominal strength, cognitive data, work injury incidence and productivity and use of health care services were evaluated. Controls and training-only group showed no changes in strength productivity or lost time. Orthoses and training-group showed no changes in strength productivity or accident rate ; however, they showed substantially less lost time. This study supports the concept of using education and prophylactic bracing to prevent back injury and reduce time loss. It appears that the use of intermittent prophylactic bracing has no adverse affects on abdominal muscle strength and may contribute to decreased lost time from work injuries Primary Prevention of Back Symptoms and Absence from Work: A Prospective Randomized Study Among Hospital Employees The personnel at a geriatric hospital were r and omized into two groups. One group was allowed to exercise during working hours to improve back muscle strength, endurance, and coordination. The other group did not participate in the exercise program and received no further advice or information. After 13 months, the training group had increased back muscle strength. One subject had been absent from work 28 days in the training group whereas 12 subjects had been absent 155 days from work because of low back pain in the control group ( P<0.004 ). The back pain complaints and intensity of back pain in the training group also decreased in a statistically significant way. Every hour spent by the physiotherapist on the training group reduced the work absence among the participants by 1.3 days, result ing in a cost/benefit ratio greater than 10 The Cost‐Effectiveness of a Back School Program in Industry: A Longitudinal Controlled Field Study To define the cost-effectiveness of a back school program in industry, a controlled longitudinal field study was carried out in a Dutch bus company. The experimental group received a program consisting of information on back care, physical fitness, nutrition, stress, and relaxation. Objective data on absenteeism were collected and compared during a 6-year period for the control and experimental groups. Results showed that a tailor-made back school program reduced absenteeism by at least 5 days per year per employee, therefore being cost-effective to industry. A reduction was not observed in incidence, but in mean length of absenteeism. This effect turned out to be persistent during a 2-year period following the program Effects of an exercise program on sick leave due to back pain. The purpose s of this study were to evaluate the effect of a weekly exercise program on short-term sick leave ( less than 50 days ) attributable to back pain and to determine whether changes in absenteeism were related to changes in cardiovascular fitness. Subjects were r and omly assigned to an exercise group ( n = 58 ) and a control group ( n = 53 ). Sick leave attributable to back pain was determined in the intervention period of 1 1/2 years and a comparable 1 1/2-year period prior to the study. In the exercise group, the number of episodes of back pain and the number of sick-leave days attributable to back pain in the intervention period decreased by over 50 %. Absenteeism attributable to back pain increased in the control group. The decrease in sick leave in the exercise group was not accompanied by any change in cardiovascular fitness. Suggestions for establishing exercise programs are given A prospective study of back belts for prevention of back pain and injury. CONTEXT Despite scientific uncertainties about effectiveness, wearing back belts in the hopes of preventing costly and disabling low back injury in employees is becoming common in the workplace. OBJECTIVE To evaluate the effectiveness of using back belts in reducing back injury cl aims and low back pain. DESIGN AND SETTING Prospect i ve cohort study. From April 1996 through April 1998, we identified material -h and ling employees in 160 new retail merch and ise stores ( 89 required back belt use ; 71 had voluntary back belt use ) in 30 states ( from New Hampshire to Michigan in the north and from Florida to Texas in the south ) ; data collection ended December 1998, median follow-up was 6(1/2 ) months. PARTICIPANTS A referred sample of 13,873 material h and ling employees provided 9377 baseline interviews and 6311 ( 67 % ) follow-up interviews ; 206 ( 1.4 % ) refused baseline interview. MAIN OUTCOME MEASURES Incidence rate of material -h and ling back injury workers'compensation cl aims and 6-month incidence rate of self-reported low back pain. RESULTS Neither frequent back belt use nor a belt-requirement store policy was significantly associated with back injury cl aim rates or self-reported back pain. Rate ratios comparing back injury cl aims of those who reported wearing back belts usually every day and once or twice a week vs those who reported wearing belts never or once or twice a month were 1.22 ( 95 % confidence interval [ CI ], 0.87 - 1.70 ) and 0.95 ( 95 % CI, 0.56 - 1.59 ), respectively. The respective odds ratios for low back pain incidence were 0.97 ( 95 % CI, 0.83 - 1.13 ) and 0.92 ( 95 % CI, 0.73 - 1.16 ). CONCLUSIONS In the largest prospect i ve cohort study of back belt use, adjusted for multiple individual risk factors, neither frequent back belt use nor a store policy that required belt use was associated with reduced incidence of back injury cl aims or low back pain. JAMA. 2000;284:2727 - 2732 An evaluation of a weightlifting belt and back injury prevention training class for airline baggage handlers. This study evaluated the efficacy of a commercially available weightlifting belt in relation to reduction of lumbar injury incident rate and severity of injuries over an 8-month period. The study used 642 baggage h and lers working for a major airline company as participants. Four treatment groups were r and omly selected : a group receiving the belt only, a group receiving a 1 h training class only, a group receiving both a belt and a 1 h training class, and a control group receiving nothing. Two treatment groups were added which contained participants who discontinued use of the belt prior to the end of an 8-month study period. Results indicated that there were no significant differences for total lumbar injury incident rate, restricted workday case injury incident rate, lost workdays and restricted workdays rate, and worker's compensation rates. There was, however, a marginal significant difference for lost workday case injury incident rate. Groups with participants who wore the belt for a while then discontinued its use had a higher lost day case injury incident rate than did either the group receiving training only or the control group. Compliance was an overriding factor as the belt question naire response indicated that 58 % of participants in the belt groups discontinued use of the belt before the end of 8 months. Comments made on the survey forms indicated that the belt was too hot. Similarly, comments suggested that the belt rubbed, pinched, and bruised ribs. Based on these results, the weightlifting belt used for this study can not be recommended for use in aid of lifting during daily work activities of baggage h and lers. Results indicate that use of the belts may, in fact, increase the risk of injury when not wearing a belt following a period of wearing a belt. As industries are experimenting with the use of belts, it is recommended that great care be taken in any further evaluation and close attention directed towards injuries which occur when not wearing the belt following a period of wearing the belt ( ie, off-the-job injuries )", 'OBJECTIVE Structured patient education programs can reduce the risk of diabetes-related complications. However, people appear to have difficulties attending face-to-face education and alternatives are needed. This review looked at the impact of computer-based diabetes self-management interventions on health status, cardiovascular risk factors, and quality of life of adults with type 2 diabetes. Cluster-Randomized Trial of a Mobile Phone Personalized Behavioral Intervention for Blood Glucose Control OBJECTIVE To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with st and ard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A cluster-r and omized clinical trial, the Mobile Diabetes Intervention Study, r and omly assigned 26 primary care practice s to one of three stepped treatment groups or a control group ( usual care ). A total of 163 patients were enrolled and included in analysis. The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period. Secondary outcomes were changes in patient-reported diabetes symptoms, diabetes distress, depression, and other clinical ( blood pressure ) and laboratory ( lipid ) values. Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support. Patients received automated, real-time educational and behavioral messaging in response to individually analyzed blood glucose values, diabetes medications, and lifestyle behaviors communicated by mobile phone. Providers received quarterly reports summarizing patient ’s glycemic control, diabetes medication management, lifestyle behaviors, and evidence -based treatment options. RESULTS The mean declines in glycated hemoglobin were 1.9 % in the maximal treatment group and 0.7 % in the usual care group, a difference of 1.2 % ( P = 0.001 ) over 12 months. Appreciable differences were not observed between groups for patient-reported diabetes distress, depression, diabetes symptoms, or blood pressure and lipid levels ( all P > 0.05 ). CONCLUSIONS The combination of behavioral mobile coaching with blood glucose data, lifestyle behaviors, and patient self-management data individually analyzed and presented with evidence -based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year Clinic-based support to help overweight patients with type 2 diabetes increase physical activity and lose weight. BACKGROUND Our objective was to test the effect of physicians providing brief health lifestyle counseling to patients with type 2 diabetes mellitus during usual care visits. METHODS We conducted a r and omized controlled trial of a 12-month intervention at 2 large community health centers, enrolling 310 patients with a body mass index ( calculated as weight in kilograms divided by height in meters squared ) of 25 or greater. In the intervention group, self-management goals for nutrition and physical activity were set using a tailored computer program. Goals were then review ed at each clinic visit by physicians. The control group received only printed health education material s. The main outcome measures included change in physical activity and body weight. RESULTS In the intervention group, recommended levels of physical activity increased from 26 % at baseline to 53 % at 12 months ( P <.001 ) compared with controls ( 30 % to 37 % ; P=.27 ), and 32 % of patients in the intervention group lost 6 or more pounds at 12 months compared with 18.9 % of controls ( odds ratio, 2.2 ; P=.006 ). CONCLUSION A brief intervention to increase the dialogue between patients and health care providers about behavioral goals can lead to increased physical activity and weight loss Improved Glycemic Control Without Hypoglycemia in Elderly Diabetic Patients Using the Ubiquitous Healthcare Service, a New Medical Information System OBJECTIVE To improve quality and efficiency of care for elderly patients with type 2 diabetes, we introduced elderly-friendly strategies to the clinical decision support system (CDSS)-based ubiquitous healthcare ( u-healthcare ) service, which is an individualized health management system using advanced medical information technology. RESEARCH DESIGN AND METHODS We conducted a 6-month r and omized, controlled clinical trial involving 144 patients aged > 60 years. Participants were r and omly assigned to receive routine care ( control, n = 48 ), to the self-monitored blood glucose ( SMBG, n = 47 ) group, or to the u-healthcare group ( n = 49 ). The primary end point was the proportion of patients achieving A1C < 7 % without hypoglycemia at 6 months. U-healthcare system refers to an individualized medical service in which medical instructions are given through the patient ’s mobile phone. Patients receive a glucometer with a public switched telephone network-connected cradle that automatically transfers test results to a hospital-based server. Once the data are transferred to the server, an automated system, the CDSS rule engine, generates and sends patient-specific messages by mobile phone. RESULTS After 6 months of follow-up, the mean A1C level was significantly decreased from 7.8 ± 1.3 % to 7.4 ± 1.0 % ( P < 0.001 ) in the u-healthcare group and from 7.9 ± 1.0 % to 7.7 ± 1.0 % ( P = 0.020 ) in the SMBG group, compared with 7.9 ± 0.8 % to 7.8 ± 1.0 % ( P = 0.274 ) in the control group. The proportion of patients with A1C < 7 % without hypoglycemia was 30.6 % in the u-healthcare group, 23.4 % in the SMBG group ( 23.4 % ), and 14.0 % in the control group ( P < 0.05 ). CONCLUSIONS The CDSS-based u-healthcare service achieved better glycemic control with less hypoglycemia than SMBG and routine care and may provide effective and safe diabetes management in the elderly diabetic patients Telecommunication Support for Rural Women With Diabetes PURPOSE The Women to Women Diabetes Project tested the use of telecommunication technology to deliver diabetes education and social support to rural women with diabetes. The aims were to ( 1 ) test the effects of the computer intervention in providing support, information, and education on selected outcomes, and ( 2 ) evaluate the women\'s attitudes toward and satisfaction with the intervention and the support provided. METHODS Thirty women were r and omized into computer and noncomputer groups and participated for 10 months. For 5 months, one group participated in a self-help support and educational group via the computer ; the other group continued to use their usual modes of support and communication. Psychosocial well-being scales were administered and attitudes were surveyed. RESULTS Improving health and higher educational levels positively influenced measures of social support and quality of life. Women who were married or who reported greater support had higher scores on the Personal Re source Question naire. The women expressed positive effects of the computer-based support group on their lives. CONCLUSIONS The intervention was enthusiastically accepted, and could be conducted effectively in isolated rural areas Online Diabetes Self-Management Program OBJECTIVE We hypothesized that people with type 2 diabetes in an online diabetes self-management program, compared with usual-care control subjects, would 1 ) demonstrate reduced A1C at 6 and 18 months, 2 ) have fewer symptoms, 3 ) demonstrate increased exercise, and 4 ) have improved self-efficacy and patient activation. In addition, participants r and omized to listserve reinforcement would have better 18-month outcomes than participants receiving no reinforcement. RESEARCH DESIGN AND METHODS A total of 761 participants were r and omized to 1 ) the program, 2 ) the program with e-mail reinforcement, or 3 ) were usual-care control subjects ( no treatment ). This sample included 110 American Indians/Alaska Natives ( AI/ANs ). Analyses of covariance models were used at the 6- and 18-month follow-up to compare groups. RESULTS At 6 months, A1C, patient activation, and self-efficacy were improved for program participants compared with usual care control subjects ( P < 0.05 ). There were no changes in other health or behavioral indicators. The AI/AN program participants demonstrated improvements in health distress and activity limitation compared with usual-care control subjects. The subgroup with initial A1C > 7 % demonstrated stronger improvement in A1C ( P = 0.01 ). At 18 months, self-efficacy and patient activation were improved for program participants. A1C was not measured. Reinforcement showed no improvement. CONCLUSIONS An online diabetes self-management program is acceptable for people with type 2 diabetes. Although the results were mixed they suggest 1 ) that the program may have beneficial effects in reducing A1C, 2 ) AI/AN population s can be engaged in and benefit from online interventions, and 3 ) our follow-up reinforcement appeared to have no value The development and evaluation of a computer-aided diabetes education program. This paper describes the development and evaluation of a computer-aided learning ( CAL ) program. The program was tested in a trial that involved 36 people with diabetes ; 20 received CAL lessons in diabetes management and 16 attended conventional diabetes classes conducted by diabetes educators. When measurements taken before and three months after the education were compared, both groups showed significant improvement in their knowledge ; the blood glucose levels of the CAL group were significantly lower but those of the conventional education group were higher. This means that the CAL program was as effective as conventional education in imparting knowledge but it was more likely to motivate people to control their glucose levels. The CAL program allows diabetes educators to spend less time on education in basic knowledge and to concentrate more on motivational and social factors that are important determinants of patient compliance. It can also benefit people with diabetes whose access to health professionals and /or conventional diabetes education is restricted The D-Net diabetes self-management program: long-term implementation, outcomes, and generalization results. BACKGROUND A prerequisite to translating research findings into practice is information on consistency of implementation, maintenance of results, and generalization of effects. This follow-up report is one of the few experimental studies to provide such information on Internet-based health education. METHODS We present follow-up data 10 months following r and omization on the " Diabetes Network ( D-Net ) " Internet-based self-management project, a r and omized trial evaluating the incremental effects of adding ( 1 ) tailored self-management training or ( 2 ) peer support components to a basic Internet-based, information-focused comparison intervention. Participants were 320 adult type 2 diabetes patients from participating primary care offices, mean age 59 ( SD = 9.2 ), who were relatively novice Internet users. RESULTS All intervention components were consistently implemented by staff, but participant website usage decreased over time. All conditions were significantly improved from baseline on behavioral, psychosocial, and some biological outcomes ; and there were few differences between conditions. Results were robust across on-line coaches, patient characteristics, and participating clinics. CONCLUSIONS The basic D-Net intervention was implemented well and improvements were observed across a variety of patients, interventionists, and clinics. There were, however, difficulties in maintaining usage over time and additions of tailored self-management and peer support components generally did not significantly improve results Long-term effects and costs of brief behavioural dietary intervention for patients with diabetes delivered from the medical office. This study evaluated the 12-month follow-up results and costs of a personalized, medical office-based intervention focused on behavioral issues related to dietary self-management. Two hundred and six adults having diabetes attending an internal medicine outpatient clinic visit were r and omized to either Usual Care or to Brief Intervention. The single session intervention involved touchscreen computer-assisted assessment that provided immediate feedback on key barriers to dietary self-management, goal setting and problem-solving counselling. Follow-up components included phone calls and videotape intervention relevant to each participant. Brief Intervention produced significantly greater improvement than Usual Care on multiple measures of change in dietary behaviour ( e.g., covariate adjusted difference of 2.2 % of calories from fat ; p = 0.023 ) and on serum cholesterol levels ( covariate adjusted difference of 15 mg/dl ; p = 0.002 ) at 12-month follow-up. There were also significant differences favouring intervention on patient satisfaction ( p < 0.02 ) but not on HbA1c levels. The costs of intervention ( $ 137 per patient ) were modest relative to many commonly used practice Outcomes of Minimal and Moderate Support Versions of an Internet-Based Diabetes Self-Management Support Program OBJECTIVE Internet and other interactive technology-based programs offer great potential for practical, effective, and cost-efficient diabetes self-management ( DSM ) programs capable of reaching large numbers of patients. This study evaluated minimal and moderate support versions of an Internet-based diabetes self-management program, compared to an enhanced usual care condition. RESEARCH DESIGN AND METHODS A three-arm practical r and omized trial was conducted to evaluate minimal contact and moderate contact versions of an Internet-based diabetes self-management program, offered in English and Spanish, compared to enhanced usual care. A heterogeneous sample of 463 type 2 patients was r and omized and 82.5 % completed a 4-month follow-up. Primary outcomes were behavior changes in healthy eating, physical activity, and medication taking. Secondary outcomes included hemoglobin A1c, body mass index, lipids, and blood pressure. RESULTS The Internet-based intervention produced significantly greater improvements than the enhanced usual care condition on three of four behavioral outcomes ( effect sizes [ d ] for healthy eating = 0.32 ; fat intake = 0.28 ; physical activity= 0.19 ) in both intent-to-treat and complete-cases analyses. These changes did not translate into differential improvements in biological outcomes during the 4-month study period. Added contact did not further enhance outcomes beyond the minimal contact intervention. CONCLUSIONS The Internet intervention meets several of the RE- AIM criteria for potential public health impact, including reaching a large number of persons, and being practical, feasible, and engaging for participants, but with mixed effectiveness in improving outcomes, and consistent results across different subgroups. Additional research is needed to evaluate longer-term outcomes, enhance effectiveness and cost-effectiveness, and underst and the linkages between intervention processes and outcomes Effects of a brief computer-assisted diabetes self-management intervention on dietary, biological and quality-of-life outcomes Objective : There is a need for practical, efficient and broad-reaching diabetes self-management interventions that can produce changes in lifestyle behaviours such as healthy eating and weight loss. The objective of this study was to evaluate such a computer-assisted intervention. Methods : Type 2 diabetes primary care patients ( n=335 ) from fee-for-service and health maintenance organization setting s were r and omized to social cognitive theory-based tailored self-management ( TSM ) or computer-aided enhanced usual care ( UC ). Intervention consisted of computer-assisted self-management assessment and feedback, tailored goal - setting, barrier identification, and problem-solving, followed by health counsellor interaction and follow-up calls. Outcomes were changes in dietary behaviours ( fat and fruit/vegetable intake ), haemoglobin A1c ( HbA1c ), lipids, weight, quality of life, and depression. Results : TSM patients reduced dietary fat intake and weight significantly more than UC patients at the 2-month follow-up. Among patients having elevated levels of HbA1c, lipids or depression at baseline, there were consistent directional trends favouring intervention, but these differences did not reach significance. The intervention proved feasible and was implemented successfully by a variety of staff. Conclusions : This relatively low-intensity intervention appealed to a large, generally representative sample of patients, was well implemented, and produced improvement in targeted behaviours. Implication s of this practical clinical trial for dissemination are discussed A Ubiquitous Chronic Disease Care system using cellular phones and the internet. AIMS The rapidly increasing prevalence of chronic diseases is an important challenge to healthcare systems worldwide. To improve the quality and efficiency of chronic disease care, we investigated the effectiveness and applicability of the Ubiquitous Chronic Disease Care ( UCDC ) system using cellular phones and the internet for overweight patients with both Type 2 diabetes and hypertension. METHODS We conducted a r and omized, controlled clinical trial over 3 months that included 123 patients at a university hospital and a community public health centre. RESULTS After 12 weeks, there were significant improvements in HbA(1c ) in the intervention group ( 7.6 + /- 0.9 % to 7.1 + /- 0.8 %, P < 0.001 ) compared with the control group ( 7.4 + /- 0.9 % to 7.6 + /- 1.0 %, P = 0.03 ). Furthermore, we observed a significant reduction in systolic and diastolic blood pressure, as well as improvements in total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels in the intervention group. Furthermore, there was a significant increase in adiponectin levels in the intervention group compared with the control group, although high-sensitivity C-reactive protein and interleukin-6 levels did not change in either group. CONCLUSIONS The novel UCDC system presented in this paper improved multiple metabolic parameters simultaneously in overweight patients with both Type 2 diabetes and hypertension [Computer assisted nutrition therapy for patients with type 2 diabetes]. OBJECTIVE To evaluate the efficacy of the " Diabetes Diet Advisor"(PC-DR vision 1.0 ) " for type 2 diabetes. METHODS One hundred and fifty type 2 diabetic patients were divided in the 2 groups. The study group included 88 type 2 diabetic patients managed by " Diabetes Diet Advisor(PC-DR vision 1.0 ) " ; the control group included 62 cases with a fixed carbohydrate content. All patients were followed up for 8 weeks. RESULTS After 8 weeks dietary therapy, the fasting blood glucose ( FBG ), cholesterol ( TC ), triglycerides ( TG ), HDL-cholesterol ( HDL- C ) and body mass index ( BMI ) in study group were all significantly less than those in the control group ( P<0.05 ). In the study group, the significant decrease were achieved in all indicates and FBG and 2hPBG decreased persistently. Twenty-five patients ( 28.41 % ) in study group and 6 patients ( 9.68 % ) in control group reduced their dosage of hypoglycemic agents or stopped drug therapy ( P=0.007 ). CONCLUSION The software " Diabetes Diet Advisor ( PC-DR vision 1.0 ) " is a useful tool of dietary management for patients with type 2 diabetes Randomized effectiveness trial of a computer-assisted intervention to improve diabetes care. OBJECTIVE There is a well-documented gap between diabetes care guidelines and the services received by patients in most health care setting s. This report presents 12-month follow-up results from a computer-assisted, patient-centered intervention to improve the level of recommended services patients received from a variety of primary care setting s. RESEARCH DESIGN AND METHODS A total of 886 patients with type 2 diabetes under the care of 52 primary care physicians participated in the Diabetes Priority Program. Physicians were stratified and r and omized to intervention or control conditions and evaluated on two primary outcomes : number of recommended laboratory screenings and recommended patient-centered care activities completed from the National Committee on Quality Assurance/American Diabetes Association Provider Recognition Program ( PRP ). Secondary outcomes were evaluated using the Problem Areas in Diabetes 2 quality of life scale, lipid and HbA1c levels, and the Patient Health Question naire-9 depression scale. RESULTS The program was well implemented and significantly improved both the number of laboratory assays and patient-centered aspects of diabetes care patients received compared with those in the control condition. There was overall improvement on secondary outcomes of lipids, HbA1c, quality of life, and depression scores ; between-condition differences were not significant. CONCLUSIONS Staff in small, mixed-payer primary care offices can consistently implement a patient-centered intervention to improve PRP measures of quality of diabetes care. Alternative explanations for why these process improvements did not lead to improved outcomes, and suggested directions for future research are discussed A randomized, controlled trial of an automated wireless messaging system for diabetes. BACKGROUND Aggressive management of blood glucose reduces future diabetes-related complications, but this is difficult to achieve. METHODS This r and omized, controlled study tested the effect of using a wireless two-way pager-based automated messaging system to improve diabetes control through facilitated self-management. The system sent health-related messages to patients, with automatic forwarding of urgent patient responses to the health care team. RESULTS Participants in both the experimental ( pager ) and the control groups experienced an average hemoglobin A1c decrease of 0.1 - 0.3 %. More patients in the pager group were normotensive, and more felt that their health care was better by the end of the study. A total of 79 % of participants enjoyed using the pager, and 68 % wanted to continue using the system. CONCLUSIONS Utilizing a wireless, automated messaging system in clinical practice is a feasible, low-cost, interactive way to facilitate diabetes self-management, which is acceptable to patients. While providing a convenient way for patients and providers to communicate, this system can support automated recording and ready retrieval of these real-time interactions WellDoc mobile diabetes management randomized controlled trial: change in clinical and behavioral outcomes and patient and physician satisfaction. BACKGROUND Less than 63 % of individuals with diabetes meet professional guidelines target of hemoglobin A1c < 7.0 %, and only 7 % meet combined glycemic, lipid, and blood pressure goals. The primary study aim was to assess the impact on A1c of a cell phone-based diabetes management software system used with web-based data analytics and therapy optimization tools. Secondary aims examined health care provider ( HCP ) adherence to prescribing guidelines and assessed HCPs\'adoption of the technology. METHODS Thirty patients with type 2 diabetes were recruited from three community physician practice s for a 3-month study and evenly r and omized. The intervention group received cell phone-based software design ed by endocrinologists and CDEs ( WellDoc Communications, Inc., Baltimore, MD ). The software provided real-time feedback on patients\'blood glucose levels, displayed patients\'medication regimens, incorporated hypo- and hyperglycemia treatment algorithms, and requested additional data needed to evaluate diabetes management. Patient data captured and transferred to secure servers were analyzed by proprietary statistical algorithms. The system sent computer-generated logbooks ( with suggested treatment plans ) to intervention patients\'HCPs. RESULTS The average decrease in A1c for intervention patients was 2.03 %, compared to 0.68 % ( P < 0.02, one-tailed ) for control patients. Of the intervention patients, 84 % had medications titrated or changed by their HCP compared to controls ( 23 %, P = 0.002 ). Intervention patients\'HCPs reported the system facilitated treatment decisions, provided organized data, and reduced logbook review time. CONCLUSIONS Adults with type 2 diabetes using WellDoc\'s software achieved statistically significant improvements in A1c. HCP and patient satisfaction with the system was clinical ly and statistically significant', "Background The relationship between training load and musculoskeletal injury is a rapidly advancing area of research in need of an up date d systematic review. A 12-month prospective cohort study of injury in international rowers Objective In this study, the injury incidence and association with type and volume of training in international rowers were described. Design A prospect i ve cohort design was used over a 12-month period. Patients 20 international rowers who were competing as part of the Irish Amateur Rowing Union squad system. Methods The rowers were interviewed monthly, and data were collected regarding their training and competition exposure as well as their injury experience. Results A mean injury rate of 3.67 per 1000 exposure hours was reported with a total of 44 injuries reported in a 12-month period. The mean number of injuries sustained per athlete was 2.2 ( 1.24 ) over the 12-month period. The area where the greatest number of injuries were reported was the lumbar spine ( 31.82 % of total injuries, 95 % CI 20 to 50 ) ( fig 2 ) followed by the knee ( 15.91 % of total injuries, 95 % CI 10 to 30 ) and the cervical spine ( 11.36 % of total injuries, 95 % CI 5 to 24 ). Half of the injuries ( 22 injuries, 50 % of total reported injuries ) were to the spine ( χ2 = 30.8, df = 9, p = 0.0003 ). Ergometer training load was the most significantly associated with injury risk ( r = 0.68, p = 0.01 ). Conclusion International rowers are at higher risk of injury than most non-contact sports and some contact sports. The high risk of lumbar spine injury and the significant association of high volume of ergometer training merit further research to reduce time and competition lost to injury Lumbar load in adolescent fast bowlers: A prospective injury study. OBJECTIVES This study aim ed to identify modifiable mechanisms associated with low back injury in adolescent cricket fast bowlers. DESIGN A prospect i ve study design examined the association between intrinsic risk factors, workload, bowling kinematics, lumbar load and low back injury incidence. METHODS Twenty-five injury free fast bowlers, aged 14 - 19 years, were assessed prior to the start of a cricket season and observed during the season for low back injuries. RESULTS The twelve bowlers who suffered a low back injury displayed ; decreased hip flexion at front foot contact ( 46±6 ° vs 51±6 ° ), increased pelvis rotation ( 287±11 ° vs 277±11 ° ) increased thorax lateral flexion ( 50±6 ° vs 40±8 ° ) at ball release, and larger peak lumbar flexion ( 10.5±4.9Nmkg(-1)m(-1 ) vs 6.9±2.5Nmkg(-1)m(-1 ) ) and lateral flexion moments ( 12.5±2.6Nmkg(-1)m(-1 ) vs 10.6±1.9Nmkg(-1)m(-1 ) ). They also exhibited reduced muscular endurance of the back extensors ( 103±33s vs 132±33s ) and increased knee valgus angle during a single leg decline squat on the dominant ( 9±3 ° vs 5±4 ° ) and non-dominant leg ( 9±4 ° vs 6±3 ° ) in comparison to uninjured bowlers. CONCLUSIONS Bowlers who experience greater lumbar loads during bowling, have reduced back extensor muscle endurance, and demonstrate impaired control of the lumbo-pelvic-hip complex, are at increased risk of low back injury. This combination of strength, control and biomechanical factors may be key mechanical elements of low back injury causation in adolescent fast bowlers Injury risk is different in team and individual youth sport. OBJECTIVES This study compared sports injury incidence in young high-level athletes from various team and individual sports and investigated if sport participation patterns are linked to injuries. DESIGN Prospect i ve cohort follow-up. METHODS Pupils from a public sports school ( 12 - 19 years ) were recruited over two separate school years ( 2008 - 2009 : 42 weeks, n=199 athletes ; 2009 - 2010 : 40 weeks, n=89 athletes ). Training and competition volume and intensity were recorded via a personal sports diary. Sports injuries ( time-loss definition ) were registered by medical staff members using a st and ardized question naire. RESULTS Injury incidence was significantly higher in team compared with individual sports ( 6.16 versus 2.88 injuries/1000h, respectively ), as a result of a higher incidence of both traumatic ( RR=2.17 ; CI95%=1.75 - 2.70 ; p<0.001 ), and overuse injuries ( RR=2.06 ; CI95%=1.46 - 2.91 ; p<0.001 ). A Cox proportional hazards regression revealed that team sports participation had a hazard ratio of 2.00 ( CI95%=1.49 - 2.68 ; p<0.001 ) compared to individual sports, with additionally previous injury being a risk and age a protective factor. The number of competitions per 100 days was significantly higher in team sports, whereas the number of intense training sessions per 100 days was significantly lower. In team sports, the number of competitions per 100 days was positively associated with injuries ( HR=1.072 ; CI95 % [ 1.033 ; 1.113 ] ; p<0.001 ), while in individual sports the number of competitions per 100 days had a protective effect ( HR=0.940 ; CI95 % [ 0.893 ; 0.989 ] ; p=0.017 ). CONCLUSIONS Team sports participation entailed a higher injury risk, whatever the injury category. Further research should eluci date the role of characteristics related to sport participation in injury causation Injury risk in professional football players with special reference to the playing position and training periodization. AIM The aim of this study was to examine injury incidence in professional football players according to the playing positions and with a special reference to training periodization. METHODS A Spanish professional team was followed prospect ively for the 2007 - 08 and 2008 - 09 seasons and exposure times and time-loss injuries were individually recorded during all training sessions and matches. Heart rate was monitored in all training sessions. RESULTS total of 114 injuries were registered during the study period ( mean injury incidence : 6.6 injuries per 1000 hours ). The frequency of injuries was not uniformly distributed by playing positions ( P<0.001 ), as forwards and central defenders sustained the greatest number of injury episodes and the highest match absence. Ligament sprains and muscle strains accounted for 50 % of all injuries and 62 % of all match absences. The highest incidence of sprains was achieved during pre-season and the beginning of the competition period. The risk to sustain a muscular strain peaked at the beginning and in the final weeks of the competition period and was related ( r=0.72 ; P<0.05 ) to mean heart rate during the training stage. CONCLUSION The results suggest that there exists a difference of injury risk according to the period of the season and therefore, injury prevention strategies should be introduced from pre-season. Moreover, training workloads should be controlled to avoid increasing the risk of muscle strains How Much Rugby is Too Much? A Seven-Season Prospective Cohort Study of Match Exposure and Injury Risk in Professional Rugby Union Players Introduction Numerous studies have documented the incidence and nature of injuries in professional rugby union, but few have identified specific risk factors for injury in this population using appropriate statistical methods. In particular, little is known about the role of previous short-term or longer-term match exposures in current injury risk in this setting. Objectives Our objective was to investigate the influence that match exposure has upon injury risk in rugby union. Method We conducted a seven-season ( 2006/7–2012/13 ) prospect i ve cohort study of time-loss injuries in 1253 English premiership professional players. Players ’ 12-month match exposure ( number of matches a player was involved in for ≥20 min in the preceding 12 months ) and 1-month match exposure ( number of full-game equivalent [ FGE ] matches in preceding 30 days ) were assessed as risk factors for injury using a nested frailty model and magnitude-based inferences. Results The 12-month match exposure was associated with injury risk in a non-linear fashion ; players who had been involved in fewer than ≈15 or more than ≈35 matches over the preceding 12-month period were more susceptible to injury. Monthly match exposure was linearly associated with injury risk ( hazard ratio [ HR ] : 1.14 per 2 st and ard deviation [ 3.2 FGE ] increase, 90 % confidence interval [ CI ] 1.08–1.20 ; likely harmful ), although this effect was substantially attenuated for players in the upper quartile for 12-month match exposures ( > 28 matches ). Conclusion A player ’s accumulated ( 12-month ) and recent ( 1-month ) match exposure substantially influences their current injury risk. Careful attention should be paid to planning the workloads and monitoring the responses of players involved in : ( 1 ) a high ( > ≈35 ) number of matches in the previous year, ( 2 ) a low ( < ≈15 ) number of matches in the previous year, and ( 3 ) a low-moderate number of matches in previous year but who have played intensively in the recent past. These findings make a major contribution to evidence -based policy decisions regarding match workload limits in professional rugby union Does direction of results of abstracts submitted to scientific conferences on drug addiction predict full publication? Background Data from scientific literature show that about 63 % of abstract s presented at biomedical conferences will be published in full. Some studies have indicated that full publication is associated with the direction of results ( publication bias ). No study has looked into the occurrence of publication bias in the field of addiction. Objectives To investigate whether the significance or direction of results of abstract s presented at the major international scientific conference on addiction is associated with full publication Methods The conference proceedings of the US Annual Meeting of the College on Problems of Drug Dependence ( CPDD ), were h and search ed for abstract s of r and omized controlled trials and controlled clinical trials that evaluated interventions for prevention, rehabilitation and treatment of drug addiction in humans ( years search ed 1993–2002 ). Data regarding the study design s and outcomes reported were extracted. Subsequent publication in peer review ed journals was search ed in MEDLINE and EMBASE data bases, as of March 2006. Results Out of 5919 abstract s presented, 581 met the inclusion criteria ; 359 ( 62 % ) conference abstract s had been published in a broad variety of peer review ed journals ( average time of publication 2.6 years, SD + /- 1.78 ). The proportion of published studies was almost the same for r and omized controlled trials ( 62.4 % ) and controlled clinical trials ( 59.5 % ) while studies that reported positive results were significantly more likely to be published ( 74.5 % ) than those that did not report statistical results ( 60.9 %. ), negative or null results ( 47.1 % ) and no results ( 38.6 % ), Abstract s reporting positive results had a significantly higher probability of being published in full, while abstract s reporting null or negative results were half as likely to be published compared with positive ones ( HR = 0.48 ; 95%CI 0.30–0.74 ) Conclusion Clinical trials were the minority of abstract s presented at the CPDD ; we found evidence of possible publication bias in the field of addiction, with negative or null results having half the likelihood of being published than positive ones Fast bowling match workloads over 5-26 days and risk of injury in the following month. OBJECTIVES This study examined whether high match fast bowling workloads in the short to medium term were associated with increased bowling injury rates. DESIGN Prospect i ve cohort study. METHODS Over a 15 year period, workload patterns for 235 individual fast bowlers during time periods from 5 to 26 days were examined to consider whether there was an increased injury rate during the month ( 28 days ) subsequent to the workload. RESULTS Fast bowlers who bowled more than 50 match overs in a 5 day period had a significant increase in injury over the next month compared to bowlers who bowled 50 overs or less RR 1.54 ( 95 % CI 1.04 - 2.29 ). For periods ranging from 12 to 26 days, there was no statistically-significant increase in injury over the next month from exceeding thresholds of certain amounts of overs, although bowlers who bowled more than 100 overs in 17 days had a non-significant increase in injury over the next month RR 1.78 ( 95 % CI 0.90 - 3.50 ). CONCLUSION There were no statistically-significant increases in subsequent injury risk for high workloads for periods of 12 - 26 days, although exceeding 100 overs in 17 days ( or less ) was associated with higher injury rates. Compression of cricket fixtures is likely to have only a minimal contribution to increased fast bowling injury rates being seen in the T20 era ( along with sudden workload increases due to transferring between forms of the game, which has been previously established as a major contributor ) The prevalence, incidence and severity of low back pain among international-level rowers Background / aims There is a paucity of prospect i ve cohort studies investigating the incidence of low back pain ( LBP ) in rowing. We investigated ( 1 ) the prevalence and incidence of LBP among international-level rowers in New Zeal and, ( 2 ) the relationship between training volume and LBP and ( 3 ) the effect of LBP on rowers ’ ability to train and compete. Methods This was a prospect i ve cohort study of 76 New Zeal and representative rowers, including 46 men ( mean age 22, SD=4 ) and 30 women ( mean age 21, SD=4 ). Data were collected using an online question naire repeated monthly for 12 months. Results The prevalence of LBP ranged from 6 % to 25 % throughout the year. The incidence of episodes of LBP was 1.67 per 1000 exposure-hours. A total of 72 episodes of LBP were reported by 40 rowers ( 53 % ) during 12 months. Of these, 45 % had an incidental effect on training. 29 % minor, 18 % moderate and 9 % had a major effect as determined by the length of time the training was interrupted. There was a high correlation between new LBP and total training hours per month ( r=0.83, p<0.01 ). A previous history of LBP was a risk factor in developing new LBP ( OR 2.06, 95 % CI 1.22 to 3.48, p=0.01 ). Age was also a risk factor, with the likelihood of developing LBP increasing for every year ( OR 1.08, 95 % CI 1.01 to 1.15, p=0.02 ). Conclusions LBP is common among New Zeal and representative rowers. There is a high correlation between training load and the development of LBP Volume of physical activity and injury occurrence in young basketball players. Participation in organised, competitive physical activity by young athletes is increasing rapidly. This is concurrent with an increase in sporting injuries in the young population. This pilot study aim ed to compare the weekly volume and types of physical activity in young basketball players injured and not injured during the season. Detailed physical activity and injury data were prospect ively collected in 46 school-level basketball players aged 14 to 18 years. Participants completed physical activity logs which documented the type of physical activity undertaken, what the activity consisted of ( i.e. training, competition ) and the level at which it was played on a daily basis. Allied health staff completed a weekly injury form. Results showed that injured and uninjured athletes participated in a similar volume of total weekly physical activity over the season. However, injured athletes ( p = 0.04 ) and athletes who specifically sustained overuse injuries ( p = 0.01 ) participated in a greater amount of basketball refereeing than uninjured athletes. Based on these findings it was concluded that greater participation in running-type physical activity such as refereeing, as an addition to training and competition, may predispose the young basketball player to increased injury risk. Future research using larger sample sizes are required to further investigate the role of participation volume and type on injury occurrence in adolescent athletes. Key pointsBasketball players participating in larger amounts of running-type physical activity, in addition to regular training and competition, may be predisposed to overuse injuryFuture studies using larger sample sizes are required to investigate the precise volumes of physical activity that increase injury riskThis would assist in the development of participation guidelines to decrease the current injury rates observed in the young athletic population An assessment of training volume in professional rugby union and its impact on the incidence, severity, and nature of match and training injuries Abstract A prospect i ve cohort study was used to assess the influence of training volume on injuries sustained by 502 professional rugby union players in Engl and. Training volumes ( excluding warm-ups, cool-downs, and recovery sessions ), player injuries, and player match exposure times were reported weekly. Higher training volumes ( > 9.1 hours per week ) did not increase the incidence of match or training injuries. However, higher training volumes did increase the severity of match injuries, particularly during the second half, and consequently result ed in a significant increase in the number of days'absence due to match injuries. Although lower-limb injuries were the most common match and training injuries, shoulder dislocations/instabilities result ed in more days'absence during weeks of higher training volumes, but the differences were not significant. The least number of days lost due to injuries occurred during weeks of intermediate training volumes ( 6.2–9.1 h per week ). Training volume was not correlated with final league position. Fitness testing, defence, and rucking and mauling components were identified as being very high- or high-risk training activities. Our results provide evidence of the benefits of modifying the volume and content of rugby union training to reduce the risk associated with injuries to professional players The 5- or 10-km Marikenloop Run: A Prospective Study of the Etiology of Running-Related Injuries in Women. Study Design Prospect i ve cohort. Background The popularity of running events is still growing, particularly among women ; however, little is known about the risk factors for running-related injuries in female runners. Objectives The aims of this study were to determine the incidence and characteristics ( site and recurrence ) of running-related injuries and to identify specific risk factors for running-related injuries among female runners training for a 5- or 10-km race. Methods Four hundred thirty-five women registered for the Marikenloop run of 5 or 10 km were recruited. Follow-up data were collected over 12 weeks using question naires, starting 8 weeks before the event and ending 4 weeks after the event. Two orthopaedic tests ( navicular drop test and extension of the first metatarsophalangeal joint ) were performed in the 8 weeks before the event. Running-related injuries, defined as running-related pain of the lower back and /or the lower extremity that restricted running for at least 1 day, were assessed at 1-, 2-, and 3-month follow-ups. Results Of 417 female runners with follow-up data ( 96 % ), 93 runners ( 22.3 % ) reported 109 running-related injuries, mainly of the hip/groin, knee, and lower leg. Multivariable Cox regression analysis showed that a weekly training distance of more than 30 km ( hazard ratio = 3.28 ; 95 % confidence interval [ CI ] : 1.23, 8.75 ) and a previous running injury longer than 12 months prior ( hazard ratio = 1.88 ; 95 % CI : 1.03, 3.45 ) were associated with the occurrence of running-related injuries. Conclusion Hip/groin, knee, and lower-leg injuries were common among female runners. Only weekly training distance ( greater than 30 km ) and previous running injury ( greater than 12 months prior ) were associated with running-related injuries in female runners training for a 5- or 10-km event. Level of Evidence Etiology, 2b. J Orthop Sports Phys Ther 2016;46(6):462 - 470. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6402 Injury history as a risk factor for incident injury in youth soccer Objectives : To determine if athletes with a self reported history of previous injury have a higher incident injury rate than athletes without a self reported injury history. Methods : A prospect i ve cohort study of Classic League soccer players playing at the level under 12 through under 18. Injury history forms were mailed to all registering Classic League soccer players in the North Carolina Youth Soccer Association during 1997–2000 ( n = 7000 ) ; 1483 ( 19 % ) returned the baseline question naire and were followed up for injuries. Results : There were 5139 player-seasons of follow up and an estimated 171 957 athlete-exposures. More than half self reported an injury history ( 59.7 % ). Overall, the unadjusted incidence rate was 4.6 ( 95 % confidence interval ( CI ) 4.3 to 4.9 ) incident injuries per 1000 athlete-exposures. Multivariate generalised Poisson regression modelling indicated that players with one previous injury had a twofold greater risk of incident injury ( IRR = 2.6 ; 95 % CI 2.0 to 3.3 ), and those with two or more previous injuries had a threefold greater risk of incident injury ( IRR = 3.0 ; 95 % CI 2.3 to 3.8 ) compared with athletes with no previous injuries. Conclusions : Injury history was associated with an increased injury rate. This suggests that, even in these youth soccer players, those with an injury history may be at higher risk Previous injury as a risk factor for injury in elite football: a prospective study over two consecutive seasons Background : Previous injury is often proposed to be a risk factor for football injury, but most studies rely on players reporting their own medical history and are thus potentially subject to recall bias. Little is known about the natural variation in injury pattern between seasons. Objectives : To study whether prospect ively recorded injuries during one season are associated with injuries sustained during the following season, and to compare injury risk and injury pattern between consecutive seasons. Methods : The medical staffs of 12 elite Swedish male football teams prospect ively recorded individual exposure and time loss injuries over two full consecutive seasons ( 2001 and 2002 ). A multivariate model was used to determine the relation between previous injury, anthropometric data, and the risk of injury. Results : The training and match injury incidences were similar between seasons ( 5.1 v 5.3 injuries/1000 training hours and 25.9 v 22.7/1000 match hours ), but analysis of injury severity and injury patterns showed variations between seasons. Players who were injured in the 2001 season were at greater risk of any injury in the following season compared with non-injured players ( hazard ratio 2.7 ; 95 % confidence interval 1.7 to 4.3, p<0.0001 ). Players with a previous hamstring injury, groin injury, and knee joint trauma were two to three times more likely to suffer an identical injury in the following season, whereas no such relation was found for ankle sprain. Age was not associated with an increased injury risk. Conclusions : This study confirmed previous results showing that previous injury is an important risk factor for football injury. Overall injury incidences were similar between consecutive seasons, indicating that an injury surveillance study covering one full season can provide a reasonable overview of the injury problem among elite football players in a specific environment. However, a prolonged study period is recommended for analyses of specific injury patterns Injury Patterns, Physiological Profile, and Performance in University Rugby Union. CONTEXT Rugby union is a physically dem and ing collision sport with high injury rates. There is a common perception that higher training loads result in greater injury risk in field-based sports. OBJECTIVES To determine injury, anthropometric, and physical-performance characteristics in junior rugby union players and investigate the interaction between training load and injury across a competitive season. DESIGN Prospect i ve cohort study. METHODS Fifty-one players ( age 19.2 ± 0.7 y ) from an under-20 university rugby union team ( forwards, n = 27 ; backs, n = 24 ) participated in a study conducted over a competition season. Training load, injury characteristics, anthropometry, physiological performance, and match time-loss injury incidence were observed. RESULTS Backs had significantly lower body mass ( ES [ 95 % CI ] = 1.6 [ 0.9, 2.2 ] ), skinfold thickness ( ES = 1.1 [ 0.5, 1.7 ] ), strength ( squat ES = 0.6 [ 0.0, 1.2 ], deadlift ES = 0.6 [ 0.0, 1.1 ], bench press ES = 0.9 [ 0.4, 1.5 ] ), lower-body power ( ES = 0.4 [ -0.2, 1.0 ] ), and higher maximal aerobic capacity ( ES = -0.3 [ -0.8, 0.3 ] ) than forwards. Match injury incidence was 107.3 injuries/1000 player hours ( forwards 91.4/1000, backs 125.5/1000 ) during preseason and 110.7 injuries/1000 player hours ( forwards 124.1/1000, backs 95.2/1000 ) during in-season. Forwards showed higher incidence of joint and ligament ( P =.049 ) and upper-limb ( P =.011 ) injuries than backs. No significant relationship between overall training load and match injury incidence was found. However, lower match injury incidence was associated with higher weekly training volume in backs ( P =.007 ). CONCLUSIONS Positional differences in body composition, performance, injury characteristics, and match injury patterns were identified in junior university rugby union players, indicating the need for position-specific training programs to reduce risk of injury The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting, internal validity ( bias and confounding ) and power, but also for external validity. DESIGN : A pilot version was first developed, based on epidemiological principles, review s, and existing checklists for r and omised studies. Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies. Using different raters, the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ), test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ), criterion validity, and respondent burden. MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version. The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ). Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good. Reliability of the subscales varied from good ( bias ) to poor ( external validity ). The Quality Index correlated highly with an existing, established instrument for assessing r and omised studies ( r 0.90 ). There was little difference between its performance with non-r and omised and with r and omised studies. Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ). CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies. It has also shown that it is possible to produce a checklist that provides a profile of the paper, alerting review ers to its particular method ological strengths and weaknesses. Further work is required to improve the checklist and the training of raters in the assessment of external validity Increase in ACL and PCL injuries after implementation of a new professional football league Abstract Purpose In the season 2008–2009, a third professional football league was established in Germany. This study analysed the influence of increased training and playing intensity on severe knee injuries in football players. Methods In a prospect i ve controlled one-season trial, injury incidence and injury patterns of players of the newly established professional football league were analysed, particularly with regard to ruptures of the anterior ( ACL ) and posterior ( PCL ) cruciate ligaments. Players of the highest amateur level served as a control group. Results Four hundred and eight players of 24 teams were allocated to two groups. The overall training exposure was significantly ( p < 0.001 ) higher in the new professional league ( 335.3 h per player ) than at the amateur level ( 286.6 h per player ). Players at both levels showed similar overall injury rates and injury patterns. However, players in the professional league had a significantly higher ( p = 0.04 ) incidence of ACL and PCL injuries, than players at the amateur level. More than 90 % of all ACL and PCL ruptures in both groups were sustained by players, who had played at least one level lower in the previous season. In addition, injuries of players who had sustained repeat injuries over the season were more severe. Conclusion The introduction of a new professional football league increased the training and playing intensity of players as well as the number of ACL and PCL ruptures. A specific injury prevention concept, particularly for players facing rapidly increasing training and playing intensity, seems to be m and atory. Level of evidence Prospect i ve controlled cohort study, Level II Reductions in pre-season training loads reduce training injury rates in rugby league players Objectives : To investigate if reductions in pre-season training loads reduced the incidence of training injuries in rugby league players, and to determine if the reductions in training loads compromised the improvements in physical fitness obtained during the pre-season preparation period. Methods : A total of 220 sub-elite rugby league players participated in this 3 year prospect i ve study. Players underwent measurements of speed, muscular power, and maximal aerobic power before and after three 4 month ( December to March ) pre-season preparation periods ( 2001–2003 ). A periodised skills and conditioning program was implemented, with training loads progressively increased in the general preparatory phase of the season ( December to February ) and reduced slightly in March in preparation for the competitive phase of the season. Training loads were calculated by multiplying the training session intensity by the duration of the training session. Following the initial season ( 2001 ), training loads were reduced through reductions in training duration ( 2002 ) and training intensity ( 2003 ). The incidence of injury was prospect ively recorded over the three pre-season periods. Results : The training loads for the 2002 and 2003 pre-season periods were significantly lower ( p<0.001 ) than those in 2001. The incidence of injury was significantly higher in the 2001 pre-season than the 2002 and 2003 pre-season periods. The increases in maximal aerobic power progressively improved across the three seasons with a 62–88 % probability that the 2002 and 2003 pre-season improvements in maximal aerobic power were of greater physiological significance than the 2001 pre-season improvements in maximal aerobic power. Conclusions : These findings demonstrate that reductions in pre-season training loads reduce training injury rates in rugby league players and result in greater improvements in maximal aerobic power High chronic training loads and exposure to bouts of maximal velocity running reduce injury risk in elite Gaelic football. OBJECTIVES To examine the relationship between chronic training loads, number of exposures to maximal velocity, the distance covered at maximal velocity, percentage of maximal velocity in training and match-play and subsequent injury risk in elite Gaelic footballers. DESIGN Prospect i ve cohort design. METHODS Thirty-seven elite Gaelic footballers from one elite squad were involved in a one-season study. Training and game loads ( session-RPE multiplied by duration in min ) were recorded in conjunction with external match and training loads ( using global positioning system technology ) to measure the distance covered at maximal velocity, relative maximal velocity and the number of player exposures to maximal velocity across weekly periods during the season. Lower limb injuries were also recorded. Training load and GPS data were modelled against injury data using logistic regression. Odds ratios ( OR ) were calculated based on chronic training load status, relative maximal velocity and number of exposures to maximal velocity with these reported against the lowest reference group for these variables. RESULTS Players who produced over 95 % maximal velocity on at least one occasion within training environments had lower risk of injury compared to the reference group of 85 % maximal velocity on at least one occasion ( OR : 0.12, p=0.001 ). Higher chronic training loads ( ≥4750AU ) allowed players to tolerate increased distances ( between 90 to 120 m ) and exposures to maximal velocity ( between 10 to 15 exposures ), with these exposures having a protective effect compared to lower exposures ( OR : 0.22 p=0.026 ) and distance ( OR=0.23, p=0.055 ). CONCLUSIONS Players who had higher chronic training loads ( ≥4750AU ) tolerated increased distances and exposures to maximal velocity when compared to players exposed to low chronic training loads ( ≤4750AU ). Under- and over-exposure of players to maximal velocity events ( represented by a U-shaped curve ) increased the risk of injury Injury patterns in Swedish elite athletics: annual incidence, injury types and risk factors Objective To estimate the incidence, type and severity of musculoskeletal injuries in youth and adult elite athletics athletes and to explore risk factors for sustaining injuries. Design Prospect i ve cohort study conducted during a 52-week period. Setting Male and female youth and adult athletics athletes ranked in the top 10 in Sweden ( n=292 ). Results 199 ( 68 % ) athletes reported an injury during the study season. Ninety-six per cent of the reported injuries were non-traumatic ( associated with overuse ). Most injuries ( 51 % ) were severe, causing a period of absence from normal training exceeding 3 weeks. Log-rank tests revealed risk differences with regard to athlete category ( p=0.046 ), recent previous injury ( > 3 weeks time-loss ; p=0.039 ) and training load rank index ( TLRI ; p=0.019 ). Cox proportional hazards regression analyses showed that athletes in the third ( HR 1.79 ; 95 % CI 1.54 to 2.78 ) and fourth TLRI quartiles ( HR 1.79 ; 95 % CI 1.16 to 2.74 ) had almost a twofold increased risk of injury compared with their peers in the first quartile and interaction effects between athlete category and previous injury ; youth male athletes with a previous serious injury had more than a fourfold increased risk of injury ( HR=4.39 ; 95 % CI 2.20 to 8.77 ) compared with youth females with no previous injury. Conclusions The injury incidence among both youth and adult elite athletics athletes is high. A training load index combing hours and intensity and a history of severe injury the previous year were predictors for injury. Further studies on measures to quantify training content and protocol s for safe return to athletics are warranted A step towards understanding the mechanisms of running-related injuries. OBJECTIVES To investigate the association between training-related characteristics and running-related injury using a new conceptual model for running-related injury generation, focusing on the synergy between training load and previous injuries, short-term running experience or body mass index ( > or < 25 kg m(-2 ) ). DESIGN Prospect i ve cohort study with a 9-month follow-up. METHODS The data of two previous studies using the same methodology were revisited. Recreational runners ( n = 517 ) reported information about running training characteristics ( weekly distance, frequency, speed ), other sport participation and injuries on a dedicated internet platform. Weekly volume ( dichotomized into < 2h and ≥ 2 h ) and session frequency ( dichotomized into < 2 and ≥ 2 ) were the main exposures because they were considered necessary causes for running-related injury. Non-training-related characteristics were included in Cox regression analyses as effect-measure modifiers. Hazard ratio was the measure of association. The size of effect-measure modification was calculated as the relative excess risk due to interaction. RESULTS One hundred sixty-seven runners reported a running-related injury. Crude analyses revealed that weekly volume < 2h ( hazard ratio = 3.29 ; 95 % confidence intervals = 2.27 ; 4.79 ) and weekly session frequency < 2 ( hazard ratio = 2.41 ; 95 % confidence intervals = 1.71 ; 3.42 ) were associated with increased injury rate. Previous injury was identified as an effect-measure modifier on weekly volume ( relative excess risk due to interaction = 4.69 ; 95 % confidence intervals = 1.42 ; 7.95 ; p = 0.005 ) and session frequency ( relative excess risk due to interaction = 2.44 ; 95 % confidence intervals = 0.48 ; 4.39 ; p = 0.015 ). A negative synergy was found between body mass index and weekly volume ( relative excess risk due to interaction = -2.88 ; 95 % confidence intervals = -5.10 ; -0.66 ; p = 0.018 ). CONCLUSIONS The effect of a runner's training load on running-related injury is influenced by body mass index and previous injury. These results show the importance to distinguish between confounding and effect-measure modification in running-related injury research The NLstart2run study: Training-related factors associated with running-related injuries in novice runners. OBJECTIVES The incidence of running-related injuries is high. Some risk factors for injury were identified in novice runners, however, not much is known about the effect of training factors on injury risk. Therefore, the purpose of this study was to examine the associations between training factors and running-related injuries in novice runners, taking the time varying nature of these training-related factors into account. DESIGN Prospect i ve cohort study. METHODS 1696 participants completed weekly diaries on running exposure and injuries during a 6-week running program for novice runners. Total running volume ( min ), frequency and mean intensity ( Rate of Perceived Exertion ) were calculated for the seven days prior to each training session. The association of these time-varying variables with injury was determined in an extended Cox regression analysis. RESULTS The results of the multivariable analysis showed that running with a higher intensity in the previous week was associated with a higher injury risk. Running frequency was not significantly associated with injury, however a trend towards running three times per week being more hazardous than two times could be observed. Finally, lower running volume was associated with a higher risk of sustaining an injury. CONCLUSIONS These results suggest that running more than 60min at a lower intensity is least injurious. This finding is contrary to our expectations and is presumably the result of other factors. Therefore, the findings should not be used plainly as a guideline for novices. More research is needed to establish the person-specific training patterns that are associated with injury Incidence of soccer injuries and their relation to training and team success One hundred-eighty players in a male soccer senior division of 12 teams were observed prospect ively for 1 year to study the risk of soccer injuries in relation to exposure and to establish the connection between training, injuries, and team success. Totally, more than 100 hours of practice were analyzed. All injuries were examined by the same orthopaedic surgeon. On the average, each team played 36 games and had 95 practice sessions with 66 % attendance of selected players. A direct correlation was noted be tween team success and the amount of training. Teams with more than average training showed a diminishing number of injuries. A high practice -to- game ratio seems to be advantageous. One injury every third game and every ninth practice session was documented. For the individual player the incidence of injury was 7.6/1000 practice hours and 16.9/1000 game hours. The incidence of injury was higher at training camps. Correlation was noted between the design of the train ing and the incidence of injuries. The duration of warming up seemed adequate, but its content did not appear to be satisfactory from a clinical point of view. Re design of the warm-up with more emphasis on flexibility and the addition of a cool-down is suggested to reduce injuries Relationship between training load and injury in professional rugby league players. OBJECTIVES To investigate the relationship between training load and injury in professional rugby league players ; DESIGN Prospect i ve cohort study ; METHODS Seventy-nine professional rugby league players ( mean±SD age, 23.3±3.8 years ) participated in this four-year study. A periodized field, strength, and power training program was implemented, with training loads progressively increased in the general preparatory phase of the season and reduced during the competitive phase of the season. Training loads and injuries were recorded for each training session. RESULTS Training load was significantly related ( P<0.05 ) to overall injury ( r=0.82 ), non-contact field injury ( r=0.82 ), and contact field injury ( r=0.80 ) rates. Significant relationships were also observed between the field training load and overall field injury ( r=0.68 ), non-contact field injury ( r=0.65 ), and contact field injury ( r=0.63 ) rates. Strength and power training loads were significantly related to the incidence of strength and power injuries ( r=0.63 ). There was no significant relationship between field training loads and the incidence of strength and power injuries. However, strength and power training loads were significantly ( P<0.01 ) associated with the incidence of contact ( r=0.75 ) and non-contact ( r=0.82 ) field training injuries. CONCLUSIONS These findings suggest that the harder rugby league players train, the more injuries they will sustain, and that high strength and power training loads may contribute indirectly to field injuries. Monitoring of training loads and careful scheduling of field and gymnasium sessions to avoid residual fatigue is warranted to minimize the effect of training-related injuries on professional rugby league players Association of Injury History and Incident Injury in Cadet Basic Military Training. PURPOSE This study aim ed to determine the association between injury history at enrollment and incident lower extremity ( LE ) injury during cadet basic training among first-year military cadets. METHODS Medically treated LE injuries during cadet basic training documented in the Defense Medical Surveillance System were ascertained in a prospect i ve cohort study of three large US military academies from 2005 to 2008. Both acute injuries ( International Classification of Disease, Ninth Revision, codes in the 800 - 900s, including fracture, dislocations, and sprains/strains ) and injury-related musculoskeletal injuries ( International Classification of Disease, Ninth Revision, codes in the 700s, including inflammation and pain, joint derangement, stress fracture, sprain/strain/rupture, and dislocation ) were included. Risk ratio ( RR ) and 95 % confidence interval ( CI ) were computed using multivariate log-binomial models stratified by gender. RESULTS During basic training, there were 1438 medically treated acute and 1719 musculoskeletal-related LE injuries in the 9811 cadets. The most frequent LE injuries were sprains/strains ( 73.6 % of acute injuries ) and inflammation and pain ( 89.6 % of musculoskeletal-related injuries ). The overall risk of incident LE injury was 23.2 % ( 95 % CI = 22.3%-24.0 % ). Cadets with a history of LE injury were at increased risk for incident LE injury. This association was identical in males ( RR = 1.74, 95 % CI = 1.55 - 1.94 ) and females ( RR = 1.74, 95 % CI = 1.52 - 1.99 ). In site-specific analyses, strong associations between injury history and incident injury were observed for hip, knee ligament, stress fracture, and ankle sprain. Injury risk was greater ( P < 0.01 ) for females ( 39.1 % ) compared with males ( 18.0 % ). The elevated injury risk in females ( RR = 2.19, 95 % CI = 2.04 - 2.36 ) was independent of injury history ( adjusted RR = 2.09, 95 % CI = 1.95 - 2.24 ). CONCLUSION Injury history upon entry to the military is associated with the incidence of LE injuries sustained during cadet basic training. Prevention programs targeted at modifiable factors in cadets with a history of LE injury should be considered Risk Factors for Injury in Subelite Rugby League Players Background Although player fatigue and playing intensity have been suggested to contribute to injuries in rugby league players, no study has confirmed if the level of physical fitness is a risk factor for injury in rugby league players. The aim of this study was to identify risk factors for injury in subelite rugby league players. Hypothesis Low physical fitness levels are risk factors for injury in subelite rugby league players. Study Design Cohort study ; Level of evidence, 2. Methods One hundred fifty-three players from a subelite rugby league club underwent preseason measurements of muscular power ( vertical jump ), speed ( 10- and 40-m sprint ), and maximal aerobic power ( multistage fitness test ) over 4 competitive seasons. All injuries sustained by players were prospect ively recorded over the 4 competitive seasons. Results The risk of injury was greater in players with low 10- and 40-m speed. Players with a low maximal aerobic power had a greater risk of sustaining a contact injury. In addition, players who completed less than 18 weeks of training before sustaining their initial injuries were at greater risk of sustaining a subsequent injury. Conclusions Subelite rugby league players with low speed and maximal aerobic power are at an increased risk of injury. In addition, players who complete less than 18 weeks of training before sustaining an initial injury are at greater risk of sustaining a subsequent injury. These findings highlight the importance of speed and endurance training to reduce the incidence of injury in subelite rugby league players", "Background Poor wound healing and scar formation remain critical problems in daily surgical practice. Generally, most attention is paid to intra- and postoperative interventions to improve wound healing after surgery, while preoperative interventions remain unsatisfactorily explored. Objectives In this systematic review, the available literature on the beneficial effects of preoperative interventions on wound healing and scar formation have been summarized and compared. Can Medical Hypnosis Accelerate Post-Surgical Wound Healing? Results of a Clinical Trial Abstract Although medical hypnosis has a long history of myriad functional applications ( pain reduction, procedural preparation etc. ), it has been little tested for site-specific effects on physical healing per se. In this r and omized controlled trial, we compared the relative efficacy of an adjunctive hypnotic intervention, supportive attention, and usual care only on early post-surgical wound healing. Eighteen healthy women presenting consecutively for medically recommended reduction mammaplasty at an ambulatory surgery practice underwent the same surgical protocol and postoperative care following preoperative r and omization ( n = 6 each ) to one of the three treatment conditions : usual care, 8 adjunctive supportive attention sessions, or 8 adjunctive hypnosis sessions targeting accelerated wound healing. The primary outcome data of interest were objective, observational measures of incision healing made at 1,7 weeks postoperatively by medical staff blind to the participants'group assignments. Data included clinical exams and digitized photographs that were scored using a wound assessment inventory ( WAI ). Secondary outcome measures included the participants'subjectively rated pain, perceived incision healing ( VAS Scales ), and baseline and post-surgical functional health status ( SF-36 ). Analysis of variance showed the hypnosis group's objective ly observed wound healing to be significantly greater than the other two groups ', p <.001, through 7 postoperative weeks ; st and ard care controls showed the smallest degree of healing. In addition, at both the 1 and 7 week post-surgical observation intervals, one-way analyses showed the hypnosis group to be significantly more healed than the usual care controls, p < 0. 02. The mean scores of the subjective assessment s of postoperative pain, incision healing and functional recovery trended similarly. Results of this preliminary trial indicate that use of a targeted hypnotic intervention can accelerate postoperative wound healing and suggest that further tests of using hypnosis to augment physical healing are warranted Effect of pantothenic acid and ascorbic acid supplementation on human skin wound healing process. A double-blind, prospective and randomized trial. This study aim ed at testing human skin wound healing improvement by a 21-day supplementation of 1.0 g ascorbic acid ( AA ) and 0.2 g pantothenic acid ( PA ). 49 patients undergoing surgery for tattoos, by the successive resections procedure, entered a double-blind, prospect i ve and r and omized study. Tests performed on both skin and scars determined : hydroxyproline concentrations, number of fibroblasts, trace element contents and mechanical properties. In the 18 supplemented patients, it was shown that in skin ( day 8) Fe increased ( p < 0.05 ) and Mn decreased ( p < 0.05 ) ; in scars ( day 21 ), Cu ( p = 0.07 ) and Mn ( p < 0.01 ) decreased, and Mg ( p < 0.05 ) increased ; the mechanical properties of scars in group A were significantly correlated to their contents in Fe, Cu and Zn, whereas no correlation was shown in group B. In blood, AA increased after surgery with supplementation, whereas it decreased in controls. Although no major improvement of the would healing process could be documented in this study, our results suggest that the benefit of AA and PA supplementation could be due to the variations of the trace elements, as they are correlated to mechanical properties of the scars Enhanced wound healing after emotional disclosure intervention. OBJECTIVES Psychological stress is believed to impair wound healing via a down-regulation of the immune system. Since previous research suggests that disclosure of tra-umatic experiences can result in an up-regulation of immune function, the present study aim ed to investigate the impact of a disclosure intervention on the progress of wound healing. DESIGN The study used a prospect i ve, longitudinal design with r and om assignment to the control ( writing about time management ) and experimental group ( writing about a traumatic event ). METHODS Participants ( N=36 ) completed question naires measuring perceived and emotional distress, loneliness, self-esteem, social support, dispositional optimism, and health-related behaviours. Accurate indication of the healing of a small punch biopsy wound was determined by using a high-resolution ultrasound scanner. RESULTS Repeated measures ANOVA indicated that the disclosure intervention impacted wound healing. Participants who wrote about traumatic events had significantly smaller wounds 14 and 21 days after the biopsy compared with those who wrote about time management. CONCLUSIONS It is concluded that a relatively brief and easy to administer intervention can have beneficial effects on wound healing. The potential for use in patient sample s is indicated Stress, Social Support, and Delayed Skin Barrier Recovery Objective : To examine the effect of a brief laboratory stressor and social support before the stressor on cardiovascular and cortisol responses, and skin barrier recovery after skin disruption. Methods : Eighty-five healthy participants ( mean age 22.9 ± 4.4 years ) underwent a “ tape-stripping ” procedure that disrupts normal skin barrier function, and were r and omly assigned to a No Stress ( reading task ), Stress ( Trier Social Stress Test ), or Stress + Social Support condition ( support from a confederate before the stressor ). Skin barrier recovery was assessed by measuring transepidermal water loss from up to 2 hours after skin disruption. Results : Compared with the No Stress condition, the stressor delayed skin barrier recovery by 10 % at 2 hours after skin disruption ( effect size, r =.29 ), and increased anxiety ( r =.24 ), negative affect ( r =.22 ), cardiovascular activity ( r values from.4–.6 ), and among male participants, cortisol levels ( r =.40 ). Social support did not influence psychological or physiological responses or skin barrier recovery. Larger physiological responses to the tasks did not predict slower skin barrier recovery. Instead, larger systolic blood pressure responses predicted faster skin barrier recovery ( r =.26 ). Conclusions : This study replicated the effects of short-term laboratory stressors on skin barrier recovery, further establishing the relevance of skin barrier recovery for future research. The support manipulation did not influence physiological responses or skin barrier recovery, suggesting that future research on social support, physiology, and objective health outcomes should focus on naturalistic social interactions, relationships, and stressors. AUCI = area under the curve with respect to increase ; BMI = body mass index ; DBP = diastolic blood pressure ; GCRC = General Clinical Research Center ; HR = heart rate ; MAP = mean arterial pressure ; SBP = systolic blood pressure ; TSST = Trier Social Stress Test ; TEWL = transepidermal water loss Improving Scar Quality: A Prospective Clinical Study Following traumatic or surgical injury to the skin, wounds do not heal by tissue regeneration but rather by scar formation. Though healing is definitely a welcomed event, the result ant scar, very often, is not aesthetically pleasing, and not infrequently, may be pathologic causing serious deformities and contractures. Management of problematic scars continues to be a frustrating endeavor with less than optimal results. Prophylactic methods of wound management to minimize serious scarring are being developed. In a previously published study, we have demonstrated improved healing of split thickness skin graft donor sites following treatment with Moist Exposed Burn Ointment ( MEBO, Julphar Gulf Pharmaceutical Industries, Ras Al-Kh aim ah, UAE ). At present, we are reporting the results of a comparative clinical prospect i ve study evaluating scar quality following primary healing of elective surgical and traumatic facial wounds with prophylactic MEBO application, topical antibiotic ointment application, and no topical therapy at all. Scars were evaluated according to the Visual Analogue Scale for scar assessment. Statistical analysis of scar assessment scores demonstrated marked prevention of unfavorable scars with improved cosmetic results following MEBO prophylactic therapy Preoperative anxiety in ambulatory surgery: The impact of an empathic patient-centered approach on psychological and clinical outcomes. OBJECTIVE This study aims to evaluate the influence of an empathic patient-centered approach on preoperative anxiety and surgical outcomes in ambulatory surgery patients. METHODS A sample of 104 patients undergoing general ambulatory surgery was r and omly assigned to the intervention ( IG ) and the control ( CG ) groups. Before surgery, the IG received personalized information through an empathic patient-centered interview. The CG received st and ardized information on surgical procedures. Anxiety was assessed before and after the preoperative interview and after the surgery. Wound healing, post-surgical recovery and satisfaction with the quality of preoperative information were assessed after the surgery. RESULTS The two groups were identical at baseline regarding anxiety, socio-demographic and clinical characteristics. After the patient-centered intervention, the IG showed lower levels of preoperative anxiety ( p<0.001 ) and pain ( p<0.001 ), better surgery recovery ( p<0.01 ) and higher levels of daily activity ( p<0.001 ) and of satisfaction with the information received ( p<0.01 ) than the CG. The IG also showed better wound healing ( tissue type, p<0.01 ; local pain, p<0.01 ). CONCLUSION An empathic patient-centered intervention can reduce preoperative anxiety and increase surgical recovery, wound healing and patient satisfaction. PRACTICE IMPLICATION S This approach is applicable in pre-surgical interviews and can potentially be used in the routine care of various surgical context Mild perioperative hypothermia and the risk of wound infection. BACKGROUND Bacterial destruction caused by free radicals, which are synthesized by neutrophils in the presence of oxygen, depends on adequate tissue perfusion. Mild perioperative hypothermia causes vasoconstriction, reducing nutrient and oxygen supply to wounds and increasing frequency of surgical wound infection. However, the causal role of hypothermia in surgical wound infection is the subject of controversy. The present work proposes the hypothesis that mild perioperative hypothermia is associated with infection of the surgical wound. METHODS A prospect i ve cohort of 290 surgical patients was studied in a second-level hospital ; 261 ( 90 % ) of the patients concluded the follow-up. The relationship of hypothermia and of other confounding factors, such as diabetes mellitus, antibiotic treatment, and wound drains with infection outcome was evaluated. One physician, blinded to patient hypothermia, gathered the data. Surgical wound infection was defined as the surgeon's diagnosis with positive culture. RESULTS Twenty subjects ( 7.6 % ) showed infection of surgical wound ; 18 ( 11.5 % ) of 156 hypothermics and two ( 2 % ) 105 normothermics ( p = 0.004 ). Hypothermia proved to be a significant independent risk of infection with relative risk of 6.3 ( p = 0.01 ). CONCLUSIONS Mild perioperative hypothermia is associated with infection of the surgical wound and its prevention is therefore justified A brief relaxation intervention reduces stress and improves surgical wound healing response: A randomised trial Psychological stress has been shown to impair wound healing, but experimental research in surgical patients is lacking. This study investigated whether a brief psychological intervention could reduce stress and improve wound healing in surgical patients. This r and omised controlled trial was conducted at a surgical centre. Inclusion criteria were English-speaking patients over 18 years booked to undergo elective laparoscopic cholecystectomy ; exclusion criteria were cancellation of surgery, medical complications, and refusal of consent. Seventy five patients were r and omised and 15 patients were excluded ; 60 patients completed the study ( 15 male, 45 female ). Participants were r and omised to receive st and ard care or st and ard care plus a 45-min psychological intervention that included relaxation and guided imagery with take-home relaxation CDs for listening to for 3 days before and 7 days after surgery. In both groups ePTFE tubes were inserted during surgery and removed at 7 days after surgery and analysed for hydroxyproline as a measure of collagen deposition and wound healing. Change in perceived stress from before surgery to 7-day follow-up was assessed using question naires. Intervention group patients showed a reduction in perceived stress compared with the control group, controlling for age. Patients in the intervention group had higher hydroxyproline deposition in the wound than did control group patients ( difference in means 0.35, 95 % CI 0.66 - 0.03 ; t(43)=2.23, p=0.03 ). Changes in perceived stress were not associated with hydroxyproline deposition. A brief relaxation intervention prior to surgery can reduce stress and improve the wound healing response in surgical patients. The intervention may have particular clinical application for those at risk of poor healing following surgery A prospective study in children: Pre- and post-surgery use of vitamin E in surgical incisions. BACKGROUND One of the main problems of elective surgery is the cosmetic result. OBJECTIVE This prospect i ve controlled study aims to determine the effects of topical vitamin E on cosmetic results in children. METHODS A single-blind study was carried out. Topical vitamin E was used on the intended incision site for at least 15 days, thrice daily, before surgery and for at least 30 days, twice daily, after surgery ( group A ). The control group received topical petrolatum-based ointment ( group B ). RESULTS No patients in group A developed keloids. A total of 96 % of patients ( or parents ) considered the cosmetic results very good. No patients had wound infection. In the control group, only 78 % of patients ( or parents ) considered the cosmetic results very good and 13 ( 6.5 % ) patients developed keloids after 6 months. There were no cases of wound infection. CONCLUSION Topical vitamin E before and after surgery improved surgical wound healing and improved cosmetic results Effects of preoperative warming on the incidence of wound infection after clean surgery: a randomised controlled trial BACKGROUND Wound infection after clean surgery is an expensive and often underestimated cause of patient morbidity, and the benefits of using prophylactic antibiotics have not been proven. Warming patients during colorectal surgery has been shown to reduce infection rates. We aim ed to assess whether warming patients before short duration, clean surgery would have the same effect. METHODS 421 patients having clean ( breast, varicose vein, or hernia ) surgery were r and omly assigned to either a non-warmed ( st and ard ) group or one of two warmed groups ( local and systemic ). We applied warming for at least 30 min before surgery. Patients were followed up and masked outcome assessment s made at 2 and 6 weeks. FINDINGS Analysis was done on an intention-to-treat basis. We identified 19 wound infections in 139 non-warmed patients ( 14 % ) but only 13 in 277 who received warming ( 5 % ; p=0.001 ). Wound scores were also significantly lower ( p=0.007 ) in warmed patients. There was no significant difference in the development of haematomas or seromas after surgery but the non-warmed group were prescribed significantly more postoperative antibiotics ( p=0.002 ). INTERPRETATION Warming patients before clean surgery seems to aid the prevention of postoperative wound infection. If applied according to the manufacturers guidelines these therapies have no known side-effects and might, with the support of further studies, provide an alternative to prophylactic antibiotics in this type of surgery Impact of Preoperative Local Water-Filtered Infrared A Irradiation on Postoperative Wound Healing: A Randomized Patient- and Observer-Blinded Controlled Clinical Trial Objective : In addition to a preoperative antibiotic single-shot prophylaxis, we tested the impact of a one-time preoperative water-filtered infrared A irradiation ( wIRA ) on postoperative wound healing of patients. Background : wIRA improves wound healing in postoperative setting s. Methods : A total of 400 consecutive patients undergoing gastrointestinal surgery were r and omly assigned to the treatment group ( A ) or placebo group ( B ). We applied wIRA for 20 minutes while patients were prepared for surgery. Patients and observer were blinded to group assignment. Primary endpoints were surgical site infections ( SSIs ), wound healing, and rate and level of pain within 30 days after surgery. Primary efficacy analysis was carried out on the basis of an intention-to-treat ( ITT ) population and a full- analysis set ( FAS ). Missing values of primary outcome variables were considered as SSIs and maximum pain levels in the ITT analysis, respectively. Results : FAS : The incidence of SSI was 9 of 178 patients ( 5.1 % ) within group A compared with 22 of 182 ( 12.1 % ) within group B [ P = 0.018 ; relative risk ( RR ) = 0.42 ; 95 % CI : 0.18–0.93 ]. ITT : 32 of 200 ( 16 % ) SSIs occurred within group A and 39 of 200 ( 20 % ) within group B ( P = 0.248 ) with an RR of 0.74 ( 95 % CI : 0.43–1.28 ). The wIRA group showed lower postoperative pain at both the ITT ( P = 0.092 ) and the FAS analysis ( P = 0.045 ). Conclusions : This trial indicates a clinical ly relevant benefit of one-time application of preoperative wIRA as a supportive addition to prophylactic antibiotics. wIRA contributes to both reduced SSI rates and postoperative pain but also effectively decreases morbidity and related expenses in the health care system Expressive Writing and Wound Healing in Older Adults: A Randomized Controlled Trial Objective To investigate whether expressive writing could speed wound reepithelialization in healthy, older adults. Methods In this r and omized controlled trial, 49 healthy older adults aged 64 to 97 years were assigned to write for 20 minutes a day either about up setting life events ( Expressive Writing ) or about daily activities ( Time Management ) for 3 consecutive days. Two weeks postwriting, 4-mm punch biopsy wounds were created on the inner, upper arm. Wounds were photographed routinely for 21 days to monitor wound reepithelialization. Perceived stress, depressive symptoms, health-related behaviors, number of doctor visits, and lipopolysaccharide-stimulated proinflammatory cytokine production were also measured throughout the study. Results Participants in the Expressive Writing group had a greater proportion of fully reepithelialized wounds at Day 11 postbiopsy compared with the Time Management group, with 76.2 % versus 42.1 % healed, & khgr;2(1, n = 40 ) = 4.83, p =.028. Ordinal logistic regression showed more sleep in the week before wounding also predicted faster healing wounds. There were no significant group differences in changes to perceived stress, depressive symptoms, health-related behaviors, lipopolysaccharide-induced proinflammatory cytokine production, or number of doctor visits over the study period. Conclusions This study extends previous research by showing that expressive writing can improve wound healing in older adults and women. Future research is needed to better underst and the underlying cognitive, psychosocial, and biological mechanisms contributing to improved wound healing from these simple, yet effective, writing exercises. Trial Registration : Australian New Zeal and Clinical Trials Registry ( trial number 343095 Influence of yoga on postoperative outcomes and wound healing in early operable breast cancer patients undergoing surgery Context : Pre- and postoperative distress in breast cancer patients can cause complications and delay recovery from surgery. Objective : The aim of our study was to evaluate the effects of yoga intervention on postoperative outcomes and wound healing in early operable breast cancer patients undergoing surgery. Methods : Ninety-eight recently diagnosed stage II and III breast cancer patients were recruited in a r and omized controlled trial comparing the effects of a yoga program with supportive therapy and exercise rehabilitation on postoperative outcomes and wound healing following surgery. Subjects were assessed at the baseline prior to surgery and four weeks later. Sociodemographic, clinical and investigative notes were ascertained in the beginning of the study. Blood sample s were collected for estimation of plasma cytokines — soluble Interleukin (IL)-2 receptor ( IL-2R ), tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Postoperative outcomes such as the duration of hospital stay and drain retention, time of suture removal and postoperative complications were ascertained. We used independent sample s t test and nonparametric Mann Whitney U tests to compare groups for postoperative outcomes and plasma cytokines. Regression analysis was done to determine predictors for postoperative outcomes. Results : Sixty-nine patients contributed data to the current analysis ( yoga : n = 33, control : n = 36 ). The results suggest a significant decrease in the duration of hospital stay ( P = 0.003 ), days of drain retention ( P = 0.001 ) and days for suture removal ( P = 0.03 ) in the yoga group as compared to the controls. There was also a significant decrease in plasma TNF alpha levels following surgery in the yoga group ( P < 0.001 ), as compared to the controls. Regression analysis on postoperative outcomes showed that the yoga intervention affected the duration of drain retention and hospital stay as well as TNF alpha levels. Conclusion : The results suggest possible benefits of yoga in reducing postoperative complications in breast cancer patients A comparison of two skin preps used in cardiac surgical procedures. Postoperative surgical site infections contribute significantly to increased patient morbidity and mortality rates and unnecessary hospital costs. Effective and efficient preoperative patient skin preparation is an important perioperative nursing intervention that decreases the number of wound contaminants and reduces the risks for postoperative surgical site infections. This study examined the effectiveness and time and material costs of two preoperative patient skin prep methods ( ie, isopropyl alcohol prep/iodophor-impregnated adhesive drape method, iodophor scrub and paint prep/plain adhesive drape method ). The isopropyl alcohol prep/iodophor-impregnated adhesive drape method clinical ly was as effective as the iodophor scrub and paint prep/plain adhesive drape method, more cost-effective when time and material s were compared, and less cost-effective when material s alone were compared. To make appropriate decisions about the use of preoperative patient skin prep methods, perioperative nurse managers and staff members need to examine and determine whether costs in time or material s have the greater impact on their surgical setting Impact of preoperative anxiolytic on surgical site infection in patients undergoing abdominal hysterectomy. BACKGROUND An increased anxiety may be associated with a higher risk of surgical site infection ( SSI ), but there is little objective data on the effect of preoperative anxiolytic interventions on SSI. To address this issue, we evaluated the effects of preoperative diazepam on postoperative SSI following abdominal hysterectomy. METHODS This r and omized, double-blinded, placebo-controlled study included 130 patients, American Society of Anesthesiologist physical status 1 or 2. Patients were r and omly assigned to receive either oral diazepam 10 mg ( n = 65 ) or placebo ( n = 65 ) the night before and 1 hour prior to surgery. The assessment instruments were the Visual Analogue Scale and the State-Trait Anxiety Inventory. SSI was diagnosed according to the criteria of the Centers for Disease Control and Prevention with st and ard follow-up of 30 days. RESULTS The relative risk ( RR ) was 1.79 ( 95 % confidence interval [ CI ] : 1.31 - 2.43 ), and the number of patients that needed to be treated was 5.2 ( 95 % CI : 2.74 - 50.76 ) to prevent 1 additional SSI. The RR for SSI in placebo-treated patients with high postoperative anxiety was 1.65 ( 95 % CI : 1.07 - 2.56 ). CONCLUSION Diazepam-treated patients showed lower postoperative anxiety and lower incidence of SSI up to 30 days after surgery compared with placebo in patients undergoing abdominal hysterectomy", 'OBJECTIVE The effect of fructose on cardiometabolic risk in humans is controversial. We conducted a systematic review and meta- analysis of controlled feeding trials to clarify the effect of fructose on glycemic control in individuals with diabetes. Height, predictors of C-peptide and cancer risk in men. BACKGROUND Excessive energy intake tends to increase circulating levels of insulin and free insulin-like growth factor-1 ( IGF-I ), which may increase risk of some cancers that are common in Western countries. However, the relative importance of these hormonal factors during pre-adulthood and adulthood is unknown. METHODS We prospect ively examined height, as a marker of pre-adult IGF-I bioactivity, and modifiable adult determinants of insulin secretion, in relation to risk of cancer, particularly Western-related cancers ( colon, pancreas, kidney, and aggressive prostate cancers ) in 47,690 male health professionals. Information about dietary and lifestyle factors for these men was collected at baseline ( 1986 ) and was up date d periodically. A C-peptide score, representing insulin secretion, was created by using body mass, physical activity, and diet in a stepwise linear regression to predict C-peptide level, in a sample of 263 cohort members. RESULTS From 1986 to 1998, we documented 3270 incident cancers ( excluding the less aggressive prostate cancers ). Greater body mass index, lower physical activity, and a Western dietary pattern were independent predictors of higher plasma C-peptide levels in the sample. A C-peptide score, based on these variables, was positively related to risk of Western-related cancers, but not to other cancer types in the entire cohort. Height was also only related to Western-related cancers. For Western-related cancers, 29 % ( 95 % CI : 16 %, 48 % ) were attributed to C-peptide scores above the first decile, 30 % ( 95 % CI : 11 %, 58 % ) to heights > or=66 inches, and 49 % ( 95 % CI : 30 %, 69 % ) to both factors combined. For total cancers, 29 % ( 95 % CI : 16 %, 46 % ) were attributable to both factors. CONCLUSIONS Maximal growth in the pre-adult period and hyperinsulinaemia during adulthood may largely underlie the excess risk of some cancers that are common in Western population s. A substantial proportion of these cancers may be modifiable in adulthood, through alterations in body weight, sedentary behaviour, and dietary patterns that stimulate hyperinsulinaemia Fructose and insulin sensitivity in patients with type 2 diabetes. The effect of dietary fructose ( 20 % of carbohydrate calories, 45 - 65 g day-1 for 4 weeks ) on glycaemic control, serum lipid, lipoprotein and apoprotein A-I and A-II concentrations and on insulin sensitivity was studied in 10 type 2 diabetic patients. The study was done in a r and omized, double-blind fashion with crystalline fructose or placebo administered evenly during 4 meals or snacks per day. The patients were hospitalized throughout the study periods. The fasting plasma glucose concentration decreased during the fructose ( from 10.7 + /- 1.4 mmol l-1 to 8.0 + /- 0.8 mmol l-1, P < 0.02 ) and the control diet ( from 10.1 + /- 0.9 mmol l-1 to 8.0 + /- 0.7 mmol l-1, P < 0.05 ). The mean diurnal blood glucose concentration also fell both during the fructose ( from 10.8 + /- 0.5 mmol l-1 to 8.4 + /- 0.3 mmol l-1, P < 0.001 ) and the control diet ( from 10.3 + /- 0.3 mmol l-1 to 8.8 + /- 0.9 mmol l-1, P < 0.01 ). The HbA1 concentration improved ( P < 0.02 ) only during the fructose diet. Insulin sensitivity increased by 34 % ( P < 0.05 ) during the fructose diet, but remained unchanged during the control period. Serum insulin, triglyceride, apoprotein A-I and A-II concentrations, body weight, blood pressure and blood lactate remained unchanged during both diets. In conclusion, substitution of moderate amounts of fructose for complex carbohydrates can improve glycaemic control and insulin sensitivity in patients with type 2 diabetes', 'OBJECTIVE To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures. Dietary factors and the incidence of hip fracture in middle-aged Norwegians. A prospective study. Dietary data from a prospect i ve study were used to relate factors influencing calcium balance ( estimates of dietary calcium intake, protein intake from nondairy animal sources ( meat, fish, and eggs ), and coffee consumption ) to the incidence of hip fracture. During the years 1977 - 1983, women and men born between 1925 and 1940 and living in one of three Norwegian counties were invited to a cardiovascular screening that included a dietary survey. The attendance rate at screening was 91.1 %, and 90.7 % of these persons ( 19,752 women and 20,035 men ) filled in and returned a semiquantitative dietary question naire. This cohort was followed for an average of 11.4 years ( range, 0.01 - 13.8 years ) with respect to hip fracture, defined as cervical or trochanteric fracture. During follow-up, 213 hip fractures were identified, excluding fractures associated with high-energy trauma and metastatic bone disease. There was no clear association between calcium intake or nondairy animal protein intake and hip fracture in this cohort. However, an elevated risk of fracture was found in women with a high intake of protein from nondairy animal sources in the presence of low calcium intake ( relative risk = 1.96 ( 95 % confidence interval 1.09 - 3.56 ) for the highest quarter of nondairy protein intake and the lowest quarter of calcium intake vs. the three lower quarters of protein intake and the three higher quarters of calcium intake ). Women who drank nine or more cups of coffee per day also had an increased risk of fracture, while there was no association between coffee consumption and hip fracture in men. Although these findings do not necessarily imply causal relations, they suggest the presence of risk factors for hip fracture that act through a negative calcium balance in this population Combined Calcium and Vitamin D3 Supplementation in Elderly Women: Confirmation of Reversal of Secondary Hyperparathyroidism and Hip Fracture Risk: The Decalyos II Study Vitamin D insufficiency and low calcium intake contribute to increase parathyroid function and bone fragility in elderly people. Calcium and vitamin D supplements can reverse secondary hyperparathyroidism thus preventing hip fractures, as proved by Decalyos I. Decalyos II is a 2-year, multicenter, r and omized, double-masked, placebo-controlled confirmatory study. The intention-to-treat population consisted of 583 ambulatory institutionalized women ( mean age 85.2 years, SD = 7.1 ) r and omized to the calcium – vitamin D3 fixed combination group ( n= 199 ) ; the calcium plus vitamin D3 separate combination group ( n= 190 ) and the placebo group ( n= 194 ). Fixed and separate combination groups received the same daily amount of calcium ( 1200 mg ) and vitamin D3 ( 800 IU ), which had similar pharmacodynamic effects. Both types of calcium-vitamin D3 regimens increased serum 25-hydroxyvitamin D and decreased serum intact parathyroid hormone to a similar extent, with levels returning within the normal range after 6 months. In a subgroup of 114 patients, femoral neck bone mineral density ( BMD ) decreased in the placebo group ( mean = –2.36 % per year, SD = 4.92 ), while remaining unchanged in women treated with calcium-vitamin D3 ( mean = 0.29 % per year, SD = 8.63 ). The difference between the two groups was 2.65 % ( 95 % CI = –0.44, 5.75 % ) with a trend in favor of the active treatment group. No significant difference between groups was found for changes in distal radius BMD and quantitative ultrasonic parameters at the os calcis. The relative risk ( RR ) of HF in the placebo group compared with the active treatment group was 1.69 ( 95 % CI = 0.96, 3.0 ), which is similar to that found in Decalyos I ( RR = 1.7 ; 95 % CI = 1.0, 2.8 ). Thus, these data are in agreement with those of Decalyos I and indicate that calcium and vitamin D3 in combination reverse senile secondary hyperparathyroidism and reduce both hip bone loss and the risk of hip fracture in elderly institutionalized women Prediction of absolute risk of non-spinal fractures using clinical risk factors and heel quantitative ultrasound Summary The relationship between osteoporosis risk factors, bone quantitative ultrasound ( QUS ) and non-spinal fracture risk was estimated in a cohort of 5,201 postmenopausal women from Spain who were prospect ively evaluated during three years. Several clinical risk factors and low heel QUS values were independently associated with non-spinal fracture risk. Introduction Low-trauma, non-spinal fractures are a growing source of morbidity and mortality in the elderly. The aim of the present study was to examine the association of heel quantitative ultrasound ( QUS ) and a series of osteoporosis and fracture risk factors, with incident low energy non-spinal fractures in a population of elderly women, and to incorporate them into fracture prediction models. Methods 5,201 women aged 65 or older were enrolled in a three-year cohort study. Participants completed an osteoporosis and fracture risk factors question naire. QUS was measured at the heel with a gel-coupled device. Cox-proportional hazard analyses were performed to evaluate the association with the first incident low-trauma non-spinal fracture. Results Three hundred and eleven women ( 6.0 % ) sustained a total of 363 low-trauma fractures, including 133 forearm/wrist, 54 hip, 50 humerus, 37 leg and 17 pelvic fractures. For every st and ard deviation decrease in the quantitative ultrasound index, the adjusted hazard ratios ( 95 % CI ) for any non-vertebral, hip, forearm/wrist, and humerus fractures were 1.31 ( 1.15–1.49 ), 1.40 ( 1.01–1.95 ), 1.50 ( 1.19–1.89 ) and 1.35 ( 0.97–1.87 ), respectively. Similar results were observed with other QUS variables. The best predictive models indicated that age, a history of falls, a previous low-trauma fracture, a family history of fracture, a calcium intake from dairy products of less than 250 mg/day, and lower values of QUS parameters were independently associated with the risk of non-spinal fractures. Conclusions Both clinical risk factors and QUS are independent predictors of risk of fragility non-spinal fractures. A prediction algorithm using these variables was developed to estimate the absolute risk of non-spinal fractures in elderly women in Spain Risk factors for proximal humerus, forearm, and wrist fractures in elderly men and women: the Dubbo Osteoporosis Epidemiology Study. Fractures of the proximal humerus, forearm, and wrist account for approximately one third of total osteoporotic fractures in the elderly. Several risk factors for these fractures were evaluated in this prospect i ve study of 739 men and 1,105 women aged > or = 60 years in Dubbo, Australia. During follow-up ( 1989 - 1996 ), the respective incidences of humerus and of forearm and wrist fractures, per 10,000 person-years, were 22.6 and 33.8 for men and 54.8 and 124.6 for women. Independent predictors of humerus fracture were femoral neck bone mineral density ( FNBMD ) ( relative risk ( RR ) = 2.3, 95 % confidence interval ( CI ) : 1.2, 4.5 ) in men and FNBMD ( RR = 2.4, 95 % CI : 1.7, 3.5 ) and height loss ( RR = 1.1, 95 % CI : 1.0, 1.2 ) in women. For forearm and wrist fractures, risk factors were FNBMD ( men : RR = 1.5, 95 % CI : 1.0, 2.3 ; women : RR = 1.5, 95 % CI : 1.2, 1.9 ) and height loss ( men : RR = 1.2, 95 % CI : 1.0, 1.3 ; women : RR = 1.1, 95 % CI : 1.0, 1.2 ). In addition, dietary calcium ( men : RR = 2.0, 95 % CI : 1.0, 3.6 ) and a history of falls ( women : RR = 1.9, 95 % CI : 1.4, 2.6 ) were also significant. These data suggest that elderly men and women largely share common risk factors for upper limb fractures and that FNBMD is the primary risk factor Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial. BACKGROUND The effect of supplementation with calcium alone on risk fractures in a healthy population is not clear. OBJECTIVE The objective was to determine whether 4 y of calcium supplementation would reduce the fracture risk during treatment and subsequent follow-up in a r and omized placebo-controlled trial. DESIGN The participants were aged < 80 y at study entry ( mean age : 61 y ), were generally healthy, and had a recent diagnosis of colorectal adenoma. A total of 930 participants ( 72 % men ; mean age : 61 y ) were r and omly assigned to receive 4 y of treatment with 3 g CaCO(3 ) ( 1200 mg elemental Ca ) daily or placebo and were followed for a mean of 10.8 y. The primary outcomes of this analysis were all fractures and minimal trauma fractures ( caused by a fall from st and ing height or lower while sitting, st and ing, or walking ). RESULTS There were 46 fractures ( 15 from minimal trauma ) in 464 participants in the calcium group and 54 ( 29 from minimal trauma ) in 466 participants in the placebo group. The overall risk of fracture differed significantly between groups during the treatment phase [ hazard ratio ( HR ) : 0.28 ; 95 % CI : 0.09, 0.85 ], but not during the subsequent posttreatment follow-up ( HR : 1.10 ; 95 % CI : 0.71, 1.69 ). Minimal trauma fractures were also less frequent in the calcium group during treatment ( HR : 0 ; 95 % CI : 0, 0.50 ). CONCLUSION Calcium supplementation reduced the risk of all fractures and of minimal trauma fractures among healthy individuals. The benefit appeared to dissipate after treatment was stopped. This trial was registered at clinical trials.gov as NCT00153816 Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women. BACKGROUND Short trials of calcium supplementation show that it reduces loss of bone density in postmenopausal women ; longer observational studies do not generally find a lower risk of hip fracture with higher-calcium diets. Fewer studies have focused on vitamin D in preventing postmenopausal osteoporosis or fractures. OBJECTIVE We assessed relations between postmenopausal hip fracture risk and calcium, vitamin D, and milk consumption. DESIGN In an 18-y prospect i ve analysis in 72 337 postmenopausal women, dietary intake and nutritional supplement use were assessed at baseline in 1980 and up date d several times during follow-up. We identified 603 incident hip fractures result ing from low or moderate trauma. Relative risks ( RRs ) from proportional hazards models were controlled for other dietary and nondietary factors. RESULTS Women consuming > or = 12.5 microg vitamin D/d from food plus supplements had a 37 % lower risk of hip fracture ( RR = 0.63 ; 95 % CI : 0.42, 0.94 ) than did women consuming < 3.5 microg/d. Total calcium intake was not associated with hip fracture risk ( RR = 0.96 ; 95 % CI : 0.68, 1.34 for > or = 1200 compared with < 600 mg/d ). Milk consumption was also not associated with a lower risk of hip fracture ( P for trend = 0.21 ). CONCLUSIONS An adequate vitamin D intake is associated with a lower risk of osteoporotic hip fractures in postmenopausal women. Neither milk nor a high-calcium diet appears to reduce risk. Because women commonly consume less than the recommended intake of vitamin D, supplement use or dark fish consumption may be prudent Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. UNLABELLED This study of 9605 community-dwelling residents supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in elderly in a northern European region known to be deficient in vitamin D, especially during winter periods. INTRODUCTION We evaluated the effect of two programs for the prevention of osteoporotic fractures leading to acute hospital admission in a population of elderly community-dwelling residents. MATERIAL S AND METHODS This was a factorial, cluster-r and omized, pragmatic, intervention study. We included 9605 community-dwelling residents aged 66 + years. We offered a prevention program of a daily supplement of 1000 mg of elemental calcium as calcium carbonate and 400 IU ( 10 microg ) of vitamin D3 to a total of 4957 participants. Another program with evaluation and suggestions for the improvement of the domestic environment was offered to a total of 5063 participants. Both programs included revision of the resident\'s current pharmaceutical treatment. We achieved information on osteoporotic fractures in the study population from the Danish Hospital Registration Data base. We defined osteoporotic fractures as low energy fractures of the proximal humerus, distal forearm, vertebral column, pelvis, cervical femur, and intertrochanteric femur. RESULTS Active participation was 50.3 % in the Calcium and Vitamin D Program and 46.4 % in the Environmental and Health Program. We observed a 16 % reduction in fracture incidence rate ( relative risk [ RR ], 0.84 ; CI, 0.72 - 0.98 ; p < 0.025 ) among male and female residents offered the Calcium and Vitamin D Program ( intention-to-prevent analysis ). CONCLUSIONS This study supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in community-dwelling elderly people in a northern European region known to be deficient in vitamin D, especially during winter periods Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study Objective To investigate associations between long term dietary intake of calcium and risk of fracture of any type, hip fractures, and osteoporosis. Design A longitudinal and prospect i ve cohort study, based on the Swedish Mammography Cohort, including a subcohort, the Swedish Mammography Cohort Clinical. Setting A population based cohort in Sweden established in 1987. Participants 61 433 women ( born between 1914 and 1948 ) were followed up for 19 years. 5022 of these women participated in the subcohort. Main outcome measures Primary outcome measures were incident fractures of any type and hip fractures, which were identified from registry data. Secondary outcome was osteoporosis diagnosed by dual energy x ray absorptiometry in the subcohort. Diet was assessed by repeated food frequency question naires. Results During follow-up, 14 738 women ( 24 % ) experienced a first fracture of any type and among them 3871 ( 6 % ) a first hip fracture. Of the 5022 women in the subcohort, 1012 ( 20 % ) were measured as osteoporotic. The risk patterns with dietary calcium were non-linear. The crude rate of a first fracture of any type was 17.2/1000 person years at risk in the lowest quintile of calcium intake, and 14.0/1000 person years at risk in the third quintile, corresponding to a multivariable adjusted hazard ratio of 1.18 ( 95 % confidence interval 1.12 to 1.25 ). The hazard ratio for a first hip fracture was 1.29 ( 1.17 to 1.43 ) and the odds ratio for osteoporosis was 1.47 ( 1.09 to 2.00 ). With a low vitamin D intake, the rate of fracture in the first calcium quintile was more pronounced. The highest quintile of calcium intake did not further reduce the risk of fractures of any type, or of osteoporosis, but was associated with a higher rate of hip fracture, hazard ratio 1.19 ( 1.06 to 1.32 ). Conclusion Gradual increases in dietary calcium intake above the first quintile in our female population were not associated with further reductions in fracture risk or osteoporosis DIETARY CALCIUM AND RISK OF HIP FRACTURE: 14-YEAR PROSPECTIVE POPULATION STUDY To assess the effect of dietary calcium intake on risk of hip fracture, a geographically defined caucasian population in southern California was studied prospect ively. Between 1973 and 1975, a quantified 24 hour diet recall was obtained by a dietician from 957 men and women aged 50 to 79 years at baseline. Follow-up to 1987 with mortality records and interviews showed 15 men and 18 women with hip fractures. The age-adjusted risk of hip fracture was inversely associated with dietary calcium whether considered as mg per day or as nutrient density ( mg per 1000 kcal ). No other nutrient was consistently associated with hip fracture in any Cox proportional hazards model that included calcium. The association between calcium and fracture persisted after adjustment for cigarette smoking, alcohol intake, exercise, and obesity. The significant independent inverse association of dietary calcium with subsequent risk of hip fracture ( relative risk = 0.6 per 198 mg/1000 kcal ) strongly supports the hypothesis that increased dietary calcium intake protects against hip fracture Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: the OFELY study. Several epidemiological studies have identified clinical factors that predict the risk of hip fractures in elderly women independently of the level of bone mineral density ( BMD ), such as low body weight, history of fractures, and clinical risk factors for falls. Their relevance in predicting all fragility fractures in all postmenopausal women, including younger ones, is unknown. The objective of this study was to identify independent predictors of all osteoporosis-related fractures in healthy postmenopausal women. We prospect ively followed for 5.3 + /- 1.1 years a cohort of 672 healthy postmenopausal women ( mean age 59.1 + /- 9.8 years ). Information on social and professional conditions, demographic data, current and past medical history, fracture history, medication use, alcohol consumption, caffeine consumption, daily calcium intake, cigarette smoking, family history of fracture, and past and recent physical activity was obtained. Anthropometric and total hip bone mineral density measurements were made. Incident falls and fractures were ascertained every year. We observed 81 osteoporotic fractures ( annual incidence, 21 per 1000 women/year ). The final model consisted of seven independent predictors of incident osteoporotic fractures : age > or = 65 years, odds ratio estimate ( OR ), 1.90 [ 95 % confidence interval ( CI ) 1.04 - 3.46 ], past falls, OR, 1.76 ( CI 1.00 - 3.09 ), total hip bone mineral density ( BMD ) < or = 0.736 g/cm(2 ), OR, 3.15 ( CI 1.75 - 5.66 ), left grip strength < or = 0.60 bar, OR, 2.05 ( CI 1.15 - 3.64 ), maternal history of fracture, OR, 1.77 ( CI 1.01 - 3.09 ), low physical activity, OR, 2.08 ( CI 1.17 - 3.69 ), and personal history of fragility fracture, OR, 3.33 ( CI 1.75 - 5.66 ). In contrast, body weight, weight loss, height loss, smoking, neuromuscular coordination assessed by three tests, and hormone replacement therapy were not independent predictors of all fragility fractures after adjustment for all variables. We found that some -- but not all -- previously reported clinical risk factors for skeletal fragility predicted all fragility fractures independently of BMD in healthy postmenopausal women, although they differed somewhat from those predicting specifically hip fractures in elderly women. These risk factors appear to reflect quality of bone structure ( previous fragility fracture ), lifestyle habits ( physical activity ), muscle function and health status ( grip strength ), heredity ( maternal history of fracture ), falls, and aging. Measurements of these variables should be included in the clinical assessment of the risk of osteoporotic fractures in postmenopausal women The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study. This placebo-controlled r and omized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal ( five years after menopause ) and six of whom were mid-postmenopausal ( five to ten years after menopause ). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause ( 3.3 in the calcium citrate group vs 2.7 in the placebo group ), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment ( + 1.03 % after two years ), whereas it declined significantly by -2.38 % after two years on placebo ( P <.001 ). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group ( -0.02 % after two years ), but it declined significantly in the placebo group ( -1.79 % after one year and -3.03 % after two years, P <.01 ). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation ( 400 mg of calcium twice daily ) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. BACKGROUND AND METHODS Laboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a r and omized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We r and omly assigned 930 subjects ( mean age, 61 years ; 72 percent men ) with a recent history of colorectal adenomas to receive either calcium carbonate ( 3 g [ 1200 mg of elemental calcium ] daily ) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to ( and including ) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period. RESULTS The subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 ( 95 percent confidence interval, 0.74 to 0.98 ; P=0.03 ). The main analysis was based on the 832 subjects ( 409 in the calcium group and 423 in the placebo group ) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group ( 31 percent ) and 159 subjects in the placebo group ( 38 percent ) ; the adjusted risk ratio was 0.81 ( 95 percent confidence interval, 0.67 to 0.99 ; P=0.04 ). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 ( 95 percent confidence interval, 0.60 to 0.96 ; P=0.02 ). The effect of calcium was independent of initial dietary fat and calcium intake. CONCLUSIONS Calcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas Risk factors for fracture in nonosteoporotic men and women. CONTEXT AND OBJECTIVE It is not known which factors are associated with fracture in nonosteoporotic elderly. The aim of this study was to assess the association between fall-related risk factors and fracture risk in men and women without osteoporosis. DESIGN This study was part of the ongoing Dubbo Osteoporosis Epidemiology Study, which was design ed as a prospect i ve population -based cohort investigation. PARTICIPANTS At baseline, 924 women and 723 men aged 60 + yr did not have osteoporosis [ bone mineral density ( BMD ) T-scores > -2.5 ]. The individuals have been followed for up to 15 yr. MAIN OUTCOME MEASURES Atraumatic fractures were prospect ively identified through radiologists\'reports. RISK FACTORS At baseline, femoral neck BMD ( FNBMD ) was measured by dual energy x-ray absorptiometry ( DXA ) ; history of fall, postural stability, and quadriceps strength was obtained. RESULTS During the follow-up period, among the nonosteoporotic group, 221 women and 105 men had sustained a fracture, accounting for 55 and 74 % of total fractures in the entire Dubbo Osteoporosis Epidemiology Study sample, respectively. The following factors were independent risk factors for any fracture : in women, age per sd ( hazard ratio, 1.2 ; 95 % CI, 1.0 - 1.3 ), postural sway per sd ( 1.1, 1.0 - 1.2 ), FNBMD per sd ( 1.6, 1.3 - 1.9 ), fall in the previous 12 months ( 2.1, 1.6 - 2.7 ), and prior fracture ( 1.8, 1.2 - 2.7 ) ; in men, age ( 1.4, 1.1 - 1.6 ), postural sway ( 1.2, 1.0 - 1.3 ), FNBMD ( 1.2, 1.0 - 1.5 ), and fall in the previous 12 months ( 1.9, 1.2 - 3.0 ). Exposure to at least one of the risk factors could account for 49 % ( women ) and 39 % ( men ) of any fractures in this population. CONCLUSION In nonosteoporotic elderly, the combination of low BMD, advancing age, fall during the last 12 months, and prior fracture could identify a subgroup of individuals with high risk of fracture Dietary calcium and hip fracture risk: The NHANES I Epidemiologic Follow-Up Study The effect of dietary calcium on hip fracture risk was examined prospect ively using the NHANES I Epidemiologic Follow-Up Study cohort, which is derived from a nationally representative sample of the United States population. A cohort of 4342 white men and postmenopausal women ages 50–74 years at baseline ( 1971–1975 ) were observed through 1987 for up to 16 years of follow-up. Quantitative estimates of calcium intake were obtained at baseline from a 24-h recall, while weekly frequency of dairy food consumption was obtained from a qualitative food frequency. By 1987, 44 men and 122 women had experienced a hip fracture according to hospital records or death certificates. In the total sample of women the risk of hip fracture was only slightly lower for the highest quartile compared with the lowest. However, although not statistically significant, the age-adjusted risk of hip fracture was approximately 50 % lower in the highest quartile of calcium intake compared with the lowest quartile in the subgroup of women who were at least 6 years postmenopausal and not taking postmenopausal hormone. The low relative risk observed among men, although interesting, must be interpreted cautiously due to small sample size. Adjusting for other risk factors did not appreciably change the results for either sex. The pattern of relative risks for calcium quartiles and by selected cutpoints was not consistent with a dose-response effect of calcium. Our results suggest that calcium may lower hip fracture risk in late menopausal women Health risks and benefits from calcium and vitamin D supplementation: Women\'s Health Initiative clinical trial and cohort study Summary The Women\'s Health Initiative ( WHI ) double-blind, placebo-controlled clinical trial r and omly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D3 daily or placebo, with average intervention period of 7.0 years. The trial was design ed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer. Introduction This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality. Methods WHI calcium and vitamin D r and omized clinical trial ( CT ) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospect i ve observational study ( OS ). Results Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [ HR ] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 ( 95 % confidence interval ( CI ), 0.38–1.00 ). In combined analyses of CT and OS data, the corresponding HR was 0.65 ( 95 % CI, 0.44–0.98 ). Supplementation effects were not apparent on the risks of myocardial infa rct ion, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive. Conclusion Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial. In a double-blind trial, 327 patients ( 57 men ) over 65 ( mean age 79.5 ) years received all possible combinations of calcium carbonate 3 g, vitamin D3 1000 iu, meth and ienone 2.5 mg and /or placebos daily for 9 months. The higher incidence of bone fractures in the placebo group was not significant. Serum calcium, phosphorus, creatinine, aspartate aminotransferase and alkaline phosphatase were followed : the greatest changes occurred with meth and ienone, which thus reduced osteoporotic activity and increased the muscular mass most effectively ; calcium carbonate had the poorest effect. Surprisingly, coronary mortality was higher among those taking all three active substances. With two treatments the increase was not significant, but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments, a significant increase in coronary deaths was seen, most significant ( P less than 0.001 ) in those receiving vitamin D3 and meth and ienone Incidence and risk factors for osteoporotic vertebral fracture in low-income community-dwelling elderly: a population-based prospective cohort study in Brazil. The São Paulo Ageing & Health (SPAH) Study Summary We ascertained the incidence and predictors of radiographic vertebral fracture in a Brazilian elderly cohort, since no data in this field have been reported in low-income countries. This is the first population -based study to demonstrate the high frequency of vertebral fracture in elderly Latin Americans. Age, prior fracture, BMD, and bone turnover were predictors of fracture. Introduction Vertebral fractures are associated with increased future fracture risk and mortality. No data on incidence of osteoporotic vertebral fracture have been reported in low-income countries where the population ’s aging has been faster. Thus, we sought to describe the incidence and risk factors for radiographic vertebral fracture in a longitudinal prospect i ve Brazilian population -based elderly cohort. Methods 707 older adults ( 449 women and 258 men ) were evaluated with spinal radiographs obtained at baseline and after a mean follow-up of 4.3 ± 0.8 years. New vertebral fracture was defined as distinct alteration in the morphology of vertebrae result ing in higher grade of deformity on the second radiograph when compared to the baseline radiograph. Clinical question naire, bone mineral density ( BMD ), and laboratory tests were performed at baseline. Multivariate Poisson regression models were used to identify independent predictors of fracture. Results The age-st and ardized incidence of vertebral fracture was 40.3/1,000 person-years in women and 30.6/1,000 in men. In women, three models of risk factors for fracture were fitted : ( 1 ) age ( relative risks ( RR ) 2.46, 95 % confidence interval ( CI ) 1.66–3.65 ), previous osteoporotic fracture ( RR 1.65, 95 % CI 1.00–2.71 ), and lumbar spine BMD ( RR 1.21, 95 % CI 1.03–1.41 ) ; ( 2 ) age ( RR 2.25, 95 % CI 1.52–3.34 ) and femoral neck BMD ( RR 1.42, 95 % CI 1.11–1.81 ) ; ( 3 ) age ( RR 2.11, 95 % CI 1.41–3.15 ) and total hip BMD ( RR 1.56, 95 % CI 1.21–2.0 ). In men, the highest quartile of cross-linked C-telopeptide ( CTx ) ( RR 1.96, 95 % CI 0.98–3.91 ) and prior fracture ( RR 2.10, 95 % CI 1.00–4.39 ) were predictors of new vertebral fracture. Conclusions This is the first population -based study to ascertain the incidence of vertebral fracture in elderly Latin Americans, confirming the high frequency of the disorder. Age, Diet and hip fractures among elderly Europeans in the EPIC cohort Background / Objectives : Evidence on the role of diet during adulthood and beyond on fracture occurrence is limited. We investigated diet and hip fracture incidence in a population of elderly Europeans, participants in the European Prospect i ve Investigation into Cancer and nutrition study.Subjects/ Methods : 29 122 volunteers ( 10 538 men, 18 584 women ) aged 60 years and above ( mean age : 64.3 ) from five countries were followed up for a median of 8 years and 275 incident hip fractures ( 222 women and 53 men ) were recorded. Diet was assessed at baseline through vali date d dietary question naires. Data were analyzed through Cox proportional-hazards regression with adjustment for potential confounders. Results : No food group or nutrient was significantly associated with hip fracture occurrence. There were suggestive inverse associations, however, with vegetable consumption ( hazard ratio ( HR ) per increasing sex-specific quintile : 0.93, 95 % confidence interval ( CI ) : 0.85–1.01 ), fish consumption ( HR per increasing sex-specific quintile : 0.93, 95 % CI : 0.85–1.02 ) and polyunsaturated lipid intake ( HR per increasing sex-specific quintile : 0.92, 95 % CI : 0.82–1.02 ), whereas saturated lipid intake was positively associated with hip fracture risk ( HR per increasing sex-specific quintile : 1.13, 95 % CI : 0.99–1.29 ). Consumption of dairy products did not appear to influence the risk ( HR per increasing sex-specific quintile : 1.02, 95 % CI : 0.93–1.12 ). Conclusions : In a prospect i ve study of the elderly, diet, including consumption of dairy products, alcohol and vitamin D, did not appear to play a major role in hip fracture incidence. There is however, weak and statistically non-significant evidence that vegetable and fish consumption and intake of polyunsaturated lipids may have a beneficial, whereas saturated lipid intake a detrimental effect Gender-specific associations between soy and risk of hip fracture in the Singapore Chinese Health Study. Although there is some epidemiologic evidence that soy may reduce risk of osteoporotic fracture in women, it is not known whether this risk reduction also occurs for men. The authors examined gender-specific associations between soy intake and hip fracture risk in the Singapore Chinese Health Study, a prospect i ve cohort of 63,257 Chinese living in Singapore. At recruitment between 1993 and 1998, each subject was administered a food frequency question naire and questions on medical history and lifestyle factors. As of December 31, 2006, 276 incident cases of hip fracture in men and 692 cases in women were identified via linkage with hospital discharge data bases. For both genders, hip fracture risk was positively associated with cigarette smoking and was inversely associated with body mass index. There was a statistically significant association of tofu equivalents, soy protein, and isoflavones with hip fracture risk among women but not among men. Compared with women in the lowest quartile of intakes for tofu equivalents ( < 49.4 g/day ), soy protein ( < 2.7 g/day ), and isoflavones ( < 5.8 mg/1,000 kcal/day ), those in the second-fourth quartiles exhibited 21%-36 % reductions in risk ( all P < 0.036 ). Risk levels were comparable across the second, third, and fourth quartiles of soy intake categories Dietary calcium, physical activity, and risk of hip fracture: a prospective study. OBJECTIVE --To determine whether low dietary calcium intake and physical inactivity are risk factors for hip fracture among subjects aged 65 and over. DESIGN --Fifteen year follow up study of a large cohort of r and omly selected elderly people living in the community, who had taken part in the 1973 - 4 survey of the Department of Health and Social Security, and for whom dietary and other data were recorded at initial interview and medical assessment. SETTING --Eight areas in Britain ( Engl and ( five ), Wales ( one ), and Scotl and ( two ]. SUBJECTS--1688 Subjects living in the community, of whom 1419 subjects ( 720 men and 699 women ) agreed to participate. 1356 Subjects completed a seven day dietary record and 983 ( 542 men and 441 women ) agreed to be assessed by a geriatrician. RESULTS --Incidence of hip fracture increased with age and was higher in women than men. Comparison with matched controls showed no evidence that the risk of hip fracture was related to calcium intake : the odds ratio for the lowest third of dietary calcium compared with the highest was 0.7 ( 95 % confidence interval 0.1 to 3.9 ) after adjustment for smoking and body mass index. The adjusted odds ratio for the lowest third of outdoor activity compared with the highest was 4.3 ( 0.7 to 26.8 ), and that for grip strength was 3.9 ( 0.7 to 23.0 ). CONCLUSIONS --Reduced intake of dietary calcium does not seem to be a risk factor for hip fracture. Further evidence is provided that physical activity in the elderly protects against hip fracture Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP diet and health study. IMPORTANCE Calcium intake has been promoted because of its proposed benefit on bone health, particularly among the older population. However, concerns have been raised about the potential adverse effect of high calcium intake on cardiovascular health. OBJECTIVE To investigate whether intake of dietary and supplemental calcium is associated with mortality from total cardiovascular disease ( CVD ), heart disease, and cerebrovascular diseases. DESIGN AND SETTING Prospect i ve study from 1995 through 1996 in California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania and the 2 metropolitan areas of Atlanta, Georgia, and Detroit, Michigan. PARTICIPANTS A total of 388 229 men and women aged 50 to 71 years from the National Institutes of Health-AARP Diet and Health Study. MAIN OUTCOME MEASURES Dietary and supplemental calcium intake was assessed at baseline ( 1995 - 1996 ). Supplemental calcium intake included calcium from multivitamins and individual calcium supplements. Cardiovascular disease deaths were ascertained using the National Death Index. Multivariate Cox proportional hazards regression models adjusted for demographic, lifestyle, and dietary variables were used to estimate relative risks ( RRs ) and 95 % CIs. RESULTS During a mean of 12 years of follow-up, 7904 and 3874 CVD deaths in men and women, respectively, were identified. Supplements containing calcium were used by 51 % of men and 70 % of women. In men, supplemental calcium intake was associated with an elevated risk of CVD death ( RR>1000 vs 0 mg/d, 1.20 ; 95 % CI, 1.05 - 1.36 ), more specifically with heart disease death ( RR, 1.19 ; 95 % CI, 1.03 - 1.37 ) but not significantly with cerebrovascular disease death ( RR, 1.14 ; 95 % CI, 0.81 - 1.61 ). In women, supplemental calcium intake was not associated with CVD death ( RR, 1.06 ; 95 % CI, 0.96 - 1.18 ), heart disease death ( 1.05 ; 0.93 - 1.18 ), or cerebrovascular disease death ( 1.08 ; 0.87 - 1.33 ). Dietary calcium intake was unrelated to CVD death in either men or women. CONCLUSIONS AND RELEVANCE Our findings suggest that high intake of supplemental calcium is associated with an excess risk of CVD death in men but not in women. Additional studies are needed to investigate the effect of supplemental calcium use beyond bone health Proteins, dietary acid load, and calcium and risk of postmenopausal fractures in the E3N French women prospective study. Excess dietary proteins and " acid ash " diets have been suspected to increase the risk of osteoporosis, but experimental and epidemiological evidence is mixed. We aim ed to determine whether the association between protein intake and the overall acid-base equilibrium of the diet ( as renal net acid excretion [ RNAE ] estimate ) and fracture risk vary according to calcium intake. During an average of 8.37 + /- 1.73 yr of follow-up, 2408 women reported a fracture ( excluding high-impact trauma ) among 36,217 postmenopausal women from the E3N prospect i ve study. We used Cox regression models to study the interaction between calcium and, respectively, proteins and RNAE, from the 1993 dietary question naire for fracture risk determination, adjusting for potential confounders. There was no overall association between fracture risk and total protein or RNAE. However, in the lowest quartile of calcium ( < 400 mg/1000 kcal ), high protein intake was associated with a significant increased fracture risk ( RR = 1.51 for highest versus lowest quartile ; 95 % CI, 1.17 - 1.94 ). An increasing fracture risk with increasing animal protein intake was also observed ( trend, p < 0.0001 ). A similar pattern of interaction for fracture risk was observed between RNAE and calcium. In this Western population of postmenopausal women with normal to high protein intake and fairly high calcium intake, there was no overall association between total protein or RNAE and fracture risk. However, there was some evidence that high protein-high acid ash diets were associated with an increased risk of fracture when calcium intake was low ( < 400 mg/1000 kcal ) Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care Abstract Objective To assess whether supplementation with calcium and cholecaliferol ( vitamin D3 ) reduces the risk of fracture in women with one or more risk factors for fracture of the hip. Design Pragmatic open r and omised controlled trial. Setting Practice nurse led clinics in primary care. Participants 3314 women aged 70 and over with one or more risk factors for hip fracture : any previous fracture, low body weight ( < 58 kg ), smoker, family history of hip fracture, or fair or poor self reported health. Intervention Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only ( control group ). Main outcome measures Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life ( measured with the SF-12 ). Results 69 % of the women who completed the follow-up question naire at 24 months were still taking supplements ( 55 % with inclusion of r and omised participants known to be alive ). After a median follow-up of 25 months ( range 18 to 42 months ), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures ( odds ratio for fracture in supplemented group 1.01, 95 % confidence interval 0.71 to 1.43 ). The odds ratio for hip fracture was 0.75 ( 0.31 to 1.78 ). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups. Conclusion We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration IS RCT N26118436, controlled trials registry Protective association of milk intake on the risk of hip fracture: results from the Framingham Original Cohort. Dairy foods are rich in bone-beneficial nutrients, yet the role of dairy foods in hip fracture prevention remains controversial. Our objective was to evaluate the association of milk, yogurt, cheese, cream, and milk + yogurt intakes with incident hip fracture in the Framingham Original Cohort. A total of 830 men and women from the Framingham Original Cohort, a prospect i ve cohort study, completed a food-frequency question naire ( 1988 to 1989 ) and were followed for hip fracture until 2008. In this population -based study, Cox-proportional hazards regression was used to estimate hazard ratios ( HR ) by categories of energy-adjusted dairy intake ( servings/wk ), adjusting for st and ard confounders and covariates. The exposure was energy-adjusted intakes of milk, yogurt, cheese, cream, and milk + yogurt ( servings/wk ). Risk of hip fracture over the follow-up was the primary outcome ; the hypothesis being tested was formulated after data collection. The mean age at baseline was 77 years ( SD 4.9, range 68 to 96 ). Ninety-seven hip fractures occurred over the mean follow-up time of 11.6 years ( range 0.04 to 21.9 years ). The mean ± SD ( servings/wk ) of dairy intakes at baseline were : milk = 6.0 ± 6.4 ; yogurt = 0.4 ± 1.3 ; cheese = 2.6 ± 3.1 ; and cream = 3.4 ± 5.5. Participants with medium ( > 1 and < 7 servings/wk ) or higher ( ≥7 servings/wk ) milk intake tended to have lower hip fracture risk than those with low ( ≤1 serving/wk ) intake ( high versus low intake HR 0.58, 95 % confidence interval [ CI ] 0.31 - 1.06, p = 0.078 ; medium versus low intake HR 0.61, 95 % CI 0.36 - 1.08, p = 0.071 ; p trend = 0.178 ]. There appeared to be a threshold for milk, with 40 % lower risk of hip fracture among those with medium/high milk intake compared with those with low intake ( p = 0.061 ). A similar threshold was observed for milk + yogurt intake ( p = 0.104 ). These associations were further attenuated after adjustment for femoral neck bone mineral density. No significant associations were seen for other dairy foods ( p range = 0.117 to 0.746 ). These results suggest that greater intakes of milk and milk + yogurt may lower risk for hip fracture in older adults through mechanisms that are partially, but not entirely, attributable to effects on bone mineral density Does increased sunlight exposure work as a strategy to improve vitamin D status in the elderly: a cluster randomised controlled trial Summary Sunlight exposure by improving vitamin D status could be a simple public health strategy in reducing falls among frail elder people. In a r and omised controlled trial, adherence to sunlight exposure was low ( median adherence, 26 % ) and no effect of increased UV exposure on falls risk was observed ( incidence rate ratio ( IRR ) 1.06, P = 0.73 ). Introduction This study aim ed to determine whether increased sunlight exposure was effective to improve vitamin D status and reduce falls in the elderly. Methods In a cluster r and omised controlled trial ( NCT00322166 at Clinical Trials.gov ), 602 residents aged 70 or more ( mean age, 86.4 years ; 71 % female ) were recruited from 51 aged care facilities in Northern Sydney, Australia. Participants were r and omised by facility to receive either increased sunlight exposure ( additional 30–40 min/day in the early morning ) with ( UV+ ) or without ( UV ) calcium supplementation ( 600 mg/day ) or neither ( control ) for a year. The co- primary endpoints were change in serum 25 hydroxy vitamin D ( 25OHD ) and falls incidence after 12 months. Results Adherence to sunlight exposure was low ( median adherence, 26 % ; IQR, 7%–45 % ). Serum 25OHD levels were low at baseline ( median, 32.9 nmol/L ) and increased only slightly depending on the number of sunlight sessions attended over 12 months ( P = 0.04 ). During the study, 327 falls occurred in 111 ( 54 % ) subjects in the control group, 326 falls in 111 ( 58 % ) subjects in the UV only group and 335 falls in 108 ( 52 % ) subjects in the UV+ group. By intention-to-treat analysis, there was no significant effect of increased UV exposure on falls risk ( IRR, 1.06 ; 95 % CI, 0.76–1.48 ; P = 0.73 ). However, in 66 participants who attended ≥130 sessions per year ( adherence, ≥50 % of 260 sessions – five per week ), falls were significantly reduced ( IRR, 0.52 ; 95 % CI, 0.31–0.88 ; P = 0.01 ) compared with the control group. Conclusions Increased sunlight exposure did not reduce vitamin D deficiency or falls risk in frail older people. This public health strategy was not effective most likely due to poor adherence to the intervention', "The paper refers to the recently published empirical data and systematic review s on the impact of diets, foods, nutrients and bioactive substance exposures in pregnancy and in early infancy, on the development of atopic disorders. Postnatal Fish Oil Supplementation in High-Risk Infants to Prevent Allergy: Randomized Controlled Trial BACKGROUND AND OBJECTIVE : Relative deficiency of dietary omega 3 polyunsaturated fatty acids ( n-3 PUFA ) has been implicated in the rising allergy prevalence in Westernized countries. Fish oil supplementation may provide an intervention strategy for primary allergy prevention. The objective of this study was to assess the effect of fish oil n-3 PUFA supplementation from birth to 6 months of age on infant allergic disease. METHODS : In a double-blind r and omized controlled trial, 420 infants at high atopic risk received a daily supplement of fish oil containing 280 mg docosahexaenoic acid and 110 mg eicosapentaenoic acid or a control ( olive oil ), from birth to age 6 months. PUFA levels were measured in 6-month-old infants ’ erythrocytes and plasma and their mothers ’ breast milk. Eczema, food allergy, asthma and sensitization were assessed in 323 infants for whom clinical follow-up was completed at 12 months of age. RESULTS : At 6 months of age, infant docosahexaenoic acid and eicosapentaenoic acid levels were significantly higher ( both P <.05 ) and erythrocyte arachidonic acid levels were lower ( P =.003 ) in the fish oil group. Although n-3 PUFA levels at 6 months were associated with lower risk of eczema ( P =.033 ) and recurrent wheeze ( P =.027 ), the association with eczema was not significant after multiple comparisons and there was no effect of the intervention per se on the primary study outcomes. Specifically, between-group comparisons revealed no differences in the occurrence of allergic outcomes including sensitization, eczema, asthma, or food allergy. CONCLUSIONS : Postnatal fish oil supplementation improved infant n-3 status but did not prevent childhood allergic disease Prenatal Vitamin D Supplementation and Child Respiratory Health: A Randomised Controlled Trial Background Observational studies suggest high prenatal vitamin D intake may be associated with reduced childhood wheezing. We examined the effect of prenatal vitamin D on childhood wheezing in an interventional study. Methods We r and omised 180 pregnant women at 27 weeks gestation to either no vitamin D, 800 IU ergocalciferol daily until delivery or single oral bolus of 200,000 IU cholecalciferol, in an ethnically stratified, r and omised controlled trial. Supplementation improved but did not optimise vitamin D status. Research ers blind to allocation assessed offspring at 3 years. Primary outcome was any history of wheeze assessed by vali date d question naire. Secondary outcomes included atopy, respiratory infection, impulse oscillometry and exhaled nitric oxide. Primary analyses used logistic and linear regression. Results We evaluated 158 of 180 ( 88 % ) offspring at age 3 years for the primary outcome. Atopy was assessed by skin test for 95 children ( 53 % ), serum IgE for 86 ( 48 % ), exhaled nitric oxide for 62 ( 34 % ) and impulse oscillometry of acceptable quality for 51 ( 28 % ). We found no difference between supplemented and control groups in risk of wheeze [ no vitamin D : 14/50 ( 28 % ) ; any vitamin D : 26/108 ( 24 % ) ( risk ratio 0.86 ; 95 % confidence interval 0.49, 1.50 ; P = 0.69 ) ]. There was no significant difference in atopy, eczema risk, lung function or exhaled nitric oxide between supplemented groups and controls. Conclusion Prenatal vitamin D supplementation in late pregnancy that had a modest effect on cord blood vitamin D level, was not associated with decreased wheezing in offspring at age three years. Trial Registration Controlled-Trials.com IS RCT Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child. BACKGROUND Some breastfed infants with atopic eczema benefit from elimination of cow milk, egg, or other antigens from their mother's diet. Maternal dietary antigens are also known to cross the placenta. OBJECTIVES To assess the effects of prescribing an antigen avoidance diet during pregnancy or lactation, or both, on maternal and infant nutrition and on the prevention or treatment of atopic disease in the child. SEARCH METHODS We search ed the Cochrane Pregnancy and Childbirth Group's Trials Register ( 6 July 2012 ). SELECTION CRITERIA All r and omized or quasi-r and omized comparisons of maternal dietary antigen avoidance prescribed to pregnant or lactating women. We excluded trials of multimodal interventions that included manipulation of the infant's diet other than breast milk or of non-dietary aspects of the infant's environment. DATA COLLECTION AND ANALYSIS We extracted data from published reports, supplemented by additional information received from the trialists we contacted. MAIN RESULTS The evidence from five trials, involving 952 participants, does not suggest a protective effect of maternal dietary antigen avoidance during pregnancy on the incidence of atopic eczema during the first 18 months of life. Data on allergic rhinitis or conjunctivitis, or both, and urticaria are limited to a single trial each and are insufficient to draw meaningful inferences. Longer-term atopic outcomes have not been reported. The restricted diet during pregnancy was associated with a slightly but statistically significantly lower mean gestational weight gain, a non-significantly higher risk of preterm birth, and a non-significant reduction in mean birthweight. The evidence from two trials, involving 523 participants, did not observe a significant protective effect of maternal antigen avoidance during lactation on the incidence of atopic eczema during the first 18 months or on positive skin-prick tests to cow milk, egg, or peanut antigen at one, two, or seven years. One crossover trial involving 17 lactating mothers of infants with established atopic eczema found that maternal dietary antigen avoidance was associated with a non-significant reduction in eczema severity. AUTHORS'CONCLUSIONS Prescription of an antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child's risk of atopic diseases, and such a diet may adversely affect maternal or fetal nutrition, or both. Prescription of an antigen avoidance diet to a high-risk woman during lactation may reduce her child's risk of developing atopic eczema, but better trials are needed. Dietary antigen avoidance by lactating mothers of infants with atopic eczema may reduce the severity of the eczema, but larger trials are needed Associations between Maternal Antioxidant Intakes in Pregnancy and Infant Allergic Outcomes Antioxidant intakes in pregnancy may influence fetal immune programming and the risk of allergic disease. We investigated associations between maternal intakes of β-carotene, vitamin C, vitamin E, copper and zinc, and infant allergic outcomes. Antioxidant intakes of pregnant women ( n = 420 ) assessed prospect ively by a food frequency question naire, were examined in relation to allergic outcomes at 1 year of age ( n = 300 ). The main relationships with allergic outcomes were seen with dietary vitamin C and copper. Specifically, higher maternal dietary vitamin C intake was associated with a reduced risk of any diagnosed infant allergic disease and wheeze. After adjustment for potential confounders the relationship with wheeze remained statistically significant. There was also an inverse linear relationship between vitamin C and food allergy. Higher dietary copper intake was associated with reduced risk of eczema, wheeze and any allergic disease. The relationship with wheeze and any allergic disease remained statistically significant in multivariate analysis, and there was also an inverse linear relationship between copper and food allergy. However, these relationships were only seen for nutrients present in food. There were no relationships between β-carotene, vitamin E or zinc and any allergic outcomes. In summary, this study suggests that maternal diet of fresh foods rich in vitamin C is associated with reduced risk of infant wheeze, and that copper intake is associated with reduced risk of several allergic outcomes Probiotics in the prevention of eczema: a randomised controlled trial Objective To evaluate a multistrain, high-dose probiotic in the prevention of eczema. Design A r and omised, double-blind, placebo-controlled, parallel group trial. Setting s Antenatal clinics, research clinic, children at home. Patients Pregnant women and their infants. Interventions Women from 36 weeks gestation and their infants to age 6 months received daily either the probiotic ( Lactobacillus salivarius CUL61, Lactobacillus paracasei CUL08, Bifidobacterium animalis subspecies lactis CUL34 and Bifidobacterium bifidum CUL20 ; total of 1010 organisms/day ) or matching placebo. Main outcome measure Diagnosed eczema at age 2 years. Infants were followed up by question naire. Clinical examination and skin prick tests to common allergens were done at 6 months and 2 years. Results The cumulative frequency of diagnosed eczema at 2 years was similar in the probiotic ( 73/214, 34.1 % ) and placebo arms ( 72/222, 32.4 % ; OR 1.07, 95 % CI 0.72 to 1.6 ). Among the secondary outcomes, the cumulative frequency of skin prick sensitivity at 2 years was reduced in the probiotic ( 18/171 ; 10.5 % ) compared with the placebo arm ( 32/173 ; 18.5 % ; OR 0.52, 95 % CI 0.28 to 0.98 ). The statistically significant differences between the arms were mainly in sensitisation to cow's milk and hen's egg proteins at 6 months. Atopic eczema occurred in 9/171 ( 5.3 % ) children in the probiotic arm and 21/173 ( 12.1 % ) in the placebo arm ( OR 0.40, 95 % CI 0.18 to 0.91 ). Conclusions The study did not provide evidence that the probiotic either prevented eczema during the study or reduced its severity. However, the probiotic seemed to prevent atopic sensitisation to common food allergens and so reduce the incidence of atopic eczema in early childhood. Trial registration Number IS RCT N26287422 Anti-infective proteins in breast milk and asthma-associated phenotypes during early childhood. BACKGROUND The impact of breast milk feeding on susceptibility to asthma in childhood is highly controversial, due in part to failure of the majority of studies in the area to adequately account for key confounders exemplified by respiratory infection history, plus the effects of recall bias. METHODS As part of a prospect i ve cohort study on the role of respiratory infections in asthma development in high-risk children, we measured the concentration of a panel of anti-infective proteins in maternal milk sample s and analyzed associations between these and subsequent atopy-, infection-, and asthma-related outcomes prospect ively to age 10 years. RESULTS We observed significant but transient inverse associations between the concentration of milk proteins and susceptibility to upper respiratory infections in year 1 only, and parallel but positive transient associations with early lower respiratory infections and atopy. No associations were seen with asthma-related outcomes. CONCLUSIONS Breast milk feeding may influence the expression of inflammatory symptoms associated with respiratory infections and atopy in early life, but these effects appear to be inconsistent and transient. The heterogeneous nature of breast-feeding effects suggests it may influence systemic immunoinflammatory function at several different levels Breast-feeding does not protect against allergic sensitization in early childhood and allergy-associated disease at age 7 years. BACKGROUND Extended breast-feeding is recommended for newborn children at risk of allergy-associated diseases, but the evidence of a protective effect on sensitization and these diseases remains elusive. OBJECTIVE The aim of this study was to investigate the effects of the duration of exclusive breast-feeding on the development of sensitization in preschool children. METHODS Information on breast-feeding was gathered by interviews involving 335 children aged 1, 6, and 12 months from the Copenhagen Prospect i ve Study on Asthma in Childhood2000 birth cohort born to mothers with a history of asthma. Skin prick test responses and specific IgE levels against 12 common inhalant and 10 food allergens were assessed longitudinally at ages ½ year, 1½ years, 4 years, and 6 years. Eczema, wheeze/asthma, and allergic rhinitis were diagnosed at the Copenhagen Prospect i ve Studies on Asthma in Childhood clinic at 7 years of age, strictly adhering to predefined algorithms. Associations between duration of exclusive breast-feeding and outcomes were analyzed by logistic regression. RESULTS We found no significant association between duration of exclusive breast-feeding and development of sensitization in the first 6 years of life ( odds ratio [ OR ] : ½ year, 1.10 [ 95 % CI, 0.90 - 1.36 ] ; 1½ years, 1.15 [ 95 % CI, 0.97 - 1.36 ] ; 4 years, 1.08 [ 95 % CI, 0.93 - 1.25 ] ; and 6 years, 0.96 [ 95 % CI, 0.84 - 1.10 ] ) or with current eczema, wheeze/asthma, and allergic rhinitis at age 7 years ( OR, 1.07 [ 95 % CI, 0.92 - 1.24 ] ; OR, 0.97 [ 95 % CI, 0.82 - 1.14 ] ; and OR, 1.02 [ 95 % CI, 0.84 - 1.23 ], respectively ). Adjusting for reverse causation by excluding children with eczema, wheeze, or a positive skin prick test response before ending exclusive breast-feeding did not alter the results. CONCLUSION Exclusive breast-feeding does not affect sensitization in early childhood or associated diseases at 7 years of age in at-risk children Early exposure to solid foods and the development of eczema in children up to 4 years of age. Early exposure to solid foods in infancy has been associated with the development of allergic diseases. However, scientific evidence for this is conflicting. The aim of this study was to examine the association between early exposure to solid foods in the infant's diet and the development of eczema up to 4 years of age. We conducted an etiologic case-control study nested in the PIPO cohort ( Prospect i ve Cohort on the Influence of Perinatal Factors on the Occurrence of Asthma and Allergies ). In this cohort data on nutrition, environmental exposures and parent-reported eczema were collected prospect ively starting from 5 months pregnancy by means of question naires administered during two home visits and semi-annual postal question naires. In addition, detailed information on the timing of introduction of solid foods at individual food item level was collected at 1 year of age. Adjusted odds ratios and 95 % confidence intervals were computed using logistic regression analysis as a measure of association between eczema and the timing of exposure to solid foods. Early introduction ( within the first 4 months ) of solid foods was inversely associated with eczema up to 4 years of age ( adj OR : 0.49 ; 95 % CI : 0.32 - 0.74 ). Moreover, we found that early exposure to solid foods was associated with a reduced risk for eczema only among children with allergic parents ( adj OR : 0.35 ; 95 % CI : 0.20 - 0.63 ), whereas no significant effect was found among children with non-allergic parents ( adj OR : 0.69 ; 95 % CI : 0.37 - 1.29 ). The results of this study show that early exposure to solid foods is associated with less parent-reported eczema in children, particularly among children with allergic parents. Therefore, the current study does not support a delayed introduction of solid foods for the prevention of eczema in childhood", "Resistance training ( RT ) is thought to be effective in preventing muscle depletion, whereas endurance training ( ET ) is known to improve exercise capacity and health-related quality of life ( HRQoL ) in chronic obstructive pulmonary disease ( COPD ). Our objectives were to assess the efficiency of combining RT with ET compared with ET alone. The effect of single set resistance training on strength and functional fitness in pulmonary rehabilitation patients. PURPOSE The primary goal of pulmonary rehabilitation ( PR ) is for patients to achieve and maintain their maximum level of independence and functioning in the community. Traditional PR uses a predominantly aerobic/endurance approach to rehabilitation with little or no inclusion of exercises to increase strength. Few studies have investigated the impact of resistance training on PR despite growing evidence supporting its efficacy to improve physical function ( functional fitness ) in both healthy individuals and those with chronic disease. The purpose of this study was to investigate the effect of single-set resistance training on strength and functional fitness outcomes in PR patients. METHODS Twenty PR patients, 60 to 81 years old, were r and omly assigned to an 8-week endurance-based PR program ( ET ) or an ET plus resistance training program ( RT ). RESULTS Strength increased in RT ( P <.05 ) and decreased in ET for both upper and lower body. Functional fitness improved ( P <.05 ) in 5 of 7 tests for RT compared with 2 tests for ET. CONCLUSIONS Single set RT can elicit significant improvements in both strength and functional fitness, which is not obtained by traditional PR alone. Our results are comparable to other studies with similar outcomes using multiple-set RT protocol s. These findings may have important implication s for program design, application, and adherence in PR The Effect of Strength Training on Functional Fitness in Older Patients with Chronic Lung Disease Enrolled in Pulmonary Rehabilitation & NA ; The purpose of this study was to compare the effects of a strength training‐enhanced program and a traditional pulmonary rehabilitation ( PR ) program on functional fitness ( FF ) in older patients with chronic obstructive pulmonary disease ( COPD ), using the Senior Fitness Test. Twenty patients were recruited from an outpatient PR program. After completing baseline measures, including muscular strength and the Senior Fitness Test, patients were r and omly assigned to the strength training program ( TR+ST, n = 10 ) or traditional PR program ( TR, n = 10 ). Patients completed 16 exercise sessions that were conducted twice a week for 8–10 weeks, after which patients repeated outcome measurements. Independent t tests were conducted to determine whether groups differed between measures. Both the TR+ST and TR groups improved on all FF measures. Moderate effect sizes were found for two of the FF measures when the groups were compared. The addition of strength training to PR may have a favorable impact on FF in older patients with COPD [Functional effects of different training in patients with COPD]. Disability and exertional dyspnea associated with chronic obstructive pulmonary disease has led to the development of rehabilitation programmes that aim to increase exercise tolerance and relief of dyspnea. To evaluate whether aerobic training ( training groups P1 and P4 ), strength training ( P2 and P5 ) or a combination of both ( P4 and P6 ) is useful, 69 patients ( 44 m/25 f ) with moderate to severe COPD were r and omised to a three week inpatient training program. The training consisted of three weekly twenty minute exercise sessions without ( P1 - P3 ) or with supplemental oxygen ( P4 - P6 ) on a calibrated ergocycle ( 70 % W(max ) ) or three weekly sessions of 20 - 25 repetitions of 2 - 4 training series ( 40 % W(max ) ) or a combination of both. In general, the programme failed to demonstrate significant changes in lung function and arterial blood gases. Evaluation of exercise capacity via the six-minute-walking test ( 6MT ) yielded a significant increase of the walking distance in all groups except P2 ( 60 - 83 m ), The time to finish a test-set of daily activities ( TAF ) was reduced in all groups ( 5 - 58 sec ) and reached significance in P1, P3, P5 and P6. After the 6MT, exertional dyspnea improved in all groups except P4 and was significant in P1 and P3 ; after the TAF, dyspnea again was reduced in all groups with a significant change in P2 and P5. These data support the hypotheses that a short term inpatient training programme is suitable to improve exercise-capacity and dyspnea. Patients with advanced disease ( P4 - P6 ) show greater benefits with strength training ( alone or in combination with aerobic training ) while for patients with moderate disease ( P1 - P3 ) aerobic training is favourable. These changes may translate into improved performance of daily activities and general well-being Aerobic and strength training in patients with chronic obstructive pulmonary disease. The purpose of this study was to evaluate whether strength training is a useful addition to aerobic training in patients with chronic obstructive pulmonary disease ( COPD ). Forty-five patients with moderate to severe COPD were r and omized to 12 wk of aerobic training alone ( AERO ) or combined with strength training ( AERO + ST ). The AERO regimen consisted of three weekly 30-min exercise sessions on a calibrated ergocycle, and the ST regimen included three series of eight to 10 repetitions of four weight lifting exercises. Measurements of peripheral muscle strength, thigh muscle cross-sectional area ( MCSA ) by computed tomographic scanning, maximal exercise capacity, 6-min walking distance ( 6MWD ), and quality of life with the chronic respiratory question naire were obtained at baseline and after training. Thirty-six patients completed the program and constituted the study group. The strength of the quadriceps femoris increased significantly in both groups ( p < 0.05 ), but the improvement was greater in the AERO + ST group ( 20 + /- 12 % versus 8 + /- 10 % [ mean + /- SD ] in the AERO group, p < 0.005 ). The thigh MCSA and strength of the pectoralis major muscle increased in the AERO + ST group by 8 + /- 13 % and 15 + /- 9 %, respectively ( p < 0.001 ), but not in the AERO group ( 3 + /- 6 % and 2 + /- 10 %, respectively, p > 0.05 ). These changes were significantly different in the two study groups ( p < 0.01 ). The increase in strength of the latissimus dorsi muscle after training was modest and of similar magnitude for both groups. The changes in peak exercise work rate, 6MWD, and quality of life were comparable in the two groups. In conclusion, the addition of strength training to aerobic training in patients with COPD is associated with significantly greater increases in muscle strength and mass, but does not provide additional improvement in exercise capacity or quality of life The effects of resistance training on functional outcomes in patients with chronic obstructive pulmonary disease Aerobic exercise training is used for rehabilitation in patients with chronic obstructive pulmonary disease ( COPD ), although it has little effect on muscle weakness and atrophy. Resistance training may be a useful addition to aerobic programs for these patients. The purpose of the present study was to investigate the effects of resistance training in addition to aerobic training on functional outcomes in patients with COPD. Seventeen COPD patients enrolled in an aerobic-based program that met twice a week were assigned to a 12-week control/aerobic [ CON : n=8 ; 63 ( 8) years ; mean ( SD ) ] or a resistance/aerobic group [ RES : n=9 ; 61 ( 7 ) years ]. RES trained an additional twice a week on 12 resistance machines, performing three sets of 8–12 repetitions at 32–64 % of their one-repetition maximum ( 1-RM ) lifts. RES ( P<0.05 ) increased upper ( 36 % ) and lower ( 36 % ) body strength, as well as lean body mass ( 5 % ), while CON showed little to no change. The 12-min walk distance increased ( P<0.05 ) in only the RES [ 676 ( 219 ) to 875 ( 172 ) m ]. Measurements of three of the eight tasks of activities of daily living improved in RES ( P<0.05 ) compared to CON. This study demonstrated that progressive resistance training was well tolerated and improved functional outcomes in COPD patients that were currently involved in an aerobic training program Upper extremity exercise training in chronic obstructive pulmonary disease. Many patients with chronic obstructive pulmonary disease ( COPD ) report greater limitation for activities involving the upper extremities than the lower extremities. Exercise training has generally emphasized lower-extremity exercise. We design ed and evaluated two simple, practical, and widely applicable upper-extremity training programs in 45 patients with COPD participating concurrently in a comprehensive, multidisciplinary pulmonary rehabilitation program. Patients were r and omly assigned to one of the following three groups : ( 1 ) gravity-resistance ( GR ) upper-extremity training ; ( 2 ) modified proprioceptive neuromuscular facilitation ( PNF ) upper-extremity training ; or ( 3 ) no upper-extremity training ( control ). Patients were evaluated before and after at least six weeks of uninterrupted training. Twenty-eight patients completed the study. Compared to controls, both GR and PNF patients demonstrated improved performance on tests specific to the training performed ( upper-extremity performance test, maximal level and endurance on isokinetic arm cycle ). There were no significant changes on isotonic arm cycle, ventilatory muscle endurance, or simulated activities of daily-living tests. Ratings of perceived breathlessness and fatigue decreased significantly in all groups for several tests. We conclude that specific upper-extremity training may be beneficial in the rehabilitation of patients with COPD and warrants further investigation Strength training increases maximum working capacity in patients with COPD--randomized clinical trial comparing three training modalities. BACKGROUND AND OBJECTIVE Skeletal muscle dysfunction contributes to exercise limitation in patients with chronic obstructive pulmonary disease ( COPD ). Strength training increases muscle strength and muscle mass, but there is an ongoing debate on the additional effect concerning the exercise capacity. The purpose of this study was to compare the effects of three different exercise modalities in patients with COPD including endurance training ( ET ), progressive strength training ( ST ) and the combination of strength training and endurance training ( CT ). DESIGN A prospect i ve r and omized trial. METHODS Thirty-six patients with COPD were r and omly allocated either to ET, ST, or CT. Muscle strength, cardiopulmonary exercise testing, lung function testing and quality of life were assessed before and after a 12-week training period. RESULTS Exercise capacity ( Wmax ) increased significantly in all three training groups with increase of peak oxygen uptake ( VO2peak ) in all three groups, reaching statistical significance in the ET group and the CT group. Muscle strength ( leg press, bench press, bench pull ) improved in all three training groups, with a higher improvement in the ST ( + 39.3 %, + 20.9 %, + 20.3 % ) and the CT group ( + 43.3 %, + 18.1 %, + 21.6 % ) compared to the ET group ( + 20.4 %, + 6.4 %, + 12.1 % ). CONCLUSIONS Progressive strength training alone increases not only muscle strength and quality of life, but also exercise capacity in patients with COPD, which may have implication s in prescription of training modality. CLINICAL TRIALS.GOV IDENTIFIER : NCT01091623 Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial BACKGROUND Pulmonary rehabilitation seems to be an effective intervention in patients with chronic obstructive pulmonary disease. We undertook a r and omised controlled trial to assess the effect of outpatient pulmonary rehabilitation on use of health care and patients'wellbeing over 1 year. METHODS 200 patients with disabling chronic lung disease ( the majority with chronic obstructive pulmonary disease ) were r and omly assigned a 6-week multidisciplinary rehabilitation programme ( 18 visits ) or st and ard medical management. Use of health services was assessed from hospital and general- practice records. Analysis was by intention to treat. FINDINGS There was no difference between the rehabilitation ( n=99 ) and control ( n=101 ) groups in the number of patients admitted to hospital ( 40 vs 41 ) but the number of days these patients spent in hospital differed significantly ( mean 10.4 [ SD 9.7 ] vs 21.0 [ 20.7 ], p=0.022 ). The rehabilitation group had more primary -care consultations at the general-practitioner's premises than did the control group ( 8.6 [ 6.8 ] vs 7.3 [ 8.3 ], p=0.033 ) but fewer primary -care home visits ( 1.5 [ 2.8 ] vs 2.8 [ 4.6 ], p=0.037 ). Compared with control, the rehabilitation group also showed greater improvements in walking ability and in general and disease-specific health status. INTERPRETATION For patients chronically disabled by obstructive pulmonary disease, an intensive, multidisciplinary, outpatient programme of rehabilitation is an effective intervention, in the short term and the long term, that decreases use of health services Effects of aerobic training and recreational activities in patients with chronic obstructive pulmonary disease The purpose of this study was to evaluate whether strength or recreational activities are a useful addition to aerobic training in patients with chronic obstructive pulmonary disease ( COPD ). Thirty-three patients with moderate to severe COPD were r and omly assigned to 12 weeks of aerobic combined with strength training ( AERO+ST ) or combined with recreational activities ( AERO+RA ). The AERO regimen consisted of three weekly 20-min walking exercise sessions ; the ST regimen included three series of 10 repetitions of four exercises ; and the RA regimen consisted of training using exercise balls to perform smoothly for instrumental activity of daily living. Baseline and after-training measurements of peripheral muscular strength and endurance, cardio respiratory fitness, and 6-min walking distance were obtained, whereas quality of life was assessed with the Short Form 36 question naire. Change in grip strength showed a significant difference between the AERO+ST group ( 8.3±6.7 % ) and the control group ( −1.3±10.5 % ), and AERO+RA group ( −4.7±5.6 % ) ( P<0.05 ). A significant increase was found in percentage change in peak & OV0312;o2 between the AERO+ST group ( 5.1±11.8 % ) and the control group ( −9.2±8.6 % ) ( P<0.05 ). In the health-related quality of life scores, there was a significant difference in mean percentage change in physical functioning between the AERO+ST group ( 7.9±24.4 % ) and the control group ( −14.8±19.1 % ) ( P<0.05 ). A significant difference was found in mean percentage change in social functioning between the AERO+RA group ( 9.4±20.0 % ) and the control group ( −14.9±23.2 % ) ( P<0.05 ). A significant difference in mean percentage change in mental health was also found between the AERO+RA group ( 12.2±12.4 % ) and the control group ( −5.0±7.8 % ) ( P<0.05 ). It is preferable to introduce various forms of exercise that use different muscles involving the whole body, such as recreational activities, as they are an appropriate approach to stimulating physical activity and to improving functional fitness gradually while improving health-related quality of life, though it is necessary to practice exercises for maintenance and improvement in patients with COPD. Die vorliegende Studie soll ermitteln, ob Krafttraining oder Freizeitaktivitäten das Aerobictraining von Patienten mit chronisch-obstruktiver Lungenerkrankung ( COPD ) sinnvoll ergänzen. Insgesamt wurden 33 Patienten mit moderater bis schlimmer COPD einem 12-wöchigen Aerobictraining mit Krafttraining ( AERO+ST ) oder einem 12-wöchigen Aerobictraining mit Freizeitaktivitäten ( AERO+RA ) r and omisiert zugeordnet. Das AERO-Programm umfasste drei 20-minütige Gehübungen pro Woche, das ST-Programm dreimal je 10 Wiederholungen mit vier Übungen und das RA-Programm ein Training mit Gymnastikbällen, die wichtige Aktivitäten i m Alltagsleben erleichtern sollten. Messungen wie periphere Muskelkraft und Ausdauer, kardiorespiratorische Fitness und 6-minütiges Gehen gegenüber Baseline und nach dem Training wurden erhalten, und die Lebensqualität wurde mittels Fragebogen SF-36 beurteilt. Veränderungen bei der Griffstärke wiesen einen signifikanten Unterschied zwischen der AERO+ST Gruppe ( 8,3±6,7 % ) und der Kontrollgruppe ( −1,3±10,5 % ) und der AERO+RA Gruppe ( −4,7±5,6 % ) auf ( P<0,05 ). Ebenfalls beobachtet wurde ein signifikanter Anstieg bei der prozentualen Veränderung von & OV0312;o2 maximal zwischen der AERO+ST Gruppe ( 5,1±11,8 % ) und der Kontrollgruppe ( −9,2±8,6 % ) ( P<0,05 ). Bei den gesundheitsbezogenen Lebensqualitäts-Scores best and ein signifikanter Unterschied in der durchschnittlichen prozentualen Veränderung bei der körperlichen Funktion zwischen der AERO+ST Gruppe ( 7,9±24,4 % ) und der Kontrollgruppe ( −14,8±19,1 % ) ( P<0,05 ). Ein signifikanter Unterschied wurde bei der durchschnittlichen prozentualen Veränderung bei der gesellschaftlichen Funktionsfähigkeit zwischen der AERO+RA Gruppe ( 9,4±20,0 % ) und der Kontrollgruppe ( −14,9±23,2 % ) beobachtet ( P<0,05 ). Außerdem beobachtet wurde ein signifikanter Unterschied in der durchschnittlichen prozentualen Veränderung in der seelischen Gesundheit zwischen der AERO+RA Gruppe ( 12,2±12,4 % ) und der Kontrollgruppe ( −5,0±7,8 % ) ( P<0,05 ). Verschiedene Übungsformen wie Freizeitaktivitäten, die verschiedene Körpermuskeln trainieren, sind als angemessener Stimulus der körperlichen Betätigung und zur allmählichen Verbesserung der funktionellen Fitness vorzuziehen, während sie gleichzeitig die gesundheitsrelevante Lebensqualität verbessern, obwohl Übungen zur Erhaltung und Verbesserung von Patienten mit COPD notwendig sind. El objetivo de este estudio fue evaluar si los ejercicios de desarrollo de fuerza o las actividades recreativas result an de utilidad, además de los ejercicios aeróbicos, en pacientes afectos de enfermedad pulmonar obstructiva crónica ( EPOC ). Se distribuyeron de manera aleatoria a 33 pacientes afectos de EPOC de moderada a grave para participar en un programa de 12 semanas de ejercicios aeróbicos combinados ya fuese con ejercicios de desarrollo", "Objective : We undertook a meta- analysis of published R and omized Controlled Trials ( RCT ) with semi-active control and sham-NF groups to determine whether Electroencephalogram-neurofeedback ( EEG-NF ) significantly improves the overall symptoms, inattention and hyperactivity/impulsivity dimensions for probably unblinded assessment ( parent assessment ) and probably blinded assessment ( teacher assessment ) in children with Attention Deficit Hyperactivity Disorder ( ADHD ). ADHD and EEG-neurofeedback: a double-blind randomized placebo-controlled feasibility study Electroencephalography (EEG)-neurofeedback has been shown to offer therapeutic benefits to patients with attention-deficit/hyperactivity disorder ( ADHD ) in several, mostly uncontrolled studies. This pilot study is design ed to test the feasibility and safety of using a double-blind placebo feedback-controlled design and to explore the initial efficacy of individualized EEG-neurofeedback training in children with ADHD. Fourteen children ( 8–15 years ) with ADHD defined according to the DSM-IV-TR criteria were r and omly allocated to 30 sessions of EEG-neurofeedback ( n = 8) or placebo feedback ( n = 6 ). Safety measures ( adverse events and sleep problems ), ADHD symptoms and global improvement were monitored. With respect to feasibility, all children completed the study and attended all study visits and training sessions. No significant adverse effects or sleep problems were reported. Regarding the expectancy, 75 % of children and their parent(s ) in the active neurofeedback group and 50 % of children and their parent(s ) in the placebo feedback group thought they received placebo feedback training. Analyses revealed significant improvements of ADHD symptoms over time, but changes were similar for both groups. This pilot study shows that it is feasible to conduct a rigorous placebo-controlled trial to investigate the efficacy of neurofeedback training in children with ADHD. However, a double-blind design may not be feasible since using automatic adjusted reward thresholds may not work as effective as manually adjusted reward thresholds. Additionally, implementation of active learning strategies may be an important factor for the efficacy of EEG-neurofeedback training. Based on the results of this pilot study, changes are made in the design of the ongoing study Neurofeedback in ADHD: a single-blind randomized controlled trial Neurofeedback treatment has been demonstrated to reduce inattention, impulsivity and hyperactivity in children with attention deficit/hyperactivity disorder ( ADHD ). However, previous studies did not adequately control confounding variables or did not employ a r and omized reinforcer-controlled design. This study addresses those method ological shortcomings by comparing the effects of the following two matched biofeedback training variants on the primary symptoms of ADHD : EEG neurofeedback ( NF ) aim ing at theta/beta ratio reduction and EMG biofeedback ( BF ) aim ing at forehead muscle relaxation. Thirty-five children with ADHD ( 26 boys, 9 girls ; 6–14 years old ) were r and omly assigned to either the therapy group ( NF ; n = 18 ) or the control group ( BF ; n = 17 ). Treatment for both groups consisted of 30 sessions. Pre- and post-treatment assessment consisted of psychophysiological measures, behavioural rating scales completed by parents and teachers, as well as psychometric measures. Training effectively reduced theta/beta ratios and EMG levels in the NF and BF groups, respectively. Parents reported significant reductions in primary ADHD symptoms, and inattention improvements in the NF group were higher compared to the control intervention ( BF, dcorr = −.94 ). NF training also improved attention and reaction times on the psychometric measures. The results indicate that NF effectively reduced inattention symptoms on parent rating scales and reaction time in neuropsychological tests. However, regarding hyperactivity and impulsivity symptoms, the results imply that non-specific factors, such as behavioural contingencies, self-efficacy, structured learning environment and feed-forward processes, may also contribute to the positive behavioural effects induced by neurofeedback training EEG Neurofeedback for ADHD Objective : Preparing for a definitive r and omized clinical trial ( RCT ) of neurofeedback ( NF ) for ADHD, this pilot trial explored feasibility of a double-blind, sham-controlled design and adherence/palatability/relative effect of two versus three treatments/week. Method : Unmedicated 6- to 12-year-olds with Diagnostic and Statistical Manual of Mental Disorders ( 4th ed. ; DSM-IV ) ADHD were r and omized to active NF versus sham-NF and to 2X versus 3X/week treatment frequency. Frequency switch was allowed after Treatment 24. Results : In two school years, 39 participants were recruited and 34 ( 87 % ) completed all 40 treatments. Child/parent guesses about assigned treatment were no better than chance. At Treatment 24, 38 % chose 2X/week and 62 % chose 3X/week. Both active NF and sham yielded large pre – post improvement on parent ratings but NF no more than sham. Conclusion : Blinding appears to work, and sham does not prevent recruitment/retention. Treatment frequency of 3X/week seems preferred over 2X/week and was as effective. A large double-blind RCT is feasible and necessary to test specific NF effectiveness In-School Neurofeedback Training for ADHD: Sustained Improvements From a Randomized Control Trial OBJECTIVE : To evaluate sustained improvements 6 months after a 40-session, in-school computer attention training intervention using neurofeedback or cognitive training ( CT ) administered to 7- to 11-year-olds with attention-deficit/hyperactivity disorder ( ADHD ). METHODS : One hundred four children were r and omly assigned to receive neurofeedback, CT, or a control condition and were evaluated 6 months postintervention. A 3-point growth model assessed change over time across the conditions on the Conners 3–Parent Assessment Report ( Conners 3-P ), the Behavior Rating Inventory of Executive Function Parent Form ( BRIEF ), and a systematic double-blinded classroom observation ( Behavioral Observation of Students in Schools ). Analysis of variance assessed community-initiated changes in stimulant medication. RESULTS : Parent response rates were 90 % at the 6-month follow-up. Six months postintervention, neurofeedback participants maintained significant gains on Conners 3-P ( Inattention effect size [ ES ] = 0.34, Executive Functioning ES = 0.25, Hyperactivity/Impulsivity ES = 0.23 ) and BRIEF subscales including the Global Executive Composite ( ES = 0.31 ), which remained significantly greater than gains found among children in CT and control conditions. Children in the CT condition showed delayed improvement over immediate postintervention ratings only on Conners 3-P Executive Functioning ( ES = 0.18 ) and 2 BRIEF subscales. At the 6-month follow-up, neurofeedback participants maintained the same stimulant medication dosage, whereas participants in both CT and control conditions showed statistically and clinical ly significant increases ( 9 mg [ P =.002 ] and 13 mg [ P <.001 ], respectively ). CONCLUSIONS : Neurofeedback participants made more prompt and greater improvements in ADHD symptoms, which were sustained at the 6-month follow-up, than did CT participants or those in the control group. This finding suggests that neurofeedback is a promising attention training treatment for children with ADHD A Proposed Multisite Double-Blind Randomized Clinical Trial of Neurofeedback for ADHD Objective : Additional treatments with persisting benefit are needed for ADHD. Because ADHD often shows excessive theta electroencephalogram ( EEG ) power, low beta, and excessive theta-beta ratio ( TBR ), a promising treatment is neurofeedback ( NF ) downtraining TBR. Although several nonblind r and omized clinical trials ( RCTs ) show a medium-large benefit for NF, a well-blinded, sham-controlled RCT is needed to differentiate specific from nonspecific effects. Method : Experts in NF, ADHD, clinical trials, and statistics collaborated to design a double-blind multisite RCT. Results / Conclusion : At four sites, 180 children aged 7 to 10 years with rigorously diagnosed ADHD and TBR ≥ 5 will be r and omized to active TBR-NF versus sham NF of equal duration, intensity, and appearance. Sham, utilizing prerecorded EEGs with participant artifacts superimposed, will keep participants and staff blind. Treatment fidelity will be trained/monitored by acknowledged NF leaders. Multidomain assessment s before, during, and after treatment ( follow-up to 2 years ) will also include tests of blinding and sham inertness Neurofeedback and Cognitive Attention Training for Children with Attention-Deficit Hyperactivity Disorder in Schools Objective : To evaluate the efficacy of 2 computer attention training systems administered in school for children with attention-deficit hyperactivity disorder ( ADHD ). Method : Children in second and fourth grade with a diagnosis of ADHD ( n = 104 ) were r and omly assigned to neurofeedback ( NF ) ( n = 34 ), cognitive training ( CT ) ( n = 34 ), or control ( n = 36 ) conditions. A 2-point growth model assessed change from pre-post intervention on parent reports ( Conners 3-Parent [ Conners 3-P ] ; Behavior Rating Inventory of Executive Function [ BRIEF ] rating scale ), teacher reports ( Swanson, Kotkin, Agler, M-Flynn and Pelham scale [ SKAMP ] ; Conners 3-Teacher [ Conners 3-T ] ), and systematic classroom observations ( Behavioral Observation of Students in Schools [ BOSS ] ). Paired t tests and an analysis of covariance assessed change in medication. Results : Children who received NF showed significant improvement compared with those in the control condition on the Conners 3-P Attention, Executive Functioning and Global Index, on all BRIEF summary indices, and on BOSS motor/verbal off-task behavior. Children who received CT showed no improvement compared to the control condition. Children in the NF condition showed significant improvements compared to those in the CT condition on Conners 3-P Executive Functioning, all BRIEF summary indices, SKAMP Attention, and Conners 3-T Inattention subscales. Stimulant medication dosage in methylpheni date equivalencies significantly increased for children in the CT ( 8.54 mg ) and control ( 7.05 mg ) conditions but not for those in the NF condition ( 0.29 mg ). Conclusion : Neurofeedback made greater improvements in ADHD symptoms compared to both the control and CT conditions. Thus, NF is a promising attention training treatment intervention for children with ADHD What future research should bring to help resolving the debate about the efficacy of EEG-neurofeedback in children with ADHD In recent years a rising amount of r and omized controlled trials, review s, and meta-analyses relating to the efficacy of electroencephalographic-neurofeedback ( EEG-NF ) in children with attention-deficit/hyperactivity disorder ( ADHD ) have been published. Although clinical reports and open treatment studies suggest EEG-NF to be effective, double blind placebo-controlled studies as well as a rigorous meta- analysis failed to find support for the efficacy of EEG-NF. Since absence of evidence does not equate with evidence of absence, we will outline how future research might overcome the present method ological limitations. To provide conclusive evidence for the presence or absence of the efficacy of EEG-NF in the treatment of ADHD, there is a need to set up a well- design ed study that ensures optimal implementation and embedding of the training, and possibly incorporates different forms of neurofeedback Is neurofeedback an efficacious treatment for ADHD? A randomised controlled clinical trial. BACKGROUND For children with attention deficit/hyperactivity disorder ( ADHD ), a reduction of inattention, impulsivity and hyperactivity by neurofeedback ( NF ) has been reported in several studies. But so far, unspecific training effects have not been adequately controlled for and /or studies do not provide sufficient statistical power. To overcome these method ological shortcomings we evaluated the clinical efficacy of neurofeedback in children with ADHD in a multisite r and omised controlled study using a computerised attention skills training as a control condition. METHODS 102 children with ADHD, aged 8 to 12 years, participated in the study. Children performed either 36 sessions of NF training or a computerised attention skills training within two blocks of about four weeks each ( r and omised group assignment ). The combined NF treatment consisted of one block of theta/beta training and one block of slow cortical potential ( SCP ) training. Pre-training, intermediate and post-training assessment encompassed several behaviour rating scales ( e.g., the German ADHD rating scale, FBB-HKS ) completed by parents and teachers. Evaluation ('placebo') scales were applied to control for parental expectations and satisfaction with the treatment. RESULTS For parent and teacher ratings, improvements in the NF group were superior to those of the control group. For the parent-rated FBB-HKS total score ( primary outcome measure ), the effect size was.60. Comparable effects were obtained for the two NF protocol s ( theta/beta training, SCP training ). Parental attitude towards the treatment did not differ between NF and control group. CONCLUSIONS Superiority of the combined NF training indicates clinical efficacy of NF in children with ADHD. Future studies should further address the specificity of effects and how to optimise the benefit of NF as treatment module for ADHD Neurofeedback for the treatment of children and adolescents with ADHD: a randomized and controlled clinical trial using parental reports Background A r and omized and controlled clinical study was performed to evaluate the use of neurofeedback ( NF ) to treat attention-deficit/hyperactivity disorder ( ADHD ) in children and adolescents. Methods The ADHD population was selected from an outpatient clinic for Child and Adolescent Mental Health in Norway. Ninety-one of the 275 children and adolescents ranging in age from 6 to 18 years ( 10.5 years ) participated in 30 sessions of an intensive NF program. The reinforcement contingency was based on the subjects ’ production of cortical beta1 activity ( 15–18 Hz ). The ADHD participants were r and omized into three groups, with 30 in the NF group, 31 controls in a group that was given methylpheni date, and 30 in a group that received NF and methylpheni date. ADHD core symptoms were reported by parents using the parent form of the Clinician ’s Manual for Assessment by Russell A. Barkley. Results Ninety-one children and adolescents were effectively r and omized by age, sex, intelligence and distribution of ADHD core symptoms. The parents reported significant effects of the treatments, but no significant differences between the treatment groups were observed. Conclusions NF was as effective as methylpheni date at treating the attentional and hyperactivity symptoms of ADHD, based on parental reports. Trial registration Current Controlled Trials Effects of neurofeedback versus stimulant medication in attention-deficit/hyperactivity disorder: a randomized pilot study. OBJECTIVE The purpose of this pilot study was to compare the effects of 30 sessions of neurofeedback ( NF ) with stimulant medication on attention-deficit/hyperactivity disorder ( ADHD ) patients. METHODS Thirty-two medication-naïve ADHD patients, ages 7 - 16, from a neuropsychiatric clinic, were r and omized to NF ( n=16 ) or drug treatment ( n=16 ). Other actions, such as parent management training, information, or support in school were given as needed, with no differences between the groups. All participants were assessed before treatment on two rating scales, each with parent and teacher forms. In addition, quantitative electroencephalogram ( QEEG ) and event-related potentials ( ERPs ), which included behavioral data from a go/no go test were administered. NF training took place in the clinic over a period of 7 - 11 months, and was followed by a repeat of the same assessment tools. The mean time interval between pre- and postassesment was not significantly different in the two groups. The 18 symptoms of ADHD ( American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. ( DSM-IV ) ) were used as the primary outcome measure. RESULTS Analysis of covariance revealed a significant difference between the groups at evaluation in favor of medication, with a large effect size. This picture was confirmed by other outcome measures. The QEEG spectral power in the theta and beta b and s did not change in either group. In ERP, the P3 no go component increased significantly in 8 of 12 patients who had a clinical ly relevant medication effect, but did not increase in the medication nonresponders or the NF group. CONCLUSIONS Our study supports effects for stimulants, but not for NF. Effects of NF may require thorough patient selection, frequent training sessions, a system for excluding nonresponders, and active transfer training. The P3 no go ERP component may be a marker for treatment response Low P-Values or Narrow Confidence Intervals: Which Are More Durable? What should be the role of P-values and confidence intervals in the interpretation of scientific results? This question is not new 1 and our field of epidemiology is far from alone in struggling with it. 2,3 I have four suggestions for authors and readers. The first is quite broad, so I offer that one before describing current practice s. I then turn to the other three. My remarks are confined to setting s in which P-values and confidence intervals accompany estimates of effect measures, such as the relative risk. Briefly, here are my suggestions. One, we should work harder than ever to avoid strict or exact interpretations of P-values and confidence intervals in observational research, where these statistics lack a theoretical basis. Two, we should stop interpreting P-values and confidence intervals as though they measure the probability of hypotheses. Three, when we want to know the probability of hypotheses, we should use Bayesian methods, which are design ed expressly for that purpose. Four, we should get serious about precision and look for narrow confidence intervals instead of low P-values to identify results that are least influenced by r and om error A randomized placebo-controlled trial of electroencephalographic (EEG) neurofeedback in children with attention-deficit/hyperactivity disorder. OBJECTIVE A double-blind, r and omized, placebo-controlled study was design ed to assess the efficacy and safety of electroencephalographic ( EEG ) neurofeedback in children with attention-deficit/hyperactivity disorder ( ADHD ). The study started in August 2008 and ended in July 2012 and was conducted at Karakter Child and Adolescent Psychiatry University Centre in Nijmegen, The Netherl and s. METHOD Forty-one children ( aged 8 - 15 years ) with a DSM-IV-TR diagnosis of ADHD were r and omly assigned to treatment with either EEG neurofeedback ( n = 22 ) or placebo neurofeedback ( n = 19 ) for 30 sessions, given as 2 sessions per week. The children were stratified by age, electrophysiologic state of arousal, and medication use. Everyone involved in the study, except the neurofeedback therapist and the principal investigator, was blinded to treatment assignment. The primary outcome was severity of ADHD symptoms on the ADHD Rating Scale IV, scored at baseline, during treatment, and at study end. Clinical improvement as measured by the Clinical Global Impressions-Improvement scale ( CGI-I ) was a secondary outcome. RESULTS While total ADHD symptoms improved over time in both groups ( F1,39 = 26.56, P <.001 ), there was no significant treatment effect, ie, group × time interaction ( F1,39 = 0.36, P =.554 ) ; the same was true for clinical improvement as measured by the CGI-I ( P =.092 ). No clinical ly relevant side effects were observed. Among the children and their parents, guessing treatment assignment was not better than chance level ( P =.224 for children, P =.643 for parents ). CONCLUSION EEG neurofeedback was not superior to placebo neurofeedback in improving ADHD symptoms in children with ADHD. TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00723684 Reprint of “Neurofeedback and standard pharmacological intervention in ADHD: A randomized controlled trial with six-month follow-up” The present study is a r and omized controlled trial that aims to evaluate the efficacy of Neurofeedback compared to st and ard pharmacological intervention in the treatment of attention deficit/hyperactivity disorder ( ADHD ). The final sample consisted of 23 children with ADHD ( 11 boys and 12 girls, 7 - 14 years old ). Participants carried out 40 theta/beta training sessions or received methylpheni date. Behavioral rating scales were completed by fathers, mothers, and teachers at pre-, post-treatment, two-, and six-month naturalistic follow-up. In both groups, similar significant reductions were reported in ADHD functional impairment by parents ; and in primary ADHD symptoms by parents and teachers. However, significant academic performance improvements were only detected in the Neurofeedback group. Our findings provide new evidence for the efficacy of Neurofeedback, and contribute to enlarge the range of non-pharmacological ADHD intervention choices. To our knowledge, this is the first r and omized controlled trial with a six-month follow-up that compares Neurofeedback and stimulant medication in ADHD A randomised controlled trial of combined EEG feedback and methylphenidate therapy for the treatment of ADHD. PURPOSE To evaluate the efficacy of combined methylpheni date and EEG feedback treatment for children with ADHD. METHODS Forty patients with ADHD were r and omly assigned to the combination group ( methylpheni date therapy and EEG feedback training ) or control group ( methylpheni date therapy and non-feedback attention training ) in a 1:1 ratio using the double-blind method. These patients, who met the DSM-IV diagnostic criteria and were aged between 7 and 16 years, had obtained optimal therapeutic effects by titrating the methylpheni date dose prior to the trial. The patients were assessed using multiple parameters at baseline, after 20 treatment sessions, after 40 treatment sessions, and in 6-month follow-up studies. RESULTS Compared to the control group, patients in the combination group had reduced ADHD symptoms and improved in related behavioural and brain functions. CONCLUSION The combination of EEG feedback and methylpheni date treatment is more effective than methylpheni date alone. The combined therapy is especially suitable for children and adolescents with ADHD who insufficiently respond to single drug treatment or experience drug side effects Neurocognitive effects of neurofeedback in adolescents with ADHD: a randomized controlled trial. OBJECTIVE Neurofeedback aims to reduce symptoms of attention-deficit/hyperactivity disorder ( ADHD ), mainly attention problems. However, the additional influence of neurofeedback over treatment as usual ( TAU ) on neurocognitive functioning for adolescents with ADHD remains unclear. METHOD By using a multicenter parallel r and omized controlled trial ( RCT ) design, male adolescents with a DSM-IV-TR diagnosis of ADHD ( mean age = 16.1 years ; range, 12 - 24 ) were r and omized to receive either a combination of TAU and neurofeedback ( n = 45 ) or TAU ( n = 26 ). R and omization was computer generated and stratified by age group ( ages 12 through 15, 16 through 20, and 21 through 24 years ). The neurofeedback intervention consisted of approximately 37 sessions over a period of 25 weeks of theta/sensorimotor rhythm training on the vertex ( Cz ). Primary neurocognitive outcomes included performance parameters derived from the D2 Test of Attention, the Digit Span backward, the Stroop Color-Word Test and the Tower of London, all assessed preintervention and postintervention. Data were collected between December 2009 and July 2012. RESULTS At postintervention, outcomes of attention and /or motor speed were improved, with faster processing times for both intervention conditions and with medium to large effect sizes ( range, ηp2 =.08-.54 ; P values <.023 ). In both groups, no improvements for higher executive functions were observed. Results might partly resemble practice effects. CONCLUSIONS Although neurocognitive outcomes improved in all adolescents receiving treatment for ADHD, no additional value for neurofeedback over TAU was observed. Hence, this study does not provide evidence for using theta/sensorimotor rhythm neurofeedback to enhance neurocognitive performance as additional intervention to TAU for adolescents with ADHD symptoms. TRIAL REGISTRATION Trialregister.nl identifier : 1759 Does EEG-neurofeedback improve neurocognitive functioning in children with attention-deficit/hyperactivity disorder? A systematic review and a double-blind placebo-controlled study. BACKGROUND The number of placebo-controlled r and omized studies relating to EEG-neurofeedback and its effect on neurocognition in attention-deficient/hyperactivity disorder ( ADHD ) is limited. For this reason, a double blind, r and omized, placebo-controlled study was design ed to assess the effects of EEG-neurofeedback on neurocognitive functioning in children with ADHD, and a systematic review on this topic was performed. METHODS Forty-one children ( 8 - 15 years ) with a DSM-IV-TR diagnosis of ADHD were r and omly allocated to EEG-neurofeedback or placebo-neurofeedback treatment for 30 sessions, twice a week. Children were stratified by age, electrophysiological state of arousal, and medication use. Neurocognitive tests of attention, executive functioning, working memory, and time processing were administered before and after treatment. Research ers, teachers, children and their parents, with the exception of the neurofeedback-therapist, were all blind to treatment assignment. Outcome measures were the changes in neurocognitive performance before and after treatment. CLINICAL TRIAL REGISTRATION www. clinical trials.gov : NCT00723684. RESULTS No significant treatment effect on any of the neurocognitive variables was found. A systematic review of the current literature also did not find any systematic beneficial effect of EEG-neurofeedback on neurocognitive functioning. CONCLUSION Overall, the existing literature and this study fail to support any benefit of neurofeedback on neurocognitive functioning in ADHD, possibly due to small sample sizes and other study limitations Distinct EEG effects related to neurofeedback training in children with ADHD: a randomized controlled trial. In a r and omized controlled trial, neurofeedback ( NF ) training was found to be superior to a computerised attention skills training concerning the reduction of ADHD symptomatology ( Gevensleben et al., 2009 ). The aims of this investigation were to assess the impact of different NF protocol s ( theta/beta training and training of slow cortical potentials, SCPs ) on the resting EEG and the association between distinct EEG measures and behavioral improvements. In 72 ( of initially 102 ) children with ADHD, aged 8 - 12, EEG changes after either a NF training ( n=46 ) or the control training ( n=26 ) could be studied. The combined NF training consisted of one block of theta/beta training and one block of SCP training, each block comprising 18 units of 50 minutes ( balanced order ). Spontaneous EEG was recorded in a two-minute resting condition before the start of the training, between the two training blocks and after the end of the training. Activity in the different EEG frequency b and s was analyzed. In contrast to the control condition, the combined NF training was accompanied by a reduction of theta activity. Protocol -specific EEG changes ( theta/beta training : decrease of posterior-midline theta activity ; SCP training : increase of central -midline alpha activity ) were associated with improvements in the German ADHD rating scale. Related EEG-based predictors were obtained. Thus, differential EEG patterns for theta/beta and SCP training provide further evidence that distinct neuronal mechanisms may contribute to similar behavioral improvements in children with ADHD Computer-Based Attention Training in the Schools for Children With Attention Deficit/Hyperactivity Disorder: A Preliminary Trial Objective. This study examined the efficacy of 2 computer-based training systems to teach children with attention deficit/hyperactivity disorder ( ADHD ) to attend more effectively. Design / methods. A total of 41 children with ADHD from 2 middle schools were r and omly assigned to receive 2 sessions a week at school of either neurofeedback ( NF ) or attention training through a st and ard computer format ( SCF ), either immediately or after a 6-month wait ( waitlist control group ). Parents, children, and teachers completed question naires pre- and postintervention. Results. Primary parents in the NF condition reported significant ( P <.05 ) change on Conners ’s Rating Scales — Revised ( CRS-R ) and Behavior Assessment Scales for Children ( BASC ) subscales ; and in the SCF condition, they reported significant ( P <.05 ) change on the CRS-R Inattention scale and ADHD index, the BASC Attention Problems Scale, and on the Behavioral Rating Inventory of Executive Functioning ( BRIEF ). Conclusion. This r and omized control trial provides preliminary evidence of the effectiveness of computer-based interventions for ADHD and supports the feasibility of offering them in a school setting EEG correlates of methylphenidate response among children with ADHD: a preliminary report BACKGROUND Recent electrophysiologic studies have found fairly consistent differences between children with attention-deficit/hyperactivity disorder ( ADHD ) and age-matched control subjects. The present study examined electroencephalogram ( EEG ) changes associated with a double blind, placebo-controlled administration of methylpheni date among children with ADHD. METHODS Subjects were 10 children, ages 8 to 13, with a primary diagnosis of ADHD. Brain electrical activity was recorded with 7 electrodes in the frontal, central, and midline areas during baseline and cognitive activation conditions. RESULTS Repeated- measures ANOVAs indicate that children exhibiting a positive medication response had reductions of theta and alpha as well as increased beta in the frontal regions, while nonresponders showed the opposite pattern ( p <.05 ). Significant correlations between improvement on a vigilance task and changes in beta activity in the frontal electrodes emerged as well. CONCLUSIONS These preliminary findings indicate that there are different electrophysiologic correlates to methylpheni date among ADHD children who are medication responders and nonresponders", "Purpose No study has summarized earlier findings on the effect of probiotic supplementation on inflammatory biomarkers. This systematic review and meta- analysis was conducted to systematic ally review the available placebo-controlled clinical trials about the effect of probiotic supplementation on several inflammatory biomarkers in adults. Effects of Probiotic and Prebiotic Supplementation on Leptin, Adiponectin, and Glycemic Parameters in Non-alcoholic Fatty Liver Disease: A Randomized Clinical Trial BACKGROUND According to previous studies, probiotic and prebiotic supplementation have desirable effects on glycemic parameters. Thus far, the effect of supplementation on the glycemic parameters and adipokines in non-alcoholic fatty liver disease ( NAFLD ) has not been assessed. Therefore, the aim of this study was to determine the effects of supplementation with probiotic and prebiotic on adiokines and glycemic parameters in the patients with NAFLD. METHODS In the present r and omized, double-blind, placebo-controlled trial, 89 patients with NAFLD were r and omly divided into three groups to receive one probiotic capsule + 16 g/d maltodextrin ( probiotic group ) or 16 g/d oligofructose powder + one placebo capsule ( prebiotic group ), and one placebo capsule + 16 g/d maltodextrin ( control group ) for 12 weeks. All the subjects in the study were advised to follow the weight loss diet and physical activity recommendations during the intervention. Fasting blood sample s were taken at baseline and after the intervention to measure leptin, adiponectin, insulin, and fasting blood sugar. RESULTS At the end of the study, serum concentrations of leptin, insulin, and HOMA-IR decreased significantly in the probiotic and prebiotic groups compared with the control group. Despite the changes within the groups, serum concentrations of adiponectin did not change significantly between the three groups. Also, fasting blood sugar did not change between the groups, but decreased in the prebiotic group. Quantitative insulin-sensitivity check index ( QUICKI ) increased significantly in probiotic and prebiotic groups compared with the control group. CONCLUSION Probiotic and prebiotic supplementation along with lifestyle intervention has a favorable impact on glycemic parameters and leptin levels compared with lifestyle intervention alone Effects of probiotic therapy in critically ill patients: a randomized, double-blind, placebo-controlled trial. BACKGROUND Multiple organ dysfunction syndrome ( MODS ) is a major cause of mortality in intensive care units. A breakdown in gut barrier function and immune dysfunction are associated with the onset of MODS. Probiotic bacteria have been shown to modulate intestinal barrier and immune function. OBJECTIVE This study assessed the efficacy of a probiotic compound in a viable and nonviable formulation in modulating intestinal permeability and immune function and preventing the onset of MODS in patients in the intensive care unit. DESIGN A double-blind, r and omized controlled trial was conducted in the intensive care unit of a tertiary care teaching hospital. Twenty-eight critically ill patients admitted to the intensive care unit were r and omly assigned to receive 1 of 3 treatments daily for 7 d : 1 ) placebo, 2 ) viable probiotics, or 3 ) equivalent probiotic sonicates. MODS scores and systemic concentrations of immunoglobulin ( Ig ) A and IgG were measured on days -1, 4, and 7, and intestinal permeability measurements were taken daily. RESULTS The patients responded to viable probiotics with a significantly larger increase in systemic IgA and IgG concentrations than in the patients who received placebo or sonicates ( P < 0.05 ). MODS scores were not significantly affected by probiotic treatment. Over the study period, intestinal permeability decreased in most patients. CONCLUSION Patients receiving viable probiotics show a greater enhancement in immune activity than do patients receiving either placebo or probiotic bacterial sonicates Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome. BACKGROUND & AIMS Probiotics can reduce symptoms of irritable bowel syndrome ( IBS ), but little is known about their effects on psychiatric comorbidities. We performed a prospect i ve study to evaluate the effects of Bifidobacterium longum NCC3001 ( BL ) on anxiety and depression in patients with IBS. METHODS We performed a r and omized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern ( based on Rome III criteria ) and mild to moderate anxiety and /or depression ( based on the Hospital Anxiety and Depression scale ) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood sample s were collected. Patients were then r and omly assigned to groups and given daily BL ( n = 22 ) or placebo ( n = 22 ) for 6 weeks. At weeks 0, 6, and 10, we determined patients'levels of anxiety and depression, IBS symptoms, quality of life, and somatization using vali date d question naires. At weeks 0 and 6, stool, urine and blood sample s were collected, and functional magnetic resonance imaging ( fMRI ) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters, and neurotrophin levels. RESULTS At week 6, 14 of 22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7 of 22 patients in the placebo group ( P =.04 ). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo. CONCLUSION In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity. Clinical Trials.gov no. NCT01276626 Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects. According to animal studies, intake of probiotic bacteria may improve glucose homeostasis. We hypothesised that probiotic bacteria improve insulin sensitivity by attenuating systemic inflammation. Therefore, the effects of oral supplementation with the probiotic bacterium Lactobacillus acidophilus NCFM on insulin sensitivity and the inflammatory response were investigated in subjects with normal or impaired insulin sensitivity. In a double-blinded, r and omised fashion, forty-five males with type 2 diabetes, impaired or normal glucose tolerance were enrolled and allocated to a 4-week treatment course with either L. acidophilus NCFM or placebo. L. acidophilus was detected in stool sample s by denaturating gradient gel electrophoresis and real-time PCR. Separated by the 4-week intervention period, two hyperinsulinaemic-euglycaemic clamps were performed to estimate insulin sensitivity. Furthermore, the systemic inflammatory response was evaluated by subjecting the participants to Escherichia coli lipopolysaccharide injection ( 0·3 ng/kg ) before and after the treatment course. L. acidophilus NCFM was detected in 75 % of the faecal sample s after treatment with the probiotic bacterium. Insulin sensitivity was preserved among volunteers in the L. acidophilus NCFM group, whereas it decreased in the placebo group. Both baseline inflammatory markers and the systemic inflammatory response were, however, unaffected by the intervention. In conclusion, intake of L. acidophilus NCFM for 4 weeks preserved insulin sensitivity compared with placebo, but did not affect the systemic inflammatory response Effect of multi-strain probiotics (multi-strain microbial cell preparation) on glycemic control and other diabetes-related outcomes in people with type 2 diabetes: a randomized controlled trial Aim Evidence of a possible connection between gut microbiota and several physiological processes linked to type 2 diabetes is increasing. However, the effect of multi-strain probiotics in people with type 2 diabetes remains unclear. This study investigated the effect of multi-strain microbial cell preparation — also refers to multi-strain probiotics — on glycemic control and other diabetes-related outcomes in people with type 2 diabetes. Design A r and omized, double-blind, parallel-group, controlled clinical trial. Setting Diabetes clinic of a teaching hospital in Kuala Lumpur, Malaysia. Participants A total of 136 participants with type 2 diabetes, aged 30–70 years, were recruited and r and omly assigned to receive either probiotics ( n = 68 ) or placebo ( n = 68 ) for 12 weeks. Outcomes Primary outcomes were glycemic control-related parameters, and secondary outcomes were anthropomorphic variables, lipid profile, blood pressure and high-sensitivity C-reactive protein. The Lactobacillus and Bifidobacterium quantities were measured before and after intervention as an indicator of successful passage of the supplement through gastrointestinal tract. Statistical analysis Intention-to-treat ( ITT ) analysis was performed on all participants, while per- protocol ( PP ) analysis was performed on those participants who had successfully completed the trial with good compliance rate. Results With respect to primary outcomes, glycated hemoglobin decreased by 0.14 % in the probiotics and increased by 0.02 % in the placebo group in PP analysis ( p < 0.05, small effect size of 0.050 ), while these changes were not significant in ITT analysis. Fasting insulin increased by 1.8 µU/mL in placebo group and decreased by 2.9 µU/mL in probiotics group in PP analysis. These changes were significant between groups at both analyses ( p < 0.05, medium effect size of 0.062 in PP analysis and small effect size of 0.033 in ITT analysis ). Secondary outcomes did not change significantly. Probiotics successfully passed through the gastrointestinal tract. Conclusion Probiotics modestly improved HbA1c and fasting insulin in people with type 2 diabetes Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut Certain therapeutic microbes, including Bifidobacteria infantis ( B. infantis ) 35624 exert beneficial immunoregulatory effects by mimicking commensal-immune interactions ; however, the value of these effects in patients with non-gastrointestinal inflammatory conditions remains unclear. In this study, we assessed the impact of oral administration of B. infantis 35624, for 6‒8 weeks on inflammatory biomarker and plasma cytokine levels in patients with ulcerative colitis ( UC ) ( n = 22 ), chronic fatigue syndrome ( CFS ) ( n = 48 ) and psoriasis ( n = 26 ) in three separate r and omized, double-blind, placebo-controlled interventions. Additionally, the effect of B. infantis 35624 on immunological biomarkers in healthy subjects ( n = 22 ) was assessed. At baseline, both gastrointestinal ( UC ) and non-gastrointestinal ( CFS and psoriasis ) patients had significantly increased plasma levels of C-reactive protein ( CRP ) and the pro-inflammatory cytokines tumor necrosis factor α ( TNF-α ) and interleukin-6 ( IL-6 ) compared with healthy volunteers. B. infantis 35624 feeding result ed in reduced plasma CRP levels in all three inflammatory disorders compared with placebo. Interestingly, plasma TNF-α was reduced in CFS and psoriasis while IL-6 was reduced in UC and CFS. Furthermore, in healthy subjects, LPS-stimulated TNF-α and IL-6 secretion by peripheral blood mononuclear cells ( P BMC s ) was significantly reduced in the B. infantis 35624-treated groups compared with placebo following eight weeks of feeding. These results demonstrate the ability of this microbe to reduce systemic pro-inflammatory biomarkers in both gastrointestinal and non-gastrointestinal conditions. In conclusion, these data show that the immunomodulatory effects of the microbiota in humans are not limited to the mucosal immune system but extend to the systemic immune system Dietary therapy with Lactobacillus GG, bovine colostrum or bovine immune colostrum in patients with juvenile chronic arthritis: Evaluation of effect on gut defence mechanisms The effect of dietary therapy with a human Lactobacillus strain GG ( ATCC 53103 ), bovine colostrum, or bovine immune colostrum with specific antibodies against anaerobic intestinal bacteria on gut defence mechanisms were studied in juvenile chronic arthritis. Thirty patients with juvenile chronic arthritis were r and omly allocated to receive a freeze-dried powder of Lactobacillus GG, or bovine colostrum, or bovine immune colostrum, for a two-week period. Immunologic and non-immunologic gut defence mechanisms were indirectly investigated in blood and faecal sample s. In patients receiving Lactobacillus GG, the median ( interquartile range ) frequency of immunoglobulin-secreting cells, determined by enzyme-linked immunospot assay, increased in the IgA class from 1840 ( 690–2530 ) to 3480 ( 1030–13 170)/106 cells ; p=0.02. Likewise the median ( interquartile range ) frequency of specific antibody-secreting cells against dietary antigens increased during the Lactobacillus GG therapy in the IgM class from 3.8 ( 1.4–5.0 ) to 11.2 (5.0–30.0)/106 cells ; p=0.02. In addition, Lactobacillus GG therapy decreased the median ( interquartile range ) activity of faecal urease, which has been associated with mucosal tissue damage, from 40.3 ( 21.7–54.3 ) to 28.6 ( 24.5–49.4 ) nmol. min−1 ( mg protein)−1 ; p=0.10, while, in patients receiving bovine colostrum, faecal urease activity increased ( from 42.2 to 80.6 ; p=0.04 ). All findings were transient. We suggest that gut defence mechanisms are disturbed in juvenile chronic arthritis and we further suggest that orally administered Lactobacillus GG has a potential to reinforce the mucosal barrier mechanisms in juvenile chronic arthritis Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. OBJECTIVES Rheumatoid arthritis ( RA ) is an inflammatory autoimmune disease in which the gut microbiota is altered. Probiotics are microorganisms that can normalize gut microbiota ; thus, they may help to alleviate RA symptoms. The objective of the present clinical trial was to assess the effects of probiotic supplementation on disease activity and inflammatory cytokines in patients with RA. METHODS Forty-six patients with RA were assigned into two groups in this r and omized, double-blind, placebo-controlled clinical trial. The patients in the probiotic group received a daily capsule that contained a minimum of 10(8 ) colony-forming units of Lactobacillus casei 01 for 8 wk. The placebo group took capsules filled with maltodextrin for the same time period. Question naires, anthropometric measurements, and fasting blood sample s were collected, and the participants were assessed by a rheumatologist at baseline and at the end of the trial. RESULTS Disease activity score was significantly decreased by the intervention, and there was a significant difference between the two groups at the end of the study ( P < 0.01 ). Three of the assessed serum proinflammatory cytokines ( tumor necrosis factor-α, interleukin-6, and interleukin-12 ) significantly decreased in the probiotic group ( P < 0.05 ) ; however, serum levels of interleukin-1 β were not significantly affected by the probiotic ( P = 0.22 ). The serum level of regulatory cytokine ( interleukin-10 ) was increased by the supplementation ( P < 0.05 ). The proportion of interleukin-10 to interleukin-12 was significantly increased in the probiotic group as well. CONCLUSIONS L. casei 01 supplementation improved the disease activity and inflammatory status of patients with RA. Further studies are warranted to confirm these results, and such confirmation may lead to the introduction of probiotics as adjunctive therapy for this population Effects of probiotics (cultured Lactobacillus subtilis/Streptococcus faecium) in the treatment of alcoholic hepatitis: randomized-controlled multicenter study Background Probiotics might reduce gut-derived microbial lipopolysaccharide ( LPS ) by restoring bowel flora in patients with alcoholic hepatitis ( AH ). We evaluated the therapeutic effects of probiotics in patients with AH. Patients and methods Between September 2010 and April 2012, 117 patients ( probiotics 60 and placebo 57 ) were prospect ively r and omized to receive the 7 days of cultured Lactobacillus subtilis/Streptococcus faecium ( 1500 mg/day ) or placebo. All patients were hospitalized and were not permitted to consume alcohol for the 7 days of the study. Liver function test, proinflammatory cytokines, LPS, and colony-forming units by stool culture were examined and compared after therapy. Results In both groups, the mean levels of aspartate aminotransferase/alanine aminotransferase, alkaline phosphatase, & ggr;-glutamyl transpeptidase, bilirubin, and prothrombin time were significantly improved after 7 days of abstinence. In the probiotics group ( baseline and after ), albumin ( 3.5±0.7 and 3.7±0.6 g/dl, P=0.038 ) and tumor necrosis factor-&agr ; ( 121±244 and 71±123 pg/ml, P=0.047 ) showed differences. In addition, the number of colony-forming units of Escherichia coli was significantly reduced ( 435±287 and 168±210, P=0.002 ). In the placebo group, the level of LPS ( 1.7±2.8 and 2.0±2.7 EU/ml ) was significantly increased. In the intergroup comparison, significant differences in the levels of tumor necrosis factor-&agr ; ( P=0.042 ) and LPS ( P=0.028 ) were observed between the groups. Conclusion Immediate abstinence is the most important treatment for patients with AH. In addition, 7 days of oral supplementation with cultured L. subtilis/S. faecium was associated with restoration of bowel flora and improvement of LPS in patients with AH Effect of Probiotic (VSL#3) and Omega-3 on Lipid Profile, Insulin Sensitivity, Inflammatory Markers, and Gut Colonization in Overweight Adults: A Randomized, Controlled Trial To evaluate the effects of probiotic ( VSL#3 ) and omega-3 fatty acid on insulin sensitivity, blood lipids, and inflammation, we conducted a clinical trial in 60 overweight ( BMI > 25 ), healthy adults, aged 40–60 years. After initial screening the subjects were r and omized into four groups with 15 per group. The four groups received, respectively, placebo, omega-3 fatty acid, probiotic VSL#3, or both omega-3 and probiotic, for 6 weeks. Blood and fecal sample s were collected at baseline and after 6 weeks. The probiotic ( VSL#3 ) supplemented group had significant reduction in total cholesterol, triglyceride, LDL, and VLDL and had increased HDL ( P < 0.05 ) value. VSL#3 improved insulin sensitivity ( P < 0.01 ), decreased hsCRP, and favorably affected the composition of gut microbiota. Omega-3 had significant effect on insulin sensitivity and hsCRP but had no effect on gut microbiota. Addition of omega-3 fatty acid with VSL#3 had more pronounced effect on HDL, insulin sensitivity and hsCRP. Subjects with low HDL, insulin resistance, and high hsCRP had significantly lower total lactobacilli and bifidobacteria count and higher E. coli and bacteroides count Randomized Controlled Trial of Strain-Specific Probiotic Formulation (Renadyl) in Dialysis Patients Background. Primary goal of this r and omized, double-blind, placebo-controlled crossover study of Renadyl in end-stage renal disease patients was to assess the safety and efficacy of Renadyl measured through improvement in quality of life or reduction in levels of known uremic toxins. Secondary goal was to investigate the effects on several biomarkers of inflammation and oxidative stress. Methods. Two 2-month treatment periods separated by 2-month washout and crossover, with physical examinations, venous blood testing, and quality of life question naires completed at each visit. Data were analyzed with SAS V9.2. Results. 22 subjects ( 79 % ) completed the study. Observed trends were as follows ( none reaching statistical significance ): decline in WBC count ( −0.51 × 109/L, P = 0.057 ) and reductions in levels of C-reactive protein ( −8.61 mg/L, P = 0.071 ) and total indoxyl glucuronide ( −0.11 mg%, P = 0.058 ). No statistically significant changes were observed in other uremic toxin levels or measures of QOL. Conclusions. Renadyl appeared to be safe to administer to ESRD patients on hemodialysis. Stability in QOL assessment is an encouraging result for a patient cohort in such advanced stage of kidney disease. Efficacy could not be confirmed definitively, primarily due to small sample size and low statistical power — further studies are warranted Effect of a probiotic preparation (VSL#3) in critically ill patients: A randomized, double-blind, placebo-controlled trial (Pilot Study) Objective : Reactive oxygen species ( ROS ) are a major contributing factor in diseases pathophysiology in critically ill patients. Oxidative stress usually occurs in critical illnesses, specifically during sepsis, and organ dysfunction. The anti-oxidative properties of probiotics may serve as a defense in intestine and overcome various oxidative stresses. The aim of this trial was to determine the effect of probiotics on inflammation, antioxidant capacity and lipid peroxidation in critically ill patients. Methodology : Forty patients admitted to the intensive care unit were enrolled in this double-blind, r and omized controlled trial. They were r and omized to receive placebo or probiotic for 7 days. Serum levels of Total Antioxidant Capacity ( TAC ), Malodialdehyde ( MDA ), C-Reactive Protein ( CRP ) and Acute Physiology and Chronic Health Evaluation ( APACHE II ) score were measured before initiation of the study and on the 7th day. Results : There was a significant difference in CRP levels and APACHE II score between two groups at the end of the study ( P= 0.003 and 0.001, respectively ). There was not a significant difference in levels of TAC and MDA between two groups. Conclusions : Administration of probiotics to critically ill patients caused reduction in inflammation and improvement of clinical outcome. However, there were not significant changes in markers of oxidative stress A randomized, double-blinded, placebo-controlled pilot study of probiotics in active rheumatoid arthritis Summary Background To examine the effect of probiotics as adjunctive therapy for the treatment of rheumatoid arthritis ( RA ). A sample size of 30 subjects was calculated to determine a moderate effect. Material / Methods A three month double-blind, placebo-controlled study was performed using probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 capsules administered orally. Inclusion criteria required at least 4 swollen and 4 tender joints and stable medications with no steroids for at least 1 month prior to and during the study. Twenty-nine patients with RA were r and omized to treatment. ACR20 responses, serum cytokine levels and safety parameters were assessed. Results Fifteen patients were r and omized to the probiotic group, and 14 to placebo. Three subjects in the probiotic ( 20 % ) and one in the placebo group ( 7 % ) achieved an ACR20 response ( p= 0.33 ). There was no statistically significant difference between individual components of the ACR20 criteria. Changes in cytokines favored placebo over probiotic. There was a significant improvement in the Health Assessment Question naire ( HAQ ) score in the probiotic group from visit 1 to visit 3 ( p=0.02 ) but no between-group differences. Conclusions Due to inclusion criteria, patients selected for the study had stable RA with chronic synovitis, and thus it may have been difficult for an adjunctive therapy to demonstrate improvement within 3 months. Although probiotics did not clinical ly improve RA as measured by the ACR20, it is interesting that there was functional improvement seen within the probiotic group compared to placebo Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial Background / Objectives : The percentage of hypercholesterolemic individuals not reaching their LDL-cholesterol ( LDL-C ) goal remains high and additional therapeutic strategies should be evaluated. The objective of this study was to evaluate the cholesterol-lowering efficacy and mechanism of action of bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242 capsules in hypercholesterolemic adults. Subjects/ Methods : A total of 127 subjects completed a r and omized, double-blind, placebo-controlled, parallel-arm, multicenter study. Subjects were r and omized to consume L. reuteri NCIMB 30242 capsules or placebo capsules over a 9-week intervention period. The primary outcome was LDL-C relative to placebo at the study end point. Results : L. reuteri NCIMB 30242 capsules reduced LDL-C by 11.64 % ( P<0.001 ), total cholesterol by 9.14 %, ( P<0.001 ), non-HDL-cholesterol ( non-HDL-C ) by 11.30 % ( P<0.001 ) and apoB-100 by 8.41 % ( P=0.002 ) relative to placebo. The ratios of LDL-C/HDL-cholesterol ( HDL-C ) and apoB-100/apoA-1 were reduced by 13.39 % ( P=0.006 ) and 9.00 % ( P=0.026 ), respectively, relative to placebo. Triglycerides and HDL-C were unchanged. High-sensitivity C-reactive protein and fibrinogen were reduced by 1.05 mg/l ( P=0.005 ) and 14.25 % ( P=0.004 ) relative to placebo, respectively. Mean plasma deconjugated bile acids were increased by 1.00 nmol/l ( P=0.025 ) relative to placebo, whereas plasma campesterol, sitosterol and stigmasterol were decreased by 41.5 %, 34.2 % and 40.7 %, respectively. Conclusions : The present results suggest that the deconjugation of intraluminal bile acids results in reduced absorption of non-cholesterol sterols and indicate that L. reuteri NCIMB 30242 capsules may be useful as an adjunctive therapy for treating hypercholesterolemia The additional effects of a probiotic mix on abdominal adiposity and antioxidant Status: A double-blind, randomized trial. OBJECTIVE To investigate whether a probiotic mix has additional effects when compared with an isolated dietary intervention on the body composition, lipid profile, endotoxemia, inflammation, and antioxidant profile. METHODS Women who had excess weight or obesity were recruited to a r and omized, double-blind trial and received a probiotic mix ( Lactobacillus acidophilus and casei ; Lactococcus lactis ; Bifidobacterium bifidum and lactis ; 2 × 1010 colony-forming units/day ) ( n = 21 ) or placebo ( n = 22 ) for 8 weeks. Both groups received a dietary prescription. Body composition was assessed by anthropometry and dual-energy X-ray absorptiometry. The lipid profile, lipid accumulation product, plasma fatty acids, lipopolysaccharide, interleukin-6, interleukin-10, tumor necrosis factor-α, adiponectin, and the antioxidant enzymes activities were analyzed. RESULTS In comparison with the dietary intervention group, the dietary intervention + probiotic mix group showed a greater reduction in the waist circumference ( -3.40 % vs. -5.48 %, P = 0.03 ), waist-height ratio ( -3.27 % vs. -5.00 %, P = 0.02 ), conicity index ( -2.43 % vs. -4.09 % P = 0.03 ), and plasma polyunsaturated fatty acids ( 5.65 % vs. -18.63 %, P = 0.04 ) and an increase in the activity of glutathione peroxidase ( -16.67 % vs. 15.62 %, P < 0.01 ). CONCLUSIONS Supplementation of a probiotic mix reduced abdominal adiposity and increased antioxidant enzyme activity in a more effective way than an isolated dietary intervention Improvements in Seasonal Allergic Disease with Lactobacillus plantarum No. 14 We conducted two r and omized, placebo-controlled, double-blind studies of Lactobacillus plantarum No. 14 ( LP14 ) in female students with seasonal allergic diseases. We also examined the mitogenic activity and cytokine inducibility of LP14 using Peyer ’s patch cells and mesenteric lymph node cells of swine. For subjects who took 8.7 × 108 of LP14, a significant improvement in ocular symptom-medication score was observed. In the placebo group, the T helper type 1 (Th1)/T helper type 2 ( Th2 ) ratio tended to decrease after a 6-week intake period, while in the LP14 group, the percentage of Th1 cells significantly increased. Post-intake eosinophil counts significantly increased in comparison to those at intake cessation in the placebo group, but it appeared to be suppressed in the LP14 group. There were no changes in fecal microflora. LP14 strongly induced the gene expression of Th1-type cytokines. This study indicates the clinical effects of LP14 on seasonal allergic diseases The effect of orally administered probiotic Lactobacillus reuteri-containing tablets in peri-implant mucositis: a double-blind randomized controlled trial. BACKGROUND AND OBJECTIVES Probiotics create a biofilm and protect the oral tissues against the action of periodontal pathogenic bacteria. The aim of this study was to evaluate the effects of the oral probiotic Lactobacillus reuteri Prodentis upon the peri-implant health of edentulous patients with dental implants and peri-implant mucositis, establishing comparisons vs implants without peri-implant disease. MATERIAL AND METHODS A double-blind, placebo-controlled, prospect i ve cross-over study was made. The patients were all edentulous and were divided into two groups, ( A ) no peri-implant disease, and ( B ) peri-implant mucositis affecting one or more implants. Patients with peri-implantitis were excluded. The dosage was one tablet every 24 h over 30 d. All patients in both groups initially received the oral probiotic Lactobacillus reuteri Prodentis, followed by placebo. Patients started with probiotic treatment during 30 d, followed by a 6 mo washout period and the administration of placebo for the same period. The following parameters were studied : crevicular fluid volume, modified plaque index, probing depth, modified gingival index, and concentrations of interleukin 1β, interleukin 6 and interleukin 8. RESULTS A total of 77 implants were evaluated in 34 patients. Group A involved 22 patients with 54 implants without peri-implant alterations, and group B, 12 patients with mucositis affecting one or more implants ( 23 implants ). After treatment with the probiotic, both the patients with mucositis and the patients without peri-implant disease showed improvements in the clinical parameters, with reductions in cytokine levels. In contrast, no such changes were observed with placebo. CONCLUSIONS After treatment with the probiotic Lactobacillus reuteri in patients with implants presenting mucositis, the clinical parameters improved, and the cytokine levels decreased - in contraposition to the observations in the placebo group. Probiotic administration may be regarded as a good alternative for both the treatment of peri-implant mucositis and its prevention, as it also improved clinical parameters in the healthy individuals. Further studies involving larger patient series are needed regarding the effects of probiotics upon peri-implant health Probiotic Therapy for the Treatment of Spondyloarthritis: A Randomized Controlled Trial Objective. To investigate the effect of an orally administered probiotic on disease activity, fatigue, quality of life, and intestinal symptoms in patients with active spondyloarthritis. Methods. Patients with active spondyloarthritis [ defined as Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) ≥ 3, Bath Ankylosing Spondylitis Functional Index ( BASFI ) ≥ 3, Maastricht Ankylosing Spondylitis Enthesitis Score ( MASES ) ≥ 2, or peripheral joint count ≥ 2 ] were r and omized to oral probiotic or placebo for 12 weeks. Patients and assessors were blinded to treatment allocation. The primary outcome measure was 10 % improvement in the BASFI. Additional outcome measures were improvements in the ASsessment s in Ankylosing Spondylitis (ASAS)-endorsed core domains : pain, spinal mobility, patient global, peripheral joint and entheseal scores, stiffness, C-reactive protein, and fatigue. The ASAS20 criteria, a composite measure of response, were also applied. Quality of life and bowel symptoms were quantified using the Ankylosing Spondylitis Quality of Life Question naire ( ASQoL ) and Dudley Inflammatory Bowel Symptom Question naire ( DISQ ). Results. Sixty-three patients were r and omized to oral probiotic ( n = 32 ) or placebo ( n = 31 ). All patients completed the trial. No significant difference was noted between groups in any of the core domains. The mean BASFI fell from 3.5 ± 2.0 to 2.9 ± 1.9 in the probiotic group and from 3.6 ± 1.9 to 3.1 ± 2.2 in the placebo group ( p = 0.839 ). The mean BASDAI fell from 4.2 ± 2.2 to 3.2 ± 2.1 in the probiotic group and 4.5 ± 2.0 to 3.9 ± 2.2 in the placebo group ( p = 0.182 ). No significant adverse events were recorded in the probiotic-treated group. Conclusion. In this r and omized controlled trial, the probiotic combination administered did not demonstrate significant benefit over placebo, despite a theoretical rationale for this therapy Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis – a pilot study Objective : To study the effects of Lactobacillus rhamnosus GG ( LGG ) on rheumatoid arthritis ( RA ). Methods : Twenty‐one RA patients were r and omised to receive 2 capsules of LGG or a placebo twice daily in double‐blind fashion for 12 months. Arthritis activity was evaluated by clinical examination, HAQ index, and laboratory tests ( e.g. ESR, CRP, pro‐ and anti‐inflammatory cytokines ). Results : There were no statistical differences in the clinical parameters, biochemical variables and HAQ index between the study groups over the intervention period. The mean number of tender and swollen joints decreased from 8.3 to 4.6 in the Lactobacillus group and from 5.5 to 4.8 in the placebo group ( p=0.41 ). According to the global assessment the RA activity was reduced in 71 % ( LGG group ) vs. 30 % ( controls ) ( p=0.15 ). Serum IL‐1β increased slightly in the LGG group ( p=0.07 ), but no differences were seen in IL‐6, TNF‐α, MPO, IL‐10 or 1L‐12. Conclusions : Although there were no statistical significant differences in the activity of RA, more subjects in the LGG group reported subjective well being. More studies on the effects of probiotic bacteria in RA are needed Effect of probiotic Bifidobacterium longum BB536 [corrected] in relieving clinical symptoms and modulating plasma cytokine levels of Japanese cedar pollinosis during the pollen season. A randomized double-blind, placebo-controlled trial. Probiotic microorganisms have been shown to be effective in the treatment of allergic inflammation and food allergy, but their efficacy remains controversial. This study tested the effect of a yogurt supplemented with a probiotic strain Bifidobacterium longum BB536 in the treatment of Japanese cedar pollinosis ( JCPsis ). Forty subjects with a clinical history of JCPsis were given yoghurt either containing BB536 ( BB536 yoghurt ) or without BB536 ( placebo yoghurt ) at 2 X 100 g per day for 14 weeks, in a r and omized, double-blind, placebo-controlled trial. Subjective symptoms and self-care measures were recorded daily and blood sample s were taken before and during the intervention ( at weeks 4, 9, and 14 ) to measure the blood parameter levels related to JCPsis. Yoghurt supplemented with BB536 significantly alleviated eye symptoms compared with placebo yoghurt ( odds ratio 0.31 ; 95 % confidence interval 0.10 - 0.97 ; p = 0.044 ). Although no statistically significant differences were detected, nasal symptoms such as itching, rhinorrhea, and blockage, as well as throat symptoms tended to be relieved with the BB536 yoghurt. BB536 tended to suppress the decreasing blood levels of interferon-gamma ( IFN-y ) and the increasing blood eosinophil rates ; a significantly higher IFN-gamma level was observed for the difference from baseline at week 4. A decreased trend in the difference from baseline levels of JCP-specific IgE levels was also observed at week 4 in the BB536 group compared with the placebo group. In conclusion, these results suggest that intake of BB536-supplemented yoghurt may relieve JCPsis symptoms, probably through a modulating effect on Th balance Effects of Probiotic Supplementation on Pancreatic β-cell Function and C-reactive Protein in Women with Polycystic Ovary Syndrome: A Randomized Double-blind Placebo-controlled Clinical Trial Background : Polycystic ovary syndrome ( PCOS ) is a polygenic endocrine disorder in women of reproductive age that lead to infertility. The aim of this study was to investigate the effects of probiotic on pancreatic β-cell function and C-reactive protein ( CRP ) in PCOS patients. Methods : This r and omized double-blind placebo-controlled clinical trial was conducted among 72 women aged 15–40 years old diagnosed with PCOS. Participants were r and omly assigned to two groups receiving : ( 1 ) Probiotic supplements ( n = 36 ), ( 2 ) placebo ( n = 36 ) for 8-week. Fasting blood sample s were taken at baseline and after 8-week of intervention. Results : Probiotic supplementation, compare with placebo, reduced fasting blood sugar ( −4.15 ± 2.87 vs. 2.57 ± 5.66 mg/dL, respectively P = 0.7 ), serum insulin levels in crude model ( −0.49 ± 0.67 vs. 0.34 ± 0.82 μIU/mL, respectively, P = 0.09 ), homeostasis model of assessment -insulin resistance score ( −0.25 ± 0.18 vs. −0.05 ± 0.18, respectively, P = 0.14 ) nonsignificantly. Serum insulin levels after adjustment with covariates reduced significantly in probiotic group ( P = 0.02 ). We did not found any significant differences in mean changes of CRP between groups ( −0.25 ± 0.18 vs. −0.05 ± 0.18, respectively, P = 0.14 ). Conclusions : A 8-week multispecies probiotics supplementation had nonsignificantly beneficial effect on pancreatic β-cell function and CRP in PCOS patients. After adjustment for some covariates, serum insulin changes were significantly different between groups Effects of Multistrain Probiotic Supplementation on Glycemic and Inflammatory Indices in Patients with Nonalcoholic Fatty Liver Disease: A Double-Blind Randomized Clinical Trial Objective : Nonalcoholic fatty liver disease ( NAFLD ) is a condition defined by exceeding triglycerides accumulation in the liver. The condition can develop into fibrosis, cirrhosis, and hepatocellular carcinoma. Considering the ever-increasing prevalence of NAFLD, the aim of the present study was to investigate the effects of probiotic supplementation on glycemic and inflammatory indices in patients with NAFLD. Methods : This r and omized clinical trial was conducted on 42 patients with NAFLD who had been referred to a gastroenterology clinic. Subjects in the intervention and control groups consumed 2 capsules/day probiotic or placebo, respectively, for 8 weeks. Fasting blood sugar ( FBS ), insulin, insulin resistance, tumor necrosis factor alpha ( TNF-α ), and interleukin 6 ( IL-6 ) were measured at baseline and at the end of the study. Results : Means of FBS, insulin, insulin resistance, and IL-6 were significantly different between groups after intervention ( p < 0.05 ), whereas TNF-α was not significantly modified ( p > 0.05 ). In the probiotic group, insulin, insulin resistance, TNF-α, and IL-6 decreased significantly at the end of the study compared to the beginning of study. Conclusion : Considering the effects of probiotic supplementation on the reduction of glycemic and inflammatory indices in patients with NAFLD, consumption of probiotics is recommended as a complementary therapy in these patients The effects of probiotic supplement on hemoglobin in chronic renal failure patients under hemodialysis: A randomized clinical trial Background : Chronic inflammation is one of the causes of anemia in chronic renal failure patients under hemodialysis. Probiotics probably establish a balance between pro- and anti-inflammatory cytokines. The study was conducted to determine the effects of probiotic supplementation on hemoglobin ( Hb ) in hemodialysis patients. Material s and Methods : A parallel clinical trial was conducted in which patients were r and omly allocated into two groups. The intervention group ( n = 18 ) was given a 500 mg probiotic supplement ( a capsule ) every day whereas the control group ( n = 18 ) received placebo ( a capsule ), both for 3 months. Hb levels and C-reactive protein ( CRP ) levels were measured for three periods. The data were analyzed in SPSS-16 using statistical tests including the t-test and repeated- measures ANOVA. Results : In the probiotic supplementation group, the mean Hb was 9.22 ± 1.04 mg/dl before the intervention and reached 10.85 ± 1.177 mg/dl afterward, while in the placebo group, the mean Hb level was 9.38 ± 0.97 mg/dl before the intervention and reached 10.03 ± 1.97 mg/dl afterward ( P > 0.05 ). During the study, the placebo caused to increase of Hb temporary, but in longer term, the effect of probiotic was more manifested. Hb levels increased in both groups although the change was not statistically significant ( P > 0.05 ). The findings showed no significant differences between the two groups in either the pre- or post-intervention CRP levels ( P = 0.239 ). Conclusion : Probiotic supplementation decreased Hb fluctuations in hemodialysis patients but did not result in a significant increase in Hb levels. Similar studies are therefore recommended to be conducted with a prolonged duration of the study or an increased probiotic dose with larger sample size to complete the results of the present study Impact of probiotic Saccharomyces boulardii on the gut microbiome composition in HIV-treated patients: A double-blind, randomised, placebo-controlled trial Dysbalance in gut microbiota has been linked to increased microbial translocation, leading to chronic inflammation in HIV- patients, even under effective HAART. Moreover, microbial translocation is associated with insufficient reconstitution of CD4+T cells, and contributes to the pathogenesis of immunologic non-response. In a double-blind, r and omised, placebo-controlled trial, we recently showed that, compared to placebo, 12 weeks treatment with probiotic Saccharomyces boulardii significantly reduced plasma levels of bacterial translocation ( Lipopolysaccharide-binding protein or LBP ) and systemic inflammation ( IL-6 ) in 44 HIV virologically suppressed patients, half of whom ( n = 22 ) had immunologic non-response to antiretroviral therapy ( < 270 CD4+Tcells/μL despite long-term suppressed viral load ). The aim of the present study was to investigate if this beneficial effect of the probiotic Saccharomyces boulardii is due to modified gut microbiome composition, with a decrease of some species associated with higher systemic levels of microbial translocation and inflammation. In this study, we used 16S rDNA gene amplification and parallel sequencing to analyze the probiotic impact on the composition of the gut microbiome ( faecal sample s ) in these 44 patients r and omized to receive oral supplementation with probiotic or placebo for 12 weeks. Compared to the placebo group, in individuals treated with probiotic we observed lower concentrations of some gut species, such as those of the Clostridiaceae family, which were correlated with systemic levels of bacterial translocation and inflammation markers. In a sub- study of these patients, we observed significantly higher parameters of microbial translocation ( LBP, soluble CD14 ) and systemic inflammation in immunologic non-responders than in immunologic responders, which was correlated with a relative abundance of specific gut bacterial groups ( Lachnospiraceae genus and Proteobacteria ). Thus, in this work, we propose a new therapeutic strategy using the probiotic yeast S. boulardii to modify gut microbiome composition. Identifying pro-inflammatory species in the gut microbiome could also be a useful new marker of poor immune response and a new therapeutic target Role of Probiotics on Gut Permeability and Endotoxemia in Patients With Acute Pancreatitis: A Double-Blind Randomized Controlled Trial Goals To study the role of probiotics on gut permeability and endotoxemia in patients with acute pancreatitis ( AP ). Background Bacterial translocation has been implicated in infective complications in AP, which has been shown to be prevented by probiotics. Study A double-blind, r and omized placebo-controlled trial was conducted. Consecutive patients with AP presenting within 72 hours after the onset of abdominal pain or who had been nil orally at the time of presentation for up to 5 days were included in the study. The probiotic group received 4 sachets of Probiotics ( 2.5 billion bacteria per sachet ) whereas the placebo group received 4 sachets of placebo for 7 days. Primary outcome measures were effect on gut permeability [ assessed by lactulose/mannitol ( L/M ) excretion in urine ] and endotoxemia assessed by endotoxin-core antibody types IgG and IgM ( EndoCab IgG and IgM ). Secondary outcome measures were mortality, total hospital/intensive care unit stay, abdominal discomfort, organ failure, C-reactive protein, and prealbumin levels. The study was prematurely stopped after the publication of probiotic prophylaxis in patients with predicted severe acute pancreatitis trial. Results From March 2007 to May 2008, 50 patients with AP were included in the study ( 26 in placebo group and 24 in probiotic group ). There was no difference after intervention in gut permeability, whereas values of C-reactive protein and immunoglobulins decreased significantly [ IgG : 140 ( 20–920 ) to 90 ( 20–600 ) GGU/mL and IgM : 65 ( 13–230 ) to 51 ( 9–240 ) GMU/mL ] in the probiotic group. No difference was observed in prealbumin values, duration of hospital/intensive care unit stay, and mortality in both the groups. Conclusions No significant trend was identified for an effect of probiotics on gut permeability or endotoxemia in AP. However, the study was underpowered owing to premature study termination", 'Genetic risk prediction of chronic conditions including obesity, diabetes and CVD currently has limited predictive power but its potential to engage healthy behaviour change has been of immense research interest. We aim ed to underst and whether the latter is indeed true by conducting a systematic review and meta- analysis investigating whether genetic risk communication affects motivation and actual behaviour change towards preventative lifestyle modification. Effect of communicating genetic and phenotypic risk for type 2 diabetes in combination with lifestyle advice on objectively measured physical activity: protocol of a randomised controlled trial Type 2 diabetes ( T2D ) is associated with increased risk of morbidity and premature mortality. Among those at high risk, incidence can be halved through healthy changes in behaviour. Information about genetic and phenotypic risk of T2D is now widely available. Whether such information motivates behaviour change is unknown. We aim to assess the effects of communicating genetic and phenotypic risk of T2D on risk-reducing health behaviours, anxiety, and other cognitive and emotional theory-based antecedents of behaviour change. In a parallel group, open r and omised controlled trial, approximately 580 adults born between 1950 and 1975 will be recruited from the on-going population -based, observational Fenl and Study ( Cambridgeshire, UK ). Eligible participants will have undergone clinical, anthropometric, and psychosocial measurements, been genotyped for 23 single-nucleotide polymorphisms associated with T2D, and worn a combined heart rate monitor and accelerometer ( Actiheart ® ) continuously for six days and nights to assess physical activity. Participants are r and omised to receive either st and ard lifestyle advice alone ( control group ), or in combination with a genetic or a phenotypic risk estimate for T2D ( intervention groups ). The primary outcome is objective ly measured physical activity. Secondary outcomes include self-reported diet, self-reported weight, intention to be physically active and to engage in a healthy diet, anxiety, diabetes-related worry, self-rated health, and other cognitive and emotional outcomes. Follow-up occurs eight weeks post-intervention. Values at follow-up, adjusted for baseline, will be compared between r and omised groups. This study will provide much needed evidence on the effects of providing information about the genetic and phenotypic risk of T2D. Importantly, it will be among the first to examine the impact of genetic risk information using a r and omised controlled trial design, a population -based sample, and an objective ly measured behavioural outcome. Results of this trial, along with recent evidence syntheses of similar studies, should inform policy concerning the availability and use of genetic risk information. Current Controlled Trials IS RCT Impact of direct-to-consumer genomic testing at long term follow-up Background There are few empirical data to inform the debate surrounding the use and regulation of direct-to-consumer ( DTC ) genome-wide disease risk tests. This study aim ed to determine the long term psychological, behavioural, and clinical impacts of genomic risk testing for common disease. Methods The Scripps Genomic Health Initiative is a prospect i ve longitudinal cohort study of adults who purchased the Navigenics Health Compass, a commercially available genomic test. Web based assessment s were administered at baseline, short ( 3 months ), and long term ( 1 year ) follow-up. Results 2240 participants completed either or both follow-ups and a subset of 1325 completed long term follow-up. There were no significant differences from baseline in anxiety ( p=0.50 ), fat intake ( p=0.34 ), or exercise ( p=0.39 ) at long term follow-up, and 96.8 % of the sample had no test related distress. Longitudinal linear mixed model analyses were consistent with results of cross-sectional analyses. Screening test completion was associated with sharing genomic test results with a physician ( 36.0 % shared ; p<0.001 ) and perceived utility of the test ( 61.5 % high perceived utility ; p=0.002 ), but was not associated with the genomic risk estimate values themselves. Conclusions Over a third of DTC genomic test recipients shared their results with their own physician during an approximate 1 year follow-up period, and this sharing was associated with higher screening test completion. Genomic testing was not associated with long term psychological risks, and most participants reportedly perceived the test to be of high personal utility Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study Objectives To assess the performance of a panel of common single nucleotide polymorphisms ( genotypes ) associated with type 2 diabetes in distinguishing incident cases of future type 2 diabetes ( discrimination ), and to examine the effect of adding genetic information to previously vali date d non-genetic ( phenotype based ) models developed to estimate the absolute risk of type 2 diabetes. Design Workplace based prospect i ve cohort study with three 5 yearly medical screenings. Participants 5535 initially healthy people ( mean age 49 years ; 33 % women ), of whom 302 developed new onset type 2 diabetes over 10 years. Outcome measures Non-genetic variables included in two established risk models — the Cambridge type 2 diabetes risk score ( age, sex, drug treatment, family history of type 2 diabetes, body mass index, smoking status ) and the Framingham offspring study type 2 diabetes risk score ( age, sex, parental history of type 2 diabetes, body mass index, high density lipoprotein cholesterol, triglycerides, fasting glucose)— and 20 single nucleotide polymorphisms associated with susceptibility to type 2 diabetes. Cases of incident type 2 diabetes were defined on the basis of a st and ard oral glucose tolerance test, self report of a doctor ’s diagnosis, or the use of anti-diabetic drugs. Results A genetic score based on the number of risk alleles carried ( range 0 - 40 ; area under receiver operating characteristics curve 0.54, 95 % confidence interval 0.50 to 0.58 ) and a genetic risk function in which carriage of risk alleles was weighted according to the summary odds ratios of their effect from meta-analyses of genetic studies ( area under receiver operating characteristics curve 0.55, 0.51 to 0.59 ) did not effectively discriminate cases of diabetes. The Cambridge risk score ( area under curve 0.72, 0.69 to 0.76 ) and the Framingham offspring risk score ( area under curve 0.78, 0.75 to 0.82 ) led to better discrimination of cases than did genotype based tests. Adding genetic information to phenotype based risk models did not improve discrimination and provided only a small improvement in model calibration and a modest net reclassification improvement of about 5 % when added to the Cambridge risk score but not when added to the Framingham offspring risk score. Conclusion The phenotype based risk models provided greater discrimination for type 2 diabetes than did models based on 20 common independently inherited diabetes risk alleles. The addition of genotypes to phenotype based risk models produced only minimal improvement in accuracy of risk estimation assessed by recalibration and, at best, a minor net reclassification improvement. The major translational application of the currently known common, small effect genetic variants influencing susceptibility to type 2 diabetes is likely to come from the insight they provide on causes of disease and potential therapeutic targets A randomized trial of the clinical utility of genetic testing for obesity: Design and implementation considerations Background Obesity rates in the United States have escalated in recent decades and present a major challenge in public health prevention efforts. Currently, testing to identify genetic risk for obesity is readily available through several direct-to-consumer companies. Despite the availability of this type of testing, there is a paucity of evidence as to whether providing people with personal genetic information on obesity risk will facilitate or impede desired behavioral responses. Purpose We describe the key issues in the design and implementation of a r and omized controlled trial examining the clinical utility of providing genetic risk information for obesity. Methods Participants are being recruited from the Coriell Personalized Medicine Collaborative, an ongoing, longitudinal research cohort study design ed to determine the utility of personal genome information in health management and clinical decision making. The primary focus of the ancillary Obesity Risk Communication Study is to determine whether genetic risk information added value to traditional communication efforts for obesity, which are based on lifestyle risk factors. The trial employs a 2 × 2 factorial design in order to examine the effects of providing genetic risk information for obesity, alone or in combination with lifestyle risk information, on participants ’ psychological responses, behavioral intentions, health behaviors, and weight. Results The factorial design generated four experimental arms based on communication of estimated risk to participants : ( 1 ) no risk feedback ( control ), ( 2 ) genetic risk only, ( 3 ) lifestyle risk only, and ( 4 ) both genetic and lifestyle risk ( combined ). Key issues in study design pertained to the selection of algorithms to estimate lifestyle risk and determination of information to be provided to participants assigned to each experimental arm to achieve a balance between clinical st and ards and method ological rigor. Following the launch of the trial in September 2011, implementation challenges pertaining to low enrollment and differential attrition became apparent and required immediate attention and modifications to the study protocol. Although monitoring of these efforts is ongoing, initial observations show a doubling of enrollment and reduced attrition. Limitations The trial is evaluating the short-term impact of providing obesity risk information as participants are followed for only 3 months. This study is built upon the structure of an existing personalized medicine study wherein participants have been provided with genetic information for other diseases. This nesting in a larger study may attenuate the effects of obesity risk information and has implication s for the generalizability of study findings. Conclusions This r and omized trial examines value of obesity genetic information, both when provided independently and when combined with lifestyle risk assessment, to motivate individuals to engage in healthy lifestyle behaviors. Study findings will guide future intervention efforts to effectively communicate genetic risk information Personalized Genetic Risk Counseling to Motivate Diabetes Prevention OBJECTIVE To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors. RESEARCH DESIGN AND METHODS We conducted a r and omized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were r and omly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top and bottom score quartiles received individual genetic counseling before being enrolled with untested control participants in a 12-week, vali date d, diabetes prevention program. Middle-risk quartile participants were not studied further. We examined the effect of this genetic counseling intervention on patient self-reported attitudes, program attendance, and weight loss, separately comparing higher-risk and lower-risk result recipients with control participants. RESULTS The 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 ± 10.6 years, 61 % were men, and average BMI was 34.8 kg/m2, with no differences among r and omization groups. Participants attended 6.8 ± 4.3 group sessions and lost 8.5 ± 10.1 pounds, with 33 of 108 ( 30.6 % ) losing ≥5 % body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects ( P > 0.05 for all but one comparison ). CONCLUSIONS Diabetes genetic risk counseling with currently available variants does not significantly alter self-reported motivation or prevention program adherence for overweight individuals at risk for diabetes The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Flaws in the design, conduct, analysis, and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Impact of Delivery Models on Understanding Genomic Risk for Type 2 Diabetes Background : Genetic information, typically communicated in-person by genetic counselors, can be challenging to comprehend ; delivery of this information online - as is becoming more common - has the potential of increasing these challenges. Methods : To address the impact of the mode of delivery of genomic risk information, 300 individuals were recruited from the general public and r and omized to receive genomic risk information for type 2 diabetes mellitus in-person from a board-certified genetic counselor or online through the testing company\'s website. Results : Participants were asked to indicate their genomic risk and overall lifetime risk as reported on their test report as well as to interpret their genomic risk ( increased, decreased, or same as population ). For each question, 59 % of participants correctly indicated their risk. Participants who received their results in-person were more likely than those who review ed their results on-line to correctly interpret their genomic risk ( 72 vs. 47 %, p = 0.0002 ) and report their actual genomic risk ( 69 vs. 49 %, p = 0.002 ). Conclusions : The delivery of personal genomic risk through a trained health professional result ed in significantly higher comprehension. Therefore, if the online delivery of genomic test results is to become more widespread, further evaluation of this method of communication may be needed to ensure the effective presentation of results to promote comprehension Behavioral Consequences of Testing for Obesity Risk Objective : There is considerable hope that genetic susceptibility testing will motivate behavior that can prevent or reduce the risk of complex conditions such as obesity. This study examined potential behavioral consequences of such testing. Methods : Participants ( n = 249 ) were r and omly assigned to review one of four vignettes that asked them to imagine that they had been tested for their risk of becoming overweight or obese. The experimental factors were test type ( genetic versus hormone test ) and risk level ( increased versus average risk for obesity ). Study measures included behavioral intentions and perceived behavioral control related to eating a healthy diet, as well as weight locus of control. Results : Participants assigned to the increased risk conditions indicated greater intentions to eat a healthy diet compared with participants assigned to the average risk conditions ( P < 0.02 ). There were significant interaction effects of risk × perceived behavioral control ( P < 0.02 ) and risk × weight locus of control ( P < 0.003 ) on dietary intentions. Individuals with low perceived behavioral control or an external weight locus of control who were told to imagine they were at average risk expressed significantly lower intentions to eat a healthy diet. A three-way interaction of body mass index, family history of overweight/obesity, and assigned risk level found the greatest effects of risk feedback among those who either had a family history or a higher body mass index ( P < 0.007 ). Conclusion : This study provides preliminary evidence that testing for susceptibility to obesity may motivate healthier behavior. However, some individuals may be susceptible to a false reassurance effect after receiving test results indicating a lack of increased risk Disclosure of Genetic Information and Change in Dietary Intake: A Randomized Controlled Trial Background Proponents of consumer genetic tests cl aim that the information can positively impact health behaviors and aid in chronic disease prevention. However, the effects of disclosing genetic information on dietary intake behavior are not clear. Methods A double-blinded, parallel group, 2∶1 online r and omized controlled trial was conducted to determine the short- and long-term effects of disclosing nutrition-related genetic information for personalized nutrition on dietary intakes of caffeine, vitamin C, added sugars, and sodium. Participants were healthy men and women aged 20–35 years ( n = 138 ). The intervention group ( n = 92 ) received personalized DNA-based dietary advice for 12-months and the control group ( n = 46 ) received general dietary recommendations with no genetic information for 12-months. Food frequency question naires were collected at baseline and 3- and 12-months after the intervention to assess dietary intakes. General linear models were used to compare changes in intakes between those receiving general dietary advice and those receiving DNA-based dietary advice. Results Compared to the control group, no significant changes to dietary intakes of the nutrients were observed at 3-months. At 12-months, participants in the intervention group who possessed a risk version of the ACE gene, and were advised to limit their sodium intake, significantly reduced their sodium intake ( mg/day ) compared to the control group ( −287.3±114.1 vs. 129.8±118.2, p = 0.008 ). Those who had the non-risk version of ACE did not significantly change their sodium intake compared to the control group ( 12-months : −244.2±150.2, p = 0.11 ). Among those with the risk version of the ACE gene, the proportion who met the targeted recommendation of 1500 mg/day increased from 19 % at baseline to 34 % after 12 months ( p = 0.06 ). Conclusions These findings demonstrate that disclosing genetic information for personalized nutrition results in greater changes in intake for some dietary components compared to general population -based dietary advice. Trial Registration Clinical Trials.gov Genetic Susceptibility Testing and Readiness to Control Weight: Results from a Randomized Controlled Trial Objective To test the hypothesis that adding obesity gene feedback ( FTO ) to simple weight control advice at a life stage with raised risk of weight gain ( university ) increases readiness to control weight. Methods Individually r and omized controlled trial comparing the effect of : ( i ) simple weight control advice plus FTO feedback ( FA ) and ( ii ) simple weight control advice only ( AO ) on readiness to engage with weight control. Differences in stage of change by genotype and differential weight control behaviors were secondary outcomes. Results Of 1,016 participants r and omized, only 279 completed follow-up, yielding 90 % power to detect a small effect for readiness to control weight. As predicted, FA participants were more likely to be in the contemplation stage than AO participants ( P = 0.023 ). Participants receiving higher-risk genetic results were at a higher stage of change than controls ( P = 0.003 ), with a trend toward a higher stage of change than those getting lower-risk results ( P = 0.051 ). Lower-risk results did not decrease weight control intentions compared with controls ( P = 0.55 ). There were no group differences in adherence to recommended weight control behaviors ( P = 0.87 ). Conclusions Adding FTO feedback to weight control advice enhanced readiness to control weight, without evidence for genetic determinism, but had no more effect on behavior than weight control advice alone Personalized Nutrition by Prediction of Glycemic Responses Elevated postpr and ial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postpr and ial glycemic response to real-life meals. We vali date d these predictions in an independent 100-person cohort. Finally, a blinded r and omized controlled dietary intervention based on this algorithm result ed in significantly lower postpr and ial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postpr and ial blood glucose and its metabolic consequences. VIDEO ABSTRACT Design and baseline characteristics of the Food4Me study: a web-based randomised controlled trial of personalised nutrition in seven European countries Abstract Improving lifestyle behaviours has considerable potential for reducing the global burden of non-communicable diseases, promoting better health across the life-course and increasing well-being. However, realising this potential will require the development, testing and implementation of much more effective behaviour change interventions than are used conventionally. Therefore, the aim of this study was to conduct a multi-centre, web-based, proof-of-principle study of personalised nutrition ( PN ) to determine whether providing more personalised dietary advice leads to greater improvements in eating patterns and health outcomes compared to conventional population -based advice. A total of 5,562 volunteers were screened across seven European countries ; the first 1,607 participants who fulfilled the inclusion criteria were recruited into the trial. Participants were r and omly assigned to one of the following intervention groups for a 6-month period : Level 0—control group — receiving conventional, non-PN advice ; Level 1—receiving PN advice based on dietary intake data alone ; Level 2—receiving PN advice based on dietary intake and phenotypic data ; and Level 3—receiving PN advice based on dietary intake, phenotypic and genotypic data. A total of 1,607 participants had a mean age of 39.8 years ( ranging from 18 to 79 years ). Of these participants, 60.9 % were women and 96.7 % were from white-European background. The mean BMI for all r and omised participants was 25.5 kg m−2, and 44.8 % of the participants had a BMI ≥ 25.0 kg m−2. Food4Me is the first large multi-centre RCT of web-based PN. The main outcomes from the Food4Me study will be su bmi tted for publication during 2015 Information and Risk Modification Trial (INFORM): design of a randomised controlled trial of communicating different types of information about coronary heart disease risk, alongside lifestyle advice, to achieve change in health-related behaviour Background Cardiovascular disease ( CVD ) remains the leading cause of death globally. Primary prevention of CVD requires cost-effective strategies to identify individuals at high risk in order to help target preventive interventions. An integral part of this approach is the use of CVD risk scores. Limitations in previous studies have prevented reliable inference about the potential advantages and the potential harms of using CVD risk scores as part of preventive strategies. We aim to evaluate short-term effects of providing different types of information about coronary heart disease ( CHD ) risk, alongside lifestyle advice, on health-related behaviours. Methods / Design In a parallel-group, open r and omised trial, we are allocating 932 male and female blood donors with no previous history of CVD aged 40–84 years in Engl and to either no intervention ( control group ) or to one of three active intervention groups : i ) lifestyle advice only ; ii ) lifestyle advice plus information on estimated 10-year CHD risk based on phenotypic characteristics ; and iii ) lifestyle advice plus information on estimated 10-year CHD risk based on phenotypic and genetic characteristics. The primary outcome is change in objective ly measured physical activity. Secondary outcomes include : objective ly measured dietary behaviours ; cardiovascular risk factors ; current medication and healthcare usage ; perceived risk ; cognitive evaluation of provision of CHD risk scores ; and psychological outcomes. The follow-up assessment takes place 12 weeks after r and omisation. The experiences, attitudes and concerns of a subset of participants will be also studied using individual interviews and focus groups. Discussion The INFORM study has been design ed to provide robust findings about the short-term effects of providing different types of information on estimated 10-year CHD risk and lifestyle advice on health-related behaviours. Trial registration Current Controlled Trials IS RCT N17721237. Registered 12 January 2015 Psychological impact of genetic testing for familial hypercholesterolemia within a previously aware population: A randomized controlled trial This trial tests the hypothesis that confirming a clinical diagnosis of familial hypercholesterolemia ( FH ) by finding a genetic mutation reduces patients\'perceptions of control over the disease and adherence to risk‐reducing behaviors. Three hundred forty‐one families, comprising 341 hypercholesterolemia prob and s and 128 adult relatives, were r and omized to one of two groups : ( a ) routine clinical diagnosis ; ( b ) routine clinical diagnosis plus genetic testing ( mutation search ing in prob and s and direct gene testing in relatives ). The main outcome measures were perceptions of control over hypercholesterolemia, adherence to cholesterol‐lowering medication, diet, physical activity, and smoking. There was no support for the main hypothesis : finding a mutation had no impact on perceived control or adherence to risk‐reducing behavior ( all P‐values > 0.10 ). While all groups believed that lowering cholesterol was an effective way of reducing the risk of a heart attack, participants in whom a mutation was found believed less strongly in the efficacy of diet in reducing their cholesterol level ( P = 0.02 at 6 months ) and showed a trend in believing more strongly in the efficacy of cholesterol‐lowering medication ( P = 0.06 at 6 months ). In conclusion, finding a mutation to confirm a clinical diagnosis of FH in a previously aware population does not reduce perceptions of control or adherence to risk‐reducing behaviors. The pattern of findings leads to the new hypothesis that genetic testing does not affect the extent to which people feel they have control over a condition, but does affect their perceptions of how control is most effectively achieved. Further work is needed to determine whether similar results will be obtained in population s with little previous awareness of their risks. © 2004 Wiley‐Liss, Does Type 2 Diabetes Genetic Testing and Counseling Reduce Modifiable Risk Factors? A Randomized Controlled Trial of Veterans Objective We examined the clinical utility of supplementing type 2 diabetes mellitus ( DM ) risk counseling with DM genetic test results and counseling. Research Design and Methods In this r and omized controlled trial, non-diabetic overweight/obese veteran out patients aged 21 to 65 years received DM risk estimates for lifetime risk, family history, and fasting plasma glucose, followed by either genetic test results ( CR+G ; N = 303 ) or control eye disease counseling ( CR+EYE ; N = 298 ). All participants received brief lifestyle counseling encouraging weight loss to reduce the risk of DM. Results The mean age was 54 years, 53 % of participants were black, and 80 % were men. There was no difference between arms in weight ( estimated mean difference between CR+G vs. CR+EYE at 3 months = 0.2 kg, 95 % CI : −0.3 to 0.7 ; at 6 months = 0.4 kg, 95 % CI : −0.3 to 1.1 ), insulin resistance, perceived risk, or physical activity at 3 or 6 months. Calorie and fat intake were lower in the CR+G arm at 3 months ( p ’s ≤ 0.05 ) but not at 6 months ( p ’s > 0.20 ). Conclusions Providing patients with genetic test results was not more effective in changing patient behavior to reduce the risk of DM compared to conventional risk counseling. Trial registration : Clinical Trials.gov NCT01060540 http:// clinical The clinical application of genetic testing in type 2 diabetes: a patient and physician survey Aims /hypothesisAdvances in type 2 diabetes genetics have raised hopes that genetic testing will improve disease prediction, prevention and treatment. Little is known about current physician and patient views regarding type 2 diabetes genetic testing. We hypothesised that physician and patient views would differ regarding the impact of genetic testing on motivation and adherence. Methods We surveyed a nationally representative sample of US primary care physicians and endocrinologists ( n = 304 ), a r and om sample of non-diabetic primary care patients ( n = 152 ) and patients enrolled in a diabetes pharmacogenetics study ( n = 89 ). Results Physicians and patients favoured genetic testing for diabetes risk prediction ( 79 % of physicians vs 80 % of non-diabetic patients would be somewhat/very likely to order/request testing, p = 0.7 ). More patients than physicians ( 71 % vs 23 %, p < 0.01 ) indicated that a ‘ high risk ’ result would be very likely to improve motivation to adopt preventive lifestyle changes. Patients favoured genetic testing to guide therapy ( 78 % of patients vs 48 % of physicians very likely to request/recommend testing, p < 0.01 ) and reported that genetic testing would make them ‘ much more motivated ’ to adhere to medications ( 72 % vs 18 % of physicians, p < 0.01 ). Many physicians ( 39 % ) would be somewhat/very likely to order genetic testing before published evidence of clinical efficacy. Conclusions /interpretationDespite the paucity of current data, physicians and patients reported high expectations that genetic testing would improve patient motivation to adopt key behaviours for the prevention or control of type 2 diabetes. This suggests the testable hypothesis that ‘ genetic ’ risk information might have greater value to motivate behaviour change compared with st and ard risk information Psychological responses to genetic testing for weight gain: a vignette study. Genetic testing for obesity risk is increasingly available to the public but few studies have examined motivational or affective reactions. Here we report findings from a " vignette " study investigating reactions to " higher-risk " and " average-risk " results for the obesity-related FTO gene in two groups : a panel sample of individuals with weight concerns, for whom testing may have treatment implication s ( n = 306, mean age = 45 years, mean BMI = 35 ) and a student sample ( n = 395, mean age = 25 years, mean BMI = 23 ), for whom testing would have implication s for obesity prevention. Participants were given FTO gene information that described higher-risk alleles as linked with modest weight gain and slightly higher risk of obesity. They responded to both higher- and average-risk vignettes, with order r and omized. Interest in genetic testing was high overall, and higher in panel respondents than students ( 93 % vs. 78 % would " probably " or " definitely " have the test ; P < 0.001 ). In students, a higher-risk result generated higher motivation to change ( d = 0.15 ; P < 0.001 ), but also slightly higher negative affect ( d = 0.03, P < 0.001 ) and fatalism ( d = 0.05, P < 0.001 ) than an average-risk result. Panel respondents also had higher motivation to change ( d = 0.17, P < 0.001 ) as well as relief about having an explanation for their body weight ( d = 0.02, P = 0.013 ) in the higher-risk condition, but no increase in fatalism or depression. These results suggest that at the level of anticipated responses to FTO gene feedback, higher-risk results had positive motivational effects with minimal changes in negative affect or fatalism. Genetic testing has the potential to be a useful clinical or preventive tool when combined with appropriate information Why prospective registration of systematic reviews makes sense Prospect i ve registration of systematic review s promotes transparency, helps reduce potential for bias and serves to avoid unintended duplication of review s. Registration offers advantages to many stakeholders in return for modest additional effort from the research ers registering their review', "BACKGROUND People with fragile X syndrome ( FXS ) have an intellectual dysfunction that can range from very mild to severe. Symptoms can include speech and language delays and behavioural difficulties such as aggression or self injurious behaviours, emotional lability, and anxiety-related problems ( for example obsessive-compulsive symptoms and perseverative behaviours ). In some cases, affected people may have an additional diagnosis of attention deficit hyperactivity disorder or an autism spectrum disorder. OBJECTIVES To review the efficacy and safety of L-acetylcarnitine in improving the psychological, intellectual, and social performance of people with FXS. Acetyl-L-carnitine (ALC) in attention-deficit/hyperactivity disorder: a multi-site, placebo-controlled pilot trial. OBJECTIVE To determine whether acetyl-L-carnitine ( ALC ), a metabolite necessary for energy metabolism and essential fatty acid anabolism, might help attention-deficit/hyperactivity disorder ( ADHD ). Trials in Down's syndrome, migraine, and Alzheimer's disease showed benefit for attention. A preliminary trial in ADHD using L-carnitine reported significant benefit. METHOD A multi-site 16-week pilot study r and omized 112 children ( 83 boys, 29 girls ) age 5 - 12 with systematic ally diagnosed ADHD to placebo or ALC in weight-based doses from 500 to 1500 mg b.i.d. The 2001 revisions of the Conners'parent and teacher scales ( including DSM-IV ADHD symptoms ) were administered at baseline, 8, 12, and 16 weeks. Analyses were ANOVA of change from baseline to 16 weeks with treatment, center, and treatment-by-center interaction as independent variables. RESULTS The primary intent-to-treat analysis, of 9 DSM-IV teacher-rated inattentive symptoms, was not significant. However, secondary analyses were interesting. There was significant ( p = 0.02 ) moderation by subtype : superiority of ALC over placebo in the inattentive type, with an opposite tendency in combined type. There was also a geographic effect ( p = 0.047 ). Side effects were negligible ; electrocardiograms, lab work, and physical exam unremarkable. CONCLUSION ALC appears safe, but with no effect on the overall ADHD population ( especially combined type ). It deserves further exploration for possible benefit specifically in the inattentive type [L-acetylcarnitine treatment on fragile X patients hyperactive behaviour]. Hyperactivity is a significant problem for almost all young males affected by fragile X syndrome ( FXS ), the most common inherited disease causing mental retardation. Therapeutical approaches are actually based on Central Nervous System ( CNS ) stimulants lacking a well defined rationale and efficacy while they further decrease the patient's limited attention span. A pilot study on 17 fragile X male treated with L-acetylcarnitine ( LAC ) over one year, showed a significant reduction of their hyperactivity behaviour tested by the Conners Abbreviated Parent-Teacher Question naire. LAC use in FXS patients derives from the hypothesis that the biochemical and physiological properties this substance has may preserve brain activity. LAC is a small, hydrosoluble molecule that easily diffuses in the extracellular space and enters any cell in the nervous system through specific transporters. Different cerebral areas use this molecule differently to metabolize glucose and lipids to provide for ATP and neurotrasmitters synthesis. The acetyl group LAC carriers represents a key metabolic signaling element possibly mediating its effect in the CNS. The exogenous administration of LAC may affect brain activity in FXS by : I ) modulation of fuel partitioning for energy production, which at the mithocondrial level is associated with the Kreb's cycle metabolic role in neurotransmitter synthesis ; II ) remodelling of lipid membrane in terms of LAC actively determining the production of polyunsaturated fatty acids ; III ) preferential effect on the attention component of the cholinergic system which relies on its peculiar modality of communication in the CNS. Based on the above premises an explorative, double-blind, placebo controlled, multicenter study is ongoing. A total population of 160 children from nine European centers will be enrolled. The objective of this study is to determine the effect of LAC on the hyperactive behaviour of FXS children as evaluated by the administration of the Conners Abbreviated Parent Question naire Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder. To determine safety and the efficacy of carnitine treatment in children with attention-deficit hyperactivity disorder ( ADHD ). The ADHD behavior was observed by parents completing the Child Behavior Checklist ( CBCL ) and by teachers completing the Conners teacher-rating score, in a r and omized, double-blind, placebo-controlled double-crossover trial. In 13/24 boys receiving carnitine, home behavior improved as assessed with the CBCL total score ( P < 0.02 ). In 13/24 boys, school behavior improved as assessed with the Conners teacher-rating score ( P < 0.05 ). Before treatment, the CBCL total and sub-scores were significantly different from those of normal Dutch boys ( P < 0.0001 ). Responders showed a significant improvement of the CBCL total scores compared to baseline ( P < 0.0001 ). In the majority of boys no side effects were seen. At baseline and after carnitine treatment, responders showed higher levels of plasma-free carnitine ( P < 0.03 ) and acetylcarnitine ( P < 0.05 ). Compared to baseline, the carnitine treatment caused in the responsive patients a decrease of 20 - 65 % ( 8 - 48 points ) as assessed by the CBCL total problem rating scale. Treatment with carnitine significantly decreased the attention problems and aggressive behavior in boys with ADHD Screening for the presence of FMR1 premutation alleles in women with fibromyalgia. Fibromyalgia is a chronic condition characterized by widespread pain, fatigue, non-restorative sleep and cognitive difficulties that affects 2 - 4 % of the general population. Recently a possible relationship between the FMR1 premutation and fibromyalgia has been pointed out. In attempt to gather more data we screened for the FMR1 CGG expansion 700 DNA sample s from unrelated fibromyalgia patients. This data might be useful for evaluating the incorporation of this test in rheumatologic procedures for women with fibromyalgia. The observed frequency of FMR1 premutation carriers ( 3 of 700, 0.4 % ) is not significantly different from the estimated rate in the general female population ( 1/250 - 1/400 ) ( P=0.539, P=0.716 ). Clinical examination of the FMR1 premutation carriers identified revealed that all of them had important neurological symptoms with regard to muscular symptoms, neurocognitive alterations and neurovegetative impairments. With regard to other clinical aspects of the disease the cases apparently did not differ from the average fibromyalgia patients. On the basis of our results an FMR1 screening among fibromyalgia female patients would not be recommended. However it would be worthwhile to further evaluate the different clinical presentations that fibromyalgia patients might present based on their FMR1 premutation carrier status Acetyl-L-Carnitine as an Adjunctive Therapy in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Placebo-Controlled Trial The objective of this study was to test whether a previous observed Acetyl-L-carnitine ( ALC ) treatment effect could be repeated in an ALC adjunctive therapy treatment trial of attention-deficit/hyperactivity disorder ( ADHD ) in children and adolescents. This was a six-week, r and omized clinical trial undertaken in an outpatient child and adolescent clinic. Subjects included 40 out patients ( 28 boys and 12 girls ) between the ages of 7–13 who met the DSM-IV-TR diagnostic criteria for ADHD. All study subjects were r and omly assigned to receive treatment using capsules of ALC doses ranging from 500 to 1,500 mg/day depending on the weight of the child plus methylpheni date at a dose of 20–30 mg/day depending on weight or Placebo plus methylpheni date at a dose of 20–30 mg/day depending on weight. The principal measure of outcome was the Teacher and Parent attention deficit/hyperactivity disorder Rating Scale- IV. No difference was observed between the two groups on the Parent and Teacher Rating Scale scores ( df = 1 ; F = 0.10 ; P = 0.74 and df = 1 ; F = 0.22 ; P = 0.63 respectively ). Side effects consisting of headache and irritability were observed more frequently in the methylpheni date plus placebo group. The results of this study do not support the application of ALC as an adjunctive therapy to methylpheni date in children and adolescents with ADHD Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease In a double-blind, placebo study, acetyl-L-carnitine was administered to 7 probable Alzheimer's disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebo-treated probable AD patients and 21 age-matched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetyl-L-carnitine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetyl-L-carnitine and placebo AD groups at entry was normalized in the acetyl-L-carnitine-treated but not in the placebo-treated patients. Similar normalization of high-energy phosphate levels was observed in the acetyl-L-carnitine-treated but not in the placebo-treated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD A double‐blind, parallel, multicenter comparison of L‐acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys Attention deficit hyperactivity disorder ( ADHD ) is a frequent behavioral problem in young boys with fragile X syndrome ( FXS ), and its treatment is critical for improving social ability. The short‐term efficacy of stimulant medications like methylpheni date ( MPH ) is well established in children with ADHD. FXS boys treated with MPH have improved attention span and socialization skills ; however their mood becomes unstable at higher doses. Therefore, alternative pharmacological treatment of ADHD symptoms is desirable. A recent study showed that carnitine has a beneficial effect on the hyperactive – impulsive behavior in boys with ADHD without side effects. Our previous placebo‐controlled trial indicated that L‐acetylcarnitine ( LAC ) reduces hyperactivity in FXS boys. The objective of this study was to determine the efficacy of LAC in a larger sample of FXS boys with ADHD. The study design was r and omized, double blind placebo controlled, parallel, and multicenter ( with eight centers involved in Italy, France, and Spain ). Sixty‐three FXS males with ADHD ( aged 6–13 years ) were enrolled ; 7 patients dropped out, 56 completed the one‐year treatment, and 51 were included in the statistical analysis. Both groups improved their behavior, showing that psychosocial intervention has a significant therapeutic effect. However, we observed a stronger reduction of hyperactivity and improvement of social behavior in patients treated with LAC, compared with the placebo group, as determined by the Conners'Global Index Parents and the Vinel and Adaptive Behavior Scale. Our results show that LAC ( 20–50 mg/kg/day ) represents a safe alternative to the use of stimulant drugs for the treatment of ADHD in FXS children. © 2008 Wiley‐Liss,", "The comparison between haemorrhoidal treatments is still unclear. Attempts have been made to adopt a unifying postoperative scoring system and thus ensure adequate comparison between clinical trials. We aim ed to systematic ally review the available outcome scores of haemorrhoidal treatment. Ligation anopexy versus hemorrhoidectomy in the treatment of second- and third-degree hemorrhoids Abstract Background The aim of the study was to compare ligation anopexy ( LA ) and conventional hemorrhoidectomy ( CH ) in treatment of second- and third-degree hemorrhoids. Methods A prospect i ve controlled r and omized clinical trial included 100 patients who underwent CH ( CH group ) and 100 patients who underwent LA ( LA group ). A detailed history was taken from all the patients. The effectiveness, safety, postoperative complications, operative time, length of hospital stay, time until first bowel movement, time until return to work, and postoperative pain score were assessed. Results There was no significant difference between groups regarding age, sex, and preoperative symptoms. The LA group had significantly shorter operative times, earlier first bowel movement, and an earlier return to work/activities. The postoperative pain score in the LA group was significantly lower than that in the CH group on days 1, 3, 7, and 14 after surgery. There was no significant difference between groups as regards postoperative complications. Conclusions LA is safe, and as effective as CH in the treatment of grade II and grade III hemorrhoids, with shorter operative times, earlier mobilization, and lower postoperative pain scores Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. The CONSORT ( Consoli date d St and ards of Reporting Trials ) Statement aims to improve the reporting of r and omized controlled trials ( RCTs ) ; however, it lacks guidance on the reporting of patient-reported outcomes ( PROs ), which are often inadequately reported in trials, thus limiting the value of these data. In this article, we describe the development of the CONSORT PRO extension based on the method ological framework for guideline development proposed by the Enhancing the Quality and Transparency of Health Research ( EQUATOR ) Network. Five CONSORT PRO checklist items are recommended for RCTs in which PROs are primary or important secondary end points. These recommendations urge that the PROs be identified as a primary or secondary outcome in the abstract, that a description of the hypothesis of the PROs and relevant domains be provided ( ie, if a multidimensional PRO tool has been used ), that evidence of the PRO instrument's validity and reliability be provided or cited, that the statistical approaches for dealing with missing data be explicitly stated, and that PRO-specific limitations of study findings and generalizability of results to other population s and clinical practice be discussed. Examples and an up date d CONSORT flow diagram with PRO items are provided. It is recommended that the CONSORT PRO guidance supplement the st and ard CONSORT guidelines for reporting RCTs with PROs as primary or secondary outcomes. Improved reporting of PRO data should facilitate robust interpretation of the results from RCTs and inform patient care Randomized clinical trial of symptom control after stapled anopexy or diathermy excision for haemorrhoid prolapse This multicentre r and omized clinical trial studied how symptoms improved after either stapled anopexy or diathermy excision of haemorrhoids Does a more extensive mucosal excision prevent haemorrhoidal recurrence after stapled haemorrhoidopexy? Long‐term outcome of a randomized controlled trial AIM The study aim ed in a multicentric r and omized controlled trial to define the role of a more extensive mucosal resection on recurrence of mucosal prolapse in patients with Stage III haemorrhoids undergoing stapled haemorrhoidopexy. METHOD In all, 135 patients were r and omized to treatment with a PPH-01/03 ( Ethicon EndoSurgery ) or an EEA ( Covidien ) stapler. They were review ed after a minimum follow-up of 4 years to determine the rate of recurrent mucosal prolapse and general condition ( wellness evaluation score ). Postoperative bowel dysfunction was assessed using the Rome III criteria. RESULTS Eighty-seven ( 65 % ) of the 135 patients ( 48 in the EEA stapler group and 37 in the PPH group ) were available for long-term follow-up. The two groups were comparable for age, gender and duration of follow-up ( mean 49.3 ± 5.4 months and 49.0 ± 5.3 months respectively ). In the EEA group, 11 ( 23 % ) patients had some degree of recurrent prolapse compared with 12 ( 32 % ) in the PPH group ( P = 0.409 ). Persistence of anal bleeding was significantly higher in the PPH group ( P = 0.04 ) while the postoperative Haemorrhoid Symptom Score was significantly better in the EEA group ( 1.73 ± 1.65 vs 3.17 ± 1.94, P < 0.001 ). The wellness evaluation score was significantly better in the EEA group ( 1.2 ± 1.27 vs 0.6 ± 1.0, P = 0.028 ). Furthermore, 7 ( 15 % ) of the patients in the EEA group complained of some evacuation disturbance compared with 13 ( 36 % ) in the PPH group ( P = 0.021 ). CONCLUSION The study failed to demonstrate any significant difference in the long-term recurrence rate of Stage III haemorrhoids using EEA or PPH. Nevertheless, use of the larger volume EEA provides better symptom resolution compared with PPH Prospective randomised multi-centre trial comparing the clinical efficacy, safety and patient acceptability of circular stapled anopexy with closed diathermy haemorrhoidectomy Objective : Unlike excisional haemorrhoidectomy, stapled anopexy ( SA ), which does not involve radical excision, has theoretical advantages, thus offering potential patient benefits. We compared the clinical efficacy, safety and patient acceptability of SA, with closed haemorrhoidectomy ( CH ). Patients and methods : 182 patients with symptomatic haemorrhoids ( grade s II, III, IV ) were r and omly assigned to receive SA or CH and were followed for up to 1 year ( 6, 12, 24, 48 weeks ) after operation. Postoperative pain, symptom control, complications, re-treatment rates, patient satisfaction, and quality of life were compared on an intention-to-treat basis. Results : Postoperative pain in the SA group ( n = 91 ) was significantly lower ( p = 0.004, Mann – Whitney U test ). At 1 year there were no significant differences in the symptom load, symptom severity or the disease severity between the two groups. Overall complication rates were similar but faecal urgency was reported more frequently following SA ( p = 0.093, Fisher ’s exact test ). Despite a similar rate of residual symptoms, prolapse control was better with CH ( p = 0.087, Fisher ’s exact test ), and more patients in the SA group required re-treatment for residual prolapse at 1 year ( p = 0.037, Fisher ’s exact test ). However, more patients rated SA as an excellent operation at 6 and 12 weeks ( p = 0.008 and 0.033, binary logistic regression ) and were willing to undergo a repeat procedure if required ( p = 0.018, Fisher ’s exact test ). Conclusion : Stapled anopexy offers a significantly less painful alternative to excisional haemorrhoidectomy and achieves a higher patient acceptability. Although the overall symptom control and safety are similar in the majority of the patients, the re-treatment rate for recurrent prolapse at 1 year is higher following SA when compared to CH Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomised controlled trial Summary Background Two commonly performed surgical interventions are available for severe ( grade II – IV ) haemorrhoids ; traditional excisional surgery and stapled haemorrhoidopexy. Uncertainty exists as to which is most effective. The eTHoS trial was design ed to establish the clinical effectiveness and cost-effectiveness of stapled haemorrhoidopexy compared with traditional excisional surgery. Methods The eTHoS trial was a large, open-label, multicentre, parallel-group, pragmatic r and omised controlled trial done in adult participants ( aged 18 years or older ) referred to hospital for surgical treatment for grade II – IV haemorrhoids. Participants were r and omly assigned ( 1:1 ) to receive either traditional excisional surgery or stapled haemorrhoidopexy. R and omisation was minimised according to baseline EuroQol 5 dimensions 3 level score ( EQ-5D-3L ), haemorrhoid grade, sex, and centre with an automated system to stapled haemorrhoidopexy or traditional excisional surgery. The primary outcome was area under the quality of life curve ( AUC ) measured with the EQ-5D-3L descriptive system over 24 months, assessed according to the r and omised groups. The primary outcome measure was analysed using linear regression with adjustment for the minimisation variables. This trial is registered with the IS RCT N registry, number IS RCT N80061723. Findings Between Jan 13, 2011, and Aug 1, 2014, 777 patients were r and omised ( 389 to receive stapled haemorrhoidopexy and 388 to receive traditional excisional surgery ). Stapled haemorrhoidopexy was less painful than traditional excisional surgery in the short term and surgical complication rates were similar between groups. The EQ-5D-3L AUC score was higher in the traditional excisional surgery group than the stapled haemorrhoidopexy group over 24 months ; mean difference −0·073 ( 95 % CI −0·140 to −0·006 ; p=0·0342 ). EQ-5D-3L was higher for stapled haemorrhoidopexy in the first 6 weeks after surgery, the traditional excisional surgery group had significantly better quality of life scores than the stapled haemorrhoidopexy group. 24 ( 7 % ) of 338 participants who received stapled haemorrhoidopexy and 33 ( 9 % ) of 352 participants who received traditional excisional surgery had serious adverse events. Interpretation As part of a tailored management plan for haemorrhoids, traditional excisional surgery should be considered over stapled haemorrhoidopexy as the surgical treatment of choice. Funding National Institute for Health Research Health Technology Assessment programme Prospective evaluation of stapled haemorrhoidopexy versus transanal haemorrhoidal dearterialisation for stage II and III haemorrhoids: three-year outcomes Introduction The aim of the study was to compare short- and medium-term outcomes of transanal haemorrhoidal dearterialisation ( THD ) versus stapled haemorrhoidopexy ( SH ) for the treatment of second- and third-degree haemorrhoids. Methods Patients with second- or third-degree haemorrhoids who failed conservative treatment were r and omly allocated to THD or SH. Preoperative and postoperative symptoms, postoperative pain, time until return to normal activities, complications, patient satisfaction and recurrence rates were all assessed prospect ively. Patients were followed up at 2, 8 months and when the study was completed. Results Twenty-eight patients ( 43 % third degree ) underwent THD and 24 ( 38 % third degree ) underwent SH. There were no significant differences in terms of postoperative pain, expected pain and analgesia requirements, but more THD patients returned to work within 4 days ( P < 0.05 ). One THD patient developed a sub-mucosal haematoma after surgery, one SH patient occlusion of the rectal lumen and two rectal bleeding. At 8-month follow-up, two SH patients complained of faecal urgency. At 38-month follow-up ( range 33–48 months ), all short-term complications resolved. Patient satisfaction ( “ excellent/good outcome ”, THD 89 vs. SH 87 % ) and recurrence rate ( THD 14 vs. SH 13 % ) were similar in the two groups. Conclusions Short-term results although similar seem to suggest SH may result in increased morbidity while return to work is quicker after THD. Medium-term results demonstrate that THD and SH have similar effectiveness Embolization of the Superior Rectal Arteries for Hemorrhoidal Disease: Prospective Results in 25 Patients. PURPOSE To evaluate efficacy and safety of superior rectal artery embolization of hemorrhoidal disease as a first-line invasive treatment. MATERIAL S AND METHODS This prospect i ve study was conducted between 2014 and 2015 on 25 consecutive patients ( 16 men and 9 women with a mean age of 53 y [ range, 30 - 76 y ] ) with grade II-III hemorrhoids refractory to medical treatment. A transfemoral superselective superior rectal artery branch embolization was performed using 2- and 3-mm diameter microcoils. Over the following 12 months, clinical outcomes were evaluated using the French bleeding score, Goligher prolapse score, visual analog scale ( VAS ) score for pain, quality -of-life score. The primary endpoint was relief of symptoms by 12 months based on a 2-point minimum improvement on VAS score and bleeding score. RESULTS At 12 months after embolization, clinical success was obtained in 18 patients ( 72 % ), 8 of whom had 2 embolizations. VAS score decreased from 4.6 to 2.3 ( P <.01 ), and bleeding score decreased from 5.5 to 2.3 ( P <.01 ). Quality -of-life and prolapse scores also showed improvement ( P <.05 ), and no patients experienced any early or late complications. Complete clinical failure was observed in 7 patients. After coil embolization, the collateral supply to the hemorrhoidal cushions was significantly related to any recurrence ( P =.001 ). CONCLUSIONS Hemorrhoidal artery coil embolization was found to be a safe and effective treatment for grade II-III hemorrhoids Randomized controlled trial comparing rubber band ligation with stapled haemorrhoidopexy for Grade II circumferential haemorrhoids: long‐term results Objective An improved underst and ing of the pathophysiology of haemorrhoids has result ed in the introduction of new surgical techniques including stapled haemorrhoidopexy ( SH ). This r and omized controlled trial compared the long‐term effectiveness of SH with rubber b and ligation ( RBL ) in the treatment of grade II circumferential symptomatic haemorrhoids The prevalence of hemorrhoids in adults Introduction Exact data on the prevalence of hemorrhoids are rare. Therefore, we design ed a study to investigate the prevalence of hemorrhoids and associated risk factors in an adult general population. Methods Between 2008 and 2009, consecutive patients were included in a prospect i ve study. They attended the Austrian national wide health care program for colorectal cancer screening at four medical institutions. A flexible colonoscopy and detailed examination were conducted in all patients. Hemorrhoids were defined according to a st and ardized grading system. Independent variables included baseline characteristics, sociodemographic data, and health status. Potential risk factors were calculated by univariate and multivariate analysis. Results Of 976 participants, 380 patients ( 38.93 % ) suffered from hemorrhoids. In 277 patients ( 72.89 % ), hemorrhoids were classified as grade I, in 70 patients ( 18.42 % ) as grade II, in 31 patients ( 8.16 % ) as grade III, and in 2 patients ( 0.53 % ) as grade IV. One hundred seventy patients ( 44.74 % ) complained about symptoms associated with hemorrhoids, whereas 210 patients ( 55.26 % ) reported no symptoms. In the univariate and multivariate analysis, body mass index ( BMI ) had a significant effect on the occurrence of hemorrhoids with p = 0.0391 and p = 0.0282, respectively. Even when correcting for other potential risk factors, an increase in the BMI of one increased the risk of hemorrhoids by 3.5 %. Conclusion Hemorrhoids occur frequently in the adult general population. Notably, a considerable number of people with hemorrhoids do not complain about symptoms. In addition, a high BMI can be regarded as an independent risk factor for hemorrhoids Long‐term results of stapled haemorrhoidopexy in a prospective single centre study of 153 patients with 1–6 years’ follow‐up Aim The long‐term results of stapled haemorrhoidopexy for prolapsed haemorrhoids were assessed using uniform methods to acquire data and pre‐set definitions of failure, recurrence, residual symptoms and impaired continence Transanal haemorrhoidal dearterialization (THD) for selected fourth-degree haemorrhoids Background Traditional treatment of fourth-degree haemorrhoidal disease ( HD ) is conventional haemorrhoidectomy and is frequently associated with significant pain and morbidity. In recent years, the use of transanal haemorrhoidal dearterialization ( THD ) for the treatment of HD has increased. The procedure aims to decrease the arterial blood flow to the haemorrhoids. Moreover, since a rectal mucopexy to treat the prolapsing component has become part of the THD technique, this treatment is also indicated for more advanced HD. The aim of this study was to assess the possible role of THD in the treatment of fourth-degree HD. Methods All patients with non-fibrotic fourth-degree HD were offered the THD procedure with mucopexy. Excision of skin tags was added to THD and mucopexy, when needed. A specific score was used to assess HD severity, ranging from 0 ( no HD ) to 20 ( worst HD ). The mean preoperative score was 18.1 ± 1.8. Results Thirty-five consecutive patients ( mean age 50.4 ± 13.8 years ; 19 men ) with fourth-degree HD were prospect ively enroled. An average of 6 arteries were identified and transfixed. Mucopexy was achieved with a 3–6 sector plication of rectal mucosa. Mean operating time was 33 ± 12 min. No intraoperative complications were recorded. Postoperative morbidity included 3 ( 8.6 % ) haemorrhoidal thromboses ( 1 requiring surgery ) and 2 ( 5.7 % ) episodes of bleeding ( 1 requiring surgical haemostasis ). Five patients ( 14.3 % ) had urinary retention requiring catheterization. At a median follow-up of 10 months ( range 2–28 months ), symptoms had resolved or significantly improved in 33 ( 94 % ) patients. Nine patients ( 25.7 % ) reported irregular bleeding, 3 patients ( 8.6 % ) mild anal pain, 4 patients ( 11.4 % ) transient anal burning and 4 patients ( 11.4 % ) tenesmus. Ten patients ( 28.6 % ) experienced some degree of residual prolapse, significant only in 2 ( 5.7 % ) who required further surgery. There was no anorectal stenosis, and no faecal incontinence was reported. At a median follow-up of 10 months, the symptomatic score was 2.5 ± 2.5 ( P < 0.005 ). Conclusion Transanal haemorrhoidal dearterialization seems to be a safe and effective treatment for fourth-degree HD providing a significant improvement of symptoms for the majority of patients. When present, persisting symptoms are mostly transient, occasional or limited in severity, and only a very few patients require further intervention. Larger series and longer follow-up to further assess the role of THD in this challenging group of pts Perianal Local Block for Stapled Anopexy Purpose This study was design ed to demonstrate the usefulness of a method of regional anesthesia for circular stapler anopexy for prolapsing hemorrhoids. Methods Thirty-three patients consented to stapled anopexy under perianal local anesthesia. Eighteen patients with stapled anopexy under general anesthesia were controls. The perianal block was applied with 40 ml of ropivacaine, 4.75 mg/ml, injected immediately peripheral to the external sphincter. A submucosal block with 15 ml of ropivacaine, 2 mg/ml, was added after applying the pursestring suture. Postoperative pain was rated by the patient for 14 days by using a ten-point visual analogue scale. Patients also su bmi tted a preoperative and postoperative ( 3–6 months ) symptom question naire to rate anal symptoms. Results No operation was converted to general anesthesia. Operation time was similar in both groups. All patients in the local anesthesia group were pain free at discharge. The sums of pain scores during 14 days for daily average pain and peak pain were similar in both groups ( average pain 23 ( local anesthesia ) vs. 35 ( general anesthesia ) ; peak pain 39 ( local anesthesia ) vs. 50 ( general anesthesia ) ; P > 0.05 ). The preoperative symptom scores were 7.8 ( local anesthesia ) vs. 8.9 ( general anesthesia ) points, and the follow-up scores were 2.2 ( local anesthesia ) and 2.7 ( general anesthesia ), a significant improvement ( P = 0.001 ) in both groups but not different between groups. Conclusions A perianal local block is easy to apply and has a high degree of acceptance among patients. The operation time, postoperative pain, and success rates of the operation equaled those of stapled anopexy performed under general anesthesia. The advantages are quicker turnover between cases and simpler management of pain-free postoperative patients in day surgery Stapled and Open Hemorrhoidectomy: Randomized Controlled Trial of Early Results The aim of the study was to compare the early results in 52 patients r and omly allocated to undergo either stapled or open hemorrhoidectomy. Seventy-four patients with grade III and IV hemorrhoids were r and omly allocated to undergo either stapled ( 37 patients ) or open ( 37 patients ) hemorrhoidectomy. Stapled hemorrhoidectomy was performed with the use of a circular stapling device. Open hemorrhoidectomy was accomplished according to the Milligan-Morgan technique. Postoperative pain was assessed by means of a visual analogue scale ( V.A.S. ). Recovery evaluation included return to pain-free defecation and normal activities. A 6-month clinical follow-up and a 17.5 ( 10 to 27)-month median telephone follow-up was obtained in all patients. Operation time for stapled hemorrhoidectomy was shorter ( median 25 [ range 15 to 49 ] minutes versus 30 [ range 20 to 44 ] minutes, p = 0.041 ). Median ( range ) V.A.S. scores in the stapled group were significantly lower ( V.A.S. score after 4 hours : 4 [ 2 to 6 ] versus 5 [ 2 to 8 ], p = 0.001 ; V.A.S. score after 24 hours : 3 [ 1 to 6 ] versus 5 [ 3 to 7 ], p = 0.000 ; V.A.S. score after first defecation : 5 [ 3 to 8 ] versus 7 [ 3 to 9 ], p = 0.000 ). Resumption of pain-free defecation was significantly faster in the stapled group ( 10 [ 6 to 14 ] days vs 12 [ 9 to 19 ] days, p = 0.001 ). At follow-up 4 weeks and 6 months postoperatively the median ( range ) symptom severity score was similar in both groups ( 1 [ 0 to 2 ] versus 0 [ 0 to 3 ], p = 0.150 and 0 [ 0 to 2 ] versus 0 [ 0 to 2 ], p = 0.731 ). At long-term follow-up occasional pain was present in 6/37 ( 16.2 ) patients in the stapled group and 7/37 ( 18.9 % ) in the Milligan-Morgan group ( p = 1.000 ) ; episodes of bleeding were reported by 8/37 ( 21.6 % ) patients in the stapled group and 5/37 ( 13.5 % ) patients in the Milligan-Morgan group ( p = 0.542 ). No problems related to continence and defecation were reported in either group. Patients were satisfied with the operation in 33/37 ( 89.2 % ) cases in the stapled group and 31/37 ( 83.8 % ) cases in the Milligan-Morgan group ( p = 0.735 ). Hemorrhoidectomy with a circular staple device is easy to perform and achieves better results than the Milligan-Morgan technique in terms of postoperative pain and recovery. Comparable results are obtained at long-term follow-up The HubBLe Trial: haemorrhoidal artery ligation (HAL) versus rubber band ligation (RBL) for symptomatic second- and third-degree haemorrhoids: a multicentre randomised controlled trial and health-economic evaluation. BACKGROUND Optimal surgical intervention for low- grade haemorrhoids is unknown. Rubber b and ligation ( RBL ) is probably the most common intervention. Haemorrhoidal artery ligation ( HAL ) is a novel alternative that may be more efficacious. OBJECTIVE The comparison of HAL with RBL for the treatment of grade II/III haemorrhoids. DESIGN A multicentre, parallel-group r and omised controlled trial. PERSPECTIVE UK NHS and Personal Social Services. SETTING 17 NHS Trusts. PARTICIPANTS Patients aged ≥ 18 years presenting with grade II/III ( second- and third-degree ) haemorrhoids, including those who have undergone previous RBL. INTERVENTIONS HAL with Doppler probe compared with RBL. OUTCOMES Primary outcome - recurrence at 1 year post procedure ; secondary outcomes - recurrence at 6 weeks ; haemorrhoid severity score ; European Quality of Life-5 Dimensions, 5-level version ( EQ-5D-5L ) ; Vaizey incontinence score ; pain assessment ; complications ; and cost-effectiveness. RESULTS A total of 370 participants entered the trial. At 1 year post procedure, 30 % of the HAL group had evidence of recurrence compared with 49 % after RBL [ adjusted odds ratio ( OR ) = 2.23, 95 % confidence interval ( CI ) 1.42 to 3.51 ; p = 0.0005 ]. The main reason for the difference was the number of extra procedures required to achieve improvement/cure. If a single HAL is compared with multiple RBLs then only 37.5 % recurred in the RBL arm ( adjusted OR 1.35, 95 % CI 0.85 to 2.15 ; p = 0.20 ). Persistence of significant symptoms at 6 weeks was lower in both arms than at 1 year ( 9 % HAL and 29 % RBL ), suggesting significant deterioration in both groups over the year. Symptom score, EQ-5D-5L and Vaizey score improved in both groups compared with baseline, but there was no difference between interventions. Pain was less severe and of shorter duration in the RBL group ; most of the HAL group who had pain had mild to moderate pain, resolving by 3 weeks. Complications were low frequency and not significantly different between groups. It appeared that HAL was not cost-effective compared with RBL. In the base-case analysis, the difference in mean total costs was £ 1027 higher for HAL. Quality -adjusted life-years ( QALYs ) were higher for HAL ; however, the difference was very small ( 0.01 ) result ing in an incremental cost-effectiveness ratio of £ 104,427 per additional QALY. CONCLUSIONS At 1 year, although HAL result ed in fewer recurrences, recurrence was similar to repeat RBL. Symptom scores, complications, EQ-5D-5L and continence score were no different, and patients had more pain in the early postoperative period after HAL. HAL is more expensive and unlikely to be cost-effective in terms of incremental cost per QALY. LIMITATIONS Blinding of participants and site staff was not possible. FUTURE WORK The incidence of recurrence may continue to increase with time. Further follow-up would add to the evidence regarding long-term clinical effectiveness and cost-effectiveness. The polysymptomatic nature of haemorrhoidal disease requires a vali date d scoring system, and the data from this trial will allow further assessment of validity of such a system. These data add to the literature regarding treatment of grade II/III haemorrhoids. The results dovetail with results from the eTHoS study [ Watson AJM, Hudson J, Wood J, Kilonzo M, Brown SR, McDonald Minimal open hemorrhoidectomy The original operation for open hemorrhoidectomy as described by Milligan – Morgan is no longer used. There is a great variation in how the operation is described in clinical trials. A number of modifications have been proposed attempting to reduce postoperative pain. An anatomical plane for the dissection was first described by Loder and Phillips [ 1 ]. They encountered small fibers passing from the internal sphincter to the anal cushions and emphasized the importance of dividing these fibers close to the cushions leaving an intact surface over the internal sphincter. Gerjy et al. described a subdermal fascia continuing into a membrane covering the internal sphincter, which was easily identified after incision of the skin of the pedicle [ 2 ]. In addition, Loder and Phillips were the first to suggest diathermy dissection and coagulation [ 1 ]. A better knowledge of hemorrhoidal vascular anatomy, demonstrating, how the arterial supply to the hemorrhoids crosses the rectal wall, has reduced the need for pedicle ligation. Seow-Chonen et al. demonstrated in a r and omized study that diathermy dissection, when compared to scissor dissection, result ed in less postoperative pain and Bessa et al. showed how diathermy coagulation of the pedicle was superior to ligation in reducing postoperative pain [ 3, 4 ]. We adapted these principles and also minimized excision of the skin and the hemorrhoid. In addition, we left a part of the hemorrhoid intra-anally to reduce any impact on anal continence. We called this modification “ minimal open hemorrhoidectomy ” ( MOH ). Material s and A validated severity score for haemorrhoids as an essential prerequisite for future haemorrhoid trials Background There is a lack of st and ardised outcomes for haemorrhoidal disease making comparison between trials difficult. A need for a very well vali date d severity score is essential to facilitate meta- analysis of comparative studies, enabling evidence -based clinical practice. Methods The Hubble trial provides a large cohort of patients with haemorrhoidal disease r and omised to rubber b and ligation ( RBL ) or haemorrhoidal artery ligation. The haemorrhoid severity score ( HSS ) was collected on each patient at baseline, 6 weeks and 1 year after intervention. This allows for the responsiveness of the HSS instrument to be examined and compared with a more specific instrument, the Vaizey incontinence score ( also collected ). Responsiveness was tested using four methods ( effect size, st and ardised response means ( SRM ), significance of change, and responsiveness statistic ). Results The four tests of responsiveness demonstrated that the HSS was more responsive to changes in the patient ’s health status following both of the interventions compared to the Vaizey question naire. For example, between baseline and 6 weeks, the RBL intervention effect size scores and SRM calculations indicated a non-significant small amount of change ( 0.20 and 0.16 respectively ). However, using the HSS, the effect size and SRM demonstrated a large magnitude of change ( 1.12 and 1.01, respectively ) which was significant. Similar results were observed at 1 year. Significance of change scores and the index of responsiveness were also higher for the HSS question naire than the Vaizey across both treatment modalities. Conclusions The HSS is a highly responsive tool for the detection of changes in haemorrhoid symptoms. It should form an essential patient-reported outcome tool for future studies on haemorrhoidal disease Doppler-guided transanal haemorrhoidal dearterialization for haemorrhoids: results from a multicentre trial. AIM This multicentre study, based on the largest patient population ever published, aims to evaluate the efficacy of Doppler-guided transanal haemorrhoidal dearterialization ( THD Doppler ) in the treatment of symptomatic haemorrhoids and to identify the factors predicting failure for an effective mid-term outcome. METHOD Eight hundred and three patients affected by Grade II ( 137, 17.1 % ), III ( 548, 68.2 % ) and IV ( 118, 14.7 % ) symptomatic haemorrhoidal disease underwent THD Doppler, with a rectal mucopexy in patients with haemorrhoidal prolapse. The disease was assessed through a specifically design ed symptom question naire and scoring system. A uni- and multivariate analyses of the potential predictive factors for failure were performed. RESULTS The morbidity rate was 18.0 %, represented mainly by pain or tenesmus ( 106 patients, 13.0 % ). Acute bleeding requiring surgical haemostasis occurred in seven patients ( 0.9 % ). No serious or life-threatening complications occurred. After a mean follow-up period of 11.1 ± 9.2 months, the overall success rate was 90.7 % ( 728 patients ), with a recurrence of haemorrhoidal prolapse, bleeding, and both symptoms in 51 ( 6.3 % ), 19 ( 2.4 % ) and 5 ( 0.6 % ) patients, respectively. Sixteen out of 47 patients undergoing re-operation had a conventional haemorrhoidectomy. All the symptoms were significantly improved in each domain of the score ( P < 0.0001 ). At multivariate analysis the absence of morbidity and performance of a distal Doppler-guided dearterialization were associated with a better outcome. CONCLUSION THD Doppler is a safe and effective therapy for haemorrhoidal disease. If this technique is to be employed, an accurate distal Doppler-guided dearterialization and a tailored mucopexy are m and atory to contain and reduce the symptoms", 'OBJECTIVE The use of behavioral interventions has been shown to improve glycemic control, however, the effectiveness of different behavioral interventions in one of the most high risk population s, African Americans, remains unclear. Our systematic review identified and examined findings of published behavioral interventions targeted at African Americans to improve glycemic control. The goal of our study was to distinguish which interventions were effective and identify areas for future research. Self-Efficacy, Problem Solving, and Social-Environmental Support Are Associated With Diabetes Self-Management Behaviors OBJECTIVE To evaluate associations between psychosocial and social-environmental variables and diabetes self-management, and diabetes control. RESEARCH DESIGN AND METHODS Baseline data from a type 2 diabetes self-management r and omized trial with 463 adults having elevated BMI ( M = 34.8 kg/m2 ) were used to investigate relations among demographic, psychosocial, and social-environmental variables ; dietary, exercise, and medication-taking behaviors ; and biologic outcomes. RESULTS Self-efficacy, problem solving, and social-environmental support were independently associated with diet and exercise, increasing the variance accounted for by 23 and 19 %, respectively. Only diet contributed to explained variance in BMI ( β = −0.17, P = 0.0003 ) and self-rated health status ( β = 0.25, P < 0.0001 ) ; and only medication-taking behaviors contributed to lipid ratio ( total – to – HDL ) ( β = −0.20, P = 0.0001 ) and A1C ( β = −0.21, P < 0.0001 ). CONCLUSIONS Interventions should focus on enhancing self-efficacy, problem solving, and social-environmental support to improve self-management of diabetes Self-management support in "real-world" settings: an empowerment-based intervention. OBJECTIVE This study examined the impact of a 6-month, empowerment-based diabetes self-management support ( DSMS ) intervention on clinical outcomes, self-care behaviors, and quality of life ( QOL ) compared to a 6-month control period. METHODS This control-intervention cohort study recruited 77 African-American adults with type 2 diabetes. Baseline, 6-month, and 12-month assessment s measured A1C, weight, body mass index ( BMI ), blood pressure, lipids, self-care behaviors, and QOL. During the control period, participants received weekly educational newsletters. During the intervention period, participants attended weekly DSMS groups as frequently as they needed. Sessions were guided by participants\'self-management questions and concerns, and also emphasized experiential learning, coping, problem-solving, and goal - setting. RESULTS The control period found significant improvements for diastolic BP ( p<0.05 ), serum cholesterol ( p<0.001 ), following a healthy diet ( p<0.01 ), and monitoring blood glucose ( p<0.01 ). The intervention period found significant additional improvements for A1C ( p<0.001 ), weight ( p<0.05 ), BMI ( p<0.05 ), and LDL ( p<0.001 ). Compared to the control period, participation in the intervention led to a significant reduction in A1C ( p<0.01 ). CONCLUSION Findings suggest that an empowerment-based, DSMS intervention is promising for improving and /or maintaining diabetes-related health, particularly A1C. PRACTICAL IMPLICATION S Incorporating empowerment principles in DSMS interventions may be useful for supporting patients\'self-management efforts in " real-world " setting TeleHealth Improves Diabetes Self-Management in an Underserved Community OBJECTIVE To conduct a 1-year r and omized clinical trial to evaluate a remote comprehensive diabetes self-management education ( DSME ) intervention, Diabetes TeleCare, administered by a dietitian and nurse/certified diabetes educator ( CDE ) in the setting of a federally qualified health center ( FQHC ) in rural South Carolina. RESEARCH DESIGN AND METHODS Participants were recruited from three member health centers of an FQHC and were r and omized to either Diabetes TeleCare, a 12-month, 13-session curriculum delivered using telehealth strategies, or usual care. RESULTS Mixed linear regression model results for repeated measures showed a significant reduction in glycated hemoglobin ( GHb ) in the Diabetes TeleCare group from baseline to 6 and 12 months ( 9.4 ± 0.3, 8.3 ± 0.3, and 8.2 ± 0.4, respectively ) compared with usual care ( 8.8 ± 0.3, 8.6 ± 0.3, and 8.6 ± 0.3, respectively ). LDL cholesterol was reduced at 12 months in the Diabetes TeleCare group compared with usual care. Although not part of the original study design, GHb was reduced from baseline to 12 and 24 months in the Diabetes TeleCare group ( 9.2 ± 0.4, 7.4 ± 0.5, and 7.6 ± 0.5, respectively ) compared with usual care ( 8.7 ± 0.4, 8.1 ± 0.4, and 8.1 ± 0.5, respectively ) in a post hoc analysis of a subset of the r and omized sample who completed a 24-month follow-up visit. CONCLUSIONS Telehealth effectively created access to successfully conduct a 1-year remote DSME by a nurse CDE and dietitian that improved metabolic control and reduced cardiovascular risk in an ethnically diverse and rural population A patient-centric, provider-assisted diabetes telehealth self-management intervention for urban minorities. This article describes the design and implementation of an online diabetes self-management intervention for a sample of inner-city African Americans with diabetes. Study participants were r and omly assigned to the treatment ( 26 ) and control ( 21 ) conditions. The results indicate that treatment group participants were more likely to achieve positive outcomes in terms of lowered hemoglobin A1c and body mass index measurements than were control group members. These findings support the development of telehealth interventions to promote effective chronic disease management in medically underserved communities Glycemic Control and Health Disparities in Older Ethnically Diverse Underserved Adults With Diabetes OBJECTIVE The Informatics for Diabetes Education and Telemedicine ( IDEATel ) project r and omized ethnically diverse underserved older adults with diabetes to a telemedicine intervention or usual care. Intervention participants had lower A1C levels over 5 years. New analyses were performed to help better underst and this difference. RESEARCH DESIGN AND METHODS IDEATel r and omized Medicare beneficiaries with diabetes ( n = 1,665 ) to receive home video visits with a diabetes educator and upload glucose levels every 4–6 weeks or usual care ( 2000–2007 ). Annual measurements included BMI, A1C ( primary outcome ), and completion of question naires. Mixed-model analyses were performed using r and om effects to adjust for clustering within primary care physicians. RESULTS At baseline, A1C levels ( mean ± SD ) were 7.02 ± 1.25 % in non-Hispanic whites ( n = 821 ), 7.58 ± 1.78 % in non-Hispanic blacks ( n = 248 ), and 7.79 ± 1.68 % in Hispanics ( n = 585 ). Over time, lower A1C levels were associated with more glucose uploads ( P = 0.02 ) and female sex ( P = 0.002 ). Blacks, Hispanics, and insulin-users had higher A1C levels than non-Hispanic whites ( P < 0.0001 ). BMI was not associated with A1C levels. Blacks and Hispanics had significantly fewer uploads than non-Hispanic whites over time. Hispanics had the highest baseline A1C levels and showed the greatest improvement in the intervention, but, unlike non-Hispanic whites, Hispanics did not achieve A1C levels < 7.0 % at 5 years. CONCLUSIONS Racial/ethnic disparities were observed in this cohort of underserved older adults with diabetes. The IDEATel telemedicine intervention was associated with improvement in glycemic control, particularly in Hispanics, who had the highest baseline A1C levels, suggesting that telemedicine has the potential to help reduce disparities in diabetes management Evaluating a problem-based empowerment program for African Americans with diabetes: results of a randomized controlled trial. OBJECTIVE The objective of this study was to evaluate the impact of a problem-based empowerment patient education program specifically tailored for urban African Americans with type 2 diabetes. RESEARCH DESIGN AND METHODS The study used a r and omized controlled trial ( RCT ) pretest/post-test design with repeated measures. Patients were r and omly assigned to either a six-week intervention group or a six-week wait-listed control group. After completing the six sessions, patients were invited to participate in one of two follow-up conditions ; attend a monthly support group or receive a monthly phone call from a nurse. Assessment measures included HbA1C, lipids, blood pressure, weight, self-management behavior and psychosocial adaptation. RESULTS Both control and intervention patients showed a broad array of small-to-modest positive changes during the six-week RCT. These gains were maintained or improved upon during the one-year follow-up period. For patients in the two follow-up conditions, a positive correlation was seen between the number of follow-up contacts and their one-year HbA1C values. CONCLUSIONS We believe that results of this study can be attributed to volunteer bias, study effects ( ie, providing study data on several occasions to patients and their physicians during the one-year study period ), and impact of the interventions. However, the study design does not allow us to examine the relative impact of these three factors on the patient improvements seen over the one-year study period Pounds off with empowerment (POWER): a clinical trial of weight management strategies for black and white adults with diabetes who live in medically underserved rural communities. OBJECTIVES We evaluated lifestyle interventions for diabetic persons who live in rural communities. METHODS We conducted a 12-month r and omized clinical trial ( n = 152 ) of " intensive-lifestyle " ( modeled after the NIH Diabetes Prevention Program ) and " reimbursable-lifestyle " ( intensive-lifestyle intervention delivered in the time allotted for Medicare reimbursement for diabetes education related to nutrition and physical activity ) interventions with usual care as a control. RESULTS Modest weight loss occurred by 6 months among intensive-lifestyle participants and was greater than the weight loss among usual-care participants ( 2.6 kg vs 0.4 kg, P<.01 ). At 12 months, a greater proportion of intensive-lifestyle participants had lost 2 kg or more than usual-care participants ( 49 % vs 25 %, P<.05 ). No differences in weight change were observed between reimbursable-lifestyle and usual-care participants. Glycated hemoglobin was reduced among all groups ( P<.05 ) but was not different between groups. CONCLUSIONS Improvement in both weight and glycemia was attainable by lifestyle interventions design ed for persons who had type 2 diabetes and lived in rural communities', "Purpose Fatigue is a subjective complaint that is believed to be multifactorial in its etiology and multidimensional in its expression. Fatigue may be experienced by individuals in different dimensions as physical, mental, and emotional tiredness. The purpose s of this study were to review and characterize the use of the 30-item Multidimensional Fatigue Symptom Inventory-Short Form ( MFSI-SF ) in published studies and to evaluate the available evidence for its psychometric properties. Effects of continuous positive airway pressure on fatigue and sleepiness in patients with obstructive sleep apnea: data from a randomized controlled trial. OBJECTIVES Complaints of fatigue are frequent in patients with obstructive sleep apnea ( OSA ) ; however, the impact of continuous positive airway pressure ( CPAP ) on fatigue remains unclear. METHODS Fifty-nine men and women with OSA were r and omly assigned to therapeutic or placebo CPAP in a double-blind fashion for a 3-week intervention period. Four outcome measures were assessed : ( 1 ) fatigue/vigor measured with the Multidimensional Fatigue Symptom Inventory -- Short Form ( MFSI-sf ), the ( 2 ) fatigue and ( 3 ) vigor subscales of the Profile of Mood States -- Short Form ( POMS ), and ( 4 ) the Epworth Sleepiness Scale ( ESS ). Data were analyzed using repeated- measures analysis of variance. RESULTS Compared with patients receiving placebo CPAP, those patients treated with therapeutic CPAP showed significant reductions in the apnea-hypopnea index, as well as decreases in both measures of fatigue and increases in vigor ( P values < 0.05 ). The beneficial effect of therapeutic treatment was most pronounced in patients with high levels of fatigue at study onset. Significant treatment effects in sleepiness scores were not observed in the entire sample ( P > 0.05 ) ; however, in a subset of patients with excessive sleepiness at the onset of treatment, ESS scores were significantly reduced with use of therapeutic CPAP ( P < 0.05 ). CONCLUSIONS Results suggest that 3 weeks of therapeutic CPAP significantly reduced fatigue and increased energy in patients with OSA. Therapeutic CPAP significantly reduced daytime sleepiness in patients who reported excessive sleepiness at the onset of treatment Cognitive complaints after breast cancer treatments: examining the relationship with neuropsychological test performance. BACKGROUND Cognitive complaints are reported frequently after breast cancer treatments. Their association with neuropsychological ( NP ) test performance is not well-established. METHODS Early-stage, posttreatment breast cancer patients were enrolled in a prospect i ve, longitudinal, cohort study prior to starting endocrine therapy. Evaluation included an NP test battery and self-report question naires assessing symptoms, including cognitive complaints. Multivariable regression models assessed associations among cognitive complaints, mood, treatment exposures, and NP test performance. RESULTS One hundred eighty-nine breast cancer patients, aged 21 - 65 years, completed the evaluation ; 23.3 % endorsed higher memory complaints and 19.0 % reported higher executive function complaints ( > 1 SD above the mean for healthy control sample ). Regression modeling demonstrated a statistically significant association of higher memory complaints with combined chemotherapy and radiation treatments ( P =.01 ), poorer NP verbal memory performance ( P =.02 ), and higher depressive symptoms ( P <.001 ), controlling for age and IQ. For executive functioning complaints, multivariable modeling controlling for age, IQ, and other confounds demonstrated statistically significant associations with better NP visual memory performance ( P =.03 ) and higher depressive symptoms ( P <.001 ), whereas combined chemotherapy and radiation treatment ( P =.05 ) approached statistical significance. CONCLUSIONS About one in five post-adjuvant treatment breast cancer patients had elevated memory and /or executive function complaints that were statistically significantly associated with domain-specific NP test performances and depressive symptoms ; combined chemotherapy and radiation treatment was also statistically significantly associated with memory complaints. These results and other emerging studies suggest that subjective cognitive complaints in part reflect objective NP performance, although their etiology and biology appear to be multifactorial, motivating further transdisciplinary research Assessment of Daily and Weekly Fatigue Among African American Cancer Survivors This investigation evaluates two common measures of cancer-related fatigue, one multidimensional/retrospective and one unidimensional/same day. Fifty-two African American survivors of diverse cancers completed fatigue visual analogue scales once daily, and the Multidimensional Fatigue Symptom Inventory-Short Form ( MFSI-SF ) once weekly, for four weeks. Zero-order correlations showed retrospective fatigue was significantly related to average, peak, and most recent same-day fatigue. Multilevel r and om coefficient modeling showed unidimensional fatigue shared the most variance with the MFSI-SF's General subscale for three weeks, and with the Vigor subscale for one week. Research ers and clinicians may wish to prioritize multidimensional measures when assessing cancer-related fatigue, if appropriate A randomized controlled trial of an internet intervention for adults with insomnia: effects on comorbid psychological and fatigue symptoms. OBJECTIVE Insomnia is frequently comorbid with other medical and psychological disorders. This secondary data analysis investigated whether an Internet-delivered cognitive behavioral therapy for insomnia ( CBT-I ) intervention could also reduce comorbid psychological and fatigue symptoms. METHOD Data from a pilot r and omized controlled trial ( RCT ) testing the efficacy of Internet-delivered CBT-I relative to a waitlist control was used to examine changes in symptoms of depression, anxiety, mental health quality of life ( QOL ), and fatigue. RESULTS Group by time interactions from repeated measures analyses revealed significant post intervention improvements in Internet participants ( n = 22 ) relative to control participants ( n = 22 ) on all psychological symptoms, mental health QOL, and fatigue. A small post hoc sub sample of Internet participants with mild or moderate depression also showed large effect size changes in these constructs ( depression, anxiety, mental health QOL, and fatigue ). CONCLUSION Internet-delivered CBT-I appears to not only improve sleep but also reduce comorbid psychological and fatigue symptoms Surviving cancer: a comparison of 5-year disease-free breast cancer survivors with healthy women. Women with breast cancer are one of the largest groups of cancer survivors. This research examined whether breast cancer has a long-term impact on quality of life ( QOL ) by comparing 5-year disease-free survivors to age-matched controls and by comparing women who sustained a recurrence to disease-free survivors. Controls were recruited using the neighborhood control methodology. QOL ( physical, emotional, social, and spiritual ) was assessed during in-person interviews. There were no differences between disease-free survivors ( n = 267 ) and controls ( n = 187 ) on many indicators of QOL. However, survivors reported more difficulties with physical functioning, more physical symptoms, and more faith than did controls ( all ps < 0.05 ). Compared to disease-free survivors, survivors with a recurrence ( n = 37 ) had a worse QOL on most indices, less positive affect, more general fatigue, and more intrusive and avoidant thoughts ( all ps < 0.05 ). There were no differences between the two groups of survivors on indices of marriage, work experiences, or spirituality. These findings suggest that the QOL of long-term survivors who remain disease-free is comparable to that of women their age with the exception of physical functioning. Women who sustain a recurrence suffer an impaired QOL in some, but not all, domains Light treatment prevents fatigue in women undergoing chemotherapy for breast cancer Purpose Fatigue is one of the most disturbing complaints of cancer patients and is often the reason for discontinuing treatment. This r and omized controlled study tested the hypothesis that increased morning bright light, compared to dim light, would result in less fatigue in women with breast cancer undergoing chemotherapy. Methods Thirty-nine women newly diagnosed with stage I – III breast cancer were r and omized to either bright white light ( BWL ) or dim red light ( DRL ) treatment and were instructed to use the light box for 30 min every morning throughout the first four cycles of chemotherapy. The Multidimensional Fatigue Symptom Inventory was administered prior to the start of chemotherapy ( baseline ), during the chemotherapy treatment week of cycle 1 ( C1TW ), the last week ( recovery week ) of cycle 1 ( C1RW ), the chemotherapy treatment week of cycle 4 ( C4TW ), and the last week ( recovery week ) of cycle 4 ( C4RW ). Results The DRL group reported increased fatigue at C1TW ( p = 0.003 ) and C4TW ( p < 0.001 ) compared to baseline, while there was no significant change from baseline in the BWL group. A secondary analysis showed that the increases in fatigue levels in the DRL group were not mediated through nor associated with changes in sleep or in circadian rhythms as measured with wrist actigraphy. Conclusions The results of this study suggest that morning bright light treatment may prevent overall fatigue from worsening during chemotherapy. Although our hypothesis that overall fatigue would improve with bright light treatment was not supported, the lack of deterioration in total fatigue scores suggests that bright morning light may be a useful intervention during chemotherapy for breast cancer Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results. OBJECTIVE In April 2005 a phase III r and omized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints : increase of lean body mass, decrease of resting energy expenditure ( REE ), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form ( MFSI-SF ). METHODS All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then r and omized to one of the following five arms : 1 ) medroxyprogesterone acetate/megestrol acetate ; 2 ) pharmacologic nutritional support containing eicosapentaenoic acid ; 3 ) L-carnitine ; 4 ) thalidomide ; or 5 ) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. RESULTS By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. CONCLUSION The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data A multi-nutrient supplement reduced markers of inflammation and improved physical performance in active individuals of middle to older age: a randomized, double-blind, placebo-controlled study Background While exercise acts to combat inflammation and aging, the ability to exercise may itself be compromised by inflammation and inflammation's impact on muscle recovery and joint inflammation. A number of nutritional supplements have been shown to reduce inflammation and improve recovery. The purpose of the current investigation was to examine the effect of a multi-nutrient supplement containing branched chain amino acids, taurine, anti-inflammatory plant extracts, and B vitamins on inflammatory status, endothelial function, physical function, and mood in middle-aged individuals. Methods Thirty-one healthy and active men ( N = 16, mean age 56 ± 6.0 yrs ) and women ( N = 15, mean age = 52 ± 7.5 yrs ) participated in this investigation. Subjects completed one 28 day cycle of placebo supplementation and one 28 day cycle of multi-nutrient supplementation ( separated by a one week washout period ) in a balanced, r and omized, double-blind, cross-over design. Subjects completed weekly perceptual logs ( PROMIS-57, KOOS ) and pre- and post- testing around the supplementation period. Testing consisted of brachial artery flow mediated dilation ( FMD ), blood measures, and physical performance on vertical jump, h and grip strength, and balance ( dispersion from center of pressure ). Significance for the investigation was p ≤ 0.05. Results IL-6 significantly decreased in both men ( from 1.2 ± 0.2 to 0.7 ± 0.4 pg·mL-1 ) and women ( from 1.16 ± 0.04 to 0.7 ± 0.4 pg·mL-1 ). Perceived energy also improved for both men ( placebo : 1.8 ± 0.7 ; supplement : 3.7 ± 0.8 AUC ) and women ( placebo : 1.2 ± 0.7 ; supplement : 2.8 ± 0.8 AUC ). Alpha-1-antichymotrypsin ( from 108.9 ± 38.6 to 55.5 ± 22.2 ug·mL-1 ), Creatine Kinase ( from 96 ± 34 to 67 ± 23 IU·L-1 ), general pain, and joint pain decreased in men only, while anxiety and balance ( from 0.52 ± 0.13 to 0.45 ± 0.12 cm ) improved in women only. Men showed increased performance in vertical jump power ( from 2642 ± 244 to 3134 ± 282 W ) and grip strength ( from 42.1 ± 5.9 to 48.5 ± 4.9 kg ). Conclusions A multi-nutrient supplement is effective in improving inflammatory status in both men and women, markers of pain, joint pain, strength, and power in men only, and both anxiety and balance ( a risk factor for hip fracture ) in women. Therefore, a multi-nutrient supplement may help middle-aged individuals to prolong physical function and maintain a healthy, active lifestyle Increased Affective Bias Revealed Using Experimental Graded Heat Stimuli in Young Depressed Adults: Evidence of “Emotional Allodynia” Objective : To examine the hypothesis that young adults with major depressive disorder ( MDD ) would show increased affective bias to painful and nonpainful experimental heat stimuli, as evidence d by an increased responsiveness to warm and hot temperatures. Pain and depression often occur together. Pain is both a sensation and an affective experience. Similarly, depression is associated frequently with somatic symptoms as well as emotional dysphoria. Existing evidence indicates that MDD may be associated with altered pain processing. However, the extent to which alterations in experimentally controlled heat pain sensations are related to increased affective bias in MDD is unknown. Method : Grade d nonnoxious and noxious heat stimuli were delivered r and omly with a thermode applied to the volar surface of the left arm of 15 unmedicated subjects with current MDD and 15 age- and gender-matched healthy comparison subjects. MDD and non-MDD subjects rated the intensity and unpleasantness of all stimuli. Results : Two main results were observed. First, MDD relative to non-MDD subjects showed decreased heat pain thresholds. Second, a significantly increased affective bias ( unpleasantness/intensity ) was observed in subjects with MDD, particularly over the range of nonnoxious heat stimuli. This bias was independent of the change in sensory pain thresholds. Conclusion : These findings represent corroborative evidence of abnormal affective heat pain processing in young adults with MDD, and suggest that MDD is associated with “ emotional allodynia, ” a qualitatively altered negative emotional response to normally nonaversive thermal stimuli. MDD = major depressive disorder Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia Chronic inflammation is one of the main features of cancer cachexia. Experimental and clinical studies showed that cyclooxygenase-2 inhibitors, such as celecoxib, may be beneficial in counteracting major symptoms of this devastating syndrome. We carried out a prospect i ve phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib ( 300 mg/day for 4 months ) on key variables of cachexia ( lean body mass, resting energy expenditure, serum levels of proinflammatory cytokines, and fatigue ) in patients with advanced cancer at different sites. A sample of 24 patients was enrolled from January to December 2008 and all were deemed assessable. A significant increase of lean body mass and a significant decrease of TNF-α were observed. Moreover, an improvement of grip strength, quality of life, performance status, and Glasgow prognostic score was shown. There were no grade 3/4 toxicities. Patient compliance was very good ; no patient had to reduce the celecoxib dosage nor interrupt treatment. Our results showed that the COX-2 selective inhibitor celecoxib is an effective single agent for the treatment of cancer cachexia. Although the treatment of cancer cachexia, a multifactorial syndrome, is more likely to yield success with a multitargeted approach ; in the present study, we were able to show that a treatment, such as celecoxib, addressing a single target, albeit very important as chronic inflammation, could have positive effects. Therefore, phase III clinical trials are warranted to test the efficacy and safety of celecoxib Cancer-related anorexia/cachexia syndrome and oxidative stress: an innovative approach beyond current treatment. OBJECTIVE Cancer-related anorexia/cachexia syndrome and oxidative stress play a key role in the progression and outcome of neoplastic disease. PATIENTS AND METHODS On the basis of our previously published studies and clinical experience, we have developed an innovative approach consisting of diet with high polyphenol content ( 400 mg ), p.o. pharmaconutritional support enriched with n - 3 fatty acids ( eicosapentaenoic acid and docosahexaenoic acid ) 2 cans ( 237 mL each ) per day, medroxiprogesterone acetate 500 mg/d, antioxidant treatment with alpha-lipoic acid 300 mg/d plus carbocysteine lysine salt 2.7 g/d plus vitamin E 400 mg/d plus vitamin A 30,000 IU/d plus vitamin C 500 mg/d, and selective cyclooxygenase-2 inhibitor Celecoxib 200 mg/d. The treatment is administered for 16 weeks. The following variables are evaluated : ( a ) clinical variables ( stage and Eastern Cooperative Oncology Group performance status ) ; ( b ) nutritional variables ( lean body mass, appetite, and resting energy expenditure ) ; ( c ) laboratory variables ( serum levels of proinflammatory cytokines, C-reactive protein, and leptin and blood levels of reactive oxygen species and antioxidant enzymes ) ; and ( d ) quality of life variables ( European Organization for Research and Treatment of Cancer QLQ-C30, EQ-5Dindex, and EQ-5DVAS ). A phase II nonr and omized study has been design ed to enroll 40 patients with advanced cancer at different sites with symptoms of cancer-related anorexia/cachexia syndrome and oxidative stress. RESULTS As of January 2004, 28 patients have been enrolled : 25 patients were evaluable and 14 of them have completed the treatment ( 20 patients have completed 2 months of treatment ). As for clinical response, five patients improved, three patients remained unchanged, and six patients worsened. The Eastern Cooperative Oncology Group performance status ( grade ) 1 remained unchanged. As for nutritional/functional variables, the lean body mass increased significantly at 2 and 4 months. As for laboratory variables, reactive oxygen species decreased significantly and proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha decreased significantly. As for quality of life, it comprehensively improved after treatment. CONCLUSIONS The treatment has been shown to be effective for clinical response, increase of lean body mass, decrease of reactive oxygen species and proinflammatory cytokines, and improvement of quality of life. The treatment has been shown to be safe with good compliance of patients. The study is in progress ( 14 further patients will be included ) A pilot study exploring the effects of a 12-week t'ai chi intervention on somatic symptoms of depression in patients with heart failure. BACKGROUND Patients with chronic heart failure ( HF ) and with elevated depression symptoms are at greater risk of morbidity and mortality. Somatic symptoms of depression are particularly prevalent in HF and are related to worse disease prognosis. T'ai chi practice is related to increased emotional well-being in various clinical population s ; however, relatively little is known about t'ai chi's effects on somatic versus cognitive symptom dimensions of depression in HF. PURPOSE The objective of the study was to measure whether a t'ai chi intervention effectively reduces somatic and /or cognitive symptoms of depression in patients with HF. METHODS Patients with HF were assigned to either t'ai chi training ( n=16 ) or a usual-care group ( n=12 ). At baseline and after the 12-week intervention period, participants were evaluated for changes in depressive symptoms using Beck Depression Inventory ( BDI ) total scores ( BDI-t ) and subcategorized scores of BDI-somatic ( BDI-s ) and BDI-cognitive ( BDI-c ), and for symptoms of fatigue using the Multidimensional Fatigue Symptom Inventory-Short Form. RESULTS Patients with HF in the t'ai chi group compared to the usual-care group had reduced BDI-s ( p≤0.017 ), but not BDI-c ( p=0.50 ) scores from pre- to postintervention. Although t'ai chi did not significantly reduce fatigue, changes in physical fatigue ( p≤0.05 ) were independently associated with changes in BDI-t scores. CONCLUSIONS T'ai chi practice reduced somatic symptoms of depression, which have been linked to worse prognosis in HF. Reductions in fatigue appear to explain some but not all of the reductions in somatic symptoms of depression A randomised controlled trial testing the feasibility and efficacy of a physical activity behavioural change intervention in managing fatigue with gynaecological cancer survivors. OBJECTIVE To determine the feasibility and efficacy of a physical activity behavioural change intervention in managing cancer-related fatigue among gynaecological cancer survivors during and post anti-cancer treatments. METHODS A two arm, single blind, r and omised controlled trial was conducted within the Northern Irel and regional Cancer Centre. Thirty three sedentary gynaecological cancer survivors ( stage I-III ; ≤3 years post diagnosis ), experiencing cancer-related fatigue ( mild-severe ) took part. Participants were r and omly assigned to a behavioural change, moderate intensity physical activity intervention ( n=16 ) or a Contact Control group ( n=17 ). The primary outcome was fatigue ( Multidimensional Fatigue Symptom Inventory-Short Form and Functional Assessment in Chronic Illness Therapy-Fatigue subscale ). Secondary outcomes included quality of life, physical functioning, positive and negative affect, depression, body composition, sleep dysfunction and self-reported physical activity. Feasibility was assessed based on the recruitment rate, programme and physical activity adherence and participants'programme evaluation, including optional focus groups ( n=16 ). RESULTS Twenty five percent of eligible women took part ( 33/134 ). Participants were 8.7 ( SD=9.1 ) months post diagnosis, with a mean age of 53 ( SD=10.3 ) years. The majority of the sample had a diagnosis of ovarian ( n=12 ) or endometrial cancer ( n=11 ). Significant differences favouring the intervention group were observed for fatigue at 12 weeks and 6 months follow-up ( 12 week : mean difference=-11.06 ; 95 % confidence interval (CI)=-21.89 to -0.23 ; effect size (d)=0.13 ; p=0.046 ; 6 month : mean difference=-19.48 ; 95 % CI=-19.67 to -19.15 ; effect size (d)=0.20 ; p=0.01 ). A mean of 10 calls ( SD=1.2 calls ) were delivered to the Physical Activity Group, and 10 ( SD=1.6 calls ) to the CC group. The intervention was positively perceived based on exit question naire and focus group findings. CONCLUSIONS A physical activity behavioural change intervention for gynaecological cancer survivors is feasible in terms of participants'programme adherence and evaluation, and the intervention demonstrates improvements in fatigue. However, confirmation in the form of a larger fully powered RCT is warranted Pre-treatment symptom cluster in breast cancer patients is associated with worse sleep, fatigue and depression during chemotherapy. OBJECTIVE The concept of symptom clusters is relatively new in cancer patients'symptom management. This study, which spanned four cycles of chemotherapy, combined three commonly seen pre-treatment symptoms in cancer patients ( i.e. sleep disturbances, fatigue and depression ) into one symptom cluster, to explore the associations between pre-treatment cluster categories and longitudinal profiles of these same symptoms during chemotherapy. METHODS This was a prospect i ve study. Seventy-six women with newly diagnosed stage I-III breast cancer, scheduled to receive at least four cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy participated. Data were collected at seven time points before and during treatment. Sleep quality was measured with the Pittsburgh Sleep Quality Index. Fatigue was measured with the Multidimensional Fatigue Symptom Inventory -- Short Form. Depressive symptoms were measured with the Center of Epidemiological Studies --Depression. Patients were divided into three groups based on the number of symptoms they experienced before the start of chemotherapy ( i.e. no symptoms, 1 - 2 symptoms or all three symptoms ) and a symptom cluster index ( SCI ) was computed. RESULTS All women reported worse sleep, more fatigue and more depressive symptoms during treatment compared with baseline ( all p's<0.01 ) ; however, those women with a higher SCI ( i.e. more symptoms pre-treatment ) continued to experience worse symptoms during treatment compared with those who began with fewer symptoms ( all p's<0.01 ). CONCLUSIONS A higher clinical ly relevant-based pre-treatment symptom cluster was associated with more sleep disturbances, greater fatigue and more depressive symptoms during chemotherapy. Specific interventions for these pre-treatment symptoms may improve the frequency and severity of these same symptoms during chemotherapy, when they are most severe and most disruptive to quality of life Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. PURPOSE A phase III, r and omized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass ( LBM ), resting energy expenditure ( REE ), and fatigue- and relevant secondary endpoints : appetite, quality of life, grip strength, Glasgow Prognostic Score ( GPS ) and proinflammatory cytokines. PATIENTS AND METHODS Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were r and omly assigned to one of five treatment arms : arm 1, medroxyprogesterone ( 500 mg/day ) or megestrol acetate ( 320 mg/day ) ; arm 2, oral supplementation with eicosapentaenoic acid ; arm 3, L-carnitine ( 4 g/day ) ; arm 4, thalidomide ( 200 mg/day ) ; and arm 5, a combination of the above. Treatment duration was 4 months. RESULTS Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM ( by dual-energy X-ray absorptiometry and by L3 computed tomography ) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5 ; interleukin (IL)-6 decreased significantly in arm 5 and arm 4 ; GPS and Eastern Cooperative Oncology Group performance status ( ECOG PS ) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. CONCLUSION The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents Initial evaluation of an Internet intervention to improve the sleep of cancer survivors with insomnia. OBJECTIVE Insomnia is a common complaint among cancer survivors. Fortunately, cognitive-behavioral therapy for insomnia ( CBT-I ) has been shown to be an effective treatment in this population. However, it is rarely implemented given its limited availability. To address this barrier, we examined the ability of an easily accessible online CBT-I program to improve insomnia symptoms in cancer survivors. METHODS Twenty-eight cancer survivors with insomnia were r and omly assigned to either an Internet insomnia intervention ( n = 14 ) or to a waitlist control group ( n = 14 ). The online program, Sleep Healthy Using The Internet, delivers the primary components of CBT-I ( sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention ). Pre- and post- assessment data were collected via online question naires and daily sleep diaries. RESULTS Participants in the Internet group showed significant improvements at post- assessment compared with those in the control group in overall insomnia severity ( F(1,26 ) = 22.8 ; p<0.001 ), sleep efficiency ( F(1,24 ) = 11.45 ; P = 0.002 ), sleep onset latency ( F(1,24 ) = 5.18 ; P = 0.03 ), soundness of sleep ( F(1,24 ) = 9.34 ; P = 0.005 ), restored feeling upon awakening ( F(1,24 ) = 11.95 ; P = 0.002 ), and general fatigue ( F(1,26 ) = 13.88 ; P = 0.001 ). Although other group × time interactions were not significant, overall adjusted effect sizes for all sleep variables as well as for fatigue, depression, anxiety, and quality of life ranged from small to large. CONCLUSIONS CBT-I delivered through an interactive, individually tailored Internet intervention may be a viable treatment option for cancer survivors experiencing insomnia Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. BACKGROUND Safe, effective interventions to improve cancer-related fatigue ( CRF ) are needed because it remains a prevalent, distressing, and activity-limiting symptom. Based on pilot data, a phase III trial was developed to evaluate the efficacy of American ginseng on CRF. METHODS A multisite, double-blind trial r and omized fatigued cancer survivors to 2000 mg of American ginseng vs a placebo for 8 weeks. The primary endpoint was the general subscale of the Multidimensional Fatigue Symptom Inventory-Short Form ( MFSI-SF ) at 4 weeks. Changes from baseline at 4 and 8 weeks were evaluated between arms by a two-sided, two- sample t test. Toxicities were evaluated by self-report and the National Cancer Institute's Common Terminology Criteria for Adverse Events ( CTCAE ) provider grading. RESULTS Three hundred sixty-four participants were enrolled from 40 institutions. Changes from baseline in the general subscale of the MFSI-SF were 14.4 ( st and ard deviation [ SD ] = 27.1 ) in the ginseng arm vs 8.2 ( SD = 24.8 ) in the placebo arm at 4 weeks ( P =.07 ). A statistically significant difference was seen at 8 weeks with a change score of 20 ( SD = 27 ) for the ginseng group and 10.3 ( SD = 26.1 ) for the placebo group ( P =.003 ). Greater benefit was reported in patients receiving active cancer treatment vs those who had completed treatment. Toxicities per self-report and CTCAE grading did not differ statistically significantly between arms. CONCLUSIONS Data support the benefit of American ginseng, 2000 mg daily, on CRF over an 8-week period. There were no discernible toxicities associated with the treatment. Studies to increase knowledge to guide the role of ginseng to improve CRF are needed Validation of a modified Rotterdam Symptom Checklist for use with cancer patients in the United States. The Rotterdam Symptom Checklist ( RSCL ) is a well-known instrument for the assessment of symptom-related distress among cancer patients. Despite its broad application, the utility of the RSCL with patients of some cancers is hindered by the omission of several important physical symptoms and method ological limitations of previous validation studies. The aims of the present study were to modify the RSCL through the addition of several physical symptoms and to subsequently vali date the modified version of the Rotterdam Symptom Checklist ( RSCL-M ) with a heterogeneous sample of cancer patients from the United States. A total of 1,005 male and female cancer patients from two midwestern states completed the RSCL-M and several other self-report instruments. Results indicated that the RSCL-M is a reliable and valid instrument for use with cancer patients in the United States and is sensitive to differences in physical distress across groups expected to have distinct symptom-related distress profiles The longitudinal relationship between fatigue and sleep in breast cancer patients undergoing chemotherapy. STUDY OBJECTIVE Fatigue and sleep disturbances are two of the most common and distressing symptoms of cancer patients. A relationship between the two symptoms was reported in symptom cluster studies ; however, only subjective measurements of sleep were examined and most studies were cross-sectional. In this study of women with breast cancer undergoing chemotherapy, we explored the longitudinal relationship between fatigue and sleep measured both subjectively and objective ly. DESIGN Prospect i ve study. Data were collected at 7 time points : before ( baseline ) and during the 3 weeks of cycle 1 and cycle 4 chemotherapy. PARTICIPANTS Ninety-seven women with newly diagnosed stage I-III breast cancer who were scheduled to receive at least four 3-week cycles of chemotherapy. MEASUREMENT AND RESULTS Objective sleep parameters were measured with an Actillume actigraph ( Ambulatory Monitoring Inc. ). Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index ( PSQI ). Fatigue was assessed with the Multidimensional Fatigue Symptom Inventory-Short Form ( MFSI-SF ). Fatigue became worse during both cycles of chemotherapy ( P-values < 0.01 ). Subjective sleep quality was poor at baseline and remained unchanged throughout treatment. Objective nighttime and daytime total sleep time increased compared to baseline during the treatment administration week of both cycles ; daytime total wake time decreased during the treatment week of both cycles and during the last 2 week of cycle 4. Mixed model results revealed that fatigue was positively associated with total PSQI scores and with objective measures of total nap time, and negatively associated with total wake time during the day ( all P-values < 0.01 ). CONCLUSION Fatigue was significantly associated with subjective reports of poor sleep and objective measures of daytime sleepiness, but not with nocturnal sleep as measured with actigraphy. This relationship between fatigue and sleep warrants further studies to explore their possible common underlying etiology The relationship between fatigue and light exposure during chemotherapy Background Fatigue is one of the most common and distressing complaints among cancer patients, not only during radiation and chemotherapy, but also for months to years after the completion of treatment. Fatigue interferes with patients ’ daily lives, reduces their quality of life, and is often a significant reason why patients discontinue treatment. We hypothesized that some of the fatigue may be related to disrupted circadian rhythms and low light exposure. The main objective of this study therefore was to investigate the association between fatigue and light exposure among patients with breast cancer. Methods As part of a larger, ongoing prospect i ve study on fatigue, sleep, and circadian rhythms in patients with breast cancer, an analysis of 63 women newly diagnosed with stage I – IIIA breast cancer and scheduled to receive four cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy was conducted. Data were collected before and during weeks 1, 2, and 3 of cycle 1 and cycle 4. Fatigue was assessed using the Short Form of Multidimensional Fatigue Symptom Inventory. Light exposure was recorded with a wrist actigraph. Results There were significant correlations between fatigue levels and light exposure ( r=−0.28 to −0.45 ) within both cycle 1 and cycle 4, such that higher levels of fatigue were associated with less light exposure. There were also significant correlations between changes in light exposure and changes in fatigue within the first 2 weeks of each cycle ( r=−0.28 to −0.52 ). Conclusions Increased fatigue was significantly correlated with decreased light exposure among patients with breast cancer. Although the cause and effect of exacerbated fatigue and decreased light exposure can not be confirmed by the current study, and lower light exposure may just in part be due to the fatigued patients spending less time outdoors in bright light, two hypotheses are proposed about the mechanisms by which light may alleviate the fatigue of patients with breast cancer. These results suggest the need for prospect i ve intervention studies of light therapy for breast-cancer-related fatigue A Phase II Study with Antioxidants, Both in the Diet and Supplemented, Pharmaconutritional Support, Progestagen, and Anti-Cyclooxygenase-2 Showing Efficacy and Safety in Patients with Cancer-Related Anorexia/Cachexia and Oxidative Stress Purpose : To test the efficacy and safety of an integrated treatment based on a pharmaconutritional support, antioxidants, and drugs, all given orally, in a population of advanced cancer patients with cancer-related anorexia/cachexia and oxidative stress. Patients and Methods : An open early-phase II study was design ed according to the Simon two-stage design. The integrated treatment consisted of diet with high polyphenols content ( 400 mg ), antioxidant treatment ( 300 mg/d α-lipoic acid + 2.7 g/d carbocysteine lysine salt + 400 mg/d vitamin E + 30,000 IU/d vitamin A + 500 mg/d vitamin C ), and pharmaconutritional support enriched with 2 cans per day (n-3)-PUFA ( eicosapentaenoic acid and docosahexaenoic acid ), 500 mg/d medroxyprogesterone acetate, and 200 mg/d selective cyclooxygenase-2 inhibitor celecoxib. The treatment duration was 4 months. The following variables were evaluated : ( a ) clinical ( Eastern Cooperative Oncology Group performance status ) ; ( b ) nutritional [ lean body mass ( LBM ), appetite, and resting energy expenditure ] ; ( c ) laboratory [ proinflammatory cytokines and leptin, reactive oxygen species ( ROS ) and antioxidant enzymes ] ; ( d ) quality of life ( European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D, and MFSI-SF ). Results : From July 2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable. Body weight increased significantly from baseline as did LBM and appetite. There was an important decrease of proinflammatory cytokines interleukin-6 ( IL-6 ) and tumor necrosis factor-α, and a negative relationship worthy of note was only found between LBM and IL-6 changes. As for quality of life evaluation, there was a marked improvement in the European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5DVAS, and multidimensional fatigue symptom inventory-short form scores. At the end of the study, 22 of the 39 patients were “ responders ” or “ high responders. ” The minimum required was 21 ; therefore, the treatment was effective and more importantly was shown to be safe. Conclusion : The efficacy and safety of the treatment have been shown by the study ; therefore, a r and omized phase III study is warranted. ( Cancer Epidemiol Biomarkers Prev 2006;15(5):1030–4", "Background and purpose : Among members of the health care team, nurses play a large role in actively engaging stroke survivors in secondary stroke prevention programs. This systematic review and meta- analysis examines the effectiveness of interventions in which nurses have a primary role on modification of risk factors among stroke survivors. Nurse-Led, Telephone-Based, Secondary Preventive Follow-Up after Stroke or Transient Ischemic Attack Improves Blood Pressure and LDL Cholesterol: Results from the First 12 Months of the Randomized, Controlled NAILED Stroke Risk Factor Trial Background Enhanced secondary preventive follow-up after stroke or transient ischemic attack ( TIA ) is necessary for improved adherence to recommendations regarding blood pressure ( BP ) and low-density lipoprotein cholesterol ( LDL-C ) levels. We investigated whether nurse-led, telephone-based follow-up was more efficient than usual care at improving BP and LDL-C levels at 12 months after hospital discharge. Methods We r and omized 537 patients to either nurse-led, telephone-based follow-up ( intervention ) or usual care ( control ). BP and LDL-C measurements were performed at 1 month ( baseline ) and 12 months post-discharge. Intervention group patients who did not meet target values at baseline received additional follow-up, including titration of medication and lifestyle counselling, to reach treatment goals ( BP < 140/90 mmHg, LDL-C < 2.5 mmol/L ). Results At 12 months, mean systolic BP, diastolic BP and LDL-C was 3.3 ( 95 % CI 0.3 to 6.3 ) mmHg, 2.3 mmHg ( 95 % CI 0.5 to 4.2 ) and 0.3 mmol/L ( 95 % CI 0.1 to 0.4 ) lower in the intervention group compared to controls. Among participants with values above the treatment goal at baseline, the difference in systolic BP and LDL-C was more pronounced ( 8.0 mmHg, 95 % CI 4.0 to 12.1, and 0.6 mmol/L, 95 % CI 0.4 to 0.9 ). A larger proportion of the intervention group reached the treatment goal for systolic BP ( 68.5 vs. 56.8 %, p = 0.008 ) and LDL-C ( 69.7 % vs. 50.4 %, p < 0.001 ). Conclusions Nurse-led, telephone-based secondary preventive follow-up, including medication adjustment, was significantly more efficient than usual care at improving BP and LDL-C levels by 12 months post-discharge. Trial Registration IS RCT N Registry IS RCT Effectiveness of a shared team approach between nurses and doctors for improved risk factor management in survivors of stroke: a cluster randomized controlled trial BACKGROUND AND PURPOSE Limited evidence exists on the benefits of organized care for improving risk factor control in patients with stroke or transient ischaemic attack. The effectiveness of an individualized management programme in reducing absolute cardiovascular disease risk in this high-risk population was determined. METHODS This was a prospect i ve, multicentre, cluster-r and omized controlled trial with blinded assessment of outcomes and intention-to-treat analysis. Patients hospitalized for stroke/transient ischaemic attack and aged ≥18 years were recruited from four hospitals. General practice s treating recruited patients were r and omized to provide either usual care or an individualized management programme comprising nurse-led education and review of care plans by stroke specialists in addition to usual care. The primary outcome was a change in cardiovascular Framingham Risk Score between baseline and 12 months. RESULTS From January 2010 to November 2013, 156 general practice s ( 280 patients ) were r and omly assigned to usual care ( control ) and 159 ( 283 patients ) to the intervention. The median age was 70.1 years ; 65 % were male. Overall, > 80 % of participants were prescribed recommended secondary prevention therapies at baseline. The primary efficacy analysis comprised 533 participants, with 30 either dying or lost to follow-up. In adjusted analyses, no significant between-group difference was found in the cardiovascular risk score at 12 months ( 0.04, 95 % confidence interval -1.7, 1.8 ). CONCLUSIONS The effectiveness of an organized secondary prevention programme for stroke may be limited in patients from high-performing hospitals with regular post-discharge follow-up and communication with general practice Structured Nursing Intervention Versus Routine Rehabilitation After Stroke Nir Z, Zolotogorsky Z, Sugarman H : Structured nursing intervention versus routine rehabilitation after stroke. Am J Phys Med Rehabil 2004;83:522–529. Objective : The goal of this study was to examine the effect of a structured, comprehensive nursing intervention on the course of rehabilitation over the first 6 mos after a first-ever stroke. Design : Intervention ( experimental ) study. The participants were 155 elderly stroke survivors who were admitted to a geriatric rehabilitation department. Stratified r and om sampling generated intervention and control groups. The intervention was design ed to work together with the routine rehabilitation program and consisted of 12 consecutive weekly meetings. The control group received only the routine rehabilitation program. Study variables were measured at entry to study and after 3- and 6-mo intervals. Results : Although there were no significant differences between the two groups at entry to study, at 3 and 6 mos after stroke, the intervention group showed better scores than the control group in functional status ( FIM ™ instrument ), depression ( Geriatric Depression Scale ), self-perceived health, self-esteem, and dietary adherence. Conclusion : The nursing intervention had both short- and long-term effects on functional, psychological, and emotional variables. Serious consideration should be given to implementing comprehensive nursing interventions during rehabilitation tailored to meet the specific needs of stroke survivors and their caregivers Secondary prevention and health promotion after stroke: can it be enhanced? The aim was to study if health outcome and secondary prevention were satisfactory 1 year after stroke and if nurse-led interventions 3 months after stroke could have impact. Design was a r and omized controlled open trial in a 1-year population. Primary outcome was health status 1 year after stroke. One month after stroke, survivors were r and omized into intervention group ( IG ) with follow-up by a specialist nurse ( SN ) after 3 months ( n = 232 ), and control group ( CG ) with st and ard care ( n = 227 ), all to be followed up 1 year after stroke. At the first follow-up, patients grade d their health, replied to the EuroQol-5 Dimensions ( EQ-5D ) health outcome questions, health problems were assessed, and supportive counseling was provided in the IG. Health problems requiring medical interventions were primarily referred to a general practitioner ( GP ). One year after stroke, 391 survivors were followed up. Systolic blood pressure ( BP ) had decreased in IG ( n = 194 ) from median 140 to 135 ( P =.05 ), but about half were above the limit 139 in both groups. A larger proportion ( 22 % ) had systolic BP > 155 in the CG ( n = 197 ) than in the IG ( 14 % ; P =.05 ). In the IG, 62 % needed referrals compared with the 75 % in the CG ( P =.009 ). Forty percent in the IG and 52.5 % in the CG ( P =.04 ) reported anxiety/depression. In the IG, 75 % and 67 % in the CG rated their general health as fairly good or very good ( P =.05 ). Although nurse-led interventions could have some effect, the results were not optimal. A more powerful strategy could be closer collaboration between the SN and a stroke clinician, before referring to primary care Recurrent stroke and cardiac risks after first ischemic stroke Background : Few population -based studies with long-term follow-up have compared risk of recurrent stroke and cardiac events after first ischemic stroke. The relative risk of these two outcomes may inform treatment decisions. Methods : In the population -based Northern Manhattan Study, first ischemic stroke patients age 40 or older were prospect ively followed for recurrent stroke, myocardial infa rct ion ( MI ), and cause-specific mortality. Fatal cardiac events were defined as death secondary to MI, congestive heart failure, sudden death/arrhythmia, and cardiopulmonary arrest. Risk of events ( with 95 % CIs ) was calculated using Kaplan – Meier survival analysis and adjusted for sex and age using Cox proportional hazard models. Results : Mean age ( n = 655 ; median follow-up 4.0 years ) was 69.7 ± 12.7 years. The risk of recurrent stroke was more than twice that of cardiac events ( including nonfatal MI ) at 30 days and approximately twice cardiac risk at 5 years. The age- and sex-adjusted 5-year risk of fatal or nonfatal recurrent stroke was 18.3 % ( 14.8 to 21.7 % ), and the 5-year risk of MI or fatal cardiac event was 8.6 % ( 6.0 to 11.2 % ). The adjusted 5-year risk of nonfatal stroke ( 14.8 %, 11.6 to 17.9 % ) was approximately twice as high as fatal cardiac events ( 6.4 %, 4.1 to 8.6 % ) and four times higher than risk of fatal stroke ( 3.7 %, 2.1 to 5.4 % ). Conclusions : Cardiac mortality is nearly twice as high as mortality owing to recurrent stroke, but long-term risk of all stroke, fatal or nonfatal, is approximately twice the risk of all cardiac events. The high risk of nonfatal recurrent stroke reinforces the importance of therapies aim ed at preventing stroke recurrence in addition to preventing cardiac events Specific antismoking advice after stroke. INTRODUCTION Many stroke survivors would benefit from modification of their lifestyle in order to reduce their risk of recurrent stroke. We investigated if tailored smoking cessation advice would yield a higher smoking cessation rate and a higher rate with sustained abstinence in ex-smokers in the intervention group than among controls. MATERIAL AND METHODS Patients admitted with an acute stroke or a transient ischaemic attack were included in a r and omised controlled trial focusing on control of lifestyle risk factors and hypertension. Here, we report the intervention focused on smoking cessation. We used multiple logistic regression analysis to identify patient characteristics associated with smoking cessation. Analyses were by intention to treat excluding those who died or suffered severe disease. RESULTS We included 254 patients with a history of smoking. Two years after inclusion, 15 of 57 ( 26 % ) baseline smokers in the intervention group had stopped smoking versus eight of 56 ( 14 % ) among controls ( p = 0.112 ). Living with a partner ( p = 0.012 ), having at least ten years of education ( p = 0.012 ), and not being exposed to smoking at home ( p = 0.036 ) were independent predictors of smoking cessation. CONCLUSION We did not achieve our aim of higher smoking cessation rates in the intervention group. Future smoking cessation interventions should be more intensive, focus on patients'social circumstances and, if possible, involve patients'relatives. FUNDING This study was supported by the Ludvig and Sara Elsass Foundation, the Lundbeck Foundation and The Danish Heart Foundation ( Grant 07 - 4-B703-A1378 - 22384F ). TRIAL REGISTRATION This protocol is registered with Clinical Trials.gov ( NCT 00253097 ) Blood pressure 1 year after stroke: the need to optimize secondary prevention. Lowering blood pressure ( BP ) in stroke survivors reduces the risk of recurrent stroke. We tested the hypothesis that a nurse-led nonpharmacologic intervention would lower the BP of participants in an intervention group compared with a control group. A total of 349 patients who had sustained acute stroke or transient ischemic attack were r and omly assigned to either usual care or to 4 home visits by a nurse. During the visits, the nurse measured and recorded BP and provided individually tailored counseling on a healthy lifestyle. A total of 303 patients completed the 1-year follow up. No change in systolic BP was noted in either the intervention group or the control group. Because of an increase in diastolic BP in the control group ( P =.03 ), a difference in mean diastolic BP between the 2 groups was found at follow-up ( P =.007 ). Mean BP at follow-up was 139/82 mm Hg in the intervention group and 142/86 mm Hg in the control group. Linear regression analysis demonstrated that BP at the point of discharge was the strongest predictor of BP 1 year later ( P <.0001 ). The proportion of patients on antihypertensive medication increased in the intervention group ( P =.002 ). Patients were compliant with antihypertensive therapy, and 92 % of the hypertensive patients in the intervention group followed the advice to see a general practitioner ( GP ) for BP checkups. At follow-up, 187 patients ( 62 % ) were hypertensive, with no difference in the rate of hypertension seen between the groups. Our data indicate that home visits by nurses did not result in a lowering of BP. Patients complied with antihypertensive therapy and GP visits in the case of hypertension. Nonetheless, the majority of patients were hypertensive at the 1-year follow up A randomized trial testing the superiority of a postdischarge care management model for stroke survivors. OBJECTIVE We sought to evaluate whether comprehensive postdischarge care management for stroke survivors is superior to organized acute stroke department care with enhanced discharge planning in improving a profile of health and well-being. METHODS This was a r and omized trial of a comprehensive postdischarge care management intervention for patients with ischemic stroke and National Institutes of Health Stroke Scale scores greater than or equal to 1 discharged from an acute stroke department. An advanced practice nurse performed an in-home assessment for the intervention group from which an interdisciplinary team developed patient-specific care plans. The advanced practice nurse worked with the primary care physician and patient to implement the plan during the next 6 months. The intervention and usual care groups were compared using a global and closed hypothesis testing strategy. Outcomes fell into 5 domains : ( 1 ) neuromotor function, ( 2 ) institution time or death, ( 3 ) quality of life, ( 4 ) management of risk, and ( 5 ) stroke knowledge and lifestyle. RESULTS Treatment effect was near 0 SD for all except the stroke knowledge and lifestyle domain, which showed a significant effect of the intervention ( P =.0003 ). CONCLUSIONS Postdischarge care management was not more effective than organized stroke department care with enhanced discharge planning in most domains in this population. The intervention did, however, fill a postdischarge knowledge gap Effectiveness of Goal-Setting Telephone Follow-Up on Health Behaviors of Patients with Ischemic Stroke: A Randomized Controlled Trial. BACKGROUND Adopting healthy behaviors is critical for secondary stroke prevention, but many patients fail to follow national guidelines regarding diet, exercise, and abstinence from risk factors. Compliance often decreases with time after hospital discharge, yet few studies have examined programs promoting long-term adherence to health behaviors. Goal setting and telephone follow-up have been proven to be effective in other areas of medicine, so this study evaluated the effectiveness of a guideline -based, goal - setting telephone follow-up program for patients with ischemic stroke. METHODS This was a multicenter, assessor-blinded, parallel-group, r and omized controlled trial. Ninety-one stroke patients were r and omized to either a control group or an intervention group. Intervention consisted of predischarge education and 3 goal - setting follow-up sessions conducted by phone. Data were collected at baseline and during the third and sixth months after hospital discharge. RESULTS Six months after discharge, patients in the intervention group exhibited significantly higher medication adherence than patients in the control group. There were no statistically significant differences in physical activity, nutrition, low-salt diet adherence, blood pressure monitoring, smoking abstinence, unhealthy use of alcohol, and modified Rankin Scale ( mRS ) scores between the 2 groups. CONCLUSIONS Goal - setting telephone follow-up intervention for ischemic stroke patients is feasible and leads to improved medication adherence. However, the lack of group differences in other health behavior subcategories and in themRS score indicates a need for more effective intervention strategies to help patients reach guideline -recommended targets Tailored interventions to improve hypertension management after stroke or TIA--phase II (TIMS II). BACKGROUND Reduction of blood pressure ( BP ) after stroke or TIA decreases stroke recurrence and is a major goal of secondary Stroke Prevention Clinics ( SPCs ). Health care providers need effective screening processes to identify those clients at highest risk of not achieving BP targets and those clients at highest risk ofnon-adherence to medication. METHODS This multicentred, r and omized controlled study used a screening process to identify SPC patients with psychosocial/cognitive deficits ( e.g., lack of confidence in the utility of medications, poor memory, mild cognitive impairment ) who were experiencing difficulty managing their BP to target values and evaluated whether a model of nurse-led case management program ( monthly telephone calls, motivational interviewingfor lifestyle change, plus home BP monitoring and use ofdosettes for medication administration ) would improve BP measures and adherence to medications. RESULTS Both intervention ( n=29 ) and usual care groups ( n=27 ) showed a trend-for'reduced BP at six months ( Median ql-q3, Systolic BR p=0.46 ; Diastolic BR p=0.37 ). Diabetic patients, irrespective of the group to which they were r and omized, were less likely to meet Best Practice Guideline targets than those without diabetes ( Chi Square test, p=0.0001 ). CONCLUSION Stroke and TIA patients with diabetes may require additional re sources and support in order to reach BP target values Utility of a Post-Hospitalization Stroke Prevention Program Managed by Nurses Abstract Goal : Evidence -based guidelines exist for the prevention and treatment of patients with cerebral ischemia. Despite these guidelines, there are gaps in clinical practice. Our study aim ed to determine if a physician-directed, nurse-case-management program could reduce individual patient vascular risk factors. Methods : Patients hospitalized with atherosclerotic cerebral ischemia with ≥ 1 major uncontrolled risk factor for stroke ( hypertension, tobacco use, dyslipidemia, diabetes ) were eligible to enroll in our study. Patients were r and omized to management by the nurse-prevention program or usual care. Patients in the usual-care group received their initial risk-factor assessment and a scheduled follow-up at 1 year. Patients in the usual-care group underwent further follow-up by primary care and /or neurology as recommended during their hospitalization or outpatient visit. Patients assigned to the prevention group received individualized education, motivational interviewing, and were aided in setting up their risk-factor modification goal plan. Additional education was tailored to each patient based on individualized risk factors. Prevention-group patients also underwent consultation with a registered dietitian and an exercise physiologist. The primary endpoint of the study was improvement of ≥ 1 major patient risk factor for occurrence of stroke to goal at 1 year. Results : At 1-year post-hospitalization, patients in the nurse-care-management group were 42 % more likely to have met the primary endpoint ( n = 18 ; 61 % nurse-managed patients ) compared with 33 % ( n = 18 ) of patients undergoing usual care ( P = 0.09 ). There was no significant reduction in minor risk factors for either patient group. Patients in the prevention group had greater reductions in low-density lipoprotein cholesterol levels ( −38 vs −4 ; P = 0.0083 ), changes in cardiovascular risk score ( −5.2 vs 1.3 ; P = 0.0033 ), and had a greater reductions in systolic blood pressure ( −12.2 vs −0.105 ; P = 0.07 ) than their usual-care counterparts ( changes shown respectively ). Patients in the prevention group were more likely to follow a prescribed diet than those in the usual-care group ( 50 % ) vs 7 %, respectively ; P = 0.0070 ) and maintain an exercise program ( 83 % vs 33 %, respectively ; P = 0.0018 ). Summary : A physician-directed, nurse case-management system for patients post-hospitalization for cerebral ischemia is feasible and may help improve long-term control of major patient risk factors for stroke. A larger trial is needed to verify trends noted in our study The impact of stroke nurse specialist input on risk factor modification: a randomised controlled trial. SIR— Interventions with an educational or counselling component have been reported to be effective in a variety of patient groups to encourage smoking cessation [ 1 ], lower blood pressure ( BP ) [ 2, 3 ], achieve modest reductions in cholesterol [ 4 ], and promote weight loss [ 5 ]. Evaluation of the impact of education on physical outcomes is lacking in stroke disease, despite evidence that inadequate provision of information may adversely affect compliance with secondary prevention and psychosocial outcomes [ 6 ]. We describe a single-blind r and omised controlled trial of health education and counselling for patients with stroke or transient ischaemic attack ( TIA ), and its effects on risk factors, satisfaction, mood and perceived health status", "The aim of this systematic review and dose-response meta- analysis was to determine the effect of Nigella Sativa ( N.S ) supplementation on liver and kidney parameters. The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies Background Adjustment for prognostic covariates can lead to increased power in the analysis of r and omized trials. However, adjusted analyses are not often performed in practice. Methods We used simulation to examine the impact of covariate adjustment on 12 outcomes from 8 studies across a range of therapeutic areas. We assessed ( 1 ) how large an increase in power can be expected in practice ; and ( 2 ) the impact of adjustment for covariates that are not prognostic. Results Adjustment for known prognostic covariates led to large increases in power for most outcomes. When power was set to 80 % based on an unadjusted analysis, covariate adjustment led to a median increase in power to 92.6 % across the 12 outcomes ( range 80.6 to 99.4 % ). Power was increased to over 85 % for 8 of 12 outcomes, and to over 95 % for 5 of 12 outcomes. Conversely, the largest decrease in power from adjustment for covariates that were not prognostic was from 80 % to 78.5 %. Conclusions Adjustment for known prognostic covariates can lead to substantial increases in power, and should be routinely incorporated into the analysis of r and omized trials. The potential benefits of adjusting for a small number of possibly prognostic covariates in trials with moderate or large sample sizes far outweigh the risks of doing so, and so should also be considered Toxicity effect of nigella sativa on the liver function of rats. PURPOSE The aim of this study was to determine the toxic effect of Nigella sativa powder on the liver function which was evaluated by measuring liver enzymes and through histopathological examination of liver tissue. METHODS Twenty four male Sprague Dawley rats were allotted r and omly to four groups including : control ( taking normal diet ) ; low dose ( supplemented with 0.01 g/kg/day Nigella sativa ) ; normal dose ( supplemented with 0.1 g/kg/day Nigella sativa ) and high dose ( supplemented with 1 g/kg/day Nigella sativa ). All of supplements administered in powder form mixed with rats'pellet for 28 days. To assess liver toxicity, liver enzymes measurement and histological study were done at the end of supplementation. RESULTS The finding revealed that there was no significant change in serum alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) between treatment groups. Histopathological study showed very minimal and mild changes in fatty degeneration in normal and high doses of Nigella sativa treated group. Inflammation and necrosis were absent. CONCLUSION The study showed that supplementation of Nigella sativa up to the dose of 1 g/kg supplemented for a period of 28 days result ed no changes in liver enzymes level and did not cause any toxicity effect on the liver function Antihypertensive effect of Nigella sativa seed extract in patients with mild hypertension Hypertension ( HT ) is a lifestyle‐related disease and dietary modifications are effective for its management and prevention. We conducted a r and omized, double‐blind, placebo‐controlled trial to evaluate the efficacy of treatment with an oral Nigella sativa ( NS ) seed extract supplement in patients with mild HT. Subjects were r and omized into three groups : a placebo and two test groups that received 100 and 200 mg of NS extract twice a day. After 8 weeks, systolic blood pressure ( SBP ) values in both case groups were found to be significantly reduced when compared with the baseline values for each group. In addition, the decrease in SBP in the two case groups was statistically significant relative to the placebo group ( P < 0.05–0.01 ). Meanwhile, diastolic blood pressure ( DBP ) values in the case groups were found to be significantly reduced from the baseline and a significant reduction was also observed in these groups ( P < 0.01 ) when compared with the placebo group. In addition, extract administration reduced both SBP and DBP in a dose‐dependent manner. Meanwhile, NS extract caused a significant decline in the level of total and low‐density‐lipoprotein (LDL)‐cholesterol relative to baseline data. No complications caused by NS were observed. The results suggest that the daily use of NS seed extract for 2 months may have a blood pressure‐lowering effect in patients with mild HT Effect of Nigella sativa supplementation over a one-year period on lipid levels, blood pressure and heart rate in type-2 diabetic patients receiving oral hypoglycemic agents: nonrandomized clinical trial BACKGROUND Diabetic patients with hypertension and dyslipidemia are at a high risk of cardiovascular complications. OBJECTIVES To determine the effect of Nigella sativa supplementation on the lipid profile, mean arterial pressure, and heart rate in persons with type 2 diabetes on oral hypoglycemic agents ( OHA ). DESIGN Single-blind, nonr and omized. SETTING Diabetes clinic of a university hospital in Saudi Arabia. PATIENTS AND METHODS Type-2 diabetic patients were recruited by purposive sampling and assigned to treatment or control at the discretion of the investigator with the patient blinded to treatment. Before the intervention and every 3 months thereafter until the end of the treatment period, the following parameters were measured : triglycerides ( TG ), total cholesterol ( TC ), low density lipoprotein cholesterol ( LDL-C ), high density lipoprotein cholesterol ( HDL-C ), systolic blood pressure ( SBP ), diastolic blood pressure ( DBP ), mean arterial pressure ( MAP ), heart rate ( HR ), and body mass index ( BMI ). Results at the baseline and each subsequent visit were compared between the two groups. MAIN OUTCOME MEASURE(S ) Lipid and cardiovascular parameters, and BMI. RESULTS Fifty-seven patients were assigned to receive N sativa 2 g daily for one year and 57 were assigned to receive an identical regimen of placebo, along with OHA. A significant decrease in HDL-C and increase in the TC/HDL-C and LDL-C/HDL-C ratios were seen in the control group. The N sativa group had a significant decline in TC, LDL-C, TC/HDL-C and LDL-C/HDL-C ratios, compared with the respective baseline data and the control group. HDL-C was significantly elevated in the N sativa group. The control group showed a significant elevation in MAP. The N sativa group had a significant reduction in SBP, DBP, MAP and HR and a significant decrease in DBP, MAP and HR as compared with the control group. CONCLUSION N sativa supplementation improves total cholesterol, mean arterial pressure and heart rate in type 2 diabetes patients on oral hypoglycemic agents. LIMITATIONS There were 9 subjects in each group lost to follow up ; thus the sample size could not be maintained as per the sample size calculation. The study was nonr and omized and thus there was a possibility of allocation bias. ( Clinical trial registration number : CTRI/2013/06/003781, Clinical Trial Registry of India ) Preliminary safety evaluation and biochemical efficacy of a Carum carvi extract: results from a randomized, triple-blind, and placebo-controlled clinical trial. Carum carvi L. ( Apiaceae ) is known as caraway, and its derivatives find wide medicinal use for health purpose s, including for gastrointestinal problems and obesity. Since there is inconsistency among the reports on the safety of this plant in humans, this research was aim ed at assessing the safety of a characterized caraway aqueous extract ( CAE ) in a r and omized, triple-blind, placebo-controlled study. Seventy, overweight and obese, healthy women were r and omly assigned into placebo ( n = 35 ) and plant extract ( n = 35 ) groups. Participants received either 30 ml/day of CAE or placebo. Subjects were examined at baseline and after 12 weeks for changes in heart rate, blood pressure, urine test, 25-item blood chemistries, and general health status. No significant changes of blood pressure, heart rate, urine specific gravity, and serum blood tests were observed between the two groups before and after treatment. However, in the complete blood count test, red blood cell levels were significantly ( p < 0.01 ) increased, and platelet distribution width was significantly decreased after the dietary CAE treatment, as compared with placebo. No negative changes were observed in the general health status of the two groups. This preliminary study suggests that the oral intake of CAE appears to be without any adverse effects at a dosage of 30 ml daily for a period of 12 weeks Efficacy of a fixed peppermint oil/caraway oil combination in non-ulcer dyspepsia. The efficacy and safety of the st and ardized herbal combination preparation of Enteroplant, consisting of peppermint oil ( 90 mg ) and caraway ( 50 mg ) in an enteric coated capsule, have been studied in a double-blind, placebo-controlled multicentre trial in patients with non-ulcer dyspepsia. A total of 45 patients were included in the trial after thorough physical and gastro-enterological examination. The primary outcome variables were the change in the intensity of pain and the global clinical impression ( Clinical Global Impression [ CGI ], Item 2 ), which were evaluated for 39 patients ( test preparation : 19, placebo : 20 ). After four weeks of treatment both target parameters were significantly improved for the group of patients treated with the peppermint oil/caraway oil combination compared to the placebo group ( p = 0.015 and 0.008, respectively ). Before the start of treatment all patients in the test preparation group reported moderate to severe pain, while by the end of the study 63.2 % of these patients were free of pain. The pain symptoms had improved in a total of 89.5 % of the patients in the active treatment group. After 4 weeks the Clinical Global Impressions were improved for 94.5 % of the patients treated with the peppermint oil/caraway oil combination. The trial medication was also superior to placebo with respect to pain frequency, medical prognosis, the severity of the disorder and the efficacy index ( CGI, Items 1 and 3 ), which were adopted as secondary end-points for evaluation of efficacy. There were similarly favourable findings for the herbal combination, compared with placebo, with respect to the reduction of other gastrointestinal symptoms. The combination preparation was found to be excellently tolerated. There was a total of 7 adverse events ( test preparation : 4, placebo : 3 ), with a causal association with the treatment being ascribed in one case for the test preparation group and one case for the placebo group Protective role of Nigella sativa in diabetic nephropathy: A randomized clinical trial. This study aims to evaluate efficacy and safety of Nigella sativa oil supplementation in patients with chronic kidney disease Stage 3 and 4 due to diabetic nephropathy. It was a prospect i ve, comparative, and open-label study. Patients were r and omized into two groups. Group 1 ( Control ) received conservative management of diabetic nephropathy, whereas Group 2 ( Test ) received N. sativa oil ( 2.5 mL, once daily and per orally ) along with conservative management for 12 weeks. Blood glucose, hemogram, and kidney function test were done at 0, 6, and 12 weeks of treatment. Significance of differences between pre- and post-treatment values in each group was assessed using Student's paired t-test and between the groups using unpaired t-test. We found a drop in blood glucose, serum creatinine, blood urea, and 24 h total urinary protein levels and a rise in glomerular filtration rate, 24 h total urinary volume, and hemoglobin level in the treatment group compared to the control group The effect of Nigella sativa Linn. seed on memory, attention and cognition in healthy human volunteers. BACKGROUND Experimental evidence s have demonstrated that Nigella sativa Linn. seed ( NS ) has positive modulation effects on aged rats with memory impairments, prevents against hippocampal pyramidal cell loss and enhances consolidation of recall capability of stored information and spatial memory in rats. NS has neuroprotective, nephroprotective, lung protective, cardioprotective, hepatoprotective activities as established by previous studies on animals. Several clinical trials with NS on human have also demonstrated beneficial effect. AIM OF THE STUDY The present study was design ed to investigate the effects of NS on memory, attention and cognition in healthy elderly volunteers. Furthermore, safety profile of NS was assessed during the nine-week study period. METHODS Forty elderly volunteers were recruited and divided r and omly into group A and group B -- each consisting of 20 volunteers. The treatment procedure for group A was 500 mg NS capsule twice daily for nine weeks and Group B received placebo instead of NS in the similar manner. All the volunteers were assessed for neuropsychological state and safety profile twice before treatment and after nine weeks. The neuropsychological tests were logical memory test, digit span test, Rey-Osterrieth complex figure test, letter cancellation test, trail making test and stroop test. Safety profile was assessed by measuring biochemical markers of Cardiac ( total cholesterol, triglycerides and high density lipoprotein cholesterol, very low density lipoprotein, low density lipoprotein cholesterol, creatine kinase-MB ) ; Liver ( aspartate aminotransferase, alanin aminotransferase, alkaline phosphatase, total protein, albumin, bilirubin ) and Kidney ( creatinine and blood urea nitrogen ) through using commercial kits. RESULTS There was significant difference ( p<0.05 ) in the score of logical memory test-I and II, total score of digit span, 30 min delayed-recall, percent score in Rey-Osterrieth complex figure test, time taken to complete letter cancellation test, time taken in trail making test-A and test-B, score in part C of stroop test due to ingestion of NS for nine weeks. There were not statistically significant changes ( p>0.05 ) in any of the biochemical markers of cardiac, liver, kidney function during this nine-week study period. CONCLUSIONS The current study demonstrates the role of NS in enhancing memory, attention and cognition. Therefore, whether NS could be considered as potential food supplement for preventing or slow progressing of Alzheimer disease needs further investigations. However, study with Alzheimer's patients with large population size for longer period of time is recommended before using NS daily and extensive phytochemical investigations are recommended for novel drug discovery from NS for treating cognitive disorders Blood pressure lowering effect of Nigella sativa L. seed oil in healthy volunteers: a randomized, double-blind, placebo-controlled clinical trial. Nigella sativa L. seeds ( N. sativa ) have been used as a traditional remedy for a wide range of diseases including hypertension. The present study was performed to explore the effects of N. sativa oil on blood pressure ( BP ) in healthy volunteers. In a double-blind, r and omized study, 70 healthy volunteers aged 34 to 63 years with systolic BP from 110 to 140 mmHg and diastolic BP from 60 to 90 mmHg were r and omly allocated to receive 2.5 mL N. sativa oil or placebo two times a day for 8 weeks. The systolic and diastolic BPs, body mass index and blood levels of aspartate transaminase, alanine transaminase, alkaline phosphatase, creatinine and blood urea nitrogen were determined at baseline and endpoint. Results showed that in N. sativa oil treated group the systolic and diastolic BPs decreased significantly compared with baseline and placebo group at the endpoint. Other parameters did not significantly change in both groups at the endpoint. No adverse effects were reported. In conclusion, oral daily administration of 5 mL N. sativa oil to healthy volunteers for 8 weeks lowers systolic and diastolic BPs without any adverse effects Effect of Nigella sativa seeds on the glycemic control of patients with type 2 diabetes mellitus. UNLABELLED Diabetes mellitus is a common chronic disease affecting millions of people world wide. St and ard treatment is failing to achieve required correction of blood glucose in many patients. Therefore, there is a need for investigating potential hypoglycemic drugs or herbs to improve glycemic control in diabetic patients. Nigella sativa seeds were used as an adjuvant therapy in patients with diabetes mellitus type 2 added to their anti-diabetic medications. A total of 94 patient were recruited and divided r and omly into three dose groups. Capsules containing Nigella sativa were administered orally in a dose of 1, 2 and 3 gm/day for three months. The effect of Nigella sativa on the glycemic control was assessed through measurement of fasting blood glucose ( FBG ), blood glucose level 2 hours postpr and ially ( 2 hPG ), and glycosylated hemoglobin ( HbA1c ). Serum C-peptide and changes in body weight were also measured. Insulin resistance and beta-cell function were calculated usin the homeostatic model assessment ( HOMA2 ). Nigella sativa at a dose of 2 gm/day caused significant reductions in FBG, 2hPG, and HbA1 without significant change in body weight. Fasting blood glucose was reduced by an average of 45, 62 and 56 mg/dl at 4, 8 and 12 weeks respectively. HbAlC was reduced by 1.52 % at the end of the 12 weeks of treatment ( P<0.0001 ). Insulin resistance calculated by HOMA2 was reduced significantly ( P<0.01 ), while B-cell function was increased ( P<0.02 ) at 12 weeks of treatment. The use of Nigella sativa in a dose of 1 gm/day also showed trends in improvement in all the measured parameters but it was not statistically significant from the baseline. However, no further increment in the beneficial response was observed with the 3 gm/day dose. The three doses of Nigella sativa used in the study did not adversely affect either renal functions or hepatic functions of the diabetic patients throughout the study period. IN CONCLUSION the results of this study indicate that a dose of 2 gm/ day of Nigella sativa might be a beneficial adjuvant to oral hypoglycemic agents in type 2 diabetic patients Effects of Nigella sativa on outcome of hepatitis C in Egypt. AIM To evaluate the safety, efficacy and tolerability of Nigella sativa ( N. sativa ) in patients with hepatitis C not eligible for interferon (IFN)-α. METHODS Thirty patients with hepatitis C virus ( HCV ) infection, who were not eligible for IFN/ribavirin therapy, were included in the present study. Inclusion criteria included : patients with HCV with or without cirrhosis, who had a contraindication to IFN-α therapy, or had refused or had a financial constraint to IFN-α therapy. Exclusion criteria included : patients on IFN-α therapy, infection with hepatitis B or hepatitis I virus, hepatocellular carcinoma, other malignancies, major severe illness, or treatment non-compliance. Various parameters, including clinical parameters, complete blood count, liver function, renal function, plasma glucose, total antioxidant capacity ( TAC ), and polymerase chain reaction, were all assessed at baseline and at the end of the study. Clinical assessment included : hepato and /or splenomegaly, jaundice, palmar erythema, flapping tremors, spider naevi, lower-limb edema, and ascites. N. sativa was administered for three successive months at a dose of ( 450 mg three times daily ). Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study. RESULTS N. sativa administration significantly improved HCV viral load ( 380808.7 ± 610937 vs 147028.2 ± 475225.6, P = 0.001 ) and TAC ( 1.35 ± 0.5 vs 1.612 ± 0.56, P = 0.001 ). After N. sativa administration, the following laboratory parameters improved : total protein ( 7.1 ± 0.7 vs 7.5 ± 0.8, P = 0.001 ), albumin ( 3.5 ± 0.87 vs 3.69 ± 0.91, P = 0.008 ), red blood cell count ( 4.13 ± 0.9 vs 4.3 ± 0.9, P = 0.001 ), and platelet count ( 167.7 ± 91.2 vs 198.5 ± 103, P = 0.004 ). Fasting blood glucose ( 104.03 ± 43.42 vs 92.1 ± 31.34, P = 0.001 ) and postpr and ial blood glucose ( 143.67 ± 72.56 vs 112.1 ± 42.9, P = 0.001 ) were significantly decreased in both diabetic and non-diabetic HCV patients. Patients with lower-limb edema decreased significantly from baseline compared with after treatment [ 16 ( 53.30 % ) vs 7 ( 23.30 % ), P = 0.004 ]. Adverse drug reactions were unremarkable except for a few cases of epigastric pain and hypoglycemia that did not affect patient compliance. CONCLUSION N. sativa administration in patients with HCV was tolerable, safe, decreased viral load, and improved oxidative stress, clinical condition and glycemic control in diabetic patients Nigella sativa oil with a calorie-restricted diet can improve biomarkers of systemic inflammation in obese women: A randomized double-blind, placebo-controlled clinical trial. BACKGROUND Inflammation is one of the primary mechanisms in the development of metabolic complications. Although anti-inflammatory characteristics of Nigella sativa ( NS ) have been indicated in animal models, clinical trials related to the effects of NS on inflammatory parameters are relatively scarce. OBJECTIVE The aim of the present study was to determine the effects of NS oil combined with a calorie-restricted diet on systemic inflammatory biomarkers in obese women. METHODS In this double-blind placebo-controlled r and omized clinical trial, 90 volunteer obese ( body mass index = 30 - 34.9 kg/m(2 ) ) women aged 25 - 50 years were recruited. Participants were r and omly divided into two groups, an intervention group ( n = 45 ) and a placebo group ( n = 45 ). Each group received either : ( 1 ) a low-calorie diet with 3 g/day of NS oil or ( 2 ) a low-calorie diet with 3 g/day placebo for 8 weeks. RESULTS A total of 84 females ( intervention group = 43 ; placebo group = 41 ) completed the trial. Subjects in the intervention group did not report any side effects with the NS oil supplementation. NS oil decreased serum levels of tumor necrosis factor-alpha ( -40.8 % vs -16.1 %, P =.04 ) and high-sensitivity C-reactive protein ( -54.5 % vs -21.4 %, P =.01 ) compared to the placebo group. However, there were no significant changes in interleukin-6 levels ( -8.6 vs -2.4 %, P =.6 ) in the NS group compared to the placebo group. CONCLUSIONS NS oil supplementation combined with a calorie-restricted diet may modulate systemic inflammatory biomarkers in obese women. However, more studies are needed to clarify the efficacy of NS oil as an adjunct therapy to improve inflammatory parameters in obese subjects Efficacy of black seed (Nigella sativa L.) on kidney stone dissolution: A randomized, double-blind, placebo-controlled, clinical trial. Pre clinical studies have shown beneficial effects of black seed ( Nigella sativa L. ) in the prevention and treatment of renal stones. Hence, we design ed a study to evaluate the renal-stone-dissolving efficacy of black seed. Sixty patients with renal stones were r and omly enrolled in two arms of a r and omized, triple-blind, placebo-controlled, clinical trial. The patients were treated by black seed capsules ( 500 mg ) or placebo two times per day for 10 weeks. Patients were assessed in terms of size of renal stones by using sonography before and after intervention. In the black seed group, 44.4 % of patients excreted their stones completely, and the size of the stones remained unchanged and decreased in 3.7 % and 51.8 % of patients, respectively. In contrast, in the placebo group, 15.3 % of the patients excreted their stones completely, 11.5 % had reduction in stone size, 15.3 % had increase in stone size, and 57.6 % had no change in their stone size. The difference in the mean size of renal stones after the study was significant between the two groups ( p < 0.05 ). N. sativa L., as compared with placebo, is demonstrated to have significant positive effects on disappearance or reduction of size of kidney stones Effectiveness, safety, and tolerability of powdered Nigella sativa (kalonji) seed in capsules on serum lipid levels, blood sugar, blood pressure, and body weight in adults: results of a randomized, double-blind controlled trial. OBJECTIVE The seed extracts from Nigella sativa is used by Unani physicians of traditional medicine ( Hakims or Tabibs ) and Ayurvedic practitioners ( Vaids ) in the treatment of several medical disorders including dyslipidemia, obesity, and hypertension. It is, therefore, important to prove or disprove the effectiveness, safety, and tolerability of powdered N. sativa ( Kalonji ) seed in capsules on serum lipid levels, blood sugar, blood pressure, and body weight in adults. DESIGN The study design was a r and omized, double-blind trial. SETTING S/LOCATION Conducted at Aga Khan University Hospital, Karachi, from February 2006 to January 2007. SUBJECTS Half of the respondents received powdered N. sativa ( Kalonji ) seed in capsule and the rest received a placebo. INTERVENTION/ OUTCOME Baseline and after-intervention variables recorded were the following : body-mass index, waist-hip ratio, blood pressure, fasting blood sugar, serum lipids, serum alanine aminotransferase, and serum creatinine. RESULTS One hundred and twenty-three ( 123 ) patients were recruited. Sixty-four ( 64 ) and 59 patients were r and omized to the intervention and the control arms, respectively. Thirty-nine ( 39 ) patients in the intervention group and 34 in the control group completed the study. Favorable impact of powdered N. sativa ( Kalonji ) seed in capsule was noted on almost all variables, but results were not statistically significant because of small sample size. CONCLUSIONS Favorable impact of powdered N. sativa ( Kalonji ) seed in capsule was noted on almost all variables, but results were not statistically significant. A larger study with adequate sample size is recommended", "OBJECTIVE The aim of this systematic review was to perform a meta- analysis of r and omized controlled trials ( RCTs ) examining the efficacy of fibrate therapy in reducing plasma concentration or activity of plasminogen activator inhibitor 1 ( PAI-1 ). Plasma homocysteine and the risk of venous thromboembolism: insights from the FIELD study Abstract Background : The lipid-lowering effect of fenofibrate is accompanied by a rise in plasma homocysteine ( HCY ), a potential risk factor for venous thromboembolism ( VTE ). This study investigated the relationship between HCY and the risk of VTE in patients treated with fenofibrate. Methods : The relationship between HCY and deep-vein thrombosis or pulmonary embolism was investigated in 9522 participants of the 5-year Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) trial. All subjects received fenofibrate during a 6-week active run-in phase before r and omization. A Cox proportional-hazards model was used to assess the effect of HCY on risk of venous thromboembolic events. Results : During active-drug run-in, HCY rose on average by 6.5 μmol/L, accompanied by a substantial rise in plasma creatinine ( + 12 % ). Fenofibrate-induced changes in HCY and creatinine were fully reversible in the placebo group but persisted in the treatment group until reversing at the end of therapy. During follow-up, 1.8 % had at least one episode of deep-vein thrombosis or pulmonary embolism : 103 on fenofibrate and 68 on placebo ( log-rank p=0.006 ). In multivariate analysis, every 5 μmol/L higher baseline HCY was associated with 19 % higher risk of VTE. Fenofibrate treatment was associated with 52 % higher risk, but the change in HCY with fenofibrate was not significantly associated with VTE after adjustment for baseline HCY. Conclusions : Hyperhomocysteinemia is prospect ively associated with VTE. Fenofibrate may predispose individuals with high pretreatment HCY towards VTE. The fenofibrate-induced increase in HCY did not, however, explain the risk associated with fenofibrate therapy Hemostatic effects of bezafibrate and ω-3 fatty acids in isolated hypertriglyceridemic patients. This study aim ed to compare the effects of ω-3 fatty acids and fibrate treatment on plasma levels and activities of hemostatic risk factors on glucose and lipid metabolism in subjects with isolated hypertriglyceridemia. Seventy-three subjects with elevated triglyceride levels were allocated into one of the following treatment options : bezafibrate ( 200 mg twice daily ), ω-3 fatty acids ( 1 g twice daily ) or placebo. Plasma lipids, glucose homeostasis markers ( fasting and 2-h post-glucose load plasma glucose levels and HOMA ), as well as plasma levels/activities of fibrinogen, factor VII and PAI-1 were determined at baseline, on the day of r and omization, and after 4 and 12 weeks of the treatment. Not only did bezafibrate improve plasma lipids, but it also increased glucose sensitivity and tended to reduce post-glucose loads of plasma glucose. Except for the reduction in plasma triglycerides, ω-3 fatty acids produced no effect on the lipid profile and insulin sensitivity. Both treatment options reduced, to similar extents, plasma levels of fibrinogen and PAI-1 and factor VII coagulant activity. Our study indicates that, although fibrates exhibit more-pronounced metabolic effects than do ω-3 fatty acids, both these treatment options are equipotent in producing a complex beneficial effect on hemostasis in isolated hypertriglyceridemic subjects Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridaemia Summary The effects of bezafibrate 400 mg/day ( slow release formulation ) on plasma lipids/lipoproteins and on selected haemostatic parameters were evaluated in a double blind cross-over study in patients with Type IIb and IV hyperlipoproteinaemia. Placebo treatment did not influence any of those parameters, but the drug significantly reduced plasma triglycerides ( −45 % ) and VLDL cholesterol, as well as causing a 12 % fall in total cholesterol and a 20 % increase in HDL cholesterol. Apo AI levels were significantly increased following bezafibrate and Apo B was reduced by about 20 %. In addition to changes in the plasma lipid profile, bezafibrate reduced the sensitivity of platelets to the aggregatory effect of collagen, with no effect on TXB2 production. Fibrinogen levels after bezafibrate treatment were significantly lowered, the effect being more marked in patients with hyperfibrinogenaemia. Bezafibrate did not influence the plasma fibrinolytic profile. It is concluded that bezafibrate, besides its beneficial effects on the plasma lipoprotein profile, can exert beneficial changes on specific haemostatic parameters Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial Summary Background Amputations in people with type 2 diabetes mellitus substantially impair their quality of life and impose high costs on health-care systems. Our aim was to assess the effect of fenofibrate on amputation events in a large cohort of patients with type 2 diabetes. Methods In the Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study, 9795 patients aged 50–75 years with type 2 diabetes were r and omly assigned by computer-generated r and omisation sequence to receive fenofibrate 200 mg per day ( n=4895 ) or matching placebo ( n=4900 ) for 5 years'duration. Information about non-traumatic amputation — a prespecified tertiary endpoint of the study —was routinely gathered. Clinicians who were masked to treatment allocation adjudicated amputations as minor or major ( below or above the ankle, respectively ). Amputations were also classified on the basis of whether or not large-vessel disease was present in the limb, to distinguish those related to large-artery atherosclerosis from those predominantly related to microvascular disease. Analysis was by intention to treat ( ITT ). The FIELD study is registered as an International St and ard R and omised Controlled Trial, number IS RCT N64783481. Findings All 9795 patients were included in the ITT population. 115 patients had one or more non-traumatic lower-limb amputations due to diabetes. Previous cardiovascular disease, microvascular disease, previous non-traumatic amputation or skin ulcer, smoking, and longer duration of diabetes were more frequent in patients who had amputations during the trial than in those who had other cardiovascular events or in those who had neither event ( all p<0·001 for three-way comparison ). Mean lipid concentrations differed between patients who had on- study amputations and those who had other cardiovascular events or neither event, but by no more than 0·2 mmol/L. The risks of first amputation ( 45 vs 70 events ; hazard ratio [ HR ] 0·64, 95 % CI 0·44–0·94 ; p=0·02 ) and minor amputation events without known large-vessel disease ( 18 vs 34 events ; 0·53, 0·30–0·94 ; p=0·027 ) were lower for patients assigned to fenofibrate than for patients assigned to placebo, with no difference between groups in risk of major amputations ( 24 vs 26 events ; 0·93, 0·53–1·62 ; p=0·79 ). Interpretation Classic markers of macrovascular and microvascular risk were associated with lower extremity amputations in patients with type 2 diabetes. Treatment with fenofibrate was associated with a lower risk of amputations, particularly minor amputations without known large-vessel disease, probably through non-lipid mechanisms. These findings could lead to a change in st and ard treatment for the prevention of diabetes-related lower-limb amputations. Funding Laboratoires Fournier SA ( now part of Solvay Pharmaceuticals ) and National Health and Medical Research Council of Australia Effects of short-term fenofibrate treatment on circulating markers of inflammation and hemostasis in patients with impaired glucose tolerance. CONTEXT Apart from lowering lipid levels, peroxisome proliferator-activated receptor ( PPAR ) alpha activators ( fibrates ) produce many other favorable effects that may contribute to their clinical effectiveness in dyslipidemic and diabetic patients. OBJECTIVE The objective of this study was to compare the impact of a short-term treatment with fenofibrate and the American Heart Association ( AHA ) step 1 diet on systemic inflammation, hemostasis, and monocyte secretory function in relationship with their metabolic actions. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS This was a prospect i ve, r and omized, placebo-controlled trial involving the group of 91 ambulatory patients with impaired glucose tolerance ( IGT ) ( diagnosed on the basis of the American Diabetes Association criteria ), r and omly divided into three groups, simultaneously treated for 30 d with the AHA step 1 diet ( n = 30 ), micronized fenofibrate ( 267 mg/d, n = 31 ), or placebo ( n = 30 ). The control group included 34 age-, sex-, and weight-matched subjects with normal glucose tolerance. Eighty-six ( 95 % ) patients and all control subjects completed the study. MAIN OUTCOME MEASURES Plasma markers of inflammation and hemostasis and monocyte release of proinflammatory cytokines were measured. RESULTS Compared with subjects with normal glucose tolerance, IGT patients exhibited higher plasma levels/activities of fibrinogen, factor VII, plasminogen activator inhibitor-1, high-sensitivity C-reactive protein, and oxidized low-density lipoproteins. Lipopolysaccharide-activated monocytes from IGT patients released significantly more TNF-alpha, IL-1beta, IL-6, and monocyte chemoattractant protein-1 in comparison with monocytes from control subjects. Thirty-day treatment with fenofibrate but not with the AHA step 1 diet : 1 ) improved lipid/lipoprotein profile and glucose metabolism, and 2 ) reversed or alleviated all the above-mentioned abnormalities. The favorable effects of fenofibrate on plasma high-sensitivity C-reactive protein and on monocyte release of TNF-alpha, IL-1beta, IL-6, and monocyte chemoattractant protein-1 did not correlate with its action on plasma lipids but was related to the improvement in insulin sensitivity and weakly to free fatty acid-lowering action. CONCLUSIONS Our study is the first to show that relatively small disturbances in glucose metabolism are associated with marked and multidirectional abnormalities in plasma markers of inflammation and hemostasis and in monocyte secretory function. Moreover, fenofibrate may exhibit early pleiotropic effects in patients with IGT Ideal Cardiovascular Health: Associations With Biomarkers and Subclinical Disease and Impact on Incidence of Cardiovascular Disease in the Framingham Offspring Study Background — The American Heart Association Cardiovascular Health score ( CVH score ) is inversely associated with cardiovascular disease ( CVD ) incidence, but the mechanisms underlying this association warrant exploration. Methods and Results — We related the CVH score to circulating biomarkers and prevalent sub clinical CVD ( defined as ≥1 of the following : increased carotid intima-media thickness or stenosis, left ventricular hypertrophy [ by ECG or echocardiography ], left ventricular systolic dysfunction, microalbuminuria, and a reduced ankle-brachial index ) in 2680 Framingham Study participants ( mean age, 58 years ; 55 % women ). After adjustment for age and sex, an ideal CVH score ( nonsmoking status, ideal body mass index, regular physical activity, healthy diet, and an optimal profile of serum cholesterol, blood pressure, and glucose ; 1 point for each ) was associated with higher circulating concentrations of natriuretic peptides ( N-terminal pro-atrial natriuretic peptide and B-type natriuretic peptide ) and lower blood concentrations of plasminogen activator inhibitor-1, aldosterone, C-reactive protein, D-dimer, fibrinogen, homocysteine, and growth differentiation factor-15 levels ( P<0.001 for all ), as well as lower odds of sub clinical disease ( odds ratio, 0.74 per 1-unit increase in CVH score ; 95 % confidence interval, 0.68–0.80 ). The incidence of CVD ( 267 events over 16 years ) was inversely associated with the CVH score in age- and sex-adjusted models ( hazard ratio, 0.77 per 1-unit increase in CVH score ; 95 % confidence interval, 0.70–0.86 ), which was slightly attenuated upon adjustment for biomarkers and sub clinical disease ( hazard ratio, 0.87 ; 95 % confidence interval, 0.78–0.97 ). Conclusion — In our prospect i ve community-based study, the inverse association between an ideal cardiovascular health score and CVD incidence was partly attributable to its favorable impact on CVD biomarker levels and sub clinical disease Effects of combination lipid therapy in type 2 diabetes mellitus. BACKGROUND We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS We r and omly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infa rct ion, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS The annual rate of the primary outcome was 2.2 % in the fenofibrate group and 2.4 % in the placebo group ( hazard ratio in the fenofibrate group, 0.92 ; 95 % confidence interval [ CI ], 0.79 to 1.08 ; P=0.32 ). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5 % in the fenofibrate group and 1.6 % in the placebo group ( hazard ratio, 0.91 ; 95 % CI, 0.75 to 1.10 ; P=0.33 ). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women ( P=0.01 for interaction ), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol ( P=0.057 for interaction ). CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infa rct ion, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. ( Clinical Trials.gov number, NCT00000620. Relationships between plasma insulin triglyceride, body mass index, and plasminogen activator inhibitor 1. Low fibrinolytic activity, as measured by euglobulin ( EFA ), has been observed in obese subjects, and hypofibrinolysis may play a role in the pathogenesis of atherosclerosis and its complications. Blood fibrinolytic activity is regulated through a complex system of activators and inhibitors, especially plasminogen activator inhibitors ( PA Inhibitors ). In a group of 35 non-diabetic subjects with a wide range of body mass index ( BMI ), EFA was negatively correlated, and PA Inhibitor activity positively correlated, with BMI and plasma insulin levels. In a population of 49 non-diabetic obese women ( differing from a control group of normal weight by lower EFA and higher level, of PA Inhibitor activity, plasma insulin and triglyceride ), the PA Inhibitor activity was positively correlated with BMI, insulin and triglyceride. The increase in PA Inhibitor activity was associated with a high value of PA Inhibitor 1 antigen measured by an immuno-radiometric assay, indicating that the increased activity was due to a high level of circulating PA Inhibitor 1. Plasma insulin was lowered in obese non-diabetic subjects, without modification of the body weight, by a 24 hour fast or by treatment with Metformin. After 24 hours'fast, ten obese subjects had lower levels of insulin and PA Inhibitor activity and an increase in EFA. Treatment for 15 days by 1.75 g Metformin ( or placebo ), on a weight maintaining diet, induced, in the Metformin group, a decrease in plasma insulin, triglyceride and PA Inhibitor activity and an increase in EFA, while no change was observed in the placebo group. ( ABSTRACT TRUNCATED AT 250 WORDS Effect of micronized fenofibrate on plasma lipoprotein levels and hemostatic parameters of hypertriglyceridemic patients with low levels of high-density lipoprotein cholesterol in the fed and fasted state. A r and omized, double-blind, placebo-controlled study was undertaken in 20 hypertriglyceridemic men [ plasma triglyceride ( TG ), > 2.3 mM ] with low levels ( < 0.9 mM ) of high-density lipoprotein cholesterol ( HDL-C ) to investigate the ability of micronized fenofibrate ( Tricor or Lipidil ; 200 mg/day ) to affect atherogenic and thrombogenic plasma risk factors in the fed and fasted state. Each patient underwent ( a ) 4 weeks of dietary stabilization, ( b ) 8 weeks of treatment with fenofibrate or placebo, ( c ) a 5-week washout period, and ( d ) 8-weeks of treatment with the alternative medication. An oral fat-loading test ( 1 g fat/kg body weight ) was carried out after both treatment periods. Before treatment, patients had a mean ( + /- SD ) total plasma TG of 3.31+/-0.93 mM ; total C, 5.75+/-0.89 mM ; HDL-C, 0.71+/-0.09 mM ; and low-density lipoprotein (LDL)-C, 3.40+/-0.68 mM. Compared with placebo, fenofibrate reduced fasting TG levels by 36 %, and triglyceride-rich lipoprotein ( TRL, d<1.006 g/ml ) -TG, and TRL-C levels by approximately 40 %. In the postpr and ial state, fenofibrate reduced total TG, TRL-TG, TRL-C, TRL-apoC-III, and TRL-apoE levels by -35 % ( all values of p<0.01 ). Fasted and fed HDL-C and apoA-I levels were increased -10 %, and total cholesterol/HDL cholesterol ratios were decreased -15 % by fenofibrate. No significant differences were observed in mean LDL-C and LDL-apoB levels. A 6 % increase in the LDL-C/LDL-apoB ratio during fenofibrate treatment indicated a shift to larger, more buoyant LDL particles. A small, but statistically significant ( p<0.01 ) increase was observed in fasted and fed Lp(a ) levels during fenofibrate treatment. Hemostatic parameters were not significantly affected by fenofibrate, except for a 12 - 15 % decrease ( p<0.05 ) in fibrinogen levels in the fasted and fed state, and a significant increase ( 43 % ; p<0.05 ) in fasting levels of plasminogen activator-inhibitor-1. These data demonstrate that micronized fenofibrate is highly effective, in both the fed and fasted state, in reducing TRL lipids and apolipoproteins, and in reducing plasma fibrinogen levels of men with an atherogenic lipoprotein profile Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients. In order to assess the efficacy of gemfibrozil on lipid and haemostatic parameters in patients with plurimetabolic syndrome, a multicenter double-blind placebo controlled, parallel study was carried out in 56 patients with primary hypertriglyceridemia and glucose intolerance. These patients had elevated PAI activity and antigen and t-PA antigen levels at rest and after venous occlusion. Gemfibrozil reduced plasma triglyceride levels ( P<0.001 ), whereas it increased free fatty acids ( P<0.05 ) and high density lipoprotein cholesterol levels ( P<0.05 ). In those patients reaching normalization of plasma triglyceride levels ( triglyceride reduction > or = 50 % ) ( n=15 ), insulin levels ( P<0.05 ) as well as the insulin resistance index were reduced by gemfibrozil treatment, suggesting an improvement of the insulin resistance index in this patient subgroup. Gemfibrozil treatment did not affect plasma fibrinolysis or fibrinogen levels, despite marked reduction of plasma triglycerides and improvement of the insulin sensitivity associated with triglyceride normalization Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t-plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Fluvastatin Alone and in Combination Treatment. AIM OF THE STUDY We studied the effects of fluvastatin and bezafibrate in monotherapy and in combination on plasma fibrinogen, t-plasminogen activator inhibitor ( PAI-1 ) and C reactive protein ( CRP ) in patients with coronary artery disease ( CAD ) and mixed hyperlipidaemia. DESIGN In this r and omised, double blind, multicentre trial 333 patients with stable angina pectoris or previous myocardial infa rct ion or coronary revascularisation and mixed hyperlipidaemia ( LDL-cholesterol 135 - 250 mg/dl and triglycerides ( TG ) 180 - 400 mg/dl ) were r and omised to fluvastatin 40 mg, bezafibrate 400 mg, fluvastatin 20 mg + bezafibrate 400 mg or fluvastatin 40 mg + bezafibrate 400 mg treatments for 24 weeks. RESULTS Plasma fibrinogen significantly decreased after treatment with the combinations fluvastatin+bezafibrate ( -14 and -16 % ) and with bezafibrate monotherapy ( -9 % ). No significant reduction was observed after fluvastatin monotherapy ( -4 % ). No significant changes were observed in PAI-1 and CRP plasma levels. Combination therapy significantly decreased both LDL-C and TG, and significantly increased HDL-C. CONCLUSIONS The combined effects on fibrinogen and plasma lipids achieved by fluvastatin and bezafibrate combination treatment might be more useful than the simple reduction of cholesterol in preventing ischaemic cardiovascular disease Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial BACKGROUND Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. METHODS The Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study was a multinational r and omised trial of 9795 patients aged 50 - 75 years with type 2 diabetes mellitus. Eligible patients were r and omly assigned to receive fenofibrate 200 mg/day ( n=4895 ) or matching placebo ( n=4900 ). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study -was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a sub study of 1012 patients, st and ardised retinal photography was done and photographs grade d with Early Treatment Diabetic Retinopathy Study ( ETDRS ) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International St and ard R and omised Controlled Trial, number IS RCT N64783481. FINDINGS Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group ( 164 [ 3.4 % ] patients on fenofibrate vs 238 [ 4.9 % ] on placebo ; hazard ratio [ HR ] 0.69, 95 % CI 0.56 - 0.84 ; p=0.0002 ; absolute risk reduction 1.5 % [ 0.7 - 2.3 ] ). In the ophthalmology sub study, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall ( 46 [ 9.6 % ] patients on fenofibrate vs 57 [ 12.3 % ] on placebo ; p=0.19 ) or in the subset of patients without pre-existing retinopathy ( 43 [ 11.4 % ] vs 43 [ 11.7 % ] ; p=0.87 ). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo ( three [ 3.1 % ] patients vs 14 [ 14.6 % ] ; p=0.004 ). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group ( HR 0.66, 95 % CI 0.47 - 0.94 ; p=0.022 ). INTERPRETATION Treatment with fen Pleiotropic Action of Short-Term Metformin and Fenofibrate Treatment, Combined With Lifestyle Intervention, in Type 2 Diabetic Patients With Mixed Dyslipidemia OBJECTIVE To compare the effect of short-term metformin and fenofibrate treatment, administered alone or in sequence, on glucose and lipid metabolism, cardiovascular risk factors, and monocyte cytokine release in type 2 diabetic patients with mixed dyslipidemia. RESEARCH DESIGN AND METHODS We studied 128 type 2 diabetic patients with mixed dyslipidemia complying throughout the study with lifestyle intervention who were r and omized twice, initially to either metformin or placebo, and then to micronized fenofibrate or placebo. RESULTS Fenofibrate alleviated diabetic dyslipidemia – induced changes in plasma high-sensitivity C-reactive protein, fibrinogen, and plasminogen activator inhibitor (PAI)-1 and in monocyte cytokine release, whereas metformin or lifestyle intervention improved mainly glucose and lipid metabolism. The strongest pleiotropic effect was observed when fenofibrate was added to metformin. CONCLUSIONS Fenofibrate, particularly administered together with metformin, is superior to metformin and lifestyle intervention in exhibiting beneficial effects on systemic inflammation, hemostasis, and monocyte secretory function in type 2 diabetic patients with mixed dyslipidemia Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. In a r and omized, double-blind five-year trial, we tested the efficacy of simultaneously elevating serum levels of high-density lipoprotein ( HDL ) cholesterol and lowering levels of non-HDL cholesterol with gemfibrozil in reducing the risk of coronary heart disease in 4081 asymptomatic middle-aged men ( 40 to 55 years of age ) with primary dyslipidemia ( non-HDL cholesterol greater than or equal to 200 mg per deciliter [ 5.2 mmol per liter ] in two consecutive pretreatment measurements ). One group ( 2051 men ) received 600 mg of gemfibrozil twice daily, and the other ( 2030 men ) received placebo. Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total, low-density lipoprotein ( LDL ), and non-HDL cholesterol and triglycerides. There were minimal changes in serum lipid levels in the placebo group. The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group -- a reduction of 34.0 percent in the incidence of coronary heart disease ( 95 percent confidence interval, 8.2 to 52.6 ; P less than 0.02 ; two-tailed test ). The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the study. There was no difference between the groups in the total death rate, nor did the treatment influence the cancer rates. The results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia Effects of fenofibrate on lipoproteins, vasomotor function, and serological markers of inflammation, plaque stabilization, and hemostasis. We investigated the effects of fenofibrate, peroxisome proliferator-activated receptors ( PPARs ) agonist, on endothelial function in patients with hypertriglyceridemia. We administered placebo or fenofibrate 200 mg daily to 25 patients with hypertriglyceridemia for 8 weeks. This study was r and omized, double-blind, placebo-controlled, crossover in design. Compared with placebo, fenofibrate significantly changed lipoprotein levels including non-HDL cholesterol and significantly improved the percent flow-mediated dilator response to hyperemia by 13 + /- 6 % ( P < 0.001 ) and lowered plasma levels of tumor necrosis factor-alpha by 13 + /- 3 % ( P < 0.001 ). Fenofibrate reduced fibrinogen and plasminogen activator inhibitor type 1 antigen levels by 17 + /- 3 and 10 + /- 3 %, respectively ( P < 0.001 and P = 0.014, respectively ). However, fenofibrate did not significantly change plasma levels of nitrate, malondialdehyde, tissue factor activity, and serological markers of plaque stabilization. Fenofibrate significantly changed lipoprotein levels and improved the percent flow-mediated dilator response to hyperemia as well as lowered levels of tumor necrosis factor-alpha ( TNF-alpha ), fibrinogen, and plasminogen activator inhibitor type 1 antigen Fibrinolytic proteins and progression of coronary artery disease in relation to gemfibrozil therapy. Impaired fibrinolytic function, mainly due to increased plasma plasminogen activator inhibitor-1 ( PAI-1 ) activity, is common in patients with manifest coronary artery disease ( CAD ) and a predictor of recurrent cardiovascular events. We investigated the relationships of plasma tissue-type plasminogen activator ( tPA ) and PAI-1 antigen levels, plasma PAI-1 activity and PAI 4/5-guanosine ( 4G/5 G ) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial ( LOCAT ). A higher tPA antigen concentration, whether baseline or on-trial, was associated with a more severe global angiographic response ( p < 0.05 ), an association mainly accounted for by progression of diffuse lesions in graft-affected segments ( change in per-patient means of average diameters of segments haemodynamically related to bypass grafts ). Plasma PAI-1 activity and mass concentration and 4G/5 G PAI-1 genotype were unrelated to angiographic outcome measurements. tPA and PAI-1 antigen increased significantly in the gemfibrozil group ( + 11.3 % and + 16.4 %, respectively, p < 0.001 ), whereas there was no treatment effect on PAI-1 activity ( median change 0.0 % ). It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men. Furthermore, pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations Gemfibrozil treatment of combined hyperlipoproteinemia. No improvement of fibrinolysis despite marked reduction of plasma triglyceride levels. Hypertriglyceridemia is linked to impaired fibrinolytic function, and lipid-lowering treatment with fibric acid derivatives could hypothetically improve fibrinolysis in this condition. We therefore conducted a double-blind, placebo-controlled, crossover study of gemfibrozil treatment on fibrinolytic function in 21 men with combined hyperlipoproteinemia. Measurements were performed at rest and during mental stress and after venous occlusion. The patients had clearly disturbed fibrinolytic function, with elevated plasminogen activator inhibitor-1 ( PAI-1 ) activity at rest ( approximately 25 U/mL ; reference, < 15 U/mL ). Gemfibrozil reduced plasma total and VLDL cholesterol as well as all triglyceride fractions, whereas HDL cholesterol increased ( P <.001 for all ). Total triglyceride levels were reduced by 57 + /- 4 % ( from 5.3 to 2.1 mmol/L ). Fasting serum insulin levels were not altered by gemfibrozil treatment. Plasma levels of PAI-1 activity and tissue-type plasminogen activator ( TPA ) activity or antigen were unaffected by gemfibrozil treatment both at rest and during the provocations. The levels of D-dimer, plasmin/antiplasmin complex, and fibrinogen were also uninfluenced by gemfibrozil treatment. Mental stress elevated plasma TPA ( P=.0036 ) and lowered PAI-1 ( P=.0012 ) activity during placebo but not gemfibrozil treatment ( P=.28 and P=.17, respectively ), but treatment effects did not differ by ANOVA on delta values ( ie, stress minus rest ). Venous occlusion reduced PAI-1 activity, whereas TPA and plasmin/antiplasmin complex increased during both treatments. Thus, gemfibrozil treatment did not improve fibrinolysis or lower fibrinogen levels in men with combined hyperlipoproteinemia despite marked reduction of plasma triglyceride levels. It seems unlikely that improved fibrinolysis explains the primary preventive effect of gemfibrozil Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients. Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator ( t-PA ), plasminogen activator inhibitor-1 ( PAI-1 ) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen. Although both fibrates effectively lowered triglyceride and cholesterol levels, no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment. However, both fibrates influenced plasma fibrinogen levels, albeit in a different way. Fibrinogen antigen levels were elevated by 17.6 % ( p < 0.05 ) and 24.3 % ( p < 0.001 ) with gemfibrozil after six and twelve weeks, respectively, whereas with ciprofibrate there was no effect. Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point, no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment. However, after twelve weeks, gemfibrozil enhanced functional fibrinogen levels by 7.2 % ( p < 0.05 ) as assessed by the Clauss mechanical assay, but decreased functional fibrinogen levels by 12.5 % ( p < 0.0001 ) when a Clauss assay based on turbidity was used. After six or twelve weeks of ciprofibrate treatment, functional fibrinogen levels were decreased by 10.1 % ( p < 0.001 ) and 10.5 % ( p < 0.0001 ), respectively on the basis of Clauss mechanical and by 14.2 % ( p < 0.001 ) and 28.2 % ( p < 0.0001 ), respectively with the Clauss turbidimetric assay. A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen ( determined by either of the two Clauss assays ) to fibrinogen antigen. Taken together, our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates, by differences in treatment period and /or by the different outcomes of various assay systems. Interestingly, the two fibrates tested both reduced the functionality of fibrinogen Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. We have investigated the effects of two fibric acid derivatives, bezafibrate mono ( 400 mg daily ) and gemfibrozil ( 600 mg b.d. ), in 29 patients with type IIb hyperlipoproteinaemia. All patients received placebo and each drug for 8 weeks in r and omised order in a double-blind, cross-over study design ed to evaluate any different effects of the drugs on serum lipoproteins, cholesteryl ester transfer protein ( CETP ), cholesteryl ester transfer activity ( CETA ), plasma fibrinogen, plasminogen activator inhibitor-I ( PAI-1 ) or paraoxonase. Serum cholesterol decreased ( P < 0.05 ) with gemfibrozil, but the effect of bezafibrate on serum cholesterol did not achieve statistical significance ( placebo 8.34 + /- 1.05 ( mean + /- S.D. ), gemfibrozil 7.70 + /- 1.23 and bezafibrate 7.8 + /- 1.37 mmol/l ). Both drugs decreased the serum triglyceride concentration ( both P < 0.001 ) ( placebo 4.39 ( 3.13 - 5.75 ) ( median ( interquartile range ) ), bezafibrate 2.26 ( 1.89 - 3.89 ) and gemfibrozil 2.00 ( 1.30 - 3.30 ) mmol/l ) and very low density lipoprotein ( VLDL ) cholesterol ( both P < 0.001 ) ( placebo 1.18 ( 0.74 - 2.30 ), bezafibrate 0.59 ( 0.34 - 0.85 ) and gemfibrozil 0.48 ( 0.34 - 0.68 ) mmol/l ). Discontinuous gradient ultracentrifugation ( DGU ) revealed that Sf 60 - 400 ( large VLDL ) decreased by more than 50 % and Sf 20 - 60 ( small VLDL ) by more than 30 % with each of the drugs ( both P < 0.001 ), neither of which affected the composition of these lipoproteins. Gemfibrozil decreased the concentration of Sf 12 - 20 lipoprotein ( intermediate density lipoprotein ; IDL ) by 23 % ( P < 0.01 ), whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance. Neither drug altered the concentration of apolipoprotein B or of total Sf 0 - 12 lipoproteins ( low density lipoprotein, ( LDL ) ). Both, however, significantly increased the quantity of free cholesterol in Sf 0 - 12 lipoproteins ( P < 0.05 ). Overall the concentration of triglycerides decreased significantly in all lipoproteins isolated by DGU ( Sf 0 - 12, Sf 12 - 20, Sf 20 - 60, Sf 60 - 400 ) on gemfibrozil treatment, but only in Sf 20 - 60 and Sf Gemfibrozil treatment increases low-density lipoprotein particle size in Type 2 diabetes mellitus but does not alter in vitro oxidizability. The aim of this study was to determine the effect of the lipid modifying agent gemfibrozil on lipid and coagulation risk factors in patients with Type 2 diabetes mellitus ( Type 2 DM ). Twenty-six subjects with Type 2 DM and dyslipidaemia were treated for 24 weeks with either gemfibrozil 600 mg orally twice daily or placebo in a double-blind r and omized trial. Lipid profiles, fibrinogen, Factor VII, and plasminogen activator inhibitor-1 ( PAI-1 ) were measured by routine laboratory methods. Low density lipoprotein ( LDL ) size was determined by gradient gel electrophoresis and the resistance of LDL to copper-induced oxidation was assessed by measuring absorbance at 234 nm. Gemfibrozil significantly reduced total cholesterol ( -0.9 ( -0.48, -1.32 ) mmol l(-1 ) ; p < 0.05 ) and triglycerides ( -2.7 ( -1.55, -1.35 ) mmol l(-1 ) ; p < 0.001 ) vs placebo. The fall in triglyceride was reflected by a fall in VLDL cholesterol levels in the gemfibrozil treated group vs placebo ( -1.31 mmol l(-1 ) ; p < 0.001 ). LDL-cholesterol level did not change but LDL particle size increased by 0.5 nm ( 0.01, 0.93 ) ; P < 0.02. The increase in particle size was inversely correlated with the change of triglyceride level ( r = -0.79, p < 0.0001 ) but did not result in any reduction of susceptibility to copper-induced oxidation. There were no significant changes in the coagulation parameters studied. Because of its ability to correct the lipid abnormalities associated with Type 2 DM particularly hypertriglyceridaemia, gemfibrozil provides a useful therapeutic option in the management of diabetic dyslipidaemia but it does not alter in vitro oxidizability of LDL Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. BACKGROUND Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We design ed the Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study to assess the effect of fenofibrate on cardiovascular disease events in these patients. METHODS We did a multinational, r and omised controlled trial with 9795 participants aged 50 - 75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we r and omly assigned patients ( 2131 with previous cardiovascular disease and 7664 without ) with a total-cholesterol concentration of 3.0 - 6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0 - 5.0 mmol/L to micronised fenofibrate 200 mg daily ( n=4895 ) or matching placebo ( n=4900 ). Our primary outcome was coronary events ( coronary heart disease death or non-fatal myocardial infa rct ion ) ; the outcome for prespecified subgroup analyses was total cardiovascular events ( the composite of cardiovascular death, myocardial infa rct ion, stroke, and coronary and carotid revascularisation ). Analysis was by intention to treat. The study was prospect ively registered ( number IS RCT N 64783481 ). FINDINGS Vital status was confirmed on all but 22 patients. Averaged over the 5 years'study duration, similar proportions in each group discontinued study medication ( 10 % placebo vs 11 % fenofibrate ) and more patients allocated placebo ( 17 % ) than fenofibrate ( 8 % ; p<0.0001 ) commenced other lipid treatments, predominantly statins. 5.9 % ( n=288 ) of patients on placebo and 5.2 % ( n=256 ) of those on fenofibrate had a coronary event ( relative reduction of 11 % ; hazard ratio [ HR ] 0.89, 95 % CI 0.75 - 1.05 ; p=0.16 ). This finding corresponds to a significant 24 % reduction in non-fatal myocardial infa rct ion ( 0.76, 0.62 - 0.94 ; p=0.010 ) and a non-significant increase in coronary heart disease mortality ( 1.19, 0.90 - 1.57 ; p=0.22 ). Total cardiovascular disease events were significantly reduced from 13.9 % to 12.5 % ( 0.89, 0.80 - 0.99 ; p=0.035 ). This finding included a 21 % reduction in coronary revascularisation ( 0.79, 0.68 - 0.93 ; p=0.003 ). Total mortality was 6.6 % in the placebo group and 7.3 % in the fenofibrate group ( p=0.18 ). Fenofibrate was associated with less albuminuria progression ( p=0.002 ), and less retinopathy needing laser treatment ( 5.2 Effects of gemfibrozil on lipids and haemostasis after myocardial infarction. The effects of gemfibrozil on haemostatic variables were studied in 43 survivors of myocardial infa rct ion with serum triglycerides ( TG ) greater than or equal to 2 mmol/l 2 weeks prior to r and omization. The study was double-blind, placebo-controlled and stratified for chronic betablockade. Twenty-two individuals were given gemfibrozil 600 mg twice daily and 21 individuals received matching placebo. After 8 weeks the TG level was unchanged in the placebo group, whereas a 44 % reduction was noted in the gemfibrozil group ( p less than 0.001 ). Fibrinogen increased in both groups, while bleeding time and platelet count were unchanged. Clotting factor VII-phospholipid complex decreased in both groups, but the change was more marked and attained statistical significance only in the gemfibrozil group ( 60 % reduction, p less than 0.01 ). By DDAVP-stimulated D-Dimer agglutination test 8 in 21 patients in the placebo group ( 38 % ) still had reduced fibronolytic capacity versus none in the gemfibrozil group ( p = 0.001 ). Thus, in this study, gemfibrozil improved reduced fibrinolytic capacity and may have reduced hypercoagulability by lowering the clotting factor VII-phospholipid complex", "AIMS Overactive bladder ( OAB ) affects over 17 % of the population and significantly effect the health-related quality of life. The treatments for OAB include first line ( lifestyle modification, pelvic floor muscle training ), second line ( anticholinergic or beta-3 agonist medications ), and third line therapies ( intradetrusor botulinum toxin injection, sacral neurostimulation [ SNM ], or percutaneous tibial nerve stimulation [ PTNS ] ). For those with urinary incontinence secondary to OAB, complete continence is the goal of therapy, though cure rates are only 5 % to 40 %. The use of combination therapies can be employed in refractory OAB, however, the efficacy of pooled modalities is relatively unknown. Our objective was to determine the volume of data supporting combination therapy in treating OAB. Prospective and randomized comparison of electrical stimulation of the posterior tibial nerve versus oxybutynin versus their combination for treatment of women with overactive bladder syndrome Objective To verify whether the combination of transcutaneous electrical neural stimulation ( TENS ) with oxybutynin in the treatment of women with overactive bladder ( OAB ) would be more effective than isolated treatments. Methods We r and omized 75 women with OAB, in three groups : GI—30 min TENS, twice a week ; GII — daily slow release 10 mg oxybutynin ; and GIII — TENS + oxybutynin ( multimodal ) ; all for 12 weeks. Patients were evaluated with vali date d question naires International Consultation on Incontinence-Short Form ( ICIQ-SF ), International Consultation on Incontinence-OAB ( ICIQ-OAB ), Symptom bother, and 3-day Voiding diary at weeks 0, 12, and 24. Results The groups were similar before treatment. After treatment, all groups significantly improved in OAB symptoms and quality of life ( QoL ). At week 12, ICIQ-OAB scores were 5.9, 4.6, and 2.9, in groups I, II, and III, respectively, p = 0.01. At week 24, GI and GIII kept the scores of the end of treatment ( week 12 ), while GII increased ICIQ-OAB from 4.6 to 9.2, p = 0.0001, ICIQ-SF from 9.8 to 13.3, p = 0.0006, and Symptom bother score from 3.4 to 7.0, p = 0.0001. Conclusions The multimodal treatment was more effective and TENS alone or in association presented longer lasting results for improvement of clinical symptoms of OAB and A comparison of the efficacy of darifenacin alone vs. darifenacin plus a Behavioural Modification Programme upon the symptoms of overactive bladder Purpose This study assessed the benefit of adding behavioural modification to darifenacin treatment for overactive bladder ( OAB ). Material s and methods The ABLE trial was a r and omised, open-label, parallel-group, multicentre study of 12 weeks of darifenacin treatment [ with voluntary up-titration from 7.5 mg once daily ( qd ) to 15 mg qd at week 2 ] alone or in combination with a Behavioural Modification Programme ( BMP ) for men and women with dry or wet OAB. Efficacy was assessed as the change in the number ( per day ) of micturitions ( primary variable ), urge urinary incontinence ( UUI ) episodes, urgency episodes, pads used and nocturnal voids. Health-related quality of life ( HRQoL ) was also evaluated. Tolerability and safety assessment s included adverse events and the number of discontinuations. Results Of 592 patients screened, 395 were r and omised, 190 to darifenacin alone and 205 to darifenacin + BMP. At baseline, the majority of subjects were dry ( mean 2.8 and three UUI episodes per day in the darifenacin and darifenacin + BMP groups respectively ). At study end, darifenacin alone and darifenacin + BMP both produced significant reductions from baseline in median numbers of micturitions, UUI episodes, urgency episodes and nocturnal voids ( all p < 0.05 ), but not in the number of pads used. HRQoL also improved. There were no significant differences between treatment groups in efficacy or HRQoL variables. Conclusions Darifenacin treatment provides a degree of normalisation of micturition variables and improvement in HRQoL that can not be further enhanced by behavioural therapy of the type used in this study. Whether behavioural modification would add benefit over darifenacin treatment in patients with more pronounced incontinence problems remains to be determined The combination of herbal medicine Weng-li-tong with Tolterodine may be better than Tolterodine alone in the treatment of overactive bladder in women: a randomized placebo-controlled prospective trial Background To assess the efficacy and safety of the herbal medicine, Weng-li-tong ( WLT ) as monotherapy or combined with tolterodine in women with overactive bladder ( OAB ). Methods A prospect i ve, r and omized, single-blind multi-center trial was performed which included 182 OAB patients treated with either placebo ( n = 26 ), WLT ( n = 52 ), tolterodine ( n = 52 ) or WLT plus tolterodine ( n = 52 ). The overactive bladder symptom score ( OABSS ) and micturition behavior were measured to evaluate treatment efficacy. Results In total, 146 patients [ placebo ( n = 23 ), WLT ( n = 39 ), tolterodine ( n = 41 ) and WLT plus tolterodine ( n = 43 ) ] completed 8 weeks of treatment. Compared to those treated with placebo, patients in three intervention groups showed significant improvements in the OABSS, voiding frequency, average voided volume and urgency incontinence. WLT had a slower onset than tolterodine or combination therapy in reducing urgency incontinence. Compared with tolterodine, WLT had a weaker effect in improving OABSS ( P = 0.022 ) and daily voiding frequency ( P = 0.034 ). The combination therapy had better efficacy than WLT or tolterodine alone in improving the OABSS, voiding frequency and voided volume. No significant differences in the changes in quality of life scores were observed among the three intervention groups. Residual urine increased significantly in tolterodine group ( P = 0.004 ), but not in combination group. WLT result ed in fewer adverse effects than tolterodine such as dry mouth ( P = 0.002 ), weak stream ( P = 0.002 ) and less residual urine ( P < 0.001 ). Conclusions WLT could improve OAB symptoms in women, while it had slower onset and weaker efficacy but fewer adverse effects than tolterodine. The combination of WLT and tolterodine was more efficacious than tolterodine alone in improving OAB symptoms. Trial registration Chinese Clinical Trial Registry [ ChiCTR-IPR-14005626 ]. Date of registration : 7 December 2014 Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study) To evaluate the potential of solifenacin 5 mg combined with mirabegron 25 or 50 mg to deliver superior efficacy compared with monotherapy, with acceptable tolerability, in the general overactive bladder ( OAB ) population with urinary incontinence ( UI ) Effectiveness and durability of solifenacin versus percutaneous tibial nerve stimulation versus their combination for the treatment of women with overactive bladder syndrome: a randomized controlled study with a follow-up of ten months ABSTRACT Purpose To assess effectiveness and durability of Solifenacin ( SS ) versus tibial nerve stimulation ( PTNS ) versus combination therapy ( PTNS + SS ) in women with overactive bladder syndrome ( OAB ). Material s and Methods 105 women with OAB were divided r and omly into three groups of 35 patients each. In group A women received SS, in group B women underwent PTNS, in group C women underwent combination of PTNS + SS. Improvements in OAB symptoms were assessed with OABSS question naire ; patients ’ quality of life was assessed with OAB-q SF question naire. Evaluation of effectiveness of treatments was performed with PGI-I question naire. OABSS and PGI-I were also assessed monthly for ten months. Results All treatments were effective on symptoms. PTNS showed a greater effectiveness than SS, but PTNS + SS was more effective than SS and PTNS. Furthermore, PTNS + SS showed a greater duration of effectiveness than PTNS and SS. Conclusions Combination of PTNS with SS showed more effectiveness and more durability than PTNS and SS alone Transcutaneous posterior tibial nerve electrostimulation with low dose trospium chloride: Could it be used as a second line treatment of overactive bladder in females. AIM To evaluate the effect of adding low dose trospium chloride with transcutaneous posterior tibial nerve stimulation ( TPTNS ) in the treatment of overactive bladder ( OAB ) in females after failure of behavioral therapy. METHODS We r and omized 30 women with OAB, in two groups : G I received 30 min TPTNS, three times a week ; GII received TPTNS plus 20 mg trospium chloride daily. OAB Symptom Score question naire ( OABSS ), Incontinence Impact Question naire-short form 7 ( IIQ-7 ), 3 day voiding diary and urodynamics at weeks 0 and 8 were evaluated. RESULTS The groups were similar before treatment. Eight weeks after treatment, the mean OABSS decreased significantly to 8.53 ± 1.30 for group II vs 10.0 ± 2.0 for GI ( P < 0.024 ). The mean IIQ-7 score decreased significantly to 51.86 ± 17.26 in group I vs 31.99 ± 9.26 in group II ( P < 0.001 ). Before treatment, 11 ( 73.3 % ) and 4 ( 26.7 % ) patients in each group had moderate and poor quality of life ( QoL ), respectively. After treatment, 6 ( 40 % ) and 14 ( 93.3 % ) had good QoL, 7 ( 46.7 % ) and 1 ( 6.7 % ) had moderate QoL in GI and GII, respectively. Two ( 13.3 % ) patients in GI had poor QoL. The mean frequency was reduced to 8.60 ± 0.83 vs 10.60 ± 2.32 for GII and GI respectively ( P = 0.006 ). The cystometric capacity increased from 263.40 ± 50.45 to 377.80 ± 112.92 mL ( P = 0.001 ) for GII vs 250.13 ± 56.24 to 296.40 ± 99.0 mL ( P = 0.026 ) for GI. CONCLUSION TPTNS combined with low dose trospium chloride proved to be more effective than TPTNS alone in the treatment of OAB in females Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). BACKGROUND Combining the β3-adrenoceptor agonist mirabegron and the antimuscarinic ( AM ) agent solifenacin may improve efficacy in the treatment of overactive bladder ( OAB ) while reducing the AM side effects. OBJECTIVE The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5 mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy. DESIGN, SETTING, AND PARTICIPANTS A phase 2, factorial design, r and omised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo. INTERVENTION A total of 1306 patients ( 66.4 % female ) were r and omised to 12 wk of treatment in 1 of 12 groups : 6 combination groups ( solifenacin 2.5, 5, or 10 mg plus mirabegron 25 or 50 mg ), 5 monotherapy groups ( solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg ), or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Change from baseline to end of treatment in mean volume voided per micturition ( MVV ) ( primary end point ) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h were analysed using an analysis of covariance model. Safety assessment s included treatment-emergent adverse events ( TEAEs ), blood pressure, pulse rate, postvoid residual ( PVR ) volume, and laboratory and electrocardiography ( ECG ) parameters. RESULTS AND LIMITATIONS Compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml ( 95 % confidence interval [ CI ], 5.4 - 30.0 ) to 26.3 ml ( 95 % CI, 12.0 - 41.0 ). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, ranging from -0.80 ( 95 % CI, -1.39 to -0.22 ) to -0.98 ( 95 % CI, -1.68 to -0.27 ). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from -0.98 ( 95 % CI, -1.78, to -0. Simplified bladder training augments the effectiveness of tolterodine in patients with an overactive bladder To compare the efficacy of tolterodine plus simplified bladder training ( BT ) with tolterodine alone in patients with an overactive bladder Percutaneous tibial nerve stimulation versus electrical stimulation with pelvic floor muscle training for overactive bladder syndrome in women: results of a randomized controlled study. INTRODUCTION This study compared percutaneous tibial nerve stimulation ( PTNS ) versus electrical stimulation with pelvic floor muscle training ( ES + PFMT ) in women with overactive bladder syndrome ( OAB ). MATERIAL S AND METHODS 60 women with OAB were enrolled. Patients were r and omized into two groups. In group A, women underwent ES with PFMT, in group B women underwent PTNS. RESULTS A statistically significant reduction in the number of daily micturitions, episodes of nocturia and urge incontinence was found in the two groups but the difference was more substantial in women treated with PTNS ; voided volume increased in both groups. Quality of life improved in both groups, whereas patient perception of urgency improved only in women treated with PTNS. Global impression of improvement revealed a greater satisfaction in patients treated with PTNS. CONCLUSION This study demonstrates the effectiveness of PTNS and ES with PFMT in women with OAB, but greater improvements were found with PTNS Comparative Effectiveness of Combined Low- and Standard-Dose Trospium and Solifenacin for Moderate Overactive Bladder Symptoms in Elderly Men and Women Objective : To increase the safety and effectiveness of treatments for overactive bladder ( OAB ) with moderate symptoms in elderly patients. Patients and Methods : Patients were examined at the Urodynamic Department of the Regional Diagnostic Center ( Vladivostok, Russian Federation ) from September 1, 2012 to December 31, 2012. The assignment of patients [ n = 177, average age 69. 4 years, 98 women ( 55.4 % ) and 79 men ( 44.6 % ) ] was r and om and blind in this placebo-controlled study. Patients were distributed into subgroups according to the method of treatment as follows : group А1 : n = 57, trospium 30 mg/day + solifenacin 10 mg/day ; group А2 : n = 61, trospium 15 mg/day + solifenacin 5 mg/day ; group А3 : n = 59, placebo. All patients underwent a urodynamic examination in accordance with international st and ards before and 2 months after treatment. ICIQ-SF question naires recommended by the International Continence Society ( ICS ) and bladder diaries were used to evaluate the clinical results. The clinical severity of the OAB symptoms and the effectiveness of the treatment were evaluated based on the frequency of episodes of incontinence ( EI ) per day. Three or fewer EI per day were considered moderate dysfunction of the lower urinary tract. Results : Groups of elderly patients with moderate symptoms of OAB who were treated with st and ard- and low-dose trospium and solifenacin demonstrated a significant increase in the median values of reflex volume, bladder capacity, and detrusor compliance and a decrease in the frequency of urination and urinary urgencies. The frequency of EI in both of the main groups decreased by almost 2-fold in comparison to the initial data and reached the following values : group А1 : 1.27 ( -1.08 ), p ≤ 0.05 ; group A2 : 1.49 ( -1.18 ), p ≤ 0.05. The correlation with the decrease in the frequency of EI in these groups was r = 0.85 ( p ≤ 0.01 ). The percentage of patients with a significant decrease ( EI ≥1.0 ) among those treated with st and ard- and low-dose trospium and solifenacin increased synchronously, prompting us to suppose the absence of a direct correlation between medicine dose and therapeutic effect for moderate OAB symptoms. Conclusion : The combination of low-dose trospium and solifenacin provides good clinical and urodynamic effects in elderly patients with moderate symptoms of OAB. Combination of these drugs in st and ard doses for such patients is excessive Combined behavioral and individualized drug therapy versus individualized drug therapy alone for urge urinary incontinence in women. PURPOSE We tested whether individualized drug therapy enhanced with behavioral training would result in better outcomes than individualized drug therapy alone. MATERIAL S AND METHODS Participants were community dwelling women with urge predominant incontinence. Using a r and omized clinical trial design women were r and omized to 8 weeks ( 4 visits ) of drug therapy alone ( 32 ) or drug therapy plus behavioral training ( 32 ). Drug therapy was individually titrated, extended release oxybutynin with proactive management of side effects. Behavioral training included pelvic floor muscle training and urge suppression techniques. The primary outcome measure was reduction in frequency of incontinence episodes on bladder diary at 8 weeks ( with followup at 6 and 12 months ). Secondary outcomes included patient satisfaction, global perception of improvement, Urogenital Distress Inventory and Incontinence Impact Question naire. RESULTS In intent to treat analysis frequency of incontinence was reduced a mean of 88.5 % in the drug alone group and 78.3 % in the combined therapy group ( p = 0.16 ). Outcomes were not significantly different between the groups in the analysis of completers ( 91.5 % vs 86.2 %, p = 0.34 ), or in either analysis at 6 or 12 months. The groups also did not differ significantly on secondary outcomes at any point. Participants in the drug alone group tended to be taking higher doses of oxybutynin at 8 weeks but the final dose did not differ significantly between the groups. Based on a conditional power calculation the trial was stopped early for futility. CONCLUSIONS When drug therapy is implemented with frequent individualized dose titration, daily bladder diaries and careful management of side effects, initiating concurrent behavioral training does not enhance outcomes for urge incontinence in women Safety and efficacy of mirabegron as ‘add‐on’ therapy in patients with overactive bladder treated with solifenacin: a post‐marketing, open‐label study in Japan (MILAI study) To examine the safety and efficacy of mirabegron as ‘ add‐on ’ therapy to solifenacin in patients with overactive bladder ( OAB ) Effects of Bladder Training and/or Tolterodine in Female Patients with Overactive Bladder Syndrome: A Prospective, Randomized Study We compared the effects of bladder training and /or tolterodine as first line treatment in female patients with overactive bladder ( OAB ). One hundred and thirty-nine female patients with OAB were r and omized to treatment with bladder training ( BT ), tolterodine ( To, 2 mg twice daily ) or both ( Co ) for 12 weeks. Treatment efficacy was measured by micturition diary, urgency scores and patients'subjective assessment of their bladder condition. Mean frequency and nocturia significantly decreased in all treatment groups, declining 25.9 % and 56.1 %, respectively, in the BT group ; 30.2 % and 65.4 %, respectively, in the To group ; and 33.5 % and 66.3 %, respectively in the Co group ( p<0.05 for each ). The decrease in frequency was significantly greater in the Co group than in the BT group ( p<0.05 ). Mean urgency score decreased by 44.8 %, 62.2 % and 60.2 % in the BT, To, and Co groups, respectively, and the improvement was significantly greater in the To and Co groups than in the BT group ( p<0.05 for each ). Although BT, To and their combination were all effective in controlling OAB symptoms, combination therapy was more effective than either method alone. Tolterodine alone may be instituted as a first-line therapy, but may be more effective when combined with bladder training Effect of Desmopressin with Anticholinergics in Female Patients with Overactive Bladder Purpose The aim of this study was to evaluate the effect of desmopressin combined with anticholinergics on daytime frequency and urgency in female patients with overactive bladder ( OAB ). Material s and Methods We included 68 female patients with OAB. Patients were r and omly assigned to receive 5 mg of solifenacin ( group I ) or 5 mg of solifenacin and 0.2 mg of desmopressin ( group II ) for 2 weeks. A pre/post-treatment 3-day voiding diary and the Urinary Distress Inventory ( UDI-6 ) and Incontinence Impact Question naire ( IIQ-7 ) were used to assess changes in voiding symptoms and quality of life ( QoL ) ; results were compared between the two groups. Results Groups I and II included 31 and 37 patients, respectively. Time to first void was 12 min later in group II ( 105 min vs. 117 min ), but this difference was not statistically significant. However, time to the second and third voids ( 203 min vs. 255 min, 312 min vs. 368 min ) and the first urgency episode ( 212 min vs. 255 min ) were significantly longer in group II. Compared with group I, patients in group II showed significant improvement in QoL scores. When improvement after treatment was defined as increase in time to first void of greater than 10 % after 2 weeks of treatment, desmopressin with anticholinergics was more effective in patients over the age of 65 years and with more than 150 ml of voided volume. Conclusions Desmopressin combined with anticholinergics was more effective than anticholinergics only in the treatment of female patients with OAB Investigation of the clinical efficacy and safety of pregabalin alone or combined with tolterodine in female subjects with idiopathic overactive bladder. AIMS To assess the efficacy and safety of pregabalin alone or in combination with tolterodine extended release ( ER ) in subjects with idiopathic OAB. METHODS This 26-week, multicenter, r and omized, double-blind, placebo-controlled, three-period crossover study enrolled women aged ≥ 18 years that were diagnosed with OAB and reported ≥ 8 micturitions/24 hr and ≥ 4 urgency episodes/week on 5-day bladder diary at baseline. Subjects were r and omized to 1 of 10 treatment sequences and received three of five treatments, each for 4 weeks with 4-week washout periods : st and ard-dose pregabalin/tolterodine ER ( 150 mg twice daily [BID]/4 mg once daily [ QD ], n=102 ), pregabalin alone ( 150 mg BID, n=105 ), tolterodine ER alone ( 4 mg QD, n=104 ), low-dose pregabalin/tolterodine ER ( 75 mg BID/2 mg QD, n=105 ), and placebo ( n=103 ). Subjects completed 5-day diaries at the end of treatment and washout periods. The primary endpoint was change from baseline to week 4 in mean voided volume ( MVV ) per micturition. The primary comparison was st and ard-dose pregabalin/tolterodine ER versus tolterodine ER alone ; secondary comparisons were pregabalin alone versus tolterodine ER alone and versus placebo. RESULTS Baseline-adjusted changes in MVV were significantly greater after treatment with st and ard-dose pregabalin/tolterodine ER ( 39.5 ml ) versus tolterodine ER alone ( 15.5 ml ; P<0.0001 ), and with pregabalin alone ( 27.4 ml ) versus tolterodine ER alone ( P=0.005 ) and placebo ( 11.9 ml ; P=0.0006 ). Treatments were generally well tolerated ; discontinuation rates due to adverse events were 4 %, 2 %, 5 %, 0 %, and 1 % with st and ard- and low-dose pregabalin/tolterodine ER, pregabalin, tolterodine ER, and placebo, respectively. CONCLUSIONS Pregabalin, alone or with tolterodine ER may offer an alternative treatment option for idiopathic OAB in women Efficacy of simplified bladder training in patients with overactive bladder receiving a solifenacin flexible‐dose regimen: results from a randomized study Study Type – Therapy ( RCT ) Level of Evidence Anticholinergic drugs, bladder retraining and their combination for urge urinary incontinence: a pilot randomised trial Bladder retraining and anticholinergic drugs in women with urge urinary incontinence need to be compared. Women with urge urinary incontinence were recruited by advertisements, from primary care and from a urogynaecology clinic. Women were r and omised using a web page to bladder retraining, anticholinergic drugs or both and followed up at 3 and 12 months. No blinding was attempted. The primary outcomes were the trial process and the Overactive Bladder Question naire ( OAB-q ) quality -of-life measure. Recruitment was much slower than anticipated. There were no differences in the OAB-q at 12 months ( 87.9 SD 11.6 bladder retraining, 81.6 SD 19.3 drug therapy and 88.9 SD 9.9 combination ) but dry mouth was more common in those taking drugs. It is feasible to run a pragmatic r and omised trial with 12-month follow-up for women with urinary urge incontinence. This will require about 500 participants per arm The effects of drug and behavior therapy on urgency and voiding frequency Introduction and hypothesisThe objective of this study was to examine the effects of drug therapy alone and combined with behavioral therapy on urgency and 24-voiding frequency in women with urge-predominant incontinence and to identify predictors of change. Methods A planned analysis of data from a multi-site, r and omized, controlled trial ( N = 307 ). Bladder diaries were used to document voids, incontinence, and urgency severity. Results Urgency scores decreased significantly within both treatment groups, but changes did not differ between groups ( p = 0.30 ). Improvement in urgency was associated with greater baseline urgency ( p < 0.0001 ) and black ethnicity ( p = 0.03 ). Voiding frequency increased with drug alone and decreased slightly with combined therapy ( p = 0.009 ), and improvement was associated with combined treatment ( p < 0.0001 ), higher baseline frequency ( p < 0.0001 ), and lower baseline incontinence episode frequency ( p = 0.001 ). Conclusions Although combined drug and behavioral therapy does not appear to improve urgency more than drug alone, it result ed in better outcomes on voiding frequency Comparison of different treatment protocols in the treatment of idiopathic detrusor overactivity: a randomized controlled trial Objective : To investigate and compare the effectiveness of various treatment protocol s for the treatment of women with idiopathic detrusor overactivity. Design : Prospect i ve, r and omized controlled trial. Setting : Departments of Physiotherapy and Rehabilitation and Obstetrics and Gynaecology, Hacettepe University. Subjects : Forty-six subjects were r and omized to three groups. Interventions : The first group received only pharmacotherapy, the second group received only physiotherapy and in the third group pharmacotherapy was combined with physiotherapy ( combined therapy group ). Main measures : All patients were evaluated at the beginning and at the end of treatment. Assessment parameters were maximum cystometric capacity, electromyographic activity of pelvic floor muscles, voiding diary parameters, the amount of urine leakage and the quality of life score. Results : The maximum cystometric capacity and the electromyographic activity of pelvic floor muscles increased significantly and the number of voids/day and incontinence episodes/day, and the amount of urine leakage reduced significantly ( P < 0.05 ) in both physiotherapy and combined therapy groups while there was no significant difference in the pharmacotherapy group. After treatment, the number of voids/day increased by 0.3 ± 3.4 in the pharmacotherapy group ( P > 0.05 ) and decreased by 5.1 ± 5.5 and 4.7 ± 5.6 in the physiotherapy and combined therapy groups, respectively ( P < 0.05 ). Statistically significant improvements were observed in all groups according to the number of voids/night and the quality of life scores at the end of the treatment. Conclusion : The physiotherapy protocol we introduced in the present study with or without anticholinergic therapy has a substantial positive impact on the treatment of female patients with idiopathic detrusor overactivity Combination of sacral neuromodulation and tolterodine for treatment of idiopathic overactive bladder in women: a clinical trial. PURPOSE To evaluate the efficacy of intermittent percutaneous needle sacral nerve stimulation ( IPN-SNS ) in women with idiopathic overactive bladder ( IOAB ) treated with tolterodine. MATERIAL S AND METHODS A total of 240 female patients diagnosed with IOAB were r and omized to receive tolterodine only treatment ( group 1, n = 120 ) or tolterodine combined with IPN-SNS ( group 2, n = 120 ). Each group included 120 participants, who were divided into subgroups depending on whether they had dry OAB ( urinary frequency and urgency ) or wet OAB ( urinary frequency and urgency with urgency incontinence ). In the treatment group, patients received percutaneous IPN-SNS plus tolterodine ( 2 mg once daily ), while in the control group, only tolterodine ( 2 mg once daily ) was administered for 3 months. The voiding diary and urodynamic parameters were monitored, and patients'psychological depression and anxiety scores were recorded before and after treatment. RESULTS There were significantly greater improvements in the conditions of first desire to void ( FDV ), max\xadimum cystometric capacity ( MCC ), and daily average volumes, as well as the daily single maximum voided volumes in group 2 ( P =.001 ) than in group 1. In addition, there were significantly greater decreases in self-rating depression scale ( SDS ) and self-rating anxiety scale ( SAS ) scores in group 2 compared with group 1 ( P <.001 ). CONCLUSION Combined treatment with tolterodine plus IPN-SNS can not only improve the symptoms of voiding dysfunction but can also reduce the concomitant depression and anxiety in women with IOAB, there\xadby improving patients'quality of life OnabotulinumtoxinA vs Sacral Neuromodulation on Refractory Urgency Urinary Incontinence in Women: A Randomized Clinical Trial. Importance Women with refractory urgency urinary incontinence are treated with sacral neuromodulation and onabotulinumtoxinA with limited comparative information. Objective To assess whether onabotulinumtoxinA is superior to sacral neuromodulation in controlling refractory episodes of urgency urinary incontinence. Design, Setting, and Participants Multicenter open-label r and omized trial ( February 2012-January 2015 ) at 9 US medical centers involving 381 women with refractory urgency urinary incontinence. Interventions Cystoscopic intradetrusor injection of 200 U of onabotulinumtoxinA ( n = 192 ) or sacral neuromodulation ( n = 189 ). Main Outcomes and Measures Primary outcome, change from baseline mean number of daily urgency urinary incontinence episodes over 6 months, was measured with monthly 3-day diaries. Secondary outcomes included change from baseline in urinary symptom scores in the Overactive Bladder Question naire Short Form ( SF ) ; range, 0 - 100, higher scores indicating worse symptoms ; Overactive Bladder Satisfaction question naire ; range, 0 - 100 ; includes 5 subscales, higher scores indicating better satisfaction ; and adverse events. Results Of the 364 women ( mean [ SD ] age, 63.0 [ 11.6 ] years ) in the intention-to-treat population, 190 women in the onabotulinumtoxinA group had a greater reduction in 6-month mean number of episodes of urgency incontinence per day than did the 174 in the sacral neuromodulation group ( -3.9 vs -3.3 episodes per day ; mean difference, 0.63 ; 95 % CI, 0.13 to 1.14 ; P =.01 ). Participants treated with onabotulinumtoxinA showed greater improvement in the Overactive Bladder Question naire SF for symptom bother ( -46.7 vs -38.6 ; mean difference, 8.1 ; 95 % CI, 3.0 to 13.3 ; P =.002 ) ; treatment satisfaction ( 67.7 vs 59.8 ; mean difference, 7.8 ; 95 % CI, 1.6 to 14.1 ; P =.01 ) and treatment endorsement ( 78.1 vs 67.6 ; mean difference ; 10.4, 95 % CI, 4.3 to 16.5 ; P <.001 ) than treatment with sacral neuromodulation. There were no differences in convenience ( 67.6 vs 70.2 ; mean difference, -2.5 ; 95 % CI, -8.1 to 3.0 ; P =.36 ), adverse effects ( 88.4 vs 85.1 ; mean difference, 3.3 ; 95 % CI, -1.9 to 8.5 ; P =.22 Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). BACKGROUND Incontinence has a greater detrimental effect on quality of life than other symptoms of overactive bladder ( OAB ) and is often difficult to treat with antimuscarinic monotherapy. OBJECTIVE To evaluate the efficacy and the safety and tolerability of combination ( solifenacin 5 mg and mirabegron 50 mg ) versus solifenacin 5 or 10 mg in OAB patients remaining incontinent after 4 wk of solifenacin 5 mg. DESIGN, SETTING, AND PARTICIPANTS OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-wk single-blind run-in were r and omised 1:1:1 to double-blind daily combination or solifenacin 5 or 10 mg for 12 wk. Patients receiving the combination were initiated on mirabegron 25 mg increasing to 50 mg after week 4. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was a change from baseline to end of treatment ( EOT ) in the mean number of incontinence episodes per 24h ( stratified rank analysis of covariance [ ANCOVA ] ). Key secondary end points were a change from baseline to EOT in the mean number of micturitions per 24h ( ANCOVA ) and number of incontinence episodes noted in a 3-d diary at EOT ( mixed-effects Poisson regression ). A trial ( BESIDE ) comparing combination treatment ( solifenacin plus mirabegron ) with one treatment alone ( solifenacin ) tested the superiority of combination versus solifenacin 5 mg, noninferiority ( and potential superiority ) of combination versus solifenacin 10 mg ( key secondary end points ), and the safety and tolerability of combination therapy versus solifenacin monotherapy. RESULTS AND LIMITATIONS A total of 2174 patients were r and omised to combination ( n=727 ), solifenacin 5 mg ( n=728 ), or solifenacin 10 mg ( n=719 ). At EOT, combination was superior to solifenacin 5 mg, with significant improvements in daily incontinence ( p=0.001 ), daily micturitions ( p<0.001 ), and incontinence noted in a 3-d diary ( p=0.014 ). Combination was noninferior to solifenacin 10 mg for key secondary end points and superior to solifenacin 10 mg for improving daily micturitions. All treatments were well tolerated. CONCLUSIONS Adding mir Low‐dose Desmopressin and Tolterodine Combination Therapy for Treating Nocturia in Women with Overactive Bladder: A Double‐blind, Randomized, Controlled Study OBJECTIVE Evaluation of safety and efficacy of desmopressin/tolterodine combination therapy in women. METHODS This double-blind, r and omized, proof-of-concept study enrolled 106 patients ( ≥18 years ), with overactive bladder ( OAB ) and nocturia, with ≥2 nocturnal voids, receiving a 3-month once-daily combination ( desmopressin 25 µg, orally-disintegrating tablets [ODT]/tolterodine 4 mg [ Detrol ® LA ] ; n = 49 ) or monotherapy ( tolterodine 4 mg/placebo ODT ; n = 57 ). Primary endpoint was change from baseline in mean number of nocturnal voids. Secondary endpoints were change from baseline in nocturnal voided volume, time to first nocturnal void, and quality -of-life. Post-hoc exploratory analysis were performed for patients with and without baseline nocturnal polyuria ( NP, n = 47 each ). RESULTS Overall population showed a non-significant reduction in mean number of nocturnal voids with combination versus monotherapy ( full analysis set : adjusted treatment contrast [ TC ], -0.34 ; P = 0.112 ). Change in mean nocturnal void volume ( TC, -64.16 mL ; P = 0.103 ), mean time to first nocturnal void ( TC, 18.00 min ; P = 0.385 ) and Nocturia Impact ( NI ) Diary © scores were comparable. In post-hoc analysis, NP patients showed a benefit with combination versus monotherapy for nocturnal void volume ( P = 0.034 ) and time to first nocturnal void ( P = 0.045 ), and a non-significant improvement in NI Diary © scores. Safety profile was comparable between treatments. A single transient event of asymptomatic clinical ly significant hyponatremia in combination group resolved subsequently. CONCLUSION Low-dose desmopressin could be safely combined with tolterodine for treating nocturia in women with OAB, with a significant benefit in women with NP. Further, prospect i ve validation studies of combination therapy are warranted in mixed NP/OAB population, based on this favorable proof-of-concept finding Patient-reported outcomes from SYNERGY, a randomized, double-blind, multicenter study evaluating combinations of mirabegron and solifenacin compared with monotherapy and placebo in OAB patients. AIMS To evaluate patient-reported outcomes ( PROs ) of combinations of solifenacin and mirabegron compared with solifenacin and mirabegron monotherapy and with placebo in patients with overactive bladder ( OAB ) from the SYNERGY trial. METHODS Following a 4-week placebo run-in, period patients ( ≥18 years ) with OAB were r and omized 2:2:1:1:1:1 to receive solifenacin 5 mg + mirabegron 25 mg ( combination 5 + 25 mg ), solifenacin 5 mg + mirabegron 50 mg, ( combination 5 + 50 mg ), solifenacin 5 mg, mirabegron 25 mg, mirabegron 50 mg or placebo for 12 weeks, followed by a 2-week washout period. At each visit, PROs related to quality of life, symptom bother, and treatment satisfaction were assessed, including OAB-q Symptom Bother score, health-related quality of life ( HRQOL ) Total score, treatment satisfaction-visual analogue scale ( TS-VAS ), and patient perception of bladder condition ( PPBC ) question naires. RESULTS Overall, 3527 patients were r and omized into the study, with 3494 receiving double-blind treatment. At end of treatment ( EoT ), both combination groups showed greater improvements in OAB-q Symptom Bother score compared with the monotherapy groups ( nominal P < 0.001 ). Statistically significant improvements in HRQOL Total scores were observed in the combination groups versus monotherapy groups ( P ≤ 0.002 ). For both combination groups, the OAB-q Symptom Bother score responder rates at EoT were statistically significantly higher versus mirabegron monotherapy ( P < 0.05 ). The mean adjusted changes from baseline to EoT for PPBC were greater in the combination groups compared with monotherapy groups. CONCLUSIONS PROs showed that combination therapy provided clear improvements and an additive effect for many HRQOL parameters, including OAB-q Symptom Bother score, HRQOL Total score, and PPBC Combined Tolterodine and Vaginal Estradiol Cream for Overactive Bladder Symptoms After Randomized Single-Therapy Treatment Objectives The aims of this study were to compare 12-week outcomes of single-therapy tolterodine ( Detrol LA ) extended release to intravaginal estrogen ( Estrace ) for overactive bladder ( OAB ) symptoms and characterize 24- and 52-week outcomes in women undergoing combined therapy. Methods A single-site r and omized, open-label trial in women with urinary frequency, urgency, nocturia, and /or urgency urinary incontinence symptoms was performed. Fifty-eight participants were r and omized to oral tolterodine extended release daily or intravaginal estradiol cream nightly for 6 weeks then twice per week. The primary outcome was change in Overactive Bladder Question naire ( OAB-q ) symptom bother score at 12 weeks. Secondary outcomes included the Health-Related Quality of Life Question naire ( HRQL ) of the OAB-q and a 3-day bladder diary. At 12 weeks, subjects were offered addition of the alternative therapy with follow-up at 24 and 52 weeks. Results There was no difference in symptom bother score improvement between the tolterodine and intravaginal estradiol groups baseline to 12 weeks ( 20.6 ± 21.7, −15.8 ± 23.3, respectively, P = 0.45 ). There was a significant within-group decrease in symptom bother score from baseline to 12 weeks ( tolterodine, P < 0.0001, and intravaginal estradiol, P = 0.002 ). Secondary outcome improvement within groups was noted in the HRQL total, urinary incontinence episodes, and median voiding frequency ( all P ⩽ 0.03 ) in the tolterodine group and in the HRQL total score ( P = 0.03 ) in the intravaginal estradiol group, with no differences between groups. Combined therapy outcomes at 24 and 52 weeks compared with single therapy at 12 weeks revealed significant improvement in symptom bother score in the intravaginal estradiol + tolterodine group at 24 and 52 weeks ( 20.0 ± 23.9, P = 0.008 ; −16.7 ± 23.3, P = 0.02, respectively ). Conclusions Significant within-group improvement in OAB-q symptom bother was noted in both the intravaginal estradiol and tolterodine groups for OAB symptoms, with no difference between groups. Greater improvement from 12-week single therapy to 24 and 52 weeks of combined therapy was noted in the group originally assigned to intravaginal estradiol. The role of combined medical therapy for OAB symptoms needs further investigation", "formation of large informatic data bases, or clinical quality registries, linking preoperative and intraoperative clinical data, imaging, genomics, and cancer and drug prescription data bases. References 1 Fischer HB, Simanski CJ, Sharp C, et al. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Postoperative pain management : number-needed-to-treat approach versus procedure-specific pain management approach. The Impact of Food Viscosity on Eating Rate, Subjective Appetite, Glycemic Response and Gastric Emptying Rate Underst and ing the impact of rheological properties of food on postpr and ial appetite and glycemic response helps to design novel functional products. It has been shown that solid foods have a stronger satiating effect than their liquid equivalent. However, whether a subtle change in viscosity of a semi-solid food would have a similar effect on appetite is unknown. Fifteen healthy males participated in the r and omized cross-over study. Each participant consumed a 1690 kJ portion of a st and ard viscosity ( SV ) and a high viscosity ( HV ) semi-solid meal with 1000 mg acetaminophen in two separate sessions. At regular intervals during the three hours following the meal, subjective appetite ratings were measured and blood sample s collected. The plasma sample s were assayed for insulin, glucose-dependent insulinotropic peptide ( GIP ), glucose and acetaminophen. After three hours, the participants were provided with an ad libitum pasta meal. Compared with the SV meal, HV was consumed at a slower eating rate ( P = 0.020 ), with postpr and ial hunger and desire to eat being lower ( P = 0.019 and P<0.001 respectively ) while fullness was higher ( P<0.001 ). In addition, consuming the HV result ed in lower plasma concentration of GIP ( P<0.001 ), higher plasma concentration of glucose ( P<0.001 ) and delayed gastric emptying as revealed by the acetaminophen absorption test ( P<0.001 ). However, there was no effect of food viscosity on insulin or food intake at the subsequent meal. In conclusion, increasing the viscosity of a semi-solid food modulates glycemic response and suppresses postpr and ial satiety, although the effect may be short-lived. A slower eating rate and a delayed gastric emptying rate can partly explain for the stronger satiating properties of high viscous semi-solid foods Does adding milk to tea delay gastric emptying? BACKGROUND Many preoperative fasting guidelines suggest that hot tea or coffee with milk added should be considered similar to solid food, allowing an interval of 6 h before commencing anaesthesia. There is little evidence to support these instructions, with recent guidelines undecided on the issue. This study aim ed to establish whether there was a clinical ly significant delay in gastric emptying associated with adding a modest amount of milk to tea. METHODS This r and omized controlled crossover study was conducted in 10 healthy volunteers. The paracetamol absorption technique and real-time ultrasound measurement of the cross-sectional area of the gastric antrum were used to assess gastric emptying after ingestion of 300 ml of black tea or 300 ml of tea with milk ( 250 ml black tea plus 50 ml of full fat milk ). RESULTS The mean difference in the time to reach the peak paracetamol concentration ( tmax ) was -8 min [ 95 % confidence interval ( CI ) -23.1 to 7 ] in favour of tea with milk. Ultrasound assessment indicated that the geometric mean of the half-time to gastric emptying ( T₁/₂ ) after tea without milk was 22.7 ( 95 % CI 12.7 - 40.9 ) min and after tea with milk 23.6 ( 95 % CI 13.5 - 41.0 ) min ( ratio 1.04 ) ( 95 % CI 0.47 - 2.29 ). CONCLUSIONS This study demonstrated no difference in gastric emptying times when a modest amount of milk was added to tea. These findings suggest that it may be acceptable to allow patients to add a small quantity of milk to their tea or coffee and follow the same fasting restrictions applied to clear fluids Ultrasound to confirm gastric tube placement in prehospital management. BACKGROUND In emergency medicine, the gastric tube ( GT ) has many purpose s, however in prehospital setting s, the only indication is gastric decompression. To date, there is lack of recommendation on the diagnostic methods to verify correct GT placement in prehospital. The aim of this study is to estimate diagnostic accuracy of ultrasound in confirming gastric tubes placement in a prehospital setting. METHOD This was a prospect i ve multicentre study conducted in two French towns ( Marseille and Grasse ) over a one-year period from May 2010 to May 2011. RESULTS One hundred and thirty patients were included in the study with an M/F sex ratio of 77/53 and a mean age of 55.7±19.8 years. The GT position was confirmed by ultrasound, with direct visualization in the gastric area in 116 of the 130 patients. In 14 cases, the ultrasound failed to visualize the tip of the GT ; these results were due in 2 cases to gas interposition and in 12 cases the GT was shown by final X-ray to be located in the end of the oesophagus. Direct visualization by ultrasound thus has a sensitivity of 98.3 % [ 94 - 99.5 ] and a specificity of 100 % [ 75.7 - 100 ], a positive predictive value of 100 % and a negative predictive value of 85.7 %, Youden's index of 0.98. GT size affects ultrasound visualization ; the larger the GT, the easier it is to see. CONCLUSION Bedside ultrasound thus appears to constitute an effective and reliable diagnostic procedure for confirming correct gastric tube placement in prehospital setting Role of caloric content on gastric emptying in humans. 1. This study examined the effects of caloric content ( caloric density and the nature of calories ) on the rate of gastric emptying using the double-sampling gastric aspiration technique. Four test meals of 600 ml ( glucose, 0.1 kcal ml-1 ; pea and whey peptide hydrolysates, both 0.2 kcal ml-1 ; milk protein, 0.7 kcal ml-1 ) were tested in six healthy subjects in r and om order on four separate occasions. 2. The glucose solution was emptied the fastest with a half-time of 9.4 + /- 1.2 min ( P < 0.05 ) and the milk protein the slowest with a half-time of 26.4 + /- 10.0 min ( P < 0.05 ) ; the pea peptide hydrolysate and whey peptide hydrolysate solutions had half-times of emptying of 16.3 + /- 5.4 and 17.2 + /- 6.1 min, respectively. The rates of gastric emptying for the peptide hydrolysate solutions derived from different protein sources were not different. 3. Despite the lower rate of gastric emptying for the milk protein solution, the rate of caloric delivery to the duodenum during the early phase of the gastric emptying process was higher than that for the other three solutions ( 46.3 + /- 6, 63.5 + /- 22, 62.5 + /- 19 and 113.8 + /- 25 cal min-1 kg-1 for the glucose, pea peptide hydrolysate, whey peptide hydrolysate and milk protein meals, respectively ; P < 0.05 ). The caloric density of the test solutions was linearly related to the half-time of gastric emptying ( r = 0.96, P < 0.05 ) as well as to the rate at which calories were delivered to the duodenum ( r = 0.99, P < 0.001 ). 4. This study demonstrates that the rate of gastric emptying is a function of the caloric density of the ingested meal and that a linear relationship exists between these variables. Furthermore, the nature of the calories seems to play a minor role in determining the rate of gastric emptying in humans Ultrasonography and gastric emptying in children: validation of a sonographic method and determination of physiological and pathological patterns Background The association between gastric emptying and gastro-esophageal reflux ( GER ) has been widely recognised from scintigraphic studies. Objective A prospect i ve study to ( a ) vali date US as a means of measuring gastric emptying, ( b ) determine physiological patterns of gastric emptying and ( c ) measure gastric emptying in symptomatic refluxers. Material s and methods Three cohorts were studied : ( a ) Ten babies in whom gastric emptying was measured by US and scintigraphy ; ( b ) gastric emptying in 330 asymptomatic children aged between 15 days and 10 years to determine physiological variations ; and ( c ) gastric emptying in 552 children with GER, manifesting as vomiting or cardiorespiratory problems. Results US and scintigraphic techniques showed general concordance in 90 % of cases. In the remaining 10 %, discordant results were related to overlapping of duodenum and stomach during scintigraphy and shadowing of the gastric antrum by air during US. Tremendous variations were induced by change of feed volume or type of formula, underlining the need for a st and ardised procedure. Twenty-two percent of cases showed a peculiar'plateau'which differed significantly from the physiological patterns. Most of these babies had esophagitis or acute life-threatening events. Conclusions Investigation of gastric emptying seems to be a key element in the assessment of children with'pathological'GER. US is a safe and cheap alternative to scintigraphy for the assessment of gastric emptying Gastric Sonography in the Fasted Surgical Patient: A Prospective Descriptive Study BACKGROUND : Aspiration pneumonia remains a serious anesthetic-related complication. A reliable diagnostic tool to assess gastric volume is currently lacking. We recently demonstrated that gastric sonography can provide reliable qualitative and quantitative information about gastric content and volume in healthy volunteers. In the current study, we performed a prospect i ve qualitative and quantitative analysis of the gastric antrum in 200 fasted patients undergoing elective surgery. METHODS : A st and ardized gastric scanning protocol was applied before anesthetic induction. Patients were classified following a 3-point grading system based solely on qualitative sonographic assessment of the antrum in the supine and right lateral decubitus positions. RESULTS : Eighty-six patients were classified as grade 0 ( empty antrum ) ; 107 patients as grade 1 ( minimal fluid volume detected only in the right lateral decubitus position ) ; and 7 patients were classified as grade 2 ( antrum clearly distended with fluid visible in both supine and lateral positions ). The 3-point grading system correlated with total gastric fluid volume as predicted by a previously reported mathematical model. Essentially grade 0 corresponds to a completely empty stomach, grade 1 corresponds to negligible fluid volumes ( 16 ± 36 mL ) within normal ranges expected for fasted patients, and grade 2 correlates with significantly higher predicted gastric fluid volumes ( 180 ± 83 mL ) beyond previously reported “ safe ” limits. One patient with a grade 2 antrum had an episode of significant regurgitation of gastric contents on emergence from anesthesia. CONCLUSION : We propose a 3-point grading system based exclusively on qualitative sonographic assessment of the gastric antrum that correlates well with predicted gastric volume. This grading system could be a promising “ biomarker ” to assess perioperative aspiration risk. Before it can be applied widely to clinical practice, this diagnostic tool needs to be further vali date d and characterized Ultrasound assessment of gastric volume in critically ill patients Purpose To assess the feasibility and validity of ultrasonographic measurement of gastric antral cross-sectional area ( usCSA ) in critically ill patients to predict gastric volume and the use of computed tomography ( CT ) as a reference to measure gastric volume. Method This single-center, prospect i ve, cross-sectional study included 55 critically ill patients who had an abdominal CT scan. usCSA measurements were performed within the hour preceding the CT scan. Gastric volumes were measured on the CT scan using semiautomatic software. The feasibility rate, performing conditions ( % “ good ” and “ poor ” ), internal and external validity of antral usCSA measurements, performed by an ICU physician, were assessed to predict gastric volume. Results Antral usCSA measurements were feasible in 95 % of cases and were positively correlated with gastric volume measured by the CT scan when performed in “ good ” conditions ( 65 % ) ( r = 0.43 ). There was good reproducibility of measurements ( intraclass correlation coefficient of 0.97, CI 95 % 0.96–0.99 ) and there was clinical ly acceptable agreement between measurements performed by radiologists and intensivists ( bias −0.12 cm2 ). The receiver operating characteristic curve identified a cutoff value of 3.6 cm2 that discriminated an “ at-risk stomach ” ( volume > 0.8 mL/kg ) at a sensitivity of 76 % and a specificity of 78 %. Conclusions Ultrasonographic measurement of antral CSA is feasible and reliable in the majority of critically ill patients. This technique could be useful to manage critically ill patients at risk of aspiration or with enteral feeding Intra- and Interrater Reliability of Ultrasound Assessment of Gastric Volume Background : Gastric sonography can provide information about gastric content and volume that can help determine aspiration risk at the bedside. The primary objective of this study is to assess the intrarater and interrater reliability of a previously vali date d method of gastric volume assessment based on gastric antral area. The secondary objective is to evaluate the agreement between two different methods to measure gastric antral area. Methods : Three independent raters performed a st and ardized gastric ultrasound assessment in healthy subjects who had been r and omly allocated to ingest a predetermined volume of clear fluid ( apple juice ) from 0 to 400 ml. Each rater measured the gastric antral area, using twice the two-diameter method and twice the free-tracing method. The rater order was allocated at r and om and raters were unaware of the volume ingested and of one-another ’s measurements. The Guidelines for Reporting Reliability and Agreement Studies were followed for conducting and reporting this study. Results : Twenty-two volunteers were studied. Ultrasound assessment of antral cross-sectional area and volume was found to have “ nearly perfect ” intrarater and interrater reliability ( correlation coefficient > 0.8 ) with maximum differences within 13 %. A Bl and –Altman analysis suggests that the free-tracing method and the two-diameter method are essentially equivalent, within a clinical ly acceptable level of agreement. Conclusions : Ultrasound assessment of gastric volume by clinical anesthesiologists is highly reproducible with high intrarater and interrater reliability. The free-tracing method to measure antral cross-sectional area is equivalent to the two-diameter method The effect of lipid droplet size on satiety and peptide secretion is intestinal site-specific. BACKGROUND & AIMS : Infusion of fat into the small intestine induces satiety. Reducing fat droplet size accelerates fat digestion, but the effect on satiety after ileal fat infusion is not known. The aim of the study was to compare the effects of fat emulsions differing in droplet size ( fine, coarse ) infused in either duodenum or ileum on satiety, gastric emptying and peptide secretion. METHODS In a r and omized single-blind crossover study 15 healthy volunteers received, after intubation with a nasoileal tube, 4 different treatments on 4 consecutive days. After consumption of a liquid meal, 6 g of fine or coarse fat emulsion was infused into duodenum or ileum. Study parameters were satiety, gastric emptying and gut peptides. These parameters were statistically evaluated using ANCOVA. RESULTS In the duodenum, Fine emulsion significantly reduced hunger, increased fullness, delayed gastric emptying, but did not affect peptide secretion versus Coarse. In the ileum, Fine emulsion did not affect hunger, fullness, or gastric emptying, but significantly increased peptide secretion versus Coarse. CONCLUSIONS Compared to larger fat droplets, smaller droplets significantly affect satiety, gastric emptying and gut peptide release, but with the effect being dependent on the intestinal location of fat delivery. DUTCH TRIALREGISTER : NTR1515 Effect of Metoclopramide on Gastric Fluid Volumes in Diabetic Patients Who Have Fasted before Elective Surgery Background : Diabetes-induced gastroparesis is believed to increase fasting gastric fluid volume before elective surgery. Metoclopramide is routinely administered preoperatively to reduce gastric fluid volume in these patients. This study compared nondiabetic controls to non – insulin-dependent and insulin-dependent diabetics to determine the effect of metoclopramide, administered before surgery, on gastric volumes in patients who fasted before surgery. Methods : Control and diabetic patients fasted preoperatively before receiving either placebo or 10 mg intravenous metoclopramide 20 min before induction of anesthesia. After intubation, a gastric tube was placed, and stomach contents were aspirated with volumes compared among the groups. Results : Both groups of diabetic patients were older than the control group, and insulin-dependent patients had a higher incidence of comorbidities compared with the non – insulin-dependent group. Fasting blood sugar and hemoglobin A1C values were higher in both insulin-dependent and non – insulin-dependent patients. Gastric fluid volumes were similar in control, non – insulin-dependent, and insulin-dependent patients ( 8.0 ± 2.6 vs. 9.6 ± 4.1 vs. 17.7 ± 2.5 ml, respectively ). In insulin-dependent diabetic patients, metoclopramide decreased gastric volume compared with placebo treatment ( 17.7 ± 2.5 vs. 7.8 ± 2.9 ml ; P = 0.027 ). After stratification, a sub population of patients with poorly controlled diabetes, regardless of type, were identified to have increased gastric residual volumes. Conclusion : In elective surgical patients who have fasted before surgery, gastric volumes are minimal, even in diabetics with severe neuropathic symptoms. Metoclopramide prophylaxis to reduce gastric volumes seems to be unnecessary unless the patient has a prolonged history of poor blood glucose control Correlation between simultaneous scintigraphic and ultrasonographic measurement of gastric emptying in patients with type 1 diabetes mellitus. OBJECTIVE To compare scintigraphic measurements of total stomach emptying of a semisolid meal with ultrasonographic measurements of changes in antral area as estimates of antral emptying in type 1 diabetic patients. METHODS Eleven patients with insulin-dependent diabetes mellitus were studied with simultaneous measurements of gastric emptying by scintigraphy and ultrasonography. Patients were imaged immediately after ingestion ( time 0 ) and every 15 minutes over 120 minutes. The gastric emptying rate was expressed as percent reduction in antral cross-sectional area from 15 to 90 minutes after meal ingestion. RESULTS Ultrasonographic measurements showed a postpr and ial maximal antral area at 15 minutes, continuously decreasing with time, and reaching a plateau 45 to 90 minutes after the end of meal ingestion, whereas the scintigraphic counts attained their maximum immediately after the meal and began to fall thereafter. Between 15 and 90 minutes, the residual radioactivity and antral ultrasonographically measured distension curves were concordant. The curves then showed a tendency toward deviation for the last 15 minutes ( median, 51 % versus 59 % at 105 minutes and 40 % versus 57 % at 120 minutes, respectively ). A strong significant correlation could be seen between the ultrasonographic gastric emptying rate and scintigraphic half-time values ( r = -0.94 ; P <.001 ). Comparing scintigraphic and ultrasonographic half-time values showed a systematic measurement error of 9.9 minutes and a r and om measurement error of 18.6 minutes. CONCLUSIONS The use of st and ardized real-time ultrasonography to determine the gastric emptying rate of semisolid meals in diabetic patients, with the use of the change in gastric antral cross-sectional area in a single section of the stomach 15 and 90 minutes postpr and ially, offers a valid method for clinical practice Gastric Sonography in the Severely Obese Surgical Patient: A Feasibility Study BACKGROUND : Gastric ultrasonography allows qualitative and quantitative assessment of gastric contents and volume in nonobese subjects. In this study, we sought to determine the feasibility of gastric ultrasound in severely obese patients ( body mass index [ BMI ] ≥35 kg/m2 ). We defined feasibility as the ability to identify a full cross section of the gastric antrum in at least 80 % of subjects when imaged in the right lateral decubitus position. METHODS : This was a prospect i ve cohort study on fasted surgical patients with BMI > 35 kg/m2. The primary outcome measure was the feasibility of gastric sonography. Secondary outcomes included the distribution of antral grade following an existing 3-point grading system. In addition, the antral cross-sectional area ( CSA ) and gastric volumes in this cohort were compared with historical data from a published study in nonobese individuals. Time to image capture, antral wall thickness, and depth of the antrum are also reported. RESULTS : Sixty patients ( BMI range 35.1–68.7 ) were studied. The antrum was identified in 95 % of subjects in the right lateral decubitus ( 95 % CI, 0.86–0.99 ) and 90 % of subjects in the supine position. Definition of antral grade ( 0–2 ) was possible in 88.3 % ( 95 % CI, 0.77–0.95 ) of cases. As expected, antral grade correlated with antral CSA and gastric volumes ( P < 0.0001 ). When compared with historical data, our results suggest that severely obese patients have a larger baseline CSA and gastric volume than nonobese patients ( P < 0.001 ) but a similar gastric volume per unit of weight ( P = 0.141 ). CONCLUSIONS : Gastric ultrasound assessment is feasible in fasted severely obese subjects. Our data also suggest that obese individuals present larger antral size and gastric volume than their nonobese counterparts Validation of a Mathematical Model for Ultrasound Assessment of Gastric Volume by Gastroscopic Examination INTRODUCTION : Pulmonary aspiration of gastric contents is a serious perioperative complication. Previous models of ultrasound gastric volume assessment are preliminary and have not been vali date d by an external “ gold st and ard. ” In the present study we propose a more accurate model based on prospect i ve data obtained from 108 patients undergoing bedside gastric sonography and upper gastrointestinal endoscopy ( UGE ). METHODS : Patients undergoing elective UGE were r and omized to ingest one of 6 predetermined volumes of apple juice after an 8-hour fasting period. A cross-sectional area of the antrum in the right lateral decubitus position ( Right lat CSA ) was measured by a blinded sonographer following a st and ardized scanning protocol. Gastric fluid was subsequently suctioned under gastroscopic vision during UGE performed by a blinded gastroenterologist and measured to the nearest milliliter. RESULTS : Data from 108 patients suggest that a previously reported model tends to overestimate gastric volume particularly at low volume states. A new best fit mathematical model to predict gastric fluid volume based on measurements of Right lat CSA is presented. This new model built on a more accurate gold st and ard can be used to estimate gastric volumes from 0 to 500 mL, in nonpregnant adults with body mass index < 40 kg/m2. CONCLUSIONS : We report a new prediction model to assess gastric fluid volume using st and ard 2-dimentional bedside ultrasound that has several advantages over previously reported models", "BACKGROUND Increasing age and post-menopausal status are associated with decreasing and rogen concentrations in females. Women with premature loss of ovarian function, such as primary ovarian insufficiency ( POI ) or iatrogenic menopause may be at increased risk for diminished testosterone levels at a relatively young age. Differentiation between a hypo and rogenic or normo and rogenic state in women with premature loss of ovarian function is problematic due to trueness and precision problems using various testosterone assays. The current meta- analysis was conducted to evaluate current literature reporting serum total testosterone concentrations under these conditions, including stratification for various testosterone assays. Hypothalamo-pituitary-adrenal axis and adrenal function before and after ovariectomy in premenopausal women. The hypothalamo-pituitary-adrenal ( HPA ) axis is modulated by sex hormones. Few data exist on the relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone ( CRH ). The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of ACTH, cortisol, testosterone, and rostenedione and 17-hydroxyprogesterone ( 17-OHP ) were assessed in nine premenopausal women ( 44 - 48 years of age ), before and after ovariectomy. The CRH test was performed before and 8 days after ovariectomy. A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed after ovariectomy. The ratio of deltamax and rostenedione/17-OHP after CRH stimulation was substantially the same before and after ovariectomy, whereas deltamax 17-OHP/cortisol was significantly lower in ovariectomized women showing increased 21- and 11beta-hydroxylase activity. The results show that the acute estrogen deficit induces changes in the HPA axis characterized by reduced stimulated secretion of ACTH and steroids but normal stimulated cortisol production Androgen levels in adult females: changes with age, menopause, and oophorectomy. CONTEXT Changes in and rogen levels across the adult female life span and the effects of natural menopause and oophorectomy have not been clearly established. OBJECTIVE The objective of this study was to document the effects of age on and rogen levels in healthy women and to explore the effects of natural and surgical menopause. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study was conducted of 1423 non-healthcare-seeking women, aged 18 - 75 yr, r and omly recruited from the community over 15 months. MAIN OUTCOME MEASURES Serum levels by age of total testosterone ( T ), calculated free T, dehydroepi and rosterone sulfate, and and rostenedione in a reference group of women free of confounding factors. Women in the reference group had no usage of exogenous steroid therapy ; no history of tubal ligation, hysterectomy, or bilateral oophorectomy ; and no hyperprolactinemia or polycystic ovarian syndrome. The effects of natural and surgical menopause on sex steroid levels were also examined. RESULTS In the reference population ( n = 595 ), total T, calculated free T, dehydroepi and rosterone sulfate, and and rostenedione declined steeply with age ( P < 0.001 ), with the decline of each being greater in the earlier than the later decades. Examination of serum and rogen levels by year in women aged 45 - 54 yr showed no independent effect of menopausal status on and rogen levels. In women aged 55 yr or older, those who reported bilateral oophorectomy and were not on exogenous steroids had significantly lower total T and free T levels than women 55 yr or older in the reference group. CONCLUSIONS We report that serum and rogen levels decline steeply in the early reproductive years and do not vary because a consequence of natural menopause and that the postmenopausal ovary appears to be an ongoing site of testosterone production. These significant variations in and rogens with age must be taken into account when normal ranges are reported and in studies of the role of and rogens in women Early postoperative changes in testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin after hysterectomy with or without concomitant oophorectomy. OBJECTIVE To investigate the cross-sectional associations of hysterectomy and oophorectomy status, chronological age, and body mass index with early postoperative plasma levels of total and free T, DHEAS, and sex hormone-binding globulin ( SHBG ). DESIGN A cross-sectional study. SETTING University hospital. PATIENT(S ) Ninety-two women age 35 - 47 years who were scheduled for hysterectomy and /or oophorectomy, advocated for benign gynecological pathologies. INTERVENTION(S ) Ninety-two eligible premenopausal women underwent hysterectomy and /or oophorectomy, with plasma T, DHEAS, and SHBG levels assayed before surgery and during the postoperative period. MAIN OUTCOME MEASURE(S ) Effects of time x operation and age x operation interactions between oophorectomized and nonoophorectomized groups and within-subject main effect of time on plasma and rogen levels. RESULT ( S ) Of 92 women, hysterectomy alone was performed in only 49 ( 53.3 % ) cases. Oophorectomy, either unilateral or bilateral, was performed in 35.8 % of cases. Age x within-group interactions exhibited an important difference ( P=.03 ) in total T levels. The time x between- and within-group interaction effects on plasma DHEAS levels of postoperative day 7, compared with day 1, were statistically significant ( P<.001 ). The effect of time x group interaction was remarkable, in terms of SHBG levels during the postoperative period. Age x oophorectomy interaction exhibited a statistically significant change of decline in DHEAS levels on postoperative day 7 ( P=.05 ). CONCLUSION ( S ) The present study demonstrated a time and operation effect decline in plasma DHEAS levels. In contrast, the time x operation interaction on SHBG levels exhibited an increase toward postoperative day 7 The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. CONTEXT In postmenopausal women, endogenous bioavailable testosterone ( T ) and estradiol ( E2 ) have been positively associated, and SHBG has been negatively associated, with incident type 2 diabetes ( T2DM ). Previous studies have not explored possible factors explaining these relationships. OBJECTIVE Our objective was to examine the association of endogenous sex hormones with incident T2DM in postmenopausal women and possible explanatory factors. DESIGN, SETTING, AND PARTICIPANTS The Multi-Ethnic Study of Atherosclerosis ( MESA ) is a prospect i ve study that included 1612 postmenopausal women aged 45 - 84 yr, followed between the years 2000 - 2006, who were not taking hormone replacement therapy, had no prevalent cardiovascular disease or diabetes, and had complete ascertainment of sex hormones. MAIN OUTCOME MEASURES T2DM was defined based on fasting glucose and /or treatment for diabetes. RESULTS There were 116 incident cases of diabetes during follow-up. Across higher quartiles of bioavailable T and E2 and lower quartiles of SHBG, we found significantly greater hazards of developing incident T2DM ( all P for trend < or=0.001 ). After adjustment for body mass index and insulin resistance estimated by homeostasis model assessment of insulin resistance, bioavailable T was no longer associated with incident T2DM. The associations of E2 and SHBG with incident T2DM were partially explained by body mass index and insulin resistance but persisted in fully adjusted models ( both P for trend < 0.02 ). Dehydroepi and rosterone had no relationship with incident T2DM. CONCLUSIONS Adiposity and insulin resistance explained most of the association of bioavailable T but only partially explained the associations of E2 and SHBG with incident T2DM among postmenopausal women Relation of demographic factors, menstrual history, reproduction and medication use to sex hormone levels in postmenopausal women In postmenopausal women, levels of estrogens, and rogens, and perhaps prolactin have been related to risk of breast and other hormonal cancers in women. However, the determinants of these hormone concentrations have not been firmly established. Associations among various demographic, menstrual, and reproductive factors, medication use and endogenous sex hormone concentrations ( estradiol, free estradiol, estrone, estrone sulfate, testosterone, free testosterone, sex hormone binding globulin, and rostenedione, dehydroepi and rosterone ( DHEA ), DHEA sulfate ( DHEAS ), dihydrotestosterone, and prolactin ) were evaluated in a cross-sectional analysis from a simple r and om sample of 274 postmenopausal women selected from the Women ’s Health Initiative Dietary Modification Trial. In multiple regression analyses on log-transformed hormones, the concentrations of DHEA, and DHEAS were negatively and statistically significantly associated with age ( both β = −0.03, P < 0.001, respectively ). Estradiol, estrone, DHEA, and free testosterone concentrations were higher in African-American than in non-Hispanic White women, but after multivariate adjustment the associations were statistically significant only for free testosterone ( β = 0.38, P = 0.01 ). Women who had a history of bilateral oophorectomy had a mean 35 % lower testosterone concentration compared with women with at least one ovary remaining ( β = −0.43, P = 0.002 ), and lower free testosterone ( β = −0.42, P = 0.04 ) after multivariate adjustment. Women who reported regular use of NSAIDs had higher DHEA concentrations ( β = 0.20, P = 0.04 ) and lower prolactin concentrations ( β = −0.18, P = 0.02 ) compared with non-users. These results suggest that while age, oophorectomy status, and NSAID use may be associated with selected sex hormone concentrations, few menstrual or reproductive factors affect endogenous sex hormones in the postmenopausal period Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. BACKGROUND The ovaries provide approximately half the circulating testosterone in premenopausal women. After bilateral oophorectomy, many women report impaired sexual functioning despite estrogen replacement. We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause. METHODS Seventy-five women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy received conjugated equine estrogens ( at least 0.625 mg per day orally ) and, in r and om order, placebo, 150 microg of testosterone, and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual-function diary completed over the telephone. RESULTS The mean ( + /-SD ) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter ( 4.2+/-2.8 pmol per liter ) during placebo treatment to 3.9+/-2.4 pg per milliliter ( 13.5+/-8.3 pmol per liter ) and 5.9+/-4.8 pg per milliliter ( 20.5+/-16.6 pmol per liter ) during treatment with 150 and 300 microg of testosterone per day, respectively ( normal range, 1.3 to 6.8 pg per milliliter [ 4.5 to 23.6 pmol per liter ] ). Despite an appreciable placebo response, the higher testosterone dose result ed in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women ( P=0.03 for both comparisons with placebo ). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from base line. The positive-well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose ( P=0.04, P=0.03, and P=0.04, respectively, for the comparison with placebo ), but the scores on the telephone-based diary did not increase significantly. CONCLUSIONS In women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being X-Autosome translocations: Cytogenetic characteristics and their consequences Summary To define the principal characteristics of X-autosome translocations, the authors present a study of 105 cases, five of which are personal observations. The autosomal pairs 15, 21, and 22 are affected by t(X-Aut ) more often than would be expected. The distribution of breakpoints on the X chromosome does not differ significantly from the expected distribution. The analysis of different patterns of inactivation seems to confirm that the inactivation could occur at r and om, but would be followed by a cellular selection favoring the better genetic balance. An estimate of the incidence of t(X-Aut ) is proposed, based upon the conclusions that only one chromosome is susceptible to translocation in meiosis in both males and females and that all affected men will be sterile, as will be 50 % of women [Subjective complaints and hormonal reactions in the first 6 weeks after hysterectomy]. Hormone profiles ( estradiol, testosterone, FSH, LH ) and typical estradiol deficiency phenomena were investigated prospect ively in the first 6 weeks after hysterectomy ( n = 50 ) and after additional bilateral adnexectomy ( n = 17 ). In the second group estradiol was replaced transdermally from the 2nd postoperative day ( estradiol patch, 0.05 mg daily ). In the 1st group 34 % of patients showed a significant decrease in estradiol, 28 % of patients a significant decrease in testosterone on the 3rd postoperative day which was no longer demonstrable after 6 weeks. In the second group no decrease in hormone levels was found. So the estradiol patch can replace estradiol to a sufficient degree and in particular physiologically even after bilateral oophorectomy Subjective complaints improved in both groups. Psychosomatic influence also seems to be of importance Postmenopausal bilateral oophorectomy is not associated with increased fracture risk in older women. UNLABELLED We studied whether oophorectomy performed after menopause is associated with an increased risk of hip or vertebral fractures in 6295 Study of Osteoporotic Fractures participants. There was no association between postmenopausal oophorectomy and the risk of hip or vertebral fractures. INTRODUCTION Bilateral oophorectomy after natural menopause has been associated with an increased risk of osteoporotic fractures, potentially because of a decline in serum estradiol and testosterone levels after the oophorectomy. We prospect ively tested this hypothesis in the Study of Osteoporotic Fractures ( SOF ). MATERIAL S AND METHODS We studied 6295 white women 65 years of age participating in the SOF who were not taking estrogen therapy at baseline. Hip fracture analyses included 708 hip fractures ; vertebral fracture analyses included 267 incident vertebral fractures. Baseline serum estradiol and free testosterone values were available in a small subset of participants. RESULTS AND CONCLUSION There were no significant differences in age, weight, or BMD between the women who underwent postmenopausal oophorectomy ( n = 583 ) and those who did not ( n = 5712 ). Free testosterone levels were significantly lower among women who had a postmenopausal oophorectomy. A history of postmenopausal oophorectomy was not associated with an increased risk of hip ( hazard ratio [ HR ] = 1.1 ; 95 % CI = 0.9 - 1.5 ) or vertebral fracture ( HR = 0.7 ; 95 % CI = 0.5 - 1.2 ). The relationship between oophorectomy and hip fracture was not altered by adding serum estradiol level ( HR = 1.3 ; 95 % CI = 0.5 - 3.2 ) or serum free testosterone level ( HR = 1.7 ; 95 % CI = 0.8 - 3.7 ) to the model. In summary, postmenopausal oophorectomy was not associated with an increased risk of hip or vertebral fracture in this cohort. These results are in contrast to previous findings, suggesting that the relationship between postmenopausal oophorectomy and fractures is not fully eluci date d and that incidental oophorectomy after menopause should still be considered carefully in each potential patient Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. OBJECTIVE To assess the association between serum adrenal cortex autoantibodies and histologically confirmed autoimmune lymphocytic oophoritis. DESIGN Controlled, prospect i ve. SETTING Tertiary research center. PATIENT(S ) Two hundred sixty-six women with 46,XX spontaneous premature ovarian failure. INTERVENTION(S ) Ovarian biopsy in 10 women. MAIN OUTCOME MEASURE(S ) Serum adrenal cortex autoantibodies assessed by indirect immunofluorescence and autoimmune oophoritis assessed by immunohistochemical lymphocyte markers. RESULT ( S ) We obtained a histologic diagnosis of autoimmune oophoritis in four women who tested positive for adrenal cortex autoantibodies and excluded this diagnosis in ovarian biopsies from six women who tested negative for adrenal cortex autoantibodies ( 4/4 vs. 0/6 ). Women with histologically confirmed autoimmune oophoritis had a greater total ovarian volume as assessed by transvaginal sonography ( 11.4 + /- 5.6 mL vs. 1.5 + /- 0.4 mL ) ( mean + /- SEM ). They were also more likely to have sub clinical adrenal insufficiency and clinical signs of and rogen deficiency ( 3/4 vs. 0/6 ). Overall, 10/266 women tested positive for adrenal cortex autoantibodies ( 3.8 %, 95 % confidence interval : 1.8%-6.5 % ). CONCLUSION ( S ) In women who present with 46,XX spontaneous premature ovarian failure as their primary concern there is a clear association between serum adrenal cortex autoantibodies and the presence of histologically confirmed autoimmune oophoritis Endogenous androgen levels and well-being: differences between premenopausal and postmenopausal women Objective : We investigated whether there is a relationship between and rogens levels and well-being in pre- and postmenopausal women. Design : We r and omly recruited 1423 women aged 18 to 75 years from the community via the electoral roll. Each provided a morning blood sample and completed the Psychological General Well Being Index question naire on the same day. Women were excluded if they took medication for any psychiatric illness, had abnormal thyroid function, or had documented polycystic ovarian syndrome. Analysis was by linear regression for well-being, including demographic and lifestyle variables as well as serum levels of and rogens. Results : We included 1224 women in the analysis. Being partnered was positively associated with well-being in premenopausal women. In postmenopausal women, well-being was positively related to age and exercising, whereas smoking, obesity, and postmenopausal hormone therapy use were each negatively associated with well-being. None of the measured and rogens ( total and free testosterone, dehydroepi and rosterone sulfate, and and rostenedione ) made an independent contribution to well-being in postmenopausal women ( n = 603 ). However, for premenopausal women ( n = 621 ), levels of dehydroepi and rosterone sulfate were independently and positively associated with the domain score for vitality. Conclusions : Our findings do not support an important independent role for and rogens as determinants of well-being in postmenopausal women. That dehydroepi and rosterone sulfate alone is associated with greater vitality in premenopausal women is of interest but requires further evaluation as an a priori hypothesis in another study Age-specific reference ranges for serum testosterone and androstenedione concentrations in women measured by liquid chromatography-tandem mass spectrometry. OBJECTIVE RIA-based sex hormone measurements offer only limited precision and specificity in the low concentration range of women. Therefore, we aim ed to establish age-specific reference ranges for serum sex hormone concentrations in women using mass spectrometry and quantile regression. METHODS AND RESULTS Data from 985 women aged 20 - 80 yr, recruited for the prospect i ve Study of Health in Pomerania, were included in the analyses. Quantile regressions models were performed to calculate the age-specific 2.5th and 97.5th percentiles for sex hormone concentrations in women. Serum total testosterone ( TT ) and and rostenedione ( AD ) concentrations were measured by liquid chromatography-t and em mass spectrometry. Measured concentrations of SHBG and TT were used to calculate free testosterone ( free T ). TT, AD, and free T concentrations showed a distinct age-related decline across 10-yr age groups ( one way ANOVA P < 0.001 ). Sex hormone reference ranges for TT, AD, and free T were determined across each single year of age and for 10-yr age groups. Reference ranges over the whole age range of 20 - 80 yr were 0.35 - 1.97 nmol/liter for TT, 0.89 - 4.56 nmol/liter for AD, and 0.0025 - 0.0253 nmol/liter for free T. Separate reference ranges were provided for pre- and postmenopausal women as well as after inclusion of women using oral contraceptives or hormone therapy ( n = 1357 ). CONCLUSION This is the first study to establish age-specific reference ranges for liquid chromatography-t and em mass spectrometry-measured TT and AD and calculated free T concentrations based on quantile regression analyses, accurately accounting for the observed low concentration range and the strong age dependency of these sex hormones in women Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study. Visceral fat ( VF ) increases with the menopause and is an independent predictor of the metabolic syndrome, diabetes, and cardiovascular disease ( CVD ) in women. Little is known about how hormonal changes during the menopausal transition are related to the increase in VF. We aim ed to determine the relationship between bioavailable testosterone and VF in middle-aged women at various stages of the menopausal transition and whether this relationship is independent of age and other CVD risk factors. The Study of Women's Health Across the Nation ( SWAN ) is a longitudinal, community-based study. This report uses baseline data from a population -based longitudinal ancillary study at the Chicago site to examine the cross-sectional relationship between testosterone and computed tomography (CT)-assessed VF in women at different stages of the menopausal transition. Included are 359 women ( 47.2 % black ), aged 42 - 60 years, who were r and omly selected from a complete community census in which a 72 % participation rate was achieved. In multivariate models, bioavailable testosterone was associated with VF independent of age, race, percent total body fat, and other cardiovascular risk factors. Bioavailable testosterone was a stronger predictor than estradiol and was interchangeable in its strength of association with sex hormone-binding globulin ( SHBG ). As bioavailable testosterone was associated with VF even after adjusting for insulin resistance, this suggests that it plays an important role in regional fat distribution. Our findings may have direct implication s in explaining the effect of menopause-related testosterone predominance on VF accumulation and subsequent cardiovascular risk Effects of aging on adrenal function in the human: responsiveness and sensitivity of adrenal androgens and cortisol to adrenocorticotropin in premenopausal and postmenopausal women. We sought to determine the effects of aging on several aspects of adrenal steroidogenesis in the hopes of characterizing the possible causes of adrenal and rogen deficiency in elderly women. To this end, we quantified basal morning concentrations of cortisol ( F ), dehydroepi and rosterone ( DHEA ), dehydroepi and rosterone sulfate ( DS ), and and rostenedione ( A4 ) and then evaluated the effects of overnight dexamethasone ( DEX ) suppression followed by adrenal responses to grade d hourly infusions of ACTH, ranging from 20 - 1280 ng/1.5 m2 x h. Finally, we performed a st and ard 0.25-mg ACTH bolus stimulation test, with sampling at 1 h thereafter. Basal serum levels of DHEA, DS, and A4 were significantly reduced ( approximately 50 % each ) in a group of 35 healthy postmenopausal women, 55 - 68 yr old, compared to those in 30 healthy, regularly menstruating women, 20 - 25 yr old. Post-DEX levels of these C19 steroids also were significantly lower in the older women than in the younger women ; the percent decrease after DEX for A4 was greater in the older women, whereas those in DHEA and DS were not age related. Basal and post-DEX levels of F were similar in both groups. Secretory responses of DS to ACTH were not informative due to its large plasma pool and slow clearance rate. The maximally stimulated levels of DHEA after ACTH bolus were significantly lower in the older women than in younger women ; those of A4 were similar in both age groups, and the maximally achieved levels of F were higher in the older women than in the younger women. The sensitivity of adrenal DHEA, A4, and F to ACTH ( defined as the minimal dose of ACTH required to significantly increase the steroid levels above basal post-DEX values ) was similar in older and younger women. The responsiveness of the steroids of interest to ACTH ( defined as the slope of the dose-response curve over the linear portion of the dose-response curve ) also was similar among younger and older women. These data demonstrate that the deficiency in adrenal and rogen production in women is restricted to the delta5-pathway steroid products ( DHEA and DS ), whereas there is no reduction in the capacity of the adrenal to produce A4 or cortisol. As DHEA and DS are likely to be produced mainly in the zona reticularis of the adrenal cortex, we propose that these data point to an alteration in that cortical zone as the cause of adrenal and rogen deficiency in aging. The reductions in A4 in aging are probably due to reduced ovarian secretion after menopause Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women. OBJECTIVE Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index ( BMI ) with circulating and rogens ( testosterone, and rostenedione and dehydroepi and rosterone sulfate ( DHEAS ) ), estrogens ( estrone and estradiol ), sex hormone-binding globulin ( SHBG ), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS A cross-sectional analysis was performed using hormonal and question naire data of 620 healthy women ( 177 pre- and 443 post-menopausal ). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS In the pre-menopausal group, BMI was not related to and rogens and IGF-I. In the post-menopausal group, estrogens, testosterone and and rostenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to and rogens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and and rogens were observed. CONCLUSIONS These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, and rogens and SHBG appear to be related to each other in post-menopausal women Measurement of total serum testosterone levels using commercially available kits: high degree of between-kit variability. OBJECTIVE The measurement of total serum testosterone has an established clinical role in the management of male hypogonadism and female and rogen excess disorders. We studied the between-kit variability and precision of six different commercially available testosterone assays and compared them with an established in-house method. DESIGN Laboratory observational prospect i ve study. SETTING Tertiary university medical center clinical laboratory. PATIENT(S ) Three groups of sample s each of men ( n = 36 ) and women ( n = 15 ) who had high, normal, or low levels of sex hormone-binding globulin ( SHBG ), respectively, were studied. INTERVENTION(S ) Individual and pooled ( male and female ) serum sample s were analyzed for total testosterone concentration using six different commercially available assays and one in-house method. MAIN OUTCOME MEASURE(S ) The between-kit variability and the effect of the mean ( + /- SD ) SHBG level were determined, the results obtained with the use of the kits and the in-house method were compared, and the intraassay variability ( i.e., precision ) was evaluated. RESULT ( S ) Male sample s demonstrated a 26.3%-40.8 % variance in the results obtained with different kits, which was greatest for sample s with the lowest SHBG levels. For female sample s, between-kit variability ranged from 57%-115 % ( average, 77 % ). The percent deviation of the results obtained with the use of commercial methods from those obtained with the use of our in-house assay was greater for men ( mean variance, 194 % ) than for women ( mean variance, 67 % ). The female pool intraassay coefficient of variation was 3.8 % with the use of the in-house method and ranged from 8.9%-21.2 % with the use of the commercial kits. The male pool intraassay coefficient of variation was 3.1 % with the use of the in-house method and ranged from 3.3%-5.5 % with the use of the commercial kits. CONCLUSION ( S ) Most commercially available kits for measuring the total serum testosterone level demonstrated significant between-kit variability, which was greatest for female sample s. Further, sample s with the lowest SHBG levels had the highest between-kit variances. These data strongly suggest that the measurement of total serum testosterone using commercial kits may have limited utility, particularly for the detection of hyper and rogenemia Determinants of serum total and free testosterone levels in women over the age of 65 years. CONTEXT Little is known about testosterone ( T ) levels and their determinants in women of late postmenopausal age. OBJECTIVE We describe levels of total and free T and selected factors that influence these levels in a r and om sample of older women. DESIGN Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65 - 98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels. RESULTS In adjusted models : 1 ) total T levels declined with age until 80, whereas free T levels did not vary by age ; 2 ) women with bilateral oophorectomy had 23 % lower total T and 16 % lower free T levels than those with at least one intact ovary ; 3 ) oral estrogen users had total and free T levels that were 47 % lower than never users ; 4 ) obese women had 47 % higher total T and 20 % higher free T levels, and overweight women had 24 % higher total T and 14 % higher free T levels, than normal weight women ; and 5 ) free T levels were 51 % higher in black women. Corticosteroid users had 75 % lower total T and 43 % lower free T levels than nonusers. CONCLUSIONS Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy. Normal menopause is associated with vascular endothelial dysfunction, an early stage of atherosclerosis. The effect of premature ovarian failure ( or premature menopause ) on endothelial function in young women is unknown. Endothelial function was assessed in 18 women with premature ovarian failure before and after 6 months of hormone therapy and was compared with the endothelial function of 20 age- and body mass index-matched premenopausal women. Brachial artery diameter was measured both during hyperemia ( an index of endothelium-dependent vasodilation ) and in response to glyceryl trinitrate ( an index of endothelium-independent vaso-dilation ). Flow-mediated dilation was significantly lower in women with premature ovarian failure at baseline ( increase in brachial artery diameter during hyperemia by 3.06 + /- 4.33 % ) than in control women ( increase by 8.84 + /- 2.15 % ; P < 0.0005 ). Glyceryl trinitrate-induced vasodilation did not differ between the groups. After hormone therapy for 6 months, flow-mediated dilation was improved in women with premature ovarian failure, increasing by more than 2-fold ( 7.41 + /- 3.86 % ; P < 0.005 compared with pretreatment ) and reaching normal values ( P not significant compared with control women ). Glyceryl trinitrate-induced vasodilation did not change after treatment in women with premature ovarian failure. Young women with premature ovarian failure have significant vascular endothelial dysfunction. Early onset of endothelial dysfunction associated with sex steroid deficiency may contribute to the increased risk of cardiovascular disease and mortality in young women with premature ovarian failure. Hormone therapy restores endothelial function within 6 months of treatment The effect of oophorectomy and hormone replacement on neurohypophyseal hormone secretion in women OBJECTIVE There is evidence to suggest that the release of neurohypophyseal hormones may be influenced by the circulating concentrations of gonadal steroids. We therefore monitored this relationship in women undergoing prophylactic bilateral oophorectomy at the time of hysterectomy with subsequent hormone replacement therapy and compared it with that in women undergoing hysterectomy with conservation of Testosterone deficiency in young women with 46,XX spontaneous premature ovarian failure. OBJECTIVE To determine whether women with 46,XX spontaneous premature ovarian failure have lower serum free-T levels than do control women. DESIGN Cross-sectional. SETTING National Institutes of Health Clinical Research Center. PATIENT(S ) Women with 46,XX spontaneous premature ovarian failure ( n = 130 ). INTERVENTION(S ) Evaluation while off any estrogen therapy and then again after receiving a st and ardized hormone regimen. Regularly menstruating control women ( n = 65 ) were sample d during the midfollicular phase. MAIN OUTCOME MEASURE(S ) Serum total T by RIA after extraction and column chromatography, free T by equilibrium dialysis, and sex hormone-binding globulin by immunoradiometric assay. RESULT ( S ) While off estrogen therapy patients had a median serum free-T concentration that was statistically significantly lower than controls ( 2.2 vs. 3.3 pg/mL ). This dropped significantly lower to 1.9 pg/mL while the patients were on physiologic transdermal E(2 ) therapy. This is despite the fact that sex hormone-binding globulin levels did not change. While on E(2 ) therapy, 13 % of women ( 95 % confidence interval, 7.9%-20.3 % ) had serum free-T levels below the lower limit of normal ( < 1.1 pg/mL ). CONCLUSION ( S ) As a group, young women with 46,XX spontaneous premature ovarian failure have reduced circulating free-T levels, both during an interval off of estrogen therapy and while on physiologic transdermal E(2 ) therapy A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. From a longitudinal prospect i ve study, 160 women with spontaneous menopause and without steroid medication were followed during the transition from pre- to postmenopause. After 12 years 152 women were still participating in the study. Blood sample s were drawn every 6 months until 1 year after the menopause and every 12 months thereafter. Measurements of bone mineral density ( BMD ) on the forearm were performed every second year. All women routinely completed a question naire concerning symptoms frequently attributed to the climacteric period. All data were grouped around the onset of the menopause, thereby allowing longitudinal evaluation of the changes in the variables from the premenopausal to the postmenopausal period. The beginning of the perimenopausal period was characterized by transitory elevations of follicle-stimulating hormone ( FSH ). A significant increase in serum levels of gonadotropins was observed for both FSH and luteinizing hormone ( LH ) from about 5 years before the menopause. Within the 6 month period around the menopause there was a further increase which culminated within the first postmenopausal year for LH and 2 - 3 years postmenopause for FSH. Thereafter, a continuous decrease in LH occurred over the following 8 years. With respect to FSH, there was a slight decline starting about 4 years postmenopause. During the premenopausal period an increasing frequency of inadequate luteal function or anovulation occurred and, in the postmenopausal years, the serum levels of progesterone ( P ) were invariably low. Gradually, the ratio between estrone ( E1 ) and 17-beta-estradiol ( E2 ) increased, reflecting the declining follicular steroidogenesis. A marked decrease in estrogen levels occurred during the 6 month period around the menopause, most pronounced in E2. During the next 3 years, the levels of E2 and E1 showed an essentially parallel, moderate decline. Around the menopause, serum levels of testosterone ( T ), delta 4- and rostenedione ( A ) and sex hormone-binding globulin ( SHBG ) showed small but significant decreases. From about 3 years postmenopause, the levels were relatively constant over the following 5 years. A decrease in BMD was observed in the postmenopause, and from about 3 years postmenopause, estradiol correlated positively with BMD. Before, as well as after the menopause, body mass index ( BMI ) showed an inverse correlation with SHBG. Postmenopausal and rostenedione correlated positively with E1, E2 and T. BMI correlated positively with E1 and E2. The concentrations of the free fraction of E2 and T are dependent on the levels of SHBG, which in turn has a negative correlation with BMI. The impact of this will influence the severity of symptoms, the degree of bone loss and the need for supplementary therapy Sex steroids and affect in the surgical menopause: a double-blind, cross-over study The effect of estrogen and /or and rogen on mood in surgically menopausal women was investigated with a prospect i ve, double-blind, cross-over design. Oophorectomized women who received either estrogen ( E ), and rogen ( A ), or a combined estrogen- and rogen preparation ( E-A ) parenterally attained lower depression scores during both treatment phases compared to a placebo group ( PL ), coincident with their higher plasma estrogen and testosterone levels. When steroids were withdrawn, depression scores of all oophorectomized women were significantly higher than those of a hysterectomized control group with intact ovaries ( CON ). The A group also had higher hostility scores than the E, PL, and CON groups. These data provide evidence of a covariation between circulating levels of estrogen and testosterone and certain affects in healthy women Extremes of endogenous testosterone are associated with increased risk of incident coronary events in older women. CONTEXT Few studies have examined whether endogenous testosterone is associated with the development of coronary heart disease ( CHD ) in women. OBJECTIVE This study tested the association of total testosterone ( total T ) and bioavailable T ( BioT ) levels with risk of incident coronary events among older community-dwelling women. DESIGN, SETTING, AND PARTICIPANTS This was a prospect i ve, population -based study of 639 postmenopausal women, aged 50 - 91 ( mean, 73.8 ) yr who had serum testosterone measurements at baseline ( 1984 - 87 ) and who were followed for incident CHD events through 2004. MAIN OUTCOME MEASURES A total of 134 incident CHD events occurred during follow-up [ 45 nonfatal myocardial infa rct ions, 79 fatal myocardial infa rct ions, and 10 coronary revascularizations ]. RESULTS The median follow-up was 12.3 yr. Age-adjusted CHD risk estimates were similar for the four highest total T quintiles relative to the lowest, suggesting a low threshold. In age-adjusted analyses, the lowest total T quintile ( < /=80 pg/ml ) was associated with a 1.62-fold increased risk of incident CHD [ 95 % confidence interval ( CI ), 1.10 - 2.39 ] compared to higher levels. BioT showed a U-shaped association with incident CHD. Age-adjusted risk for the lowest and highest BioT quintiles relative to the third were 1.79 ( 95 % CI, 1.03 - 3.16 ) and 1.96 ( 95 % CI, 1.13 - 3.41 ), respectively. Additional adjustment for lifestyle, adiposity, estradiol, and ovarian status, or for CHD risk factor covariates, had minimal influence on results. CONCLUSIONS An optimal range of testosterone may exist for cardiovascular health in women, with increased risk of CHD events at low levels of testosterone overall and at high levels of the bioavailable fraction of testosterone Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. OBJECTIVE To assess the efficacy and safety of a 300 mug/d testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women on concomitant estrogen therapy. METHODS Five hundred thirty-three women with hypoactive sexual desire disorder who had undergone previous hysterectomy and bilateral oophorectomy were enrolled in a 24-week, multicenter, double-blind, placebo-controlled trial. Patients were r and omly assigned to receive placebo or the testosterone patch twice weekly. The primary efficacy endpoint was change from baseline at week 24 in the frequency of total satisfying sexual activity, measured by the Sexual Activity Log. Secondary measures included sexual desire using the Profile of Female Sexual Function and personal distress as measured by the Personal Distress Scale. Hormone levels, adverse events, and clinical laboratory measures were review ed. RESULTS Total satisfying sexual activity significantly improved in the testosterone patch group compared with placebo after 24 weeks ( mean change from baseline, 1.56 compared with 0.73 episodes per 4 weeks, P =.001 ). Treatment with the testosterone patch also significantly improved sexual desire ( mean change, 10.57 compared with 4.29, P <.001 ) and decreased personal distress ( P =.009 ). Serum free, total, and bioavailable testosterone concentrations increased from baseline. Overall, adverse events were similar in both groups ( P >.05 ). The incidence of and rogenic adverse events was higher in the testosterone group ; most and rogenic adverse events were mild. CONCLUSION In surgically menopausal women with hypoactive sexual desire disorder, a 300 mug/d testosterone patch significantly increased satisfying sexual activity and sexual desire, while decreasing personal distress, and was well tolerated through up to 24 weeks of use Effects of testosterone and estrogen replacement on memory function Objective : Testosterone insufficiency has been associated with psychosexual problems, reduced psychological well-being, and negative metabolic consequences, whereas less is known about the effects on cognition. The aim of this study was to investigate the effect of adding testosterone to estrogen therapy on memory functions in oophorectomized women. Methods : In a r and omized, double-blind, placebo-controlled design, women with surgically induced menopause ( n = 50 ; mean [ SD ] age, 54.0 [ 2.9 ] y ) received estradiol valerate in combination with testosterone undecanoate or placebo. The women were assessed with a self-report question naire regarding memory and neuropsychological tests for verbal and spatial episodic memory and incidental learning at baseline, at the time of crossover, and after completion of treatment. Results : Testosterone undecanoate 40 mg added to estrogen therapy had a negative effect on immediate but not delayed verbal memory at 24 weeks. Subjective and objective memory showed some correspondence as the women in the estrogen + placebo treatment group rated decreased everyday memory problems at 24 weeks compared with baseline. This was not observed in the women in the estrogen + testosterone treatment. Verbal attention span deteriorated from baseline with estrogen + placebo treatment but not with the estrogen + testosterone treatment. However, there was no significant treatment effect between the two groups. Conclusions : Adding testosterone to estrogen treatment deteriorated immediate verbal memory compared with estrogen + placebo, while other memory functions were unaffected", 'OBJECTIVE To develop an evidence -based guideline to help clinicians make decisions about when and how to safely taper and stop benzodiazepine receptor agonists ( BZRAs ) ; to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes. The effects of substituting zopiclone in withdrawal from chronic use of benzodiazepine hypnotics Abstract Twenty-four volunteers ( 19 women and five men ) with insomnia and a history of chronic use of benzodiazepine hypnotics participated in a r and omized, double blind, controlled clinical trial. The study was design ed to assess the effects of substituting zopiclone ( ZOP ) – as an hypnotic – among chronic users of flunitrazepam ( FLU ), and to compare the subsequent withdrawal of ZOP with placebo controlled withdrawal of FLU. During the 5 weeks of a withdrawal protocol, sleep and physiological parameters were assessed by polysomnographic measures for 11 nights and by nightly actigraphic recordings for weeks 1, 3, and 5. Subjective effects of the withdrawal process were evaluated with daily sleep diaries, and with various weekly self-report symptom checklists. Paired t-tests performed on differences in objective sleep parameters between baseline and the last weeks of the withdrawal program showed a significant decrease in sleep quality within the FLU group, but not in the ZOP group. Subjective sleep diaries consistently reflected the objective ly measured changes in sleep throughout the withdrawal program, indicating significant changes in sleep parameters only in the FLU group. The results obtained from the self report inventories aim ed at assessing withdrawal symptoms, however, revealed no differences between the baseline week and the termination week of the program in any of the groups. After completing the pharmacological withdrawal, all subjects received a short-term cognitive behavioral intervention focused on improving their coping strategies with symptoms of insomnia ; they were evaluated immediately after concluding the intervention, and at 3 and 12 month follow-ups Cognitive-behavioural, pharmacological and psychosocial predictors of outcome during tapered discontinuation of benzodiazepine. Eighty-six participants wishing to stop benzodiazepine and who met DSM-IV ( Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychological Association, 1994 ) criteria for anxiety disorder or insomnia were assessed pre- and post-taper on clinical, pharmacological and psychosocial measures. An initial cohort of 41 participants received treatment as usual ( taper only ) plus physician counselling in the same clinic setting. A second cohort of 45 participants were r and omly allocated to group cognitive-behavioural therapy ( CBT ) plus taper, or group support ( GS ) plus taper. At 3 months follow-up, the outcomes in both the CBT and the GS subgroups were equivalent. Intention to treat analysis revealed a slight advantage to the CBT over the GS group and the CBT group showed higher self-efficacy post-taper. Over all 86 participants, a high-baseline level of psychological distress, anxiety and dosage predicted a poor outcome, but increase in self-efficacy contributed to a successful outcome particularly in those with initially poor baseline predictors. Although there was a decrease in positive affect during preliminary stages of tapered discontinuation compared to baseline, there was no significant overall increase in negative affect Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care. BACKGROUND Benzodiazepines are extensively used in primary care, but their long-term use is associated with adverse health outcomes and dependence. AIMS To analyse the efficacy of two structured interventions in primary care to enable patients to discontinue long-term benzodiazepine use. METHOD A multicentre three-arm cluster r and omised controlled trial was conducted, with r and omisation at general practitioner level ( trial registration IS RCT N13024375 ). A total of 532 patients taking benzodiazepines for at least 6 months participated. After all patients were included, general practitioners were r and omly allocated ( 1:1:1 ) to usual care, a structured intervention with follow-up visits ( SIF ) or a structured intervention with written instructions ( SIW ). The primary end-point was the last month self-declared benzodiazepine discontinuation confirmed by prescription cl aims at 12 months. RESULTS At 12 months, 76 of 168 ( 45 % ) patients in the SIW group and 86 of 191 ( 45 % ) in the SIF group had discontinued benzodiazepine use compared with 26 of 173 ( 15 % ) in the control group. After adjusting by cluster, the relative risks for benzodiazepine discontinuation were 3.01 ( 95 % CI 2.03 - 4.46, P<0.0001 ) in the SIW and 3.00 ( 95 % CI 2.04 - 4.40, P<0.0001 ) in the SIF group. The most frequently reported withdrawal symptoms were insomnia, anxiety and irritability. CONCLUSIONS Both interventions led to significant reductions in long-term benzodiazepine use in patients without severe comorbidity. A structured intervention with a written individualised stepped-dose reduction is less time-consuming and as effective in primary care as a more complex intervention involving follow-up visits Withdrawal from benzodiazepines by initially switching to zopiclone. Withdrawal from hypnotics can produce a variety of problems, especially sleep difficulties, some of which may arise from the multiple actions of most hypnotics, thus producing a range of rebound effects. This study examined whether switching patients to a hypnotic with a narrower range of action and of a different class would reduce these problems. One hundred and thirty-four patients participated ; they were r and omly allocated to one of three methods of switching from " previous hypnotic " to zopiclone ( a cyclopyrrolone ). The methods were gap ( an interval between taking the two drugs ) ; abuttal ( taking zopiclone immediately on stopping previous drug ) ; and overlap ( gradually reducing previous drug after starting zopiclone ). The main findings were that zopiclone was associated with better sleep and increased alertness ; the abuttal method was the best method of switching ; and no serious side effects from zopiclone were reported. It was concluded that zopiclone has a useful role in benzodiazepine withdrawal, and that immediate substitution is the best method Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. The Johns Hopkins Precursors Study, a long-term prospect i ve study, was used to study the relation between self-reported sleep disturbances and subsequent clinical depression and psychiatric distress. A total of 1,053 men provided information on sleep habits during medical school at The Johns Hopkins University ( classes of 1948 - 1964 ) and have been followed since graduation. During a median follow-up period of 34 years ( range 1 - 45 ), 101 men developed clinical depression ( cumulative incidence at 40 years, 12.2 % ), including 13 suicides. In Cox proportional hazards analysis adjusted for age at graduation, class year, parental history of clinical depression, coffee drinking, and measures of temperament, the relative risk of clinical depression was greater in those who reported insomnia in medical school ( relative risk ( RR ) 2.0, 95 % confidence interval ( CI ) 1.2 - 3.3 ) compared with those who did not and greater in those with difficulty sleeping under stress in medical school ( RR 1.8, 95 % CI 1.2 - 2.7 ) compared with those who did not report difficulty. There were weaker associations for those who reported poor quality of sleep ( RR 1.6, 95 % CI 0.9 - 2.9 ) and sleep duration of 7 hours or less ( RR 1.5, 95 % CI 0.9 - 2.3 ) with development of clinical depression. Similar associations were observed between reports of sleep disturbances in medical school and psychiatric distress assessed in 1988 by the General Health Question naire. These findings suggest that insomnia in young men is indicative of a greater risk for subsequent clinical depression and psychiatric distress that persists for at least 30 years Tapering off long-term benzodiazepine use with or without group cognitive-behavioural therapy: three-condition, randomised controlled trial. BACKGROUND Benzodiazepine withdrawal programmes have never been experimentally compared with a nonintervention control condition. AIMS To evaluate the efficacy and feasibility of tapering off long-term benzodiazepine use in general practice, and to evaluate the value of additional group cognitive-behavioural therapy ( CBT ). METHOD A 3-month r and omised, 3-month controlled trial was conducted in which 180 people attempting to discontinue long-term benzodiazepine use were assigned to tapering off plus group CBT, tapering off alone or usual care. RESULTS Tapering off led to a significantly higher proportion of successful discontinuations than usual care ( 62 % nu. 21 % ). Adding group CBT did not increase the success rate ( 58 % v. 62 % ). Neither successful discontinuation nor intervention type affected psychological functioning. Both tapering strategies showed good feasibilityin general practice. CONCLUSIONS Tapering off is a feasible and effective way of discontinuing long-term benzodiazepine use in general practice. The addition of group CBT is of limited value Gradual withdrawal from benzodiazepines in residents of homes for the elderly: experience and suggestions for future research Objective A r and omised, controlled clinical trial was performed to study the long-term effect of gradual withdrawal from benzodiazepines on the daily functioning of residents of homes for the elderly. The planned sample size was not achieved due to recruitment and follow-up problems. Results The results in this small sample nevertheless suggest that gradual withdrawal from benzodiazepines is possible in residents of homes for the elderly, and that it can have a positive effect on their daily functioning. No major withdrawal symptoms were observed, although there was a decrease in sleep quality during withdrawal. Conclusion The findings are promising for further research, but research ers should anticipate the problems inherent in executing a trial with institutionalised elderly subjects Hypnotic taper with or without self-help treatment of insomnia: a randomized clinical trial. This study aim ed to assess the efficacy of a minimal intervention focusing on hypnotic discontinuation and cognitive-behavioral treatment ( CBT ) for insomnia. Fifty-three adult chronic users of hypnotics were r and omly assigned to an 8-week hypnotic taper program, used alone or combined with a self-help CBT. Weekly hypnotic use decreased in both conditions, from a nearly nightly use at baseline to less than once a week at posttreatment. Nightly dosage ( in lorazepam equivalent ) decreased from 1.67 mg to 0.12 mg. Participants who received CBT improved their sleep efficiency by 8 %, whereas those who did not remained stable. Total wake time decreased by 52 min among CBT participants and increased by 13 min among those receiving the taper schedule alone. Total sleep time remained stable throughout withdrawal in both CBT and taper conditions. The present findings suggest that a systematic withdrawal schedule might be sufficient in helping chronic users stop their hypnotic medication. The addition of a self-help treatment focusing on insomnia, a readily available and cost-effective alternative to individual psychotherapy, produced greater sleep improvement Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. BACKGROUND Older adults are the main recipients of repeat prescriptions for benzodiazepine ( BZD ) hypnotics. BZDs can impair cognitive function and may not aid sleep when taken continuously for years. This study therefore aim ed to determine if withdrawing from BZDs leads to changes in patients\'cognitive function, quality of life, mood and sleep. METHOD One hundred and ninety-two long-term users of BZD hypnotics, aged > or = 65 years, were identified in 25 general practice s. One hundred and four who wished to withdraw were r and omly allocated to one of two groups under double-blind, placebo controlled conditions : group A\'s BZD dose was tapered from week 1 of the trial ; group B were given their usual dose for 12 weeks and then it was tapered. An additional group ( C ) of 35 patients who did not wish to withdraw from BZDs participated as\'continuers \'. All patients were assessed at 0, 12 and 24 weeks and 50 % were reassessed at 52 weeks. RESULTS Sixty per cent of patients had taken BZDs continuously for > 10 years ; 27 % for > 20 years. Of all patients beginning the trial, 80 % had successfully withdrawn 6 months later. There was little difference between groups A and B, but these groups differed from continuers ( C ) in that the performance of the withdrawers on several cognitive/psychomotor tasks showed relative improvements at 24 or 52 weeks. Withdrawers and continuers did not differ in sleep or BZD withdrawal symptoms. CONCLUSIONS These results have clear implication s for clinical practice. Withdrawal from BZDs produces some subtle cognitive advantages for older people, yet little in the way of withdrawal symptoms or emergent sleep difficulties. These findings also suggest that, taken long-term, BZDs do not aid sleep Efficacy of an Internet-based behavioral intervention for adults with insomnia. CONTEXT Insomnia is a major health problem with significant psychological, health, and economic consequences. However, availability of one of the most effective insomnia treatments, cognitive behavioral therapy, is significantly limited. The Internet may be a key conduit for delivering this intervention. OBJECTIVE To evaluate the efficacy of a structured behavioral Internet intervention for adults with insomnia. DESIGN, SETTING, AND PARTICIPANTS Forty-five adults were r and omly assigned to an Internet intervention ( n = 22 ) or wait-list control group ( n = 23 ). Forty-four eligible participants ( mean [ SD ] age, 44.86 [ 11.03 ] years ; 34 women ) who had a history of sleep difficulties longer than 10 years on average ( mean [ SD ], 10.59 [ 8.89 ] years ) were included in the analyses. INTERVENTION The Internet intervention is based on well-established face-to-face cognitive behavioral therapy incorporating the primary components of sleep restriction, stimulus control, sleep hygiene, cognitive restructuring, and relapse prevention. MAIN OUTCOME MEASURES The Insomnia Severity Index and daily sleep diary data were used to determine changes in insomnia severity and the main sleep variables, including wake after sleep onset and sleep efficiency. RESULTS Intention-to-treat analyses showed that scores on the Insomnia Severity Index significantly improved from 15.73 ( 95 % confidence interval [ CI ], 14.07 to 17.39 ) to 6.59 ( 95 % CI, 4.73 to 8.45 ) for the Internet group but did not change for the control group ( 16.27 [ 95 % CI, 14.61 to 17.94 ] to 15.50 [ 95 % CI, 13.64 to 17.36 ] ) ( F(1,42 ) = 29.64 ; P <.001 ). The Internet group maintained their gains at the 6-month follow-up. Internet participants also achieved significant decreases in wake after sleep onset ( 55 % [ 95 % CI, 34 % to 76 % ] ) and increases in sleep efficiency ( 16 % [ 95 % CI, 9 % to 22 % ] ) compared with the nonsignificant control group changes of wake after sleep onset ( 8 % [ 95 % CI, -17 % to 33 % ) and sleep efficiency ( 3 % ; 95 % CI, -4 % to 9 % ). CONCLUSIONS Participants who received the Internet intervention for insomnia significantly improved their sleep, whereas the control group did not have a significant change. The Internet appears to have considerable potential in delivering a structured behavioral program for insomnia. TRIAL REGISTRATION clinical trials.gov Identifier : NCT00328250 Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. BACKGROUND Benzodiazepines are the most frequently used drug for the treatment of insomnia. Prolonged use of benzodiazepine therapy is not recommended. However, many patients, particularly older patients, have difficulties discontinuing therapy. Melatonin, a hormone that is produced at night by the pineal gl and, promotes normal sleep in humans and augments sleep induction by benzodiazepine therapy. OBJECTIVE To assess whether the administration of melatonin could facilitate the discontinuation of benzodiazepine therapy in patients with insomnia. METHODS Thirty-four subjects receiving benzodiazepine therapy were enrolled in the 2-period study. In period 1, patients received ( double-blinded ) melatonin ( 2 mg in a controlled-release formulation ) or a placebo nightly for 6 weeks. They were encouraged to reduce their benzodiazepine dosage 50 % during week 2, 75 % during weeks 3 and 4, and to discontinue benzodiazepine therapy completely during weeks 5 and 6. In period 2, melatonin was administered ( single-blinded ) for 6 weeks to all subjects and attempts to discontinue benzodiazepine therapy were resumed. Benzodiazepine consumption and subjective sleep- quality scores were reported daily by all patients. All subjects were then allowed to continue melatonin therapy and follow-up re assessment s were performed 6 months later. RESULTS By the end of period 1, 14 of 18 subjects who had received melatonin therapy, but only 4 of 16 in the placebo group, discontinued benzodiazepine therapy ( P =.006 ). Sleep- quality scores were significantly higher in the melatonin therapy group ( P =.04 ). Six additional subjects in the placebo group discontinued benzodiazepine therapy when given melatonin in period 2. The 6-month follow-up assessment s revealed that of the 24 patients who discontinued benzodiazepine and received melatonin therapy, 19 maintained good sleep quality. CONCLUSION Controlled-release melatonin may effectively facilitate discontinuation of benzodiazepine therapy while maintaining good sleep quality Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. IMPORTANCE The American Board of Internal Medicine Foundation Choosing Wisely Campaign recommends against the use of benzodiazepine drugs for adults 65 years and older. The effect of direct patient education to catalyze collaborative care for reducing inappropriate prescriptions remains unknown. OBJECTIVE To compare the effect of a direct-to-consumer educational intervention against usual care on benzodiazepine therapy discontinuation in community-dwelling older adults. DESIGN, SETTING, AND PARTICIPANTS Cluster r and omized trial ( EMPOWER [ Eliminating Medications Through Patient Ownership of End Results ] study [ 2010 - 2012, 6-month follow-up ] ). Community pharmacies were r and omly allocated to the intervention or control arm in nonstratified, blocked groups of 4. Participants ( 303 long-term users of benzodiazepine medication aged 65 - 95 years, recruited from 30 community pharmacies ) were screened and enrolled prior to r and omization : 15 pharmacies r and omized to the educational intervention included 148 participants and 15 pharmacies r and omized to the " wait list " control included 155 participants. Participants, physicians, pharmacists, and evaluators were blinded to outcome assessment. INTERVENTIONS The active arm received a deprescribing patient empowerment intervention describing the risks of benzodiazepine use and a stepwise tapering protocol. The control arm received usual care. MAIN OUTCOMES AND MEASURES Benzodiazepine therapy discontinuation at 6 months after r and omization, ascertained by pharmacy medication renewal profiles. RESULTS A total of 261 participants ( 86 % ) completed the 6-month follow-up. Of the recipients in the intervention group, 62 % initiated conversation about benzodiazepine therapy cessation with a physician and /or pharmacist. At 6 months, 27 % of the intervention group had discontinued benzodiazepine use compared with 5 % of the control group ( risk difference, 23 % [ 95 % CI, 14%-32 % ] ; intracluster correlation, 0.008 ; number needed to treat, 4 ). Dose reduction occurred in an additional 11 % ( 95 % CI, 6%-16 % ). In multivariate subanalyses, age greater than 80 years, sex, duration of use, indication for use, dose, previous attempt to taper, and concomitant polypharmacy ( 10 drugs or more per day ) did not have a significant interaction effect with benzodiazepine therapy discontinuation. CONCLUSIONS AND RELEVANCE Direct-to-consumer education effectively elicits shared decision making around the overuse of medications that increase the risk of harm in older adults. TRIAL REGISTRATION clinical trials.gov Identifier : NCT01148186 Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation. We compared the effect of abrupt discontinuation of therapeutic doses of short half-life and long half-life benzodiazepines in 57 benzodiazepine-dependent patients ( daily use, greater than 1 year ). Despite the use of a mean daily dose of 14.1 mg of diazepam equivalents, there were notable residual symptoms of anxiety and depression present at intake ( Hamilton Rating Scale for Anxiety score, 17.0 ; Hamilton Rating Scale for Depression score, 14.0 ). Benzodiazepine intake was stabilized for 3 weeks before double-blind assignment to placebo ( n = 47 ), or continued benzodiazepine use ( n = 10 ). Clinical assessment s were performed daily, including benzodiazepine plasma levels. Depending on the outcome criteria used, anywhere from 58 % to 100 % of patients were judged to have experienced a withdrawal reaction, with a peak severity at 2 days for short half-life and 4 to 7 days for long half-life benzodiazepines. Relapse onto benzodiazepines occurred in 27 % of patients who were receiving long half-life benzodiazepines and in 57 % of patients who were receiving short half-life benzodiazepines. Baseline predictors of relapse were nonpanic diagnoses, a higher benzodiazepine dose, and a higher Eysenck neuroticism score. A short half-life and higher daily doses were associated with greater withdrawal severity, as were personality traits, such as dependency and neuroticism, less education and higher baseline levels of anxious and depressive symptoms. Patients who were able to remain free of benzodiazepines for at least 5 weeks obtained lower levels of anxiety than before benzodiazepine discontinuation. These results provide a detailed picture of the symptoms, time course, and multidimensional determinants of the benzodiazepine withdrawal syndrome Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering: a randomized trial. BACKGROUND Long-term use of hypnotics is not recommended because of risks of dependency and adverse effects on health. The usual clinical management of benzodiazepine dependency is gradual tapering, but when used alone this method is not highly effective in achieving long-term discontinuation. We compared the efficacy of tapering plus cognitive-behavioural therapy for insomnia with tapering alone in reducing the use of hypnotics by older adults with insomnia. METHODS People with chronic insomnia who had been taking a benzodiazepine every night for more than 3 months were recruited through media advertisements or were referred by their family doctors. They were r and omly assigned to undergo either cognitive-behavioural therapy plus gradual tapering of the drug ( combined treatment ) or gradual tapering only. The cognitive-behavioural therapy was provided by a psychologist in 8 weekly small-group sessions. The tapering was supervised by a physician, who met weekly with each participant over an 8-week period. The main outcome measure was benzodiazepine discontinuation, confirmed by blood screening performed at each of 3 measurement points ( immediately after completion of treatment and at 3- and 12-month follow-ups ). RESULTS Of the 344 potential participants, 65 ( mean age 67.4 years ) met the inclusion criteria and entered the study. The 2 study groups ( 35 subjects in the combined treatment group and 30 in the tapering group ) were similar in terms of demographic characteristics, duration of insomnia and hypnotic dosage. Immediately after completion of treatment, a greater proportion of patients in the combined treatment group had withdrawn from benzodiazepine use completely ( 77 % [ 26/34 ] v. 38 % [ 11/29 ] ; odds ratio [ OR ] 5.3, 95 % confidence interval [ CI ] 1.8 - 16.2 ; OR after adjustment for initial benzodiazepine daily dose 7.9, 95 % CI 2.4 - 30.9 ). At the 12-month follow-up, the favourable outcome persisted ( 70 % [ 23/33 ] v. 24 % [ 7/29 ] ; OR 7.2, 95 % CI 2.4 - 23.7 ; adjusted OR 7.6, 95 % CI 2.5 - 26.6 ) ; similar results were obtained at 3 months. INTERPRETATION A combination of cognitive-behavioural therapy and benzodiazepine tapering was superior to tapering alone in the management of patients with insomnia and chronic benzodiazepine use. The beneficial effects were sustained for up to 1 year. Applying this multidisciplinary approach in the community could help reduce benzodiazepine use by older people Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper. We compared the effect on withdrawal severity and acute outcome of a 25 % per week taper of short half-life vs long half-life benzodiazepines in 63 benzodiazepine-dependent patients. Patients unable to tolerate taper were permitted to slow the taper rate. Ninety percent of patients experienced a withdrawal reaction, but it was rarely more than mild to moderate. Nonetheless, 32 % of long half-life and 42 % of short half-life benzodiazepine-treated patients were unable to achieve a drug-free state. The most difficulty was experienced in the last half of taper. Baseline personality, high Eysenck neuroticism, female sex, and mild-to-moderate alcohol use were found to be more significant predictors of withdrawal severity than the daily benzodiazepine dose or benzodiazepine half-life. These findings suggest that personality factors contribute significantly to the patient\'s difficulties with gradual benzodiazepine discontinuation of therapeutic doses of benzodiazepines Predictors of Long-Term Benzodiazepine Abstinence in Participants of a Randomized Controlled Benzodiazepine Withdrawal Program Objective : To identify predictors of resumed benzodiazepine use after participation in a benzodiazepine discontinuation trial. Method : We performed multiple Cox regression analyses to predict the long-term outcome of a 3-condition, r and omized, controlled benzodiazepine discontinuation trial in general practice. Results : Of 180 patients, we completed follow-up for 170 ( 94 % ). Of these, 50 ( 29 % ) achieved long-term success, defined as no use of benzodiazepines during follow-up. Independent predictors of success were as follows : offering a taper-off program with group therapy ( hazard ratio [ HR ] 2.4 ; 95 % confidence interval [ CI ], 1.5 to 3.9 ) or without group therapy ( HR 2.9 ; 95%CI, 1.8 to 4.8 ) ; a lower daily benzodiazepine dosage at the start of tapering off ( HR 1.5 ; 95%CI, 1.2 to 1.9 ) ; a substantial dosage reduction by patients themselves just before the start of tapering off ( HR 2.1 ; 95%CI, 1.4 to 3.3 ) ; less severe benzodiazepine dependence, as measured by the Benzodiazepine Dependence Self-Report Question naire Lack of Compliance subscale ( HR 2.4 ; 95%CI, 1.1 to 5.2 ) ; and no use of alcohol ( HR 1.7 ; 95%CI, 1.2 to 2.5 ). Patients who used over 10 mg of diazepam equivalent, who had a score of 3 or more on the Lack of Compliance subscale, or who drank more than 2 units of alcohol daily failed to achieve long-term abstinence. Conclusions : Benzodiazepine dependence severity affects long-term taper outcome independent of treatment modality, benzodiazepine dosage, psychopathology, and personality characteristics. An identifiable subgroup needs referral to specialized care Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. OBJECTIVE This study evaluated the effectiveness of a supervised benzodiazepine taper, singly and combined with cognitive behavior therapy, for benzodiazepine discontinuation in older adults with chronic insomnia. METHOD Seventy-six older adult out patients ( 38 women, 38 men ; mean age of 62.5 years ) with chronic insomnia and prolonged use ( mean duration of 19.3 years ) of benzodiazepine medication for sleep were r and omly assigned for a 10-week intervention consisting of a supervised benzodiazepine withdrawal program ( N=25 ), cognitive behavior therapy for insomnia ( N=24 ), or supervised withdrawal plus cognitive behavior therapy ( N=27 ). Follow-up assessment s were conducted at 3 and 12 months. The main outcome measures were benzodiazepine use, sleep parameters, and anxiety and depressive symptoms. RESULTS All three interventions produced significant reductions in both the quantity ( 90 % reduction ) and frequency ( 80 % reduction ) of benzodiazepine use, and 63 % of the patients were drug-free within an average of 7 weeks. More patients who received medication taper plus cognitive behavior therapy ( 85 % ) were benzodiazepine-free after the initial intervention, compared to those who received medication taper alone ( 48 % ) and cognitive behavior therapy alone ( 54 % ). The patients in the two groups that received cognitive behavior therapy perceived greater subjective sleep improvements than those who received medication taper alone. Polysomnographic data showed an increase in the amount of time spent in stages 3 and 4 sleep and REM sleep and a decrease in total sleep time across all three conditions from baseline to posttreatment. Initial benzodiazepine reductions were well maintained up to the 12-month follow-up, and sleep improvements became more noticeable over this period. No significant withdrawal symptoms or \ No newline at end of file +- eval_runtime: 820.6405 +- eval_samples_per_second: 2.463 +- eval_steps_per_second: 0.617 +- step: 0 + +## Model description + +More information needed + +## Intended uses & limitations + +More information needed + +## Training and evaluation data + +More information needed + +## Training procedure + +### Training hyperparameters + +The following hyperparameters were used during training: +- learning_rate: 2e-05 +- train_batch_size: 4 +- eval_batch_size: 4 +- seed: 42 +- gradient_accumulation_steps: 8 +- total_train_batch_size: 32 +- optimizer: Adam with betas=(0.9,0.999) and epsilon=1e-08 +- lr_scheduler_type: linear +- lr_scheduler_warmup_ratio: 0.1 +- num_epochs: 10 +- mixed_precision_training: Native AMP +- label_smoothing_factor: 0.1 + +### Framework versions + +- Transformers 4.21.0.dev0 +- Pytorch 1.10.0 +- Datasets 2.3.3.dev0 +- Tokenizers 0.12.1