Quality of Life in Patients and Their Spouses and Cohabitating Partners in the Year Following a Cancer Biopsy (the Couples Cope Study): Protocol for a Prospective Observational Study.

BACKGROUND: Receiving a diagnosis of cancer is a profound and often very stressful experience. Few studies have prospectively recruited patients prior to receiving a new diagnosis of cancer and included spouses or partners. OBJECTIVE: The aim of the Couples Cope Study is to understand the impact of undergoing a diagnostic biopsy and receiving a new cancer diagnosis on quality of life (QoL) in both patients and their spouses or partners, as well as on the quality of their relationship. This protocol paper describes the study design and assesses the feasibility of recruitment and retention. METHODS: Study staff reviewed the schedules of collaborating physicians using specific encounter codes to identify patients scheduled for breast or prostate biopsies. Potential participants were prescreened via the electronic health record and sent a recruitment letter at least 2 to 3 weeks prior to their biopsy procedure. Patients subsequently underwent a phone screening to determine eligibility. Patients who enrolled provided study staff with contact information for their spouses or partners. All consent forms were completed online. Surveys were completed online prior to receiving the biopsy results (baseline), and at 1, 3, 6, and 9 months after the biopsy. Study staff engaged in ongoing, personalized contact with participants and sent assessment completion reminders via phone and email. RESULTS: A total of 2294 patients undergoing a breast or prostate biopsy were identified and 69% (n=1582) were eligible for phone screening following electronic health record prescreening. Of the 431 patients who underwent phone screening, 75% (n=321) were eligible to participate. Of the eligible patients, 72% (n=231) enrolled and 82% (n=190) of enrolled patients had an accompanying partner or spouse who also enrolled. A total of 77% (34/44) of patients who received a cancer diagnosis and 72% (26/36) of their spouses or partners were retained through 9 months, while 80% (53/66) of patients who received a benign diagnosis and 68% (42/62) of their partners were retained. CONCLUSIONS: Prospective recruitment of patients undergoing diagnostic biopsy and their partners is feasible and requires both strategic collaboration with providers and concerted prescreening and recruitment efforts by study staff. Importantly, this study was able to conduct all study activities online without disrupting clinical workflow and without requiring patients and their spouses or partners to come into the laboratory. Consideration should be given to the ratio of biopsies to cancer diagnoses, which can vary significantly by cancer type. Prospective studies are needed and can inform our ability to provide effective support earlier to couples facing a possible cancer diagnosis. Future studies should examine other tumor types that have received less attention in QoL studies, include behavioral and neurobiological assessments beyond self-report measures, and follow couples beyond 9 months in order to examine long-term effects on QoL. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52361.

Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial (PRISM-RCT) in Chinese patients with young-onset diabetes: design, methods and baseline characteristics.

INTRODUCTION: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines. RESEARCH DESIGN AND METHODS: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications. RESULTS: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes. CONCLUSIONS: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events. TRIAL REGISTRATION NUMBER: NCT04049149.

Sorted-Cell Sequencing on HCC Specimens Reveals EPS8L3 as a Key Player in CD24/CD13/EpCAM-Triple Positive, Stemness-Related HCC Cells.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with varying levels of liver tumor initiating or cancer stem cells in the tumors. We aimed to investigate the expression of different liver cancer stem cell (LCSC) markers in human HCCs and identify their regulatory mechanisms in stemness-related cells. METHODS: We used an unbiased, single-marker sorting approach by flow cytometry, fluorescence-activated cell sorting, and transcriptomic analyses on HCC patients' resected specimens. Knockdown approach was used, and relevant functional assays were conducted on the identified targets of interest. RESULTS: Flow cytometry on a total of 60 HCC resected specimens showed significant heterogeneity in the expression of LCSC markers, with CD24, CD13, and EpCAM mainly contributing to this heterogeneity. Concomitant expression of CD24, CD13, and EpCAM was detected in 32 HCC samples, and this was associated with advanced tumor stages. Transcriptomic sequencing on the HCC cells sorted for these individual markers identified epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3) as a common gene associated with the 3 markers and was functionally validated in HCC cells. Knocking down EPS8L3 suppressed the expression of all 3 markers. To search for the upstream regulation of EPS8L3, we found SP1 bound to EPS8L3 promoter to drive EPS8L3 expression. Furthermore, using Akt inhibitor MK2206, we showed that Akt signaling-driven SP1 drove the expression of the 3 LCSC markers. CONCLUSIONS: Our findings suggest that Akt signaling-driven SP1 promotes EPS8L3 expression, which is critical in maintaining the downstream expression of CD24, CD13, and EpCAM. The findings provide insight into potential LCSC-targeting therapeutic strategies.

Randomized controlled trial of a positive emotion regulation intervention to reduce stress in family caregivers of individuals with Alzheimer's disease: protocol and design for the LEAF 2.0 study.

BACKGROUND: Caring for a loved one with Alzheimer's disease can be stressful, resulting in poorer emotional and physical health among family caregivers. Although supportive resources for caregivers are available, distance, caregiver health, and the daily demands of caregiving are barriers to access. Based on research demonstrating the importance of positive emotions in coping with stress, our previous trial showed that dementia caregivers who participated in facilitated, web-based delivery of a positive emotion regulation intervention called LEAF (Life Enhancing Activities for Family caregivers) experienced increased positive emotion and decreased depression and anxiety. Building on this evidence, the LEAF 2.0 study aims to test whether web-based, self-guided delivery can confer similar benefits for caregivers of individuals with Alzheimer's disease. METHODS: This paper presents the design and methods for LEAF 2.0, a 3-arm web-based randomized controlled trial (N = 500) in which family caregivers of patients with Alzheimer's disease (AD) are randomized to (1) the LEAF intervention facilitated remotely via the web (N = 200), (2) the LEAF intervention self-guided online (N = 200), or (3) an emotion reporting control (N = 100), which then crosses over to the intervention after approximately 6 months, half to the facilitated arm and half to the self-guided arm. We aim to (1) compare the effect of the facilitated and self-guided LEAF positive emotion interventions to an emotion reporting control condition on AD caregiver well-being (positive emotion, depression, anxiety, and perceived stress) and secondary outcomes (caregiving burden, caregiving self-efficacy, positive aspects of caregiving, quality of care, and AD patient quality of life); (2) assess whether effects are mediated by improvements in positive emotion or other aspects of caregiver well-being; and (3) test whether caregiver age or gender or the care recipient's dementia severity moderates the effects of the intervention. DISCUSSION: If demonstrated to be effective, LEAF can be widely disseminated and ultimately have a significant impact on the stress experienced by AD caregivers and the well-being of people living with Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03610698.

Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Associations Between Program Doximity Reputation Rank and Well-Being in General Surgery Residents.

INTRODUCTION: Burnout and mistreatment are prevalent among surgical residents with considerable program-level variation. Applicants consider "program reputation," among other factors, when ranking programs. Although highly subjective, the only available measure of program reputation is from a physician survey by Doximity. It is unknown how program reputation is associated with resident well-being and mistreatment. METHODS: Resident burnout and personal accomplishment were assessed via the 2019 post-American Board of Surgery In-Training Examination survey. Additional outcomes included mistreatment, thoughts of attrition, and suicidality. Residents were stratified into quartiles based on their program's Doximity reputation rank. Multivariable logistic regression models examined the relationship between each outcome with Doximity rank quartile. RESULTS: 6956 residents (85.6% response rate) completed the survey. Higher-ranked programs had significantly higher burnout rates (top-quartile 41.3% versus bottom-quartile 33.2%; odds ratio [OR] 1.35, 95% confidence interval [CI] 1.04-1.76). There was no significant difference in personal accomplishment by program rank (OR 1.26, 95% CI 0.86-1.85). There also was no significant association between program rank and sexual harassment (OR 0.90, 95% CI 0.70-1.17), gender discrimination (OR 1.14, 95% CI 0.86-1.52), racial discrimination (OR 1.18, 95% CI 0.91-1.54), or bullying (OR 1.03, 95% CI 0.76-1.40). Suicidality (P = 0.97) and thoughts of attrition (P = 0.80) were also not associated with program rank. CONCLUSIONS: Surgical residents at higher-ranked programs report higher rates of burnout but have similar rates of mistreatment and personal accomplishment. Higher-ranked programs should be particularly vigilant to trainee burnout, and all programs should employ targeted interventions to improve resident well-being. This study highlights the need for greater transparency in reporting objective program-level quality measures pertaining to resident well-being.

Reciprocal interactions between malignant cells and macrophages enhance cancer stemness and M2 polarization in HBV-associated hepatocellular carcinoma.

Background: The tumor microenvironment of cancers has emerged as a crucial component in regulating cancer stemness and plays a pivotal role in cell-cell communication. However, the specific mechanisms underlying these phenomena remain poorly understood. Methods: We performed the single-cell RNA sequencing (scRNA-seq) on nine HBV-associated hepatocellular carcinoma (HCC) patients. The heterogeneity of the malignant cells in pathway functions, transcription factors (TFs) regulation, overall survival, stemness, as well as ligand-receptor-based intercellular communication with macrophages were characterized. The aggressive and stemness feature for the target tumor subclone was validated by the conduction of in vitro assays including sphere formation, proliferation, Annexin V apoptosis, flow cytometry, siRNA library screening assays, and multiple in vivo preclinical mouse models including mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection. Results: Our analysis yielded a comprehensive atlas of 31,664 cells, revealing a diverse array of malignant cell subpopulations. Notably, we identified a stemness-related subclone of HCC cells with concurrent upregulation of CD24, CD47, and ICAM1 expression that correlated with poorer overall survival. Functional characterization both in vitro and in vivo validated S100A11 as one of the top downstream mediators for tumor initiation and stemness maintenance of this subclone. Further investigation of cell-cell communication within the tumor microenvironment revealed a propensity for bi-directional crosstalk between this stemness-related subclone and tumor-associated macrophages (TAMs). Co-culture study showed that this interaction resulted in the maintenance of the expression of cancer stem cell markers and driving M2-like TAM polarization towards a pro-tumorigenic niche. We also consolidated an inverse relationship between the proportions of TAMs and tumor-infiltrating T cells. Conclusions: Our study highlighted the critical role of stemness-related cancer cell populations in driving an immunosuppressive tumor microenvironment and identified the S100A11 gene as a key mediator for stemness maintenance in HCC. Moreover, our study provides support that the maintenance of cancer stemness is more attributed to M2 polarization than the recruitment of the TAMs.

Genome-Wide DNA Methylation Profiling as Frontline Diagnostics for Central Nervous System Embryonal Tumors in Hong Kong.

This paper examines the link between CNS tumor biology and heterogeneity and the use of genome-wide DNA methylation profiling as a clinical diagnostic platform. CNS tumors are the most common solid tumors in children, and their prognosis remains poor. This study retrospectively analyzed pediatric patients with CNS embryonal tumors in Hong Kong between 1999 and 2017, using data from the territory-wide registry and available formalin-fixed paraffin-embedded tumor tissue. After processing archival tumor tissue via DNA extraction, quantification, and methylation profiling, the data were analyzed by using the web-based DKFZ classifier (Molecular Neuropathology (MNP) 2.0 v11b4) and t-SNE analysis. Methylation profiles were deemed informative in 85 samples. Epigenetic data allowed molecular subgrouping and confirmed diagnosis in 65 samples, verified histologic diagnosis in 8, and suggested an alternative diagnosis in 12. This study demonstrates the potential of DNA methylation profiling in characterizing pediatric CNS embryonal tumors in a large cohort from Hong Kong, which should enable regional and international collaboration in future pediatric neuro-oncology research.

Aberrant p16, p53 and Ki-67 immunohistochemistry staining patterns can distinguish solitary keratoacanthoma from cutaneous squamous cell carcinoma.

Keratoacanthoma (KA) is widely considered a benign, usually self-resolving, neoplasm distinct from cutaneous squamous cell carcinoma (cSCC), while some consider KA to be indistinguishable from cSCC. Published studies indicate utility for p16, p53, Ki-67 immunostaining and elastic van Gieson (EVG) in the assessment of KA and cSCC. We compared clinical features and staining patterns for p16, p53, Ki-67 and EVG in fully excised KA, cSCC with KA-like features (cSCC-KAL) and other cSCC (cSCC-OTHER). Significant differences between KA, cSCC-KAL and cSCC-OTHER were found for head and neck location (20%, 86%, 84%), and duration <5 months (95%, 63%, 36%). KA shows both a mosaic pattern for p16 (>25-90% of neoplasm area) and peripheral graded pattern for p53 (up to 50% moderate and strong nuclear staining) in 92% compared with 0% of cSCC-KAL and 0% of cSCC-OTHER. In contrast, a highly aberrant pattern (usually null) for one or both p16 and p53, was present in 0% of KA, 83.8% of cSCC-KAL and 90.9% of cSCC-OTHER. Abnormal distribution of Ki-67 beyond the peripheral 1-3 cells was uncommon in KA (4.2%) and common in cSCC-KAL (67.6%) and cSCC-OTHER (88.4%). Moderate to striking entrapment of elastic and collagen fibres was present in the majority of KA (84%), cSCC-KAL (81%) and cSCC-OTHER (65%). KA are clinically distinct neoplasms typically of short duration occurring preferentially outside the head and neck and generally lacking aberrations of p16, p53 and Ki-67, compared with cSCC that have high rates of aberrant or highly aberrant p16, p53 and Ki-67, but EVG lacked specificity.

Childbearing, Infertility, and Career Trajectories Among Women in Medicine.

Importance: Although women are increasingly represented within medicine, gender disparities persist in time to promotion, achievement of academic rank, and appointment to leadership positions, with no narrowing of this gap over time. Career-specific fertility and family building challenges among women physicians may contribute to ongoing disparities and academic attrition. Objective: To evaluate delayed childbearing and infertility among women in medicine and investigate the extent to which women physicians may alter career trajectories to accommodate family building and parenthood. Design, Setting, and Participants: This survey study was conducted among women physicians, with surveys distributed through medical society electronic mailing lists (listserves) and social media from March to August 2022. Main Outcomes and Measures: Baseline demographic information and fertility knowledge were assessed. Descriptive data on delayed childbearing, infertility, use of assisted reproductive technology, and career alterations to accommodate parenthood were collected. Factors associated with timing of pregnancy and family building regret were assessed using Likert-type scales. Group differences in fertility knowledge, delayed childbearing, infertility, and family building regret were evaluated using χ2 analyses. Results: A total of 1056 cisgender women (mean [SD] age, 38.3 [7.7] years) were surveyed across level of training (714 attending physicians [67.6%] and 283 residents or fellows [26.8%]), specialty (408 surgical [38.6%] and 638 nonsurgical [60.4%] specialties), and practice setting (323 academic [45.2%], 263 private [24.9%], and 222 community [21.0%] settings). Among respondents, 1036 individuals [98.1%] resided in the US. Overall, 910 respondents (86.2%) were married or partnered and 690 respondents (65.3%) had children. While 824 physicians (78.0%) correctly identified the age of precipitous fertility decline, 798 individuals (75.6%) reported delaying family building and 389 individuals (36.8%) had experienced infertility. Concerning measures taken to accommodate childbearing or parenthood, 199 women (28.8%) said they had taken extended leave, 171 women (24.8%) said they had chosen a different specialty, 325 women (47.1%) said they had reduced their work hours, 171women (24.8%) said they had changed their practice setting, and 326 women (47.2%) said they had passed up opportunities for career advancement among those with children. Additionally, 30 women with children (4.3%) had left medicine entirely. Conclusions and Relevance: In this survey study, women physicians reported that career-related pressures influenced the timing of childbearing and led to marked alterations to career trajectories to accommodate family building and parenthood. These findings suggest that fertility and family building concerns among women in medicine may contribute to ongoing gender disparities and attrition and represent a potentially critical area for policy reform and future change.

Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes.

OBJECTIVE: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. RESEARCH DESIGN AND METHODS: We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases. RESULTS: We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13-1.30]; P = 2.4 × 10-8) and BP (ß ± SE 0.130 ± 0.017; P = 4.1 × 10-14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10-4). Patients with CC genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9 × 10-8 < P < 3.6 × 10-5), those with CT genotype had no difference (0.0726 < P < 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10-3). CONCLUSIONS: We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.

A MAPS Vaccine Induces Multipronged Systemic and Tissue-Resident Cellular Responses and Protects Mice against Mycobacterium tuberculosis.

Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. To date, the mainstay of vaccination involves the use of Mycobacterium bovis bacillus Calmette-Guérin (BCG), a live-attenuated vaccine that confers protection against extrapulmonary disease in infants and children but not against lung disease. Thus, there is an urgent need for novel vaccines. Here, we show that a multicomponent acellular vaccine (TB-MAPS) induces robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4+ and CD8+ T cells, and promotes trained innate immunity mediated by γδT and NKT cells in mice. When tested in a mouse aerosol infection model, TB-MAPS significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate. IMPORTANCE Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. Here, we evaluate a novel vaccine which induces a broad immune response to Mycobacterium tuberculosis including robust antibody responses and long-lived systemic and tissue-resident memory Th1, Th17, and cytotoxic CD4+ and CD8+ T cells. When tested in a mouse aerosol infection model, this vaccine significantly reduced bacterial loads in the lungs and spleens to the same extent as BCG. When used in conjunction with BCG, TB-MAPS further enhanced BCG-mediated protection, especially in the lungs, further supporting this construct as a promising TB vaccine candidate.

National Comparison of Program Director Perceptions vs. Resident Reports of the Learning Environment and Well-Being.

OBJECTIVE: Our research objectives were to (1) assess the correlation between PD perceptions and their residents' reported experiences and (2) identify PD and program characteristics associated with alignment between PD perceptions and their residents' reports. DESIGN, SETTING, PARTICIPANTS: A survey was administered to US general surgery residents following the 2019 American Board of Surgery In-Training Examination (ABSITE) to study wellness (burnout, thoughts of attrition, and suicidality) and mistreatment (gender discrimination, sexual harassment, racial/ethnic/religious discrimination, bullying). General surgery program directors (PDs) were surveyed about the degree to which they perceived mistreatment and wellness within their programs. Concordance between PDs' perceptions and their residents' reports was assessed using Spearman correlations. Multivariable logistic regression models examined factors associated with alignment between PDs and residents. RESULTS: Of 6,126 residents training at SECOND Trial-enrolled programs, 5,240 (85.5%) responded to the ABSITE survey. All 212 PDs of programs enrolled in the SECOND Trial (100%) responded to the PD survey. Nationally, the proportion of PDs perceiving wellness issues was similar to the proportion of residents reporting them (e.g., 54.9% of PDs perceive that burnout is a problem vs. 40.1% of residents experience at least one burnout symptom weekly); however, the proportion of PDs perceiving mistreatment vastly underestimated the proportion of residents reporting it (e.g., 9.3% of all PDs perceive vs. 65.9% of all residents report bullying). Correlations between PDs' perceptions of problems within their program and their residents' reports were weak for racial/ethnic/religious discrimination (r = 0.176, p = 0.019), sexual harassment (r = 0.180, p = 0.019), burnout (r = 0.198, p = 0.007), and thoughts of attrition (r = 0.193, p = 0.007), and non-existent for gender discrimination, bullying, or suicidality. Multivariable regression models did not identify any program or PD characteristics that were consistently associated with improved resident-program director alignment. CONCLUSIONS: Resident and PD perceptions were generally disparate regarding mistreatment, burnout, thoughts of attrition, and suicidality. Reconciling this discrepancy is critical to enacting meaningful change to improve the learning environment and resident well-being.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

A SART data cost-effectiveness analysis of planned oocyte cryopreservation versus in vitro fertilization with preimplantation genetic testing for aneuploidy considering ideal family size.

OBJECTIVE: To determine the cost-effectiveness of planned oocyte cryopreservation (OC) as a strategy for delayed childbearing to achieve 1 or 2 live births (LB) compared with in vitro fertilization (IVF) and preimplantation genetic testing for aneuploidy (PGT-A) at advanced reproductive age. DESIGN: Decision tree model with sensitivity analyses using data from the Society for Assisted Reproductive Technology Clinical Outcome Reporting System and other clinical sources. SETTING: Not applicable. PATIENT(S): A data-driven simulated cohort of patients desiring delayed childbearing with an ideal family size of 1 or 2 LB. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Probability of achieving ≥1 or 2 LB, average and maximum cost per patient, cost per percentage point increase in chance of LB, and population-level cost/LB. RESULT(S): For those desiring 1 LB, planned OC at age 33 with warming at age 43 decreased the average total cost per patient from $62,308 to $30,333 and increased the likelihood of LB from 50% to 73% when compared with no OC with up to 3 cycles of IVF/PGT-A at age 43. For those desiring 2 LB, 2 cycles of OC at age 33 and warming at age 40 yielded the lowest cost per patient and highest likelihood of achieving 2 LB ($51,250 and 77%, respectively) when compared withpursuing only 1 cycle of OC ($75,373 and 61%, respectively), no OC and IVF/PGT-A with embryo banking ($79,728 and 48%, respectively), or no OC and IVF/PGT-A without embryo banking ($79,057 and 19%, respectively). Sensitivity analyses showed that OC remained cost-effective across a wide range of ages at cryopreservation. For 1 LB, OC achieved the highest likelihood of success when pursued before age 32 and remained more effective than IVF/PGT-A when pursued before age 39, and for 2 LB, 2 cycles of OC achieved the highest likelihood of success when pursued before age 31 and remained more effective than IVF/PGT-A when pursued before age 39. CONCLUSION(S): Among patients planning to postpone childbearing, OC is cost-effective and increases the odds of achieving 1 or 2 LB when compared with IVF/PGT-A at a more advanced reproductive age.

Host Respiratory Transcriptome Signature Associated with Poor Outcome in Children with Influenza-Staphylococcus aureus Pneumonia.

Respiratory coinfection of influenza with Staphylococcus aureus often causes severe disease; methicillin-resistant S. aureus (MRSA) coinfection is frequently fatal. Understanding disease pathogenesis may inform therapies. We aimed to identify host and pathogen transcriptomic (messenger RNA) signatures from the respiratory compartment of pediatric patients critically ill with influenza-S. aureus coinfection (ISAC), signatures that predict worse outcomes. Messenger RNA extracted from endotracheal aspirate samples was evaluated for S. aureus and host transcriptomic biosignatures. Influenza-MRSA outcomes were worse, but of 190 S. aureus virulence-associated genes, 6 were differentially expressed between MRSA-coinfected versus methicillin-susceptible S. aureus-coinfected patients, and none discriminated outcome. Host gene expression in patients with ISAC was compared with that in patients with influenza infection alone. Patients with poor clinical outcomes (death or prolonged multiorgan dysfunction) had relatively reduced expression of interferons and down-regulation of interferon γ-induced immune cell chemoattractants CXCL10 and CXCL11. In ISAC, airway host but not pathogen gene expression profiles predicted worse clinical outcomes.

Knowledge of Fertility and Perspectives About Family Planning Among Female Physicians.

Importance: Pervasive gender disparities exist in medicine regarding promotion, achievement of academic rank, and appointment to leadership positions. Fertility and childbearing concerns may contribute to these disparities. Objective: To assess fertility knowledge and concerns and evaluate barriers to family building and impact on academic attrition reported by female physicians. Design, Setting, and Participants: This qualitative study used mixed methods; first, structured 1:1 interviews exploring fertility knowledge and family-building concerns were conducted among 16 female physicians between November 2019 and May 2020. Transcripts were coded in Dedoose and used to develop a survey instrument with subsequent pilot testing conducted among 24 female physicians between April 2020 and September 2020. Data analysis was performed from January 2021 to March 2021. Main Outcomes and Measures: Fertility knowledge, perceptions of peer and institutional support surrounding childbearing, factors contributing to delayed childbearing, and impact of family planning on career decisions. Results: Among 16 women who completed qualitative interviews, 4 (25%) were Asian, 1 (6%) was Black, 1 (6%) was multiracial, and 10 (63%) were White; mean (SD) age was 34.9 (4.0) years. Evaluation of fertility knowledge revealed 3 notable themes: (1) inadequate formal fertility education, (2) informal learning through infertility experiences of patients, peers, or personal struggles, and (3) desire to improve medical education through early introduction and transparent discussions about infertility. Exploration of childbearing concerns similarly revealed several salient themes: (1) high incidence of delayed childbearing, (2) perceived lack of peer and administrative support, and (3) impact of family building on career trajectory. These themes were borne out in pilot testing of the survey instrument: of 24 female physicians (7 Asian women [27%], 1 Black woman [4%], 1 Hispanic or Latinx woman [4%], 1 multiracial woman [4%], 15 White women [58%]; mean [SD] age, 36.1 [6.7] years), 17 (71%) had delayed childbearing and 16 (67%) had altered their career for family-building reasons. Conclusions and Relevance: Qualitative interviews identified fertility and family building concerns among female physicians and were used to develop a tailored survey for women in medicine. These findings suggest that female physicians may delay childbearing and make substantial accommodations in their careers to support family building. A large-scale national survey is needed to better characterize the unique fertility, childbearing, and parenting needs of women in academic medicine to better understand how these concerns may contribute to academic attrition.

Undergraduate support for university smoke-free and vape-free campus policies and student engagement: a quasi-experimental intervention.

BackgroundCollege campuses have policies restricting smoking/vaping on campus. Previous studies involving mostly European-American students showed smoking prevalence declines following implementation of such policies.ObjectiveTo evaluate a social media campaign promotive of stronger campus support for an existing campus no-smoking/no-vaping policy where most (∼75%) of the undergraduates were non-European-American. A demographically comparable university served as a no-intervention control.ParticipantsTarget was 200 random intercept surveys at each university during fall 2016, spring 2017. Of 800 respondents, 681 were undergraduates.MethodsBaseline and post-intervention surveys assessed awareness of and support for campus-wide smoke-free/vape-free policies. Staged smoke-free/vape-free policy violations assessed students' propensity to intervene in support of the policy.ResultsRespondent support for the no-smoking/no-vaping policy did not change.ConclusionsThe social media campaign and Policy Ambassadors program did not increase support for the campus no-smoking/no-vaping policy. Most (∼90%) respondents agreed that the campus no-smoking/no-vaping policy was important for public health.

Assessing Resident Well-Being After the ABSITE: A Bad Time to Ask?

Assess the association of residents' exam performance and transient emotions with their reports of burnout, suicidality, and mistreatment. Background: An annual survey evaluating surgical resident well-being is administered following the American Board of Surgery In-Training Examination (ABSITE). One concern about administering a survey after the ABSITE is that stress from the exam may influence their responses. Methods: A survey was administered to all general surgery residents following the 2018 ABSITE assessing positive and negative emotions (scales range from 0 to 12), as well as burnout, suicidality over the past 12 months, and mistreatment (discrimination, sexual harassment verbal/emotional or physical abuse) in the past academic year. Multivariable hierarchical regressions assessed the associations of exam performance and emotions with burnout, suicidality, and mistreatment. Results: Residents from 262 programs provided complete responses (N = 6987, 93.6% response rate). Residents reported high mean positive emotion (M = 7.54, SD = 2.35) and low mean negative emotion (M = 5.33, SD = 2.43). While residents in the bottom ABSITE score quartile reported lower positive and higher negative emotion than residents in the top 2 and 3 quartiles, respectively (P < 0.005), exam performance was not associated with the reported likelihood of burnout, suicidality, or mistreatment. Conclusions: Residents' emotions after the ABSITE are largely positive. Although poor exam performance may be associated with lower positive and higher negative emotion, it does not seem to be associated with the likelihood of reporting burnout, suicidality, or mistreatment. After adjusting for exam performance and emotions, mistreatment remained independently associated with burnout and suicidality. These findings support existing evidence demonstrating that burnout and suicidality are stable constructs that are robust to transient stress and/or emotions.

What They Are Not Telling Us: Analysis of Nonresponders on a National Survey of Resident Well-Being.

To characterize nonrespondents to a national survey about trainee well-being, examine response patterns to questions of sensitive nature, and assess how nonresponse biases prevalence estimates of mistreatment and well-being. Background: Surgical trainees are at risk for burnout and mistreatment, which are discernible only by self-report. Therefore, prevalence estimates may be biased by nonresponse. Methods: A survey was administered with the 2018 and 2019 American Board of Surgery In-Training Examinations assessing demographics, dissatisfaction with education and career, mistreatment, burnout, thoughts of attrition, and suicidality. Responders in 2019 were characterized as survey "Completers," "Discontinuers" (quit before the end), and "Selective Responders" (selectively answered questions throughout). Multivariable logistic regression assessed associations of respondent type with mistreatment and well-being outcomes, adjusting for individual and program characteristics. Longitudinal survey identifiers linked survey responses for eligible trainees between 2018 and 2019 surveys to further inform nonresponse patterns. Results: In 2019, 6956 (85.6%) of 8129 eligible trainees initiated the survey, with 66.5% Completers, 17.5% Discontinuers, and 16.0% Selective Responders. Items with the highest response rates included dissatisfaction with education and career (93.2%), burnout (86.3%), thoughts of attrition (90.8%), and suicidality (94.4%). Discontinuers and Selective Responders were more often junior residents and racially/ethnically minoritized than Completers. No differences were seen in burnout and suicidality rates between Discontinuers, Selective Responders, and Completers. Non-White or Hispanic residents were more likely to skip questions about racial/ethnic discrimination than non-Hispanic White residents (21.2% vs 15.8%; odds ratio [OR], 1.35; 95% confidence interval [CI], 1.19-1.53), particularly when asked to identify the source. Women were not more likely to omit questions regarding gender/gender identity/sexual orientation discrimination (OR, 0.91; 95% CI, 0.79-1.04) or its sources (OR, 1.02; 95% CI, 0.89-1.16). Both Discontinuers and Selective Responders more frequently reported physical abuse (2.5% vs 1.1%; P = 0.001) and racial discrimination (18.3% vs 13.6%; P < 0.001) on the previous survey (2018) than Completers. Conclusions: Overall response rates are high for this survey. Prevalence estimates of burnout, suicidality, and gender discrimination are likely minimally impacted by nonresponse. Nonresponse to survey items about racial/ethnic discrimination by racially/ethnically minoritized residents likely results in underestimation of this type of mistreatment.