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We conducted systematic reviews of predefined clinical questions and used the Grading of Recommendations, Assessment, Development and Evaluations approach to develop recommendations for the periendoscopic management of anticoagulant and antiplatelet drugs during acute gastrointestinal (GI) bleeding and the elective endoscopic setting. The following recommendations target patients presenting with acute GI bleeding: For patients on warfarin, we suggest against giving fresh frozen plasma or vitamin K; if needed, we suggest prothrombin complex concentrate (PCC) compared with fresh frozen plasma administration; for patients on direct oral anticoagulants (DOACs), we suggest against PCC administration; if on dabigatran, we suggest against the administration of idarucizumab, and if on rivaroxaban or apixaban, we suggest against andexanet alfa administration; for patients on antiplatelet agents, we suggest against platelet transfusions; and for patients on cardiac acetylsalicylic acid (ASA) for secondary prevention, we suggest against holding it, but if the ASA has been interrupted, we suggest resumption on the day hemostasis is endoscopically confirmed. The following recommendations target patients in the elective (planned) endoscopy setting: For patients on warfarin, we suggest continuation as opposed to temporary interruption (1-7 days), but if it is held for procedures with high risk of GI bleeding, we suggest against bridging anticoagulation unless the patient has a mechanical heart valve; for patients on DOACs, we suggest temporarily interrupting rather than continuing these; for patients on dual antiplatelet therapy for secondary prevention, we suggest temporary interruption of the P2Y12 receptor inhibitor while continuing ASA; and if on cardiac ASA monotherapy for secondary prevention, we suggest against its interruption. Evidence was insufficient in the following settings to permit recommendations. With acute GI bleeding in patients on warfarin, we could not recommend for or against PCC administration when compared with placebo. In the elective periprocedural endoscopy setting, we could not recommend for or against temporary interruption of the P2Y12 receptor inhibitor for patients on a single P2Y12 inhibiting agent. We were also unable to make a recommendation regarding same-day resumption of the drug vs 1-7 days after the procedure among patients prescribed anticoagulants (warfarin or DOACs) or P2Y12 receptor inhibitor drugs because of insufficient evidence., (Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology.)

Objectives: To study the association between Medicare's wage index adjustment and the differential use of labor-intensive surgical procedures and medical device-intensive minimally invasive clinical procedures across the United States., Study Design: We combine a conceptual model and an empirical investigation of its predictions, applied to aortic valve replacement, to study the relationship between variation in Medicare wage index payment adjustment across hospital referral regions (HRRs) and the utilization of transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in these areas., Methods: Using detailed individual Medicare claims data for 2013-2018 and a novel geographical crosswalk to nest information on Medicare's wage index and utilization of TAVR and SAVR, we estimate a mixed effects Poisson regression model across HRRs to test our hypotheses., Results: We find regional variation in Medicare wage index adjustment levels to be correlated with differential TAVR and SAVR utilization and growth over time. In particular, in HRRs where the wage index is half the national mean there is a 35% decline in the rate of TAVR use and in HRRs where the wage index is 50% higher than the national mean there is a 52% increase in the rate of TAVR use., Conclusions: Consistent with our framework and hypothesis, our results highlight the importance of adjusting Medicare hospital inpatient payments for device-intensive procedures. Absent such adjustment, access to appropriate interventions may be reduced in areas with low wage index, and lower reimbursement, when driven by wage index adjustment, may influence the treatment approach selected.

Background: The comparative effectiveness of differing dosages of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) on clinical and patient-reported outcomes in clinical practice in the United States is unknown. This study sought to characterize associations between the dosing of GDMT and outcomes for patients with HFrEF in U.S. clinical practice., Methods: This analysis included 4832 outpatients who had chronic HFrEF across 150 practices in the U.S. in the Change the Management of Patients with Heart Failure (CHAMP-HF) registry with no contraindication and available dosing data for at least 1 GDMT at baseline. Baseline dosing of angiotensin-converting enzyme (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) therapies were examined. For each medication class, multivariable models assessed associations between medication dosing and clinical outcomes over 24 months (all-cause mortality, HF hospitalization) and patient-reported outcomes at 12 months (change in the Kansas City Cardiomyopathy Questionnaire Overall Summary score [KCCQ-OS])., Results: After adjustment, compared with target dosing, lower dosing was associated with higher all-cause mortality for ACEIs/ARBs/ARNIs (50% to < 100% target dosage, HR 1.16 [95% CI 0.87-1.55]; < 50% target dosage, HR 1.37 [95% CI 1.05-1.79]; none, HR 1.75 [95% CI 1.32-2.34; overall P< 0.001) and beta-blockers (50% to < 100% target dosage, HR 1.30 [95% CI 1.00-1.69]; < 50% target dosage, HR 1.41 [95% CI 1.11-1.79; none, HR 1.24 [95% CI 0.92-1.67]; overall P= 0.042). Lower dosing of ACEIs/ARBs/ARNIs was independently associated with higher risk of HF hospitalization (50% to < 100% target dosage, HR 1.08 [95% CI 0.90-1.30]; < 50% target dosage, HR 1.23 [1.04-1.47]; none, HR 1.29 [1.04-1.60]; overall P= 0.046), but beta-blocker dosing was not (overall P= 0.085). Target dosing of MRAs was not associated with risk of mortality or HF hospitalization. For each GDMT, compared with target dosing, lower dosing was not associated with change in the KCCQ-OS at 12 months, with the potential exception of worsening KCCQ-OS scores with lower dosing of ACEIs/ARBs/ARNIs., Conclusions: In this contemporary U.S. outpatient HFrEF registry, target dosing of ACEI/ARB/ARNI and beta-blocker therapy was associated with reduced mortality and was variably associated with HF hospitalization and patient-reported outcomes. MRA dosing was not associated with outcomes. The totality of these findings support the benefits of target dosing of GDMT in routine practice, as tolerated, with unmeasured differences among patients receiving differing dosages potentially explaining the differing results seen here compared with randomized clinical trials., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The emergence of non-native fungal pathogens is a growing threat to global health, biodiversity, conservation biology, food security and the global economy. Moreover, a thorough understanding of the spread and emergence of pathogens among invasive and native host populations, as well as genetic analysis of the structure of co-invasive host populations, is crucial in terms of conservation biology and management strategies. Here we combined extensive catchment sampling, molecular detection tools and genomic signatures to i) assess the prevalence of the rosette agent Sphaerothecum destruens in invasive and native fish populations in contrasting french regions, and ii) characterize the genetic diversity and population structure of its co-invasive and asymptomatic carrier Pseudorasbora parva. Although S. destruens was not detected in all the fish collected its presence in contrasting freshwater ecosystems suggests that the disease may already be widespread in France. Furthermore, our results show that the detection of S. destruens DNA in its asymptomatic carrier P. parva is still limited. Finally, we found that P. parva populations show a homogeneous genetic and geographical structuring, which raises the possibility of the occurrence of successive introduction events in France from their native and invasive range., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

While general mechanisms by which Plasmodium ookinetes invade the mosquito midgut have been studied, details regarding the interface of the ookinete, specifically its barriers to invasion, such as the proteolytic milieu, the chitin-containing, protein cross-linked peritrophic matrix, and the midgut epithelium, remain to be understood. Here, we review our knowledge of Plasmodium chitinases and the mechanisms by which they mediate ookinetes crossing the peritrophic matrix. The integration of new genomic insights into previous findings advances our understanding of Plasmodium evolution. Recently obtained Plasmodium species genomic data enable identification of the conserved residues in the experimentally demonstrated hetero-multimeric, high-molecular-weight complex comprised of a short chitinase covalently linked to binding partners, von Willebrand factor A domain-related protein (WARP) and secreted ookinete adhesive protein (SOAP). Artificial intelligence-based high-resolution structural modeling using the DeepMind AlphaFold algorithm yielded highly informative three-dimensional structures and insights into how short chitinases, WARP, and SOAP may interact at the atomic level to form the ookinete-secreted peritrophic matrix invasion complex. Elucidating the significance of the divergence of ookinete-secreted micronemal proteins among Plasmodium species may lead to a better understanding of the ookinete invasion machinery and the coevolution of Plasmodium -mosquito interactions.

The paternal experience of family mealtimes is an emerging field within qualitative literature. Previous quantitative studies suggest that differences exist between fathers' and mothers' mealtime behaviours, particularly in response to fussy eating. However, qualitative research has not yet focused exclusively on fathers' fussy eating experiences. This metasynthesis aimed to provide insights into the general paternal experience, inclusive of their fussy eating responses. Thematic synthesis methodology was adopted to achieve this process and consisted of a systematic search resulting in the inclusion of 16 studies (18 papers). The direct quotations presented within each study were subjected to three stages of analysis to produce three analytical themes, supported by eight descriptive themes. The analytical themes presented were: (1) environmental influences on fathers' mealtime experiences; (2) attitudes and emotions of fathers during mealtimes; and (3) observable behaviours of fathers during mealtimes. These themes highlighted the complexity of the mealtime experience from a paternal perspective. Multidirectional relationships were identified between each mealtime component (i.e., the environment, attitudes, emotions and behaviours) as evidenced by the paternal commentary presented. The findings also provided insights into fathers' fussy eating experiences, recognising that fathers should be considered as individuals in the presence of mealtime intervention.

Background: Due to increased risks of contrast nephropathy, chronic kidney disease (CKD) can deter consideration of invasive management for patients with myocardial infarction (MI). Black patients have a higher prevalence of CKD. Whether racial disparities exist in the use of invasive MI management for patients with CKD presenting with MI is unknown., Methods: We examined 717 012 White and 99 882 Black patients with MI treated from 2008 to 2017 at 914 hospitals in the National Cardiovascular Data Registry Chest Pain-MI Registry. CKD status was defined as estimated glomerular filtration rate (eGFR) ≥90 mL/(min·1.73 m 2 ; no CKD), eGFR <90 but ≥60 (mild), eGFR <60 but ≥30 (moderate), and eGFR <30 or dialysis (severe). We used multivariable logistic regression models to examine the interaction of race and CKD severity in invasive MI management., Results: Among those with MI, Black patients were more likely than White patients to have CKD (eGFR <90; 61.4% versus 58.5%; P <0.001). Among those with MI and CKD, Black patients were more likely than White patients to have severe CKD (21.2% versus 12.4%; P <0.001). Patients with CKD were more likely than those without CKD to have diabetes or heart failure; Black patients with CKD were more likely to have these comorbidities when compared with White patients with CKD (all P <0.0001). Black race and CKD were associated with a lower likelihood of invasive management (adjusted odds ratio, 0.78 [95% CI, 0.75-0.81]; adjusted odds ratio, 0.72 [95% CI, 0.70-0.74]; P <0.001 for both). At eGFR levels ≥10, Black patients were significantly less likely than White patients to undergo invasive management., Conclusions: Black patients with MI and mild or moderate CKD were less likely to undergo invasive management compared with White patients with similar CKD severity. National efforts are needed to address racial disparities that may remain in the invasive management of MI.

Objective: Meeting recommended provider contact hours in multicomponent pediatric weight management (PWM) programs is difficult when patient retention is low. Our objective was to examine associations between individual patient characteristics, program characteristics, and patient retention. Methods: Using the Pediatric Obesity Weight Evaluation Registry, a prospective longitudinal study of 32 PWM programs, we included children (≤18 years; n  = 6502) enrolled for a full year. We examined associations between retention (any follow-up visit) and patient and program characteristics using multivariable models with site-clustering random effects. Results: Sixty-seven percent of children had at least one follow-up visit, whereas 12% had four or more visits. Compared with non-Hispanic white children, non-Hispanic black children were less likely to have a follow-up visit [adjusted odds ratio (aOR) = 0.79], whereas Hispanic children (any race) were more likely (aOR = 1.22). Children with Medicaid had similar retention to those with private insurance. Retention did not differ by age, gender, weight status, or comorbidities, nor by program characteristics. Conclusions: Few characteristics of PWM programs are clearly associated with retention, indicating that a variety of formats can support continued treatment and likely reflect the influence of unmeasured characteristics. Clearer ways to identify and overcome barriers for individual patients will be needed to improve retention in PWM.

Glioblastoma (GBM) is the most common adult neural malignancy and the deadliest. The standard of care is optimal, safe, cytoreductive surgery followed by combined radiation therapy and alkylating chemotherapy with temozolomide. Recurrence is common and therapeutic options in the recurrent setting are limited. The dismal prognosis of GBM has led to novel treatments being a serious roadblock in the field, with most new treatments failing to show efficacy. Targeted therapies have shown some success in many cancers, but GBM remains one of the most difficult to treat, especially in recurrence. New chemotherapeutic directions need to be explored, possibly expanding the targeted chemotherapy spectrum in previously unforeseen ways. In this perspective paper, we will explain why AVIL, an actin-binding protein recently found to be overexpressed in GBM and a driving force for GBM, could prove versatile in the fight against cancer. By looking at AVIL and its potential to regulate FOXM1 and LIN28B, we will be able to highlight a way to improve outcomes for GBM patients who normally have very little hope.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 16.6% of reproductive-age women. PCOS symptoms in adolescents comprise oligomenorrhoea/amenorrhoea and biochemical and/or clinical hyperandrogenism. Long-term health risks of PCOS patients include infertility, metabolic syndrome, type 2 diabetes and cardiovascular disease. Genetic factors have been proven to play a role in development of the syndrome and its symptoms., Objective: To investigate single nucleotide variants (SNVs) in the GNRHR, ESR2, LHCGR and FSHR genes in adolescent patients with PCOS and their association with PCOS symptoms., Methods: We conducted a cross-sectional study comprising of 152 adolescents: 63 patients with PCOS, 22 patients at risk of developing PCOS and 67 healthy controls. Participants were recruited from out-patients attending a gynaecologist at the Children's Clinical University Hospital, Riga, Latvia, between January 2017 and December 2020. Genomic DNA was extracted from whole blood, and SNVs in the GNRHR, ESR2, LHCGR and FSHR genes were genotyped. The distributions of SNV genotypes were compared among the three groups and genotype-phenotype associations within the PCOS group were evaluated., Results: No statistically significant differences were found in the distributions of genotypes for GNRHR (rs104893837), ESR2 (rs4986938), LHCGR (rs2293275) and FSHR (rs6166, rs6165, rs2349415) among PCOS patients, risk patients and healthy controls. Within the PCOS group, ESR2 rs4986938 minor allele homozygous patients had a significantly higher level of total testosterone than major allele homozygous patients and heterozygous patients. A significantly higher total testosterone level was also observed in PCOS patients carrying the LHCGR rs2293275 minor allele compared with major allele homozygous patients., Conclusions: The SNVs ESR2 rs4986938 and LHCGR rs2293275 play a role in the phenotypic characteristics of PCOS. To fully uncover their influence on the development of PCOS and its symptoms, further studies of larger cohorts and a follow up of this study sample through to adulthood are required. Furthermore, studies of adolescent PCOS patients conducted prior to the latest European Society of Human Reproduction and Embryology (ESHRE) criteria (2018) should be re-evaluated as the study groups might include risk patients according to these updated criteria, thereby potentially significantly impacting the published results.

Background: The gold-standard treatment for acute exacerbation of chronic obstructive pulmonary disease (ae-COPD) is non-invasive ventilation (NIV). However, NIV failures may be observed, and invasive mechanical ventilation (IMV) is required. Extracorporeal CO₂ removal (ECCO₂R) devices can be an alternative to intubation. The aim of the study was to assess ECCO₂R effectiveness and safety., Methods: Patients with consecutive ae-COPD who experienced NIV failure were retrospectively assessed over two periods of time: before and after ECCO₂R device implementation in our ICU in 2015 (Xenios AG)., Results: Both groups (ECCO₂R: n=26, control group: n=25) were comparable at baseline, except for BMI, which was significantly higher in the ECCO₂R group (30 kg/m² vs 25 kg/m²). pH and PaCO₂ significantly improved in both groups. The mean time on ECCO₂R was 5.4 days versus 27 days for IMV in the control group. Four patients required IMV in the ECCO₂R group, of whom three received IMV after ECCO₂R weaning. Seven major bleeding events were observed with ECCO₂R, but only three led to premature discontinuation of ECCO₂R. Eight cases of ventilator-associated pneumonia were observed in the control group. Mean time spent in the ICU and mean hospital stay in the ECCO₂R and control groups were, respectively, 18 vs 30 days, 29 vs 49 days, and the 90-day mortality rates were 15% vs 28%., Conclusions: ECCO₂R was associated with significant improvement of pH and PaCO₂ in patients with ae-COPD failing NIV therapy. It also led to avoiding intubation in 85% of cases, with low complication rates., Trial Registration Number: ClinicalTrials.gov, NCT04882410. Date of registration 12 May 2021, retrospectively registered.https://www.clinicaltrials.gov/ct2/show/NCT04882410., Competing Interests: Competing interests: Rita Serbouti, from Fresenius Medical Care France, Medical affairs, helped train staff in Extracorporeal CO2 Removal Device and contributed to proofreading this paper. No financial support from the industry was received., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Wound healing after pectoral port implantation is a major factor determining the success or failure of the procedure. Infection and wound dehiscence can endanger the functionality of the port system and impede chemotherapy. The cosmetic result is important for patient satisfaction as well., Methods: From August 2015 to July 2017, adult patients with an indication for port implantation were entered into a prospective, randomized and controlled single-center study. The skin incision was closed either with tissue adhesive or with an intracutaneous suture. The primary endpoints were the total score of the scar evaluated by the patient and the investigator on the POSAS scale (Patient and Observer Scar Assessment Scale: 6 [normal skin] to 60 points), blinded assessment of photographic documentation by ten evaluating physicians, and the patient's reported quality of life. The calculation of case numbers was based only on the patients' overall POSAS assessment, which was tested for non-inferiority. The secondary endpoints were other complications (infection, dehiscence) and the duration of wound closure (trial registration number NCT02551510)., Results: 156 patients (60 ± 13 years, 64% women) participated in the study. The patient-assessed total POSAS score of tissue adhesive revealed non-inferiority to suturing (adhesive 11.7 ± 5.8 vs. suture 10.1 ± 4.0, p for non-inferiority <0.001). Both the investigators in their POSAS assessments and the blinded physician evaluators in their assessment of photographically documented wounds rated wound closure by suturing better than closure with tissue adhesive. No significant differences were found between groups with respect to quality of life or the frequency of wound infection or dehiscence., Conclusion: Closure of the upper cutaneous layer with tissue adhesive is a suitable and safe method of wound closure after port implantation.

The development and approval of brincidofovir for the treatment of smallpox, a disease that was eradicated from the world over 40 years ago, has resulted in the second antiviral approved via the Medical Countermeasure Initiative (MCMi) to combat this disease. Approval of brincidofovir required a unique regulatory approach based on the FDA Animal Rule, and development was supported by many years of research and collaboration among academic investigators, the pharmaceutical industry and multiple government agencies. This article summarizes the FDA regulatory pathway and describes the challenges involved., (Published by Elsevier B.V.)

Background: Echocardiographic parameters have been poorly investigated for estimating cardiovascular risk in patients with sepsis and new-onset atrial fibrillation. We aim to assess the prevalence of transesophageal echocardiographic abnormalities and their relationship with cardiovascular events in mechanically ventilated patients with sepsis and new-onset atrial fibrillation., Methods: In this prospective multicenter pilot study, left atrial/left atrial appendage (LA/LAA) dysfunction, severe aortic atheroma, and left ventricular systolic dysfunction were assessed using an initial transesophageal echocardiographic study, which was repeated after 48-72 h to detect LA/LAA thrombus formation. The study outcome was a composite of cardiovascular events at day 28, including arterial thromboembolic events (ischemic stroke, non-cerebrovascular arterial thromboembolism, LA/LAA thrombus), major bleeding, and all-cause death., Results: The study population comprised 94 patients (septic shock 63%; 35% women; median age 69 years). LA/LAA dysfunction, severe aortic atheroma, and left ventricular systolic dysfunction were detected in 17 (19%), 22 (24%), and 27 (29%) patients, respectively. At day 28, the incidence of cardiovascular events was 46% (95% confidence interval [CI]: 35 to 56). Arterial thromboembolic events and major bleeding occurred in 7 (7%) patients (5 ischemic strokes, 1 non-cerebrovascular arterial thromboembolism, 2 left atrial appendage thrombi) and 18 (19%) patients, respectively. At day 28, 27 patients (29%) died. Septic shock (hazard ratio [HR]: 2.36; 95% CI 1.06 to 5.29) and left ventricular systolic dysfunction (HR: 2.06; 95% CI 1.05 to 4.05) were independently associated with cardiovascular events., Conclusions: Transesophageal echocardiographic abnormalities are common in mechanically ventilated patients with sepsis and new-onset atrial fibrillation, but only left ventricular systolic dysfunction was associated with cardiovascular events at day 28., (© 2021. The Author(s).)

Background: Immune checkpoint inhibitors (ICIs) have transformed the management of advanced malignancies but are associated with diarrhea and colitis. The objective of our systematic review and meta-analysis was to determine the incidence and outcomes of ICI-associated diarrhea and colitis. Bibliographic databases were searched through August 13, 2019, for observational studies of ICI therapy reporting the incidence and/or treatment of diarrhea or colitis. The primary outcome was ICI-associated diarrhea and colitis. Meta-analyses were performed with random-effects models. Twenty-five studies (N=12,661) were included. All studies had a high risk of bias in at least 1 domain. The overall incidence of diarrhea/colitis was 12.8% [95% confidence interval (CI), 8.8-18.2, I2=96.5]. The incidence was lower in patients treated with anti-programmed cell death 1/programmed death-ligand 1 (4.1%, 95% CI, 2.6-6.5) than in those treated with anti-cytotoxic T-cell lymphocyte-associated antigen 4 (20.1%, 95% CI, 15.9-25.1). The remission of diarrhea and/or colitis was higher in patients treated with corticosteroids plus biologics (88.4%, 95% CI, 79.4-93.8) than in those treated with corticosteroids alone (58.3%, 95% CI, 49.3-66.7, Q=18.7, P<0.001). ICI were permanently discontinued in 48.1% of patients (95% CI, 17.8-79.1). ICI were restarted after temporary interruption in 48.6% of patients (95% CI, 18.2-79.4) of whom 17.0% (95% CI, 6.4-30.0) experienced recurrence. Real-world incidence of ICI-associated diarrhea/colitis exceeds 10%. These events lead to permanent ICI discontinuation in just over 50% of patients, while <20% have recurrence of symptoms if ICI are resumed. Further studies are needed to identify patients who would benefit from early treatment with biologics as well as appropriate patients to resume ICI therapy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease., Methods: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed., Results: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod., Conclusions: Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.)., (Copyright © 2021 Massachusetts Medical Society.)

Background and Purpose: Depression is common after stroke and is often treated with antidepressant medications (AD). ADs have also been hypothesised to improve stroke recovery, although recent randomised trials were neutral. We investigated the patterns of in-hospital AD initiation after ischaemic stroke and association with clinical and readmission outcomes., Methods: All Medicare fee-for-service beneficiaries aged 65 or older hospitalised for ischaemic stroke in participating Get With The Guidelines-Stroke hospitals between April and December 2014 were eligible for this analysis. Outcome measures included days alive and not in a healthcare institution (home time), all-cause mortality and readmission within 1-year postdischarge. Propensity score (PS)-adjusted logistic regression models were used to evaluate the associations between AD use and each outcome measure. We also compared outcomes in patients prescribed selective serotonin reuptake inhibitors (SSRIs) AD versus those prescribed non-SSRI ADs., Results: Of 21 805 AD naïve patients included in this analysis, 1835 (8.4%) were started on an AD at discharge. Patients started on an AD had higher rates of depression and prior ischaemic stroke, presented with higher admission National Institutes of Health Stroke Scale score and were less likely to be discharged home. Similarly, patients started on an SSRI had lower rates of discharge to home. Adjusting for stroke severity, patients started on an AD had worse all-cause mortality, all-cause readmission, major adverse cardiac events, readmission for depression and decreased home-time. However, AD use was also associated with an increased risk for the sepsis, a falsification endpoint, suggesting the presence of residual confounding., Conclusions: Patients with ischaemic stroke initiated on AD therapy are at increased risk of poor clinical outcomes and readmission even after PS adjustment, suggesting that poststroke depression requiring medication is a poor prognostic sign. Further research is needed to explore the reasons why depression is associated with worse outcome, and whether AD treatment modifies this risk or not., Competing Interests: Competing interests: DLB discloses the following relationships—Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Coinvestigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acute gastrointestinal bleeding (GIB) remains a common cause of hospitalisation. However, interpretation and comparisons of published studies in GIB have been hampered by disparate study methodology., Aims: To make recommendations about outcome measures to be used in future randomised controlled trials (RCTs) of patients with acute bleeding from any GI source (nonvariceal UGI, variceal, small bowel, or colon) and suggest new RCTs in acute GIB for future peer-reviewed funding., Methods: As part of a National Institutes of Health conference entitled "Hemostatic Outcomes in Clinical Trials", a group of GIB experts performed targeted critical reviews of available evidence with the goal of proposing a bleeding outcome that could potentially be applied to different disciplines. In addition, the panel sought to develop a clinically meaningful primary endpoint specifically for acute GIB, potentially allowing a more contemporary regrouping of clinically relevant outcomes., Results: The primary endpoint proposed was a composite outcome of further bleeding within 30 days after randomisation leading to red blood cell transfusion, urgent intervention (repeat endoscopy; interventional radiology or surgery), or death. Secondary outcomes may include the individual components of the primary outcome, length of hospitalisation, serious adverse events, and health care resource utilisation., Conclusion: The proposed endpoint may help move the GIB field forward by focusing on the most clinically relevant outcomes for patients with acute GIB of all types and informing study design and importance of sample size determination for future RCTs in GIB., (© 2021 John Wiley & Sons Ltd.)

Introduction: Direct oral anticoagulants (DOACs) have partial renal clearance and generally require dosage adjustments based on renal function. While current US and European guidance recommends dose adjustments in patients with moderate chronic kidney disease (CKD), it is unclear how often this is done appropriately in routine clinical practice., Methods: We examined rates of appropriate and inappropriate dosing in patients with atrial fibrillation (AF) and moderate CKD, as determined by creatinine clearance (CrCl) of 30-50 mL/min calculated with the Cockcroft-Gault formula. Descriptive statistics were used to describe the rate of appropriate and inappropriate dosing as well as event rates., Results: Among 1134 patients (8.5% of the overall ORBIT-AF II registry) with AF and CrCl 30-50 mL/min, the median age was 82 (25th, 75th percentile: 78, 86), 38% were male, and the median CHA 2 DS 2 VASC score was 4 (25th, 75th percentile: 4, 5). At baseline, more than one-third (34%) of patients with moderate CKD were inappropriately dosed with DOACs. When evaluating the specific prescribed doses in those with moderate CKD, 15% (N = 170/1134) were underdosed, 66% (743/1134) were appropriately dosed, and 20% (N = 221/1134) were overdosed. There were no significant differences in comorbid medical conditions between patients with moderate CKD who were appropriately and inappropriately dosed with a DOAC., Conclusion: In routine clinical practice, prescribing of DOACs in patients with AF with moderate CKD is often inconsistent with drug labeling, with up to one-third of patients being inappropriately dosed., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

The health benefits and importance of family mealtimes have been extensively documented. Picky eating can impact this complex activity and has numerous extrinsic (or external) and intrinsic (or internal) features. Occupational therapists work with children and their families by looking at both intrinsic and extrinsic influences and are therefore well-placed to work within this context. This scoping review comprises a comprehensive search of key health industry databases using pre-determined search terms. A robust screening process took place using the authors pre-agreed inclusion and exclusion criteria. There were 80 studies that met the inclusion criteria, which were then mapped using content analysis. The most common assessments used to identify picky eating relied on parental reports and recall. Often additional assessments were included in studies to identify both the intrinsic and extrinsic features and presentation. The most common reported intrinsic features of the child who is a picky eater included increased sensitivity particularly to taste and smell and the child's personality. Extrinsic features which appear to increase the likelihood of picky eating are authoritarian parenting, rewards for eating, and pressuring the child to eat. Most commonly reported extrinsic features that decrease the likelihood of picky eating are family meals, responsive parents, and involving the child in the preparation of food. In conclusion, there is a lack of published papers addressing the role of occupational therapists in the assessment and identification of picky eating in children. There appears to be a complex interplay between intrinsic and extrinsic features which impact caregiver responses and therefore on the picky eater.

Aims: Improving the health status (symptoms, function, and quality of life) of patients with heart failure with reduced ejection fraction (HFrEF) is a primary treatment goal. Angiotensin receptor neprilysin inhibitors (ARNI) improve short-term health status in clinical practice, but the sustainability of these improvements is unknown., Methods and Results: In CHAMP-HF, a multicentre observational study of outpatients with HFrEF, patients initiated on ARNI were propensity score matched 1:2 to patients not using ARNI with Cox regression modelling time to ARNI initiation, adjusted for sociodemographic and clinical variables, medical history, medications, and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Repeated measures models for the overall KCCQ score and each domain compared the health status trajectories of patients initiated on ARNI vs. not. Among 3930 participants, 746 (19.0%) began ARNI, of whom 576 were matched to 1152 non-ARNI patients. Prior to matching, participants initiated on ARNI were younger, non-Hispanic, had lower EFs, more commonly had a history of ventricular arrhythmia, were less likely to be taking an ACEI/ARB, and more likely to be treated with beta-blockers and mineralocorticoid receptor antagonists. There were no differences after matching. In the matched cohort, participants initiated on ARNI experienced improved health status by 3 months that persisted through 12 months [KCCQ Overall Summary Score (OSS) = 73.4 vs. 70.8; P < 0.001], with the largest benefit observed in the KCCQ Quality of Life domain (68.7 vs. 64.7; P < 0.001). Similar health status benefits were noted through 18 months (KCCQ-OSS = 73.9 vs. 71.3; P < 0.001). A responder analysis showed that 12 patients would need to be initiated on ARNI for one to experience at least a large improvement (≥10 points) in health status benefit at 12 months., Conclusions: In outpatient practice, ARNI therapy was associated with improved health status by 3 months and continued to 18 months after initiating therapy., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Fresh frozen plasma (FFP) transfusion is often used in the management of acute variceal haemorrhage (AVH) despite best practice advice suggesting otherwise., Objective: We investigated if FFP transfusion affects clinical outcomes in AVH., Design, Setting and Patients: We performed a retrospective cohort study of 244 consecutive, eligible patients admitted to five tertiary health care centres between 2013 and 2018 with AVH., Main Outcome Measurements: Multivariable regression analyses were used to study the association of FFP transfusion with mortality at 42 days (primary outcome) and failure to control bleeding at 5 days and length of stay (secondary outcomes)., Results: Patients who received FFP transfusion (n = 100) had higher mean Model for End Stage Liver Disease (MELD) score and more severe variceal bleeding than those who did not received FFP transfusion (n = 144). Multivariable analysis showed that FFP transfusion was associated with increased odds of mortality at 42 days (odds ratio [OR] 9.41, 95% confidence interval [CI] 3.71-23.90). FFP transfusion was also associated with failure to control bleeding at 5 days (OR 3.87, 95% CI 1.28-11.70) and length of stay >7 days (adjusted OR 1.88, 95% CI 1.03-3.42). The independent association of FFP transfusion with mortality at 42 days persisted when the cohort was restricted to high-risk patients and in patients without active bleeding., Limitations and Conclusions: Fresh frozen plasma transfusion in AVH is independently associated with poor clinical outcomes. As this an observational study, there may be residual bias due to confounding; however, we demonstrate no benefit and potential harm with FFP transfusions in AVH., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aim: Guidelines recommend risk stratification scores in patients presenting with gastrointestinal bleeding (GIB), but such scores are uncommonly employed in practice. Automation and deployment of risk stratification scores in real time within electronic health records (EHRs) would overcome a major impediment. This requires an automated mechanism to accurately identify ("phenotype") patients with GIB at the time of presentation. The goal is to identify patients with acute GIB by developing and evaluating EHR-based phenotyping algorithms for emergency department (ED) patients., Methods: We specified criteria using structured data elements to create rules for identifying patients and also developed multiple natural language processing (NLP)-based approaches for automated phenotyping of patients, tested them with tenfold cross-validation for 10 iterations (n = 7144) and external validation (n = 2988) and compared them with a standard method to identify patient conditions, the Systematized Nomenclature of Medicine. The gold standard for GIB diagnosis was the independent dual manual review of medical records. The primary outcome was the positive predictive value., Results: A decision rule using GIB-specific terms from ED triage and ED review-of-systems assessment performed better than the Systematized Nomenclature of Medicine on internal validation and external validation (positive predictive value = 85% confidence interval:83%-87% vs 69% confidence interval:66%-72%; P < 0.001). The syntax-based NLP algorithm and Bidirectional Encoder Representation from Transformers neural network-based NLP algorithm had similar performance to the structured-data fields decision rule., Conclusions: An automated decision rule employing GIB-specific triage and review-of-systems terms can be used to trigger EHR-based deployment of risk stratification models to guide clinical decision making in real time for patients with acute GIB presenting to the ED., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

To address literature gaps on treatment with real-world evidence, this study compared effectiveness, safety, and cost outcomes in NVAF patients with coronary or peripheral artery disease (CAD, PAD) prescribed apixaban versus other oral anticoagulants. NVAF patients aged ≥65 years co-diagnosed with CAD/PAD initiating warfarin, apixaban, dabigatran, or rivaroxaban were selected from the US Medicare population (January 1, 2013 to September 30, 2015). Propensity score matching was used to match apixaban versus warfarin, dabigatran, and rivaroxaban cohorts. Cox models were used to evaluate the risk of stroke/systemic embolism (SE), major bleeding (MB), all-cause mortality, and a composite of stroke/myocardial infarction/all-cause mortality. Generalized linear and two-part models were used to compare stroke/SE, MB, and all-cause costs between cohorts. A total of 33,269 warfarin-apixaban, 9,335 dabigatran-apixaban, and 33,633 rivaroxaban-apixaban pairs were identified after matching. Compared with apixaban, stroke/SE risk was higher in warfarin (hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.61 to 2.31), dabigatran (HR: 1.69; 95% CI: 1.18 to 2.43), and rivaroxaban (HR: 1.24; 95% CI: 1.01 to 1.51) patients. MB risk was higher in warfarin (HR: 1.67; 95% CI: 1.52 to 1.83), dabigatran (HR: 1.37; 95% CI: 1.13 to 1.68), and rivaroxaban (HR: 1.87; 95% CI: 1.71 to 2.05) patients vs apixaban. Stroke/SE- and MB-related medical costs per-patient per-month were higher in warfarin, dabigatran, and rivaroxaban patients versus apixaban. Total all-cause health care costs were higher in warfarin and rivaroxaban patients compared with apixaban patients. In conclusion, compared with apixaban, patients on dabigatran, rivaroxaban, or warfarin had a higher risk of stroke/SE, MB, and event-related costs., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. Depending on the diagnostic criteria applied, it occurs in up to 16.6% of the general female population. Congenital adrenal hyperplasia includes a group of autosomal recessive disorders, the most common of which is non-classical congenital adrenal hyperplasia (NCAH) caused by mutations in the CYP21A2 gene. PCOS and NCAH have similar clinical manifestations (hyperandrogenemia, i.e., hirsutism, acne, alopecia, and increased androgen levels in the blood) and potential impact on long-term health (infertility, increased risk of type 2 diabetes, and cardiovascular disease. Consequently, it is thought that NCAH mutations in the heterozygous state may play a role in PCOS development and phenotypic expression., Objective: To determine the prevalence of the most common pathogenic alleles of the CYP21A2 gene in adolescents with PCOS and adolescents at risk of PCOS development, and to compare the results with healthy adolescents matched for gynecological age., Methods: A cross-sectional study was conducted with 55 PCOS patients, 23 risk patients (with hyperandrogenism but a normal menstrual cycle), and 49 healthy adolescents. Genetic variations in the CYP21A2 gene were analyzed using a standard Multiplex Ligation-dependent Probe Amplification test (SALSA MLPA Probemix P050-C1 CAH; MRC Holland)., Results: No significant differences were found among the three groups regarding the frequency of carriers of NCAH variations in the heterozygous state. It was found that the I172N carrier in the PCOS group had a significantly higher Global Acne Grading Scale score than PCOS patients without this variation ( p = 0.038). Within the control group of healthy adolescents, compound heterozygous carriers (IVS2-12A > G and -113G > A) had a significantly higher body mass index than non-carriers ( p = 0.036)., Conclusion: We found no differences in the incidence of NCAH-causing variations in the heterozygous state in adolescent PCOS patients, risk adolescents (with hirsutism but normal menstruation), and healthy adolescents. Future studies of larger cohorts and rarer pathogenic CYP21A2 gene variations are required.

Background: In patients with heart failure and reduced ejection fraction (HFrEF), angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), or angiotensin receptor neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonists (MRA), and beta-blockers (βB) are underutilized. It is unknown if patients with and without comorbidities have similar ACEi/ARB/ARNI, MRA, and βB prescription patterns., Methods: Baseline data from the CHAMP-HF (Change the Management of Patients with Heart Failure) registry were categorized by history of atrial fibrillation, asthma/chronic lung disease, obstructive sleep apnea, and depression. Using multivariate hierarchical logistic models, associations of ACEi/ARB/ARNI, MRA and βB medication use and dose by comorbidities were assessed after adjusting for patient characteristics., Results: Of 4,815 HFrEF patients from 152 CHAMP-HF sites, ACEi/ARB/ARNI use was lower in patients with more comorbidities, and generally, MRA use was low and βB use was high. In adjusted analyses, patients with HFrEF and comorbid obstructive sleep apnea, vs. without, were more likely to be prescribed ARNI (OR [95% CI]: 1.25 [1.00, 1.55]); P = .047 and MRA (1.31 [1.11, 1.55]); P = .002 and less likely to be prescribed ACEi (0.74 [0.63, 0.88]); P < .001. Patients with atrial fibrillation, vs. without, were less likely to receive ACEi/ARB (0.82 [0.71, 0.95]); P = .006 and any study medication (0.81 [0.67, 0.97]); P = .020. Comorbid lung disease and history of depression were not associated with HFrEF prescriptions., Conclusions: Renin-angiotensin-aldosterone blockade therapy prescription and dose varied by comorbidity status, but βB therapy did not. In quality efforts, leaders need to consider use and dosing of prescriptions in light of prevalent comorbidities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We performed systematic reviews addressing predefined clinical questions to develop recommendations with the GRADE approach regarding management of patients with overt upper gastrointestinal bleeding. We suggest risk assessment in the emergency department to identify very-low-risk patients (e.g., Glasgow-Blatchford score = 0-1) who may be discharged with outpatient follow-up. For patients hospitalized with upper gastrointestinal bleeding, we suggest red blood cell transfusion at a threshold of 7 g/dL. Erythromycin infusion is suggested before endoscopy, and endoscopy is suggested within 24 hours after presentation. Endoscopic therapy is recommended for ulcers with active spurting or oozing and for nonbleeding visible vessels. Endoscopic therapy with bipolar electrocoagulation, heater probe, and absolute ethanol injection is recommended, and low- to very-low-quality evidence also supports clips, argon plasma coagulation, and soft monopolar electrocoagulation; hemostatic powder spray TC-325 is suggested for actively bleeding ulcers and over-the-scope clips for recurrent ulcer bleeding after previous successful hemostasis. After endoscopic hemostasis, high-dose proton pump inhibitor therapy is recommended continuously or intermittently for 3 days, followed by twice-daily oral proton pump inhibitor for the first 2 weeks of therapy after endoscopy. Repeat endoscopy is suggested for recurrent bleeding, and if endoscopic therapy fails, transcatheter embolization is suggested., (Copyright © 2021 by The American College of Gastroenterology.)

Guidelines from national and international professional societies on upper gastrointestinal bleeding highlight the important clinical issues but do not always identify specific management strategies pertaining to individual patients. Optimal treatment should consider the personal needs of an individual patient and the pertinent resources and experience available at the point of care. This article integrates international guidelines and consensus into three stages of management: pre-endoscopic assessment and treatment, endoscopic evaluation and haemostasis and postendoscopic management. We emphasise the need for personalised management strategies based on patient characteristics, nature of bleeding lesions and the clinical setting including available resources., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: It is unclear how New York Heart Association (NYHA) functional class compares with patient-reported outcomes among patients with heart failure (HF) in contemporary US clinical practice., Objective: To characterize longitudinal changes and concordance between NYHA class and the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS), and their associations with clinical outcomes., Design, Setting, and Participants: This cohort study included 2872 US outpatients with chronic HF with reduced ejection fraction across 145 practices enrolled in the CHAMP-HF registry between December 2015 and October 2017. All patients had complete NYHA class and KCCQ-OS data at baseline and 12 months. Longitudinal changes and correlations between the 2 measure were examined. Multivariable models landmarked at 12 months evaluated associations between improvement in NYHA and KCCQ-OS from baseline to 12 months with clinical outcomes occurring from months 12 through 24. Statistical analyses were performed from March to August 2020., Exposure: Change in health status, as defined by 12-month change in NYHA class or KCCQ-OS., Main Outcomes and Measures: All-cause mortality, HF hospitalization, and mortality or HF hospitalization., Results: In total, 2872 patients were included in this analysis (median [interquartile range] age, 68 [59-75] years; 872 [30.4%] were women; and 2156 [75.1%] were of White race). At baseline, 312 patients (10.9%) were NYHA class I, 1710 patients (59.5%) were class II, 804 patients (28.0%) were class III, and 46 patients (1.6%) were class IV. For KCCQ-OS, 1131 patients (39.4%) scored 75 to 100 (best health status), 967 patients (33.7%) scored 50 to 74, 612 patients (21.3%) scored 25 to 49, and 162 patients (5.6%) scored 0 to 24 (worst health status). At 12 months, 1002 patients (34.9%) had a change in NYHA class (599 [20.9%] with improvement; 403 [14.0%] with worsening) and 2158 patients (75.1%) had a change of 5 or more points in KCCQ-OS (1388 [48.3%] with improvement; 770 [26.8%] with worsening). The most common trajectory for NYHA class was no change (1870 [65.1%]), and the most common trajectory for KCCQ-OS was an improvement of at least 10 points (1047 [36.5%]). After adjustment, improvement in NYHA class was not associated with subsequent clinical outcomes, whereas an improvement of 5 or more points in KCCQ-OS was independently associated with decreased mortality (hazard ratio, 0.59; 95% CI, 0.44-0.80; P < .001) and mortality or HF hospitalization (hazard ratio, 0.73; 95% CI, 0.59-0.89; P = .002)., Conclusions and Relevance: Findings of this cohort study suggest that, in contemporary US clinical practice, compared with NYHA class, KCCQ-OS is more sensitive to clinically meaningful changes in health status over time. Changes in KCCQ-OS may have more prognostic value than changes in NYHA class.

Acute gastrointestinal bleeding is the most common gastrointestinal cause for hospitalization. For high-risk patients requiring intensive care unit stay, predicting transfusion needs during the first 24 h using dynamic risk assessment may improve resuscitation with red blood cell transfusion in admitted patients with severe acute gastrointestinal bleeding. A patient cohort admitted for acute gastrointestinal bleeding (N = 2,524) was identified from the Medical Information Mart for Intensive Care III (MIMIC-III) critical care database and separated into training (N = 2,032) and internal validation (N = 492) sets. The external validation patient cohort was identified from the eICU collaborative database of patients admitted for acute gastrointestinal bleeding presenting to large urban hospitals (N = 1,526). 62 demographic, clinical, and laboratory test features were consolidated into 4-h time intervals over the first 24 h from admission. The outcome measure was the transfusion of red blood cells during each 4-h time interval. A long short-term memory (LSTM) model, a type of Recurrent Neural Network, was compared to a regression-based models on time-updated data. The LSTM model performed better than discrete time regression-based models for both internal validation (AUROC 0.81 vs 0.75 vs 0.75; P < 0.001) and external validation (AUROC 0.65 vs 0.56 vs 0.56; P < 0.001). A LSTM model can be used to predict the need for transfusion of packed red blood cells over the first 24 h from admission to help personalize the care of high-risk patients with acute gastrointestinal bleeding.

Background: Recurrent acute pancreatitis (RAP) may be a presenting feature of and an indication for resection of pancreatic cysts, including intra-ductal papillary mucinous neoplasm (IPMN). Few data are available regarding the prevalence of malignancy and post-operative RAP in this population., Aim: To study the role of resection to help prevent RAP and analyze if presentation as RAP would be a predictor for malignancy., Methods: This retrospective study assessed 172 patients who underwent surgical resection of pancreatic cystic neoplasms at a university hospital between 2002 and 2016. The prevalence of preoperative high-risk cyst features, and of neoplasia was compared between patients with and without RAP. To identify the cause of pancreatitis, all the patients had a detailed history of alcohol, smoking, medications obtained, and had cross-sectional imaging (contrast-enhanced computed tomography/magnetic resonance imaging) and endoscopic ultrasound to look for gallstone etiology and other structural causes for pancreatitis. The incidence of RAP post-resection was the primary outcome., Results: IPMN accounted for 101 cases (58.7%) {[branch duct (BD) 59 (34.3%), main duct (MD) 42] (24.4%)}. Twenty-nine (16.9%) presented with RAP (mean 2.2 episodes): 15 had BD-IPMN, 8 MD-IPMN, 5 mucinous cystic neoplasm and 1 serous cystic neoplasm. Malignancy was similar among those with vs without RAP for all patients [6/29 (20.7%) vs 24/143 (16.8%)] and IPMN patients [6/23 (26.1%) vs 23/78 (29.5%)], although tended to be higher with RAP in BD-IPMN, [5/15 (33.3%) vs 3/44 (6.8%), P = 0.04]. At mean follow-up of 7.2 years, 1 (3.4%) RAP patient had post-resection RAP. The mean episodes of acute pancreatitis before vs after surgery were 3.4 vs 0.02 ( P < 0.0001)., Conclusion: Malignancy was not increased in patients with pancreatic cystic neoplasms who have RAP compared to those without RAP. In addition, specific cyst charac-teristics were not clearly associated with RAP. The incidence of RAP was markedly decreased in almost all patients following cyst resection., Competing Interests: Conflict-of-interest statement: They authors declare that they have no conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: Existing scores are not accurate at predicting mortality in upper (UGIB) and lower (LGIB) gastrointestinal bleeding. We aimed to develop and validate a new pre-endoscopy score for predicting mortality in both UGIB and LGIB., Design and Setting: International cohort study. Patients presenting to hospital with UGIB at six international centres were used to develop a risk score for predicting mortality using regression analyses. The score's performance in UGIB and LGIB was externally validated and compared with existing scores using four international datasets. We calculated areas under receiver operating characteristics curves (AUROCs), sensitivities, specificities and outcome among patients classified as low risk and high risk., Participants and Results: We included 3012 UGIB patients in the development cohort, and 4019 UGIB and 2336 LGIB patients in the validation cohorts. Age, Blood tests and Comorbidities (ABC) score was closer associated with mortality in UGIB and LGIB (AUROCs: 0.81-84) than existing scores (AUROCs: 0.65-0.75; p≤0.02). In UGIB, patients with low ABC score (≤3), medium ABC score (4-7) and high ABC score (≥8) had 30-day mortality rates of 1.0%, 7.0% and 25%, respectively. Patients classified low risk using ABC score had lower mortality than those classified low risk with AIMS65 (threshold ≤1) (1.0 vs 4.5%; p<0.001). In LGIB, patients with low, medium and high ABC scores had in-hospital mortality rates of 0.6%, 6.3% and 18%, respectively., Conclusions: In contrast to previous scores, ABC score has good performance for predicting mortality in both UGIB and LGIB, allowing early identification and targeted management of patients at high or low risk of death., Competing Interests: Competing interests: IG is a consultant, has a financial interest and is a member of the Medical Advisory Board of MOTUS GI. IG is a consultant for Boston Scientific, Symbionix and GI View. KO has received editorial fees for reviews on the same topic., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Parenteral nutrition (PN) is a complex, high-alert medication that contains up to 40 different ingredients. Surveys have shown that current electronic health record (EHR) systems may lack functionality for safe and optimal delivery of PN. A gap analysis was performed by a multihospital system to identify opportunities to enhance the current PN process using the EHR utilized by the organization., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Aiming to prevent the spread of contagious diseases has long been a central tenet of public health. In the present time, divisive political responses to mask wearing to prevent SARS-CoV-2 transmission have competed with sound public health advice for public attention. Here, we draw parallels in terms of individualism versus societal solidarity between the slow and ponderous development of transmission-blocking vaccines for malaria and advocacy for mask wearing to prevent COVID-19.

Background: The best timing for early invasive therapy in non-ST-segment elevation myocardial infarction (NSTEMI) patients remains controversial. We sought to determine the optimal timing of early catheterization in order to improve long-term outcomes in elderly (>65  years old) patients with NSTEMI., Methods: Using data from the CRUSADE registry linked to Medicare claims, we evaluated the association of early catheterization within the first 24  h or earlier time cut-points of NSTEMI presentation with long-term mortality among older Medicare beneficiaries., Results: Of 15  575 NSTEMI patients from 398 CRUSADE hospitals (2003-2006), 3880 (24.9%) received early (≤12  h) catheterization. Compared with those undergoing later catheterization, patients treated early were younger and had less comorbid illness. Relative to those treated later, patients receiving early catheterization had similar 1-year all-cause mortality (11.8% vs 11.9%, P  =  0.90). Using on- vs off-hour presentation as an instrumental variable, balancing potential measured and unmeasured confounders, early and later catheterization patients had nonsignificant differences in 1-year mortality (+5.6% [-11.5%, +22.7%]). Similar results were observed in clinically relevant subgroups, such as age (< or ≥75  years), gender, diabetes status, Global Registry of Acute Coronary Events score (< or ≥140), presence of heart failure, and sensitivity analyses of alternative definitions of early catheterization (≤6 and ≤24  h)., Conclusions: Among older NSTEMI patients, we found that <24  h or earlier (neither <6 nor 12  h) of catheterization timing were not significantly associated with differences in long-term mortality., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To evaluate differences in the proportion of uterine fibroid (UF) treatments that are uterine-sparing between Black women and White women and identify factors that could explain disparities. Methods: Women at age 18-54 years who were enrolled from 10 clinical sites in the United States into the Comparing Options for Management: Patient-Centered Results for UFs (COMPARE-UF) treatment registry completed questionnaires before their UF procedure. UF symptoms and quality of life were assessed by questionnaires. Details on UF imaging and treatment (hysterectomy, myomectomy, or uterine artery embolization [UAE]) were collected from each patient's medical record. Random-effects logistic regression was used to assess the association between race and the odds of having a uterine-sparing procedure versus hysterectomy. Subgroup analyses compared each uterine-sparing procedure with hysterectomy. Results: In this cohort of 1141 White women and 1196 Black women, Black women tended to be younger (median 41.0 vs. 42.0 years) and report worse symptoms, pain, and function on every scale compared with White women. Black women were more likely to have had a prior UF treatment compared with White women (22.8% vs. 14.6%). White women had more hysterectomies (43.6% vs. 32.2%) and myomectomies (50.9% vs. 50.2%) versus Black women. Black women had more UAEs (15.1% vs. 4.7%) than White women. After adjusting for clinical site and other variables, Black women had greater odds than White women of having a myomectomy (odds ratio [OR] = 2.41, 95% confidence interval [CI] = 1.63-3.56) or a UAE versus hysterectomy (OR = 4.24, 95% CI = 2.41-7.46). Conclusion: In these participants, Black women were more likely to schedule a uterine-sparing UF treatment and a nonsurgical UF treatment than their White counterparts; this may not be true for all women. Longer comparative effectiveness studies are needed to inform women about the durability of UF treatments. Greater understanding of factors influencing treatment selection is needed as are studies that include women without access to tertiary care centers. Clinical Trial Registration: Clinicaltrials.gov, NCT02260752 (enrollment start: November 2015).

Aims: The aim of our study was to investigate heterogeneity of health status treatment response of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF)., Methods and Results: We leveraged data from CHAMP-HF, an observational registry of 140 US clinics and 5026 outpatients with chronic HFrEF, where health status was serially assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Scale (range from 0 to 100; ≥20-point improvement is a very large improvement). In 334 patients newly initiated on sacubitril/valsartan, we used hierarchical multivariable logistic regression (13 patient-level characteristics as well as baseline KCCQ-12 score) to calculate the odds ratio (OR) of any characteristic being associated with a very large health status improvement. A total of 104/334 (31.1%) of patients achieved the primary endpoint, where only worse baseline health status [KCCQ-12 score of 0-60 points had an OR = 0.86/5-point higher score (CI 0.79, 0.93)], and those with a KCCQ-12 score of 60-80 points had an OR = 0.61/5-point higher score (0.45-0.82), which was associated with a very large benefit. No other patient characteristic was associated with a very large health status improvement (P > 0.05)., Conclusions: We found that, after initiation of sacubitril/valsartan, only worse baseline health status was associated with very large health status improvement. Accordingly, a trial of therapy-particularly in those with worse symptoms, function, and quality of life-and assessing treatment response are likely to be the best prospective strategy., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

The rhotic sound /r/ is one of the latest-emerging sounds in English, and many children receive treatment for residual errors affecting /r/ that persist past the age of 9. Auditory-perceptual abilities of children with residual speech errors are thought to be different from their typically developing peers. This study examined auditory-perceptual acuity in children with residual speech errors affecting /r/ and the relation of these skills to production accuracy, both before and after a period of treatment incorporating visual biofeedback. Identification of items along an /r/-/w/ continuum was assessed prior to treatment. Production accuracy for /r/ was acoustically measured from standard/r/stimulability probes elicited before and after treatment. Fifty-nine children aged 9-15 with residual speech errors (RSE) affecting /r/ completed treatment, and forty-eight age-matched controls who completed the same auditory-perceptual task served as a comparison group. It was hypothesized that children with RSE would show lower auditory-perceptual acuity than typically developing speakers and that higher auditory-perceptual acuity would be associated with more accurate production before treatment. It was also hypothesized that auditory-perceptual acuity would serve as a mediator of treatment response. Results indicated that typically developing children have more acute perception of the /r/-/w/ contrast than children with RSE. Contrary to hypothesis, baseline auditory-perceptual acuity for /r/ did not predict baseline production severity. For baseline auditory-perceptual acuity in relation to biofeedback efficacy, there was an interaction between auditory-perceptual acuity and gender, such that higher auditory-perceptual acuity was associated with greater treatment response in female, but not male, participants.

The Scaling Individuals and Classifying Misconceptions (SICM) model is an advanced psychometric model that can provide feedback to examinees' misconceptions and a general ability simultaneously. These two types of feedback are represented by a discrete and a continuous latent variable, respectively, in the SICM model. The complex structure of the SICM model brings difficulties in estimating both misconception profile and ability efficiently in a linear test. To overcome this challenge, this study proposes a flexible computerized adaptive test (FCAT) design as a new test delivery method to increase test efficiency by administering an individualized test to examinees. We propose three item selection methods and two transition criteria to determine adaptive steps based on the needs of estimating one or two latent variables. Through two simulation studies, we demonstrate how to select an appropriate item selection method for an adaptive step and what transition criterion should be used between two adaptive steps. Results reveal the combination of the item selection method and the transition criterion could improve the estimation accuracy of a specific latent variable to a different extent and thus provide further guidance in designing an FCAT., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background & Aims: Fecal microbiota transplantation (FMT) is used commonly for treatment of Clostridioides difficile infections (CDIs), although prospective safety data are limited and real-world FMT practice and outcomes are not well described. The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers., Methods: Patients undergoing FMT in clinical practices across North America were eligible. Participating investigators enter de-identified data into an online platform, including FMT protocol, baseline patient characteristics, CDI cure and recurrence, and short and long-term safety outcomes., Results: Of the first 259 participants enrolled at 20 sites, 222 had completed short-term follow-up at 1 month and 123 had follow-up to 6 months; 171 (66%) were female. All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank). One-month cure occurred in 200 patients (90%); of these, 197 (98%) received only 1 FMT. Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence. Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%)., Conclusions: This prospective real-world study demonstrated high effectiveness of FMT for CDI with a good safety profile. Assessment of new conditions at long-term follow-up is planned as this registry grows and will be important for determining the full safety profile of FMT., (Copyright © 2021. Published by Elsevier Inc.)

Background and Aims: Proton pump inhibitors (PPIs) are widely prescribed and have effects on gut ion absorption and urinary ion concentrations. PPIs might therefore protect against or contribute to development of kidney stones. We investigated the association between PPI use and kidney stones., Methods: We performed a retrospective study using data from the Women's Veteran's Cohort Study, which comprised men and women, from October 1, 1999 through September 30, 2017. We collected data from 465,891 patients on PPI usage over time, demographics, laboratory results, comorbidities, and medication usage. Time-varying Cox proportional hazards and propensity matching analyses determined risk of PPI use and incident development of kidney stones. Use of histamine-2 receptor antagonists (H2RAs) was measured and levothyroxine use was a negative control exposure., Results: PPI use was associated with kidney stones in the unadjusted analysis, with PPI use as a time-varying variable (hazard ratio [HR], 1.74; 95% CI, 1.67-1.82), and persisted in the adjusted analysis (HR, 1.46; CI, 1.38-1.55). The association was maintained in a propensity score-matched subset of PPI users and nonusers (adjusted HR, 1.25; CI 1.19-1.33). Increased dosage of PPI was associated with increased risk of kidney stones (HR, 1.11; CI, 1.09-1.14 for each increase in 30 defined daily doses over a 3-month period). H2RAs were also associated with increased risk (adjusted HR, 1.47; CI 1.31-1.64). We found no association, in adjusted analysis, of levothyroxine use with kidney stones (adjusted HR, 1.06; CI 0.94-1.21)., Conclusions: In a large cohort study of veterans, we found PPI use to be associated with a dose-dependent increase in risk of kidney stones. H2RA use also has an association with risk of kidney stones, so acid suppression might be an involved mechanism. The effect is small and should not change prescribing for most patients., (Published by Elsevier Inc.)

Adverse reactions to sunscreens are uncommon in relation to their widespread use [Loden et al. Br J Dermatol. 2011;165(2):255-62; Jansen et al. J Am Acad Dermatol. 2013;69(6):867 e861-814; quiz 881-862] and can be related to both active and inactive ingredients in sunscreen products [DiNardo et al. J Cosmet Dermatol. 2018;17(1):15-19; Barrientos et al. Contact Dermatitis. 2019;81(2):151-52]. Pathogenetically, the main cutaneous adverse reaction patterns to sunscreens can be divided into allergic and irritant contact dermatitis, phototoxic and photoallergic contact dermatitis, contact urticaria, and, in solitary cases, anaphylactic reactions [Lautenschlager et al. Lancet. 2007;370(9586):528-37]. A summary is provided in Table 1. Nearly all adverse effects due to active sunscreen ingredients reported to date are related to the organic UV filters, which are sometimes also referred to as "chemical UV filters." This imbalance is attributable to the lipophilic character and small molecular size of the organic UV filters that allow skin penetration, which is the basic requirement to initiate the sensitization [Stiefel et al. Int J Cosmet Sci. 2015;37(1):2-30]. In contrast, cutaneous adverse reactions to inorganic UV filters, initially termed "physical UV filters" owing to their firstly known "physical" mechanism of action through reflection and scattering [Stiefel et al. Int J Cosmet Sci. 2015;37(1):2-30], are only reported by case reports. Neither zinc oxide nor titanium dioxide possesses relevant skin-irritating properties or sensitization potential [Lau-tenschlager et al. Lancet. 2007;370(9586):528-37]. Adverse reactions to UV filters currently approved in the European Union as listed in the Annex VI (updated November 7, 2019) are summarized in Table 2., (© 2021 S. Karger AG, Basel.)

The rhomboid protease PARL is a critical regulator of mitochondrial homeostasis through its cleavage of substrates such as PINK1, PGAM5, and Smac/Diablo, which have crucial roles in mitochondrial quality control and apoptosis. However, the catalytic properties of PARL, including the effect of lipids on the protease, have never been characterized in vitro. To address this, we isolated human PARL expressed in yeast and used FRET-based kinetic assays to measure proteolytic activity in vitro. We show that PARL activity in detergent is enhanced by cardiolipin, a lipid enriched in the mitochondrial inner membrane. Significantly higher turnover rates were observed for PARL reconstituted in proteoliposomes, with Smac/Diablo being cleaved most rapidly at a rate of 1 min -1 . In contrast, PGAM5 is cleaved with the highest efficiency (k cat /K M ) compared with PINK1 and Smac/Diablo. In proteoliposomes, a truncated β-cleavage form of PARL, a physiological form known to affect mitochondrial fragmentation, is more active than the full-length enzyme for hydrolysis of PINK1, PGAM5, and Smac/Diablo. Multiplex profiling of 228 peptides reveals that PARL prefers substrates with a bulky side chain such as Phe in P1, which is distinct from the preference for small side chain residues typically found with bacterial rhomboid proteases. This study using recombinant PARL provides fundamental insights into its catalytic activity and substrate preferences that enhance our understanding of its role in mitochondrial function and has implications for specific inhibitor design., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The leaded protective gear worn, patient and endoscopist positioning, and longer average procedural time place endoscopists who perform endoscopic retrograde cholangiopancreatography (ERCP) at an increased risk of injuries as compared to other endoscopists. While multiple studies have investigated the prevalence of various pain symptoms and injuries among endoscopists, only one has been carried out in endoscopists who perform ERCP, and none have investigated potential predisposing risk factors. Our aim was thus to assess the prevalence of these pain symptoms, injuries, and potential risk factors., Methods: An anonymous electronic survey containing 23 questions was sent to 3276 gastroenterologists. Only providers that performed ERCPs were asked to respond., Results: A total of 203 surveys were completed. Of the 203 respondents, 91% reported a musculoskeletal pain symptom. The most prevalent pain symptoms were neck pain (24%) and lower back pain (17%). In total, 48% of respondents reported a musculoskeletal injury. In total, 32% attributed these injuries to performing ERCPs. The most prevalent musculoskeletal injuries were De Quervain's tenosynovitis (16%) and cervical radiculopathy (12%). Only 25% of participants had received any education/training on ergonomics in endoscopy., Conclusions: The majority of endoscopists who perform ERCPs suffer from a musculoskeletal pain symptom, and almost half report a musculoskeletal injury. Further investigation regarding risk factors and preventative strategies is warranted. This information can then be incorporated into ergonomics education which only a small proportion of advanced endoscopists report having received any training in.

Background: The coronavirus disease 2019 (COVID-19) pandemic brought about abrupt changes in the way health care is delivered, and the impact of transitioning outpatient clinic visits to telehealth visits on processes of care and outcomes is unclear., Methods: We evaluated ordering patterns during cardiovascular telehealth clinic visits in the Duke University Health System between March 15 and June 30, 2020 and 30-day outcomes compared with in-person visits in the same time frame in 2020 and in 2019., Results: Within the Duke University Health System, there was a 33.1% decrease in the number of outpatient cardiovascular visits conducted in the first 15 weeks of the COVID-19 pandemic, compared with the same time period in 2019. As a proportion of total visits initially booked, 53% of visits were cancelled in 2020 compared to 35% in 2019. However, patients with cancelled visits had similar demographics and comorbidities in 2019 and 2020. Telehealth visits comprised 9.3% of total visits initially booked in 2020, with younger and healthier patients utilizing telehealth compared with those utilizing in-person visits. Compared with in-person visits in 2020, telehealth visits were associated with fewer new (31.6% for telehealth vs 44.6% for in person) or refill (12.9% vs 15.6%, respectively) medication prescriptions, electrocardiograms (4.3% vs 31.4%), laboratory orders (5.9% vs 21.8%), echocardiograms (7.3% vs 98%), and stress tests (4.4% vs 6.6%). When adjusted for age, race, and insurance status, those who had a telehealth visit or cancelled their visit were less likely to have an emergency department or hospital encounter within 30 days compared with those who had in-person visits (adjusted rate ratios (aRR) 0.76 [95% 0.65, 0.89] and aRR 0.71 [95% 0.65, 0.78], respectively)., Conclusions: In response to the perceived risks of routine medical care affected by the COVID-19 pandemic, different phenotypes of patients chose different types of outpatient cardiology care. A better understanding of these differences could help define necessary and appropriate mode of care for cardiology patients., Competing Interests: Declaration of Competing Interest No conflicts relevant to this work for all authors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rhomboid proteases are a ubiquitous superfamily of serine intramembrane peptidases that play a role in a wide variety of cellular processes. The mammalian mitochondrial rhomboid protease, Presenilin-Associated Rhomboid Like (PARL), is a critical regulator of mitochondrial homeostasis through the cleavage of its substrates, which have roles in mitochondrial quality control and apoptosis. However, neither structural nor functional information for this important protease is available, because the expression of eukaryotic membrane proteins to sufficient levels in an active form often represents a major bottleneck for in vitro studies. Here we present an optimized protocol for expression and purification of the human PARL protease using the eukaryotic expression host Pichia pastoris. The PARL gene construct was generated in tandem with green fluorescent protein (GFP), which allowed for the selection of high expressing clones and monitoring during the large-scale expression and purification steps. We discuss the production protocol with precise details for each step. The protocol yields 1 mg of pure PARL per liter of yeast culture.

Objectives: The authors sought to evaluate the association of heart failure hospitalization (HFH) with guideline-directed medical therapy (GDMT) prescribing patterns among patients with heart failure with reduced ejection fraction (HFrEF)., Background: HFH represents an important opportunity to titrate GDMT among patients with HFrEF., Methods: The CHAMP-HF (Change the Management of Patients With Heart Failure) registry is a prospective registry of adults with HFrEF (ejection fraction ≤40%). Using data from the CHAMP-HF registry (N = 4,365), adjusted time-to-event models were created to study the association of HFH with GDMT prescribing patterns., Results: HFH (compared with no HFH) was positively associated with initiation of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA). HFH positively associated with dose escalation of ACE inhibitor/ARB (probability ratio: 1.71, 95% confidence interval [CI]: 1.36 to 2.16) and MRA (probability ratio: 8.71, 95% CI: 4.19 to 18.10). In those on prior therapy, HFH was associated with discontinuation and de-escalation of all classes of GDMT. ACE inhibitor/ARB, angiotensin receptor-neprilysin inhibitor, beta-blocker, and MRA de-escalation/discontinuation after HFH was associated with increased risk of all-cause mortality with hazard ratios of 3.82 (95% CI: 2.42 to 6.03), 4.76 (95% CI: 2.06 to 11.03), 2.94 (95% CI: 2.04 to 4.25), and 4.81 (95% CI: 2.61 to 8.87), respectively., Conclusions: HFH positively associated with changes in GDMT, including initiation, dose escalation, discontinuation, and dose de-escalation. De-escalation/discontinuation of GDMT after HFH associated with increased risk of all-cause mortality. Educational endeavors are needed to ensure GDMT is not inappropriately held in the setting of HFH. For those in whom GDMT must be held/decreased, improvement tools at discharge and post-discharge titration clinics may help ensure lifesaving GDMT regimens remain optimized., Competing Interests: Author Disclosures The CHAMP HF registry and this study were funded by Novartis. Dr. DeVore has received research funding from the American Heart Association, Amgen, Bayer, Intra-Cellular Therapies, Luitpold Pharmaceuticals, the National Heart, Lung, and Blood Institute, Novartis, and PCORI; and has provided consulting services for Amgen, AstraZeneca, Bayer, InnaMed, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, and Zoll. Dr. Albert has been a consultant for Amgen, AstraZeneca, Boston Scientific, and Novartis. Dr. Spertus has been a consultant for Novartis, Amgen, Bayer, Janssen, United Healthcare, and AstraZeneca; has served on the board of directors for Blue Cross Blue Shield of Kansas City; and has equity in Health Outcomes Sciences and copyright ownership of KCCQ, SAQ and PAQ. Dr. Duffy is an employee of Novartis. Dr. Hernandez has received research funding from AstraZeneca, American Regent, Novartis, and Verily; and has provided consulting services for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, and Novartis. Dr. Fonarow has been a consultant for Abbott, Amgen, CHF Solutions, Janssen, Medtronic, Merck, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)