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Context: Evidence has suggested that physical and sexual activity might be triggers of acute cardiac events.Objective: To assess the effect of episodic physical and sexual activity on acute cardiac events using data from case-crossover studies.Data Sources: MEDLINE and EMBASE (through February 2, 2011) and Web of Science (through October 6, 2010).Study Selection: Case-crossover studies investigating the association between episodic physical or sexual activity and myocardial infarction (MI) or sudden cardiac death (SCD).Data Extraction: Two reviewers extracted descriptive and quantitative information from each study. We calculated summary relative risks (RRs) using random-effects meta-analysis and absolute event rates based on US data for the incidence of MI and SCD. We used the Fisher P value synthesis method to test whether habitual physical activity levels modify the triggering effect and meta-regression to quantify the interaction between habitual levels of physical activity and the triggering effect.Results: We identified 10 studies investigating episodic physical activity, 3 studies investigating sexual activity, and 1 study investigating both exposures. The outcomes of interest were MI (10 studies), acute coronary syndrome (1 study), and SCD (3 studies). Episodic physical and sexual activity were associated with an increase in the risk of MI (RR = 3.45; 95% confidence interval [CI], 2.33-5.13, and RR = 2.70; 95% CI, 1.48-4.91, respectively). Episodic physical activity was associated with SCD (RR = 4.98; 95% CI, 1.47-16.91). The effect of triggers on the absolute rate of events was limited because exposure to physical and sexual activity is infrequent and their effect is transient; the absolute risk increase associated with 1 hour of additional physical or sexual activity per week was estimated as 2 to 3 per 10,000 person-years for MI and 1 per 10,000 person-years for SCD. Habitual activity levels significantly affected the association of episodic physical activity and MI (P < .001), episodic physical activity and SCD (P < .001), and sexual activity and MI (P = .04); in all cases, individuals with lower habitual activity levels had an increased RR for the triggering effect. For every additional time per week an individual was habitually exposed to physical activity, the RR for MI decreased by approximately 45%, and the RR for SCD decreased by 30%.Conclusion: Acute cardiac events were significantly associated with episodic physical and sexual activity; this association was attenuated among persons with high levels of habitual physical activity. [ABSTRACT FROM AUTHOR]

Clinical prediction models (CPMs) are tools that compute the risk of an outcome given a set of patient characteristics and are routinely used to inform patients, guide treatment decision-making, and resource allocation. Although much hope has been placed on CPMs to mitigate human biases, CPMs may potentially contribute to racial disparities in decision-making and resource allocation. While some policymakers, professional organizations, and scholars have called for eliminating race as a variable from CPMs, others raise concerns that excluding race may exacerbate healthcare disparities and this controversy remains unresolved. The Guidance for Unbiased predictive Information for healthcare Decision-making and Equity (GUIDE) provides expert guidelines for model developers and health system administrators on the transparent use of race in CPMs and mitigation of algorithmic bias across contexts developed through a 5-round, modified Delphi process from a diverse 14-person technical expert panel (TEP). Deliberations affirmed that race is a social construct and that the goals of prediction are distinct from those of causal inference, and emphasized: the importance of decisional context (e.g., shared decision-making versus healthcare rationing); the conflicting nature of different anti-discrimination principles (e.g., anticlassification versus antisubordination principles); and the importance of identifying and balancing trade-offs in achieving equity-related goals with race-aware versus race-unaware CPMs for conditions where racial identity is prognostically informative. The GUIDE, comprising 31 key items in the development and use of CPMs in healthcare, outlines foundational principles, distinguishes between bias and fairness, and offers guidance for examining subgroup invalidity and using race as a variable in CPMs. This GUIDE presents a living document that supports appraisal and reporting of bias in CPMs to support best practice in CPM development and use., (© 2024. The Author(s).)

Introduction: Keloids are lesions characterized by the growth of dense fibrous tissue extending beyond original wound boundaries. Research into the natural history of keloids and potential differences by sociodemographic factors in the USA is limited. This real-world, retrospective cohort study aimed to characterize a population of patients with keloids compared with matched dermatology and general cohorts., Methods: Patients with ≥ 2 International Classification of Diseases codes for keloid ≥ 30 days apart and a confirmed keloid diagnosis from clinical notes enrolled in the OM1 Real-World Data Cloud between 1 January 2013 and 18 March 2022 were age- and sex-matched 1:1:1 to patients without keloids who visited dermatologists ("dermatology cohort") and those who did not ("general cohort"). Results are presented using descriptive statistics and analysis stratified by cohort, race, ethnicity, household income, and education., Results: Overall, 24,453 patients with keloids were matched to 23,936 dermatology and 24,088 general patients. A numerically higher proportion of patients with keloids were Asian or Black. Among available data for patients with keloids, 67.7% had 1 keloid lesion, and 68.3% had keloids sized 0.5 to < 3 cm. Black patients tended to have larger keloids. Asian and Black patients more frequently had > 1 keloid than did white patients (30.6% vs. 32.5% vs. 20.5%). Among all patients with keloids who had available data, 56.4% had major keloid severity, with major severity more frequent in Black patients. Progression was not significantly associated with race, ethnicity, income, or education level; 29%, 25%, and 20% of the dermatology, keloid, and general cohorts were in the highest income bracket (≥ US$75,000). The proportion of patients with income below the federal poverty line (< US$22,000) and patterns of education level were similar across cohorts., Conclusion: A large population of patients in the USA with keloids was identified and characterized using structured/unstructured sources. A numerically higher proportion of patients with keloids were non-white; Black patients had larger, more severe keloids at diagnosis., (© 2023. The Author(s).)

Several observational studies have compared apixaban with rivaroxaban in patients with non-valvular atrial fibrillation (NVAF), but these analyses may be confounded by unmeasured characteristics. This study used provider prescribing preference (PPP) as an instrumental variable (IV) to assess the association between prescriber choice of rivaroxaban vs. apixaban and the study outcomes of stroke/systemic embolism (SE), major bleeding, and death in a retrospective cohort of NVAF patients in the US. Initiators of either medication were linked to their prescribers and followed until the first of the study outcome, the end of rivaroxaban/apixaban use, or 365 days after initiation. PPP for each patient was the percent of rivaroxaban initiations issued by the provider for the prior 10 NVAF patients. Cox regression models tested associations between quintiles of PPP and each outcome. A total of 61,155 patients and 1726 providers were included. The IV was a strong predictor of rivaroxaban prescription (OR = 17.9; 95% CI: 16.6, 19.3). There were statistically significant associations between increasing preference for rivaroxaban and rates of major bleeding (ptrend = 0.041) and death (ptrend = 0.031), but not stroke/SE (ptrend = 0.398). This analysis provides evidence of the relative safety of apixaban over rivaroxaban for the risk of major bleeding and death.

Background The use of digital breast tomosynthesis (DBT) is increasing over digital mammography (DM) following studies demonstrating lower recall rates (RRs) and higher cancer detection rates (CDRs). However, inconsistent interpretation of evidence on the risks and benefits of mammography has resulted in varying screening mammography recommendations. Purpose To evaluate screening outcomes among women in the United States who underwent routine DM or DBT mammographic screening. Materials and Methods This retrospective cohort study included women aged 40-79 years who underwent DM or DBT screening mammograms between January 2014 and December 2020. Outcomes of RR, CDR, positive predictive value of recall (PPV1), biopsy rate, and positive predictive value of biopsy (PPV3) were compared between DM and DBT with use of adjusted multivariable logistic regression models. Results A total of 2 528 063 screening mammograms from 1 100 447 women (mean age, 57 years ± 10 [SD]) were included. In crude analyses, DBT (1 693 727 screening mammograms vs 834 336 DM screening mammograms) demonstrated lower RR (10.3% [95% CI: 10.3, 10.4] for DM vs 8.9% [95% CI: 8.9, 9.0] for DBT; P < .001) and higher CDR (4.5 of 1000 screening mammograms [95% CI: 4.3, 4.6] vs 5.3 of 1000 [95% CI: 5.2, 5.5]; P < .001), PPV1 (4.3% [95% CI: 4.2, 4.5] vs 5.9% [95% CI: 5.7, 6.0]; P < .001), and biopsy rates (14.5 of 1000 screening mammograms [95% CI: 14.2, 14.7] vs 17.6 of 1000 [95% CI: 17.4, 17.8]; P < .001). PPV3 was similar between cohorts (30.0% [95% CI: 29.2, 30.9] for DM vs 29.3% [95% CI: 28.7, 29.9] for DBT; P = .16). After adjustment for age, breast density, site, and index year, associations remained stable with respect to statistical significance. Conclusion Women undergoing digital breast tomosynthesis had improved screening mammography outcomes compared with women who underwent digital mammography. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae and Seo in this issue.

Protein expression in plants by agroinfiltration and subsequent purification is increasingly used for the biochemical characterization of plant proteins. In this chapter we describe the purification of secreted, His-tagged proteases from the apoplast of agroinfiltrated Nicotiana benthamiana using immobilized metal affinity chromatography (IMAC). We show quality checks for the purified protease and discuss potential problems and ways to circumvent them. As a proof of concept, we produce and purify tomato immune protease Pip1 and demonstrate that the protein is active after purification., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cell-mediated immunity is a specific target of several medications used to prevent or treat rejection in orthotopic heart transplantation. Low absolute lymphocyte count (ALC) has potential to be a useful and accessible clinical indicator of overall infection risk. Though some studies have demonstrated this association in other transplant populations, it has not been assessed in heart transplant recipients., Methods: A single-center retrospective cohort study examined adult heart transplant recipients transplanted between 2000 and 2018. The exposure of interest was ALC ≤0.75 × 103 cells/µL at 1 month posttransplant, and the primary endpoint was a composite outcome of infection (including cytomegalovirus [CMV], herpes simplex I/II or varicella zoster virus [HSV/VZV], bloodstream infection [BSI], invasive fungal infection [IFI]) or death occurring after 1 month and before 1 year posttransplant. A multivariable Cox proportional hazards model was created to control for confounders identified using clinical judgment and statistical criteria., Results: Of 375 subjects analyzed, 101 (27%) developed the composite outcome (61 CMV, 3 HSV/VZV, 19 BSI, 10 IFI, 8 deaths). Lymphopenia (ALC ≤0.75 × 103 cells/µL) at 1 month was associated with a >2-fold higher rate of the composite outcome (hazard ratio [HR], 2.26 [95% confidence interval {CI}, 1.47-3.46]; P < .001) compared to patients without lymphopenia at 1 month. After adjustment for confounding variables, the presence of lymphopenia remained statistically significantly associated with the composite outcome (HR, 1.72 [95% CI, 1.08-2.75]; P = .02)., Conclusions: ALC measured at 1 month after heart transplant is associated with an increased risk of infectious outcomes or death in the ensuing 11 months. This is a simple, accessible laboratory measure., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: To assess whether the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and a shorter version of this tool can identify clinical prediction models (CPMs) that perform poorly at external validation., Study Design and Setting: We evaluated risk of bias (ROB) on 102 CPMs from the Tufts CPM Registry, comparing PROBAST to a short form consisting of six PROBAST items anticipated to best identify high ROB. We then applied the short form to all CPMs in the Registry with at least 1 validation (n=556) and assessed the change in discrimination (dAUC) in external validation cohorts (n=1,147)., Results: PROBAST classified 98/102 CPMS as high ROB. The short form identified 96 of these 98 as high ROB (98% sensitivity), with perfect specificity. In the full CPM registry, 527 of 556 CPMs (95%) were classified as high ROB, 20 (3.6%) low ROB, and 9 (1.6%) unclear ROB. Only one model with unclear ROB was reclassified to high ROB after full PROBAST assessment of all low and unclear ROB models. Median change in discrimination was significantly smaller in low ROB models (dAUC -0.9%, IQR -6.2-4.2%) compared to high ROB models (dAUC -11.7%, IQR -33.3-2.6%; P<0.001)., Conclusion: High ROB is pervasive among published CPMs. It is associated with poor discriminative performance at validation, supporting the application of PROBAST or a shorter version in CPM reviews., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Prognostic tools, such as risk calculators, improve the patient-physician informed decision-making process. These tools are limited for breast cancer patients when assessing surgical complication risk preoperatively., Objective: In this study, we aimed to assess predictors associated with acute postoperative complications for breast cancer patients and then develop a predictive model that calculates a complication probability using patient risk factors., Methods: We performed a retrospective cohort study using the National Surgical Quality Improvement Program (NSQIP) database from 2005 to 2017. Women diagnosed with ductal carcinoma in situ or invasive breast cancer who underwent either breast conservation or mastectomy procedures were included in this predictive modeling scheme. Four models were built using logistic regression methods to predict the following composite outcomes: overall, infectious, hematologic, and internal organ complications. Model performance, accuracy and calibration measures during internal/external validation included area under the curve, Brier score, and Hosmer-Lemeshow statistic, respectively., Results: A total of 163,613 women met the inclusion criteria. The area under the curve for each model was as follows: overall, 0.70; infectious, 0.67; hematologic, 0.84; and internal organ, 0.74. Brier scores were all between 0.04 and 0.003. Model calibration using the Hosmer-Lemeshow statistic found all p-values to be > 0.05. Using model coefficients, individualized risk can be calculated on the web-based Breast Cancer Surgery Risk Calculator (BCSRc) platform ( www.breastcalc.org )., Conclusion: We developed an internally and externally validated risk calculator that estimates a breast cancer patient's unique risk of acute complications following each surgical intervention. Preoperative use of the BCSRc can potentially help stratify patients with an increased complication risk and improve expectations during the decision-making process., (© 2021. Society of Surgical Oncology.)

Background: There are many clinical prediction models (CPMs) available to inform treatment decisions for patients with cardiovascular disease. However, the extent to which they have been externally tested, and how well they generally perform has not been broadly evaluated., Methods: A SCOPUS citation search was run on March 22, 2017 to identify external validations of cardiovascular CPMs in the Tufts Predictive Analytics and Comparative Effectiveness CPM Registry. We assessed the extent of external validation, performance heterogeneity across databases, and explored factors associated with model performance, including a global assessment of the clinical relatedness between the derivation and validation data., Results: We identified 2030 external validations of 1382 CPMs. Eight hundred seven (58%) of the CPMs in the Registry have never been externally validated. On average, there were 1.5 validations per CPM (range, 0-94). The median external validation area under the receiver operating characteristic curve was 0.73 (25th-75th percentile [interquartile range (IQR)], 0.66-0.79), representing a median percent decrease in discrimination of -11.1% (IQR, -32.4% to +2.7%) compared with performance on derivation data. 81% (n=1333) of validations reporting area under the receiver operating characteristic curve showed discrimination below that reported in the derivation dataset. 53% (n=983) of the validations report some measure of CPM calibration. For CPMs evaluated more than once, there was typically a large range of performance. Of 1702 validations classified by relatedness, the percent change in discrimination was -3.7% (IQR, -13.2 to 3.1) for closely related validations (n=123), -9.0 (IQR, -27.6 to 3.9) for related validations (n=862), and -17.2% (IQR, -42.3 to 0) for distantly related validations (n=717; P <0.001)., Conclusions: Many published cardiovascular CPMs have never been externally validated, and for those that have, apparent performance during development is often overly optimistic. A single external validation appears insufficient to broadly understand the performance heterogeneity across different settings.

Background: Studies on the impact of the novel SARS-CoV-2 virus (COVID) for healthcare workers (HCWs) rarely include the full spectrum of hospital workers, including less visible patient support roles. In the early days of the pandemic, COVID testing was preferentially available to HCWs. The objective of this study was to understand how individual experiences for all HCWs during the pandemic were associated with perceptions of access to, and receipt of COVID testing ., Methods: All hospital employees (n = 6736) in a single academic medical center in Boston, Massachusetts were invited to participate in a cross-sectional survey regarding perceived access to, and receipt of COVID testing during the first wave of the pandemic (March - August 2020). Responses were linked to human resources data. Log binomial univariate and multivariable models were used to estimate associations between individual and employment variables and COVID testing., Results: A total of 2543 employees responded to the survey (38 %). The mean age was 40 years (± 14). Respondents were female (76 %), white (55 %), worked as nurses (27 %), administrators (22 %) and patient support roles (22 %); 56 % of respondents wanted COVID testing. Age (RR 0.91, CI 0.88-0.93), full time status (RR 0.85, CI 0.79-0.92), employment tenure (RR 0.96, CI 0.94-0.98), changes in quality of life (RR 0.94, CI 0.91-0.96), changes in job duties (RR 1.19, CI 1.03-1.37), and worry about enough paid sick leave (RR 1.21, CI 1.12-1.30) were associated with interest in testing. Administrators (RR 0.64, CI 0.58-0.72) and patient support staff (RR 0.85, CI 0.78-0.92) were less likely than nurses to want testing. Age (RR 1.04, CI 1.01-1.07), material hardships (RR 0.87, CI 0.79-0.96), and employer sponsored insurance (RR 1.10, CI 1.00-1.22) were associated with receiving a COVID test. Among all employees, only administrative/facilities staff were less likely to receive COVID testing (RR 0.69, CI 0.59-0.79)., Conclusions: This study adds to our understanding of how hospital employees view availability of COVID testing. Hazard pay or other supports for hospital workers may increase COVID testing rates. These findings may be applicable to perceived barriers towards vaccination receipt., (© 2021. The Author(s).)

Temperature passively affects biological processes involved in plant growth. Therefore, it is challenging to study the dedicated temperature signalling pathways that orchestrate thermomorphogenesis, a suite of elongation growth-based adaptations that enhance leaf-cooling capacity. We screened a chemical library for compounds that restored hypocotyl elongation in the pif4-2-deficient mutant background at warm temperature conditions in Arabidopsis thaliana to identify modulators of thermomorphogenesis. The small aromatic compound 'Heatin', containing 1-iminomethyl-2-naphthol as a pharmacophore, was selected as an enhancer of elongation growth. We show that ARABIDOPSIS ALDEHYDE OXIDASES redundantly contribute to Heatin-mediated hypocotyl elongation. Following a chemical proteomics approach, the members of the NITRILASE1-subfamily of auxin biosynthesis enzymes were identified among the molecular targets of Heatin. Our data reveal that nitrilases are involved in promotion of hypocotyl elongation in response to high temperature and Heatin-mediated hypocotyl elongation requires the NITRILASE1-subfamily members, NIT1 and NIT2. Heatin inhibits NIT1-subfamily enzymatic activity in vitro and the application of Heatin accordingly results in the accumulation of NIT1-subfamily substrate indole-3-acetonitrile in vivo. However, levels of the NIT1-subfamily product, bioactive auxin (indole-3-acetic acid), were also significantly increased. It is likely that the stimulation of hypocotyl elongation by Heatin might be independent of its observed interaction with NITRILASE1-subfamily members. However, nitrilases may contribute to the Heatin response by stimulating indole-3-acetic acid biosynthesis in an indirect way. Heatin and its functional analogues present novel chemical entities for studying auxin biology., (© 2021 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

The plant apoplast is a harsh environment in which hydrolytic enzymes, especially proteases, accumulate during pathogen infection. However, the defense functions of most apoplastic proteases remain largely elusive. We show here that a newly identified small cysteine-rich secreted protein PC2 from the potato late blight pathogen Phytophthora infestans induces immunity in Solanum plants only after cleavage by plant apoplastic subtilisin-like proteases, such as tomato P69B. A minimal 61 amino acid core peptide carrying two key cysteines, conserved widely in most oomycete species, is sufficient for PC2-induced cell death. Furthermore, we showed that Kazal-like protease inhibitors, such as EPI1, produced by P. infestans prevent PC2 cleavage and dampen PC2 elicited host immunity. This study reveals that cleavage of pathogen proteins to release immunogenic peptides is an important function of plant apoplastic proteases., (© 2020 The Authors New Phytologist © 2020 New Phytologist Foundation.)

Objectives: The CathPCI Data Extraction and Longitudinal Trend Analysis study was designed to determine the feasibility of conducting prospective surveillance of a large national registry to perform comparative safety analyses of medical devices. We sought to determine whether the complementary use of retrospective case data could improve safety signal detection time., Design: We performed a simulated surveillance study of the comparative safety of the Mynx vascular closure device (VCD) with propensity score matched alternate VCD recipients, using both retrospective and prospective cohort data., Setting: Centers within the USA using the National Cardiovascular Data Registry (NCDR) CathPCI Registry., Participants: Percutaneous coronary intervention cases captured within the NCDR CathPCI Registry from July 1, 2009 to September 30, 2013 were included in the analysis., Interventions: None., Main Outcome Measures: Absolute and relative risk (RR) of any vascular complication (a composite of bleeding at access site, hematoma at access site, retroperitoneal bleeding, and other vascular complications requiring treatment); time to signal detection., Results: A safety alert was detected for the primary outcome of "any vascular complication" after 15 months of surveillance and was sustained for the study duration (absolute risk of any vascular complication, 1.20% vs 0.73%, RR, 1.63; 95% CI 1.50 to 1.79; p<0.001). The safety signal was identified 12 months earlier with the use of retrospective case data than during the initial study., Conclusions: Prospective, active surveillance of cardiovascular registries is feasible to perform comparative analyses of medical devices. Retrospective data may complement prospective surveillance to improve time to signal detection, indicating the need for earlier prospective application of safety surveillance for devices new to the market., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recent evidence suggests that there is often substantial variation in the benefits and harms across a trial population. We aimed to identify regression modeling approaches that assess heterogeneity of treatment effect within a randomized clinical trial., Methods: We performed a literature review using a broad search strategy, complemented by suggestions of a technical expert panel., Results: The approaches are classified into 3 categories: 1) Risk-based methods (11 papers) use only prognostic factors to define patient subgroups, relying on the mathematical dependency of the absolute risk difference on baseline risk; 2) Treatment effect modeling methods (9 papers) use both prognostic factors and treatment effect modifiers to explore characteristics that interact with the effects of therapy on a relative scale. These methods couple data-driven subgroup identification with approaches to prevent overfitting, such as penalization or use of separate data sets for subgroup identification and effect estimation. 3) Optimal treatment regime methods (12 papers) focus primarily on treatment effect modifiers to classify the trial population into those who benefit from treatment and those who do not. Finally, we also identified papers which describe model evaluation methods (4 papers)., Conclusions: Three classes of approaches were identified to assess heterogeneity of treatment effect. Methodological research, including both simulations and empirical evaluations, is required to compare the available methods in different settings and to derive well-informed guidance for their application in RCT analysis.

Rcr3 is a secreted protease of tomato that is targeted by fungal effector Avr2, a secreted protease inhibitor of the fungal pathogen Cladosporium fulvum. The Avr2-Rcr3 complex is recognized by receptor-like protein Cf-2, triggering hypersensitive cell death (HR) and disease resistance. Avr2 also targets Rcr3 paralog Pip1, which is not required for Avr2 recognition but contributes to basal resistance. Thus, Rcr3 acts as a guarded decoy in this interaction, trapping the fungus into a recognition event. Here we show that Rcr3 evolved > 50 million years ago (Mya), whereas Cf-2 evolved <6Mya by co-opting the pre-existing Rcr3 in the Solanum genus. Ancient Rcr3 homologs present in tomato, potato, eggplants, pepper, petunia and tobacco can be inhibited by Avr2 with the exception of tobacco Rcr3. Four variant residues in Rcr3 promote Avr2 inhibition, but the Rcr3 that co-evolved with Cf-2 lacks three of these residues, indicating that the Rcr3 co-receptor is suboptimal for Avr2 binding. Pepper Rcr3 triggers HR with Cf-2 and Avr2 when engineered for enhanced inhibition by Avr2. Nicotiana benthamiana (Nb) is a natural null mutant carrying Rcr3 and Pip1 alleles with deleterious frame-shift mutations. Resurrected NbRcr3 and NbPip1 alleles were active proteases and further NbRcr3 engineering facilitated Avr2 inhibition, uncoupled from HR signalling. The evolution of a receptor co-opting a conserved pathogen target contrasts with other indirect pathogen recognition mechanisms.

The machine learning community has become alert to the ways that predictive algorithms can inadvertently introduce unfairness in decision-making. Herein, we discuss how concepts of algorithmic fairness might apply in healthcare, where predictive algorithms are being increasingly used to support decision-making. Central to our discussion is the distinction between algorithmic fairness and algorithmic bias. Fairness concerns apply specifically when algorithms are used to support polar decisions (i.e., where one pole of prediction leads to decisions that are generally more desired than the other), such as when predictions are used to allocate scarce health care resources to a group of patients that could all benefit. We review different fairness criteria and demonstrate their mutual incompatibility. Even when models are used to balance benefits-harms to make optimal decisions for individuals (i.e., for non-polar decisions)-and fairness concerns are not germane-model, data or sampling issues can lead to biased predictions that support decisions that are differentially harmful/beneficial across groups. We review these potential sources of bias, and also discuss ways to diagnose and remedy algorithmic bias. We note that remedies for algorithmic fairness may be more problematic, since we lack agreed upon definitions of fairness. Finally, we propose a provisional framework for the evaluation of clinical prediction models offered for further elaboration and refinement. Given the proliferation of prediction models used to guide clinical decisions, developing consensus for how these concerns can be addressed should be prioritized., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Proteolytic cascades regulate immunity and development in animals, but these cascades in plants have not yet been reported. Here we report that the extracellular immune protease Rcr3 of tomato is activated by P69B and other subtilases (SBTs), revealing a proteolytic cascade regulating extracellular immunity in solanaceous plants. Rcr3 is a secreted papain-like Cys protease (PLCP) of tomato that acts both in basal resistance against late blight disease ( Phytophthora infestans ) and in gene-for-gene resistance against the fungal pathogen Cladosporium fulvum ( syn. Passalora fulva) Despite the prevalent model that Rcr3-like proteases can activate themselves at low pH, we found that catalytically inactive proRcr3 mutant precursors are still processed into mature mRcr3 isoforms. ProRcr3 is processed by secreted P69B and other Asp-selective SBTs in solanaceous plants, providing robust immunity through SBT redundancy. The apoplastic effector EPI1 of P. infestans can block Rcr3 activation by inhibiting SBTs, suggesting that this effector promotes virulence indirectly by preventing the activation of Rcr3(-like) immune proteases. Rcr3 activation in Nicotiana benthamiana requires a SBT from a different subfamily, indicating that extracellular proteolytic cascades have evolved convergently in solanaceous plants or are very ancient in the plant kingdom. The frequent incidence of Asp residues in the cleavage region of Rcr3-like proteases in solanaceous plants indicates that activation of immune proteases by SBTs is a general mechanism, illuminating a proteolytic cascade that provides robust apoplastic immunity., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Aim: Despite broad interest in advancing personalized medicine, most evidence is currently derived from average results of clinical trials that may obscure heterogeneity of trial participants. Little is known currently about how patients view heterogeneity in trials and whether they can participate in methodological discussions about this concept. Materials & methods: In structured discussions with three focus groups involving 22 participants, we assessed how representatives of patient communities have used research to guide individual treatment decisions. Discussion themes were organized into a framework describing patient decision-making in four steps: decisions patients make in the course of care; information used to make decisions; sources for information; and quality of information. Results/conclusion: Patients prioritize information that reflects their own characteristics, preferences and values. They struggle applying clinical research to their own case.

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.

Background While many clinical prediction models (CPMs) exist to guide valvular heart disease treatment decisions, the relative performance of these CPMs is largely unknown. We systematically describe the CPMs available for patients with valvular heart disease with specific attention to performance in external validations. Methods and Results A systematic review identified 49 CPMs for patients with valvular heart disease treated with surgery (n=34), percutaneous interventions (n=12), or no intervention (n=3). There were 204 external validations of these CPMs. Only 35 (71%) CPMs have been externally validated. Sixty-five percent (n=133) of the external validations were performed on distantly related populations. There was substantial heterogeneity in model performance and a median percentage change in discrimination of -27.1% (interquartile range, -49.4%--5.7%). Nearly two-thirds of validations (n=129) demonstrate at least a 10% relative decline in discrimination. Discriminatory performance of EuroSCORE II and Society of Thoracic Surgeons (2009) models (accounting for 73% of external validations) varied widely: EuroSCORE II validation c-statistic range 0.50 to 0.95; Society of Thoracic Surgeons (2009) Models validation c-statistic range 0.50 to 0.86. These models performed well when tested on related populations (median related validation c-statistics: EuroSCORE II, 0.82 [0.76, 0.85]; Society of Thoracic Surgeons [2009], 0.72 [0.67, 0.79]). There remain few (n=9) external validations of transcatheter aortic valve replacement CPMs. Conclusions Many CPMs for patients with valvular heart disease have never been externally validated and isolated external validations appear insufficient to assess the trustworthiness of predictions. For surgical valve interventions, there are existing predictive models that perform reasonably well on related populations. For transcatheter aortic valve replacement (CPMs additional external validations are needed to broadly understand the trustworthiness of predictions.

Purpose: The liver is critically involved in drug metabolism pathways and the potential for hepatic toxicity is significant with specific cancer therapeutics. Variations in the definition of liver function thresholds that may generate heterogeneity of toxicity and efficacy outcomes across therapeutics trials in cancer require assessment., Methods: A random sample of therapeutic trials in cancer (n = 500, general category), trials using hepatotoxic drugs (abiraterone, pazopanib: n = 181), trials using drugs metabolized by the liver (doxorubicin, vincristine: n = 606), and therapeutic trials in hepatic dysfunction (n = 49) were each identified on clinicaltrials.gov. Definitions of liver function thresholds and their distribution were collated and categorized in each group., Results: A third of all trials listed on clinicaltrials.gov across the four categories failed to provide an explicit definition of liver function. Among trials with an explicit definition, a combination of bilirubin and transaminase levels was used in 33-64%, whereas a miscellaneous combination of definitions (in the general category consisting of 11 unique liver function parameters creating 17 unique combinations) was used 29-58% of the time across the four categories of studies. The Child-Pugh or National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were rarely employed (0-12% studies). Allowance for Gilbert's disease in bilirubin thresholds was identified in only 6-23% studies and for liver metastases in 2-15% of studies., Conclusions: There is a marked heterogeneity in the liver function definitions used across cancer clinical trials even when the potential for drug toxicity and altered drug metabolism is significant. Harmonization of criteria will streamline eligibility and mitigate variations in key outcomes across trials.

Purpose: Distribution and outcomes of traumatic injury of the esophagus (TIE) in pediatric versus adult populations are unknown. Our study sought to perform a descriptive analysis of TIE in children and adults., Methods: We reviewed the National Trauma Data Bank (NTDB) for the years 2010-2015. Demographics, characteristics, and outcomes of pediatric (age < 16 years) and adult TIE patients were described and compared., Results: Among 526,850 pediatric and 3,838,895 adult trauma patients, 90 pediatric (0.02%) and 1,411 (0.04%) adult TIE patients were identified. Demographics and esophageal injury severity did not differ. Children were more likely to sustain blunt trauma (63% versus 37%), with the most common mechanism being transportation-related accidents, were less-severely injured (median ISS 14 versus 22), and had fewer associated injuries (79% versus 95%) and complications (30% versus 51%) (all p < 0.001). Children had shorter hospitalizations (median 5 versus 10 days) and were more likely to be discharged home (84% versus 64%) (both p = 0.01). In-hospital mortality did not differ significantly between children and adults (10% versus 19%, p = 0.09)., Conclusion: TIE in the pediatric population has unique characteristics compared to adults: it is more likely to be a result of blunt trauma, has lower injury burden, and has more favorable clinical outcomes.

Objective: Identify inhaler use characteristics among English (ESP) and non-English speaking patients (NSP) to develop quality improvement efforts., Methods: Outpatients were surveyed for technique confidence, education, preferences and disease control. We compared characteristics between ESP and NSP., Results: Of 197 respondents, 75% were ESP, 25% were NSP. Compared to NSP, ESP responders were more likely female (57% vs 31%, p = 0.001), used inhalers for a longer time (10 vs 6 years, p = 0.008) and had higher rates of metered dose inhaler use (85% vs. 60%, p < 0.001). Both language groups had similar confidence in inhaler use, after adjustment for age, gender and duration of use. Similar rates of inhaler technique education were reported by ESP and NSP at the initial visit. More NSP reported receiving education at subsequent visits (54% vs. 72%, p = 0.03). Education for both groups was mostly performed by a clinician. Both language groups reported low internet use for learning proper technique, low interest in a separate education session, preferred an active learning method., Conclusions: These findings will be used to further develop quality inhaler education efforts at our institution., Practical Implications: Local patient preferences should be considered when designing inhaler education programs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Existing literature on traumatic injury of the esophagus (TIE) is limited. We aimed to describe the clinical characteristics and outcomes of TIE. We reviewed the National Trauma Data Bank for the years 2010-2015. We described the demographics, characteristics, and outcomes of adult (age ≥16 years) TIE patients and also compared those factors in blunt versus penetrating TIE. The association between TIE and mortality was analyzed using multivariable logistic regression. Thousand four hundred eleven adult TIE patients were identified (37 per 100,000 trauma patients, 95% confidence intervals (CI): 35, 39). TIE patients were younger (38 vs 52 years), more likely to be male (81% vs 62%), and more severely injured (Injury Severity Score ≥ 25: 45% vs 7%) than patients without TIE (all P < 0.001). TIE was observed 16 times more frequently with penetrating injuries (257 per 100,000, 95% CI: 240, 270) than with blunt injuries (16 per 100,000, 95% CI: 15, 18). Inhospital TIE mortality was 19 per cent. TIE patients had greater risk of mortality than other trauma patients, after adjusting for age, gender, and Injury Severity Score (odds ratio = 1.4, 95% CI: 1.1, 1.7). Mortality in blunt and penetrating TIE did not differ. Although extremely rare, TIE is independently associated with a marked increase in mortality, even after adjusting for other risk factors.

Background Current strategies for ensuring the postmarket safety of medical devices are limited by small sample size and reliance on voluntary reporting of adverse events. Prospective, active surveillance of clinical registries may provide early warnings in the postmarket evaluation of medical device safety but has not been demonstrated in national clinical data registries. Methods and Results The CathPCI DELTA (Data Extraction and Longitudinal Trend Analysis) study was designed to assess the feasibility of prospective, active safety surveillance of medical devices within a national cardiovascular registry. We sought to assess the ability of our surveillance strategy to avoid false safety alerts by conducting an active safety surveillance study of aspiration thrombectomy catheters using data within the National Cardiovascular Data Registry CathPCI registry, where no difference in safety outcomes were anticipated for the primary in-hospital safety outcome of death and major adverse cardiovascular events (MACE). We performed a propensity-matched analysis of 5 aspiration thrombectomy catheter devices used during percutaneous coronary intervention among 95 925 patients presenting with ST-segment-elevation myocardial infarction between January 1, 2011 and September 30, 2013. After 33 months of surveillance, no safety alerts were triggered for the primary safety endpoints of death or MACE, with no between-catheter differences observed. The absolute risk of death during acute hospitalization ranged from 5.11% to 5.32% among the most commonly used aspiration thrombectomy catheter devices, with relative risks for death ranging from 0.96 to 1.03. The absolute risk of MACE ranged from 9.78% to 10.18%, with relative risks for MACE ranging from 0.99 to 1.02. There were no statistically significant differences in the rates of death or MACE between any of the aspiration thrombectomy catheter devices analyzed. Conclusions The CathPCI DELTA study demonstrates that prospective, active safety surveillance of national clinical registries is feasible to provide near-real-time safety assessments of new medical devices.

Current guidance for evaluation of kidney function and drug dosing emphasize using measured or estimated glomerular filtration rate (GFR) rather than measured or estimated creatinine clearance or serum creatinine (Scr) alone. We assessed the definitions of kidney function thresholds for eligibility in cancer clinical trials. A random sample of active Phase I-III trials with cisplatin (n = 465) and studies in cancer with decreased kidney function (n = 74) were identified from clinicaltrials.gov. Among cisplatin trials, kidney function thresholds were defined by Scr alone or a composite of Scr or creatinine clearance in 46% (212/465) of studies. Only 2% (n = 11) used GFR. Among trials in participants with decreased kidney function, the proportion utilizing GFR (14%, 10/74) was modestly higher. Imprecise and logically inconsistent kidney function thresholds are in frequent use in clinical trials in cancer and may cause harm from either toxicity or impaired efficacy. We recommend the adoption and harmonization of recommended standards.

Exposure of male mice to early life stress alters the levels of specific sperm miRNAs that promote stress-associated behaviors in their offspring. To begin to evaluate whether similar phenomena occur in men, we searched for sperm miRNA changes that occur in both mice and men exposed to early life stressors that have long-lasting effects. For men, we used the Adverse Childhood Experience (ACE) questionnaire. It reveals the degree of abusive and/or dysfunctional family experiences when young, which increases risks of developing future psychological and physical disorders. For male mice, we used adolescent chronic social instability (CSI) stress, which not only enhances sociability defects for >1 year, but also anxiety and defective sociability in female offspring for multiple generations through the male lineage. Here we found a statistically significant inverse correlation between levels of multiple miRNAs of the miR-449/34 family and ACE scores of Caucasian males. Remarkably, we found members of the same sperm miRNA family are also reduced in mice exposed to CSI stress. Thus, future studies should be designed to directly test whether reduced levels of these miRNAs could be used as unbiased indicators of current and/or early life exposure to severe stress. Moreover, after mating stressed male mice, these sperm miRNA reductions persist in both early embryos through at least the morula stage and in sperm of males derived from them, suggesting these miRNA changes contribute to transmission of stress phenotypes across generations. Since offspring of men exposed to early life trauma have elevated risks for psychological disorders, these findings raise the possibility that a portion of this risk may be derived from epigenetic regulation of these sperm miRNAs.

Objective: The aim of this study was to assess the impact of a revolving loan fund (RLF) on timing of device insertion and long-acting reversible contraception (LARC) access among a high-risk urban population at 3 Boston community health centers., Design: Three health centers were identified to implement a RLF. Each clinic received $5000 from the RLF to purchase LARC devices. Data collected through medical record review retrospectively 1 year prior to start of the RLF and prospectively for 1 year thereafter included patient demographics, type of LARC selected, patient's date of documented interest in a LARC device, and date of insertion. The effect of a RLF on delay to LARC insertion was tested using negative binomial regression, controlling for site and potential confounding variables between the pre- and post-RLF periods., Setting: Three urban community health centers., Participants: Reproductive-aged women who received family planning services at the 3 participating health centers., Main Outcome Measures: Increasing access to LARC and decreasing wait times to LARC insertion after implementation of the RLF., Results: Data on 133 patients in the pre-RLF group and 205 in the post-RLF group were collected. There were no statistically significant differences in demographic or clinical characteristics between the 2 time periods. LARC uptake increased significantly from the pre- to post-RLF period, specifically among implant users. There was a statistically significant decrease in the mean number of days in delay from interest to insertion from the pre- to post-RLF period (pre-RLF: 31.3 ± 50.6 days; post-RLF: 13.6 ± 16.7 days, adjusted P < .001). The reasons for the delay did not differ significantly between the 2 time periods., Conclusion: The RLF decreased wait time for the devices and increased overall insertion rates. This may serve as a promising solution to improve LARC access in community health centers. This project could be expanded to include more health centers, creating a city wide RLF. This expansion could allow for further data analysis, including unintended pregnancy rates with LARC delay, LARC continuation rates, and sustainability of a RLF.

This study explores the racial and ethnic differences in presentation, severity, and treatment of patients with pulmonary arterial hypertension (PAH) in a large multicenter registry. African American and Hispanic patients are more likely to present with associated PAH compared to non-Hispanic whites. Hispanic patients with PAH were less likely to be treated with PAH-specific medications compared to non-Hispanic whites.

Objective: To determine the association between H. pylori infection and risk of incident diabetes in adults at high risk for diabetes who participated in the Diabetes Prevention Program (DPP) study., Methods: In a nested case-control study conducted among 421 adults with newly diagnosed diabetes and 421 matched controls, we examined the association between serological status of H. pylori at baseline and risk of incident diabetes over a mean follow-up period of 2.6years. Using data from the baseline visit of the DPP, we also examined the cross-sectional association between presence of H. pylori antibodies and insulin sensitivity, insulin secretion and the disposition index-like measure after a 75-g oral glucose tolerance test (OGTT)., Results: At baseline, H. pylori antibodies were present in 40% of participants who developed diabetes and 39% of controls. After adjusting for matching factors, there was no association between exposure to H. pylori and incident diabetes (odds ratio [OR] of 1.04 (95% CI, 0.77 to 1.40). In cross-sectional analyses, H. pylori status was not significantly associated with insulin sensitivity and disposition index-like measure from OGTT., Conclusions: In adults at high risk for diabetes, H. pylori seropositivity was not associated with risk of developing diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The effect of prior malignancy on the risk of developing, and prognosis of, acute lymphoblastic leukemia (ALL) is unknown. This observational study utilized the California Cancer Registry to estimate the risk of developing ALL after a prior malignancy using standardized incidence ratios (SIRs, 95% confidence intervals). ALL occurring after a malignancy with an SIR>1 (increased-risk (IR) malignancies) was considered secondary ALL (s-ALL). Adjusted hazard ratios (aHRs, 95% confidence intervals) compared the effect of s-ALL with de novo ALL on overall survival. A total of 14 481 patients with ALL were identified (1988-2012) and 382 (3%) had a known prior malignancy. Any prior malignancy predisposed patients to developing ALL: SIR 1.62 (1.45-1.79). Hematologic malignancies (SIR 5.57, 4.38-6.98) and IR-solid tumors (SIR 2.11, 1.73-2.54) increased the risk of developing ALL. s-ALL increased the risk of death compared with de novo ALL (aHR 1.38 (1.16-1.63)) and this effect was more pronounced among younger patients (age<40 years: aHR 4.80 (3.15-7.30); age⩾40 years: aHR 1.40 (1.16-1.69)) (interaction P<0.001). This population-based study demonstrates that s-ALL is a distinct entity that occurs after specific malignancies and carries a poor prognosis compared with de novo ALL, particularly among patients <40 years of age.

Recent studies on plant-pathogen interactions have exposed a new strategy used by plant pathogens: decoy effectors that protect virulence factors. Examples of these "bodyguards" include the recently discovered PsXLP1 from Phytophthora sojae and truncated TALEs from Xanthomonas oryzae. These examples suggest important roles for seemingly non-functional effector proteins in distracting the host., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Multiple myeloma/plasmacytoma-like posttransplantation lymphoproliferative disorder (PTLD-MM) is a rare complication of solid organ transplantation. Case series have shown variable outcomes, and survival data in the modern era are lacking., Patients and Methods: A cohort of 212 PTLD-MM patients was identified in the Scientific Registry of Transplant Recipients between 1999 and 2011. Overall survival (OS) was estimated by the Kaplan-Meier method, and the effects of treatment and patient characteristics on OS were evaluated by Cox proportional hazards models. OS in 185 PTLD-MM patients was compared to 4048 matched controls with multiple myeloma (SEER-MM) derived from Surveillance, Epidemiology, and End Results (SEER) data., Results: Men comprised 71% of patients; extramedullary disease was noted in 58%. Novel therapeutic agents were used in 19% of patients (more commonly during 2007-2011 vs. 1999-2006; P = .01), reduced immunosuppression in 55%, and chemotherapy in 32%. Median OS was 2.4 years and improved in the later time period (adjusted hazard ratio [aHR], 0.64, P = .05). Advanced age, creatinine > 2 g/dL, white race, and use of OKT3 were associated with inferior OS in multivariable analysis. OS of PTLD-MM patients is significantly inferior to SEER-MM patients (aHR, 1.6, P < .001). Improvements in OS over time differed between PTLD-MM and SEER-MM. Median OS of patients diagnosed from 2000 to 2005 was shorter for PTLD-MM than SEER-MM patients (18 vs. 47 months, P < .001). There was no difference among those diagnosed from 2006 to 2010 (44 months vs. median not reached, P = .5; interaction P = .08)., Conclusion: Age at diagnosis, elevated creatinine, white race, and OKT3 were associated with inferior survival in patients with PTLD-MM. Survival of PTLD-MM is inferior to SEER-MM, although significant improvements in survival have been documented., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Autosomal dominant polycystic kidney disease (ADPKD) affects millions of people worldwide. Vasopressin promotes disease progression., Study Design: A randomized controlled trial with equal (1:1) allocation., Setting & Participants: This trial examined the effect of combining a low-osmolar (low-sodium [1,500mg/d], low-protein [0.8g per kilogram of body weight]) diet and adjusted water intake on vasopressin secretion in 34 patients with ADPKD., Intervention: Participants were randomly assigned to receive a low-osmolar diet followed by adjusted water intake to achieve urine osmolality ≤ 280mOsm/kg water versus no intervention for 2 weeks., Outcome: The primary outcome of the study was change (delta) in copeptin levels and urine osmolality between the intervention and control groups from baseline to 2 weeks., Measurements: Fasting plasma copeptin level, 24-hour urine osmolality, and total solute intake., Results: Baseline characteristics of the 2 groups were similar. Mean plasma copeptin levels and urine osmolality declined from 6.2±3.05 (SD) to 5.3±2.5pmol/L (P=0.02) and from 426±193 to 258±117mOsm/kg water (P=0.01), respectively, in the intervention group compared to a nonsignificant change in the control group (from 4.7±3.6 to 5.07±4pmol/L [P=0.2] and 329±159 to 349±139mOsm/kg water [P=0.3], respectively). The change in copeptin levels (primary outcome) and urine osmolality was statistically significant between the intervention and control groups (delta copeptin, -0.86±1.3 vs +0.39±1.2pmol/L [P=0.009]; delta urine osmolality, -167±264 vs +20±80mOsm/kg water [P=0.007], respectively). Total urinary solute decreased in only the intervention group and significantly differed between groups at week 1 (P=0.03), reducing mean water prescription from 3.2 to 2.6L/d., Limitations: Small sample size and short follow-up., Conclusions: We developed a stepwise dietary intervention that led to a significant reduction in vasopressin secretion in patients with ADPKD. Furthermore, this intervention led to a reduction in water required for vasopressin reduction., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Systemic arterial stiffness is recognized as a major contributor to development of left ventricular dysfunction and failure; however, the relationship of systemic arterial properties and the right ventricle (RV) is unknown., Methods and Results: The associations between systemic arterial measures (total arterial compliance [TAC], systemic vascular resistance [SVR], and aortic augmentation index [AI]) and RV morphology (mass, end-systolic [RVESV] and end-diastolic volume [RVEDV], and ejection fraction [RVEF]) were examined using data from the Multi-Ethnic Study of Atherosclerosis. All analyses were adjusted for anthropometric, demographic, and clinical variables and the corresponding left ventricular parameter. A total of 3842 subjects without clinical cardiovascular disease were included with a mean age of 61 years, 48% male, 39% non-Hispanic white, 25% Chinese-American, 23% Hispanic, and 13% black. RV measures were within normal range for age and sex. A 1-mL/mm Hg decrease in TAC was associated with 3.9-mL smaller RVESV, 7.6-mL smaller RVEDV, and 2.4-g lower RV mass. A 5-Wood-unit increase in SVR was associated with 0.6-mL decrease in RVESV, 1.7-mL decrease in RVEDV, and 0.4-g decrease in RV mass. A 1% increase in AI was associated with 0.2-mL decrease in RVEDV. We found significant effect modification by age, sex, and race for some of these relationships, with males, whites, and younger individuals having greater decreases in RV volumes and mass., Conclusions: Markers of increased systemic arterial load were associated with smaller RV volumes and lower RV mass in a population of adults without clinical cardiovascular disease., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: For patients and health care providers who are considering spinal manipulative therapy of the neck, it is crucial to establish if it is a trigger for cervical artery dissection and/or stroke, and if it is, the magnitude of the risk., Discussion: We discuss the biological plausibility of how neck manipulation could cause cervical artery dissection. We also discuss how case misclassification threatens the validity of influential published studies that have investigated the relationship between neck manipulation and dissection. Our position is supported by the fact that the largest epidemiologic studies of neck manipulation safety with respect to neurological outcomes have relied on International Classification of Diseases-9 codes for case identification. However, the application of these codes in prior studies failed to identify dissections (rather than strokes in general) and so conclusions from those studies are invalid., Conclusion: There are several methodological challenges to understanding the association between neck manipulation and vertebral artery dissection. Addressing these issues is critical because even a modest association between neck manipulation and cervical artery dissection could translate into a significant number of avoidable dissections given the widespread use of neck manipulation by providers from various backgrounds. We believe that valid case classification, accurate measurement of manipulative procedures, and addressing reverse causation bias should be top priorities for future research.

Background: Foregut duplication cysts are rare congenital anomalies that require surgical intervention with approximately 10%-15% of all gastrointestinal duplication cysts originating from the esophagus. Consensus is lacking among surgeons regarding closure of the esophageal muscle layer after resection of an esophageal duplication cyst and long-term outcomes are poorly documented. Therefore, we conducted the first study comparing complication rates in patients undergoing closure versus nonclosure of the esophageal muscle layer after esophageal duplication cyst resection., Materials and Methods: A retrospective cohort study at Boston Children's Hospital, Massachusetts General Hospital, Brigham and Women's Hospital, and the Floating Hospital for Children at Tufts Medical Center was conducted. Patients undergoing resection of esophageal duplication cysts between 1990 and 2012 were classified according to whether the esophageal muscle layer was closed or left open. Demographic data, surgical technique, preoperative symptoms, and both short-term (<30 d) and long-term (≥30 d) complication rates were abstracted from patient medical records., Results: Twenty-five patients were identified with a median age of 15-y old (range, 2 mo to 68-y old) and an average follow-up of 1 y. Eleven patients had the esophageal muscle layer closed after surgical resection (44%). Of those 11 patients, one developed a short-term complication, dysphagia (9%, 95% CI: 2%, 38%). Only one patient returned to the operating room, after 30 d, for an upper endoscopy after developing symptoms of gastroesophageal reflux disease. Of the 14 patients who had their muscle layer left open, three patients (21%, 95% CI: 8%, 48%) developed short-term complications, two of whom required surgical intervention within 30 d. Furthermore, two additional patients required surgical intervention after 30 d for a long-term complication (diverticulum and cyst recurrence)., Conclusions: Surgical complications occurred more frequently in patients who had the muscle layer left open after resection of an esophageal duplication cyst. In addition, most patients requiring reoperation for both short-term and long-term complications occurred in this group. Though small, this study is the first to evaluate the complications after resecting esophageal duplication cysts. Our results suggest that closing the esophageal muscle layer after removal of an esophageal duplication cyst may be indicated to prevent both complications and the need for reoperations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Metformin has been associated with improved colorectal cancer survival, but investigations are limited by small numbers of patients and confounding by diabetic severity. We examined the association between metformin use and overall survival (OS) in patients with diabetes and colorectal cancer in a large population of U.S. veterans, while adjusting for measures of diabetic severity., Methods: Patients diagnosed with colorectal cancer from January 2001 to December 2008 were identified from the Veterans Affairs Central Cancer Registry. Multivariable models were used to examine the adjusted association of OS with diabetes and use of antidiabetic medications., Results: There were 21,352 patients diagnosed with colorectal cancer identified (n = 16,355 nondiabetic patients, n = 2,038 diabetic patients on metformin, n = 2,136 diabetic patients on medications other than metformin, n = 823 diabetic patients not on antidiabetic medication). Diabetic patients had a significantly worse OS than nondiabetic patients, but metformin users had only a 10% increase in death (HR adj 1.10; 95% CI, 1.03-1.17, P = 0.004), as compared with 22% for users of other antidiabetic medications (HR adj 1.22; 95% CI, 1.15-1.29, P < 0.0001). Among colorectal cancer patients with diabetes, metformin users had a 13% improved OS versus patients taking other antidiabetic medications (HR adj 0.87; 95% CI, 0.79-0.95, P = 0.003), while diabetic patients not on any antidiabetic medications did not differ with respect to OS (HR adj 1.02; 95% CI, 0.90-1.15, P = 0.76)., Conclusions: Among diabetics with colorectal cancer, metformin use is associated with improved survival, despite adjustments for diabetes severity and other risk factors., Impact: These data lend further support to the conduct of randomized studies of possible anticancer effects of metformin among patients with colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(10); 1418-25. ©2016 AACR., (©2016 American Association for Cancer Research.)

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.)