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Importance: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication of COVID-19 infection. Data on midterm outcomes are limited., Objective: To characterize the frequency and time course of cardiac dysfunction (left ventricular ejection fraction [LVEF] <55%), coronary artery aneurysms (z score ≥2.5), and noncardiac involvement through 6 months after MIS-C., Design, Setting, and Participants: This cohort study enrolled participants between March 2020 and January 2022 with a follow-up period of 2 years. Participants were recruited from 32 North American pediatric hospitals, and all participants met the 2020 Centers for Disease Control and Prevention case definition of MIS-C., Exposure: MIS-C after COVID-19 infection., Main Outcomes and Measures: Outcomes included echocardiography core laboratory (ECL) assessments of LVEF and maximum coronary artery z scores (zMax); data collection on cardiac and noncardiac sequelae during hospitalization and at 2 weeks, 6 weeks, and 6 months after discharge; and age-appropriate Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health Instruments at follow-up. Descriptive statistics, linear regression models, and Kaplan-Meier analysis were used., Results: Of 1204 participants (median [IQR] age, 9.1 [5.6-12.7] years; 724 male [60.1%]), 325 self-identified with non-Hispanic Black race (27.0%) and 324 with Hispanic ethnicity (26.9%). A total of 548 of 1195 participants (45.9%) required vasoactive support, 17 of 1195 (1.4%) required extracorporeal membrane oxygenation, and 3 (0.3%) died during hospitalization. Of participants with echocardiograms reviewed by the ECL (n = 349 due to budget constraints), 131 of 322 (42.3%) had LVEF less than 55% during hospitalization; of those with follow-up, all but 1 normalized by 6 months. Black race (vs other/unknown race), higher C-reactive protein level, and abnormal troponin level were associated with lowest LVEF (estimate [SE], -3.09 [0.98]; R2 = 0.14; P =.002). Fifteen participants had coronary artery z scores of 2.5 or greater at any time point; 1 participant had a large/giant aneurysm. Of the 13 participants with z scores of 2.5 or greater during hospitalization, 12 (92.3%) had normalized by 6 months. Return to greater than 90% of pre-MIS-C health status (energy, sleep, appetite, cognition, and mood) was reported by 711 of 824 participants (86.3%) at 2 weeks, increasing to 548 of 576 (95.1%) at 6 months. Fatigue was the most common symptom reported at 2 weeks (141 of 889 [15.9%]), falling to 3.4% (22 of 638) by 6 months. PROMIS Global Health parent/guardian proxy median T scores for fatigue, global health, and pain interference improved significantly from 2 weeks to 6 months (fatigue, 56.1 vs 48.9; global health, 48.8 vs 51.3; pain interference, 53.0 vs 43.3; P < .001) and by the 6-week visit were at least equivalent to prepandemic population norms., Conclusions and Relevance: Results of this cohort study suggest that although children and young adults with MIS-C can have severe disease during the acute phase, most recovered quickly and had a reassuring midterm prognosis.

There are scant studies of associations between the pubertal status at neutering and subsequent health outcomes of female dogs. This study examined health data for Labrador and Golden Retriever crossbreed bitches neutered by ovariohysterectomy either before (PrePN, n = 155) or after (PostPN, n = 151) puberty using a prospective study design. Data were extracted from an electronic database containing detailed health records for all bitches. Cruciate ligament disease occurred in significantly more PrePN ( n = 11) than PostPN bitches ( n = 1; Yates Chi-square = 6.784, D.F. = 1, p = 0.009), and PrePN bitches had lower probabilities of remaining free from osteoarthritis (χ 2 = 5.777, D.F. = 1, p = 0.016). Additionally, PrePN bitches were diagnosed with atopic dermatitis (PrePN: 3.9 ± 0.6 years, PostPN: 1.6 ± 0.3 years; Mann-Whitney U test = 90.5, p = 0.008) and perivulval dermatitis (PrePN: 4.7 ± 0.9 years, PostPN: 0.8 ± 0.1 years; Mann-Whitney U test = 40.0, p = 0.002) at significantly older ages and had lower probabilities of remaining free from otitis externa (χ 2 = 7.090, D.F. = 1, p = 0.008). No associations were identified between the pubertal status at neutering and the incidence of any urogenital disease, including urinary incontinence, which was diagnosed in a small number of bitches (one PrePN and six PostPN). The results suggest that prepubertal neutering may have a detrimental effect on some future musculoskeletal and immune diseases in bitches of these crossbreeds, providing important information to support neutering policies and to help maintain optimal dog welfare.

Introduction: This study investigates the intersection of ballistic injuries, geography, and Area Deprivation Index (ADI). We hypothesized that both ADI and geography are correlated with incidence of upper extremity ballistic injuries. Further, we characterize and compare 2 distinct upper extremity gunshot injury populations presenting to our institution: those sustaining violent ballistic injuries and those who suffer an accidental, self-inflicted injury. Our purpose is to evaluate the impact of geography and ADI on the pattern of upper extremity gunshot injuries in Illinois and Missouri., Materials and Methods: This was a retrospective review of adult patients sustaining ballistic injury to the upper extremity at a single urban level I trauma center over 10 years (n = 797). Seven hundred thirty patients had home addresses in Illinois or Missouri; these addresses were geocoded and included for analysis. Mechanism of injury was self-reported. ADI was measured from the 2019 Neighborhood Atlas, in which deprivation increases from 1 to 100. Comparisons between groups were conducted with unpaired t tests, Fisher exact test, or χ2 testing, where appropriate., Results: Addresses constituted 259 unique census tracts, and the average number of upper extremity gunshot wound incidents per tract was 3, with a maximum of 22; 15.4% of census block tracts made up almost half (48.4%) of the total ballistic injuries in the study period; 97.7% of violent injuries occurred in Urban areas, as compared with only 60% of accidental injuries ( P < 0.05). ADI and incidence of upper extremity ballistic injury were positively correlated. ADI varied significantly between patients sustaining violent (median, 94; mean, 86.1) versus accidental self-inflicted (median, 79; mean, 70.9) injuries ( P < 0.05). Fifty percent of violent injuries in our data set occurred in block groups from the 2 most deprived quintiles., Conclusions: Upper extremity gunshot wounds in general are concentrated in census blocks with high ADI. Violent injuries in particular are more likely to occur in urban areas with high ADI, whereas patients with accidental, self-inflicted injuries are more geographically and socioeconomically diverse. These differing populations require unique approaches to reduce incidence and morbidity., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Digital replantation is a challenging and at-time tedious operation, but if approached thoughtfully and with reasonable expectations can be a reliable and rewarding undertaking. This article summarizes technical considerations for digital replantations involving flexor tendon zone II. The article has been ordered according to the recommended sequence of a structure-by-structure repair in a non-thumb digit. Special considerations are described for thumb, multiple digits, and heterotopic replantation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: The perinatal transition's impact on systemic right ventricle (SRV) cardiac hemodynamics is not fully understood. Standard clinical image analysis tools fall short of capturing comprehensive diastolic and systolic measures of these hemodynamics., Objectives: Compare standard and novel hemodynamic echocardiogram (echo) parameters to quantify perinatal changes in SRV and healthy controls., Methods: We performed a retrospective study of 10 SRV patients with echocardiograms at 33-weeks gestation and at day of birth and 12 age-matched controls. We used in-house developed analysis algorithms to quantify ventricular biomechanics from four-chamber B-mode and color Doppler scans. Cardiac morphology, hemodynamics, tissue motion, deformation, and flow parameters were measured., Results: Tissue motion, deformation, and index measurements did not reliably capture biomechanical changes. Stroke volume and cardiac output were nearly twice as large for the SRV compared to the control RV and left ventricle (LV) due to RV enlargement. The enlarged RV exhibited disordered flow with higher energy loss (EL) compared to prenatal control LV and postnatal control RV and LV. Furthermore, the enlarged RV demonstrated elevated vortex strength (VS) and kinetic energy (KE) compared to both the control RV and LV, prenatally and postnatally. The SRV showed reduced relaxation with increased early filling velocity (E) compared prenatally to the LV and postnatally to the control RV and LV. Furthermore, increased recovery pressure (ΔP) was observed between the SRV and control RV and LV, prenatally and postnatally., Conclusions: The novel hydrodynamic parameters more reliably capture the SRV alterations than traditional parameters., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following commpeting interests: BAM, MCB, and PPV have intellectual property filings for each analysis algorithm in the analysis method used in this manuscript. BAM and PPV are involved with Cordian Technologies, a start-up founded by PPV, which licenses the technologies used in this work. RMP has a significant interest in Larimar Therapeutics, Inc., which is unrelated to this work. He also has funding from NHLBI as a co-investigator (1P01HL134599), and as site PI on an NHLBI consortium project (UG1HL135678). YHL receives partial salary support from NHLBI (R21-HL156045-01), (Copyright: © 2024 Meyers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Fontan-associated liver disease (FALD) refers to structural and functional changes of the liver caused by the physiology of the Fontan palliation. Currently, liver biopsy is the gold standard to assess liver fibrosis of FALD., Aim: Investigate biomarkers correlating with severity of liver biopsy fibrosis in FALD., Methods: A retrospective study of post-Fontan patients ≥ 10 years of age who underwent liver biopsy was conducted. Advanced liver disease (ALD) was defined as bridging fibrosis and/or cirrhosis on liver biopsy. AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4) and Liver Stiffness Measurement (LSM) from FibroScan were used as non-invasive fibrosis scores., Results: Sixty-six patients (26/47; 55.3% adults and 13/19 children; 68.4%) had ALD on biopsy. ALD was associated with lower platelet count (151 vs. 198 K/uL, p = 0.003), higher APRI (0.64 vs. 0.32, p = 0.01), higher FIB-4 (0.64 vs. 0.32, p = 0.02). Liver fibrosis score correlated with APRI (0.34, p = 0.02) and FIB-4 (0.47, p = 0.001) in adults. LSM had a high sensitivity at 81.3% with 45.5% specificity at a cut-off 18.5 kPa., Conclusions: APRI and FIB-4 had modest discrimination to identify adults with advanced liver disease, but not children, indicating that these values may be followed as a marker of FALD progression in older patients., Competing Interests: Conflict of interest All authors have no conflicts of interest to disclose., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele ( Taz PM ) that phenocopies BTHS clinical traits. As Taz PM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile Taz PM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile Taz PM hearts. However, adult Taz PM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult Taz PM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.

Background: Prophylactic antibiotics are variably prescribed after isolated upper extremity gunshot wounds (UE GSWs). The risk of infection and factors influencing prescribing practice remain poorly understood, and clinical practice guidelines are lacking., Methods: Adults with isolated UE GSWs over a 10-year period were included. Medical records were reviewed for demographic and injury variables, comorbidities, surgical treatments, antibiotic administration, infectious complications, and follow-up duration. Infection rate was calculated. Bivariate and multivariable linear regression analyses were used to identify patient-related and injury-related factors predictive of prophylactic antibiotic prescription., Results: A total of 281 patients were eligible for inclusion. Prophylactic antibiotics were prescribed at discharge for 111 patients (40%). Multivariable analysis revealed that patients with more distal injuries and ballistic fractures were significantly more likely to receive prophylactic antibiotics. Of patients with at least 30-day postinjury follow-up, 6% developed infections., Conclusion: Prophylactic antibiotic administration after UE GSWs was inconsistent but more common in patients with ballistic fractures and injuries in the hand. The overall incidence of infection was found to lie between 3% and 6%. The rate of infection in the antibiotic prophylaxis (2%-6%) group was similar to that in the no-antibiotic (5%-7%) group, suggesting that antibiotic prophylaxis may not have a large impact on infectious risk. However, because this study is nonrandomized, and because this study is underpowered for multivariable modeling of infectious risk, it remains possible that subgroups of this population may still benefit from antibiotic prophylaxis., 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.

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults., Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science., Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions., Clinical Trials.gov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Brett Anderson reported receiving direct support for work not related to RECOVER work/publications from Genentech and the National Institute of Allergy and Immunology. Walter Dehority reported receiving grant support from Merck and participating in research for the Moderna COVID-19 pediatric vaccine trial and the Pfizer Paxlovid trial. Alex Fiks reported receiving support from NJM insurance and personal consulting fees not related to this paper from Rutgers University and the American Academy of Pediatrics. Ashraf Harahsheh reported serving as a scientific advisory board member unrelated to this paper for OP2 DRUGS. Lawrence Kleinman reported serving as an unpaid member of the Board of Directors for the DARTNet Institute, as a principle investigator at Quality Matters, Inc., and as the Vice Chair for the Borough of Metuchen Board of Health. Dr. Kleinman also reported grant support for work not related to RECOVER work/publications from NIH, HRSA, and the Robert Wood Johnson Foundation. Dr. Kleinman also reported minority individual stock ownership in Apple Computer, Sanofi SA, Experion, GlaxoSmithKline, Magyar Bank, Regeneron Pharmaceuticals, JP Morgan Chase, and Amgen Inc. Torri Metz reported participating as a Principle Investigator in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She is also a principle investigator for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Joshua Milner reported serving as a member of the Scientific Advisory Board for Blueprint Medicines, in a capacity unrelated to RECOVER work/publications. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Gross et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Nerve injuries from gunshot wounds (GSWs) to the upper arm can cause significant morbidity and loss of function. However, indications for surgical exploration and nerve reconstruction remain unclear as both low- and high-grade injuries can present with an abnormal neurological examination., Methods: Adult patients presenting with a history of isolated GSW to the upper arm between 2010 and 2019 at a single urban level 1 trauma center were screened for inclusion in this retrospective study. Patient demographics, neurological examination findings, concurrent injuries, and intraoperative findings were gathered. Bivariate analysis was performed to characterize factors associated with nerve injuries., Results: There were 139 adult patients with isolated brachial GSWs, and 49 patients (35%) presented with an abnormal neurological examination and significantly associated with concurrent humerus fractures (39% vs 21%, P = .026) and brachial artery injuries (31% vs 2%, P < .001). Thirty of these 49 patients were operatively explored. Fifteen patients were found to have observed nerve injuries during operative exploration including 8 patients with nerve transections. The radial nerve was the most commonly transected nerve (6), and among the 16 contused nerves, the median (8) was most common., Conclusion: Nerve injury from upper arm GSWs is common with directly traumatized nerves confirmed in at least 39% and nerve transection in at least 16% of patients with an abnormal neurological examination. Timely referral to a hand and/or peripheral nerve surgeon for close clinical follow-up, appropriate diagnosis, and any necessary surgical reconstruction with nerve grafts, tendon transfers, and nerve transfers is recommended., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MAP has received research funding from 3M and Checkpoint and is a scientific consultant for KLISBio. DC, DT, AGE, DJB, RMP, ACVH, KGS, and SEM have no financial disclosures or conflicts of interest to report.

Background: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages., Objectives: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease., Methods: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis., Primary Endpoint: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy., Results: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels., Conclusions: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472)., Competing Interests: Funding Support and Author Disclosures This trial was supported by the Bristol Myers Squibb/Pfizer Alliance, in collaboration with the NHLBI-funded Pediatric Heart Network (grant numbers: HL135646, HL135665, HL135666, HL135678, HL135680, HL135682, HL135683, HL135685, HL135689, HL135691). Bristol Myers Squibb provided all financing and drugs for this trial; managed the trial data, adjudication process, and clinical sites; and was involved in the design of the study. The Pediatric Heart Network (PHN) provided scientific input on the trial design and contributed organizational infrastructure including the Data and Safety Monitoring Board, Protocol Review Committee, Publications and Presentations Committee, and additional logistical support for United States–based sites. Editorial support was provided by Caudex and was funded by Bristol Myers Squibb. Any publication-related fees will be funded by Bristol Myers Squibb. In collaboration with the trial steering committee, Bristol Myers Squibb was involved in the writing of this manuscript and decision to submit the paper for publication. Dr Payne has received grants or contracts from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), Friedreich Ataxia Research Alliance, and Additional Ventures non-profit organization; has received royalties or license from inventions: Wake Forest University, Larimar Therapeutics, and Indiana University; has received consulting fees from Larimar Therapeutics Inc.; has received support for attending meetings or travel from Indiana University School of Medicine; has 2 patents pending at Indiana University School of Medicine; is chair or is on the Data and Safety Monitoring Board (DSMB) for NIH study on Friedreich Ataxia; has served on the scientific advisory board for Friedreich Ataxia Research Alliance; and has stock in Larimar Therapeutics, Inc. Dr Glatz has received grants or contracts from NIH/NHLBI. Dr Male has received payment or honoraria from Anthos, AstraZeneca, Bayer, Chiesi, Janssen, and Norgine; and has a leadership or fiduciary role in Pediatric Anti-thrombotic Trials Leadership & Steering (Pedi-ATLAS) Group. Dr Brandão has received participation in an advisory committee for AstraZeneca (Andexxa in pediatrics) and Boehringer Ingelheim (dabigatran in children). Dr VanderPluym has received grants or contracts from the Georgia Claire Bowen Foundation; has received consulting fees from AstraZeneca and Merck; and participates in an advisory committee for the Valor Trial (Veriguciat in pediatric heart failure), and Andexxa in pediatrics in Europe. Dr Kochilas has received grants or contracts from NIH/NHLBI, Department of Defense, and Novartis Pharma; and participates in the Mitochondrial transplant study: Boston Children’s Hospital. Dr Stiller has received consulting fees from Janssen and Novartis; and has received payment or honoraria from Bristol Myers Squibb. Dr Cnota has received grants or contracts from NIH/NHLBI and Additional Ventures nonprofit organization; has received support for attending meetings or travel from the American Heart Association CSSP committee; and has participated on the NIH-NHLBI DSMB, Advisory Board for Inozyme Pharma. Dr Rahkonen has received payment or honoraria from Bristol Myers Squibb. Dr Adorisio has received grants or contracts from HORIZON 2022, Ministry of Italian Public Health; and has received consulting fees and payment or honoraria from PTC Therapeutics. Dr Stoica has been a co-applicant on research grants from local charities, National Institute of Health Research, the Health Foundation, and industry (Livanova, Admedus); has received payment or honoraria from LeMaitre Vascular; has received payment for expert testimony; and was audit co-lead in the Society of Cardiothoracic Surgeons of Great Britain and Ireland and at the National Institute of Cardiovascular Outcomes and Research. Dr May has received institutional support for conference fees. Dr Saraiva has a conflict of interest with AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received consulting fees from AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received payment or honoraria from AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received payment for expert testimony from AstraZeneca; has received support for attending meetings or travel from Novo Nordisk, AstraZeneca, and Boehringer; and has participated in the Allbert Einstein Academic Research Organization, Brazil. Dr Rubio has stock in BMS (obtained in 2001). Dr Meador has Concurrent employment with AtriCure effective September 2022. Ms Wheaton has a contract between HealthCore (now known as Carelon Research) and BMS to conduct the SAXOPHONE study. Dr Ajavon-Hartmann and Ms Mills are employees of and have stock options in Bristol Myers Squibb. Drs Jarugula, Reedy, and Dyme and Ms Carlson-Taneja are employees of Bristol Myers Squibb. Dr Monagle has received patents planned, issued, or pending from University of Melbourne and McMaster University: No commercial interests or connections since 2011. No current licensing agreements and no ongoing negotiations to license. Expect patents to expire in the next couple of years - Thrombin generation assay. Inventors: Berry LR, Ignjatovic V, Monagle PT, Chan AKC. U.S. patent, patent no. 8138308, “Modified Peptide Substrate”, issued 20 March 2012 “Enzyme Measurement Assay Using a Modified Substrate Comprising a Substrate Attached to a Macromolecule via a Spacer”: India patent no. 244241, issued November 25, 2010; Europe patent application, serial no. 06840527.3, issued October 2019; China patent application, serial no. 200680053447, filed December 21, 2006; and Japan patent application, serial no. 2008-547812, filed December 21, 2006. Dr Monagle has participated in Bayer Einstein junior suite of studies (Rivaroxaban in children): steering committee and writing committee; is an unpaid site investigator for the Bristol Myers Squibb SAXOPHONE study (apixaban in children): steering committee and writing committee; has been a site investigator (Unpaid, Ongoing) for Janssen; is an unpaid advisory board member for Milvexian; is an unpaid advisory board member for Takeda; is an unpaid advisory board member for Ceprotinin; and is an Associate Investigator for AstraZeneca, Takeda, Stago, Bayer, Janssen, and Pfizer. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, the U.S. Department of Health and Human Services, or Bristol Myers Squibb/Pfizer Alliance. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO 2 ), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO 2 , work rate at the ventilatory anaerobic threshold (VAT), VO 2 at VAT, and ventilatory efficiency (VE/VCO 2 ) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO 2 , baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO 2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Upper Extremity gunshot wounds represent a significant strain on community and hospital resources, and reports of their epidemiology are varied. We hypothesized that demographic and socioeconomic variables would be associated with variable injury patterns and management, and that two distinct populations would be affected by upper extremity ballistic injury based on violent versus accidental, self-inflicted mechanism., Materials & Methods: Retrospective review of all adult patients sustaining ballistic injury to the upper extremity at a single urban Level I trauma center over 10 years (n = 797). Demographic, injury pattern, treatment, and outcomes data were collected. Comparisons between groups were conducted with unpaired t-tests and chi-square testing where appropriate., Results: Most patients were male (89.1%) and mean age was 30.1 years (18-83). Violence accounted for 89.1% of injuries. Black individuals were disproportionately affected at 87% of patients. Shoulder injuries were most common (34%), and wrist least common (7%). Demographics and injury pattern varied significantly between patients sustaining violent injury and those with self-inflicted mechanisms. Patients sustaining violent injury were most often young, Black men more likely to be injured proximally, whereas patients with self-inflicted injuries were more likely to be older, Caucasian men with more comorbidities injured distally. Cumulatively, 35.3% of patients required operative intervention. Distal injuries were more likely operative. The most commonly injured structure across all levels was bone (53%), and 54.3% of fractures required operation. Median follow-up was 24.5 months. Complication rate was 13.6%., Conclusions: Gunshot wounds of the upper extremity create complex patterns of injury which vary based on level of injury and mechanism. Violent and self-inflicted injuries occur in dissimilar populations and result in distinctive injury patterns., Competing Interests: Declaration of Competing Interest The Authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults., Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's RE searching COV ID to E nhance R ecovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of five cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study ( n =10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n=6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n=6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n=600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science., Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions., Clinical Trialsgov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT05172011.

The Mustard procedure was an early cardiac surgery for transposition of the great arteries (TGA). Despite being successful, it has been associated with long-term arrhythmias and heart failure. A key factor complicating management in adults with congenital heart disease (CHD) is the deficiency of biomarkers predicting outcome. Soluble suppression of tumorogenicity-2 (sST2) is secreted by cardiomyocytes in response to mechanical strain and fibrosis. We hypothesized that adults with a Mustard procedure would have higher levels of sST2 than healthy individuals, and this would correlate with clinical outcome. We performed a single-center study in patients managed during childhood with a Mustard procedure versus age-matched controls. Clinical and demographic data were collected and biomarkers (sST2, cTnI, BNP, lipid panel, insulin, and glucose) were obtained. There were 18 patients (12 male) in the Mustard cohort and 18 patients (6 male) in the control group (22-49 years, mean of 35.8 vs. mean 32.6 years, respectively, p = ns). Nine Mustard subjects were NYHA class II, and 9 subjects were class III. The control group was asymptomatic. sST2 in the Mustard group was elevated in 56% vs. 17% in controls (p = 0.035). Of the Mustard subjects with elevated sST2, 60% had elevated cTnI and BNP, and 90% had low HDL. Over five years, the Mustard patients with elevated sST2 values had greater medication use, arrhythmias, hospitalizations, and ablation/pacer implantations than Mustard subjects with normal sST2. Mustard subjects with elevated sST2 had other biomarker abnormalities and clinically worse outcomes. Thus, sST2 may add a predictive value to cardiac-related morbidity and mortality., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A comparison between the performance of spayed female racing Greyhounds and those suppressed with norethisterone acetate (NTA) was made. Previous work by the author has shown that the racing performance of spayed bitches is the same as that of entire bitches in anoestrus, i.e. spaying is just a permanent anoestrus. The aim was to assess any performance difference between suppression and anoestrus, and thus to determine the effect of norethisterone acetate on race performance. The study was designed as a retrospective case-control. Raceform data was obtained for female racing Greyhounds which had raced, and which were either spayed or suppressed with norethisterone acetate. Analysis showed that suppressed bitches run on average 0.049 to 0.061 s slower over 480 m (centralised models). Since endogenous progesterone (P4) has been linked with reduced race performance, it is logical that progesterone analogues like NTA should have a similar effect. It is likely that the depression in performance is dose-related, but not quantifiable with the current dataset., Competing Interests: Declaration of Competing Interest The author expresses no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Importance: Data are limited regarding adverse reactions after COVID-19 vaccination in patients with a history of multisystem inflammatory syndrome in children (MIS-C). The lack of vaccine safety data in this unique population may cause hesitancy and concern for many families and health care professionals., Objective: To describe adverse reactions following COVID-19 vaccination in patients with a history of MIS-C., Design, Setting, and Participants: In this multicenter cross-sectional study including 22 North American centers participating in a National Heart, Lung, and Blood Institute, National Institutes of Health-sponsored study, Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC), patients with a prior diagnosis of MIS-C who were eligible for COVID-19 vaccination (age ≥5 years; ≥90 days after MIS-C diagnosis) were surveyed between December 13, 2021, and February 18, 2022, regarding COVID-19 vaccination status and adverse reactions., Exposures: COVID-19 vaccination after MIS-C diagnosis., Main Outcomes and Measures: The main outcome was adverse reactions following COVID-19 vaccination. Comparisons were made using the Wilcoxon rank sum test for continuous variables and the χ2 or Fisher exact test for categorical variables., Results: Of 385 vaccine-eligible patients who were surveyed, 185 (48.1%) received at least 1 vaccine dose; 136 of the vaccinated patients (73.5%) were male, and the median age was 12.2 years (IQR, 9.5-14.7 years). Among vaccinated patients, 1 (0.5%) identified as American Indian/Alaska Native, non-Hispanic; 9 (4.9%) as Asian, non-Hispanic; 45 (24.3%) as Black, non-Hispanic; 59 (31.9%) as Hispanic or Latino; 53 (28.6%) as White, non-Hispanic; 2 (1.1%) as multiracial, non-Hispanic; and 2 (1.1%) as other, non-Hispanic; 14 (7.6%) had unknown or undeclared race and ethnicity. The median time from MIS-C diagnosis to first vaccine dose was 9.0 months (IQR, 5.1-11.9 months); 31 patients (16.8%) received 1 dose, 142 (76.8%) received 2 doses, and 12 (6.5%) received 3 doses. Almost all patients received the BNT162b2 vaccine (347 of 351 vaccine doses [98.9%]). Minor adverse reactions were observed in 90 patients (48.6%) and were most often arm soreness (62 patients [33.5%]) and/or fatigue (32 [17.3%]). In 32 patients (17.3%), adverse reactions were treated with medications, most commonly acetaminophen (21 patients [11.4%]) or ibuprofen (11 [5.9%]). Four patients (2.2%) sought medical evaluation, but none required testing or hospitalization. There were no patients with any serious adverse events, including myocarditis or recurrence of MIS-C., Conclusions and Relevance: In this cross-sectional study of patients with a history of MIS-C, no serious adverse events were reported after COVID-19 vaccination. These findings suggest that the safety profile of COVID-19 vaccination administered at least 90 days following MIS-C diagnosis appears to be similar to that in the general population.

Background: The opioid abuse crisis is rampant in the United States. Children and adolescents are unique risk groups in this crisis; age-specific concerns include accidental ingestion and association with high-risk behaviors. Studies aimed at disposal are limited in pediatric patients. Our study aimed to determine whether an educational brochure detailing a simple opioid disposal method using dish soap could enhance disposal in postoperative pediatric patients., Methods: A prospective survey study of pediatric plastic surgery patients at the St. Louis Children's Hospital was performed from January to December 2020. Patients were assigned into two groups: those who received the educational brochure at the time of surgery and those who did not. In clinic, patient caretakers completed anonymous preoperative and/or postoperative surveys regarding opioid use and disposal., Results: Surveys of 326 patients were analyzed (188 preoperative, 120 pre/postoperative, and 18 postoperative). Prescribed opioids were all consumed in 19% of patients. Receiving the educational brochure significantly increased the opioid disposal of leftover medications: 78% versus 35% (OR 6.52, 95% CI [2.03, 21.37], p < 0.001). Although not statistically significant owing to small sample size (p = 0.09), 71.4% of families with excess opioids in the home preoperatively retained unused postoperative opioids versus 31.6% without preoperative opioids., Conclusions: Postoperative opioids are overprescribed for most pediatric plastic surgery patients. A simple brochure significantly increases proper postoperative opioid disposal, representing a cost-effective, convenient, risk-free method to decrease opioid misuse and accumulation in our communities., Competing Interests: Conflict of interest statement All authors have nothing to disclose. The funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in writing of the report; or the decision to submit the article for publication. The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. None of the authors has financial interest in any of the products, devices, or drugs mentioned in this manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Friedreich Ataxia (FA) is a rare and often fatal autosomal recessive disease in which a mitochondrial protein, frataxin (FXN), is severely reduced in all tissues. With loss of FXN, mitochondrial metabolism is severely disrupted. Multiple therapeutic approaches are in development, but a key limitation is the lack of biomarkers reflecting the activity of FXN in a timely fashion. We predicted this dysregulated metabolism would present a unique metabolite profile in blood of FA patients versus Controls (Con). Plasma from 10 FA and 11 age and sex matched Con subjects was analyzed by targeted mass spectrometry and untargeted NMR. This combined approach yielded quantitative measurements for 540 metabolites and found 59 unique metabolites (55 from MS and 4 from NMR) that were significantly different between cohorts. Correlation-based network analysis revealed several clusters of pathway related metabolites including a cluster associated with one‑carbon (1C) metabolism composed of formate, sarcosine, hypoxanthine, and homocysteine. Receiver operator characteristics analyses demonstrated an excellent ability to discriminate between Con and FA with AUC values >0.95. These results are the first reported metabolomic analyses of human patients with FA. The metabolic perturbations, especially those related to 1C metabolism, may serve as a valuable biomarker panel of disease progression and response to therapy. The identification of dysregulated 1C metabolism may also inform the search for new therapeutic targets related to this pathway., Competing Interests: Declaration of Competing Interest Dr. Payne is a consultant for Larimar Therapeutics, Inc., which had no participation or input in this project. Dr. O'Connell declares no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research., Competing Interests: This work was supported in part by the Herman B Wells Center from the Riley Children’s Foundation. Dr Payne has received support from a grant from the National Heart, Lung, and Blood Institute (1P01HL134599); has received consulting fees from Larimar Therapeutics, Inc, which had no input on the content or writing of this manuscript and is unaware of this work., (© 2022 The Author.)

Soft tissue reconstruction remains an intractable clinical challenge as current surgical options and synthetic implants may produce inadequate outcomes. Soft tissue deficits may be surgically reconstructed using autologous adipose tissue, but these procedures can lead to donor site morbidity, require multiple procedures, and have highly variable outcomes. To address this clinical need, we developed an "off-the-shelf" adipose extracellular matrix (ECM) biomaterial from allograft human tissue (Acellular Adipose Tissue, AAT). We applied physical and chemical processing methods to remove lipids and create an injectable matrix that mimicked the properties of lipoaspirate. Biological activity was assessed using cell migration and adipogenesis assays. Characterization of regenerative immune properties in a murine muscle injury model revealed that allograft and xenograft AAT induced pro-regenerative CD4 + T cells and macrophages with xenograft AAT additionally attracting eosinophils secreting interleukin 4 (Il4). In immunocompromised mice, AAT injections retained similar volumes as human fat grafts but lacked cysts and calcifications seen in the fat grafts. The combination of AAT with human adipose-derived stem cells (ASCs) resulted in lower implant volumes. However, tissue remodeling and adipogenesis increased significantly in combination with ASCs. Larger injected volumes of porcine-derived AAT demonstrated biocompatibility and greater retention when applied allogeneicly in Yorkshire cross pigs. AAT was implanted in healthy volunteers in abdominal tissue that was later removed by elective procedures. AAT implants were well tolerated in all human subjects. Implants removed between 1 and 18 weeks demonstrated increasing cellular infiltration and immune populations, suggesting continued tissue remodeling and the potential for long-term tissue replacement., (© 2022. The Author(s).)

Children with Friedreich's ataxia (FA) are at risk of perioperative morbidity and mortality from severe unpredictable heart failure. There is currently no clear way of identifying patients at highest risk. We used myocardial perfusion reserve (MPR), an MRI technique used to assess the maximal myocardial blood flow above baseline, to help determine potential surgical risk in FA subjects. In total, seven children with genetically confirmed FA, ages 8-17 years, underwent MPR stress testing using regadenoson. Six of the seven demonstrated impaired endocardial perfusion during coronary hyperemia. The same six were also found to have evidence of ongoing myocardial damage as illustrated by cardiac troponin I leak (range 0.04-0.17 ng/mL, normal < 0.03 ng/mL). None of the patients had a reduced ejection fraction (range 59-74%) or elevated insulin level (range 2.46-14.23 mCU/mL). This retrospective study shows that children with FA develop MPR defects early in the disease process. It also suggests MPR may be a sensitive tool to evaluate underlying cardiac compromise and could be of use in directing surgical management decisions in children with FA., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Breast surgery encompasses oncologic, reconstructive, and cosmetic procedures. With the recent focus on the over-prescribing of opioids in the literature, it is important to assess the effectiveness and safety of non-opioid pain medication regimens including nonsteroidal anti-inflammatory drugs (NSAIDs) or NSAID pain medications. Clinicians have differing opinions on the safety of perioperative (relating to, occurring in, or being the period around the time of a surgical operation) NSAIDs for breast surgery given the unclear risk/benefit ratio. NSAIDs have been shown to decrease inflammation, pain, and fever, while potentially increasing the risks of bleeding complications., Objectives: To assess the effects of perioperative NSAID use versus non-NSAID analgesics (other pain medications) in women undergoing any form of breast surgery., Search Methods: The Cochrane Breast Information Specialist searched the Cochrane Breast Cancer Group (CBCG) Specialized Register, CENTRAL (the Cochrane Library), MEDLINE, Embase, The WHO International Clinical Trials Registry Platform (ICTRP) and Clinicaltrials.gov registries to 21 September 2020. Full articles were retrieved for potentially eligible trials., Selection Criteria: We considered all randomized controlled trials (RCTs) looking at perioperative NSAID use in women undergoing breast surgery., Data Collection and Analysis: Two review authors independently screened studies, extracted data and assessed risk of bias, and certainty of the evidence using the GRADE approach. The main outcomes were incidence of breast hematoma within 90 days (requiring reoperation, interventional drainage, or no treatment) of breast surgery and pain intensity 24 hours following surgery, incidence rate or severity of postoperative nausea, vomiting or both, bleeding from any location within 90 days, need for blood transfusion, other side effects of NSAID use, opioid use within 24 hours of surgery, length of hospital stay, breast cancer recurrence, and non-prescribed NSAID use. Data were presented as risk ratios (RRs) for dichotomous outcomes and standardized mean differences (SMDs) for continuous outcomes., Main Results: We included 12 RCTs with a total of 1596 participants. Seven studies compared NSAIDs (ketorolac, diclofenac, flurbiprofen, parecoxib and celecoxib) to placebo. Four studies compared NSAIDs (ketorolac, flurbiprofen, ibuprofen, and celecoxib) to other analgesics (morphine, hydrocodone, hydromorphone, fentanyl). One study compared NSAIDs (diclofenac) to no intervention. NSAIDs compared to placebo Most outcomes are judged to have low-certainty evidence unless stated otherwise. There may be little to no difference in the incidence of breast hematomas within 90 days of breast surgery (RR 0.33, 95% confidence interval (CI) 0.05 to 2.02; 2 studies, 230 participants; I 2 = 0%). NSAIDs may reduce pain intensity 24 (± 12) hours following surgery compared to placebo (SMD -0.26, 95% CI -0.49 to -0.03; 3 studies, 310 participants; I 2 = 73%). There may be little to no difference in the incidence rates or severities of postoperative nausea, vomiting, or both (RR 1.15, 95% CI 0.58 to 2.27; 4 studies, 939 participants; I 2 = 81%), bleeding from any location within 90 days (RR 1.05, 95% CI 0.89 to 1.24; 2 studies, 251 participants; I 2 = 8%), or need for blood transfusion compared to placebo groups, but we are very uncertain (RR 4.62, 95% CI 0.23 to 91.34; 1 study, 48 participants; very low-certainty evidence). There may be no difference in other side effects (RR 1.12, 95% CI 0.44 to 2.86; 2 studies, 251 participants; I 2 = 0%). NSAIDs may reduce opioid use within 24 hours of surgery compared to placebo (SMD -0.45, 95% CI -0.85 to -0.05; 4 studies, 304 participants; I 2 = 63%). NSAIDs compared to other analgesics There is little to no difference in the incidence of breast hematomas within 90 days of breast surgery, but we are very uncertain (RR 0.33, 95% CI 0.01 to 7.99; 1 study, 100 participants; very low-certainty evidence). NSAIDs may reduce pain intensity 24 (± 12) hours following surgery (SMD -0.68, 95% CI -0.97 to -0.39; 3 studies, 200 participants; I 2 = 89%; low-certainty evidence) and probably reduce the incidence rates or severities of postoperative nausea, vomiting, or both compared to other analgesics (RR 0.18, 95% CI 0.06 to 0.57; 3 studies, 128 participants; I 2 = 0%; moderate-certainty evidence). There is little to no difference in the development of bleeding from any location within 90 days of breast surgery or in other side effects, but we are very uncertain (bleeding: RR 0.33, 95% CI 0.01 to 7.99; 1 study, 100 participants; other side effects: RR 0.11, 95% CI 0.01 to 1.80; 1 study, 48 participants; very low-certainty evidence). NSAIDs may reduce opioid use within 24 hours of surgery compared to other analgesics (SMD -6.87, 95% CI -10.93 to -2.81; 3 studies, 178 participants; I 2 = 96%; low-certainty evidence). NSAIDs compared to no intervention There is little to no difference in pain intensity 24 (± 12) hours following surgery compared to no intervention, but we are very uncertain (SMD -0.54, 95% CI -1.09 to 0.00; 1 study, 60 participants; very low-certainty evidence)., Authors' Conclusions: Low-certainty evidence suggests that NSAIDs may reduce postoperative pain, nausea and vomiting, and postoperative opioid use. However, there was very little evidence to indicate whether NSAIDs affect the rate of breast hematoma or bleeding from any location within 90 days of breast surgery, the need for blood transfusion and incidence of other side effects compared to placebo or other analgesics. High-quality large-scale RCTs are required before definitive conclusions can be made., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Children and young adults with single ventricle (SV) heart disease frequently develop heart failure (HF) that is intractable and difficult to treat. Our understanding of the molecular and biochemical reasons underlying this is imperfect. Thus, there is an urgent need for biomarkers that predict outcome and provide a rational basis for treatment, and advance our understanding of the basis of HF., Objective: We sought to determine if a metabolomic approach would provide biochemical signatures of HF in SV children and young adults. If significant, these analytes might serve as biomarkers to predict outcome and inform on the biological mechanism(s) of HF., Methods: We applied a multi-platform metabolomics approach composed of mass spectrometry (MS) and nuclear magnetic resonance (NMR) which yielded 495 and 26 metabolite measurements respectively. The plasma samples came from a cross-sectional set of young SV subjects, ages 2-19 years with ten control (Con) subjects and 16 SV subjects. Of the SV subjects, nine were diagnosed as congestive HF (SVHF), and 7 were not in HF. Metabolomic data were correlated with clinical status to determine if there was a signature associated with HF., Results: There were no differences in age, height, weight or sex between the 3 cohorts. However, statistical analysis of the metabolomic profiles using ANOVA revealed 44 metabolites with significant differences between cohorts including 41 profiled by MS and 3 by NMR. These metabolites included acylcarnitines, amino acids, and bile acids, which distinguished Con from all SV subjects. Furthermore, metabolite profiles could distinguish between SV and SVHF subjects., Conclusion: These are the first data to demonstrate a clear metabolomic signature associated with HF in children and young adults with SV. Larger studies are warranted to determine if these findings are predictive of progression to HF in time to provide intervention., (© 2021. The Author(s).)

MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by β-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte-specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline-rich protein 1a (Sprr1a) as a potentially novel target of miR-150. Our studies further reveal that Sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular SPRR1A is upregulated in patients with HF and that Sprr1a knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic Sprr1a. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.

Background: Breast reconstruction is an option for women undergoing mastectomy for breast cancer. Previous studies have reported underutilization of reconstructive surgery. This study aims to examine the role demographic, clinical and socio-economic factors may have on patients' decisions to undergo breast reconstruction., Methods: We analyzed data from our institutional database. Using multivariable and multinomial logistic regression, we compared breast cancer patients who had undergone mastectomy-only to those who had immediate breast reconstruction (overall and by type of reconstruction)., Results: We analyzed data on 1459 women who underwent mastectomy during the period 2003-2015. Of these, 475 (32.6%) underwent mastectomy-only and 984 (67.4%) also underwent immediate breast reconstruction. After adjusting for potential confounders, older age (OR = 0.18, 95%CI:0.08-0.40), Asian race (OR = 0.29, 95%CI:0.19-0.45), bilateral mastectomy (OR = 0.71, 95%CI:0.56-0.90), and higher stage of disease (OR = 0.44, 95%CI:0.26-0.74) were independent risk factors for not receiving immediate breast reconstruction. Furthermore, patients with Medicare or Medicaid insurance were less likely than patients with private insurance to receive an autologous reconstruction. There was no evidence for changes over time in the way socio-demographic and clinical factors were related to receiving immediate breast reconstruction after mastectomy., Conclusions: Clinical characteristics, sociodemographic factors like age, race and insurance coverage affect the decision for reconstructive surgery following mastectomy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Evidence is limited for BREAST-Q scores in women without breast cancer or breast surgery to establish baseline values for clinical interpretation. The primary aim of this study was to compare differences in breast satisfaction and quality of life in women without breast cancer and without breast surgery to patients undergoing breast reconstruction using the BREAST-Q., Methods: The authors performed a single-center, patient-reported outcomes comparative study. A sample of 300 women attending gynecology appointments completed a study-specific demographics form and preoperative BREAST-Q reconstruction module. Eligible women had no history of breast cancer or breast surgery and were not currently pregnant (control group). The authors compared prospectively collected control group data to demographics and preoperative and 12-month postoperative BREAST-Q scores in 300 breast reconstruction patients, retrospectively selected from a prospectively collected registry., Results: Control group BREAST-Q scores were higher in Satisfaction with Breasts (mean, 59.3 versus 55.3; p < 0.042) and Physical Well-being Chest scores (mean, 84.1 versus 78.8; p < 0.001), and lower for Physical Well-being Abdomen scores (mean, 81.9 versus 88.7; p < 0.001) when compared to breast reconstruction patients' preoperative scores. When compared with breast reconstruction patients' 12-month postoperative scores, control group scores were lower in Satisfaction with Breasts (mean, 59.3 versus 65.5; p < 0.002) and Psychosocial Well-being (mean, 69.5 versus 76.2; p < 0.001) and higher in Physical Well-being Chest (mean, 84.1 versus 78.2; p < 0.001)., Conclusions: The authors found differences in preoperative and 12-month postoperative BREAST-Q scores between breast reconstruction patients and a comparable control population. Establishing normative BREAST-Q data could serve as an important baseline for breast outcomes research and better understanding of patients' ability to recover quality of life following reconstruction., Clinical Question/level of Evidence: Risk, II.

Background: Breast satisfaction in general female populations is relatively unknown and prior research populations do not reflect our community., Objectives: We sought to assess breast satisfaction in a cohort of female participants utilizing the BREAST-Q and determine the impact of participant-related factors., Methods: Females with no history of breast cancer or breast surgery attending gynecology appointments completed preoperative BREAST-Q reconstruction modules and demographic forms in this prospective, single-center, patient-reported outcomes study. We also assessed participant-related factors capable of influencing BREAST-Q scores., Results: Three hundred females were included. Increasing body mass index had significant associations with lower Satisfaction with Breasts and Psychosocial Well-being scores. Increasing age was associated with significantly lower Sexual Well-being scores. African Americans had significantly higher scores for Satisfaction with Breasts, Psychosocial Well-being, and Sexual Well-being compared with Caucasians. Bra cup sizes A and C were associated with significantly higher Psychosocial Well-being scores than other sizes. Bra cup sizes A, B, and C were associated with significantly higher Sexual Well-being and Physical Well-being: Chest scores than larger sizes. Bra cup sizes B and C were associated with significantly higher Physical Well-being: Abdomen scores than size DD. Bra cup size A was associated with significantly higher Satisfaction with Breasts scores than sizes DD and >DD. Bra cup size C was associated with significantly higher Satisfaction with Breasts scores than larger sizes., Conclusions: Body mass index, age, race, and bra cup sizes significantly impact BREAST-Q scores in our population. Determining normative BREAST-Q scores in female populations could represent important baselines for breast outcomes research., Level of Evidence: 2., (© 2020 The Aesthetic Society. Reprints and permission: journals.permissions@oup.com.)

Background: Patient-reported lower satisfaction with the abdomen preoperatively is a strong predictor of undergoing DIEP flap surgery. The authors evaluated physical well-being of the abdomen before and after flap-based breast reconstruction to determine potential predictors for decreased postoperative abdominal well-being., Methods: The authors retrospectively analyzed an institutional breast reconstruction registry, selecting patients who underwent abdominally based autologous flap breast reconstruction from 2010 to 2015. The authors' primary outcome was the Physical Well-being of the Abdomen domain from the BREAST-Q, measured preoperatively and at 6- and 12-month follow-up visits after final reconstruction. The authors classified two patient groups: those who experienced a clinically important worsening of Physical Well-being of the Abdomen score and those who did not. The authors used the chi-square test, t test, and Wilcoxon rank sum test, and multivariable logistic regression to identify potential predictors., Results: Of 142 women identified, 74 (52 percent) experienced clinically important worsening of physical well-being of the abdomen, whereas 68 (48 percent) did not. The first group experienced a 25-point (95 percent CI, 22 to 28) decrease and the latter an 8-point (95 percent CI, 5 to 10) decrease in score compared to baseline. Multivariable analysis showed an association between higher baseline score and race, with higher odds of decreased score at the 12-month follow-up. A higher baseline RAND-36 general health score, bilateral reconstruction, and a lower body mass index demonstrated a trend for clinically important worsening of physical well-being of the abdomen., Conclusions: More than half of flap-based breast reconstruction patients experienced clinically important worsening of abdominal well-being after final breast reconstruction. Clinicians may use these findings to identify patients at higher risk of worsened postoperative abdominal well-being., Clinical Question/level of Evidence: Risk, III.

Objective: In the past decade women have comprised nearly half of U.S. medical school graduates. However, women remain underrepresented among surgical residents and practicing surgeons. We conducted the current study to assess recent trends in the female-to-male (F:M) ratios among residents and physicians pursuing careers in surgery., Design: We used retrospective population statistics published by the American Medical Association and the Accreditation Council for Graduate Medical Education from 2000 to 2016. We compared trends of female-to-male ratios among residents and surgeons in surgical subspecialties to evaluate for potential differences over time., Setting: Published online population statistics., Participants: We stratified both board-certified surgeons and surgical residents by sex and specialty., Results: From 2000 to 2013, the proportion of female surgeons among all female physicians remained constant (12%-13%). The proportion of board-certified female surgeons to all surgeons increased (from 15% in 2000 to 25% in 2013). The F:M ratios of board-certified surgeons in neurosurgery and orthopedic surgery were 1:10.6 and 1:13.9, with resident ratios 1:4.8 and 1:5.9, respectively. One specialty with increasingly equivalent ratios is plastic surgery with integrated resident F:M ratios of 1:3.1 in 2008 to 1:1.4 in 2015, and board-certified plastic surgeons of 1:9.2 in 2008 to 1:5.3 in 2013., Conclusion: Although the gender gap is narrowing, women continue to be underrepresented in surgical specialties. It is important for fields with disproportionate representation to be aware of these differences and take steps toward creating and supporting a more diverse workforce., (Copyright © 2019 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Aims: To examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium., Methods and Results: Hand1 is expressed within the cardiomyocytes of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5-13.5. Hand gene dosage plays an important role in ventricular morphology and the contribution of Hand1 to congenital heart defects requires further interrogation. Conditional ablation of Hand1 was carried out using either Nkx2.5 knockin Cre (Nkx2.5Cre) or α-myosin heavy chain Cre (αMhc-Cre) driver. Interrogation of transcriptome data via ingenuity pathway analysis reveals several gene regulatory pathways disrupted including translation and cardiac hypertrophy-related pathways. Embryo and adult hearts were subjected to histological, functional, and molecular analyses. Myocardial deletion of Hand1 results in morphological defects that include cardiac conduction system defects, survivable interventricular septal defects, and abnormal LV papillary muscles (PMs). Resulting Hand1 conditional mutants are born at Mendelian frequencies; but the morphological alterations acquired during cardiac development result in, the mice developing diastolic heart failure., Conclusion: Collectively, these data reveal that HAND1 contributes to the morphogenic patterning and maturation of cardiomyocytes during embryogenesis and although survivable, indicates a role for Hand1 within the developing conduction system and PM development., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking., Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide., Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group ( P =0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P =0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P =0.014), and work rate (+3.8 versus +0.34 W, P =0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level., Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Objective: General surgery and surgical subspecialty residents account for nearly 19% of US medical residents; however, it is well known that many surgical residents fail to graduate from their residency training program. We sought to comprehensively evaluate recent trends in nonprogression rates among surgical residents., Design: This is a retrospective study on residents during the 2007 to 2016 academic years. We calculated the annualized progression failure rate by extracting the total number of residents who progress to the next level of training per year, total number of residents who failed to progress per year, and reasons for discontinuing residency. Proportions of residents who failed to progress were calculated to estimate potential differences in progression failure rates among different specialties across time., Setting: We evaluated information provided by the Accreditation Council for Graduate Medical Education during the 2007 to 2016 academic years., Participants: Surgical and nonsurgical residents of Accreditation Council for Graduate Medical Education accredited programs during the period 2007 to 2016., Results: Overall, 2.67% of surgical residents did not progress to the next level each year. This proportion is higher in surgical specialties than in nonsurgical ones. Nonprogression rates for individual surgical specialties ranged from 0.4% to 4.1% on average per year. In addition, observed changes in rates and reasons for attrition varied across individual specialties. Of the surgical residents who failed to progress, more than 50% transferred to a different program, 40% withdrew, and 9% were dismissed., Conclusions: Our findings indicate that surgical residents are more likely to leave their initial residency program prior to completion than residents in medical specialties. Annualized ratios among subspecialties vary. General surgeons were the most likely and otolaryngology residents the least likely to discontinue their training., (Copyright © 2019 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Assessing workforce diversity over time is essential to understanding how it has evolved and anticipating its future. We conducted the current study to evaluate gender, racial/ethnic, and duty trends over the past decade in general surgery and surgical subspecialties., Design: This is a cross-sectional study. We calculated ratios and relative changes to assess potential differences of physicians' characteristics across time and surgical subspecialties., Setting: We evaluated data acquired by the Association of American Medical Colleges., Participants: We extracted data from the 2000 to 2013 including the overall number of surgeons, surgeon race/ethnicity, gender, and primary professional activity., Results: During 2000 to 2013, the total number of surgeons increased 11.5%, reaching 172,062 active surgeons and residents, the majority of whom were White (64%) or male (75%). However, from 2000 to 2013, most specialties showed some improvement in terms of including minorities and females. Most surgeons (98%) participate in patient care while a small portion are devoted to other activities (e.g., administrative, research, teaching; 2%). Both groups increased over the study period., Conclusions: Our findings suggest that the face of surgery is changing. Continuous monitoring of the surgical workforce is important to anticipate future needs and to serve a diverse patient population., (Copyright © 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

The 2018 FARA Biomarker Meeting highlighted the current state of development of biomarkers for Friedreich's ataxia. A mass spectroscopy assay to sensitively measure mature frataxin (reduction of which is the root cause of disease) is being developed. Biomarkers to monitor neurological disease progression include imaging, electrophysiological measures and measures of nerve function, which may be measured either in serum and/or through imaging-based technologies. Potential pharmacodynamic biomarkers include metabolic and protein biomarkers and markers of nerve damage. Cardiac imaging and serum biomarkers may reflect cardiac disease progression. Considerable progress has been made in the development of biomarkers for various contexts of use, but further work is needed in terms of larger longitudinal multisite studies, and identification of novel biomarkers for additional use cases., Competing Interests: Financial & competing interests disclosure The Friedreich’s Ataxia Research Alliance sponsored and funded the 2019 FARA Biomarker Meeting, with support from several companies. SH Subramony receives financial support from Reata, Takeda, Biohaven, Acceleron. Advisory board participation with Reata and Avexis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Background: The enhanced recovery after surgery pathway was introduced in 1997 as a multimodal approach to reduce preventable postoperative harm and shorten hospital length of stay. However, there is yet no widely accepted enhanced recovery after surgery protocol for microsurgical breast reconstruction. The authors conducted a systematic review and meta-analysis of the current literature on enhanced recovery after surgery for microsurgical breast reconstruction with regard to postoperative length of stay and morbidity., Methods: The PubMed, Embase, Cochrane, Scopus, and Web of Science databases were searched for all studies published before June of 2016 containing original data on enhanced recovery after surgery in microsurgical breast reconstruction in relation to postoperative length of stay and morbidity. Studies were screened using eligibility criteria. Meta-analysis, odds ratio, and 95 percent confidence interval were used to pool acquired data., Results: The initial search identified 86 studies. Two independent screeners identified four original articles with a total of 676 patients. Length of stay was significantly shorter for patients on an enhanced recovery after surgery pathway (mean difference, -1.23; 95 percent CI, -1.50 to -0.96; p < 0.001; I = 0 percent; random effects model). Enhanced recovery was not associated with changes in 30-day postoperative morbidity; specifically, no significant difference was observed in rates of partial flap loss (p = 0.44), total flap loss (p = 0.91), breast hematoma (p = 0.69), donor-site infection (p = 0.53), urinary tract infection (p = 0.29), and pneumonia (p = 0.42)., Conclusion: The authors' review suggests that enhanced recovery after surgery in microsurgical breast reconstruction is associated with a reduced length of stay, and is not associated with increased postoperative morbidity.

It is common for patients diagnosed with severe traumatic brain injury or intracranial tumors to undergo multiple craniotomy and cranioplasty procedures. In the setting of infection, these patients can develop scalp wounds with no local options. A reverse flow anterolateral thigh (ALT) flap for coverage of a complex multifocal scalp wound in a patient with exposed cranioplasty mesh and multiple prior operations without necessitating vein grafts was presented. This might be the first reverse flow free ALT flap to be reported in head and neck reconstruction.

Objectives: Hand injuries result in major healthcare costs from lack of productivity and disability. With rapid industrialization, the incidence of hand injuries is expected to rise in low- and middle-income countries (LMICs). However, estimates of burden and validated outcome tools are needed for effective resource allocation in the management of these injuries., Study Design: We conducted a systematic review to evaluate the burden of hand injuries in LMICs according to Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines., Methods: We searched PubMed, Scopus, Embase, Cochrane Library, PAIS International, African Index Medicus, Global Health, IMMEMR, IMSEAR, Wholis and Bdenf, Lilacs, Scielo, WPRIM, and WHO International Clinical Trials Registry Platform to detect eligible articles with no restrictions on length of follow-up, type of hand injury, or date., Results: We included 17 articles after screening 933 eligible articles based on title, abstract, and full-text screening. There was significant heterogeneity and low quality of evidence. All included articles suggest that hand injuries were associated with work limitations for the majority of patients, and residual pain can further limit their activities. Direct and indirect costs related to treatment account for a major healthcare burden with limited evidence on estimates of long-term cost from disability., Conclusions: The present systematic review highlights the paucity of high-quality data on the epidemiology, management, and burden of hand injuries in LMICs. The data are heterogeneous, and comprehensive metrics are lacking. Because hand injuries can account for a significant proportion of injury-related disability, reducing the overall burden of hand injuries is of utmost importance., (Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sciatic nerve damage in cattle could lead to pain, paralysis and lameness, creating welfare and productivity issues. Damage following intramuscular injection is highlighted in some clinical texts although there is no indication of prevalence. This cross-sectional study investigated the anatomical size and position of the sciatic nerve in four dairy cattle type cadavers. To evaluate the risk of iatrogenic damage, 54 participants placed needles in the dorsal gluteal region of two cadavers each, as per their routine intramuscular injection method. The distance from needle tip to the sciatic nerve was estimated for each. Sixty-nine per cent of injections were placed within 5 cm of the sciatic nerve. Direct nerve puncture occurred in the cadaver in poorest body condition. A short questionnaire revealed that 70 per cent of the participants regularly used the dorsal gluteal region for intramuscular injection and 50 per cent commonly used a volume of ≥20 mL at a single site. It is concluded that the sciatic nerve is at considerable risk of iatrogenic damage. The neck should be promoted as the optimum site for intramuscular injection and improved guidelines are required if the gluteal region is to remain in common use. A lateral site, between the tuber coxae and tuber ischium, is recommended., Competing Interests: Competing interests: None declared., (© British Veterinary Association (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich's ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3-KO and SIRT3-KO/FXN-KO (double KO [dKO]) models. The improvement in cardiac function upon NMN treatment in the FXN-KO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio-protection, SIRT3 mediates NMN-induced improvements in both cardiac and extracardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich's ataxia patients.

Background: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes., Objectives: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan., Methods: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five., Results: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts., Conclusions: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and loss of SIRT3 increases susceptibility of the heart to stress-induced cardiac hypertrophy and ischemic injury. The underlying pathophysiology of heart failure in FRDA is unclear. The purpose of this study was to examine in detail the physiologic and acetylation changes of the heart that occur over time in a model of FRDA heart failure. We predicted that increased mitochondrial protein acetylation would be associated with a decrease in heart function in a model of FRDA., Methods: A conditional mouse model of FRDA cardiomyopathy with ablation of FXN (FXN KO) in the heart was compared to healthy controls at postnatal days 30, 45 and 65. We evaluated hearts using echocardiography, cardiac catheterization, histology, protein acetylation and expression., Results: Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function., Conclusion: These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.

Plants sequester intermediates of metabolic pathways into different cellular compartments, but the mechanisms by which these molecules are transported remain poorly understood. Monoterpene indole alkaloids, a class of specialized metabolites that includes the anticancer agent vincristine, antimalarial quinine and neurotoxin strychnine, are synthesized in several different cellular locations. However, the transporters that control the movement of these biosynthetic intermediates within cellular compartments have not been discovered. Here we present the discovery of a tonoplast localized nitrate/peptide family (NPF) transporter from Catharanthus roseus, CrNPF2.9, that exports strictosidine, the central intermediate of this pathway, into the cytosol from the vacuole. This discovery highlights the role that intracellular localization plays in specialized metabolism, and sets the stage for understanding and controlling the central branch point of this pharmacologically important group of compounds.

There is an intimate interplay between cellular metabolism and the pathophysiology of disease. Mitochondria are essential to maintaining and regulating metabolic function of cells and organs. Mitochondrial dysfunction is implicated in diverse diseases, such as cardiovascular disease, diabetes and metabolic syndrome, neurodegeneration, cancer, and aging. Multiple reversible post-translational protein modifications are located in the mitochondria that are responsive to nutrient availability and redox conditions, and which can act in protein-protein interactions to modify diverse mitochondrial functions. Included in this are physiologic redox signaling via reactive oxygen and nitrogen species, phosphorylation, O-GlcNAcylation, acetylation, and succinylation, among others. With the advent of mass proteomic screening techniques, there has been a vast increase in the array of known mitochondrial post-translational modifications and their protein targets. The functional significance of these processes in disease etiology, and the pathologic response to their disruption, are still under investigation. However, many of these reversible modifications act as regulatory mechanisms in mitochondria and show promise for mitochondrial-targeted therapeutic strategies. This review addresses the current knowledge of post-translational processing and signaling mechanisms in mitochondria, and their implications in health and disease.