Search

A woman in her 70s with a past history of breast cancer in remission presented with several months of dyspnoea, skin tightness and Raynaud's phenomenon. Physical examination was significant for hypertension, hypoxaemia, sclerodactyly, diffuse crackles on auscultation and mild respiratory distress. Work-up revealed elevated serum creatinine, elevated right ventricular systolic pressure on echocardiography and nuclear bone scan findings of osseous metastatic disease. Captopril was initiated with concern for scleroderma renal crisis. The scleroderma panel was positive for RNA polymerase 11 and 155. Vertebral biopsy was diagnostic of recurrent breast cancer. Through multidisciplinary discussion, rituximab was initiated, and malignancy treatment was deferred; however, the patient developed several complications and ultimately elected to pursue inpatient hospice. In the setting of recurrent breast cancer, this case is suggestive of paraneoplastic scleroderma. The presence of underlying malignancy is an important consideration in new cases of scleroderma, and multidisciplinary management is key to determining treatment preference., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objective: Women are less likely to receive guideline-recommended cardiovascular care, but evaluation of sex-based disparities in cardiac surgical procedures is limited. Receipt of concomitant atrial fibrillation (AF) procedures during nonmitral cardiac surgery was compared by sex for patients with preoperative AF., Methods: Patients with preoperative AF undergoing coronary artery bypass grafting and/or aortic valve replacement at any of the 33 hospitals in Michigan from 2014 to 2022 were included. Patients with prior cardiac surgery, transcatheter AF procedure, or emergency/salvage status were excluded. Hierarchical logistic regression identified predictors of concomitant AF procedures, account for hospital and surgeon as random effects., Results: Of 5460 patients with preoperative AF undergoing nonmitral cardiac surgery, 24% (n = 1291) were women with a mean age of 71 years. Women were more likely to have paroxysmal (vs persistent) AF than men (80% vs 72%; P < .001) and had a higher mean predicted risk of mortality (5% vs 3%; P < .001). The unadjusted rate of concomitant AF procedure was 59% for women and 67% for men (P < .001). After risk adjustment, women had 26% lower adjusted odds of concomitant AF procedure than men (adjusted odds ratio, 0.74; 95% CI, 0.64-0.86; P < .001). Female sex was the risk factor associated with the lowest odds of concomitant AF procedure., Conclusions: Women are less likely to receive guideline recommended concomitant AF procedure during nonmitral surgery. Identification of barriers to concomitant AF procedure in women may improve treatment of AF., Competing Interests: Conflict of Interest Statement Dr Ailawadi is a consultant for Abbott, Edwards, Medtronic, Anteris, Atricure, and Gore. All other authors reported no conflicts of interest. Support for MSTCVS-QC is provided by Blue Cross and Blue Shield of Michigan (BCBSM) and Blue Care Network as part of the BCBSM Value Partnerships program. Although BCBSM and MSTCVS-QC work collaboratively, the opinions, beliefs and viewpoints expressed by the author do not necessarily reflect the opinions, beliefs and viewpoints of BCBSM or any of its employees. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Analysis of single cancer cells is critical to obtain accurate patient diagnosis and prognosis. In this work, we report the selective dielectrophoretic capture and electrochemical analysis of single melanoma cells at an array of interlocked spiral bipolar electrodes (iBPEs). Following dielectrophoretic capture, individual melanoma cells are hydrodynamically transferred into picoliter-scale chambers for subsequent analysis. The interlocked spiral end of the iBPE (the sensing pole) is utilized to read out an electrochemical enzyme-linked immunosorbent assay (eELISA), which quantifies the expression of a cell surface antigen, melanoma cell adhesion marker (MCAM). The opposite pole of each BPE is located in a fluidically isolated compartment containing reagents for electrogenerated chemiluminescence (ECL), such that luminescence reports iBPE current. In a preliminary device design, the ECL intensity was insufficient to detect MCAM expression on single cells. To achieve single-cell analysis, we decreased the gap size between the interlocked spirals tenfold (5.0 μm to 0.5 μm), thereby creating a more sensitive biosensor by enhanced redox cycling of the product of eELISA. This work is significant because it allows for the selective isolation and sensitive analysis of individual melanoma cells in a device amenable to point-of-care (POC) application by combining dielectrophoresis (DEP) with interdigitated bipolar electrodes (IDBPEs).

Neuron-microglia interactions dictate the development of neuronal circuits in the brain. However, the factors that support and broadly regulate these processes across developmental stages are largely unknown. Here, we find that IL34, a neuron-derived cytokine, is upregulated in development and plays a critical role in supporting and maintaining neuroprotective, mature microglia in the anterior cingulate cortex (ACC) of mice. We show that IL34 mRNA and protein is upregulated in neurons in the second week of postnatal life and that this increase coincides with increases in microglia number and expression of mature, homeostatic markers, e.g., TMEM119. We also found that IL34 mRNA is higher in more active neurons, and higher in excitatory (compared to inhibitory) neurons. Genetic KO of IL34 prevents the functional maturation of microglia and results in an anxiolytic phenotype in these mice by adulthood. Acute, low dose blocking of IL34 at postnatal day (P)15 in mice decreased microglial TMEM119 expression and increased aberrant microglial phagocytosis of thalamocortical synapses within the ACC. In contrast, viral overexpression of IL34 early in life (P1-P8) caused early maturation of microglia and prevented microglial phagocytosis of thalamocortical synapses during the appropriate neurodevelopmental refinement window. Taken together, these findings establish IL34 as a key regulator of neuron-microglia crosstalk in postnatal brain development, controlling both microglial maturation and synapse engulfment.

Objective: Our statewide thoracic quality collaborative has implemented multiple quality improvement initiatives to improve lung cancer nodal staging. We subsequently implemented a value-based reimbursement initiative to further incentivize quality improvement. We compare the impact of these programs to steer future quality improvement initiatives., Methods: Since 2016, our collaborative focused on improving lymph node staging for lung cancer by leveraging unblinded, hospital-level metrics and collaborative feedback. In 2021, a value-based reimbursement initiative was implemented with statewide yearly benchmark rates for (1) preoperative mediastinal staging for ≥T2N0 lung cancer, and (2) sampling ≥5 lymph node stations. Participating surgeons would receive additional reimbursement if either benchmark was met. We reviewed patients from January 2015 to March 2023 at the 21 participating hospitals to determine the differential effects on quality improvement., Results: We analyzed 6228 patients. In 2015, 212 (39%) patients had ≥5 nodal stations sampled, and 99 (51%) patients had appropriate preoperative mediastinal staging. During 2016 to 2020, this increased to 2253 (62%) patients and 739 (56%) patients, respectively. After 2020, 1602 (77%) patients had ≥5 nodal stations sampled, and 403 (73%) patients had appropriate preoperative mediastinal staging. Interrupted time-series analysis demonstrated significant increases in adequate nodal sampling and mediastinal staging before value-based reimbursement. Afterward, preoperative mediastinal staging rates briefly dropped but significantly increased while nodal sampling did not change., Conclusions: Collaborative quality improvement made significant progress before value-based reimbursement, which reinforces the effectiveness of leveraging unblinded data to a collaborative group of thoracic surgeons. Value-based reimbursement may still play a role within a quality collaborative to maintain infrastructure and incentivize participation., Competing Interests: Conflict of Interest Statement R.R. receives consulting fees from Intuitive, Genentech, AtriCure, Medtronic, and On Target Labs. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

A qualitative, community-engaged assessment was conducted to identify needs and priorities for infant obesity prevention programs among mothers participating in home visiting programs. Thirty-two stakeholders (i.e., community partners, mothers, home visitors) affiliated with a home visiting program serving low-income families during the prenatal to age three period participated in group level assessment sessions or individual qualitative interviews. Results indicated families face many challenges to obesity prevention particularly in terms of healthy eating. An obesity prevention program can address these challenges by offering realistic feeding options and non-judgmental peer support, improving access to resources, and tailoring program content to individual family needs and preferences. Informational needs, family factors in healthy eating outcomes, and the importance of access and awareness of programs were also noted. To ensure the cultural- and contextual-relevance of infant obesity prevention programs for underserved populations, needs and preferences among community stakeholders and the focal population should be used as a roadmap for intervention development., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Zika virus (ZIKV) infection during pregnancy poses significant threats to maternal and fetal health, leading to intrauterine fetal demise and severe developmental malformations that constitute congenital Zika syndrome (CZS). As such, the development of a safe and effective ZIKV vaccine is a critical public health priority. However, the safety and efficacy of such a vaccine during pregnancy remain uncertain. Historically, the conduct of clinical trials in pregnant women has been challenging. Therefore, clinically relevant animal pregnancy models are in high demand for testing vaccine efficacy. We previously reported that a marmoset pregnancy model of ZIKV infection consistently demonstrated vertical transmission from mother to fetus during pregnancy. Using this marmoset model, we also showed that vertical transmission could be prevented by pre-pregnancy vaccination with Zika purified inactivated virus (ZPIV) vaccine. Here, we further examined the efficacy of ZPIV vaccination during pregnancy. Vaccination during pregnancy elicited virus neutralizing antibody responses that were comparable to those elicited by pre-pregnancy vaccination. Vaccination also reduced placental pathology, viral burden and vertical transmission of ZIKV during pregnancy, without causing adverse effects. These results provide key insights into the safety and efficacy of ZPIV vaccination during pregnancy and demonstrate positive effects of vaccination on the reduction of ZIKV infection, an important advance in preparedness for future ZIKV outbreaks., (© 2024. The Author(s).)

Zika virus (ZIKV) is a significant threat to pregnant women and their fetuses as it can cause severe birth defects and congenital neurodevelopmental disorders, referred to as congenital Zika syndrome (CZS). Thus, a safe and effective ZIKV vaccine for pregnant women to prevent in utero ZIKV infection is of utmost importance. Murine models of ZIKV infection are limited by the fact that immunocompetent mice are resistant to ZIKV infection. As such, interferon-deficient mice have been used in some preclinical studies to test the efficacy of ZIKV vaccine candidates against lethal virus challenge. However, interferon-deficient mouse models have limitations in assessing the immunogenicity of vaccines, necessitating the use of immunocompetent mouse pregnancy models. Using the human stat2 knock-in (hSTAT2KI) mouse pregnancy model, we show that vaccination with a purified formalin-inactivated Zika virus (ZPIV) vaccine prior to pregnancy successfully prevented vertical transmission. In addition, maternal immunity protected offspring against postnatal challenge for up to 28 days. Furthermore, passive transfer of human IgG purified from hyper-immune sera of ZPIV vaccinees prevented maternal and fetal ZIKV infection, providing strong evidence that the neutralizing antibody response may serve as a meaningful correlate of protection., (© 2024. The Author(s).)

Purpose: Despite ongoing efforts to improve surgical education, surgical residents face gaps in their training. However, it is unknown if differences in the training of surgeons are reflected in the patient outcomes of those surgeons once they enter practice. This study aimed to compare the patient outcomes among new surgeons performing partial colectomy-a common procedure for which training is limited-and cholecystectomy-a common procedure for which training is robust., Method: The authors retrospectively analyzed all adult Medicare claims data for patients undergoing inpatient partial colectomy and inpatient cholecystectomy between 2007 and 2018. Generalized additive mixed models were used to investigate the associations between surgeon years in practice and risk-adjusted rates of 30-day serious complications and death for patients undergoing partial colectomy and cholecystectomy., Results: A total of 14,449 surgeons at 4,011 hospitals performed 340,114 partial colectomy and 355,923 cholecystectomy inpatient operations during the study period. Patients undergoing a partial colectomy by a surgeon in their 1st vs 15th year of practice had higher rates of serious complications (5.22% [95% CI, 4.85%-5.60%] vs 4.37% [95% CI, 4.22%-4.52%]; P < .01) and death (3.05% [95% CI, 2.92%-3.17%] vs 2.83% [95% CI, 2.75%-2.91%]; P < .01). Patients undergoing a cholecystectomy by a surgeon in their 1st vs 15th year of practice had similar rates of 30-day serious complications (4.11% vs 3.89%; P = .11) and death (1.71% vs 1.70%; P = .93)., Conclusions: Patients undergoing partial colectomy faced a higher risk of serious complications and death when the operation was performed by a new surgeon compared to an experienced surgeon. Conversely, patient outcomes following cholecystectomy were similar for new and experienced surgeons. More attention to partial colectomy during residency training may benefit patients., (Copyright © 2023 by the Association of American Medical Colleges.)

Objectives: In January 2016, our statewide quality improvement collaborative focused on 3 metrics of adequate lymph node harvest during lung cancer surgery: (1) rates of pathologic examination of 10 lymph nodes or more; (2) sampling 5 or more lymph node stations or more within the hilum or mediastinum; and (3) pathologic nodal upstaging (pathologic nodal stage higher than clinical nodal stage). Unblinded, hospital-level outcomes were presented at biannual meetings, and opportunities for education or improvement were discussed. We set out to describe this quality improvement initiative and the subsequent impact on surgical lymphadenectomies statewide., Methods: We retrospectively reviewed patients undergoing lobectomy for stage IA to IIIA non-small-cell lung cancer from July 2015 to December 2020 at the 16 participating centers., Results: The study cohort included 3753 patients. The rates of examining 10 lymph nodes or more statewide increased from 215 lobectomies (44.0%) in 2015 to 522 lobectomies (78.9%) in 2020 (P < .001). Similar trends were noted statewide for 5 lymph node stations or more, which increased from 193 lobectomies (39.6%) to 531 lobectomies (80.3%) in 2020 (P < .001). The overall rate of nodal upstaging was more variable year to year and generally declined over time (P = .004)., Conclusions: Our statewide quality improvement initiative improved rates of appropriate lymph node staging for surgically treated non-small cell lung cancer compared with national rates. This work demonstrates the power that a "community of practice" philosophy can have on surgical treatment of lung cancer. Quality improvement interventions including transparent data-driven discussions and collaboration can help guide future quality improvement initiatives and should be readily transferrable to other clinical domains., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Opioid prescribing guidelines have significantly decreased overprescribing and post-discharge use after cardiac surgery; however, limited recommendations exist for general thoracic surgery patients, a similarly high-risk population. We examined opioid prescribing and patient-reported use to develop evidence-based, opioid prescribing guidelines after lung cancer resection., Methods: This prospective, statewide, quality improvement study was conducted between January 2020 to March 2021 and included patients undergoing surgical resection of a primary lung cancer across 11 institutions. Patient-reported outcomes at 1-month follow-up were linked with clinical data and Society of Thoracic Surgery (STS) database records to characterize prescribing patterns and post-discharge use. The primary outcome was quantity of opioid used after discharge; secondary outcomes included quantity of opioid prescribed at discharge and patient-reported pain scores. Opioid quantities are reported in number of 5-mg oxycodone tablets (mean ± standard deviation)., Results: Of the 602 patients identified, 429 met inclusion criteria. Questionnaire response rate was 65.0%. At discharge, 83.4% of patients were provided a prescription for opioids of mean size 20.5±13.1 pills, while patients reported using 8.2±13.0 pills after discharge (P<0.001), including 43.7% who used none. Those not taking opioids on the calendar day prior to discharge (32.4%) used fewer pills (4.4±8.1 vs. 11.7±14.9, P<0.001). Refill rate was 21.5% for patients provided a prescription at discharge, while 12.5% of patients not prescribed opioids at discharge required a new prescription before follow-up. Pain scores were 2.4±2.5 for incision site and 3.0±2.8 for overall pain (scale 0-10)., Conclusions: Patient-reported post-discharge opioid use, surgical approach, and in-hospital opioid use before discharge should be used to inform prescribing recommendations after lung resection., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1621/coif). RMA reports grants and travel expenses when proctoring for Edwards Lifesciences, Intuitive Surgical, and Ethicon – Johnson & Johnson. JR Martin reports consulting fees and webinars for Terumo. CMB reports consulting fees from Heron Therapeutics, Vertex Pharmaceuticals, Benter Foundation, and Alosa Health, as well as receiving payment for providing expert testimony. ACC previously served as the President of the Michigan Society of Thoracic & Cardiovascular Surgeons. The other authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Zika virus (ZIKV) infection during pregnancy causes severe developmental defects in newborns, termed congenital Zika syndrome (CZS). Factors contributing to a surge in ZIKV-associated CZS are poorly understood. One possibility is that ZIKV may exploit the antibody-dependent enhancement of infection mechanism, mediated by cross-reactive antibodies from prior dengue virus (DENV) infection, which may exacerbate ZIKV infection during pregnancy. In this study, we investigated the impact of prior DENV infection or no DENV infection on ZIKV pathogenesis during pregnancy in a total of four female common marmosets with five or six fetuses per group. The results showed that negative-sense viral RNA copies increased in the placental and fetal tissues of DENV-immune dams but not in DENV-naïve dams. In addition, viral proteins were prevalent in endothelial cells, macrophages, and neonatal Fc receptor-expressing cells in the placental trabeculae and in neuronal cells in the brains of fetuses from DENV-immune dams. DENV-immune marmosets maintained high titers of cross-reactive ZIKV-binding antibodies that were poorly neutralizing, raising the possibility that these antibodies might be involved in the exacerbation of ZIKV infection. These findings need to be verified in a larger study, and the mechanism involved in the exacerbation of ZIKV infection in DENV-immune marmosets needs further investigation. However, the results suggest a potential negative impact of preexisting DENV immunity on subsequent ZIKV infection during pregnancy in vivo.

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β 1 and β 2 adrenergic receptors (β 1 AR and β 2 AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β 2 AR over the β 1 AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β 2 AR, as well as a less stable binding pocket for constrained epinephrine in the β 1 AR. The differences in the amino acid sequence of the extracellular vestibule of the β 1 AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β 2 AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs., (© 2023. The Author(s).)

Objective: To evaluate whether the Functional Activities Questionnaire (FAQ), a commonly used measure of functional status in neurodegenerative disease research, performs equivalently across demographically diverse subgroups of participants., Method: The FAQs from 30,613 National Alzheimer's Coordinating Center participants were evaluated with a hybrid graded response model-logistic ordinal regression approach to determine the presence of differential item functioning (DIF) within five demographic groups: education, ethnicity, race, language, and sex., Results: Measurable DIF was observed for FAQ items in all groups; however, measures of effect size, latent trait distributions, and item characteristic curves suggested that the impact was minimal for research and practice., Conclusions: The FAQ is able to provide minimally biased assessments of daily functioning across diverse participants, suggesting potential value for offsetting disparities in diagnosis and treatment., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Previous studies have identified postoperative complications as being associated with readmission after lobectomy. However, these studies have not adequately accounted for the timing of complications or accounted for institutional effects. Our objectives were to examine readmission rates after lobectomy and identify factors associated with readmission., Methods: Patients aged >18 years undergoing lobectomy for lung cancer between 2015 and 2019 were identified from a statewide database. Patients with in-hospital mortality, missing data regarding discharge status, 30-day readmission status, and discharge location were excluded. Data regarding The Society of Thoracic Surgeons postoperative complications were abstracted by hospital data managers to determine the timing of occurrence (index admission vs readmission). Logistic mixed-model analysis, with hospitals as the random intercept to account for clustering data structure and assess hospital-specific effect on readmission, was performed., Results: The overall readmission rate was 6.9% (184 of 2686). The most common complication was air leak ≥5 days in 17.4% (467 of 2686). Variables significantly predictive of more readmission were predischarge postoperative complications and Zubrod score ≥1. Variables predictive of less readmission were increasing length of stay and having been operated on at institutions with higher cumulative volume or having postdischarge follow-up visit protocol ≤7 days from discharge. The C statistic for the final model was 0.80., Conclusions: Patients who experience postoperative complications are at increased risk for readmission, whereas follow-up ≤7 days was predictive of less risk for readmission. Efforts at reducing readmissions should focus on decreasing postoperative complication rates, the timing of discharge for patients experiencing complications, as well as decreasing length of time between discharge and clinic follow-up., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Nearly 40% of patients with atrial fibrillation (AF) undergoing mitral valve surgery do not receive concomitant ablation despite societal guidelines. We assessed barriers to implementation of this evidence-based practice through a survey of cardiac surgeons in 2 statewide quality collaboratives., Methods: Adult cardiac surgeons across 2 statewide collaboratives were surveyed on their knowledge and practice regarding AF ablation. Questions concerning experience, clinical practice, case scenarios, and barriers to implementation were included., Results: Among 66 respondents (66 of 135; 48.9%), the majority reported "very comfortable/frequently use" cryoablation (53 of 66; 80.3%) and radiofrequency (55 of 66; 83.3%). Only 12.1% (8/66) were not aware of the recommendations. Approximately one-half of the respondents reported learning AF ablation in fellowship (50.0%; 33 of 66) or attending courses (47.0%; 31 of 66). Responses to clinical scenarios demonstrated wide variability in practice patterns. One-half of the respondents reported no barriers; others cited increased cross-clamp time, excessive patient risk, and arrhythmia incidence as obstacles. Desired interventions included cardiology/electrophysiology support, protocols, pacemaker rate information, and education in the form of site visits, videos and proctors., Conclusions: Knowledge of evidence-based recommendations and practice patterns vary widely. These data identify several barriers to implementation of concomitant AF ablation and suggest specific interventions (mentorship/support, protocols, research, and education) to overcome these barriers., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the safety of performing urgent or emergent cardiac surgery within 5 days of a patient taking a direct oral anticoagulant (DOAC)., Design: A multicenter retrospective registry study., Setting: Thirty-three hospitals in a quality collaborative from 2017 to 2019., Participants: Patients were included if they underwent urgent or emergent coronary artery bypass grafting (CABG). Patients were excluded if they received any anticoagulant or antiplatelet agent besides DOACs, heparin, or aspirin., Interventions: Patients were stratified based upon the receipt of a DOAC within 5 days of their surgery. Patient cohorts included DOAC within 2 days, DOAC within 3-to-5 days, and no anticoagulation. Data were unavailable on the specific DOAC agent taken prior to admission., Measurements and Main Results: There were 7,201 patients included, with 94 on DOACs. Intraoperative blood transfusion was required in 23.9% of patients on no anticoagulant, 26.2% on a DOAC within 3-to-5 days of surgery (odds ratio [OR] 0.98; 95% CI 0.46-2.11), and 30.3% on a DOAC within 2 days (OR 0.99; 95% CI 0.37-2.67). Five or more intraoperative blood products were required in 4.4% on no anticoagulant, 1.7% on DOAC within 3-to-5 days (OR 0.33; 95% CI 0.04-2.71), and 6.1% on DOAC within 2 days (OR 0.47; 95% CI 0.06-4.05). No difference in mortality was observed among the 3 groups (2.9% v 3.3% v 3.0%; p = 0.67)., Conclusions: For urgent or emergent CABGs, no significant differences in minor bleeding, major bleeding, or mortality were observed in patients taking a DOAC within 5 days of surgery. This study was hypothesis-generating for performing urgent or emergent surgery sooner than 5 days after holding DOACs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Whether all patients will require an opioid prescription after cardiac surgery is unknown. We performed a multicenter analysis to identify patient predictors of not receiving an opioid prescription at the time of discharge home after cardiac surgery., Methods: Opioid-naïve patients undergoing coronary artery bypass grafting and/or valve surgery through a sternotomy at 10 centers from January to December 2019 were identified retrospectively from a prospectively maintained data set. Opioid-naïve was defined as not taking opioids at the time of admission. The primary outcome was discharge without an opioid prescription. Mixed-effects logistic regression was performed to identify predictors of discharge without an opioid prescription, and postdischarge opioid prescribing was monitored to assess patient tolerance of discharge without an opioid prescription., Results: Among 1924 eligible opioid-naïve patients, mean age was 64 ± 11 years, and 25% were women. In total, 28% of all patients were discharged without an opioid prescription. On multivariable analysis, older age, longer length of hospital stay, and undergoing surgery during the last 3 months of the study were independent predictors of discharge without an opioid prescription, whereas depression, non-Black and non-White race, and using more opioid pills on the day before discharge were independent predictors of receiving an opioid prescription. Among patients discharged without an opioid prescription, 1.8% (10 of 547) were subsequently prescribed an opioid., Conclusions: Discharging select patients without an opioid prescription after cardiac surgery appears well tolerated, with a low incidence of postdischarge opioid prescriptions. Increasing the number of patients discharged without an opioid prescription may be an area for quality improvement., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the alignment between graduating surgical trainee operative performance and a prior survey of surgical program director expectations., Background: Surgical trainee operative training is expected to prepare residents to independently perform clinically important surgical procedures., Methods: We conducted a cross-sectional observational study of US general surgery residents' rated operative performance for Core general surgery procedures. Residents' expected performance on those procedures at the time of graduation was compared to the current list of Core general surgery procedures ranked by their importance for clinical practice, as assessed via a previous national survey of general surgery program directors. We also examined the frequency of individual procedures logged by residents over the course of their training., Results: Operative performance ratings for 29,885 procedures performed by 1861 surgical residents in 54 general surgery programs were analyzed. For each Core general surgery procedure, adjusted mean probability of a graduating resident being deemed practice-ready ranged from 0.59 to 0.99 (mean 0.90, standard deviation 0.08). There was weak correlation between the readiness of trainees to independently perform a procedure at the time of graduation and that procedure's historical importance to clinical practice ( p = 0.22, 95% confidence interval 0.01-0.41, P = 0.06). Residents also continue to have limited opportunities to learn many procedures that are important for clinical practice., Conclusion: The operative performance of graduating general surgery residents may not be well aligned with surgical program director expectations., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Prior work has established that high socioeconomic deprivation is associated with worse short- and long-term outcomes for patients undergoing coronary artery bypass grafting (CABG). The relationship between socioeconomic status and 90-day episode spending is poorly understood. In this observational cohort analysis, we evaluated whether socioeconomically disadvantaged patients were associated with higher expenditures during 90-day episodes of care after isolated CABG., Methods: We linked clinical registry data from 8728 isolated CABG procedures from January 1, 2012, to December 31, 2018, to Medicare fee-for-service claims data. Our primary exposure variable was patients in the top decile of the Area Deprivation Index. Linear regression was used to compare risk-adjusted, price-standardized 90-day episode spending for deprived against nondeprived patients as well as component spending categories: index hospitalization, professional services, post acute care, and readmissions., Results: A total of 872 patients were categorized as being in the top decile. Mean 90-day episode spending for the 8728 patients in the sample was $55 258 (SD, $26 252). Socioeconomically deprived patients had higher overall 90-day spending compared with nondeprived patients ($61 579 vs $54 557; difference, $3003; P = .001). Spending was higher in socioeconomically deprived patients for index hospitalizations (difference, $1284; P = .005), professional services (difference, $379; P = .002), and readmissions (difference, $1188; P = .008). Inpatient rehabilitation was the only significant difference in post-acute care spending (difference, $469; P = .011)., Conclusions: Medicare spending was higher for socioeconomically deprived CABG in Michigan, indicating systemic disparities over and above patient demographic factors., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

The formation of pathological bone deposits within soft tissues, termed heterotopic ossification (HO), is common after trauma. However, the severity of HO formation varies substantially between individuals, from relatively isolated small bone islands through to extensive soft tissue replacement by bone giving rise to debilitating symptoms. The aim of this study was to identify novel candidate therapeutic molecular targets for severe HO. We conducted a genome-wide scan in men and women with HO of varying severity following hip replacement for osteoarthritis. HO severity was dichotomized as mild or severe, and association analysis was performed with adjustment for age and sex. We next confirmed expression of the gene encoded by the lead signal in human bone and in primary human mesenchymal stem cells. We then examined the effect of gene knockout in a murine model of osseous trans-differentiation, and finally we explored transcription factor phosphorylation in key pathways perturbed by the gene. Ten independent signals were suggestively associated with HO severity, with KIF26B as the lead. We subsequently confirmed KIF26B expression in human bone and upregulation upon BMP2-induced osteogenic differentiation in primary human mesenchymal stem cells, and also in a rat tendo-Achilles model of post-traumatic HO. CRISPR-Cas9 mediated knockout of Kif26b inhibited BMP2-induced Runx2 , Sp7/Osterix , Col1A1 , Alp , and Bglap / Osteocalcin expression and mineralized nodule formation in a murine myocyte model of osteogenic trans-differentiation. Finally, KIF26B deficiency inhibited ERK MAP kinase activation during osteogenesis, whilst augmenting p38 and SMAD 1/5/8 phosphorylation. Taken together, these data suggest a role for KIF26B in modulating the severity of post-traumatic HO and provide a potential novel avenue for therapeutic translation.

Background: Cardiovascular outcomes are worse among individuals from areas with limited socioeconomic resources. This study evaluated the relationship between high socioeconomic deprivation and isolated coronary artery bypass grafting (CABG) outcomes., Methods: We linked statewide Society of Thoracic Surgeons Adult Cardiac Surgery Database data to Medicare Fee-for-Service records for 10 423 Michigan residents undergoing isolated CABG between January 2012 and December 2018. High socioeconomic deprivation was defined as residing in the highest decile of the ZIP Code-level area deprivation index (ADI). Multivariable logistic regression estimated the relationship between top ADI decile and major morbidity, in-hospital mortality, and operative mortality. Survival analyses evaluated long-term survival comparing patients in the top vs not in the top ADI decile., Results: A total of 1036 patients were in the top decile of ADI (ADI >82.4), and they were more likely to be female, Black, and have a higher predicted risk of mortality. Patients in the top ADI decile had significantly higher rates of major morbidity (17.4% vs 11.4%; adjusted odds ratio, 1.26; 95% CI, 1.04-1.54; P = .021) and in-hospital mortality (3.2% vs 1.3%, adjusted odds ratio, 1.84; 95% CI, 1.18-2.86, P = .007) but not operative mortality. The adjusted hazard of mortality was 16% higher for patients residing in the top ADI decile (95% CI, 1.01-1.33; P = .032)., Conclusions: Isolated CABG patients residing in the highest areas of socioeconomic deprivation differed with respect to demographic and clinical characteristics and experienced worse short- and long-term outcomes compared with those not in the top ADI decile., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Workplace-based assessment is increasingly prevalent in surgical education, especially for assessing operative skill. With current implementations, not all observed clinical performances are assessed, in part because trainees often have discretion about when they seek assessment. As a result, these samples of observed operative performances may not be representative of the full breadth of experience of surgical trainees. Therefore, analyses of these samples may be biased. We aimed to benchmark patterns of procedures logged in the SIMPL operative performance assessment system against records of trainee experience in Accreditation Council for Graduate Medical Education (ACGME) case logs., Design: We analyzed SIMPL longitudinal intraoperative performance assessments from categorical trainees in US general surgery residency programs. We compared overall patterns of how procedures are logged in SIMPL and in ACGME case logs using a Pearson correlation, and we examined differences in how individual procedures are logged in each system using Fisher's exact test., Results: Total procedure frequency from the SIMPL dataset was strongly correlated with total procedure frequency from ACGME case logs (r = 0.86, 95% CI 0.80-0.90). A subset of these procedures (10 of 116 procedures) was logged more frequently in the SIMPL dataset. These 10 procedures accounted for 56% of SIMPL observations and 30% of ACGME logged cases. Case complexity was comparable for assessments initiated by residents and faculty., Conclusions: Samples of intraoperative performance ratings gathered using the SIMPL application largely resemble ACGME case logs. There is no evidence to indicate that residents preferentially select fewer complex cases for assessment., Competing Interests: DECLARATION OF COMPETING INTEREST The authors have no conflicts of interest to disclose., (Copyright © 2021 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To develop, implement, and assess implementation outcomes for a developmental monitoring and referral program for children in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC)., Methods: Based on Centers for Disease Control and Prevention's Learn the Signs. Act Early. campaign, the program was developed and replicated in two phases at 20 demographically diverse WIC clinics in eastern Missouri. Parents were asked to complete developmental milestone checklists for their children, ages 2 months to 4 years, during WIC eligibility recertification visits; WIC staff referred children with potential concerns to their healthcare providers for developmental screening. WIC staff surveys and focus groups were used to assess initial implementation outcomes., Results: In both phases, all surveyed staff (n = 46) agreed the program was easy to use. Most (≥ 80%) agreed that checklists fit easily into clinic workflow and required ≤ 5 min to complete. Staff (≥ 55%) indicated using checklists with ≥ 75% of their clients. 92% or more reported referring one or more children with potential developmental concerns. According to 80% of staff, parents indicated checklists helped them learn about development and planned to share them with healthcare providers. During the second phase, 18 of 20 staff surveyed indicated the program helped them learn when to refer children and how to support parents, and 19 felt the program promoted healthy development. Focus groups supported survey findings, and all clinics planned to sustain the program., Conclusions: Initial implementation outcomes supported this approach to developmental monitoring and referral in WIC. The program has potential to help low-income parents identify possible concerns and access support., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Zika virus (ZIKV) is a mosquito-borne arbovirus that can cause severe congenital birth defects. The utmost goal of ZIKV vaccines is to prevent both maternal-fetal infection and congenital Zika syndrome. A Zika purified inactivated virus (ZPIV) was previously shown to be protective in non-pregnant mice and rhesus macaques. In this study, we further examined the efficacy of ZPIV against ZIKV infection during pregnancy in immunocompetent C57BL6 mice and common marmoset monkeys (Callithrix jacchus). We showed that, in C57BL/6 mice, ZPIV significantly reduced ZIKV-induced fetal malformations. Protection of fetuses was positively correlated with virus-neutralizing antibody levels. In marmosets, the vaccine prevented vertical transmission of ZIKV and elicited neutralizing antibodies that remained above a previously determined threshold of protection for up to 18 months. These proof-of-concept studies demonstrate ZPIV's protective efficacy is both potent and durable and has the potential to prevent the harmful consequence of ZIKV infection during pregnancy., (© 2022. The Author(s).)

Over the past five decades, tremendous effort has been devoted to computational methods for predicting properties of ligands-i.e., molecules that bind macromolecular targets. Such methods, which are critical to rational drug design, fall into two categories: physics-based methods, which directly model ligand interactions with the target given the target's three-dimensional (3D) structure, and ligand-based methods, which predict ligand properties given experimental measurements for similar ligands. Here, we present a rigorous statistical framework to combine these two sources of information. We develop a method to predict a ligand's pose-the 3D structure of the ligand bound to its target-that leverages a widely available source of information: a list of other ligands that are known to bind the same target but for which no 3D structure is available. This combination of physics-based and ligand-based modeling improves pose prediction accuracy across all major families of drug targets. Using the same framework, we develop a method for virtual screening of drug candidates, which outperforms standard physics-based and ligand-based virtual screening methods. Our results suggest broad opportunities to improve prediction of various ligand properties by combining diverse sources of information through customized machine-learning approaches., Competing Interests: Competing interest statement: Stanford University has filed a patent application related to this work., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: Collaborative quality consortia can facilitate implementation of quality measures arising from clinical databases. Our statewide general thoracic surgery (GTS) collaborative investigated the influences of cigarette smoking status on mortality and major morbidity following lobectomy for lung cancer., Methods: Society of Thoracic Surgeons General Thoracic Surgery Database records were identified from 14 institutions participating in a statewide thoracic surgical quality collaborative between 2012 and 2017. We excluded patients with nonelective procedures, stage 0 tumors, American Society of Anesthesiologists class VI disease, and missing clinical characteristics. Outcomes analysis included the combined mortality and major postoperative morbidity rates and the influence of patient characteristics, including smoking status, on composite rate and on postoperative complications., Results: The study cohort included 2267 patient records for analysis. Overall combined mortality and major morbidity rate was 10.2% (n = 231). Postoperative 30-day mortality was 1.5%, and major morbidity 9.6%. Significant predictors of the combined outcome included male sex (P = .004), body mass index (P < .001), Zubrod score (P = .02), smoking pack-years (P = .03), and thoracotomy (P < .001). Higher American Society of Anesthesiologists disease class and advanced tumor stage were marginally associated with worse combined outcome (P = .06). Smoking status; that is, current, past (no smoking within 30 days), or never smoked, was not associated with worse combined outcome (P = .56) and had no significant influence on major complications., Conclusions: Smoking status was not associated with worse outcomes; however, smoking dose (pack-years) was associated with worse combined mortality and major morbidity. A statewide quality collaborative provides constructive feedback for participating institutions and surgeons, promoting quality improvement in perioperative patient care strategies and improved outcomes., (Copyright © 2020. Published by Elsevier Inc.)

Background: Despite the risk of new persistent opioid use after cardiac surgery, postdischarge opioid use has not been quantified and evidence-based prescribing guidelines have not been established., Methods: Opioid-naive patients undergoing primary cardiac surgery via median sternotomy between January and December 2019 at 10 hospitals participating in a statewide collaborative were selected. Clinical data were linked to patient-reported outcomes collected at 30-day follow-up. An opioid prescribing recommendation stratified by inpatient opioid use on the day before discharge (0, 1-3, or ≥4 pills) was implemented in July 2019. Interrupted time-series analyses were performed for prescription size and postdischarge opioid use before (January to June) and after (July to December) guideline implementation., Results: Among 1495 patients (729 prerecommendation and 766 postrecommendation), median prescription size decreased from 20 pills to 12 pills after recommendation release (P < .001), while opioid use decreased from 3 pills to 0 pills (P < .001). Change in prescription size over time was +0.6 pill/month before and -0.8 pill/month after the recommendation (difference = -1.4 pills/month; P = .036). Change in patient use was +0.6 pill/month before and -0.4 pill/month after the recommendation (difference = -1.0 pills/month; P = .017). Pain levels during the first week after surgery and refills were unchanged. Patients using 0 pills before discharge (n = 710) were prescribed a median of 0 pills and used 0 pills, while those using 1 to 3 pills (n = 536) were prescribed 20 pills and used 7 pills, and those using greater than or equal to 4 pills (n = 249) were prescribed 32 pills and used 24 pills., Conclusions: An opioid prescribing recommendation was effective, and prescribing after cardiac surgery should be guided by inpatient use., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Self-assessment is critical to professional self-regulation yet many trainees may not reliably self-evaluate. We examine the gap between resident and faculty perceptions of trainee operative performance and contributing factors., Methods: Surgery resident and faculty evaluations of trainee performance were collected from 14 academic institutions using smartphone-based performance assessments. Differences in resident/faculty ratings evaluating the same procedure were analyzed using descriptive statistics and Bayesian mixed models., Results: Of 7382 evaluations, 46% trainees and faculty performance ratings were discrepant (r = 0.47), with 80% residents rating themselves lower than faculty in those cases. This gap existed regardless of case complexity and widened as trainees gained experience. Trainees who overrated themselves had the lowest mean performance scores from faculty., Conclusion: Half of residents perceived their performance differently from faculty, and this difference widened for senior residents. Future focus should be to provide opportunity for trainees to improve skills to reliably assess themselves before graduation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To determine how gene expression profiles in osteoarthritis joint tissues relate to patient phenotypes and whether molecular subtypes can be reproducibly captured by a molecular classification algorithm., Methods: We analysed RNA sequencing data from cartilage and synovium in 113 osteoarthritis patients, applying unsupervised clustering and Multi-Omics Factor Analysis to characterise transcriptional profiles. We tested the association of the molecularly defined patient subgroups with clinical characteristics from electronic health records., Results: We detected two patient subgroups in low-grade cartilage (showing no/minimal degeneration, cartilage normal/softening only), with differences associated with inflammation, extracellular matrix-related and cell adhesion pathways. The high-inflammation subgroup was associated with female sex (OR 4.12, p=0.0024) and prescription of proton pump inhibitors (OR 4.21, p=0.0040). We identified two independent patient subgroupings in osteoarthritis synovium: one related to inflammation and the other to extracellular matrix and cell adhesion processes. A seven-gene classifier including MMP13, APOD, MMP2, MMP1, CYTL1 , IL6 and C15orf48 recapitulated the main axis of molecular heterogeneity in low-grade knee osteoarthritis cartilage (correlation ρ =-0.88, p<10 -10 ) and was reproducible in an independent patient cohort ( ρ =-0.85, p<10 -10 )., Conclusions: These data support the reproducible stratification of osteoarthritis patients by molecular subtype and the exploration of new avenues for tailored treatments., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β 1 AR and β 2 AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β 1 AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human β 1 AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107. Structural comparison revealed that the catecholamine-binding pockets are identical between β 1 AR and β 2 AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.

Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.

Objective: To assess whether standardized screening and service navigation improve access to primary care in low wage workers., Methods: Four rapid plan-do-study-act cycles were conducted over an 8-week period. Each cycle consisted of four core interventions. Data were collected every 2 to 3 days, then analyzed on run charts and aggregate data tables., Results: Effective care was achieved by increasing the percentage of patients with a primary care provider from 52% to 79%. Patients' perception of health increased from 3.6 to 4.4 and team communication and support score increased from 3.9 to 4.2 on a 5-point Likert scale., Conclusions: Patient engagement and a standardized referral process aids in the establishment of routine, effective care. Application of "smart phrases" in electronic health records provides sustainability for use in other occupational medicine practices.

Purpose: The purpose of this study was to examine how combinations of adverse childhood events (ACEs) contribute to the risk of postpartum depression and the mediating role of prenatal social support., Methods: The Adverse Childhood Experiences Scale Questionnaire and the Edinburgh Postnatal Depression Scale Questionnaire were used to measure the study's exposure and outcome. Among a cohort of 419 mothers enrolled in a home visiting (HV) program, latent class analyses were used to identify classes of ACEs exposure. General linear models assessed the risk of postpartum depression, and prenatal social support was examined as a mediator., Results: Four distinct classes of ACE exposure were identified. On the Edinburgh Postnatal Depression scale, mothers who were classified in Classes 1-3 scored higher by 2.6-4.4 points compared with women in Class 0. ACE class was found to be indirectly associated with postpartum depression scores through prenatal social support., Conclusions: Identifying combinations of ACEs in an HV program has the potential to improve the characterization of ACEs among low-income perinatal women in the United States. Elucidating how these combinations contribute to the risk of postpartum depression has the potential to identify women at increased risk, which can help HV programs prioritize prevention efforts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Examine the concordance of perceived operative autonomy between attendings and resident trainees., Design: Faculty and trainees rated trainee operative autonomy using the 4-level Zwisch scale over a variety of cases and training years. The respective ratings were then compared to explore the effects of experience, gender, case complexity, trainee, trainer, and other covariates to perceived autonomy., Setting: This study was conducted over 14 general surgery programs in the United States, members of the Procedural Learning and Safety Collaborative., Participants: Participants included faculty and categorical trainees from 14 general surgery programs., Results: A total of 8681 observations was obtained. The sample included 619 unique residents and 457 different attendings. A total of 598 distinct procedures was performed. In 60% of the cases, the autonomy ratings between trainees and attendings were concordant, with only 3.5% of cases discrepant by more than 1 level. An autonomy perception gap was modeled based on the discrepancy between the trainee and attending Zwisch ratings for the same case. The mean Zwisch score expected for a trainee was lower than the attending across all scenarios. Trainees were more likely to perceive relatively more autonomy in the second half of the year. The autonomy perception gap decreased with increasing case complexity. As trainees gained experience, the perception gap increased with trainees underestimating autonomy., Conclusions: Trainees and attendings generally demonstrated concordance on autonomy perception scores. However, in 40% of cases, a perception gap exists between trainee and attending with the trainee generally underestimating autonomy. The gap worsens as the trainee progresses through residency. This perception gap suggests that attendings and trainees could be better aligned on teaching goals and expectations., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

The D2 dopamine receptor (DRD2) is a therapeutic target for Parkinson's disease 1 and antipsychotic drugs 2 . DRD2 is activated by the endogenous neurotransmitter dopamine and synthetic agonist drugs such as bromocriptine 3 , leading to stimulation of G i and inhibition of adenylyl cyclase. Here we used cryo-electron microscopy to elucidate the structure of an agonist-bound activated DRD2-G i complex reconstituted into a phospholipid membrane. The extracellular ligand-binding site of DRD2 is remodelled in response to agonist binding, with conformational changes in extracellular loop 2, transmembrane domain 5 (TM5), TM6 and TM7, propagating to opening of the intracellular G i -binding site. The DRD2-G i structure represents, to our knowledge, the first experimental model of a G-protein-coupled receptor-G-protein complex embedded in a phospholipid bilayer, which serves as a benchmark to validate the interactions seen in previous detergent-bound structures. The structure also reveals interactions that are unique to the membrane-embedded complex, including helix 8 burial in the inner leaflet, ordered lysine and arginine side chains in the membrane interfacial regions, and lipid anchoring of the G protein in the membrane. Our model of the activated DRD2 will help to inform the design of subtype-selective DRD2 ligands for multiple human central nervous system disorders.

Muscarinic toxins (MTs) are natural toxins produced by mamba snakes that primarily bind to muscarinic acetylcholine receptors (MAChRs) and modulate their function. Despite their similar primary and tertiary structures, MTs show distinct binding selectivity toward different MAChRs. The molecular details of how MTs distinguish MAChRs are not well understood. Here, we present the crystal structure of M 1 AChR in complex with MT7, a subtype-selective anti-M 1 AChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for M 1 AChR and the mechanism by which it regulates receptor function. Through in vitro engineering of MT7 finger regions that was guided by the structure, we have converted the selectivity from M 1 AChR toward M 2 AChR, suggesting that the three-finger fold is a promising scaffold for developing G protein-coupled receptor modulators., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the β 2 -adrenergic receptor (β 2 AR), AS408, that binds to the membrane-facing surface of transmembrane segments 3 and 5, as revealed by X-ray crystallography. AS408 disrupts a water-mediated polar network involving E122 3.41 and the backbone carbonyls of V206 5.45 and S207 5.46 . The AS408 binding site is adjacent to a previously identified molecular switch for β 2 AR activation formed by I 3.40 , P 5.50 and F 6.44 . The structure reveals how AS408 stabilizes the inactive conformation of this switch, thereby acting as a negative allosteric modulator for agonists and positive allosteric modulator for inverse agonists.

Objective: We examined the impact of video editing and rater expertise in surgical resident evaluation on operative performance ratings of surgical trainees., Design: Randomized independent review of intraoperative video., Setting: Operative video was captured at a single, tertiary hospital in Boston, MA., Participants: Six common general surgery procedures were video recorded of 6 attending-trainee dyads. Full-length and condensed versions (n = 12 videos) were then reviewed by 13 independent surgeon raters (5 evaluation experts, 8 nonexperts) using a crossed design. Trainee performance was rated using the Operative Performance Rating Scale, System for Improving and Measuring Procedural Learning (SIMPL) Performance scale, the Zwisch scale, and ten Cate scale. These ratings were then standardized before being compared using Bayesian mixed models with raters and videos treated as random effects., Results: Editing had no effect on the Operative Performance Rating Scale Overall Performance (-0.10, p = 0.30), SIMPL Performance (0.13, p = 0.71), Zwisch (-0.12, p = 0.27), and ten Cate scale (-0.13, p = 0.29). Additionally, rater expertise (evaluation expert vs. nonexpert) had no effect on the same scales (-0.16 (p = 0.32), 0.18 (p = 0.74), 0.25 (p = 0.81), and 0.25 (p = 0.17)., Conclusions: There is little difference in operative performance assessment scores when raters use condensed videos or when raters who are not experts in surgical resident evaluation are used. Future validation studies of operative performance assessment scales may be facilitated by using nonexpert surgeon raters viewing videos condensed using a standardized protocol., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: In the United States mortality rates for patients treated with dialysis differ by racial and/or ethnic (racial/ethnic) group. Mortality outcomes for patients undergoing maintenance dialysis in the United States territories may differ from patients in the United States 50 states., Design, Setting, Participants, & Measurements: This retrospective cohort study of using US Renal Data System data included 1,547,438 adults with no prior transplantation and first dialysis treatment between April 1, 1995 and September 28, 2012. Cox proportional hazards regression was used to calculate hazard ratios (HRs) of death for the territories versus 50 states for each racial/ethnic group using the whole cohort and covariate-matched samples. Covariates included demographics, year of dialysis initiation, cause of kidney failure, comorbid conditions, dialysis modality, and many others., Results: Of 22,828 patients treated in the territories (American Samoa, Guam, Puerto Rico, Virgin Islands), 321 were white, 666 were black, 20,299 were Hispanic, and 1542 were Asian. Of 1,524,610 patients in the 50 states, 838,736 were white, 444,066 were black, 182,994 were Hispanic, and 58,814 were Asian. The crude mortality rate (deaths per 100 patient-years) was lower for whites in the territories than the 50 states (14 and 29, respectively), similar for blacks (18 and 17, respectively), higher for Hispanics (27 and 16, respectively), and higher for Asians (22 and 15). In matched analyses, greater risks of death remained for Hispanics (HR, 1.65; 95% confidence interval, 1.60 to 1.70; P <0.001) and Asians (HR, 2.01; 95% confidence interval, 1.78 to 2.27; P <0.001) living in the territories versus their matched 50 states counterparts. There were no significant differences in mortality among white or black patients in the territories versus the 50 states., Conclusions: Mortality rates for patients undergoing dialysis in the United States territories differ substantially by race/ethnicity compared with the 50 states. After matched analyses for comparable age and risk factors, mortality risk no longer differed for whites or blacks, but remained much greater for territory-dwelling Hispanics and Asians., (Copyright © 2020 by the American Society of Nephrology.)

Purpose: Medical educators have developed no standard way to assess the operative performance of surgical residents. Most residency programs use end-of-rotation (EOR) evaluations for this purpose. Recently, some programs have implemented workplace-based "microassessment" tools that faculty use to immediately rate observed operative performance. The authors sought to determine (1) the degree to which EOR evaluations correspond to workplace-based microassessments and (2) which factors most influence EOR evaluations and directly observed workplace-based performance ratings and how the influence of those factors differs for each assessment method., Method: In 2017, the authors retrospectively analyzed EOR evaluations and immediate postoperative assessment ratings of surgical trainees from a university-based training program from the 2015-2016 academic year. A Bayesian multivariate mixed model was constructed to predict operative performance ratings for each type of assessment., Results: Ratings of operative performance from EOR evaluations vs workplace-based microassessment ratings had a Pearson correlation of 0.55. Postgraduate year (PGY) of training was the most important predictor of operative performance ratings on EOR evaluations: Model estimates ranged from 0.62 to 1.75 and increased with PGY. For workplace-based assessment, operative autonomy rating was the most important predictor of operative performance (coefficient = 0.74)., Conclusions: EOR evaluations are perhaps most useful in assessing the ability of a resident to become a surgeon compared with other trainees in the same PGY of training. Workplace-based microassessments may be better for assessing a trainee's ability to perform specific procedures autonomously, thus perhaps providing more insight into a trainee's true readiness for operative independence.

In embryonic development, cell shape changes are essential for building functional organs, but in many cases, the mechanisms that precisely regulate these changes remain unknown. We propose that fluid-like drag forces generated by the motion of an organ through surrounding tissue could generate changes to its structure that are important for its function. To test this hypothesis, we study the zebrafish left-right organizer, Kupffer's vesicle (KV), using experiments and mathematical modeling. During development, monociliated cells that comprise KV undergo region-specific shape changes along the anterior-posterior axis that are critical for KV function: anterior cells become long and thin, whereas posterior cells become short and squat. Here, we develop a mathematical vertex-like model for cell shapes that incorporates both tissue rheology and cell motility and constrain the model parameters using previously published rheological data for the zebrafish tailbud as well as our own measurements of the KV speed. We find that drag forces due to dynamics of cells surrounding KV could be sufficient or work in concert with previously identified mechanisms to drive KV cell shape changes during KV development. More broadly, these results suggest that cell shape changes during embryonic development and beyond could be driven by dynamic forces not typically considered in models or experiments., (Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.)