tbuckley/cabot-search huggingface dataset:
Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture
Authors: Kenneth W. Lyles, Cathleen S. Colón-Emeric, Jay S. Magaziner, Jonathan D. Adachi, Carl F. Pieper, Carlos Mautalen, Lars Hyldstrup, Chris Recknor, Lars Nordsletten, Kathy A. Moore, Catherine Lavecchia, Jie Zhang, Peter Mesenbrink, Patricia K. Hodgson, Ken Abrams, John J. Orloff, Zebulun Horowitz, Erik Fink Eriksen, Steven Boonen
Journal: New England Journal of Medicine (2007)

Mortality is increased after a hip fracture, and strategies that improve outcomes are needed.In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture.The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups.An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].).
Sidestep cutting technique and knee abduction loading: implications for ACL prevention exercises
Authors: Eirik Kristianslund, Oliver Faul, Roald Bahr, Grethe Myklebust, Tron Krosshaug
Journal: British Journal of Sports Medicine (2012)

<h3>Background</h3> Sidestep cutting technique is essential in programmes to prevent anterior cruciate ligament (ACL) injury. A better understanding of how technique affects potentially harmful joint loading may improve prevention programmes. The purpose of this study was to investigate the effect of sidestep cutting technique on maximum knee abduction moments. <h3>Methods</h3> Cross-sectional study. Whole-body kinematics and knee joint kinetics were calculated in 123 female handball players (mean±SD, 22.5±7.0 years, 171±7 cm, 67±7 kg) performing sidestep cutting. Three cuts from each side were analysed. Linear regression was applied between selected technique factors and maximum knee abduction moment during the first 100 ms of the contact phase. Furthermore, we investigated to what degree the abduction moment originated from the magnitude of the ground reaction force (GRF) or the knee abduction moment arm of the GRF. <h3>Findings</h3> Technique factors explained 62% of the variance in knee abduction moments. Cut width, knee valgus, toe landing, approach speed and cutting angle were the most significant predictors. An increase in one of these factors of 1 SD increased the knee abduction moment from 12% to 19%. The effect of the moment arm of the GRF was more important than the force magnitude for maximum knee abduction moments. <h3>Interpretation</h3> Lower knee abduction loads during sidestep cutting may be achieved if cuts are performed as narrow cuts with low knee valgus and toe landings. These factors may be targeted in ACL injury prevention programmes.
Myelodysplastic Syndromes: It Is All in the Genes
Authors: Mikkael A. Sekeres
Journal: Journal of Clinical Oncology (2012)

REFERENCES 1. Hershman DL, Wilde ET, Wright JD, et al: Uptake and economic impact of first-cycle colony-stimulating factor use during adjuvant treatment of breast cancer. J Clin Oncol 30:806-812, 2012 2. Mukherjee S: The Emperor of All Maladies. New York, NY, Scribner, 2010, pp 423-429 3. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 4. Giordano SH, Duan Z, Kuo Y-F, et al: Impact of a scientific presentation on community treatment patterns for primary breast cancer. J Natl Cancer Inst 98:382-388, 2006 5. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 6. Muss HB, Berry DA, Cirrincione C, et al: Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: The Cancer and Leukemia Group B Experience. J Clin Oncol 25:3699-3704, 2007 7. Piccart-Gebhart MJ: Mathematics and oncology: A match for life? J Clin Oncol 21:1425-1428, 2003 8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005 9. Venturini M, Del Mastro L, Aitini E, et al: Dose-dense adjuvant chemotherapy in early breast cancer patients: Results from a randomized trial. J Natl Cancer Inst 97:1724-1733, 2005 10. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658-1667, 2006 11. Bonilla L, Ben-Aharon I, Vidal L, et al: Dose-dense chemotherapy in nonmetastatic breast cancer: A systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst 102:1845-1854, 2010 12. Citron ML: Dose-dense chemotherapy: Principles, clinical results and future perspectives. Breast Care (Basel) 3:251-255, 2008 13. Hershman D, Neugut AI, Jacobson JS, et al: Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 99:196-205, 2007 14. Smith TJ, Hillner BE: Bending the cost curve in cancer care. N Engl J Med 364:2060-2065, 2011 15. Goldhirsch A, Wood WC, Coates AS, et al: Strategies for subtypes: Dealing with the diversity of breast cancer—Highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 22:1736-1747, 2011
Non-invasive EEG-based brain-computer interfaces in patients with disorders of consciousness
Authors: Emilia Mikołajewska, Dariusz Mikołajewski
Journal: Military Medical Research (2014)

Disorders of consciousness (DoCs) are chronic conditions resulting usually from severe neurological deficits. The limitations of the existing diagnosis systems and methodologies cause a need for additional tools for relevant patients with DoCs assessment, including brain-computer interfaces (BCIs). Recent progress in BCIs' clinical applications may offer important breakthroughs in the diagnosis and therapy of patients with DoCs. Thus the clinical significance of BCI applications in the diagnosis of patients with DoCs is hard to overestimate. One of them may be brain-computer interfaces. The aim of this study is to evaluate possibility of non-invasive EEG-based brain-computer interfaces in diagnosis of patients with DOCs in post-acute and long-term care institutions.
Toxicology of Haloalkane Propellants and Fire Extinguishants
Authors: K C Back, E W V Stee
Journal: The Annual Review of Pharmacology and Toxicology (1977)

Low molecular weight halogenated alkanes, particularly certain fluoroalkanes, are of toxicological interest because of their industrial use as fire extinguishing agents, refrigerants, and solvents. Some fluoroalkanes also find use as aerosol propellants and are of interest to industrial and public health agencies because of widespread consumer use of pressurized household products and drugs. They also have a potential for abuse, particularly among drug-oriented youth. Another fluoroalkane, halothane, has been in common use in most hospitals since 1954 as an inhalation anesthetic. Pharmacologically significant exposure of the human organism to these com­ pounds, whether by design or accident, is usually by inhalation. Many compounds have a relatively high vapor pressure at ordinary conditions, so that they readily mix with air in pharmacologically significant concentrations. Fluoroalkanes readily diffuse through cell membranes because of their lipid solubility. Availability to the alveolar membrane, coupled with lipid solubility, results in a potential for quantita­ tively significant pulmonary absorption of fluoroalkanes. Fluoroalkanes as a rule are not pulmonary irritants. In low concentrations acute inhalation is not an unpleasant experience, nor does prolonged esposure result in pathological changes in the upper respiratory tract or lungs. In somewhat higher concentrations inspiration may be resisted, but this is likely to be a consequence of the activation of certain reflexes such as the Kratschmer reflex. A very extensive review of the literature concerning general fluorocarbon toxicity was written by Clayton in 1967 (1). More recently, in 1974, Aviado (2) reviewed
Importance of NAD(P)H Oxidase–Mediated Oxidative Stress and Contractile Type Smooth Muscle Myosin Heavy Chain SM2 at the Early Stage of Atherosclerosis
Authors: Shinichi Itoh, Seiji Umemoto, Mitsuyuki Hiromoto, Yoichi Toma, Yasuaki Tomochika, Shumpei Aoyagi, Masakazu Tanaka, Takashi Fujii, Masunori Matsuzaki
Journal: Circulation (2002)

Increased vascular oxidative stress induced by hyperlipidemia may alter the phenotype of vascular smooth muscle (SM) cells and play a crucial role in the progression of atherosclerosis. To clarify the mechanisms underlying vascular dysfunction and oxidative stress in hypercholesterolemia, we compared the effects of antioxidant probucol with those of pravastatin on aortic stiffness, phenotypic modulation, oxidative stress, and NAD(P)H oxidase essential subunit p22(phox) expression in aortic medial SM cells of cholesterol-fed rabbits by using color image analysis of immunostained sections.Japanese white male rabbits were fed either normal chow or 1% cholesterol diet for 14 weeks. After the first 7 weeks, cholesterol-fed rabbits were further divided into 3 groups: those fed with cholesterol feed only and those additionally given pravastatin (10 mg/d) or probucol (1.3 g/d) for the last 7 weeks. Within 7 weeks of treatment, probucol improved aortic stiffness more effectively than did pravastatin, inhibiting phenotypic modulation by selectively upregulating contractile-type SM myosin heavy chain isoform SM2 and by reducing both p22(phox) and superoxide content in medial SM cells of cholesterol-fed rabbit aorta. No significant differences in cholesterol levels, superoxide content, and endothelial NO synthase levels in the intima, aortic morphology and fibrosis, and synthetic-type myosin heavy chain in medial SM cells were observed between the 2 drug-treated groups.These results suggest that oxidative stress and SM2 in medial SM cells might be important factors for vascular dysfunction, and strategies aimed at blocking NAD(P)H oxidase and upregulating SM2 may have therapeutic potential against the progression of atherosclerosis in hypercholesterolemia.
The Insulin Receptor/Insulin-Like Growth Factor Receptor Family as a Therapeutic Target in Oncology
Authors: Michael Pollak
Journal: Clinical Cancer Research (2012)

Over the past decade, encouraging preclinical and early clinical data concerning the relevance of the insulin receptor/insulin-like growth factor (IGF) receptor family to neoplasia led to ambitious clinical trial programs of more than a dozen drug candidates that target these receptors. These candidates include antireceptor antibodies, antiligand antibodies, receptor-specific tyrosine kinase inhibitors, and agents such as picropodophyllin and metformin that have novel mechanisms of action. Several recently reported phase III clinical trials of anti-IGF-I receptor antibodies have been disappointing and are sufficient to disprove the hypothesis that the antibodies tested have large favorable impacts on unselected patients with cancer. However, many of these trials were designed prior to recent insights concerning pathophysiology and predictive biomarkers. Future studies are required, but it will be important to optimize their design rather than simply repeat the approaches taken to date.
Old drug, new tricks: haloperidol inhibits secretion of proinflammatory cytokines
Authors: R J Moots, Z Al-Saffar, D Hutchinson, S P Golding, S P Young, P A Bacon, P J McLaughlin
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVES</h3> It was noted that treatment of a patient with acute mania by haloperidol was associated with marked improvement in activity of rheumatoid arthritis. The objective of this study was to examine the effects of haloperidol on inflammatory cytokine release in vitro, as a potential mechanism to explain the in vivo anti-inflammatory effects of haloperidol. <h3>METHODS</h3> The effect of haloperidol on the production of inflammatory cytokines interleukin 1β (IL1β) and tumour necrosis factor α (TNFα) was measured in bacterial lipopolysaccharide stimulated whole blood cultures and on the promonocyte cell line THP-1, using commercial and in house enzyme linked immunosorbent assays to measure cytokine concentrations. <h3>RESULTS</h3> Haloperidol inhibited lipopolysaccharide stimulated production of both IL1β and TNFα in vitro in a dose dependent manner and over a prolonged time period. Marked inhibition was seen over a range of concentrations of haloperidol from 0.5 μg/ml to 50 μg/ml, including those predicted to occur in the patient’s blood. <h3>CONCLUSIONS</h3> Haloperidol treatment seemed to alleviate inflammation in rheumatoid arthritis. In vitro experiments would suggest that the mechanism is by direct inhibition of proinflammatory cytokine release. This phenomenon requires further investigation and may potentially lead to the development of novel treatment.
Independent prognostic significance of minimal residual disease status in chronic lymphocytic leukaemia
Authors: Marwan Kwok, Andy Rawstron, Abraham Varghese, Paul Evans, Sheila O'Connor, Chi Doughty, Darren Newton, Paul Moreton, Peter Hillmen
Journal: The Lancet (2014)

BackgroundEradication of minimal residual disease (MRD) is an independent predictor of survival outcome in patients with chronic lymphocytic leukaemia (CLL) receiving fludarabine and cyclophosphamide (FC) or fludarabine, cyclophosphamide, and rituximab (FCR) as first-line treatment. However, the independent prognostic relevance of MRD status in other therapeutic settings is not clear. The goal of this study was to investigate the independent importance of achieving MRD negativity in CLL on progression-free survival (PFS) and overall survival (OS) with different treatments in frontline and relapsed or refractory settings compared with known prognostic markers.MethodsWe included all patients at our centre in Leeds and associated hospitals in West and North Yorkshire who had completed treatment for CLL from 1996 to 2007, achieved at least a partial response, and received an MRD assessment from a bone-marrow specimen after treatment. MRD assessments were done by multiparametric flow cytometry using CD5–CD19 in combination with CD20, CD22, CD32, CD38, CD79b, and CD81 in accordance with the international harmonised approach. 133 patients (17 receiving fludarabine, 65 fludarabine-based combination therapies, 26 alemtuzumab, and 25 other treatment including chlorambucil and autologous stem-cell transplantation) were followed up for a median of 5·2 years (IQR 3·0–7·3) to assess PFS and OS.FindingsMRD negativity (defined as less than one CLL cell in 10 000 leucocytes) at the end of therapy independently correlated with both PFS (hazard ratio [HR] 3·22 [95% CI 2·09–4·97], Cox proportional hazards model p<0·001) and OS (1·62 [1·12–2·33], p=0·005) in multivariate analysis when analysed against age, disease stage, adverse cytogenetics ([del]17p, [del]11q, or both deletions), previous therapy, the type and line of therapy, clinical response, and cytopenia. Clinical response was significant in univariate analysis for PFS and OS but not in multivariate analysis. The greatest effect of achieving MRD negativity was seen in patients receiving first-line treatment (n=57), with 5-year PFS of 81% in MRD-negative patients (n=24) versus 16% in MRD-positive (n=33) patients and 10-year OS of 53% versus 24%, respectively. MRD-negative patients with (del)17p, (del)11q, or both achieved better PFS (median 59 months vs 31) and OS (78 vs 64) than did MRD-positive individuals without such adverse cytogenetic abnormalities.InterpretationMRD status is a powerful independent predictor of survival outcome in CLL across a range of therapeutic approaches including in frontline and relapse settings. MRD negativity is the most appropriate therapeutic goal for CLL patients who are fit enough for such an approach.FundingNone.
Defining airflow obstruction
Authors: Martin R. Miller
Journal: European Respiratory Journal (2015)

The authors of the article published recently in the European Respiratory Journal on the prevalence and correlates of airflow obstruction in >317 000 never-smoking Chinese subjects concluded that they found inconsistent associations with exposures to household air pollution and went on to outline what future work needed to be done [1]. In the first instance, they should present table 5 having reanalysed their data using just lower limits of normal (LLNs) to define airflow obstruction. Their figure 3 shows the expected underdiagnosis of airflow obstruction in those aged <55 years when using the Global Initiative for Chronic Obstructive Lung (GOLD) criterion of forced expiratory volume in 1 s/forced vital capacity <0.7 when compared with the LLN. Probably just over half their subjects are below this age. All further analysis in table 5 of their paper [1] used the flawed [2] GOLD definition. The authors state that because the baseline variables in table 4 (apart from age) had similar associations with airflow obstruction by the two definitions (GOLD and LLN), they only went on to use the GOLD definition. In doing so, their analysis only included 10 325 subjects (table 3) who had airflow obstruction by the GOLD definition and the additional 8166 who had airflow obstruction by LLN were classed in their analysis as "no obstruction", and so will confound and defeat any analysis looking for associations between markers of indoor pollution and airflow obstruction. They must rerun their analysis using all 18 491 subjects with airflow obstruction by LLN. A presentation at the 2014 European Respiratory Society International Congress, Neupane et al. [3] found that in female Nepalese cooks, they could not detect a significant association between indoor pollution and airflow obstruction when using the GOLD criteria but they did find a significant association when using LLN criteria. Using the GOLD rather than LLN to define obstruction may reduce studies' power to detect associations with exposures <http://ow.ly/DgZW9>
Complement receptor mediates enhanced flavivirus replication in macrophages.
Authors: M J Cardosa, J S Porterfield, S Gordon
Journal: The Journal of Experimental Medicine (1983)

Evidence is presented that M phi complement receptors (CR3) mediate IgM-dependent enhancement of flavivirus replication in the presence of complement. Enhancement is blocked by pretreatment of macrophages with monoclonal antibody Ml/70, which inhibits CR3 binding, but not by pretreatment with monoclonal antibody 2.4G2, which inhibits FcR binding.
Effects of exposure to CS
Authors: R B Douglas
Journal: Journal of the Royal Society of Medicine (2003)

Karagama and co-workers (April 2003 JRSM1) looked for physical sequelae in thirty-four individuals exposed to CS spray within the confines of a single decked 72-seat coach. Usefully, they divided the cohort into individuals with exposure directly onto the face and individuals with indirect exposure within the confined environment. They recorded the symptoms experienced one hour, one month, and ten months after exposure. As might have been expected,2 the main symptoms were ocular (10 out of 10 exposed directly and 22 out of 24 exposed indirectly) followed by respiratory (10 out of 10 for the direct group and 13 out of 24 for the indirect group). Only 1 of the indirect group reported a rash whereas 3 out of 10 of the direct group reported rashes. This would concur with the report of Schmutz et al.3 regarding cutaneous accidents with CS and CN: these workers concluded that, when properly suspended in air, these agents mainly affect the eyes and have only minor effects on the skin, whereas when applied directly onto the skin they produce extreme irritation with erythema and vesicles. The effects seem to develop in two stages. First there is redness and a burning sensation on the face; then, next day, oedema ensues with swelling of the eyelids. Oozing rapidly turns to crusts and, in the absence of treatment, infection is the rule. In a recent case I was supplied with dated serial colour photographs that fitted the above description. The lesions were unilateral, indicating use at very short range (also reported by Schmutz). In two previous cases, photographic evidence was lacking but the general practitioner's description in the medical records was similar and he had prescribed antibiotics prophylactically.

In their follow-up examinations at 8-10 months, Karagama et al. found no differences between the directly and indirectly exposed groups for respiratory or other effects, and they conclude that there was no convincing evidence of long-term physical sequelae. However, the possibility of long-term respiratory damage cannot always readily be dismissed. In 1992 Hu and Christiana4 reported a case in which a previously healthy woman aged 21 with no wheezing or asthma or family history of asthma or atopy was inadvertently exposed to CS gas in a nightclub. From the results of spirometry over time and the response to treatment with the appropriate medication together with monitored symptoms they diagnosed the development of RADS (reactive airways dysfunction syndrome), a non-specific form of asthma that typically follows a single massive exposure to an irritant.
Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial
Authors: Willem Kuyken, Rachel Hayes, Barbara Barrett, Richard Byng, Tim Dalgleish, David Kessler, Glyn Lewis, Edward Watkins, Claire Brejcha, Jessica Cardy, Aaron Causley, Suzanne Cowderoy, Alison Evans, Felix Gradinger, Surinder Kaur, Paul Lanham, Nicola Morant, Jonathan Richards, Pooja Shah, Harry Sutton, Rachael Vicary, Alice Weaver, Jenny Wilks, Matthew Williams, Rod S Taylor, Sarah Byford
Journal: The Lancet (2015)