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Background: Guidelines for stroke prevention recommend development of sex-specific stroke risk scores. Incorporating sex in Clinical Prediction Models (CPMs) may support sex-specific clinical decision making. To better understand their potential to guide sex-specific care, we conducted a field synopsis of the role of sex in stroke-related CPMs., Methods and Results: We identified stroke-related CPMs in the Tufts Predictive Analytics and Comparative Effectiveness CPM Database, a systematic summary of cardiovascular CPMs published from January 1990 to May 2012. We report the proportion of models including the effect of sex on stroke incidence or prognosis, summarize the directionality of the predictive effects of sex, and explore factors influencing the inclusion of sex. Of 92 stroke-related CPMs, 30 (33%) contained a coefficient for sex or presented sex-stratified models. Only 12/58 (21%) CPMs predicting outcomes in patients included sex, compared to 18/30 (60%) models predicting first stroke (P<0.0001). Sex was most commonly included in models predicting stroke among a general population (69%). Female sex was consistently associated with reduced mortality after ischemic stroke (n=4) and higher risk of stroke from arrhythmias or coronary revascularization (n=5). Models predicting first stroke versus outcomes among patients with stroke (odds ratio=5.75, 95% CI 2.18-15.14, P<0.001) and those developed from larger versus smaller sample sizes (odds ratio=4.58, 95% CI 1.73-12.13, P=0.002) were significantly more likely to include sex., Conclusions: Sex is included in a minority of published CPMs, but more frequently in models predicting incidence of first stroke. The importance of sex-specific care may be especially well established for primary prevention., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Women are still under-represented in the senior ranks of academic medicine. As local surveys represent a critical initial step in addressing the challenges of gender disparities in academic promotion within institutions, we surveyed faculty at an academic medical centre to identify factors to improve the academic advancement of women., Methods: We conducted an electronic survey of all full-time faculty members in a Department of Medicine assessing academic rank and factors important in consideration for promotion., Results: 106 faculty members (46 %) responded to the survey; 40 % of the respondents were women. There was a statistically significant gender gap in faculty rank (p = 0.002), with only 2 of 17 full professor positions occupied by women. Among faculty who had not yet requested promotion, women were more likely to report that they did not think an academic promotion would benefit them (69 vs. 32 % in men, p = 0.01), and to report a lack of encouragement for requesting promotion (50 vs. 29 %, p = 0.08)., Conclusions: Targeting the perceived value of academic promotion among women faculty, increasing junior faculty mentorship and modifying annual review processes could address gender disparities in academic medicine ranks.

Background: Several widely used risk scores for cardiovascular disease (CVD) incorporate sex effects, yet there has been no systematic summary of the role of sex in clinical prediction models (CPMs). To better understand the potential of these models to support sex-specific care, we conducted a field synopsis of sex effects in CPMs for CVD., Methods and Results: We identified CPMs in the Tufts Predictive Analytics and Comparative Effectiveness CPM Registry, a comprehensive database of CVD CPMs published from January 1990 to May 2012. We report the proportion of models including sex effects on CVD incidence or prognosis, summarize the directionality of the predictive effects of sex, and explore factors influencing the inclusion of sex. Of 592 CVD-related CPMs, 193 (33%) included sex as a predictor or presented sex-stratified models. Sex effects were included in 78% (53/68) of models predicting incidence of CVD in a general population, versus only 35% (59/171), 21% (12/58), and 17% (12/72) of models predicting outcomes in patients with coronary artery disease, stroke, and heart failure, respectively. Among sex-including CPMs, women with heart failure were at lower mortality risk in 8 of 8 models; women undergoing revascularization for coronary artery disease were at higher mortality risk in 10 of 12 models. Factors associated with the inclusion of sex effects included the number of outcome events and using cohorts at-risk for CVD (rather than with established CVD)., Conclusions: Although CPMs hold promise for supporting sex-specific decision making in CVD clinical care, sex effects are included in only one third of published CPMs., (© 2016 American Heart Association, Inc.)

Objective: To assess the degree of agreement between propensity score studies and randomized clinical trials in critical care research., Data Sources: Propensity score studies published in highly cited critical care or general medicine journals or included in a previous systematic review; corresponding randomized clinical trials included in Cochrane Systematic Reviews or published in PubMed., Study Selection: We identified propensity score studies of the effects of therapeutic interventions on short- or long-term mortality. We systematically matched propensity score studies to randomized clinical trials based on patient selection criteria, interventions, and outcomes., Data Extraction: We appraised the methods of included studies and extracted treatment effect estimates to compare the results of propensity score studies and randomized clinical trials. When multiple studies were identified for the same topic, we performed meta-analyses to obtain summary treatment effect estimates., Data Synthesis: We matched 21 propensity score studies with 58 randomized clinical trials in 18 distinct comparisons (median, one propensity score study and two randomized clinical trials per comparison), for short- and long-term mortality. We found one statistically significant difference between designs (hyperoncotic albumin vs crystalloid fluids) among these 18 comparisons. Propensity score studies did not produce systematically higher (or lower) treatment effect estimates compared with randomized clinical trials, but estimates from the two designs differed by more than 30% in one third of the comparisons examined. Observational studies in critical care met widely accepted methodological standards for propensity score analyses., Conclusions: Across diverse critical care topics, propensity score studies published in high-impact journals produced results that were generally consistent with the findings of randomized clinical trials. However, caution is needed when interpreting propensity score studies because occasionally their results contradict those of randomized clinical trials and there is no reliable way to predict disagreements.

Background: Communication errors are considered one of the major causes of sentinel events. Our aim was to assess the process of patient handoff among junior surgical residents and to determine ways in which to improve the handoff process., Methods: We conducted nationwide surveys that included all accredited general surgery residency programs in the United States and Canada., Results: Of the 244 American and 17 Canadian accredited surgical residency programs contacted, 65 (27%) and 12 (71%), respectively, participated in the survey. Of the American and Canadian respondents, 66% and 69%, respectively, were from postgraduate year (PGY) 1, and 32% and 29%, respectively, were from PGY 2; 85 (77%) and 50 (96%), respectively, had not received any training about patient handoff before their surgical residency, and 27% and 64%, respectively, reported that the existing handoff system at their institutions did not adequately protect patient safety. Moreover, 29% of American respondents and 37% of Canadian respondents thought that the existing handoffs did not support continuity of patient care. Of the American residents, 67% and 6% reported receiving an incomplete handoff that resulted in minor and major patient harm, respectively. These results mirrored those from Canadian residents (63% minor and 7% major harm). The most frequent factor reported to improve the patient handoff process was standardization of the verbal handoff., Conclusion: Our survey results indicate that the current patient handoff system contributes to patient harm. More efforts are needed to establish standardized forms of verbal and written handoff to ensure patient safety and continuity of care.

Objectives: β-Lactam antibiotics are commonly used in outpatient parenteral antimicrobial therapy (OPAT), but data regarding outcomes of long-term therapy are limited. The purpose of this study was to compare treatment success, readmission and antibiotic switch rates in patients treated with β-lactam antibiotics as OPAT., Methods: We carried out a retrospective review of all patients, discharged from Tufts Medical Center with cefazolin, ceftriaxone, ertapenem or oxacillin, between January 2009 and June 2013. A competing risks analysis was used to compare the cumulative incidence of first occurrence of treatment success, antibiotic switch and 30 day readmission for each drug., Results: Four hundred patients were identified (cefazolin n = 38, ceftriaxone n = 104, ertapenem n = 128 and oxacillin n = 130). Baseline demographics were similar. Treatment success rates were higher for ceftriaxone and ertapenem (cefazolin 61%, ceftriaxone 81%, ertapenem 73% and oxacillin 58%; P < 0.001). Thirty-day all-cause readmissions were similar (cefazolin 21%, ceftriaxone 14%, ertapenem 20% and oxacillin 15%; P = 0.46). In 400 OPAT courses, 37 out of 50 antibiotic switches were accomplished without readmission. Adverse drug events (ADEs) were the most common reason for outpatient antibiotic switches (31/37, 84%). The ADE rate was higher for the oxacillin group (cefazolin 2.0 versus ceftriaxone 1.5 versus ertapenem 2.9 versus oxacillin 8.4 per 1000 OPAT days; P < 0.001)., Conclusions: OPAT with β-lactam antibiotics is effective, but antibiotic switches for adverse events were more frequent with oxacillin use. Clinicians should be cognizant of the risk of readmissions and ADEs in OPAT patients, as the value of OPAT lies in reducing patient morbidity and readmissions by managing ADEs and preventing clinical failures., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The purpose of this study was to determine the predictors of mortality in patients with pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF)., Background: PH is commonly associated with HFpEF. The predictors of mortality for patients with these conditions are not well characterized., Methods: In a prospective cohort of patients with right heart catheterization, we identified 73 adult patients who had pulmonary hypertension due to left heart disease (PH-LHD) associated with HFpEF (left ventricular ejection fraction ≥50% by echocardiography); hemodynamically defined as a mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure >15 mm Hg. PH severity was classified according to the diastolic pressure gradient (DPG). Cox proportional hazards ratios were used to estimate the associations between clinical variables and mortality. Receiver-operating characteristic curves were used to evaluate the ability of hemodynamic measurements to predict mortality., Results: The mean age for study subjects was 69 ± 12 years and 74% were female. Patients classified as having combined post-capillary PH and pre-capillary PH (DPG ≥7) were not at increased risk of death as compared to patients with isolated post-capillary PH (DPG <7). A baseline pulmonary arterial capacitance (PAC) of <1.1 ml/mm Hg was 91% sensitive in predicting mortality, with better discriminatory ability than DPG, transpulmonary gradient, or pulmonary vascular resistance (area under the curve of 0.73, 0.50, 0.45, and 0.37, respectively). Fifty-seven subjects underwent acute vasoreactivity testing with inhaled nitric oxide. Acute vasodilator response by the Rich or Sitbon criteria was not associated with improved survival., Conclusions: PAC is the best predictor of mortality in our cohort and may be useful in describing phenotypic subgroups among those with PH-LHD associated with HFpEF. Acute vasodilator testing did not predict outcome in our cohort but needs to be further investigated., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Bolivian sex workers were more likely than other employed women to report tuberculosis screening only if they reported HIV screening. Of all women with household tuberculosis exposure, <40% reported screening for themselves or their children. Coupling tuberculosis screening with sex workers' mandatory HIV screenings may be a cost-efficient disease-control strategy., (Copyright © 2014 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.)

Objective: We aimed to detect C-reactive protein (CRP) in neonatal saliva and evaluate its diagnostic utility., Study Design: Salivary and serum samples (n = 89) were collected from 40 neonates. Salivary CRP levels were determined using an enzyme-linked immunosorbent assay; serum CRP was measured per hospital protocol. Correlation coefficients with 95% confidence intervals and robust linear regression measured association while receiver-operator characteristic curves described the accuracy of salivary CRP in discriminating abnormal serum CRP thresholds of ≥10 and 5 mg/L. Corresponding sensitivities and specificities were calculated for these salivary cutpoints., Results: The area under the curve for salivary CRP in predicting serum CRP levels of ≥10 and 5 mg/L were 0.81 and 0.76, respectively. The corresponding sensitivity and specificity for raw salivary CRP to discriminate a serum CRP of ≥5 mg/L was 0.54 and 0.95, respectively. The corresponding sensitivity and specificity for raw salivary CRP to discriminate a serum CRP of ≥10 mg/L was 0.64 and 0.94, respectively. A statistically significant correlation was observed between serum and salivary CRP (r = 0.62, p < 0.001)., Conclusion: C-reactive protein is detectable in neonatal saliva and can predict abnormal serum CRP thresholds. Salivary CRP analysis represents a feasible screening tool for detecting abnormal serum CRP levels.

Background: Spinal manipulation has been associated with cervical arterial dissection and stroke but a causal relationship has been questioned by population-based studies. Earlier studies identified cases using International Classification of Diseases Ninth Revision (ICD-9) codes specific to anatomic stroke location rather than stroke etiology. We hypothesize that case misclassification occurred in these previous studies and an underestimation of the strength of the association. We also predicted that case misclassification would differ by patient age., Methods: We identified cases in the Veterans Health Administration database using the same strategy as the prior studies. The electronic medical record was then screened for the word "dissection." The presence of atraumatic dissection was determined by medical record review by a neurologist., Results: Of 3690 patients found by ICD-9 codes over a 30-month period, 414 (11.2%) had confirmed cervical artery dissection with a positive predictive value of 10.5% (95% confidence interval [CI] 9.6%-11.5%). The positive predictive value was higher in patients less than 45 years of age vs 45 years of age or older (41% vs 9%, P < .001). We reanalyzed a previous study, which reported no association between spinal manipulation and cervical artery dissection (odds ratio [OR] = 1.12, 95% CI .77-1.63) and recalculated an odds ratio of 2.15 (95% CI .98-4.69). For patients less than 45 years of age, the OR was 6.91 (95% CI 2.59-13.74)., Conclusions: Prior studies grossly misclassified cases of cervical dissection and mistakenly dismissed a causal association with manipulation. Our study indicates that the OR for spinal manipulation exposure in cervical artery dissection is higher than previously reported., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Phosphoenolpyruvate carboxylase (PEPC) is a key enzyme of C4 photosynthesis. Besides, non-photosynthetic isoforms of PEPC are found in bacteria and all types of plants, although not in animals or fungi. A single residue in the allosteric feedback inhibitor site of PEPC was shown to adjust the affinity of the photosynthetic and non-photosynthetic isoforms for feedback inhibition by metabolites of the C4 pathway. Here, we applied computational screening and biochemical analyses to identify molecules that selectively inhibit C4 PEPC, but have no effect on the activity of non-photosynthetic PEPCs. We found two types of selective inhibitors, catechins and quinoxalines. Binding constants in the lower μM range and a strong preference for C4 PEPC qualify the quinoxaline compounds as potential selective herbicides to combat C4 weeds., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

When examining the evidence on therapeutic interventions to answer a comparative effectiveness research question, one should consider all studies that are informative on the interventions' causal effects. "Single group studies" evaluate outcomes longitudinally in cohorts of subjects who are managed with a single treatment strategy. Because these studies are "missing" a direct, concurrent comparison group, they are typically deemed non-informative on comparative effectiveness. However, in principle, single group studies can provide information on causal treatment effects by extrapolating expected outcomes in the "missing" untreated arm. Single group studies rely on before-after, implicit, or historical comparisons as a proxy for an ideal comparison group. The validity of these comparisons must be carefully examined on a case-by-case basis. While in many cases, researchers will disagree on whether such extrapolations are reasonable; circumstances exist where such studies are generally acceptable as a source of evidence. This article provides an overview of issues related to the interpretation of single group studies with a focus on the assumptions required to support their consideration in comparative effectiveness reviews. We discuss the various settings in which single group studies are employed, common research designs that systematic reviewers need to interpret, and challenges associated with using these designs to inform comparative effectiveness questions., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background: Factors associated with readmission for patients prescribed outpatient parenteral antibiotic therapy (OPAT) at hospital discharge have not been definitively identified. The study aim was to develop a model of 30-day readmissions for OPAT patients., Methods: A database comprising 782 OPAT patients treated between 2009 and 2011 at a single academic center was created. Variables collected included patient demographics, comorbidities, infections, and antibiotic classes. Final model discrimination was assessed using the c-statistic, and calibration was examined graphically., Results: Mean patient age was 58 years (range, 18-95 years), 43% were women, and the most common diagnoses were bacteremia (24%), osteomyelitis (20%), and pyelonephritis (13%). The unplanned 30-day readmission rate was 26%. The leading indications for readmission were non-infection related (30%), worsening infection (29%), and new infection (19%). The final regression model consisted of age (odds ratio [OR], 1.09 per decade; 95% confidence interval [CI], 0.99-1.21), aminoglycoside use (OR, 2.33; 95% CI, 1.17-4.57), resistant organisms (OR, 1.57; 95% CI, 1.03-2.36), and number of prior hospital discharges without intravenous antibiotics in the past 12 months (OR, 1.20 per prior admission; 95% CI, 1.09-1.32). The c-statistic was 0.61 and the highest-risk quintile of patients had almost a 3-fold higher rate of readmission compared to the lowest., Conclusions: Patients prescribed OPAT are at risk for readmission. A subgroup of patients at especially high risk can be identified using easily obtainable clinical characteristics at the time of hospital discharge. More intensive interventions to prevent OPAT readmissions should be targeted and tested with those at highest risk.

Purpose: To assess whether pediatric trauma patients initially evaluated at referring institutions met Massachusetts statewide trauma field triage criteria for stabilization and immediate transfer to a Pediatric Trauma Center (PTC) without pre-transfer CT imaging., Methods: A 3-year retrospective cohort study was completed at our level 1 PTC. Patients with CT imaging at referring institutions were classified according to a triage scheme based on Massachusetts statewide trauma field triage criteria. Demographic data and injury profile characteristics were abstracted from patient medical records and our pediatric trauma registry., Results: A total of 262 patients with 413 CT scans were reviewed from 2008 to 2011. 172 patients scanned (66%, 95% CI: 60%, 71%) met criteria for immediate transfer to a pediatric trauma center. Notably, 110 scans (27% of the total performed at referring institutions) were duplicated within four hours upon arrival to our PTC. GCS score <14 (45%) was the most common requirement for transfer, and CT scan of the head was the most frequent scan obtained (53%)., Conclusion: The majority of pediatric trauma patients were subjected to CT scans at referring institutions despite meeting Massachusetts trauma triage guidelines that call for stabilization and immediate transfer to a pediatric trauma center without any CT imaging., (© 2014.)

Background: Observational studies have associated metformin use with lower colorectal cancer (CRC) incidence but few studies have examined metformin's influence on CRC survival. We examined the relationships among metformin use, diabetes, and survival in postmenopausal women with CRC in the Women's Health Initiative (WHI) clinical trials and observational study., Methods: 2066 postmenopausal women with CRC were followed for a median of 4.1 years, with 589 deaths after CRC diagnosis from all causes and 414 deaths directly attributed to CRC. CRC-specific survival was compared among women with diabetes with metformin use (n=84); women with diabetes with no metformin use (n=128); and women without diabetes (n=1854). Cox proportional hazard models were used to estimate associations among metformin use, diabetes and survival after CRC. Strategies to adjust for potential confounders included: multivariate adjustment with known predictors of colorectal cancer survival and construction of a propensity score for the likelihood of receiving metformin, with model stratification by propensity score quintile., Results: After adjusting for age and stage, CRC specific survival in women with diabetes with metformin use was not significantly different compared to that in women with diabetes with no metformin use (HR 0.75; 95% CI 0.40-1.38, p=0.67) and to women without diabetes (HR 1.00; 95% CI 0.61-1.66, p=0.99). Following propensity score adjustment, the HR for CRC-specific survival in women with diabetes with metformin use compared to non-users was 0.78 (95% CI 0.38-1.55, p=0.47) and for overall survival was 0.86 (95% CI 0.49-1.52; p=0.60)., Conclusions: In postmenopausal women with CRC and DM, no statistically significant difference was seen in CRC specific survival in those who used metformin compared to non-users. Analyses in larger populations of colorectal cancer patients are warranted., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To determine if serum screen analytes identify preeclamptic patients at risk for small-for-gestational age newborns, maternal laboratory abnormalities and preterm delivery (<37 weeks gestation)., Study Design: Using a retrospective cohort of 102 preeclamptic patients, associations between serum screen analytes and newborn birth-weight percentile, gestational age (GA) at delivery and maternal pre-delivery laboratory abnormalities were evaluated using correlation coefficients and local polynomial regression., Result: Inhibin-A and maternal serum alpha fetoprotein were inversely correlated with newborn birth-weight percentile (-0.27, P=0.006; -0.35, P=0.00004) and delivery GA (r=-0.42, P<0.0001; r=-0.26, P=0.008) and positively correlated with pre-delivery aspartate aminotransferase (r=0.22, P=0.03; r=0.21, P=0.04) and lactate dehydrogenase (r=0.33, P=0.0007; r=0.29, P=0.004). A positive correlation was noted between both second-trimester beta human chorionic gonadotropin and estriol and maternal pre-delivery creatinine (0.28, P=0.004; 0.4, P<0.0001, respectively). Hundred percent of patients with ≥ 2 abnormal analytes delivered before 37 weeks gestation., Conclusion: Preeclamptic patients with abnormal serum screen analytes are more likely to have small-for-gestational age newborns, deliver preterm and have pre-delivery laboratory abnormalities.

Background: Case series suggest that long-term use of proton pump inhibitors (PPIs) is associated with hypomagnesemia, but the current literature lacks systematically collected data. Our aim was to examine whether hypomagnesemia at the time of hospital admission is associated with out-of-hospital use of PPIs., Study Design: Nested case-control study matched for age and sex., Setting & Participants: Data were collected retrospectively from a tertiary acute-care facility. Eligible cases consisted of 402 adults with hypomagnesemia (serum magnesium <1.4 mEq/L) at the time of hospital admission to medical services, age- and sex-matched with 402 control individuals with normal serum magnesium levels (1.4-2.0 mEq/L)., Predictor: Out-of-hospital PPI use was identified in the hospital record. An omeprazole equivalent dose was calculated when possible. Covariates included the Charlson-Deyo comorbidity index, diabetes, diuretic use, estimated glomerular filtration rate, and gastroesophageal reflux., Outcome: Multivariable conditional logistic regression analyses were used to examine the association of PPI use with hypomagnesemia at the time of hospital admission., Results: PPI use was not associated with hypomagnesemia (adjusted OR, 0.82; 95% CI, 0.61-1.11). Neither PPI type nor omeprazole equivalent daily dose was associated with hypomagnesemia. Sensitivity analyses of PPI use restricted to patients with esophageal disorders (adjusted OR, 1.00; 95% CI, 0.69-1.45), severe hypomagnesemia (magnesium, ≤1.0 mEq/L; adjusted OR, 0.78; 95% CI, 0.13-4.61), or estimated glomerular filtration rate ≥60 mL/min/1.73 m(2) (adjusted OR, 0.84; 95% CI, 0.53-1.34) were unrevealing., Limitations: Exposure misclassification; hospitalized patients on medical services may not be representative of a broader ambulatory-based population., Conclusions: In a hospital-based adult population, out-of-hospital PPI use is not associated with hypomagnesemia at the time of hospital admission to medical services. In light of these inconclusive results, prospective cohort studies are needed to address this rare potential medication-related adverse effect., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: A test dose is used to detect intravascular injection during neuraxial block in pediatrics. Accidental intravascular epidural local anesthetic injection might be unrecognized in anesthetized children leading to potential life-threatening complications. In children, sevoflurane anesthesia blunts the hemodynamic response when intravascular cathecolamines are administered. No studies have explored the hemodynamics and the criteria for a positive test dose result following phenylephrine in sevoflurane anesthetized children., Methods: Healthy children undergoing minor procedures were randomly assigned to receive intravenous placebo, or 5 μg∙kg(-1) phenylephrine (n = 11/group) during sevoflurane anesthesia. Hemodynamic response was assessed using electrocardiography, pulse oxymetry and non-invasive blood pressure monitoring for 5 min following drug administration in anesthetized patients., Results: All patients receiving phenylephrine showed a decreased heart rate (HR) but not all of them met the positive criterion for test dose response. Overall, at 1 min, patients receiving phenylephrine showed a 25% decrease in HR from the baseline while an increase in blood pressure was noticed in 54% of patients receiving phenylephrine., Discussion: Phenylephrine might be a future indicator of positive intravascular test dose. Further investigation is needed to find out the phenylephrine dose that elicits a reliable hemodynamic response and whether phenylephrine needs to be dose age-adjusted in order to appreciate relevant hemodynamic changes in children receiving neuraxial blocks undergoing general anesthesia., (© 2013 Blackwell Publishing Ltd.)

Objective: To evaluate the longitudinal relationship between bone mineral density (BMD) and BMD changes and the progression of knee osteoarthritis (OA), as measured by cartilage outcomes., Methods: We used observational cohort data from the Vitamin D for Knee Osteoarthritis trial. Bilateral femoral neck BMD values as well as knee magnetic resonance imaging (MRI) scans in each subject were obtained at baseline and subsequently at 12 months and 24 months. The change in total cartilage volume and tibial and femoral cartilage thickness was measured by manual cartilage segmentation of 2 sequential knee MRI scans in each subject. Multivariable linear regression models were used to examine the associations of baseline BMD and BMD change with the cartilage outcomes, adjusting for baseline age, sex, body mass index, malalignment, and vitamin D treatment. Model fit and assumptions were validated., Results: A total of 127 subjects were eligible for analysis. Longitudinal BMD loss was associated with loss of cartilage volume (β = 1.25 per 0.1 gm/cm(2) , P = 0.02) and loss of tibial cartilage thickness (β = 0.028, P = 0.03). BMD loss of a magnitude greater than the least significant change (<-4.7%) was associated with 1.02% cartilage volume loss per year (P = 0.005), 0.014 mm femoral cartilage thickness loss (P = 0.04), and 0.021 mm tibial cartilage thickness loss per year (P = 0.009). There were no significant associations between baseline BMD and any of the cartilage outcomes., Conclusion: Longitudinal BMD loss is associated with progressive cartilage loss in knees with OA. Further work to clarify the basis of this relationship could reveal novel therapeutic targets for knee OA., (Copyright © 2013 by the American College of Rheumatology.)

The C4-photosynthetic carbon cycle is an elaborated addition to the classical C3-photosynthetic pathway, which improves solar conversion efficiency. The key enzyme in this pathway, phosphoenolpyruvate carboxylase, has evolved from an ancestral non-photosynthetic C3 phosphoenolpyruvate carboxylase. During evolution, C4 phosphoenolpyruvate carboxylase has increased its kinetic efficiency and reduced its sensitivity towards the feedback inhibitors malate and aspartate. An open question is the molecular basis of the shift in inhibitor tolerance. Here we show that a single-point mutation is sufficient to account for the drastic differences between the inhibitor tolerances of C3 and C4 phosphoenolpyruvate carboxylases. We solved high-resolution X-ray crystal structures of a C3 phosphoenolpyruvate carboxylase and a closely related C4 phosphoenolpyruvate carboxylase. The comparison of both structures revealed that Arg884 supports tight inhibitor binding in the C3-type enzyme. In the C4 phosphoenolpyruvate carboxylase isoform, this arginine is replaced by glycine. The substitution reduces inhibitor affinity and enables the enzyme to participate in the C4 photosynthesis pathway.

Objective: Uric acid is known to be elevated in preeclampsia. We sought to determine if uric acid levels on admission correlate with the length of expectant management in preterm patients with preeclampsia., Study Design: A retrospective chart review was conducted on singleton preeclamptic pregnancies delivered between 24 0/7 and 37 0/7 weeks' gestation at Tufts Medical Center between January 2005 and December 2007. Patients with a multiple gestation and those transferred or discharged before delivery were excluded. Data regarding signs and symptoms of preeclampsia, laboratory values, pregnancy complications and outcome were abstracted from the medical records. Correlation between admission uric acid level and days of expectant management was assessed. The relative risk (RR) was used to estimate the effect of uric acid levels on expectant management length >7 days. Mantel-Haenszel χ(2) values were used to construct 95% confidence intervals (CIs) around the RR., Result: Four hundred seventy-one charts were reviewed. Of these, 190 met inclusion criteria. In all, 55 patients (28.9%) were managed expectantly for >1 week. Admission uric acid level correlated with days of expectant management (P<0.0001). Uric acid levels at admission were categorized as ≤4.0 mg dl(-1) (low uric acid level), 4.1 to 6.0 mg dl(-1) (medium) and ≥6.1 mg dl(-1) (high). Relative to women with high uric acid levels at admission, we observed a sevenfold higher rate of extending expectant management for >1 week among women with low uric acid level (7.0; 95% CI: 3.34 to 14.68). Women with medium uric acid levels at admission also had a higher likelihood of prolonging pregnancy relative to women with high uric acid levels (RR: 2.81; 95% CI: 1.32 to 5.96) (P-value for trend <0.0001)., Conclusion: Admission uric acid levels correlate with the length of expectant management in preterm patients with preeclampsia. Pregnancy prolongation for >1 week is significantly more likely in patients with low and medium uric acid levels at the time of admission. Uric acid levels may be helpful in assessing disease severity and counseling preeclamptic patients regarding likelihood of extended expectant management.

A striking disparity exists across the globe, with essentially no large-scale longitudinal studies ongoing in regions that will be significantly affected by the oncoming non-communicable disease epidemic. The successful implementation of cohort studies in most low-resource research environments presents unique challenges that may be aided by coordinated training programs. Leaders of emerging cohort studies attending the First World Cohort Integration Workshop were surveyed about training priorities, unmet needs and potential cross-cohort solutions to these barriers through an electronic pre-workshop questionnaire and focus groups. Cohort studies representing India, Mexico, Nigeria, South Africa, Sweden, Tanzania and Uganda described similar training needs, including on-the-job training, data analysis software instruction, and database and bio-bank management. A lack of funding and protected time for training activities were commonly identified constraints. Proposed solutions include a collaborative cross-cohort teaching platform with web-based content and interactive teaching methods for a range of research personnel. An international network for research mentorship and idea exchange, and modifying the graduate thesis structure were also identified as key initiatives. Cross-cohort integrated educational initiatives will efficiently meet shared needs, catalyze the development of emerging cohorts, speed closure of the global disparity in cohort research, and may fortify scientific capacity development in low-resource settings., (Copyright © 2012 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.)

Aims: Randomized controlled trials (RCTs) are the gold standard for assessing the efficacy of therapeutic interventions because randomization protects from biases inherent in observational studies. Propensity score (PS) methods, proposed as a potential solution to confounding of the treatment-outcome association, are widely used in observational studies of therapeutic interventions for acute coronary syndromes (ACS). We aimed to systematically assess agreement between observational studies using PS methods and RCTs on therapeutic interventions for ACS., Methods and Results: We searched for observational studies of interventions for ACS that used PS methods to estimate treatment effects on short- or long-term mortality. Using a standardized algorithm, we matched observational studies to RCTs based on patients' characteristics, interventions, and outcomes ('topics'), and we compared estimates of treatment effect between the two designs. When multiple observational studies or RCTs were identified for the same topic, we performed a meta-analysis and used the summary relative risk for comparisons. We matched 21 observational studies investigating 17 distinct clinical topics to 63 RCTs (median = 3 RCTs per observational study) for short-term (7 topics) and long-term (10 topics) mortality. Estimates from PS analyses differed statistically significantly from randomized evidence in two instances; however, observational studies reported more extreme beneficial treatment effects compared with RCTs in 13 of 17 instances (P = 0.049). Sensitivity analyses limited to large RCTs, and using alternative meta-analysis models yielded similar results., Conclusion: For the treatment of ACS, observational studies using PS methods produce treatment effect estimates that are of more extreme magnitude compared with those from RCTs, although the differences are rarely statistically significant.

Multiple studies have assessed parity as a risk factor for lung cancer but results have been inconclusive. We searched MEDLINE (through August 2010) and the Institute of Scientific Information Web of Knowledge database (through April 2011) to identify studies investigating the association of parity with lung cancer and allowing the calculation of dose-response trends using a linear model. Between-study heterogeneity was assessed using Cochran's Q statistic and the I(2) index. Summary per-child relative risks (RRs) with their 95% confidence interval (CI) were estimated using random effects meta-analysis. Sixteen eligible studies (8077 lung cancer patients; 350,295 unaffected individuals) provided data for meta-analysis. There was significant between-study heterogeneity (p<0.001; I(2)=73%). The summary per livebirth RR was 0.98 (95% CI, 0.95-1.02), indicating no effect of parity on lung cancer risk. Results were consistent in case-control (n=11), RR=0.99 (95% CI, 0.94-1.04), and cohort studies (n=5), RR=0.97 (95% CI, 0.92-1.03). Studies not including small-cell lung cancer patients found a borderline protective effect of parity, RR=0.94 (95% CI, 0.88-1.00). In contrast, no effect was observed in studies including small-cell lung cancer patients, RR=1.00 (95% CI, 0.98-1.03); p for difference=0.05. Overall, there was little evidence of a dose-response relationship between increasing number of livebirths and lung cancer; however, studies have produced heterogeneous results. Future studies should include analyses in well-defined histological disease subgroups., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma., Methods: Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982., Findings: 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment., Interpretation: Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma., Funding: MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA., Competing Interests: AY received consulting fees in relation to this study from Methylgene. He also provided consultancy to Celgene, Seattle Genetics, Novartis, Syndax, and Sanofi. JB, ZL, MD, and TP are employees of Methylgene. RW is an employee of Celgene. REM is a previous employee of Methylgene and has stock ownership in the company. YO, GB, JK, MF, SN, AC, DB, AG, YJ, JKP and LJM dclare that they have no conflict of interest, (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non-cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value <0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value ≤0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET.

Epidemiologic and biologic evidence suggests that lung cancer has different clinical and biological characteristics in women, and that estrogen may contribute to the pathogenesis of non-small cell lung cancer (NSCLC). We investigated whether germline variation in the estrogen receptor-beta gene (ESR2) is associated with lung cancer risk among 1021 female cases and 826 female controls enrolled in the Lung Cancer Susceptibility Study at the Massachusetts General Hospital from 1992 to 2004. Four haplotype-tagging polymorphisms (htSNPs) (rs3020450, rs1256031, rs1256049, rs4986938) captured the common genetic variation across the ESR2 locus from a set of markers culled from healthy controls from a public database and sequencing the coding regions of 95 breast cancer cases. Using the expectation-maximization algorithm, five common haplotypes were resolved (CCGC (43%), TCAT (287%), TCAC (11%), CCAC (9%) and CCAT (6%)). Multivariate logistic regression was used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) for individual htSNPs and haplotype scores. Neither the four individual htSNPs nor their resolved haplotypes were associated with lung cancer risk in the entire population, nor in strata defined by parity (yes versus no), age (<50 years versus ≥ 50 years) or smoking history (current-, former-, never-smokers). Our findings indicate that ESR2 is not associated with risk of lung cancer in women., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess the development of anal cancer in women diagnosed with a human papillomavirus-related cervical, vulvar, or vaginal neoplasm., Methods: Using data from National Cancer Institute's Surveillance, Epidemiology and End Results program from 1973 through 2007, 189,206 cases with either in situ or invasive cervical, vulvar, or vaginal neoplasm were followed for 138,553,519 person-years for the development of subsequent primary anal cancer. Standardized incidence ratios were calculated from the observed number of subsequent anal cancers compared with those expected based on age-, race-, and calendar year-specific rates in the nonaffected population., Results: Anal cancer developed in 255 women with a history of in situ or invasive gynecologic neoplasm, aggregate standardized incidence ratio of 13.6 (95% confidence interval [CI] 11.9-15.3), indicating a 13-fold increase in anal cancer compared with expected. The standardized incidence ratio for anal cancer incidence among women with in situ vulvar cancer was 22.2 (95% CI 16.7-28.4) and was 17.4 (95% CI 11.5-24.4) for those with invasive vulvar cancer. The standardized incidence ratio for anal cancer incidence in women with in situ cervical cancer was 16.4 (95% CI 13.7-19.2) and was 6.2 (95% CI 4.1-8.7) for women with invasive cervical cancer. The standardized incidence ratio for anal cancer incidence among women with in situ vaginal cancer was 7.6 (95% CI 2.4-15.6) and was 1.8 (95% CI 0.2-5.3) for invasive vaginal cancer., Conclusion: Women with human papillomavirus-related gynecologic neoplasm are at higher risk for developing anal cancer compared with the general population. This high-risk population may benefit from close observation and screening for anal cancer.

Patterns of lung cancer incidence suggest that gender-associated factors may influence lung cancer risk. Given the association of parity with risk of some women's cancers, the authors hypothesized that childbearing history may also be associated with lung cancer. Women enrolled in the Lung Cancer Susceptibility Study at Massachusetts General Hospital (Boston, Massachusetts) between 1992 and 2004 (1,004 cases, 848 controls) were available for analysis of the association between parity and lung cancer risk. Multivariate logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. After results were controlled for age and smoking history, women with at least 1 child had 0.71 times the odds of lung cancer as women without children (odds ratio = 0.71, 95% confidence interval: 0.52, 0.97). A significant linear trend was found: Lung cancer risk decreased with increasing numbers of children (P < 0.001). This inverse association was stronger in never smokers (P = 0.12) and was limited to women over age 50 years at diagnosis (P = 0.17). Age at first birth was not associated with risk. The authors observed a protective association between childbearing and lung cancer, adding to existing evidence that reproductive factors may moderate lung cancer risk in women.

Proper attachment to the extracellular matrix is essential for cell survival. Detachment from the extracellular matrix results in an apoptotic process termed anoikis. Anoikis induction in MCF-10A mammary epithelial cells is due not only to loss of survival signals following integrin disengagement, but also to consequent downregulation of epidermal growth factor (EGFR) and loss of EGFR-induced survival signals. Here we demonstrate that G(1)/S arrest by overexpression of the cyclin-dependent kinase inhibitors p16(INK4a), p21(Cip1), or p27(Kip1) or by treatment with mimosine or aphidicolin confers anoikis resistance in MCF-10A cells. G(1)/S arrest-mediated anoikis resistance involves suppression of the BH3-only protein Bim. Furthermore, in G(1)/S-arrested cells, Erk phosphorylation is maintained in suspension and is necessary for Bim suppression. Following G(1)/S arrest, known proteins upstream of Erk, including Raf and Mek, are not activated. However, retained Erk activation under conditions in which Raf and Mek activation is lost is observed, suggesting that G(1)/S arrest acts at the level of Erk dephosphorylation. Thus, anoikis resistance by G(1)/S arrest is mediated by a mechanism involving Bim suppression through maintenance of Erk activation. These results provide a novel link between cell cycle arrest and survival, and this mechanism could contribute to the survival of nonreplicating, dormant tumor cells that avert apoptosis during early stages of metastasis.

Epithelial cells must adhere to the extracellular matrix (ECM) for survival, as detachment from matrix triggers apoptosis or anoikis. Integrins are major mediators of adhesion between cells and ECM proteins, and transduce signals required for cell survival. Recent evidence suggests that integrin receptors are coupled to growth factor receptors in the regulation of multiple biological functions; however, mechanisms involved in coordinate regulation of cell survival are poorly understood and mediators responsible for anoikis have not been well characterized. Here, we identify the pro-apoptotic protein Bim as a critical mediator of anoikis in epithelial cells. Bim is strongly induced after cell detachment and downregulation of Bim expression by RNA interference (RNAi) inhibits anoikis. Detachment-induced expression of Bim requires a lack of beta(1)-integrin engagement, downregulation of EGF receptor (EGFR) expression and inhibition of Erk signalling. Overexpressed EGFR was uncoupled from integrin regulation, resulting in the maintenance of Erk activation in suspension, and a block in Bim expression and anoikis. Thus, Bim functions as a key sensor of integrin and growth factor signals to the Erk pathway, and loss of such coordinate regulation may contribute to tumour progression.