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Objective:  This study aimed to systematically document the reported omega-3 levels in commercially available prenatal supplements in the United States and Canada, and compare these levels to recommended intakes in pregnancy., Study Design:  Commercial prenatal supplements were identified using the Dietary Supplement Label Database ( n  = 50) and the Licensed Natural Health Products Database ( n  = 18). Mean omega-3 levels and the proportion of products meeting recommendations for pregnant women were tabulated., Results:  Average omega-3 levels were 368 ± 33 mg in the United States and 404 ± 72 mg in Canada. Seventy percent of products in the United States and 61% in Canada contained the amount of omega-3 levels recommended for pregnant women with sufficient intakes. Sixteen percent of products in the United States and 28% in Canada contained the dose recommended for pregnant women with insufficient intakes., Conclusion:  These results illustrate that commercial prenatal supplements contain a wide variety of omega-3 fatty acid levels that may or may not be consistent with recommended intake levels., Key Points: · most pregnant women consume inadequate amounts of omega-3 fatty acids.. · omega-3 fatty acids can help prevent preterm birth.. · new guidelines recommend increased intakes of omega-3 fatty acids during pregnancy.. · prenatal supplements contain a wide variety of omega-3 fatty acid levels.. · omega-3 levels in prenatal supplements may or may not be consistent with recommended intake levels.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Peritumoral edema on staging magnetic resonance imaging (MRI) is associated with higher local recurrence in soft tissue sarcoma (STS). This may relate to the presence of satellite malignant cells that are difficult to distinguish from benign atypia, leading to over- or undertreatment. This study evaluated a novel targeted molecular approach to identify malignancy in STS peritumoral planes as a means to improve personalized care., Methods: In the targeted molecular approach, whole-exome sequencing was employed to identify tumor-specific variants (TSVs), and peritumoral planes were assayed for malignancy, defined as two or more TSVs/plane, using droplet digital polymerase chain reaction (PCR). Feasibility was evaluated using a retrospective cohort (n = 8) in which planes with cellular atypia were tested. A prospective cohort (n = 8) then assayed all peritumoral planes with radiologic edema., Results: The targeted molecular approach identified malignancy in three of eight cases with cellular atypia of unknown significance (37.5%) and five of eight cases with peritumoral edema on staging MRI (62.5%). Peritumoral regions were heterogeneous; in none of the malignant cases did all sampled planes have evidence of tumor. Malignancy was also identified in regions without cellular atypia. Both cases with a local recurrence had molecular evidence of malignancy outside the main mass despite R0 margins., Conclusion: This study describes a novel personalized approach to detect malignancy in peritumoral regions in STS and is the first to identify molecular evidence of tumor outside the main mass. While development of a clinical tool is underway, these findings support the current approach of treating all peritumoral edema as malignant., Competing Interests: Disclosure Miguel Alfonso V. Principe, Nalan Gokgoz, Patrick Prochazka, Victoria S. Coward, Sidharth Saini, Sonya MacParland, Rebecca Gladdy, Peter Ferguson, Jay S. Wunder, Irene L. Andrulis, Peter Chung, Anthony M. Griffin, Lawrence M. White, Brendan C. Dickson, and Kim M. Tsoi have no potential conflicts of interest to declare that may be relevant to the contents of this study., (© 2024. Society of Surgical Oncology.)

Background: Albumin is used commonly across a wide range of clinical settings to improve hemodynamics, to facilitate fluid removal, and to manage complications of cirrhosis. The International Collaboration for Transfusion Medicine Guidelines developed guidelines for the use of albumin in patients requiring critical care, undergoing cardiovascular surgery, undergoing kidney replacement therapy, or experiencing complications of cirrhosis., Study Design and Methods: Cochairs oversaw the guideline development process and the panel included researchers, clinicians, methodologists, and a patient representative. The evidence informing this guideline arises from a systematic review of randomized clinical trials and systematic reviews, in which multiple databases were searched (inception through November 23, 2022). The panel reviewed the data and formulated the guideline recommendations using Grading of Recommendations Assessment, Development, and Evaluation methodology. The guidelines were revised after public consultation., Results: The panel made 14 recommendations on albumin use in adult critical care (three recommendations), pediatric critical care (one recommendation), neonatal critical care (two recommendations), cardiovascular surgery (two recommendations), kidney replacement therapy (one recommendation), and complications of cirrhosis (five recommendations). Of the 14 recommendations, two recommendations had moderate certainty of evidence, five recommendations had low certainty of evidence, and seven recommendations had very low certainty of evidence. Two of the 14 recommendations suggested conditional use of albumin for patients with cirrhosis undergoing large-volume paracentesis or with spontaneous bacterial peritonitis. Twelve of 14 recommendations did not suggest albumin use in a wide variety of clinical situations where albumin commonly is transfused., Interpretation: Currently, few evidence-based indications support the routine use of albumin in clinical practice to improve patient outcomes. These guidelines provide clinicians with actionable recommendations on the use of albumin., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. C. receives research support from Canadian Blood Services and Octapharma and serves on the board of directors of the Canadian Hematology Society. N. J. S. is a director of the National Board of Echocardiography and receives royalties from Wolters Kluwer. A. B. is an employee of Canadian Blood Services. H. K. is an employee of Canadian Blood Services. E. G. C. receives research funding (related to albumin) from Department of Medicine, The Ottawa Hospital and University of Ottawa, The Ottawa Hospital Academic Medical Organization, Kidney Foundation of Canada, and Physician Services Incorporated Foundation; is an editorial board member of the Canadian Journal of Kidney Health and Disease; and is a member of the Contrast-Associated Acute Kidney Injury guideline panel for the Canadian Association of Radiologists. B. R. is a guideline methodologist for American Thoracic Society, the Society of Critical Care Medicine, and Canadian Blood Services; is the Knowledge Translation director for Canadian Critical Care Society; is the grants and manuscripts chair for Canadian Critical Care Trials Group, and in a guideline group member for multiple guidelines. S. R. B. is the chair of the Clinical Pharmacy and Pharmacology section for the Society of Critical Care Medicine (not albumin use related), is a paid consultant for Wolters Kluwer (Lexicomp), is a Society of Critical Care Medicine Social Media Committee member, is a Surviving Sepsis Campaign Research Committee member, and has received a research grant from the National Institute of General Medicine Sciences. L. C. is a guideline group member for the British Society of Gastroenterology (management of ascites in liver cirrhosis), is involved in peer-reviewed publications (multiple topics including relevant to albumin use), received lecturer honoraria for the Canadian Liver Conference 2022, is a hepatology consultant for the Royal Free Hospital London, and is a Liver Committee member of the British Society of Gastroenterology. M. F. receives consultant fees from Cerus Corporation and Biocogniv, Inc.; has received honoraria from Grifols (none were albumin related); is a board member for Project Santa Fe Foundation and the American Board of Pathology; is the Histocompatibility and Identity Testing Committee Chair for College of American Pathologists; is co-team leader for the Biomedical Excellence for Safer Transfusion (BEST)Collaborative; and is the Editorial Committee co-chair for the ICTMG. R. J. has received fellowship funding from Canadian Blood Services, is an employee of William Osler Health System and the University of Cincinnati Medical Center, and is a panel member for ICTMG Platelet Utilization guideline development group. K. P. serves on the board of directors in North America for International Society for Blood Transfusion (ISBT), is a 2023 Association for the Advancement of Blood and Biotherapies (AABB) Red Blood Cells (RBC) guideline panel member, and is a member of the National Advisory Committee of Blood and Blood Products. P. S. S. is director of the Canadian Neonatal Network, director of the Canadian Preterm Birth Network, director of the International Network to Evaluate Outcomes of Neonates, and an external advisory board member for the Canadian Perinatal Surveillance system (none related to albumin manufacturers). H. S. is a consultant for Terumo and Cerus (not albumin related). Z. M. S. is a consultant and advisory board member of Grifols, Fresenius Kabi, and Novartis; receives research funding from Erydel and Fresenius Kabi; serves on the board of directors for the BEST Collaborative and International Council for Commonality in Blood Banking Automation (ICCBBA), Inc.; is the AABB Committee Chair; is vice chair, treasurer, and committee chair for ICCBBA, Inc.; is treasurer for BEST Collaborative; and has a family member (child) who is a summer intern with Grifols, Inc. T. T. is a paid consultant for Inter-View Partners France, A+A, Bayer HealthCare SAS, BVA, Axess Research, and All Global; has received honoraria from AbbeVie, Gilead Sciences, Advanz Pharma France, and Ipsen Pharma; in the principal investigator of randomized controlled trial Albumin Administration in Cirrhotic Patients With Bacterial Infection and a Systemic Inflammatory Response Syndrome Unrelated to Spontaneous Bacterial Peritonitis (ALB-CIRINF) (ClinicalTrials.gov Identifier, NCT01359813) published in 2015; and is a member of the Liver Cirrhosis-related Complications (LCC)-International Special Interest Group. B. W. is a resident physician at Loma Linda University Medical Center. S. S. is chair of the ICTMG and is an employee of National Health Service Blood and Transplant (NHSBT), a blood service operator in England. However, NHSBT is not a manufacturer of the intervention. N. S. is an employee of Canadian Blood Services; receives research funding from the Canadian Institutes for Health Research (Transfusion Requirements in Younger Patients Undergoing Cardiac Surgery [TRICS-IV] RBC transfusion in young cardiac patients; not related to albumin); is an advisory board member for Fresenius Kabius and Janssen; has received honoraria from the International Financial Corporation of the World Bank, Canadian Blood Services, and Ferring; and serves on the PKD guideline panel and ICTMG guideline panels (Fetal Neonatal Alloimmune Thrombocytopenia [FNAIT], Hemolytic Disease of the Newborn [HDN], platelet transfusion, RBC specifications). None declared (D. F., S. A., M. N., C. P., S. R.). See Appendix 8 for the ICTMG Conflict of Interest Policy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

New therapies are being developed for breast cancer, and in this process, some "old" biomarkers are reutilized and given a new purpose. It is not always recognized that by changing a biomarker's intended use, a new biomarker assay is created. The Ki-67 biomarker is typically assessed by immunohistochemistry (IHC) to provide a proliferative index in breast cancer. Canadian laboratories assessed the analytical performance and diagnostic accuracy of their Ki-67 IHC laboratory-developed tests (LDTs) of relevance for the LDTs' clinical utility. Canadian clinical IHC laboratories enrolled in the Canadian Biomarker Quality Assurance Pilot Run for Ki-67 in breast cancer by invitation. The Dako Ki-67 IHC pharmDx assay was employed as a study reference assay. The Dako central laboratory was the reference laboratory. Participants received unstained slides of breast cancer tissue microarrays with 32 cases and performed their in-house Ki-67 assays. The results were assessed using QuPath, an open-source software application for bioimage analysis. Positive percent agreement (PPA, sensitivity) and negative percent agreement (NPA, specificity) were calculated against the Dako Ki-67 IHC pharmDx assay for 5%, 10%, 20%, and 30% cutoffs. Overall, PPA and NPA varied depending on the selected cutoff; participants were more successful with 5% and 10%, than with 20% and 30% cutoffs. Only 4 of 16 laboratories had robust IHC protocols with acceptable PPA for all cutoffs. The lowest PPA for the 5% cutoff was 85%, for 10% was 63%, for 20% was 14%, and for 30% was 13%. The lowest NPA for the 5% cutoff was 50%, for 10% was 33%, for 20% was 50%, and for 30% was 57%. Despite many years of international efforts to standardize IHC testing for Ki-67 in breast cancer, our results indicate that Canadian clinical LDTs have a wide analytical sensitivity range and poor agreement for 20% and 30% cutoffs. The poor agreement was not due to the readout but rather due to IHC protocol conditions. International Ki-67 in Breast Cancer Working Group (IKWG) recommendations related to Ki-67 IHC standardization cannot take full effect without reliable fit-for-purpose reference materials that are required for the initial assay calibration, assay performance monitoring, and proficiency testing., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Environmental factors play an important role in inflammatory bowel diseases (IBD; Crohn's disease, [CD], ulcerative colitis [UC]). As part of the Crohn's & Colitis Challenges 2024 agenda, the Environmental Triggers workgroup summarized the progress made in the field of environmental impact on IBD since the last Challenges cycle in this document. The workgroup identified 4 unmet gaps in this content area pertaining to 4 broad categories: (1) Epidemiology; (2) Exposomics and environmental measurement; (3) Biologic mechanisms; and (4) Interventions and Implementation. Within epidemiology, the biggest unmet gaps were in the study of environmental factors in understudied populations including racial and ethnic minority groups and in populations witnessing rapid rise in disease incidence globally. The workgroup also identified a lack of robust knowledge of how environmental factors may impact difference stages of the disease and for different disease-related end points. Leveraging existing cohorts and targeted new prospective studies were felt to be an important need for the field. The workgroup identified the limitations of traditional questionnaire-based assessment of environmental exposure and placed high priority on the identification of measurable biomarkers that can quantify cross-sectional and longitudinal environmental exposure. This would, in turn, allow for identifying the biologic mechanisms of influence of environmental factors on IBD and understand the heterogeneity in effect of such influences. Finally, the working group emphasized the importance of generating high-quality data on effective environmental modification on an individual and societal level, and the importance of scalable and sustainable methods to deliver such changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Myelomeningocele (MMC) is a neural tube defect disease. Antenatal repair of fetal MMC is an alternative to postnatal repair. Many agents can be used as tocolytics during the in utero fetal repair such as β2-agonists and oxytocin receptor antagonists, with possible maternal and fetal repercussions. This study aims to compare maternal arterial blood gas analysis between terbutaline or atosiban, as tocolytic agents, during intrauterine MMC repair., Methods: Retrospective cohort study. Patients were divided into two groups depending on the main tocolytic agent used during intrauterine MMC repair: atosiban (16) or terbutaline (9). Maternal arterial blood gas samples were analyzed on three moments: post induction (baseline, before the start of tocolysis), before extubation, and two hours after the end of the surgery., Results: Twenty-five patients were included and assessed. Before extubation, the terbutaline group showed lower arterial pH (7.347 ± 0.05 vs. 7.396 ± 0.02 for atosiban, p = 0.006) and higher arterial lactate (28.33 ± 12.76 mg.dL -1 vs. 13.06 ± 6.35 mg.dL -1 , for atosiban, p = 0.001) levels., Conclusions: Patients who received terbutaline had more acidosis and higher levels of lactate, compared to those who received atosiban, during intrauterine fetal MMC repair., Competing Interests: Conflicts of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Anestesiologia. Published by Elsevier España S.L.U. All rights reserved.)

Background: Alarms alert healthcare professionals of deviations from normal/physiologic status. However, alarm fatigue may occur when their high pitch and diversity overwhelm clinicians, possibly leading to alarms being disabled, paused, and/or ignored. We aimed to determine whether a staff educational program on customizing alarm settings of bedside monitors may decrease inconsistent alarms in the Post-Anesthesia Care Unit (PACU)., Methods: This is a prospective, analytic, quantitative, pragmatic, open-label, single-arm study. The outcome was evaluated on PACU admission before (P1) and after (P2) the implementation of the educational program. The heart rate, blood pressure, and oxygen saturation alarms were selected for clinical consistency., Results: A total of 260 patients were included and 344 clinical alarms collected, with 270 (78.4%) before (P1), and 74 (21.6%) after (P2) the intervention. Among the 270 alarms in P1, 45.2% were inconsistent (i.e., false alarms), compared to 9.4% of the 74 in P2. Patients with consistent alarms occurred in 30% in the P1 and 27% in the P2 (p = 0.08). Patients with inconsistent alarms occurred in 25.4% in the P1 and in 3.8% in the P2. Ignored consistent alarms were reduced from 21.5% to 2.6% (p = 0.004) in the P2 group. The educational program was a protective factor for the inconsistent clinical alarm (OR = 0.11 [95% CI 0.04-0.3]; p < 0.001) after adjustments for age, gender, and ASA physical status., Conclusion: Customizing alarm settings on PACU admission proved to be a protective factor against inconsistent alarm notifications of multiparametric monitors., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Sociedade Brasileira de Anestesiologia. Published by Elsevier España S.L.U. All rights reserved.)

Gastric cancer (GC) is one of the most common types of cancer and is associated with relatively low survival rates. Despite its considerable burden, there is limited guidance for Canadian clinicians on the management of unresectable metastatic GC and gastroesophageal junction cancer (GEJC). Therefore, we aimed to discuss best practices and provide expert recommendations for patient management within the current Canadian unresectable GC and GEJC landscape. A multidisciplinary group of Canadian healthcare practitioners was assembled to develop expert recommendations via a working group. The often-rapid progression of unresectable GC and GEJC and the associated malnutrition have a significant impact on the patient's quality of life and ability to tolerate treatment. Hence, recommendations include early diagnosis, identification of relevant biomarkers to improve personalized treatment, and relevant support to manage comorbidities. A multidisciplinary approach including early access to registered dietitians, personal support networks, and palliative care services, is needed to optimize possible outcomes for patients. Where possible, patients with unresectable GC and GEJC would benefit from access to clinical trials and innovative treatments.

Background: The cumulative effect of postpartum weight retention from each pregnancy in a woman's life may contribute to her risk of ultimately developing type 2 diabetes and cardiovascular disease. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the trajectories of cardiovascular risk factors over the first 5-years after pregnancy., Methods: In this prospective observational cohort study, 330 women (mean age 35.7 ± 4.3 years, mean pre-pregnancy body mass index 25.2 ± 4.8 kg/m 2 , 50.9% primiparous) underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, oral glucose tolerance test, insulin sensitivity/resistance (Matsuda index, HOMA-IR), C-reactive protein (CRP), adiponectin) at 1-year, 3-years, and 5-years postpartum. Based on the magnitude of weight change between pre-pregnancy and 5-years postpartum, they were stratified into the following 3 groups: weight loss (n = 100), weight gain 0-6% (n = 110), and weight gain ≥ 6% (n = 120)., Results: At 1-year postpartum, cardiovascular risk factors did not differ between the groups. However, an adverse risk factor profile progressively emerged in the weight retention groups at 3- and 5-years. Indeed, after covariate adjustment, there was stepwise worsening (from the weight loss group to weight gain 0-6% to weight gain ≥ 6% group) of the following cardiovascular risk factors at 5-years: triglycerides (p = 0.001), HDL (p = 0.02), LDL (p = 0.01), apolipoprotein-B (p = 0.003), Matsuda index (p < 0.0001), HOMA-IR (p < 0.0001), fasting glucose (p = 0.07), and CRP (p = 0.01). Moreover, on logistic regression analyses, weight gain ≥ 6% emerged as an independent predictor of pre-diabetes/diabetes at 5-years (adjusted OR = 3.40, 95%CI: 1.63-7.09)., Conclusion: Postpartum weight retention predicts trajectories of worsening cardiovascular risk factors and glucose intolerance over the first 5-years after delivery, consistent with its postulated contribution to future vascular disease in women., (© 2024. The Author(s).)

Aim: The aim of this study was to assess which treatment modality regarding scaffold selection for immature permanent teeth with pulpal necrosis will be the most successful for regenerative endodontic treatment (RET)., Methodology: PubMed, Cochrane, Web of Science and Embase, and additional records until August 2022 were searched providing a total of 3021 articles, and nine of these articles were included for quantitative synthesis. The reviewers selected eligible randomized controlled trials and extracted pertinent data. Network meta-analysis was conducted to estimate treatment effects for primary outcomes (clinical and radiographic healing) and secondary outcomes (apical closure, root length and root wall thickness increase) following RET [mean difference (MD); 95% credible interval (CrI) and surface under the cumulative ranking curve (SUCRA)]. The quality of the included studies was appraised by the revised Cochrane risk of bias tool, and the quality of evidence was assessed using the GRADE approach., Results: Six interventions from nine included studies were identified: blood clot scaffold (BC), blood clot scaffold with basic fibroblast growth factor, blood clot scaffold with collagen, platelet pellet, platelet-rich plasma (PRP) and platelet-rich fibrin (PRF). The PRP scaffold showed the greatest increase in root lengthening at 6-12 months (MD = 4.2; 95% CrI, 1.2 to 6.8; SUCRA = 89.0%, very low confidence). PRP or PRF achieved the highest level of success for primary and secondary outcomes at 1-6 and 6-12 months. Blood clot scaffold (with collagen or combined with basic fibroblast growth factor (bFGF)) achieved the highest level of success for secondary outcomes beyond 12 months follow-up. A very low to low quality of evidence suggests that both PRP and PRF exhibit the greatest success evaluating primary and secondary outcomes within 12 months postoperatively compared to the traditional blood clot scaffold protocol., Conclusion: Limited evidence suggests both PRP and PRF exhibit success in the short-term, not long-term. The value of this information stems in its recommendation for future randomized trials prioritizing both of these materials in their protocol., (© 2023 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Background: Grade Group 1 (GG1) prostate cancer should be managed with active surveillance (AS). Global uptake of AS remains disappointingly slow and heterogeneous. Removal of cancer labels has been proposed to reduce GG1 overtreatment. We sought to determine the impact of GG1 disease terminology on individual's perceptions and decision making., Methods: Discrete choice experiments were conducted on 3 cohorts: healthy men, canonical partners (partners), and patients with GG1 (patients). Participants reported preferences in a series of vignettes with 2 scenarios each, permuting key opinion leader-endorsed descriptors: biopsy (adenocarcinoma, acinar neoplasm, prostatic acinar neoplasm of low malignant potential [PAN-LMP], prostatic acinar neoplasm of uncertain malignant potential), disease (cancer, neoplasm, tumor, growth), management decision (treatment, AS), and recurrence risk (6%, 3%, 1%, <1%). Influence on scenario selection were estimated by conditional logit models and marginal rates of substitution. Two additional validation vignettes with scenarios portraying identical descriptors except the management options were embedded into the discrete choice experiments., Results: Across cohorts (194 healthy men, 159 partners, and 159 patients), noncancer labels PAN-LMP or prostatic acinar neoplasm of uncertain malignant potential and neoplasm, tumor, or growth were favored over adenocarcinoma and cancer (P < .01), respectively. Switching adenocarcinoma and cancer labels to PAN-LMP and growth, respectively, increased AS choice by up to 17%: healthy men (15%, 95% confidence interval [CI] = 10% to 20%, from 76% to 91%, P < .001), partners (17%, 95% CI = 12% to 24%, from 65% to 82%, P < .001), and patients (7%, 95% CI = 4% to 12%, from 75% to 82%, P = .063). The main limitation is the theoretical nature of questions perhaps leading to less realistic choices., Conclusions: "Cancer" labels negatively affect perceptions and decision making regarding GG1. Relabeling (ie, avoiding word "cancer") increases proclivity for AS and would likely improve public health., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Planned hysterectomy at the time of cesarean delivery may be reasonable in cases other than placenta accreta spectrum disorders. Our objective was to synthesize the published literature on the indications and outcomes for planned cesarean hysterectomy., Data Sources: We performed a systematic review of published literature from the following databases from inception (1946) to June 2021: MEDLINE, PubMed, EMBASE, Cochrane CENTRAL, DARE, and clinicaltrials.gov., Study Selection: We included all study designs where subjects underwent planned cesarean delivery with simultaneous hysterectomy. Emergency procedures and those performed for placenta accreta spectrum disorders were excluded., Data Extraction and Synthesis: The primary outcome was surgical indication, though other surgical outcomes were evaluated when data permitted. Quantitative analysis was limited to studies published in 1990 or later. Risk of bias was assessed using an adaptation of the ROBINS-I tool., Conclusion: The most common indication for planned cesarean hysterectomy was malignancy, with cervical cancer being the most frequent. Other indications included permanent contraception, uterine fibroids, menstrual disorders, and chronic pelvic pain. Common complications included bleeding, infection, and ileus. The surgical skill for cesarean hysterectomy continues to be relevant in contemporary obstetrical practice for reproductive malignancy and several benign indications. Although the data indicate relatively safe outcomes, these studies show significant publication bias and, therefore, further systematic study of this procedure is justified., Prospero Registration Number: CRD42021260545, registered June 16, 2021., (Copyright © 2023 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objectives: Describe the current practice of Canadian obstetricians-gynaecologists in managing placenta accreta spectrum (PAS) disorders from suspicion of diagnosis to delivery planning and explore the impact of the latest national practice guidelines on this topic., Methods: We distributed a cross-sectional bilingual electronic survey to Canadian obstetricians-gynaecologists in March-April 2021. Demographic data and information on screening, diagnosis, and management were collected using a 39-item questionnaire. The survey was validated and pretested among a sample population. Descriptive statistics were used to present the results., Results: We received 142 responses. Almost 60% of respondents said they had read the latest Society of Obstetricians and Gynaecologists of Canada clinical practice guideline on PAS disorders, published in July 2019. Nearly 1 in 3 respondents changed their practice following this guideline. Respondents highlighted the importance of 4 key points: (1) limiting travel to thereby remain close to a regional care centre, (2) preoperative anemia optimization, (3) performance of cesarean-hysterectomy leaving the placenta in situ (83%), (4) access via midline laparotomy (65%). Most respondents recognized the importance of perioperative blood loss reduction strategies such as tranexamic acid and perioperative thromboprophylaxis via sequential compression devices and low-molecular-weight heparin until full mobilization., Conclusions: This study demonstrates the impact of the Society of Obstetricians and Gynaecologists of Canada's PAS clinical practice guideline on management choices made by Canadian clinicians. Our study highlights the value of a multidisciplinary approach to reducing maternal morbidity in individuals facing surgery for a PAS disorder and the importance of regionalized care that is resourced to provide maternal-fetal medicine and surgical expertise, transfusion medicine, and critical care support., (Copyright © 2023 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Tumor budding (TB), the presence of single cells or small clusters of up to 4 tumor cells at the invasive front of colorectal cancer (CRC), is a proven risk factor for adverse outcomes. International definitions are necessary to reduce interobserver variability. According to the current international guidelines, hotspots at the invasive front should be counted in hematoxylin and eosin (H&E)-stained slides. This is time-consuming and prone to interobserver variability; therefore, there is a need for computer-aided diagnosis solutions. In this study, we report an artificial intelligence-based method for detecting TB in H&E-stained whole slide images. We propose a fully automated pipeline to identify the tumor border, detect tumor buds, characterize them based on the number of tumor cells, and produce a TB density map to identify the TB hotspot. The method outputs the TB count in the hotspot as a computational biomarker. We show that the proposed automated TB detection workflow performs on par with a panel of 5 pathologists at detecting tumor buds and that the hotspot-based TB count is an independent prognosticator in both the univariate and the multivariate analysis, validated on a cohort of n = 981 patients with CRC. Computer-aided detection of tumor buds based on deep learning can perform on par with expert pathologists for the detection and quantification of tumor buds in H&E-stained CRC histopathology slides, strongly facilitating the introduction of budding as an independent prognosticator in clinical routine and clinical trials., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite considerable improvement in outcomes for preterm infants, rates of bronchopulmonary dysplasia (BPD) remain high, affecting an estimated 33% of very low birthweight infants, with corresponding long-term respiratory and neurosensory issues. Systemic corticosteroids can address the inflammation underlying BPD, but the optimal regimen for prevention of this disease, balancing of the benefits with the potentially meaningful risks of systemic corticosteroids, continues to be a medical quandary. Numerous studies have shown that systemic corticosteroids, particularly dexamethasone and hydrocortisone, effectively treat or prevent BPD. However, concerning short and long-term side effects have been reported and the optimal approach to corticosteroid treatment remains unclear., Objectives: To determine whether differences in efficacy and safety exist between high-dose dexamethasone, moderate-dose dexamethasone, low-dose dexamethasone, hydrocortisone, and placebo in the prevention of BPD, death, the composite outcome of death or BPD, and other relevant morbidities, in preterm infants through a network meta-analysis, generating both pairwise comparisons between all treatments and rankings of the treatments., Search Methods: We searched the Cochrane Library for all systematic reviews of systemic corticosteroids for the prevention of BPD and searched for completed and ongoing studies in the following databases in January 2023: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial databases., Selection Criteria: We included randomized controlled trials (RCTs) in preterm infants (< 37 weeks' gestation) at risk for BPD that evaluated systemic corticosteroids (high-dose [≥ 4 mg/kg cumulative dose] dexamethasone, moderate-dose [≥ 2 to < 4 mg/kg] dexamethasone, low-dose [< 2 mg/kg] dexamethasone, or hydrocortisone) versus control or another systemic corticosteroid., Data Collection and Analysis: Our main information sources were the systematic reviews, with reference to the original manuscript only for data not included in these reviews. Teams of two paired review authors independently performed data extraction, with disagreements resolved by discussion. Data were entered into Review Manager 5 and exported to R software for network meta-analysis (NMA). NMA was performed using a frequentist model with random-effects. Two separate networks were constructed, one for early (< seven days) initiation of treatment and one for late (≥ seven days) treatment initiation, to reflect the different patient populations evaluated. We assessed the certainty of evidence derived from the NMA for our primary outcomes using principles of the GRADE framework modified for application to NMA., Main Results: We included 59 studies, involving 6441 infants, in our analyses. Only six of the included studies provided direct comparisons between any of the treatment (dexamethasone or hydrocortisone) groups, forcing network comparisons between treatments to rely heavily on indirect evidence through comparisons with placebo/no treatment groups. Thirty-one studies evaluated early corticosteroid treatment, 27 evaluated late corticosteroid treatment, and one study evaluated both early and late corticosteroid treatments. Early treatment (prior to seven days after birth): Benefits:NMA for early treatment showed only moderate-dose dexamethasone to decrease the risk of BPD at 36 weeks' postmenstrual age (PMA) compared with control (RR 0.56, 95% CI 0.39 to 0.80; moderate-certainty evidence), although the other dexamethasone dosing regimens may have similar effects compared with control (high-dose dexamethasone, RR 0.71, 95% CI 0.50 to 1.01; low-certainty evidence; low-dose dexamethasone, RR 0.83, 95% CI 0.67 to 1.03; low-certainty evidence). Other early treatment regimens may have little or no effect on the risk of death at 36 weeks' PMA. Only moderate-dose dexamethasone decreased the composite outcome of death or BPD at 36 weeks' PMA compared with control (RR 0.77, 95% CI 0.60 to 0.98; moderate-certainty evidence)., Harms: Low-dose dexamethasone increased the risk for cerebral palsy (RR 1.92, 95% CI 1.12 to 3.28; moderate-certainty evidence) compared with control. Hydrocortisone may decrease the risk of major neurosensory disability versus low-dose dexamethasone (RR 0.65, 95% CI 0.41 to 1.01; low-certainty evidence). Late treatment (at seven days or later after birth): Benefits: NMA for late treatment showed high-dose dexamethasone to decrease the risk of BPD both versus hydrocortisone (RR 0.66, 95% CI 0.51 to 0.85; low-certainty evidence) and versus control (RR 0.72, CI 0.59 to 0.87; moderate-certainty evidence). The late treatment regimens evaluated may have little or no effect on the risk of death at 36 weeks' PMA. High-dose dexamethasone decreased risk for the composite outcome of death or BPD compared with all other treatments (control, RR 0.69, 95% CI 0.59 to 0.80, high-certainty evidence; hydrocortisone, RR 0.69, 95% CI 0.58 to 0.84, low-certainty evidence; low-dose dexamethasone, RR 0.73, 95% CI 0.60 to 0.88, low-certainty evidence; moderate-dose dexamethasone, RR 0.76, 95% CI 0.62 to 0.93, low-certainty evidence)., Harms: No effect was observed for the outcomes of major neurosensory disability or cerebral palsy. The evidence for the primary outcomes was of overall low certainty, with notable deductions for imprecision and heterogeneity across the networks., Authors' Conclusions: While early treatment with moderate-dose dexamethasone or late treatment with high-dose dexamethasone may lead to the best effects for survival without BPD, the certainty of the evidence is low. There is insufficient evidence to guide this therapy with regard to plausible adverse long-term outcomes. Further RCTs with direct comparisons between systemic corticosteroid treatments are needed to determine the optimal treatment approach, and these studies should be adequately powered to evaluate survival without major neurosensory disability., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Like many implemented organizational changes, quality improvement (QI) projects demonstrate frequent decline after implementation. Factors associated with successfully sustained change are leadership, change characteristics, system capacity for changes and the resources required, and processes to maintain, evaluate, and communicate results. This review uses lessons from change theory and behavioral sciences to discuss change and sustainment of improvement efforts, to list models to support maintenance, and to provide evidence-based practical suggestions to enable the sustainability of QI interventions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Several non-pharmacological, pharmacological, and surgical approaches have been explored to prevent or treat a PDA., Objectives: To summarise Cochrane Neonatal evidence on interventions (pharmacological or surgical) for the prevention of PDA and related complications, and interventions for the management of asymptomatic and symptomatic PDA in preterm infants., Methods: We searched the Cochrane Database of Systematic Reviews on 20 October 2022 for ongoing and published Cochrane Reviews on the prevention and treatment of PDA in preterm (< 37 weeks' gestation) or low birthweight (< 2500 g) infants. We included all published Cochrane Reviews assessing the following categories of interventions: pharmacological therapy using prostaglandin inhibitor drugs (indomethacin, ibuprofen, and acetaminophen), adjunctive pharmacological interventions, invasive PDA closure procedures, and non-pharmacological interventions. Two overview authors independently checked the eligibility of the reviews retrieved by the search, and extracted data from the included reviews using a predefined data extraction form. Any disagreements were resolved by discussion with a third overview author. Two overview authors independently assessed the methodological quality of the included reviews using the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews) tool. We reported the GRADE certainty of evidence as assessed by the respective review authors using summary of findings tables., Main Results: We included 16 Cochrane Reviews, corresponding to 138 randomised clinical trials (RCT) and 11,856 preterm infants, on the prevention and treatment of PDA in preterm infants. One of the 16 reviews had no included studies, and therefore, did not contribute to the results. Six reviews reported on prophylactic interventions for the prevention of PDA and included pharmacological prophylaxis with prostaglandin inhibitor drugs, prophylactic surgical PDA ligation, and non-pharmacologic interventions (chest shielding during phototherapy and restriction of fluid intake); one review reported on the use of indomethacin for the management of asymptomatic PDA; nine reviews reported on interventions for the management of symptomatic PDA, and included pharmacotherapy with prostaglandin inhibitor drugs in various routes and dosages, surgical PDA ligation, and adjunct therapies (use of furosemide and dopamine in conjunction with indomethacin). The quality of reviews varied. Two reviews were assessed to be high quality, seven reviews were of moderate quality, five of low quality, while two reviews were deemed to be of critically low quality. For prevention of PDA, prophylactic indomethacin reduces severe intraventricular haemorrhage (IVH; relative risk (RR) 0.66, 95% confidence interval (CI) 0.53 to 0.82; 14 RCTs, 2588 infants), and the need for invasive PDA closure (RR 0.51, 95% CI 0.37 to 0.71; 8 RCTs, 1791 infants), but it does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability (RR 1.02, 95% CI 0.90 to 1.15; 3 RCTs, 1491 infants). Prophylactic ibuprofen probably marginally reduces severe IVH (RR 0.67, 95% CI 0.45 to 1.00; 7 RCTs, 925 infants; moderate-certainty evidence), and the need for invasive PDA closure (RR 0.46, 95% CI 0.22 to 0.96; 7 RCTs, 925 infants; moderate-certainty evidence). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (RR 1.09, 95% CI 0.07 to 16.39; 1 RCT, 48 infants). Necrotising enterocolitis (NEC) was lower with both prophylactic surgical ligation (RR 0.25, 95% CI 0.08 to 0.83; 1 RCT, 84 infants), and fluid restriction (RR 0.43, 95% CI 0.21 to 0.87; 4 RCTs, 526 infants). For treatment of asymptomatic PDA, indomethacin appears to reduce the development of symptomatic PDA post-treatment (RR 0.36, 95% CI 0.19 to 0.68; 3 RCTs, 97 infants; quality of source review: critically low). For treatment of symptomatic PDA, all available prostaglandin inhibitor drugs appear to be more effective in closing a PDA than placebo or no treatment (indomethacin: RR 0.30, 95% CI 0.23 to 0.38; 10 RCTs, 654 infants; high-certainty evidence; ibuprofen: RR 0.62, 95% CI 0.44 to 0.86; 2 RCTs, 206 infants; moderate-certainty evidence; early administration of acetaminophen: RR 0.35, 95% CI 0.23 to 0.53; 2 RCTs, 127 infants; low-certainty evidence). Oral ibuprofen appears to be more effective in PDA closure than intravenous (IV) ibuprofen (RR 0.38, 95% CI 0.26 to 0.56; 5 RCTs, 406 infants; moderate-certainty evidence). High-dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (RR 0.37, 95% CI 0.22 to 0.61; 3 RCTs, 190 infants; moderate-certainty evidence). With respect to adverse outcomes, compared to indomethacin administration, NEC appears to be lower with ibuprofen (any route; RR 0.68, 95% CI 0.49 to 0.94; 18 RCTs, 1292 infants; moderate-certainty evidence), oral ibuprofen (RR 0.41, 95% CI 0.23 to 0.73; 7 RCTs, 249 infants; low-certainty evidence), and with acetaminophen (RR 0.42, 95% CI 0.19 to 0.96; 4 RCTs, 384 infants; low-certainty evidence). However, NEC appears to be increased with a prolonged course of indomethacin versus a shorter course (RR 1.87, 95% CI 1.07 to 3.27; 4 RCTs, 310 infants)., Authors' Conclusions: This overview summarised the evidence from 16 Cochrane Reviews of RCTs regarding the effects of interventions for the prevention and treatment of PDA in preterm infants. Prophylactic indomethacin reduces severe IVH, but does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability. Prophylactic ibuprofen probably marginally reduces severe IVH (moderate-certainty evidence), while the evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH. All available prostaglandin inhibitor drugs appear to be effective in symptomatic PDA closure compared to no treatment (high-certainty evidence for indomethacin; moderate-certainty evidence for ibuprofen; low-certainty evidence for early administration of acetaminophen). Oral ibuprofen appears to be more effective in PDA closure than IV ibuprofen (moderate-certainty evidence). High dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (moderate-certainty evidence). There are currently two ongoing reviews, one on fluid restriction for symptomatic PDA, and the other on invasive management of PDA in preterm infants., (Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Importance: Approximately 60% of women develop a uterine niche after a cesarean delivery (CD). A niche is associated with various gynecological symptoms including abnormal uterine bleeding, pain, and infertility, but there is little consensus in the literature on the distinction between the sonographic finding of a niche and the constellation of associated symptoms., Objective: To achieve consensus on defining the clinical condition that constitutes a symptomatic uterine niche and agree upon diagnostic criteria and uniform nomenclature for this condition., Design, Setting, and Participants: A consensus based modified electronic Delphi (eDelphi) study, with a predefined Rate of Agreement (RoA) of 70% or higher. Experts were selected according to their expertise with niche-related consultations, publications, and participation in expert groups and received online questionnaires between November 2021 and May 2022., Main Outcomes and Measures: Definition, nomenclature, symptoms, conditions to exclude, and diagnostic criteria of an illness caused by a symptomatic uterine niche., Results: In total, 31 of the 60 invited experts (51.7%) participated, of whom the majority worked in university-affiliated hospitals (28 of 31 [90.3%]), specialized in benign gynecology (20 of 31 [64.5%]), and worked in Europe (24 of 31 [77.4%]). Three rounds were required to achieve consensus on all items. All participants underlined the relevance of a new term for a condition caused by a symptomatic niche and its differentiation from a sonographic finding only. Experts agreed to name this condition cesarean scar disorder, defined as a uterine niche in combination with at least 1 primary or 2 secondary symptoms (RoA, 77.8%). Defined primary symptoms were postmenstrual spotting, pain during uterine bleeding, technical issues with catheter insertion during embryo transfer, and secondary unexplained infertility combined with intrauterine fluid. Secondary symptoms were dyspareunia, abnormal vaginal discharge, chronic pelvic pain, avoiding sexual intercourse, odor associated with abnormal blood loss, secondary unexplained infertility, secondary infertility despite assisted reproductive technology, negative self-image, and discomfort during participation in leisure activities. Consensus was also achieved on certain criteria that should be met and conditions that should be excluded before making the diagnosis., Conclusions and Relevance: In this modified Delphi study, a panel of 31 international niche experts reached consensus for the constellation of symptoms secondary to a uterine niche and named it cesarean scar disorder.

Background: Pain is an important dimension of quality-of-life in patients with metastatic castrate-sensitive prostate cancer (mCSPC). However, it is unclear if dynamic change in pain over time can predict for overall survival (OS) or progression-free survival (PFS) in these patients., Methods: This is an exploratory analysis of LATITUDE, a phase III randomized study, in which men with de novo mCSPC were randomized to receive either ADT plus abiraterone versus ADT alone. Information was collected on patient-reported worst pain score (WPS) and pain-interference score (PIS) from the Brief Pain Inventory-Short Form. A Bayesian joint modelling approach was used determine the association of dynamic change in WPS and PIS with OS and PFS., Results: Overall, 1125 patients with at least 3 measurements on pain scores were eligible. On Cox multivariable regression, increase in baseline WPS was associated with inferior OS (hazard ratio [HR] 1.049 [95% confidence intervals [CI] 1.015-1.085]; time dependent area under curve [tAUC] 0.64) and PFS (HR 1.045 [1.011-1.080]; tAUC: 0.64). Increase in baseline PIS was associated with inferior OS (HR 1.062 [1.020-1.105]; tAUC: 0.63) but not with PFS (HR 1.038 [0.996-1.08]). On independent joint models, an increase in the current value of WPS by 1-unit was associated with inferior OS (HR 1.316 [1.258-1.376]; tAUC 0.74) and PFS (HR 1.319 [1.260-1.382]; tAUC 0.70). Similar association was seen for increase in the current value of PIS with OS (HR 1.319 [1.261-1.381]; tAUC 0.73) and PFS (HR 1.282 [1.224-1.344]; tAUC 0.73)., Conclusions: The above findings highlight the potential dynamic interplay between patient-reported pain with OS and PFS in mCSPC. Compared to baseline pain, such dynamic assessment of pain was found to have superior predictive ability and thus has the potential to tailor subsequent treatment based on response to initial therapy beyond its role as a very important dimension of quality-of-life., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To develop a score assessing the probability of relapse in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)., Methods: Long-term follow-up data from GPA and MPA patients included in five consecutive randomised controlled trials were pooled. Patient characteristics at diagnosis were entered into a competing-risks model, with relapse as the event of interest and death the competing event. Univariate and multivariate analyses were computed to identify variables associated with relapse and build a score, which was then validated in an independent cohort of GPA or MPA patients., Results: Data collected from 427 patients (203 GPA, 224 MPA) at diagnosis were included. Mean±SD follow-up was 80.6±51.3 months; 207 (48.5%) patients experienced ≥1 relapse. Relapse risk was associated with proteinase 3 (PR3) positivity (HR=1.81 (95% CI 1.28 to 2.57); p<0.001), age ≤75 years (HR=1.89 (95% CI 1.15 to 3.13); p=0.012) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² (HR=1.67 (95% CI 1.18 to 2.33); p=0.004) at diagnosis. A score, the French Vasculitis Study Group Relapse Score (FRS), from 0 to 3 points was modelised: 1 point each for PR3-antineutrophil cytoplasmic antibody positivity, eGFR ≥30 mL/min/1.73 m² and age ≤75 years. In the validation cohort of 209 patients, the 5-year relapse risk was 8% for a FRS of 0, 30% for 1, 48% for 2 and 76% for 3., Conclusion: The FRS can be used at diagnosis to assess the relapse risk in patients with GPA or MPA. Its value for tailoring the duration of maintenance therapy should be evaluated in future prospective trials., Competing Interests: Competing interests: MS: Roche-Chugai, Vifor Pharma, Novartis, Boerhinger Ingelheim (consulting), Novartis (research grant)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Platelet transfusions are used across multiple patient populations to prevent and correct bleeding. This scoping review aimed to map the currently available systematic reviews (SRs) and evidence-based guidelines in the field of platelet transfusion., Materials and Methods: A systematic literature search was conducted in seven databases for SRs on effectiveness (including dose and timing, transfusion trigger and ratio to other blood products), production modalities and decision support related to platelet transfusion. The following data were charted: methodological features of the SR, population, concept and context features, outcomes reported, study design and number of studies included. Results were synthesized in interactive evidence maps., Results: We identified 110 SRs. The majority focused on clinical effectiveness, including prophylactic or therapeutic transfusions compared to no platelet transfusion (34 SRs), prophylactic compared to therapeutic-only transfusion (8 SRs), dose, timing (11 SRs) and threshold for platelet transfusion (15 SRs) and the ratio of platelet transfusion to other blood products in massive transfusion (14 SRs). Furthermore, we included 34 SRs on decision support, of which 26 evaluated viscoelastic testing. Finally, we identified 22 SRs on platelet production modalities, including derivation (4 SRs), pathogen inactivation (6 SRs), leucodepletion (4 SRs) and ABO/human leucocyte antigen matching (5 SRs). The SRs were mapped according to concept and clinical context., Conclusion: An interactive evidence map of SRs and evidence-based guidelines in the field of platelet transfusion has been developed and identified multiple reviews. This work serves as a tool for researchers looking for evidence gaps, thereby both supporting research and avoiding unnecessary duplication., (© 2022 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Background: The different management strategies for patent ductus arteriosus (PDA) in preterm infants are expectant management, surgery, or medical treatment with non-selective cyclo-oxygenase inhibitors. Randomized controlled trials (RCTs) have suggested that paracetamol may be an effective and safe agent for the closure of a PDA., Objectives: To determine the efficacy and safety of paracetamol as monotherapy or as part of combination therapy via any route of administration, compared with placebo, no intervention, or another prostaglandin inhibitor, for prophylaxis or treatment of an echocardiographically-diagnosed PDA in preterm or low birth weight infants., Search Methods: We searched CENTRAL, MEDLINE, Embase, and three trials registers on 13 October 2021, and one other database on 1 March 2022. We also checked references and contacted study authors to identify additional studies., Selection Criteria: We included RCTs and quasi-RCTs in which paracetamol (single-agent or combination therapy) was compared to no intervention, placebo, or other agents used for closure of PDA, irrespective of dose, duration, and mode of administration in preterm infants. Two independent authors reviewed the search results and made a final selection of potentially eligible articles through discussion., Data Collection and Analysis: We performed data collection and analyses in accordance with the methods of Cochrane Neonatal. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of ductal closure after the first course of treatment; all-cause mortality during initial hospital stay; and necrotizing enterocolitis (NEC)., Main Results: For this update, we included 27 studies enrolling 2278 infants. We considered the overall risk of bias in the 27 studies to vary from low to unclear. We identified 24 ongoing studies. Paracetamol versus ibuprofen  There was probably little to no difference between paracetamol and ibuprofen for failure of ductal closure after the first course (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.18; 18 studies, 1535 infants; moderate-certainty evidence). There was likely little to no difference between paracetamol and ibuprofen for all-cause mortality during hospital stay (RR 1.09, 95% CI 0.80 to 1.48; 8 studies, 734 infants; moderate-certainty evidence), and for NEC (RR 1.30, 95% CI 0.87 to 1.94; 10 studies, 1015 infants; moderate-certainty evidence). Paracetamol versus indomethacin There was little to no difference between paracetamol and indomethacin for failure of ductal closure after the first course (RR 1.02, 95% CI 0.78 to 1.33; 4 studies, 380 infants; low-certainty evidence). There was little to no difference between paracetamol and indomethacin for all-cause mortality during hospital stay (RR 0.86, 95% CI 0.39 to 1.92; 2 studies, 114 infants; low-certainty evidence). The rate of NEC may be lower in the paracetamol group (3.7%) versus the indomethacin group(9.2%) (RR 0.42, 95% CI 0.19 to 0.96; 4 studies, 384 infants; low-certainty evidence).  Prophylactic paracetamol versus placebo/no intervention Prophylactic paracetamol (17%) compared to placebo/no intervention (61%) may reduce failure of ductal closure after one course (RR 0.27, 95% CI 0.18 to 0.42; 3 studies, 240 infants; low-certainty evidence). There was little to no difference between prophylactic paracetamol and placebo/no intervention for all-cause mortality during hospital stay (RR 0.59, 95% CI 0.24 to 1.44; 3 studies, 240 infants; low-certainty evidence). No studies reported on NEC.  Early paracetamol treatment versus placebo/no intervention Early paracetamol treatment (28%) compared to placebo/no intervention (79%) may reduce failure of ductal closure after one course when used before 14 days' postnatal age (RR 0.35, 95% CI 0.23 to 0.53; 2 studies, 127 infants; low-certainty evidence). No studies reported on all-cause mortality during hospital stay or NEC.  Late paracetamol treatment versus placebo/no intervention  There was little to no difference between late paracetamol and placebo for failure of ductal closure after one course of treatment when used at or after 14 days' postnatal age (RR 0.85, 95% CI 0.72 to 1.01; 1 study, 55 infants; low-certainty evidence) or NEC (RR 1.04, 95% CI 0.07 to 15.76; 1 study, 55 infants; low-certainty evidence). No data were reported for all-cause mortality during hospital stay.  Paracetamol combined with ibuprofen versus ibuprofen combined with placebo or no intervention There was little to no difference between paracetamol plus ibuprofen compared to ibuprofen plus placebo or no intervention for failure of ductal closure after the first course (RR 0.77, 95% CI 0.43 to 1.36; 2 studies, 111 infants; low-certainty evidence). There was little to no difference between paracetamol plus ibuprofen compared to ibuprofen plus placebo or no intervention for NEC (RR 0.33, 95% CI 0.01 to 7.45; 1 study, 24 infants; low-certainty evidence). No data were reported for all-cause mortality during hospital stay.  AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests that there is probably little or no difference in effectiveness between paracetamol and ibuprofen; low-certainty evidence suggests that there is probably little or no difference in effectiveness between paracetamol and indomethacin; low-certainty evidence suggests that prophylactic paracetamol may be more effective than placebo/no intervention; low-certainty evidence suggests that early paracetamol treatment may be more effective than placebo/no intervention; low-certainty evidence suggests that there is probably little or no difference between late paracetamol treatment and placebo, and probably little or no difference in effectiveness between the combination of paracetamol plus ibuprofen versus ibuprofen alone for the closure of PDA after the first course of treatment. The majority of neonates included in these studies were of moderate preterm gestation. Thus, establishing the efficacy and safety of paracetamol for PDA treatment in extremely low birth weight (ELBW: birth weight < 1000 grams) and extremely low gestational age neonates (ELGANs < 28 weeks' gestation) requires further studies., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Rationale: Acute respiratory failure (ARF) is a frequent complication following hematopoietic cell transplantation (HCT). We aimed to characterize the etiologies of ARF in patients who died in the intensive care unit following HCT based on autopsy findings. We then evaluated agreement between the clinical and pathologic diagnosis., Methods: We performed a chart review of all HCT patients who died and underwent autopsy in our ICU between 2006-2016. We evaluated the presumed clinical diagnosis and confidence in the diagnosis by chart review, the pathologic diagnosis on autopsy, and whether the clinical-pathologic diagnoses were concordant. When there was discordance, we evaluated whether knowledge of the pathology could have changed management., Results: Thirteen patients underwent autopsy after dying. Infection was the presumed cause in 11/13 cases. The clinical and pathologic diagnoses were concordant in 6/13(46%). In the seven discordant cases (all clinically diagnosed as infection), autopsy revealed two non-infectious inflammatory causes, one post-transplant lymphoproliferative disorder, and three non-bacterial infectious etiology. Pathologic findings may have changed management in 7/13(54%) cases., Conclusions: In a subset of HCT-recipients who died from respiratory failure, discordance was frequent between clinical and pathologic diagnoses. The risks and benefits of obtaining tissue to improve our diagnostic accuracy requires further evaluation., (© 2022. Crown.)

Objective: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906., Methods: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy., Results: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay., Conclusions: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake., (Copyright © 2022 Boehringer Ingelheim Pharma GmbH & CoKG. Published by Elsevier GmbH.. All rights reserved.)

Purpose: The purpose of this work is to describe the association between body mass index (BMI) and (1) management option for localized prostate cancer (PCa) and (2) disease-specific quality of life (ds-QoL) after treatment or active surveillance., Subjects/patients and Methods: We analysed data from men with localized PCa managed with radical prostatectomy (RP), radiation therapy (RT), or active surveillance (AS) in a prospective, population-based cohort study. We evaluated the association between BMI and management option with multivariable multinomial logistic regression analysis. The association between BMI and ds-QoL was assessed using multivariable longitudinal linear regression. Regression models were adjusted for baseline domain scores, demographics, and clinicopathologic characteristics., Results: A total of 2378 men were included (medians [quartiles]: age 64 [59-69] years; BMI 27 kg/m 2 ; 77% were non-Hispanic white); 29% were obese (BMI ≥ 30). Accounting for demographic and clinicopathologic features, BMI ≥ 28 kg/m 2 was inversely associated with the likelihood of receiving RP (compared with RT) and became statistically significant at BMI ≥ 33 kg/m 2 (maximum adjusted relative risk ratio = 0.80, 95% CI 0.67 to 0.95, p  = 0.013 for BMI ≥ 33 vs. 25). Conversely, BMI was not significantly associated with the likelihood of receiving AS compared with RT. After stratification by management option, obese men who underwent definitive treatment were not found to have clinically worse ds-QoL. Obese men initially on AS appeared to have worse urinary incontinence than nonobese men, but this was not significant on an as-treated sensitivity analysis., Conclusions: Among men with localized PCa, those with BMI ≥ 33 kg/m 2 were less likely to receive surgery than radiation. Obesity was not associated with ds-QoL in men undergoing definitive treatment, nor in men who remained on AS., Competing Interests: The authors have no competing interests., (© 2022 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Objective: Compare maternal and perinatal outcomes between emergency and electively scheduled cesarean-hysterectomy for placenta accreta spectrum (PAS) disorders., Method: Single-center retrospective cohort study including 125 cases of antenatally suspected and pathologically confirmed PAS disorders. Maternal and perinatal outcomes were analyzed. Multivariate logistic regression was used to test associations. Survival curves exploring risk factors for emergency birth were sought., Results: 25 (20%) and 100 (80%) patients had emergency and electively scheduled birth, respectively. Emergency birth had a higher estimated blood loss (2772 [2256.75] vs. 1561.19 [1152.95], P < 0.001), with a higher rate of coagulopathy (40% vs. 6%; P < 0.001) and bladder injury (44% vs. 13%; P < 0.001); and was associated with increased rates of blood transfusion (aOR 4.9, CI95% 1.3-17.5, P = 0.01), coagulopathy (aOR 16.4, CI95% 2.6-101.4, P = 0.002) and urinary tract injury (aOR 6.96, CI95% 1.5-30.7, P = 0.01). Gestational age at birth was lower in the emergency group (31.55 [4.75] vs. 35.19 [2.77], P = 0.001), no difference in perinatal mortality was found. A sonographically short cervix and/or history of APH had an increased cumulative risk of emergency birth with advancing gestational age., Conclusion: Patients with PAS disorders managed in a tertiary center by a multidisciplinary team requiring emergency birth have increased maternal morbidity and poorer perinatal outcomes than those with electively scheduled birth., (© 2022 International Federation of Gynecology and Obstetrics.)

Objective: To synthesize the published literature to better understand the association between cesarean scar defects (CSDs) and abnormal uterine bleeding (AUB). In particular, we aimed to evaluate the risk and pattern(s) of CSD-associated AUB in addition to exploring the relationship between defect morphology with bleeding symptoms., Design: Systematic review and meta-analysis., Setting: Not applicable., Patients: Patients with CSD and reports of uterine bleeding as an outcome were identified in 60 studies from database searches., Interventions: Studies that investigated CSD (as defined by investigators) and reported uterine bleeding, menstrual bleeding, or AUB as an outcome were included., Main Outcome Measures: The prevalence and risk of AUB (intermenstrual, postmenstrual, and unscheduled bleeding) in patients with confirmed CSD., Results: Nine studies reported on the prevalence of AUB in patients with a confirmed CSD. Patients with CSD were more likely to experience AUB, compared with those without CSD (relative risk, 3.47; 95% confidence interval [CI], 2.02-5.97; 6 studies, 1,385 patients; I 2 = 67%). In a population of patients with at least 1 cesarean delivery, the prevalence of AUB in those with CSD was 25.5% (95% CI, 14.7-40.5; 6 studies, 667 patients, I 2 = 93%). However, symptom prevalence was much higher in patients presenting for imaging for a gynecologic indication where the prevalence of AUB in the presence of a CSD was 76.4% (95% CI, 67.8-83.3; 5 studies, 505 patients; I 2 = 71%). The mean menstrual duration in symptomatic patients with CSD was 13.4 days (95% CI, 12.6-14.2; 19 studies, 2,095 patients; I 2 = 96%), and the mean duration of early-cycle intermenstrual bleeding was 6.8 days (95% CI, 5.7-7.8 days; 9 studies, 759 patients; I 2 = 93%). The most common descriptor of CSD-associated AUB was "brown discharge". Patients with larger CSD experienced more bleeding symptoms., Conclusion: There is a strong and consistent association between patients with CSD and AUB. These patients experience a unique bleeding pattern, namely prolonged menstruation and early-cycle intermenstrual bleeding. These data should provide impetus for including CSD as a distinct entity in AUB classification systems. High heterogeneity in our results calls for standardization of nomenclature and outcome reporting for this condition., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The ventilatory care of patients with acute respiratory distress syndrome (ARDS) is evolving as our understanding of physiologic mechanisms of respiratory failure improves. Despite several decades of research, the mortality rate for ARDS remains high. Over the years, we continue to expand strategies to identify and mitigate ventilator-induced lung injury. This now includes a greater understanding of the benefits and harms associated with spontaneous breathing., Competing Interests: Disclosure The authors have no financial disclosures., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Background: Intra-operative internal carotid artery (ICA) injury during transnasal endoscopic surgery is a potentially catastrophic event. Such an injury is life-threatening in the immediate setting, with a reported peri-operative mortality rate of 10%. Nasal packing, muscle patches, direct vessel closure, and endovascular techniques have been described as useful strategies for managing ICA bleeds. The objective of this study was to develop a formalized management protocol for intra-operative ICA injury through engagement with a multi-disciplinary panel., Methods: A modified Delphi method including literature review, iterative rounds of stakeholder feedback, and expert panel discussions was used to develop a management protocol for ICA injury during transnasal endoscopic surgery. The 10-person multi-disciplinary panel included otolaryngologists, neurosurgeons, interventional neuroradiologists, anesthesiologists, and operating room nursing staff., Results: After three rounds of stakeholder engagement with the expert panel, consensus was reached on important elements to include within the protocol. The protocol was divided in three categories: Alert, Control, and Transfer. 'Alert' focusses on early communication with anesthesia and nursing staff. 'Control' focusses on techniques to expose the injury and obtain hemostasis or adequate tamponade. Lastly, 'Transfer' describes the process of contacting neuro-interventional radiology and safely transferring the patient. A one-page handout of the protocol was developed for placement in operating theatres., Conclusion: Due to the life-threatening nature of ICA injury, it is imperative that endoscopic sinus and skull base surgeons are prepared to manage this complication. Using a modified Delphi method with a multidisciplinary expert panel, a protocol for management of intra-operative ICA injury was developed., (© 2022. The Author(s).)