query: Having a main partner worsens HIV outcomes.

title: Stable partnership and progression to AIDS or death in HIV infected patients receiving highly active antiretroviral therapy: Swiss HIV cohort study.

text:
OBJECTIVES To explore the association between a stable partnership and clinical outcome in HIV infected patients receiving highly active antiretroviral therapy (HAART).
 DESIGN Prospective cohort study of adults with HIV (Swiss HIV cohort study).
 SETTING Seven outpatient clinics throughout Switzerland.
 PARTICIPANTS The 3736 patients in the cohort who started HAART before 2002 (median age 36 years, 29% female, median follow up 3.6 years).
 MAIN OUTCOME MEASURES Time to AIDS or death (primary endpoint), death alone, increases in CD4 cell count of at least 50 and 100 above baseline, optimal viral suppression (a viral load below 400 copies/ml), and viral rebound.
 RESULTS During follow up 2985 (80%) participants reported a stable partnership on at least one occasion. When starting HAART, 52% (545/1042) of participants reported a stable partnership; after five years of follow up 46% (190/412) of participants reported a stable partnership. In an analysis stratified by previous antiretroviral therapy and clinical stage when starting HAART (US Centers for Disease Control and Prevention group A, B, or C), the adjusted hazard ratio for progression to AIDS or death was 0.79 (95% confidence interval 0.63 to 0.98) for participants with a stable partnership compared with those without. Adjusted hazards ratios for other endpoints were 0.59 (0.44 to 0.79) for progression to death, 1.15 (1.06 to 1.24) for an increase in CD4 cells of 100 counts/microl or more, and 1.06 (0.98 to 1.14) for optimal viral suppression.
 CONCLUSIONS A stable partnership is associated with a slower rate of progression to AIDS or death in HIV infected patients receiving HAART.

title: Hepatitis C virus infection in a large cohort of homosexually active men: independent associations with HIV-1 infection and injecting drug use but not sexual behaviour.

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OBJECTIVE To determine the prevalence and risk factors for hepatitis C virus (HCV) infection in a cohort of homosexually active men, with particular reference to assessing sexual transmission.
 DESIGN Prevalence based on cross-sectional testing for HCV (c100 protein) antibody in a cohort using sera stored between 1984 and 1989, and assessment of risk factors using a case-control analysis based on questionnaire data from HCV positive and negative subjects.
 SUBJECTS/SETTING 1038 homosexually active men who were participating in a prospective study established to identify risk factors for AIDS. They had been recruited through private and public primary care and sexually transmissible disease (STD) services in central Sydney.
 MAIN OUTCOME MEASURES Prevalence of HCV antibody and its association with human immunodeficiency virus type 1 (HIV-1) infection and other STDs, number of sexual partners, sexual practices and recreational drug use.
 RESULTS Overall, 7.6% of subjects tested were seropositive for HCV antibody. In univariate analysis, HCV infection was significantly associated with injecting drug use (IDU) (OR = 8.18, p < 0.0001) and HIV infection (OR = 3.14, p < 0.0001) and with self reported history of syphilis (OR = 1.88, p = 0.016), anogenital herpes (OR = 1.93, p = 0.017), gonorrhoea (OR = 2.43, p = 0.009) and hepatitis B (OR = 1.92, p = 0.010). In case control analysis, similar sexual behaviours (partner numbers and practices) were reported by HCV positive and HCV negative subjects except that HCV negative subjects more frequently reported engaging than HCV positive subject in unprotected receptive anal intercourse without ejaculation (OR = 0.61, p = 0.034), unprotected insertive (OR = 0.59, p = 0.039) and receptive (OR = 0.56, p = 0.016) oro-anal intercourse (rimming) and insertive fisting (OR = 0.48, p = 0.034). In multiple logistic regression analyses, only HIV-1 infection (OR = 3.18, p < 0.0001) and IDU in the previous six months (OR = 7.24, p < 0.0001) remained significantly associated with the presence of HCV antibody.
 CONCLUSIONS IDU was the major behavioural risk factor for HCV infection. If sexual or another from of transmission did occur, it may have been facilitated by concurrent HIV-1 infection.

title: Prevalence of Kaposi sarcoma-associated herpesvirus infection in homosexual men at beginning of and during the HIV epidemic.

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CONTEXT Some studies have inferred that an epidemic of Kaposi sarcoma-associated herpesvirus (KSHV) infection in homosexual men in the United States occurred concurrently with that of human immunodeficiency virus (HIV), but there have been no direct measurements of KSHV prevalence at the beginning of the HIV epidemic.
 OBJECTIVES To determine the prevalence of KSHV infection in homosexual men in San Francisco, Calif, at the beginning of the HIV epidemic in 1978 and 1979 and to examine changes in prevalence of KSHV at time points from 1978 through 1996 in light of changes in sexual behavior.
 DESIGN, SETTING, AND PARTICIPANTS Analysis of a clinic-based sample (n = 398) derived from the San Francisco City Clinic Cohort (ages 18-66 years) (n = 2666 for analyses herein) and from population-based samples from the San Francisco Men's Health Study (MHS) (ages 25-54 years) (n = 825 and 252) and the San Francisco Young Men's Health Study (YMHS) (ages 18-29 years) (n = 428-976, and 557); behavioral studies were longitudinal and KSHV prevalence studies were cross-sectional.
 MAIN OUTCOME MEASURES Antibodies against KSHV and HIV; sexual behaviors.
 RESULTS The prevalence of KSHV infection in 1978 and 1979 was 26.5% of 235 (a random sample) overall (weighted for HIV infection) vs 6.9% (128/1842) for HIV in the San Francisco City Clinic Cohort sample. The prevalence of KSHV infection remained essentially unchanged between an MHS sample of 252 in 1984 and 1985 (29.6%) and a YMHS sample of 557 in 1995 and 1996 (26.4%), while HIV prevalence dropped from 49.5% of 825 in 1984 and 1985 (MHS) to 17.6% of 428 in 1992 and 1993 (YMHS). The proportion of men practicing unprotected receptive anal intercourse with 1 or more partners declined from 54% to 11% during the 1984 through 1993 period (MHS) with similar though slightly higher values in the YMHS in 1992 and 1993; whereas for unprotected oral intercourse it ranged between 60% and 90% in the 1984 through 1996 period (MHS and YMHS).
 CONCLUSIONS Infection with KSHV was already highly prevalent in homosexual men when the HIV epidemic began in San Francisco, and its prevalence has been maintained at a nearly constant level. Any declines in the incidence of Kaposi sarcoma do not appear to be caused by a decline in KSHV transmission.

title: Caregiver burden in HIV-positive and HIV-negative partners of men with AIDS.

text: This study examines factors associated with caregiver burden in 82 HIV-positive (HIV+) and 162 HIV-negative (HIV-) partners of men with AIDS. We expected HIV+ caregivers to report more burden than HIV- caregivers because of the toll of their disease on their resources. HIV+ caregivers did report more burden and, compared with the HIV- caregivers, they were more religious or spiritual, had less income, and coped by using more positive reappraisal and cognitive escape-avoidance and by seeking social support. Comparisons of HIV+ caregivers with 61 HIV+ partners of healthy men indicated that most differences between HIV+ and HIV- caregivers were associated with HIV seropositivity rather than caregiving. However, of the variables associated with HIV seropositivity, only religiosity or spirituality contributed independently to burden in HIV+ caregivers, suggesting a relatively weak link between HIV seropositivity and caregiver burden. The model explained 62% of the variance in burden in HIV+ caregivers and 36% of the variance in HIV- caregivers.

title: Patient Outcomes with Teaching Versus Nonteaching Healthcare: A Systematic Review

text: Background  Extensive debate exists in the healthcare community over whether outcomes of medical care at teaching hospitals and other healthcare units are better or worse than those at the respective nonteaching ones. Thus, our goal was to systematically evaluate the evidence pertaining to this question.       Methods and Findings  We reviewed all studies that compared teaching versus nonteaching healthcare structures for mortality or any other patient outcome, regardless of health condition. Studies were retrieved from PubMed, contact with experts, and literature cross-referencing. Data were extracted on setting, patients, data sources, author affiliations, definition of compared groups, types of diagnoses considered, adjusting covariates, and estimates of effect for mortality and for each other outcome. Overall, 132 eligible studies were identified, including 93 on mortality and 61 on other eligible outcomes (22 addressed both). Synthesis of the available adjusted estimates on mortality yielded a summary relative risk of 0.96 (95% confidence interval [CI], 0.93–1.00) for teaching versus nonteaching healthcare structures and 1.04 (95% CI, 0.99–1.10) for minor teaching versus nonteaching ones. There was considerable heterogeneity between studies (I2 = 72% for the main analysis). Results were similar in studies using clinical and those using administrative databases. No differences were seen in the 14 studies fully adjusting for volume/experience, severity, and comorbidity (relative risk 1.01). Smaller studies did not differ in their results from larger studies. Differences were seen for some diagnoses (e.g., significantly better survival for breast cancer and cerebrovascular accidents in teaching hospitals and significantly better survival from cholecystectomy in nonteaching hospitals), but these were small in magnitude. Other outcomes were diverse, but typically teaching healthcare structures did not do better than nonteaching ones.       Conclusions  The available data are limited by their nonrandomized design, but overall they do not suggest that a healthcare facility's teaching status on its own markedly improves or worsens patient outcomes. Differences for specific diseases cannot be excluded, but are likely to be small.

title: Integrating nutrition security with treatment of people living with HIV: lessons from Kenya.

text:
BACKGROUND The increased caloric requirements of HIV-positive individuals, undesirable side effects of treatment that may be worsened by malnutrition (but alleviated by nutritional support), and associated declines in adherence and possible increased drug resistance are all justifications for developing better interventions to strengthen the nutrition security of individuals receiving antiretroviral treatment.
 OBJECTIVE To highlight key benefits and challenges relating to interventions aimed at strengthening the nutrition security of people living with HIV who are receiving antiretroviral treatment.
 METHODS Qualitative research was undertaken on a short-term nutrition intervention linked to the provision of free antiretroviral treatment for people living with HIV in western Kenya in late 2005 and early 2006.
 RESULTS Patients enrolled in the food program while on treatment regimens self-reported greater adherence to their medication, fewer side effects, and a greater ability to satisfy increased appetite. Most clients self-reported weight gain, recovery of physical strength, and the resumption of labor activities while enrolled in dual (food supplementation and treatment) programs. Such improvements were seen to catalyze increased support from family and community.
 CONCLUSIONS These findings provide further empirical support to calls for a more holistic and comprehensive response to the coexistence of AIDS epidemics with chronic nutrition insecurity. Future work is needed to clarify ways of bridging the gap between short-term nutritional support to individuals and longer-term livelihood security programming for communities affected by AIDS. Such interdisciplinary research will need to be matched by intersectoral action on the part of the agriculture and health sectors in such environments.

title: Variation in antibiotic prescribing and its impact on recovery in patients with acute cough in primary care: prospective study in 13 countries.

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OBJECTIVE To describe variation in antibiotic prescribing for acute cough in contrasting European settings and the impact on recovery.
 DESIGN Cross sectional observational study with clinicians from 14 primary care research networks in 13 European countries who recorded symptoms on presentation and management. Patients followed up for 28 days with patient diaries.
 SETTING Primary care.
 PARTICIPANTS Adults with a new or worsening cough or clinical presentation suggestive of lower respiratory tract infection.
 MAIN OUTCOME MEASURES Prescribing of antibiotics by clinicians and total symptom severity scores over time.
 RESULTS 3402 patients were recruited (clinicians completed a case report form for 99% (3368) of participants and 80% (2714) returned a symptom diary). Mean symptom severity scores at presentation ranged from 19 (scale range 0 to 100) in networks based in Spain and Italy to 38 in the network based in Sweden. Antibiotic prescribing by networks ranged from 20% to nearly 90% (53% overall), with wide variation in classes of antibiotics prescribed. Amoxicillin was overall the most common antibiotic prescribed, but this ranged from 3% of antibiotics prescribed in the Norwegian network to 83% in the English network. While fluoroquinolones were not prescribed at all in three networks, they were prescribed for 18% in the Milan network. After adjustment for clinical presentation and demographics, considerable differences remained in antibiotic prescribing, ranging from Norway (odds ratio 0.18, 95% confidence interval 0.11 to 0.30) to Slovakia (11.2, 6.20 to 20.27) compared with the overall mean (proportion prescribed: 0.53). The rate of recovery was similar for patients who were and were not prescribed antibiotics (coefficient -0.01, P<0.01) once clinical presentation was taken into account.
 CONCLUSIONS Variation in clinical presentation does not explain the considerable variation in antibiotic prescribing for acute cough in Europe. Variation in antibiotic prescribing is not associated with clinically important differences in recovery.
 TRIAL REGISTRATION Clinicaltrials.gov NCT00353951.

title: Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection.

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CONTEXT Use of antiretroviral drugs, including protease inhibitors, for treatment of human immunodeficiency virus (HIV) infection has been anecdotally associated with hepatotoxicity, particularly in persons coinfected with hepatitis C or B virus.
 OBJECTIVES To ascertain if incidence of severe hepatotoxicity during antiretroviral therapy is similar for all antiretroviral drug combinations, and to define the role of chronic viral hepatitis in its development.
 DESIGN Prospective cohort study.
 SETTING University-based urban HIV clinic.
 PATIENTS A total of 298 patients who were prescribed new antiretroviral therapies between January 1996 and January 1998, 211 (71%) of whom received protease inhibitors as part of combination therapy (median follow-up, 182 days) and 87 (29%) of whom received dual nucleoside analog regimens (median follow-up, 167 days). Chronic hepatitis C and B virus infection was present in 154 (52%) and 8 (2.7%) patients, respectively.
 MAIN OUTCOME MEASURE Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of serum alanine aminotransferase and aspartate aminotransferase, evaluated before and during therapy.
 RESULTS Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients (95% confidence interval [CI], 7.2%-14.4%). Ritonavir use was associated with a higher incidence of toxicity (30%; 95% CI, 17.9% -44.6%). However, no significant difference was detected in hepatotoxicity incidence in other treatment groups, ie, nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI, 1.2%-16.2%), saquinavir (5.9%; 95% CI, 0.15%-28.7%), and indinavir(6.8%; 95% CI, 3.0%-13.1 %). Although chronicviral hepatitis was associated with an increased risk of severe hepatotoxicity among patients prescribed nonritonavir regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic hepatitis C or B virus infection (88%) did not experience significant toxic effects. Rate of severe toxicity with use of any protease inhibitor in patients with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). In multivariate logistic regression, only ritonavir (adjusted odds ratio [AOR], 8.6; 95% CI, 3.0-24.6) and a CD4 cell count increase of more than 0.05 x 10(9)/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated with severe hepatotoxicity. No irreversible outcomes were seen in patients with severe hepatotoxicity.
 CONCLUSIONS Our data indicate that use of ritonavir may increase risk of severe hepatotoxicity. Although hepatotoxicity may be more common in persons with chronic viral hepatitis, these data do not support withholding protease inhibitor therapy from persons coinfected with hepatitis B or C virus.

title: Immunophenotypic analysis of AIDS-related diffuse large B-cell lymphoma and clinical implications in patients from AIDS malignancies consortium clinical trials 010 and 034

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PURPOSE Diffuse large B-cell lymphoma (DLBCL) represents a clinically heterogeneous disease. Models based on immunohistochemistry predict clinical outcome. These include subdivision into germinal center (GC) versus non-GC subtypes; proliferation index (measured by expression of Ki-67), and expression of BCL-2, FOXP1, or B-lymphocyte-induced maturation protein (Blimp-1)/PRDM1. We sought to determine whether immunohistochemical analyses of biopsies from patients with DLBCL having HIV infection are similarly relevant for prognosis.
 PATIENTS AND METHODS We examined 81 DLBCLs from patients with AIDS in AMC010 (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] v CHOP-rituximab) and AMC034 (etoposide, doxorubicin, vincristine, prednisone, and dose-adjusted cyclophosphamide plus rituximab concurrent v sequential) clinical trials and compared the immunophenotype with survival data, Epstein-Barr virus (EBV) positivity, and CD4 counts.
 RESULTS The GC and non-GC subtypes of DLBCL did not differ significantly with respect to overall survival or CD4 count at cancer presentation. EBV could be found in both subtypes of DLBCL, although less frequently in the GC subtype, and did not affect survival. Expression of FOXP1, Blimp-1/PRDM1, or BCL-2 was not correlated with the outcome in patients with AIDS-related DLBCL.
 CONCLUSION These data indicate that with current treatment strategies for lymphoma and control of HIV infection, commonly used immunohistochemical markers may not be clinically relevant in HIV-infected patients with DLBCL. The only predictive immunohistochemical marker was found to be Ki-67, where a higher proliferation index was associated with better survival, suggesting a better response to therapy in patients whose tumors had higher proliferation rates.


query: HbA1c consistently overestimates glycemic control in black individuals with Sickle cell trait (SCT).

title: Association of Sickle Cell Trait With Hemoglobin A1c in African Americans

text: Importance Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. Objective To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans. Design, Setting, and Participants Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. Exposures Presence of SCT. Main Outcomes and Measures Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure. Results The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, −0.29%; 95% CI, −0.35% to −0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of −0.30% (95% CI, −0.39% to −0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons). Conclusions and Relevance Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.

title: Reversing the tide — diagnosis and prevention of T2DM in populations of African descent

text: Abstract | Populations of African descent are at the forefront of the worldwide epidemic of type 2 diabetes mellitus (T2DM). The burden of T2DM is amplified by diagnosis after preventable complications of the disease have occurred. Earlier detection would result in a reduction in undiagnosed T2DM, more accurate statistics, more informed resource allocation and better health. An underappreciated factor contributing to undiagnosed T2DM in populations of African descent is that screening tests for hyperglycaemia, specifically, fasting plasma glucose and HbA1c, perform sub‐optimally in these populations. To offset this problem, combining tests or adding glycated albumin (a nonfasting marker of glycaemia), might be the way forward. However, differences in diet, exercise, BMI, environment, gene‐environment interactions and the prevalence of sickle cell trait mean that neither diagnostic tests nor interventions will be uniformly effective in individuals of African, Caribbean or African‐American descent. Among these three populations of African descent, intensive lifestyle interventions have been reported in only the African‐American population, in which they have been found to provide effective primary prevention of T2DM but not secondary prevention. Owing to a lack of health literacy and poor glycaemic control in Africa and the Caribbean, customized lifestyle interventions might achieve both secondary and primary prevention. Overall, diagnosis and prevention of T2DM requires innovative strategies that are sensitive to the diversity that exists within populations of African descent.

title: Advantages and pitfalls of fructosamine and glycated albumin in the diagnosis and treatment of diabetes.

text: The efficient diagnosis and accurate monitoring of diabetic patients are cornerstones for reducing the risk of diabetic complications. The current diagnostic and prognostic strategies in diabetes are mainly based on two tests, plasma (or capillary) glucose and glycated hemoglobin (HbA1c). Nevertheless, these measures are not foolproof, and their clinical usefulness is biased by a number of clinical and analytical factors. The introduction of other indices of glucose homeostasis in clinical practice such as fructosamine and glycated albumin (GA) may be regarded as an attractive alternative, especially in patients in whom the measurement of HbA1c may be biased or even unreliable. These include patients with rapid changes of glucose homeostasis and larger glycemic excursions, and patients with red blood cell disorders and renal disease. According to available evidence, the overall diagnostic efficiency of GA seems superior to that of fructosamine throughout a broad range of clinical settings. The current method for measuring GA is also better standardized and less vulnerable to preanalytical variables than those used for assessing fructosamine. Additional advantages of GA over HbA1c are represented by lower reagent cost and being able to automate the GA analysis on many conventional laboratory instruments. Although further studies are needed to definitely establish that GA can complement or even replace conventional measures of glycemic control such as HbA1c, GA may help the clinical management of patients with diabetes in whom HbA1c values might be unreliable.

title: The prevalence of congenital malformations is still higher in pregnant women with pregestational diabetes despite near-normal HbA1c: a literature review.

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AIMS/HYPOTHESIS We assessed the association between congenital malformations and maternal hyperglycemia in pregnant women with pregestational (type 1 or type 2) diabetes and investigated if the rate of congenital malformations was similar in women with near-normal glycemic control compared to the background population. We also assessed the association between congenital malformations and maternal hyperglycemia in pregnant women with pregestational diabetes with special focus on women with near-normal HbA1c in early pregnancy.    MATERIALS AND METHODS This is a literature review based on an electronic literature search of the databases PubMed, Cochrane, Embase and Web of Science conducted in July 2017 using the search terms diabetes, pregnancy, HbA1c or glycemic control and congenital anomaly or congenital anomaly. We included original papers in English published after 1997 with data on congenital malformations and HbA1c in at least 250 women with pregestational diabetes.
 RESULTS Nine papers with in total 6225 women with type 1 diabetes and 2334 women with type 2 diabetes were included. The prevalence of congenital malformations was 6.4% in women with type 1 diabetes and 4.3% in women with type 2 diabetes and for the combined group of women with pregestational diabetes, the relative risk compared to the background population was 3.2. In women with HbA1c < 53 mmol/mol (7.0%) in early pregnancy or HbA1c 53-64 mmol/mol (7.0-8.0%) the prevalence of congenital malformations was 4.3 and 3.7%, respectively, with a relative risk of 2.2 and 1.9, respectively.
 CONCLUSIONS In pregnant women with pregestational diabetes the prevalence of congenital abnormalities was threefold higher in women with pregestational diabetes compared to the background population. However, HbA1c below 53 mmol/mol (7.0%) in early pregnancy was also associated with a two times increased risk of congenital malformations compared to the background population.

title: Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial

text: Importance Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection. Objectives To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes. Design, Setting, and Patients Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use. Interventions Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks. Main Outcomes and Measures The primary end point was change in hemoglobing A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events. Results Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, −0.7% to −1.9%) and subcutaneous semaglutide (−1.9%) and placebo (−0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, –0.4% to –1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, −2.1 kg to −6.9 kg) and subcutaneous semaglutide (−6.4 kg) vs placebo (−1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, –0.9 to –5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common. Conclusions and Relevance Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety. Trial Registration clinicaltrials.gov Identifier: NCT01923181

title: Fructosamine Is a Useful Indicator of Hyperglycaemia and Glucose Control in Clinical and Epidemiological Studies – Cross-Sectional and Longitudinal Experience from the AMORIS Cohort

text:
CONTEXT Fructosamine is a glycemic biomarker which may be useful for indication and control of diabetes respectively.
 OBJECTIVE The objective of the study was to evaluate fructosamine as an indicator of hyperglycaemia and glucose control in subjects with diabetes.
 DESIGN, SETTING & PATIENTS From the AMORIS cohort, subjects with serum glucose, fructosamine and HbA1c from the same examination were studied cross-sectionally and longitudinally (n = 10,987; 5,590 overnight-fasting). The guidelines of the American Diabetes Association were followed for classification of prediabetes and diabetes. Separate analyses were performed in patients with a newly detected or a known diagnosis of type 1 or type 2 diabetes respectively.
 RESULTS All three biomarkers were strongly correlated. With regard to the association between fructosamine and HbA1c Pearson linear correlation coefficients in the range of 0.67-0.75 were observed in fasting and non-fasting subjects with type 1 or type 2 diabetes. Analyses of glucose control in fasting patients with type 2 diabetes having all three biomarkers measured at three separate occasions within on average 290 days of the index examination showed similar trends over time for glucose, fructosamine and HbA1c. Discrimination of subjects with and without diabetes across the range of fructosamine levels was good (area under curve (AUC) 0.91-0.95) and a fructosamine level of 2.5 mmol/L classified subjects to diabetes with a sensitivity of 61% and a specificity of 97%.
 CONCLUSIONS Fructosamine is closely associated with HbA1c and glucose respectively and may be a useful biomarker of hyperglycaemia and glucose control in clinical and epidemiological studies.

title: Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial.

text:
CONTEXT Observational studies suggest that surgically induced loss of weight may be effective therapy for type 2 diabetes.
 OBJECTIVE To determine if surgically induced weight loss results in better glycemic control and less need for diabetes medications than conventional approaches to weight loss and diabetes control.
 DESIGN, SETTING, AND PARTICIPANTS Unblinded randomized controlled trial conducted from December 2002 through December 2006 at the University Obesity Research Center in Australia, with general community recruitment to established treatment programs. Participants were 60 obese patients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes.
 INTERVENTIONS Conventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustable gastric banding with conventional diabetes care.
 MAIN OUTCOME MEASURES Remission of type 2 diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA1c] value <6.2% while taking no glycemic therapy). Secondary measures included weight and components of the metabolic syndrome. Analysis was by intention-to-treat.
 RESULTS Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up. Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group. Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001). Remission of type 2 diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2 = 0.52, P < .001). There were no serious complications in either group.
 CONCLUSIONS Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss. These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed.
 TRIAL REGISTRATION actr.org Identifier: ACTRN012605000159651.

title: Hyperglycemia is associated with increased bone mineral density and decreased trabecular bone score in elderly Japanese men: The Fujiwara-kyo osteoporosis risk in men (FORMEN) study.

text:
PURPOSE Patients with type 2 diabetes mellitus (T2DM) have an increased fracture risk despite having higher areal bone mineral density (aBMD). This study aimed to clarify the association between glycemic and insulin resistance status and bone microarchitecture, and whether pentosidine and bone turnover markers play any roles in the association.
 METHODS A total of 2012 community-dwelling men aged ≥65years completed baseline measurements of spine aBMD, fasting plasma glucose (FPG) and serum insulin, hemoglobin A1c (HbA1c), osteocalcin, type I procollagen N-terminal propeptide, type I collagen C-terminal crosslinking telopeptide, tartrate-resistant acid phosphatase isoenzyme 5b, pentosidine, height and weight and an interview regarding past disease history. Homeostasis model assessment-insulin resistance (HOMA-IR) was also calculated. T2DM was defined as physician-diagnosed middle age or elderly-onset diabetes mellitus, or according to biochemical test results. To evaluate bone microarchitecture, trabecular bone score (TBS) was calculated at the same vertebrae as those used for aBMD measurement.
 RESULTS After excluding participants who had a disease history and/or were taking medications affecting bone metabolism, 1683 men (age, 72.9±5.2years) were analyzed. Men with T2DM had significantly higher aBMD compared to those without T2DM. There was no significant difference in TBS. However, FPG, HbA1c and HOMA-IR levels were significantly inversely correlated with TBS after adjusting for age, BMI and aBMD. Multivariate linear regression analyses revealed that glycemic indices (FPG and HbA1c) were significantly associated with increased aBMD and decreased TBS, and that HOMA-IR was associated only with TBS. These associations did not change after further adjusting for bone turnover makers and pentosidine levels.
 CONCLUSIONS Hyperglycemia and elevated insulin-resistance were associated with low TBS independently of bone turnover and pentosidine levels.

title: Hemoglobin concentration in white, black, and Oriental children: is there a need for separate criteria in screening for anemia?

text: The concentration of hemoglobin in blacks was found to be 0.5 to 1.0 g/dl lower than that of income-matched whites in several large surveys. This difference could be a racial characteristic of blacks, or it might be due to a higher frequency of genetic traits such as thalassemia minor and hemoglobinopathies, or to environmental factors such as iron deficiency. To help in making this distinction, we analyzed the data from multiphasic examinations (1973 to 1975) on 1718 white, 741 black, and 315 Oriental healthy, nonindigent children between 5 and 14 years of age. In the entire population, the median hemoglobin concentration averaged 0.5 g/dl lower in blacks than in whites of both sexes (t test, P less than 0.001). The differences still averaged 0.5 g/dl (P less than 0.001) after exclusion of all those with abnormal hemoglobin by electrophoresis (Hgb S and C) and those whose mean corpuscular volume was more than 5% below the normal mean for age (to exclude iron deficiency or thalassemia minor). The data strengthen the impression that blacks normally have a concentration of hemoglobin averaging about 0.5 g/dl less than in whites. If this is the case, about 10% of normal blacks will be mistakenly designated anemic, if the same norms are applied.

title: Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes.

text: Bile acids are recognized as metabolic modulators. The present study was aimed at evaluating the effects of a potent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acid concentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreased HbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 and three-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines and the liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucose lowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in the distal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetes mellitus.

title: Development of leukemia in donor cells after allogeneic stem cell transplantation--a survey of the European Group for Blood and Marrow Transplantation (EBMT).

text: Leukemia in donor cells (donor cell leukemia; DCL) has been reported as a rare but severe complication of allogeneic stem cell transplantation (SCT). However, the incidence, potential pathogenetic factors, therapeutic options and outcome of patients suffering from DCL and the leukemia risk of their donors are not well defined. A questionnaire survey was carried out within European Blood and Marrow Transplantation Group (EBMT) centers. Ninety-one EBMT centers participated in this survey, covering 10489 allogeneic SCT between 12/1982 and 09/2003. Fourteen cases of DCL, most with a myeloid phenotype (7 cases of acute myeloid leukemia, 3 each of acute lymphocytic leukemia and 1 case of chronic myeloid leukemia) were identified. Demonstration of donor cell origin included molecular analysis of chimerism in most cases. DCL type and cytogenetic alterations were independent from the original disease. The median time between transplantation and diagnosis of DCL was 17 months (4-164). No type of conditioning, donor, graft manipulation, graft-versus-host disease prophylaxis or subsequent complications were identified as risk factors for DCL. Chemotherapy induced remissions in DCL and 2 of 5 patients remain alive in remission after a second transplant. None of the stem cell donors developed hematologic malignancies (median follow-up period of 9 years; range 6-30 years). DCL is an extremely rare complication of allogeneic SCT in which treatment attempts with chemotherapy and a second SCT are justified. Donors are not at an increased risk of developing hematologic malignancies.

title: Longitudinal Genome-Wide Association of Cardiovascular Disease Risk Factors in the Bogalusa Heart Study

text: Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are pre-symptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P = 9.7 x 10(-24)), and rs445925 at APOE with LDL levels (combined P = 8.7 x 10(-19)). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children.

title: Rare Variants Create Synthetic Genome-Wide Associations

text: Genome-wide association studies (GWAS) have now identified at least 2,000 common variants that appear associated with common diseases or related traits (http://www.genome.gov/gwastudies), hundreds of which have been convincingly replicated. It is generally thought that the associated markers reflect the effect of a nearby common (minor allele frequency >0.05) causal site, which is associated with the marker, leading to extensive resequencing efforts to find causal sites. We propose as an alternative explanation that variants much less common than the associated one may create "synthetic associations" by occurring, stochastically, more often in association with one of the alleles at the common site versus the other allele. Although synthetic associations are an obvious theoretical possibility, they have never been systematically explored as a possible explanation for GWAS findings. Here, we use simple computer simulations to show the conditions under which such synthetic associations will arise and how they may be recognized. We show that they are not only possible, but inevitable, and that under simple but reasonable genetic models, they are likely to account for or contribute to many of the recently identified signals reported in genome-wide association studies. We also illustrate the behavior of synthetic associations in real datasets by showing that rare causal mutations responsible for both hearing loss and sickle cell anemia create genome-wide significant synthetic associations, in the latter case extending over a 2.5-Mb interval encompassing scores of "blocks" of associated variants. In conclusion, uncommon or rare genetic variants can easily create synthetic associations that are credited to common variants, and this possibility requires careful consideration in the interpretation and follow up of GWAS signals.

title: Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants aged 60 years and older with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study

text:
BACKGROUND Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults.
 METHODS In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured.
 FINDINGS Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park. Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park. In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk. By contrast, these beneficial responses were attenuated after walking on Oxford Street. In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles. In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles.
 INTERPRETATION Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases. Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease. Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects.
 FUNDING British Heart Foundation.

title: Preconception Care and the Risk of Congenital Anomalies in the Offspring of Women With Diabetes Mellitus: A Meta-Analysis

text: Preconception care (PCC) and strict periconceptional glycemic control are both used to minimize the risk of congenital birth defects in offspring of women with type 1 or type 2 diabetes mellitus (DM). These malformations are ascribed in large measure to poor periconceptional control. This study evaluated PCC by a meta-analysis of published studies of PCC in women with DM, published from 1970 to 2000. Two reviewers independently abstracted the data, and the rate and relative risk (RR) of major and minor malformations were pooled from eligible studies using a random effects model. Early first-trimester values of glycosylated hemoglobin were recorded. Eight retrospective and eight prospective cohort studies were included; they were carried out in Europe, the United Kingdom, the United States, and Israel. Most participants had type 1 DM, but three studies included women with type 2 DM. Women given PCC tended to be about 2 years older on average than the others. Methods of PCC were quite variable, although most centers provided some maternal education about the pregnancy risks associated with poor glycemic control. In seven studies reporting early gestational glycosylated hemoglobin values, mean levels were consistently lower in PCC patients. Among 2104 offspring, the pooled rate for major and minor anomalies was 2.4% in the PCC group and 7.7% in non-PCC recipients, for a pooled RR of 0.32. Among 2651 offspring, major malformations were less prevalent in the PCC group (2.1 vs. 6.5%; pooled RR = 0.36). Comparable results were obtained when only prospective studies were analyzed and in studies where the infant examiners were unaware of the mothers' PCC status. The lowest risk of major anomalies was in a study that administered folic acid periconceptionally to its PCC recipients; the RR was 0.11. This meta-analysis, which included both retrospective and prospective studies, demonstrates an association of PCC with a significantly lower risk of congenital anomalies in the offspring of women with established DM. The lowered risk was accompanied by significantly lower glycosylated hemoglobin values in the first trimester in recipients of PCC.

title: Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial

text:
AIMS patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control.
 METHODS AND RESULTS we analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76-1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66-1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36-1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81-1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70-0.91; HR: 0.78, 95% CI: 0.65-0.93; and HR: 0.62, 95% CI: 0.39-1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86-1.12).
 CONCLUSION ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events.

title: Thiazolidinediones improve beta-cell function in type 2 diabetic patients.

text: Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic beta-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved beta-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fasting plasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c 8.2+/-0.3%]. Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU.m-2.min-1) clamp with [3-(3)H]glucose. T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo. Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, and insulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (all P<0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index [DeltaISR(AUC)/Deltaglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8+/-0.7 (PIO+drug-naïve diabetics), +0.7+/-0.3 (PIO+sulfonylurea-treated diabetics), and 0.7+/-0.2 (ROSI+sulfonylurea-withdrawn diabetics) vs. -0.2+/-0.3 in the two placebo groups (P<0.01, all TZDs vs. placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass, and Rd and inversely with decreased plasma glucose and FFA during the OGTT. In T2DM patients, TZD treatment leads to improved beta-cell function, which correlates strongly with improved glycemic control.

title: Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease.

text:
CONTEXT Vaso-occlusion is central to the painful crises and acute and chronic organ damage in sickle cell disease. Abnormal nitric oxide-dependent regulation of vascular tone, adhesion, platelet activation, and inflammation contributes to the pathophysiology of vaso-occlusion. Nitric oxide may have promise as a mechanism-of-disease-based therapy for treatment of vaso-occlusion.
 OBJECTIVE To explore the efficacy and safety of inhaled nitric oxide (INO) for treatment of vaso-occlusive crisis in pediatric patients.
 DESIGN Prospective, double-blind, placebo-controlled, randomized clinical trial with enrollment between September 1999 and October 2001.
 SETTING Urban, tertiary care children's hospital in the United States.
 PARTICIPANTS Twenty patients aged 10 to 21 years with sickle cell disease and severe acute vaso-occlusive crisis.
 INTERVENTION Patients were randomly assigned to receive INO (80 ppm with 21% final concentration of inspired oxygen; n = 10), or placebo (21% inspired oxygen; n = 10) for 4 hours.
 MAIN OUTCOME MEASURES Change in pain at 4 hours of inhalation compared with preinhalation pain, measured on a 10-cm visual analog scale (VAS); secondary outcome measures were pain over 6 hours, parenteral narcotic use over 24 hours, duration of hospitalization, blood pressure, oxygen saturation, and methemoglobin concentration.
 RESULTS Preinhalation VAS pain scores were similar in the INO and placebo groups (P =.80). The decrease in VAS pain scores at 4 hours was 2.0 cm in the INO group and 1.2 cm in the placebo group (P =.37). Repeated-measures analysis of variance for hourly pain scores showed a 1-cm/h greater reduction in the INO group than the placebo group (P =.02). Morphine use over 6 hours was significantly less in the INO group (mean cumulative use, 0.29 vs 0.44 mg/kg; P =.03) but was not different over 4 hours (0.26 vs 0.32 mg/kg; P =.21) or 24 hours (0.63 vs 0.91 mg/kg; P =.15). Duration of hospitalization was 78 and 100 hours in the INO and placebo groups, respectively (P =.19). No INO toxicity was observed.
 CONCLUSIONS Results of this exploratory study suggest that INO may be beneficial for acute vaso-occlusive crisis. These preliminary results warrant further investigation.

title: Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations

text: The recent success of genome-wide association studies (GWAS) is now followed by the challenge to determine how the reported susceptibility variants mediate complex traits and diseases. Expression quantitative trait loci (eQTLs) have been implicated in disease associations through overlaps between eQTLs and GWAS signals. However, the abundance of eQTLs and the strong correlation structure (LD) in the genome make it likely that some of these overlaps are coincidental and not driven by the same functional variants. In the present study, we propose an empirical methodology, which we call Regulatory Trait Concordance (RTC) that accounts for local LD structure and integrates eQTLs and GWAS results in order to reveal the subset of association signals that are due to cis eQTLs. We simulate genomic regions of various LD patterns with both a single or two causal variants and show that our score outperforms SNP correlation metrics, be they statistical (r(2)) or historical (D'). Following the observation of a significant abundance of regulatory signals among currently published GWAS loci, we apply our method with the goal to prioritize relevant genes for each of the respective complex traits. We detect several potential disease-causing regulatory effects, with a strong enrichment for immunity-related conditions, consistent with the nature of the cell line tested (LCLs). Furthermore, we present an extension of the method in trans, where interrogating the whole genome for downstream effects of the disease variant can be informative regarding its unknown primary biological effect. We conclude that integrating cellular phenotype associations with organismal complex traits will facilitate the biological interpretation of the genetic effects on these traits.

title: Association between pre-diabetes, type 2 diabetes and trabecular bone score: The Vietnam Osteoporosis Study.

text:
AIMS Trabecular bone score (TBS) is a surrogate indicator of bone microarchitecture. The presenent study sought to examine the association between type 2 diabetes (T2D) and trabecular bone score (TBS) in adult Vietnamese men and women.
 METHODS The study was part of the Vietnam Osteoporosis Study, in which 2702 women and 1398 men aged ≥30 yrs were recruited from the general community in Ho Chi Minh City. HbA1c levels were measured by the ADAMS™ A1c HA-8160 (Arkray, Kyoto, Japan), and classified into 3 groups: normal if HbA1c <5.7%; pre-diabetes (5.7 to 6.4%); and diabetes (>6.4%). TBS was evaluated by iNsight Software, version 2.1 (Medimaps, Merignac, France) on lumbar spine BMD scan (Hologic Horizon). Differences in TBS between diabetic status were analyzed by the multivariable regression model with adjustment for age and body mass index.
 RESULTS The prevalence of pre-diabetes and diabetes in men and women was 30.2% and 8.3%, respectively. In women, TBS was lower in pre-diabetes (-0.02; P<0.001) and diabetes (-0.02; P<0.001) compared with normal individuals. In men, there was no statistically significant difference in TBS between diabetic status. Moreover, TBS was significantly inversely correlated with HbA1c levels in women (P = 0.01), but not in men (P = 0.89).
 CONCLUSION Women, but not men, with type 2 diabetes and pre-diabetes have lower TBS than individuals without diabetes. These data suggest that diabetes and prediabetes are associated with deterioration of bone microarchitecture.


query: Headaches are correlated with cognitive impairment.

title: Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study

text:
OBJECTIVE To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition.
 DESIGN Population based, cross sectional study.
 SETTING Epidemiology of Vascular Ageing study, Nantes, France.
 PARTICIPANTS 780 participants (mean age 69, 58.5% women) with detailed headache assessment.
 MAIN OUTCOME MEASURES Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid). Cognitive function was assessed by a battery of tests including the mini-mental state examination.
 RESULTS 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms. An association was found between any history of severe headache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third. The association pattern was similar for all headache types. Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum and brain stem. Evidence was lacking for cognitive impairment for any headache type with or without brain lesions.
 CONCLUSIONS In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities. Migraine with aura was the only headache type associated with brain infarcts. Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking.

title: A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches.

text: Forty-one recurrent tension headache sufferers were randomly assigned to either cognitive-behavioral therapy (administered in a primarily home-based treatment protocol) or to amitriptyline therapy (with dosage individualized at 25, 50, or 75 mg/day). Cognitive-behavioral therapy and amitriptyline each yielded clinically significant improvements in headache activity, both when improvement was assessed with patient daily recordings (56% and 27% reduction in headache index, respectively), and when improvement was assessed with neurologist ratings of clinical improvement (94% and 69% of patients rated at least moderately improved, respectively). In instances where differences in treatment effectiveness were observed (headache index, somatic complaints, perceptions of control of headache activity), cognitive-behavioral therapy yielded somewhat more positive outcomes than did amitriptyline. Neither treatment, however, eliminated headache problems.

title: Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial.

text:
CONTEXT Chronic tension-type headaches are characterized by near-daily headaches and often are difficult to manage in primary practice. Behavioral and pharmacological therapies each appear modestly effective, but data are lacking on their separate and combined effects.
 OBJECTIVE To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for chronic tension-type headaches.
 DESIGN AND SETTING Randomized placebo-controlled trial conducted from August 1995 to January 1998 at 2 outpatient sites in Ohio.
 PARTICIPANTS Two hundred three adults (mean age, 37 years; 76% women) with diagnosis of chronic tension-type headaches (mean, 26 headache d/mo).
 INTERVENTIONS Participants were randomly assigned to receive tricyclic antidepressant (amitriptyline hydrochloride, up to 100 mg/d, or nortriptyline hydrochloride, up to 75 mg/d) medication (n = 53), placebo (n = 48), stress management (eg, relaxation, cognitive coping) therapy (3 sessions and 2 telephone contacts) plus placebo (n = 49), or stress management therapy plus antidepressant medication (n = 53).
 MAIN OUTCOME MEASURES Monthly headache index scores calculated as the mean of pain ratings (0-10 scale) recorded by participants in a daily diary 4 times per day; number of days per month with at least moderate pain (pain rating >/=5), analgesic medication use, and Headache Disability Inventory scores, compared by intervention group.
 RESULTS Tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headache-related disability than placebo, but antidepressant medication yielded more rapid improvements in headache activity. Combined therapy was more likely to produce clinically significant (>/=50%) reductions in headache index scores (64% of participants) than antidepressant medication (38% of participants; P =.006), stress management therapy (35%; P =.003), or placebo (29%; P =.001). On other measures the combined therapy and its 2 component therapies produced similar outcomes.
 CONCLUSIONS Our results indicate that antidepressant medication and stress management therapy are each modestly effective in treating chronic tension-type headaches. Combined therapy may improve outcome relative to monotherapy.

title: The association between common physical impairments and dementia in low and middle income countries, and, among people with dementia, their association with cognitive function and disability. A 10/66 Dementia Research Group population-based study.

text:
OBJECTIVE Chronic physical comorbidity is common in dementia. However, there is an absence of evidence to support good practice guidelines for attention to these problems. We aimed to study the extent of this comorbidity and its impact on cognitive function and disability in population-based studies in low and middle income countries, where chronic diseases and impairments are likely to be both common and undertreated.
 METHODS A multicentre cross-sectional survey of all over 65 year old residents (n = 15 022) in 11 catchment areas in China, India, Cuba, Dominican Republic, Venezuela, Mexico and Peru. We estimated the prevalence of pain, incontinence, hearing and visual impairments, mobility impairment and undernutrition according to the presence of dementia and its severity, and, among those with dementia, the independent contribution of these impairments to cognitive function and disability, adjusting for age, gender, education and dementia severity.
 RESULTS Incontinence, hearing impairment, mobility impairment and undernutrition were consistently linearly associated with the presence of dementia and its severity across regions. Among people with dementia, incontinence, hearing impairment and mobility impairment were independently associated with disability in all regions while the contributions of pain, visual impairment and undernutrition were inconsistent. Only hearing impairment made a notable independent contribution to cognitive impairment.
 CONCLUSIONS There is an urgent need for clinical trials of the feasibility, efficacy and cost-effectiveness of regular physical health checks and remediation of identified pathologies, given the considerable comorbidity identified in our population based studies, and the strong evidence for independent impact upon functioning.

title: Ankle brachial index as a predictor of cognitive impairment in the general population: ten-year follow-up of the Edinburgh Artery Study.

text:
OBJECTIVES To determine whether the ankle brachial index (ABI, a marker of generalized atherosclerosis) is associated with cognitive impairment after 10 years in older people.
 DESIGN Cohort study (Edinburgh Artery Study).
 SETTING Eleven general practices in Edinburgh, Scotland.
 PARTICIPANTS Seven hundred seventeen men and women aged 55 to 74 from the general population, followed for 10 years.
 MEASUREMENTS ABI measured at baseline and major cognitive functions (including premorbid function using the National Adult Reading Test, NART) tested after 10 years.
 RESULTS After adjustment for age and sex, a low ABI was associated with lower scoring (bottom tertile vs top tertile) on Raven's Matrices (odds ratio (OR)=1.6, 95% confidence interval (CI) =1.0-2.6), Verbal Fluency (OR =1.8, 95% CI =1.1-3.0), and Digit Symbol Test (OR =2.3, 95% CI =1.3-4.2), suggesting that the ABI is predictive of poorer performance in nonverbal reasoning, verbal fluency, and information processing speed. The association between ABI and the Digit Symbol Test remained significant after further adjustment for premorbid cognitive function (tested using the NART), suggesting that the ABI is also predictive of decline in information processing speed (from premorbid ability to that measured here in older age).
 CONCLUSION The ABI may be useful in identifying older individuals at higher risk of cognitive impairment. In the future, preventive measures developed to target individuals with a low ABI should consider measures to reduce vascular-related cognitive decline as well as cardiovascular events, in an effort to reduce the incidence and consequences of subsequent cognitive impairment and dementia.

title: Biofeedback and relaxation in the treatment of migraine headaches: comparative effectiveness and physiological correlates.

text: Twenty-seven migraine headache patients were divided into three equal groups which received thermal biofeedback, frontalis EMG biofeedback, or relaxation training. Training was given under "massed" practice conditions (nine sessions per week) and consisted of 18 training sessions and six test-generalisation sessions. While improvements in headaches were observed in all groups, the best improvements took place in the thermal biofeedback group, which had almost complete elimination of migraine attacks by the end of training, and maintained that performance as long as six months after training. Examination of the patterns of skin temperature and EMG changes in the three groups over the course of training also points to a relationship between skin temperature control and reduction in migraine headache symptomatology, and suggests that this relationship is worthy of further investigation.

title: Disturbance in cerebral spinal fluid sphingolipid content is associated with memory impairment in subjects infected with the human immunodeficiency virus

text: Despite widespread use of antiretroviral therapies to control replication of the human immunodeficiency virus (HIV), dysfunctions of cognition that are collectively termed HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of those infected by the virus. Currently there is not a biomarker that can identify HIV-infected people who are at risk for the development of HAND. Previous studies have identified particular sphingolipid species that are dysregulated in HAND, but the neurocognitive correlates of these biochemical findings are not currently understood. To address this question, we compared cerebrospinal fluid (CSF) levels of sphingomyelin, ceramide, and sterol species with performance on standard neurological tests designed to assess the function of multiple cognitive and motor domains in HIV-infected subjects. We found that sphingomyelin:ceramide ratios for acyl chain lengths of C16∶0, C18∶0, C22∶0, and C24∶0 were associated with worse performance on several indices of memory. The most striking finding was for the acyl chain of C18∶0 that consistently associatedwith performance onmultiple tests of memory. These findings suggest that the sphingomyelin:ceramide ratio for C18∶0 may be a reasonable surrogate marker for memory dysfunction in HIV-infected subjects.

title: Synaptic Determinants of Rett Syndrome

text: There is mounting evidence showing that the structural and molecular organization of synaptic connections is affected both in human patients and in animal models of neurological and psychiatric diseases. As a consequence of these experimental observations, it has been introduced the concept of synapsopathies, a notion describing brain disorders of synaptic function and plasticity. A close correlation between neurological diseases and synaptic abnormalities is especially relevant for those syndromes including also mental retardation in their symptomatology, such as Rett syndrome (RS). RS (MIM312750) is an X-linked dominant neurological disorder that is caused in the majority of cases by mutations in methyl-CpG-binding protein 2 (MeCP2). This review will focus on the current knowledge of the synaptic alterations produced by mutations of the gene MeCP2 in mouse models of RS and will highlight prospects experimental therapies currently in use. Different experimental approaches have revealed that RS could be the consequence of an impairment in the homeostasis of synaptic transmission in specific brain regions. Indeed, several forms of experience-induced neuronal plasticity are impaired in the absence of MeCP2. Based on the results presented in this review, it is reasonable to propose that understanding how the brain is affected by diseases such as RS is at reach. This effort will bring us closer to identify the neurobiological bases of human cognition.

title: The use of mouse models to understand and improve cognitive deficits in Down syndrome

text: Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS) by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development.

title: Identifying common impairments in frail and dependent older people: validation of the COPE assessment for non-specialised health workers in low resource primary health care settings

text:
BACKGROUND Frail and dependent older people in resource-poor settings are poorly served by health systems that lack outreach capacity. The COPE (Caring for Older PEople) multidimensional assessment tool is designed to help community health workers (CHWs) identify clinically significant impairments and deliver evidence-based interventions   METHODS Older people (n = 150) identified by CHWs as frail or dependent, were assessed at home by the CHW using the structured COPE assessment tool, generating information on impairments in nutrition, mobility, vision, hearing, continence, cognition, mood and behaviour. The older people were reassessed by local physicians who reached a clinical judgment regarding the presence or absence of the same impairments based upon clinical examination guided by the EASY-Care assessment tool.
 RESULTS The COPE tool was considered easy to administer, and gave CHWs a sense of empowerment to understand and act upon the needs of older people. Agreement between COPE assessment by CHW and clinician assessors was modest (ranged from 45.8 to 91.3 %) for most impairments. However, the prevalence of impairments was generally higher according to clinicians, particularly for visual impairment (98.7 vs 45.8 %), cognitive impairment (78.4 vs. 38.2 %) and depression (82.0 vs. 59.9 %). Most cases identified by WHO-COPE were clinician confirmed (positive predictive values - 72.2 to 98.5 %), and levels of disability and needs for care among those identified by COPE were higher than those additionally identified by the clinician alone.
 CONCLUSIONS The COPE is a feasible tool for the identification of specific impairments in frail dependent older people in the community. Those identified are likely to be confirmed as having clinically relevant problems by clinicians working in the same service, and the COPE may be particularly effective at targeting attention upon those with the most substantial unmet needs.

title: Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages.

text: HIV-1 replication within macrophages of the CNS often results in cognitive and motor impairment, which is known as HIV-associated dementia (HAD) in its most severe form. IFN-beta suppresses viral replication within these cells during early CNS infection, but the effect is transient. HIV-1 eventually overcomes this protective innate immune response to resume replication through an unknown mechanism, initiating the progression toward HAD. In this article, we show that Suppressor of Cytokine Signaling (SOCS)3, a molecular inhibitor of IFN signaling, may allow HIV-1 to evade innate immunity within the CNS. We found that SOCS3 is elevated in an in vivo SIV/macaque model of HAD and that the pattern of expression correlates with recurrence of viral replication and onset of CNS disease. In vitro, the HIV-1 regulatory protein transactivator of transcription induces SOCS3 in human and murine macrophages in a NF-kappaB-dependent manner. SOCS3 expression attenuates the response of macrophages to IFN-beta at proximal levels of pathway activation and downstream antiviral gene expression and consequently overcomes the inhibitory effect of IFN-beta on HIV-1 replication. These studies indicate that SOCS3 expression, induced by stimuli present in the HIV-1-infected brain, such as transactivator of transcription, inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. This consequence of SOCS3 expression in vitro, supported by a correlation with increased viral load and onset of CNS disease in vivo, suggests that SOCS3 may allow HIV-1 to evade the protective innate immune response within the CNS, allowing the recurrence of viral replication and, ultimately, promoting progression toward HAD.

title: Relationship of collegiate football experience and concussion with hippocampal volume and cognitive outcomes.

text:
IMPORTANCE Concussion and subconcussive impacts have been associated with short-term disrupted cognitive performance in collegiate athletes, but there are limited data on their long-term neuroanatomic and cognitive consequences.
 OBJECTIVE To assess the relationships of concussion history and years of football experience with hippocampal volume and cognitive performance in collegiate football athletes.
 DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study conducted between June 2011 and August 2013 at a US psychiatric research institute specializing in neuroimaging among collegiate football players with a history of clinician-diagnosed concussion (n = 25), collegiate football players without a history of concussion (n = 25), and non-football-playing, age-, sex-, and education-matched healthy controls (n = 25).    EXPOSURES History of clinician-diagnosed concussion and years of football experience.
 MAIN OUTCOMES AND MEASURES High-resolution anatomical magnetic resonance imaging was used to quantify brain volumes. Baseline scores on a computerized concussion-related cognitive battery were used for cognitive assessment in athletes.
 RESULTS Players with and without a history of concussion had smaller hippocampal volumes relative to healthy control participants (with concussion: t48 = 7.58; P < .001; mean difference, 1788 μL; 95% CI, 1317-2258 μL; without concussion: t48 = 4.35; P < .001, mean difference, 1027 μL; 95% CI, 556-1498 μL). Players with a history of concussion had smaller hippocampal volumes than players without concussion (t48 = 3.15; P < .001; mean difference, 761 μL; 95% CI, 280-1242 μL). In both athlete groups, there was a statistically significant inverse relationship between left hippocampal volume and number of years of football played (t46 = -3.62; P < .001; coefficient = -43.54; 95% CI, -67.66 to -19.41). Behavioral testing demonstrated no differences between athletes with and without a concussion history on 5 cognitive measures but did show an inverse correlation between years of playing football and reaction time (ρ42 = -0.43; 95% CI, -0.46 to -0.40; P = .005).
 CONCLUSIONS AND RELEVANCE Among a group of collegiate football athletes, there was a significant inverse relationship of concussion and years of football played with hippocampal volume. Years of football experience also correlated with slower reaction time. Further research is needed to determine the temporal relationships of these findings.

title: Insulin Signaling and Dietary Restriction Differentially Influence the Decline of Learning and Memory with Age

text: Of all the age-related declines, memory loss is one of the most devastating. While conditions that increase longevity have been identified, the effects of these longevity-promoting factors on learning and memory are unknown. Here we show that the C. elegans Insulin/IGF-1 receptor mutant daf-2 improves memory performance early in adulthood and maintains learning ability better with age but, surprisingly, demonstrates no extension in long-term memory with age. By contrast, eat-2 mutants, a model of Dietary Restriction (DR), exhibit impaired long-term memory in young adulthood but maintain this level of memory longer with age. We find that crh-1, the C. elegans homolog of the CREB transcription factor, is required for long-term associative memory, but not for learning or short-term memory. The expression of crh-1 declines with age and differs in the longevity mutants, and CREB expression and activity correlate with memory performance. Our results suggest that specific longevity treatments have acute and long-term effects on cognitive functions that decline with age through their regulation of rate-limiting genes required for learning and memory.

title: Prevalence of frequent headache in a population sample.

text:
PURPOSE Patients with daily or near-daily headaches are commonly seen in neurology practices and in headache subspecialty centers, but there is little information on the prevalence of this condition in the general population. We present the first US-based study describing the prevalence and characteristics of frequent headache in the general population.
 METHODS In Baltimore County, Maryland, 13 343 individuals 18 to 65 years of age were selected by random-digit dialing and interviewed by telephone about their headaches. Subjects reporting 180 or more headaches per year were classified as having frequent headache. Three mutually exclusive subtypes of frequent headache were identified: frequent headache with migrainous features, chronic tension-type headache, and unclassified frequent headache.
 RESULTS The overall prevalence of frequent headache was 4.1% (5.0% female, 2.8% male; 1.8:1 female to male ratio). Frequent headache was 33% more common in Caucasians (4.4%) than in African Americans (3.3%). In both males and females, prevalence was highest in the lowest educational category. Among frequent headache sufferers, more than half (52% female, 56% male) met criteria for chronic tension-type headache, almost one third (33% female, 25% male) met criteria for frequent headache with migrainous features, and the remainder (15% female, 19% male) were unclassified. Overall, 30% of female and 25% of male frequent headache sufferers met International Headache Society (IHS) criteria for migraine (with or without aura).
 CONCLUSIONS Frequent headache is common in the general population and is more prevalent in Caucasians and in those with less than a high school education. Chronic tension-type headache is more common than frequent headache with migrainous features, though the latter is more disabling. Although more common in females than males, the female preponderance of frequent headache is less marked than in migraine. The sex ratio varies by frequent headache subtype.

title: Perceived age as clinically useful biomarker of ageing: cohort study.

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OBJECTIVE To determine whether perceived age correlates with survival and important age related phenotypes.
 DESIGN Follow-up study, with survival of twins determined up to January 2008, by which time 675 (37%) had died.
 SETTING Population based twin cohort in Denmark.
 PARTICIPANTS 20 nurses, 10 young men, and 11 older women (assessors); 1826 twins aged >or=70.
 MAIN OUTCOME MEASURES Assessors: perceived age of twins from photographs. Twins: physical and cognitive tests and molecular biomarker of ageing (leucocyte telomere length).
 RESULTS For all three groups of assessors, perceived age was significantly associated with survival, even after adjustment for chronological age, sex, and rearing environment. Perceived age was still significantly associated with survival after further adjustment for physical and cognitive functioning. The likelihood that the older looking twin of the pair died first increased with increasing discordance in perceived age within the twin pair-that is, the bigger the difference in perceived age within the pair, the more likely that the older looking twin died first. Twin analyses suggested that common genetic factors influence both perceived age and survival. Perceived age, controlled for chronological age and sex, also correlated significantly with physical and cognitive functioning as well as with leucocyte telomere length.
 CONCLUSION Perceived age-which is widely used by clinicians as a general indication of a patient's health-is a robust biomarker of ageing that predicts survival among those aged >or=70 and correlates with important functional and molecular ageing phenotypes.

title: Tricyclic antidepressants and headaches: systematic review and meta-analysis

text:
OBJECTIVE To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches.
 DESIGN Meta-analysis.
 DATA SOURCES Medline, Embase, the Cochrane Trials Registry, and PsycLIT. Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks.
 DATA EXTRACTION Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index.
 RESULTS 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference -1.29, 95% confidence interval -2.18 to -0.39 and -0.70, -0.93 to -0.48) but not compared with selective serotonin reuptake inhibitors (-0.80, -2.63 to 0.02 and -0.20, -0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=-0.11, 95% confidence interval -0.63 to -0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97).
 CONCLUSIONS Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time.

title: Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes.

text:
OBJECTIVE To investigate the frequency of depressive and anxiety disorders in patients with chronic daily headache.
 BACKGROUND There is a lack of data in the literature on the extent of psychiatric comorbidity in patients with different subtypes of chronic daily headache.
 METHODS We recruited consecutive patients with chronic daily headache seen in a headache clinic from November 1998 to December 1999. The subtypes of chronic daily headache were classified according to the criteria proposed by Silberstein et al. A psychiatrist evaluated the patients according to the structured Mini-International Neuropsychiatric Interview to assess the comorbidity of depressive and anxiety disorders.
 RESULTS Two hundred sixty-one patients with chronic daily headache were recruited. The mean age was 46 years, and 80% were women. Transformed migraine was diagnosed in 152 patients (58%) and chronic tension-type headache in 92 patients (35%). Seventy-eight percent of patients with transformed migraine had psychiatric comorbidity, including major depression (57%), dysthymia (11%), panic disorder (30%), and generalized anxiety disorder (8%). Sixty-four percent of patients with chronic tension-type headache had psychiatric diagnoses, including major depression (51%), dysthymia (8%), panic disorder (22%), and generalized anxiety disorder (1%). The frequency of anxiety disorders was significantly higher in patients with transformed migraine after controlling for age and sex (P =.02). Both depressive and anxiety disorders were significantly more frequent in women.
 CONCLUSION Psychiatric comorbidity, especially major depression and panic disorders, was highly prevalent in patients with chronic daily headache seen in a headache clinic. These results demonstrate that women and patients with transformed migraine are at higher risk of psychiatric comorbidity.

title: Amitriptyline is effective in chronic but not in episodic tension-type headache: pathogenetic implications.

text: The tricyclic antidepressant, amitriptyline, is an effective drug for the treatment of chronic tension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis of an episodic type of headache such as migraine. However, its efficacy in episodic tension-type headache has not yet been clarified. We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressed patients with either chronic or episodic tension-type headache in an open-label study. Amitriptyline significantly reduced (P < 0.05) frequency and duration of headache as well as analgesic consumption in chronic, but not in episodic, tension-type headache. Further placebo-controlled trials, possibly with higher doses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explained in terms of different involvement of central nociception and of peripheral myofascial factors in the chronic and in the episodic forms of tension-type headache.

title: Efficacy and tolerability of amitriptylinoxide in the treatment of chronic tension-type headache: a multi-centre controlled study.

text: Amitriptyline is the medication of first choice in the treatment of chronic tension-type headache. In 197 patients with chronic tension-type headache (87M and 110F with a mean age of 38 +/- 13 (18-68)) efficacy and tolerability of 60-90 mg amitriptylinoxide (AO) were compared with 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a four weeks' baseline phase and 12 weeks of treatment. The primary study endpoint was a reduction of at least 50% of the product of headache duration and frequency and a reduction of at least 50% in headache intensity. Statistics used were Fisher's exact test and analysis of variance. No significant difference emerged between AO, AM and PL with respect to the primary study endpoint. Treatment response occurred in 30.3% of the AO, 22.4% of the AM and 21.9% of the PL group. A reduction in headache duration and frequency of at least 50% was found in 39.4% on AO, in 25.4% on AM and in 26.6% on PL (PAO-PL = .1384, PAM-PL = 1.000, PAO-AM = .0973). A reduction in headache intensity of at least 50% was found in 31.8% on AO, in 26.9% on AM and in 26.6% on PL (PAO-PL = .5657, PAM-PL = 1.000, PAO-AM = .5715). Trend analysis with respect to a significant reduction of headache intensity (p < 0.05) and the product of headache duration and frequency revealed a superior effect of AO.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial.

text:
CONTEXT Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking.
 OBJECTIVE To determine whether physical activity reduces the rate of cognitive decline among older adults at risk.
 DESIGN AND SETTING Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership.
 PARTICIPANTS We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment.
 INTERVENTION Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity.
 MAIN OUTCOME MEASURE Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months.
 RESULTS In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly.
 CONCLUSIONS In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period.
 TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12605000136606.