DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer.

BACKGROUND Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients. METHODS A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation. RESULTS Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95% CI, 1.03 to 17.72) as well as in the combined cohort (HR, 2.74; 95% CI, 1.42 to 5.27) in multivariate analysis. CONCLUSIONS Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.

Clinical benefit response in pancreatic cancer trials revisited.

OBJECTIVES Clinical benefit response (CBR), based on changes in pain, Karnofsky performance status, and weight, is an established palliative endpoint in trials for advanced gastrointestinal cancer. We investigated whether CBR is associated with survival, and whether CBR reflects a wide-enough range of domains to adequately capture patients' perception. METHODS CBR was prospectively evaluated in an international phase III chemotherapy trial in patients with advanced pancreatic cancer (n = 311) in parallel with patient-reported outcomes (PROs). RESULTS The median time to treatment failure was 3.4 months (range: 0-6). The majority of the CBRs (n = 39) were noted in patients who received chemotherapy for at least 5 months. Patients with CBR (n = 62) had longer survival than non-responders (n = 182) (hazard ratio = 0.69; 95% confidence interval: 0.51-0.94; p = 0.013). CBR was predicted with a sensitivity and specificity of 77-80% by various combinations of 3 mainly physical PROs. A comparison between the duration of CBR (n = 62, median = 8 months, range = 4-31) and clinically meaningful improvements in the PROs (n = 100-116; medians = 9-11 months, range = 4-24) showed similar intervals. CONCLUSION CBR is associated with survival and mainly reflects physical domains. Within phase III chemotherapy trials for advanced gastrointestinal cancer, CBR can be replaced by a PRO evaluation, without losing substantial information but gaining complementary information.

Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

BACKGROUND Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. METHODS In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

Intestinal cholesterol absorption, treatment with atorvastatin, and cardiovascular risk in hemodialysis patients.

BACKGROUND Hemodialysis patients are high absorbers of intestinal cholesterol; they benefit less than other patient groups from statin therapy, which inhibits cholesterol synthesis. OBJECTIVES This study sought to investigate whether the individual cholesterol absorption rate affects atorvastatin's effectiveness to reduce cardiovascular risk in hemodialysis patients. METHODS This post-hoc analysis included 1,030 participants in the German Diabetes and Dialysis Study (4D) who were randomized to either 20 mg of atorvastatin (n = 519) or placebo (n = 511). The primary endpoint was a composite of major cardiovascular events. Secondary endpoints included all-cause mortality and all cardiac events. Tertiles of the cholestanol-to-cholesterol ratio, which is an established biomarker of cholesterol absorption, were used to identify high and low cholesterol absorbers. RESULTS A total of 454 primary endpoints occurred. On multivariate time-to-event analyses, the interaction term between tertiles and treatment with atorvastatin was significantly associated with the risk of reaching the primary endpoint. Stratified analysis by cholestanol-to-cholesterol ratio tertiles confirmed this effect modification: atorvastatin reduced the risk of reaching the primary endpoint in the first tertile (hazard ratio [HR]: 0.72; p = 0.049), but not the second (HR: 0.79; p = 0.225) or third tertiles (HR: 1.21; p = 0.287). Atorvastatin consistently significantly reduced all-cause mortality and the risk of all cardiac events in only the first tertile. CONCLUSIONS Intestinal cholesterol absorption, as reflected by cholestanol-to-cholesterol ratios, predicts the effectiveness of atorvastatin to reduce cardiovascular risk in hemodialysis patients. Those with low cholesterol absorption appear to benefit from treatment with atorvastatin, whereas those with high absorption do not benefit.

Cryptococcal Antigenemia in Immunocompromised Human Immunodeficiency Virus Patients in Rural Tanzania: A Preventable Cause of Early Mortality

Background.  Cryptococcal meningitis is a leading cause of death in people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome. The World Health Organizations recommends pre-antiretroviral treatment (ART) cryptococcal antigen (CRAG) screening in persons with CD4 below 100 cells/µL. We assessed the prevalence and outcome of cryptococcal antigenemia in rural southern Tanzania. Methods.  We conducted a retrospective study including all ART-naive adults with CD4 <150 cells/µL prospectively enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2008 and 2012. Cryptococcal antigen was assessed in cryopreserved pre-ART plasma. Cox regression estimated the composite outcome of death or loss to follow-up (LFU) by CRAG status and fluconazole use. Results.  Of 750 ART-naive adults, 28 (3.7%) were CRAG-positive, corresponding to a prevalence of 4.4% (23 of 520) in CD4 <100 and 2.2% (5 of 230) in CD4 100-150 cells/µL. Within 1 year, 75% (21 of 28) of CRAG-positive and 42% (302 of 722) of CRAG-negative patients were dead or LFU (P<.001), with no differences across CD4 strata. Cryptococcal antigen positivity was an independent predictor of death or LFU after adjusting for relevant confounders (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.29-4.83; P = .006). Cryptococcal meningitis occurred in 39% (11 of 28) of CRAG-positive patients, with similar retention-in-care regardless of meningitis diagnosis (P = .8). Cryptococcal antigen titer >1:160 was associated with meningitis development (odds ratio, 4.83; 95% CI, 1.24-8.41; P = .008). Fluconazole receipt decreased death or LFU in CRAG-positive patients (HR, 0.18; 95% CI, .04-.78; P = .022). Conclusions.  Cryptococcal antigenemia predicted mortality or LFU among ART-naive HIV-infected persons with CD4 <150 cells/µL, and fluconazole increased survival or retention-in-care, suggesting that targeted pre-ART CRAG screening may decrease early mortality or LFU. A CRAG screening threshold of CD4 <100 cells/µL missed 18% of CRAG-positive patients, suggesting guidelines should consider a higher threshold.

Effect of Pulmonary Hypertension Hemodynamic Presentation on Clinical Outcomes in Patients With Severe Symptomatic Aortic Valve Stenosis Undergoing Transcatheter Aortic Valve Implantation: Insights From the New Proposed Pulmonary Hypertension Classification.

BACKGROUND Pulmonary hypertension (PH) frequently coexists with severe aortic stenosis, and PH severity has been shown to predict outcomes after transcatheter aortic valve implantation (TAVI). The effect of PH hemodynamic presentation on clinical outcomes after TAVI is unknown. METHODS AND RESULTS Of 606 consecutive patients undergoing TAVI, 433 (71.4%) patients with severe aortic stenosis and a preprocedural right heart catheterization were assessed. Patients were dichotomized according to whether PH was present (mean pulmonary artery pressure, ≥25 mm Hg; n=325) or not (n=108). Patients with PH were further dichotomized by left ventricular end-diastolic pressure into postcapillary (left ventricular end-diastolic pressure, >15 mm Hg; n=269) and precapillary groups (left ventricular end-diastolic pressure, ≤15 mm Hg; n=56). Finally, patients with postcapillary PH were divided into isolated (n=220) and combined (n=49) subgroups according to whether the diastolic pressure difference (diastolic pulmonary artery pressure-left ventricular end-diastolic pressure) was normal (<7 mm Hg) or elevated (≥7 mm Hg). Primary end point was mortality at 1 year. PH was present in 325 of 433 (75%) patients and was predominantly postcapillary (n=269/325; 82%). Compared with baseline, systolic pulmonary artery pressure immediately improved after TAVI in patients with postcapillary combined (57.8±14.1 versus 50.4±17.3 mm Hg; P=0.015) but not in those with precapillary (49.0±12.6 versus 51.6±14.3; P=0.36). When compared with no PH, a higher 1-year mortality rate was observed in both precapillary (hazard ratio, 2.30; 95% confidence interval, 1.02-5.22; P=0.046) and combined (hazard ratio, 3.15; 95% confidence interval, 1.43-6.93; P=0.004) but not isolated PH patients (P=0.11). After adjustment, combined PH remained a strong predictor of 1-year mortality after TAVI (hazard ratio, 3.28; P=0.005). CONCLUSIONS Invasive stratification of PH according to hemodynamic presentation predicts acute response to treatment and 1-year mortality after TAVI.

Adenocarcinomas of the upper third of the rectum and the rectosigmoid junction seem to have similar prognosis as colon cancers even without radiotherapy, SAKK 40/78

Purpose To investigate the prognosis of adenocarcinomas of the upper third of the rectum and the rectosigmoid-junction without radiotherapy. Methods Patients from a multicenter randomized controlled trial from 1987–1993 on adjuvant chemotherapy for R0-resected colorectal cancers with stage I–III disease were retrospectively allocated: cancers of the lower two-thirds of the rectum (11 cm or less from anal-verge, Group A, n = 205), of the upper-third of the rectum and rectosigmoid-junction (>11–20 cm from anal-verge, Group B, n = 142), and of the colon (>20 cm from anal-verge, Group C, n = 378). The total mesorectal excision (TME) technique had not been introduced yet. The adjuvant chemotherapy turned out to be ineffective. None of the patients received neoadjuvant or adjuvant radiotherapy. Results The patients had a regular follow-up (median, 8.0 years). The 5-year disease-free survival (DFS) rate was 0.54 (95%CI, 0.47–0.60) in Group A, 0.68 (95%CI, 0.60–0.75) in Group B, and 0.69 (95%CI, 0.64–0.74) in Group C. The 5-year overall survival (OS) rate was 0.64 (95%CI, 0.57–0.71) in Group A, 0.79 (95%CI, 0.71–0.85) in Group B, and 0.77 (95%CI, 0.73–0.81) in Group C. Compared with Group C, patients in Group A had a significantly worse OS (hazard ratio [HR] for death 2.10) and a worse DFS (HR for relapse/death 1.93), while patients in Group B had a similar OS (HR 1.12) and DFS (HR 1.07). Conclusions Adenocarcinomas of the upper third of the rectum and the rectosigmoid-junction seem to have similar prognosis as colon cancers. Even for surgeons not familiar with the TME technique, preoperative radiotherapy may be avoided for most rectosigmoid cancers above 11 cm from anal-verge.

Impact of the Ebola epidemic on general and HIV care in Macenta, Forest Guinea, 2014.

OBJECTIVE The current Ebola epidemic massively affected the Macenta district in Forest Guinea. We aimed at investigating its impact on general and HIV care at the only HIV care facility in the district. DESIGN Prospective observational single-facility study. METHODS Routinely collected data on use of general hospital services and HIV care were linked to Ebola surveillance data published by the Guinea Ministry of Health. In addition, we compared retention among HIV-infected patients enrolled into care in the first semesters of 2013 and 2014. RESULTS Throughout 2014, service offer was continuous and unaltered at the facility. During the main epidemic period (August-December 2014), compared with the same period of 2013, there were important reductions in attendance at the primary care outpatient clinic (-40%), in HIV tests done (-46%), in new diagnoses of tuberculosis (-53%) and in patients enrolled into HIV care (-47%). There was a smaller reduction in attendance at the HIV follow-up clinic (-11%). Kaplan-Meier estimates of retention were similar among the patients enrolled into care in 2014 and 2013. In a multivariable Cox regression analysis, the year of enrolment was not associated with attrition (hazard ratio 1.02; 95% confidence interval: 0.72-1.43). CONCLUSION The Ebola epidemic resulted in an important decrease in utilization of the facility despite unaltered service offer. Effects on care of HIV-positive patients enrolled prior to the epidemic were limited. HIV care in such circumstances is challenging, but not impossible.

Transient detectable viremia and the risk of viral rebound in patients from the Swiss HIV Cohort Study.

BACKGROUND Temporary increases in plasma HIV RNA ('blips') are common in HIV patients on combination antiretroviral therapy (cART). Blips above 500 copies/mL have been associated with subsequent viral rebound. It is not clear if this relationship still holds when measurements are made using newer more sensitive assays. METHODS We selected antiretroviral-naive patients that then recorded one or more episodes of viral suppression on cART with HIV RNA measurements made using more sensitive assays (lower limit of detection below 50 copies/ml). We estimated the association in these episodes between blip magnitude and the time to viral rebound. RESULTS Four thousand ninety-four patients recorded a first episode of viral suppression on cART using more sensitive assays; 1672 patients recorded at least one subsequent suppression episode. Most suppression episodes (87 %) were recorded with TaqMan version 1 or 2 assays. Of the 2035 blips recorded, 84 %, 12 % and 4 % were of low (50-199 copies/mL), medium (200-499 copies/mL) and high (500-999 copies/mL) magnitude respectively. The risk of viral rebound increased as blip magnitude increased with hazard ratios of 1.20 (95 % CI 0.89-1.61), 1.42 (95 % CI 0.96-2.19) and 1.93 (95 % CI 1.24-3.01) for low, medium and high magnitude blips respectively; an increase of hazard ratio 1.09 (95 % CI 1.03 to 1.15) per 100 copies/mL of HIV RNA. CONCLUSIONS With the more sensitive assays now commonly used for monitoring patients, blips above 200 copies/mL are increasingly likely to lead to viral rebound and should prompt a discussion about adherence.

The J-curve in HIV: low and moderate alcohol intake predicts mortality but not the occurrence of major cardiovascular events.

OBJECTIVES In HIV-negative populations light to moderate alcohol consumption is associated with a lower cardiovascular morbidity and mortality than alcohol abstention. Whether the same holds true for HIV-infected individuals has not been evaluated in detail. DESIGN Cohort study METHODS:: Adults on antiretroviral therapy in the Swiss HIV Cohort Study with follow-up after August 2005 were included. We categorized alcohol consumption into: abstention, low (1-9 g/d), moderate (10-29 g/d in females and 10-39g/d in men) and high alcohol intake. Cox proportional hazards models were used to describe the association between alcohol consumption and cardiovascular disease free survival (combined endpoint) as well as cardiovascular disease events (CADE) and overall survival. Baseline and time-updated risk factors for CADE were included in the models. RESULTS Among 9,741 individuals included, there were 788 events of major CADE or death during 46,719 years of follow-up, corresponding to an incidence of 1.69 events/100 person-years. Follow-up according to alcohol consumption level was 51% abstention, 20% low, 23% moderate and 6% high intake. As compared to abstention, low (hazard ratio 0.79, 95% confidence interval 0.63-0.98) and moderate alcohol intake (0.78, 0.64-0.95) were associated with a lower incidence of the combined endpoint. There was no significant association between alcohol consumption and CADE. CONCLUSIONS Compared to abstention, low and moderate alcohol intake were associated with a better CADE-free survival. However, this result was mainly driven by mortality and the specific impact of drinking patterns and type of alcoholic beverage on this outcome remains to be determined.

Childhood cancer and residential exposure to highways: a nationwide cohort study.

Children living near highways are exposed to higher concentrations of traffic-related carcinogenic pollutants. Several studies reported an increased risk of childhood cancer associated with traffic exposure, but the published evidence is inconclusive. We investigated whether cancer risk is associated with proximity of residence to highways in a nation-wide cohort study including all children aged <16 years from Swiss national censuses in 1990 and 2000. Cancer incidence was investigated in time to event analyses (1990-2008) using Cox proportional hazards models and incidence density analyses (1985-2008) using Poisson regression. Adjustments were made for socio-economic factors, ionising background radiation and electromagnetic fields. In time to event analysis based on 532 cases the adjusted hazard ratio for leukaemia comparing children living <100 m from a highway with unexposed children (≥500 m) was 1.43 (95 % CI 0.79, 2.61). Results were similar in incidence density analysis including 1367 leukaemia cases (incidence rate ratio (IRR) 1.57; 95 % CI 1.09, 2.25). Associations were similar for acute lymphoblastic leukaemia (IRR 1.64; 95 % CI 1.10, 2.43) and stronger for leukaemia in children aged <5 years (IRR 1.92; 95 % CI 1.22, 3.04). Little evidence of association was found for other tumours. Our study suggests that young children living close to highways are at increased risk of developing leukaemia.

Effect of Health Risk Assessment and Counselling on Health Behaviour and Survival in Older People: A Pragmatic Randomised Trial.

BACKGROUND Potentially avoidable risk factors continue to cause unnecessary disability and premature death in older people. Health risk assessment (HRA), a method successfully used in working-age populations, is a promising method for cost-effective health promotion and preventive care in older individuals, but the long-term effects of this approach are unknown. The objective of this study was to evaluate the effects of an innovative approach to HRA and counselling in older individuals for health behaviours, preventive care, and long-term survival. METHODS AND FINDINGS This study was a pragmatic, single-centre randomised controlled clinical trial in community-dwelling individuals aged 65 y or older registered with one of 19 primary care physician (PCP) practices in a mixed rural and urban area in Switzerland. From November 2000 to January 2002, 874 participants were randomly allocated to the intervention and 1,410 to usual care. The intervention consisted of HRA based on self-administered questionnaires and individualised computer-generated feedback reports, combined with nurse and PCP counselling over a 2-y period. Primary outcomes were health behaviours and preventive care use at 2 y and all-cause mortality at 8 y. At baseline, participants in the intervention group had a mean ± standard deviation of 6.9 ± 3.7 risk factors (including unfavourable health behaviours, health and functional impairments, and social risk factors) and 4.3 ± 1.8 deficits in recommended preventive care. At 2 y, favourable health behaviours and use of preventive care were more frequent in the intervention than in the control group (based on z-statistics from generalised estimating equation models). For example, 70% compared to 62% were physically active (odds ratio 1.43, 95% CI 1.16-1.77, p = 0.001), and 66% compared to 59% had influenza vaccinations in the past year (odds ratio 1.35, 95% CI 1.09-1.66, p = 0.005). At 8 y, based on an intention-to-treat analysis, the estimated proportion alive was 77.9% in the intervention and 72.8% in the control group, for an absolute mortality difference of 4.9% (95% CI 1.3%-8.5%, p = 0.009; based on z-test for risk difference). The hazard ratio of death comparing intervention with control was 0.79 (95% CI 0.66-0.94, p = 0.009; based on Wald test from Cox regression model), and the number needed to receive the intervention to prevent one death was 21 (95% CI 12-79). The main limitations of the study include the single-site study design, the use of a brief self-administered questionnaire for 2-y outcome data collection, the unavailability of other long-term outcome data (e.g., functional status, nursing home admissions), and the availability of long-term follow-up data on mortality for analysis only in 2014. CONCLUSIONS This is the first trial to our knowledge demonstrating that a collaborative care model of HRA in community-dwelling older people not only results in better health behaviours and increased use of recommended preventive care interventions, but also improves survival. The intervention tested in our study may serve as a model of how to implement a relatively low-cost but effective programme of disease prevention and health promotion in older individuals. TRIAL REGISTRATION International Standard Randomized Controlled Trial Number: ISRCTN 28458424.

Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality.

OBJECTIVE To determine the effect of nonadherence to antiretroviral therapy (ART) on virologic failure and mortality in naive individuals starting ART. DESIGN Prospective observational cohort study. METHODS Eligible individuals enrolled in the Swiss HIV Cohort Study, started ART between 2003 and 2012, and provided adherence data on at least one biannual clinical visit. Adherence was defined as missed doses (none, one, two, or more than two) and percentage adherence (>95, 90-95, and <90) in the previous 4 weeks. Inverse probability weighting of marginal structural models was used to estimate the effect of nonadherence on viral failure (HIV-1 viral load >500 copies/ml) and mortality. RESULTS Of 3150 individuals followed for a median 4.7 years, 480 (15.2%) experienced viral failure and 104 (3.3%) died, 1155 (36.6%) reported missing one dose, 414 (13.1%) two doses and, 333 (10.6%) more than two doses of ART. The risk of viral failure increased with each missed dose (one dose: hazard ratio [HR] 1.15, 95% confidence interval 0.79-1.67; two doses: 2.15, 1.31-3.53; more than two doses: 5.21, 2.96-9.18). The risk of death increased with more than two missed doses (HR 4.87, 2.21-10.73). Missing one to two doses of ART increased the risk of viral failure in those starting once-daily (HR 1.67, 1.11-2.50) compared with those starting twice-daily regimens (HR 0.99, 0.64-1.54, interaction P = 0.09). Consistent results were found for percentage adherence. CONCLUSION Self-report of two or more missed doses of ART is associated with an increased risk of both viral failure and death. A simple adherence question helps identify patients at risk for negative clinical outcomes and offers opportunities for intervention.

Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Safety of Prasugrel Loading Doses in Patients Pre-Loaded With Clopidogrel in the Setting of Primary Percutaneous Coronary Intervention: Results of a Nonrandomized Observational Study.

OBJECTIVES The aim of this study was to assess the safety of the concurrent administration of a clopidogrel and prasugrel loading dose in patients undergoing primary percutaneous coronary intervention. BACKGROUND Prasugrel is one of the preferred P2Y12 platelet receptor antagonists for ST-segment elevation myocardial infarction patients. The use of prasugrel was evaluated clinically in clopidogrel-naive patients. METHODS Between September 2009 and October 2012, a total of 2,023 STEMI patients were enrolled in the COMFORTABLE (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI]) and the SPUM-ACS (Inflammation and Acute Coronary Syndromes) studies. Patients receiving a prasugrel loading dose were divided into 2 groups: 1) clopidogrel and a subsequent prasugrel loading dose; and 2) a prasugrel loading dose. The primary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding in hospital at 30 days. RESULTS Of 2,023 patients undergoing primary percutaneous coronary intervention, 427 (21.1%) received clopidogrel and a subsequent prasugrel loading dose, 447 (22.1%) received a prasugrel loading dose alone, and the remaining received clopidogrel only. At 30 days, the primary safety endpoint was observed in 1.9% of those receiving clopidogrel and a subsequent prasugrel loading dose and 3.4% of those receiving a prasugrel loading dose alone (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.25 to 1.30, p = 0.18). The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) bleeding score tended to be higher in prasugrel-treated patients (p = 0.076). The primary safety endpoint results, however, remained unchanged after adjustment for these differences (clopidogrel and a subsequent prasugrel loading dose vs. prasugrel only; HR: 0.54 [95% CI: 0.23 to 1.27], p = 0.16). No differences in the composite of cardiac death, myocardial infarction, or stroke were observed at 30 days (adjusted HR: 0.66, 95% CI: 0.27 to 1.62, p = 0.36). CONCLUSIONS This observational, nonrandomized study of ST-segment elevation myocardial infarction patients suggests that the administration of a loading dose of prasugrel in patients pre-treated with a loading dose of clopidogrel is not associated with an excess of major bleeding events. (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI] [COMFORTABLE]; NCT00962416; and Inflammation and Acute Coronary Syndromes [SPUM-ACS]; NCT01000701).