Injectable Estradiol Use in Transgender and Gender-Diverse Individuals in the U.S.: A Multicenter Retrospective Study.

Context: Guidelines for use of injectable estradiol esters (valerate [EV] and cypionate [EC]) among transgender and gender diverse (TGD) individuals designated male at birth vary considerably, with many providers noting supraphysiologic serum estradiol concentrations based on current dosing recommendations.

Objectives: 1. Determine dose of injectable estradiol (subcutaneous [SC] and intramuscular [IM]) needed to reach guideline-recommended estradiol concentrations for TGD adults using EC/EV.

Fixation of Expression Divergences by Natural Selection in Coding Genes.

Functional divergences of coding genes can be caused by divergences in their coding sequences and expression. However, whether and how expression divergences and coding sequence divergences coevolve is not clear. Gene expression divergences in differentiated cells and tissues recapitulate developmental models within a species, while gene expression divergences between analogous cells and tissues resemble traditional phylogenies in different species, suggesting that gene expression divergences are molecular traits that can be used for evolutionary studies.

Gender and Authorship in Annals of Surgery: A nineteen-year review including the pandemic.

Objective: We examined article submission data from the Annals of Surgery to assess gender bias in publishing.

Background: Medicine has long been a male-dominated practice, particularly in surgical fields. A key criterion for promotion in academic medicine is the publication record.

Assessing the role of mitonuclear interactions on mitochondrial function and organismal fitness in natural populations.

Mitochondrial function depends on the effective interactions between proteins and RNA encoded by the mitochondrial and nuclear genomes. Evidence suggests that both genomes respond to thermal selection and promote adaptation. However, the contribution of their epistatic interactions to life history phenotypes in the wild remains elusive.

Model for Urgency for Liver Transplantation in Hepatocellular Carcinoma: A Practical Model to Prioritize Patients With Hepatocellular Carcinoma on the Liver Transplant Waiting List.

Background & Aims: Currently, patients with hepatocellular carcinoma (HCC) in the United States are assigned a uniform score relative to the median Model for End-Stage Liver Disease (MELD) at transplant after a minimum 6-month waiting period. The authors developed a risk stratification model for patients with HCC using the available and objective variables at time of listing.

Methods: Adult liver transplant candidates with approved HCC exception in the Organ Procurement and Transplantation Network database from 2015-2022 were identified.

Evaluating the utility of multi-gene, multi-disease population-based panel testing accounting for uncertainty in penetrance estimates.

Panel germline testing allows for the efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency, estimated penetrances, and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates.

Benchmarking clinical risk prediction algorithms with ensemble machine learning for the noninvasive diagnosis of liver fibrosis in NAFLD.

Background And Aims: Ensemble machine-learning methods, like the superlearner, combine multiple models into a single one to enhance predictive accuracy. Here we explore the potential of the superlearner as a benchmarking tool for clinical risk prediction, illustrating the approach to identifying significant liver fibrosis among patients with NAFLD.

Approach And Results: We used 23 demographic/clinical variables to train superlearner(s) on data from the NASH-clinical research network observational study (n = 648) and validated models with data from the FLINT trial (n = 270) and National Health and Nutrition Examination Survey (NHANES) participants with NAFLD (n = 1244).

The effect of socioeconomic status on pediatric heart transplant outcomes at a single institution between 2013 and 2022.

Background: Disparities in pediatric heart transplant outcomes based on socioeconomic status (SES) have been previously observed. However, there is a need to reevaluate these associations in contemporary settings with advancements in transplant therapies and increased awareness of health disparities. This retrospective study aims to investigate the relationship between SES and outcomes for pediatric heart transplant patients.

Barriers to Family Building Among Physicians and Medical Students.

Importance: Physicians and medical students who desire to build families face significant barriers due to the structure and culture of medicine.

Objective: To understand the barriers and facilitators to family building for all people in medicine-not only individuals who can become pregnant-through an open-ended, qualitative analysis of survey responses.

Design, Setting, And Participants: This qualitative study used a survey conducted in April and May 2021 with a broad sample of physicians and medical students.

Heterogeneous Treatment Effects of Intensive Glycemic Control on Kidney Microvascular Outcomes and Mortality in ACCORD.

Significance Statement: Identifying and quantifying treatment effect variation across patients is the fundamental challenge of precision medicine. Here we quantify heterogeneous treatment effects of intensive glycemic control in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, considering three outcomes of interest-a composite kidney outcome (driven by macroalbuminuria), all-cause mortality, and first assisted hypoglycemic event. We demonstrate that the effects of intensive glycemic control vary with risk of kidney failure, as predicted by the kidney failure risk equation (KFRE).

Low infectivity among asymptomatic patients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test at a tertiary care center, 2020-2022.

We used a strand-specific RT-qPCR to evaluate viral replication as a surrogate for infectiousness among 242 asymptomatic inpatients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test. Only 21 patients (9%) had detectable SARS-CoV-2 minus-strand RNA. Because most patients were found to be noninfectious, our findings support the suspension of asymptomatic admission testing.

Benchmarking clinical risk prediction algorithms with ensemble machine learning: An illustration of the superlearner algorithm for the non-invasive diagnosis of liver fibrosis in non-alcoholic fatty liver disease.

Background And Aims: Ensemble machine learning (ML) methods can combine many individual models into a single 'super' model using an optimal weighted combination. Here we demonstrate how an underutilized ensemble model, the superlearner, can be used as a benchmark for model performance in clinical risk prediction. We illustrate this by implementing a superlearner to predict liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

Heterogeneous treatment effects of intensive glycemic control on kidney microvascular outcomes in ACCORD.

Objective: Clear criteria to individualize glycemic targets are lacking. In this post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD), we evaluate whether the kidney failure risk equation (KFRE) can identify patients who disproportionately benefit from intensive glycemic control on kidney microvascular outcomes.

Research Design And Methods: We divided the ACCORD trial population in quartiles based on 5-year kidney failure risk using the KFRE.

Statistical methods for Mendelian models with multiple genes and cancers.

Risk evaluation to identify individuals who are at greater risk of cancer as a result of heritable pathogenic variants is a valuable component of individualized clinical management. Using principles of Mendelian genetics, Bayesian probability theory, and variant-specific knowledge, Mendelian models derive the probability of carrying a pathogenic variant and developing cancer in the future, based on family history. Existing Mendelian models are widely employed, but are generally limited to specific genes and syndromes.

Validation of Breast Cancer Risk Models by Race/Ethnicity, Family History and Molecular Subtypes.

(1) Background: The purpose of this study is to compare the performance of four breast cancer risk prediction models by race, molecular subtype, family history of breast cancer, age, and BMI. (2) Methods: Using a cohort of women aged 40-84 without prior history of breast cancer who underwent screening mammography from 2006 to 2015, we generated breast cancer risk estimates using the Breast Cancer Risk Assessment tool (BCRAT), BRCAPRO, Breast Cancer Surveillance Consortium (BCSC) and combined BRCAPRO+BCRAT models. Model calibration and discrimination were compared using observed-to-expected ratios (O/E) and the area under the receiver operator curve (AUC) among patients with at least five years of follow-up.

Multi-syndrome, multi-gene risk modeling for individuals with a family history of cancer with the novel R package PanelPRO.

Identifying individuals who are at high risk of cancer due to inherited germline mutations is critical for effective implementation of personalized prevention strategies. Most existing models focus on a few specific syndromes; however, recent evidence from multi-gene panel testing shows that many syndromes are overlapping, motivating the development of models that incorporate family history on several cancers and predict mutations for a comprehensive panel of genes. We present PanelPRO, a new, open-source R package providing a fast, flexible back-end for multi-gene, multi-cancer risk modeling with pedigree data.

A likelihood-based approach to assessing frequency of pathogenicity among variants of unknown significance in susceptibility genes.

Commercialized multigene panel testing brings unprecedented opportunities to understand germline genetic contributions to hereditary cancers. Most genetic testing companies classify the pathogenicity of variants as pathogenic, benign, or variants of unknown significance (VUSs). The unknown pathogenicity of VUSs poses serious challenges to clinical decision-making.

Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects.

Purpose: To evaluate the effects of multiple doses of loperamide on the pharmacokinetics and safety of a single oral dose of neratinib.

Methods: This was an open-label, two-period, fixed-sequence study. Twenty healthy adult subjects received an oral dose of neratinib 240 mg daily on Days 1-4 of Period 1 followed by a 7-day washout.

Matrix Linear Models for High-Throughput Chemical Genetic Screens.

We develop a flexible and computationally efficient approach for analyzing high-throughput chemical genetic screens. In such screens, a library of genetic mutants is phenotyped in a large number of stresses. Typically, interactions between genes and stresses are detected by grouping the mutants and stresses into categories, and performing modified -tests for each combination.

Longitudinal study of leukocyte DNA methylation and biomarkers for cancer risk in older adults.

Background: Changes in DNA methylation over the course of life may provide an indicator of risk for cancer. We explored longitudinal changes in CpG methylation from blood leukocytes, and likelihood of future cancer diagnosis.

Methods: Peripheral blood samples were obtained at baseline and at follow-up visit from 20 participants in the Health, Aging and Body Composition prospective cohort study.

Profiling DNA methylation differences between inbred mouse strains on the Illumina Human Infinium MethylationEPIC microarray.

The Illumina Infinium MethylationEPIC provides an efficient platform for profiling DNA methylation in humans at over 850,000 CpGs. Model organisms such as mice do not currently benefit from an equivalent array. Here we used this array to measure DNA methylation in mice.

Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial.

Background: Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study.

A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib.

Background: This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health-related quality of life of dacomitinib (PF-00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild-type non-small cell lung cancer (NSCLC).

Methods: Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild-type or known EGFR-sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21-day cycles.

Benefit-to-harm ratio of thromboprophylaxis for patients undergoing major orthopaedic surgery. A systematic review.

Surgeons consider the benefit-to-harm ratio when making decisions regarding the use of anticoagulant venous thromboembolism (VTE) prophylaxis. We evaluated the benefit-to-harm ratio of the use of newer anticoagulants as thromboprophylaxis in patients undergoing major orthopaedic surgery using the likelihood of being helped or harmed (LHH), and assessed the effects of variation in the definition of major bleeding on the results. A systematic literature search was performed to identify phase II and phase III studies that compared regulatory authority-approved newer anticoagulants to the low-molecular-weight heparin enoxaparin in patients undergoing major orthopaedic surgery.