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Abstract: Hemophilia is an X-linked congenital bleeding disorder for which factor replacement is life-saving but complicated by the sequelae of chronic hepatitis C virus (HCV) infection acquired decades ago. Although antiviral therapy clears HCV and reduces end-stage liver disease (ESLD), it may not reverse cirrhosis or prevent hepatocellular cancer (HCC). This was a retrospective cohort study of 121 men with hemophilia and HCV infection cared for at the Hemophilia Center of Western Pennsylvania to determine the incidence and predictors of ESLD and HCC. ESLD and HCC predictors were analyzed using Fisher exact test, and HCV-associated outcomes by Kaplan-Meier time-to-event and Cox proportional hazards regression analyses. At a mean 54 years (36-80) duration of HCV, ESLD occurred in 24 (19.8%), 0.365 per 100 person-years (py); and HCC in 7 (5.8%), 0.106 per 100 py. All 46 (38.0%) alive when HCV antiviral therapy became available, received it. Overall, 31 (25.6%) were HIV+. The leading causes of death were ESLD in 11 (32.3%), bleeding in 9 (26.5%), and HCC in 6 (17.6%). Major risk factors for ESLD included platelets <100 × 103/μL (odds ratio [OR], 6.009; P = .012) and HIV infection (OR, 3.883; P = .001). The major predictors of HCC were ESLD (OR, 11.476; P = .003) and platelets <100 000/μL (OR, 6.159; P = .014). No antiviral-treated patient developed ESLD, P = .001. For men with hemophilia, the sequelae of chronic HCV infection were significant. The major risk factors for ESLD were platelets <100 000/μL and HIV infection. Despite antiviral therapy, ESLD is the most significant predictor of HCC, and ESLD is the leading cause of death., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Depression is a common pregnancy complication yet is often under-detected and, subsequently, undertreated. Data collected through mobile health tools may be used to support the identification of depression symptoms in pregnancy., Methods: An observational cohort study of 2062 pregnancies collected self-reports of patient history, mood, pregnancy-specific symptoms, and written language using a prenatal support app. These app inputs were used to model depression risk in subsequent 30- and 60-day periods throughout pregnancy. A selective inference lasso modeling approach examined the individual and additive value of each type of patient-reported app input., Results: Depression models ranged in predictive power (AUC value of 0.64-0.83), depending on the type of inputs. The most predictive model included personal history, daily mood, and acute pregnancy-related symptoms (e.g., severe vomiting, cramping). Across models, daily mood was the strongest indicator of depression symptoms in the following month. Models that retained natural language inputs typically improved predictive accuracy and offered insight into the lived context associated with experiencing depression., Limitations: Our findings are not generalizable beyond a digitally literate patient population that is self-motivated to report data during pregnancy., Conclusions: Simple patient reported data, including sparse language, shared directly via digital tools may support earlier depression symptom identification and a more nuanced understanding of depression context., Competing Interests: Declaration of competing interest Drs. Krishnamurti and Simhan are co-founders of Naima Health LLC, which provided the data for this study. However, no financial or material compensation was provided by Naima Health LLC to fund this work. The remaining authors report no conflicts of interest. To manage any conflict of interest, the University of Pittsburgh instituted a conflict-of-interest management plan for this research, which included assigning an independent data steward to the project. Under this plan, the two authors with a conflict of interest did not access the raw data or code, although they were engaged in analyses planning and interpretation of the output., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Adolescent relationship abuse (ARA) is prevalent among adolescents, including those who identify as Latine. However, there is limited research that has considered the cultural and structural mechanisms that may impact ARA experiences among Latine youth. Further, although parents play a crucial role in ARA prevention, few studies have investigated how adolescent-parent differences in acculturation and discrimination are associated with ARA. The objective of this exploratory study of Latine families was to examine how acculturation, discrimination, and adolescent-parent acculturation/discrimination differences relate to ARA victimization and perpetration. Parent-adolescent dyads recruited from clinic and community-based settings in Pittsburgh and Kansas City completed matched surveys. Parent-adolescent acculturation and discrimination differences were calculated using multilevel linear models. Multivariable logistic regression was used to examine associations among ARA victimization and perpetration and adolescent-reported acculturation, adolescent-reported discrimination, and adolescent-parent acculturation and discrimination differences. One hundred eighty-two adolescents and their parent/caregiver ( n  = 364) completed a matched survey in English or Spanish from March 2020 to March 2021. Forty-three percent of adolescents reported that they had started dating; of these 35% and 24% reported ARA victimization and perpetration, respectively. Higher levels of adolescent-reported acculturation conflict were associated with lower ARA victimization (adjusted odds ratio [aOR]: 0.24; 95% confidence interval, CI [0.08, 0.75]); conversely, higher adolescent-reported discrimination was associated with ARA victimization (aOR: 2.50 [1.30, 4.60]) and perpetration (aOR: 2.10 [1.10, 3.90]). Wider adolescent-parent acculturation differences in Spanish language (aOR: 3.40 [1.04, 11.30]) and interpersonal discrimination (aOR: 2.40 [1.10, 5.20]) were associated with increased ARA victimization. Results underscore the importance of discrimination in understanding ARA experiences among Latine youth. Future work should consider developing culturally and linguistically affirming ARA prevention programs for Latine adolescents and parents., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared a potential conflict of interest (e.g., a financial relationship with the commercial organizations or products discussed in this article) as follows: E. Miller receives royalties for writing content for UptoDate, Wolter Kluwers, Inc. The authors have no other conflicts of interest relevant to this article to disclose.

Background: Unlike adults, children experienced stronger and longer vector replication in plasma and shedding in saliva following rVSVΔG-ZEBOV-GP vaccination. The resulting risks of immunosuppression or immune hyperactivation leading to increased Adverse Events (AEs) and altered antibody responses are concerns that have been addressed in the present manuscript., Methods: Children aged 1-12 years living in Gabon received either rVSVΔG-ZEBOV-GP (ERVEBO®) vaccine or the varicella-zoster virus (VZV) vaccine (VZV). The concentration of rVSVΔG vector in blood and saliva, the occurrence of AEs up to day 28; the anti-rVSVΔG-ZEBOV-GP and anti-VZV IgG antibody titres, neutralising and avidity functions of anti-rVSVΔG-ZEBOV-GP by day 365; were assessed in serum. (PACTR202005733552021) FINDINGS: In the rVSVΔG-ZEBOV-GP group, 70% and 7% of children had >0 copies/ml of rVSVΔG respectively in plasma by day 3 and in saliva by day 14 after vaccination, with no detection on day 28. Significantly higher but transient AEs occurred in the rVSVΔG-ZEBOV-GP group. Both vaccines induced seroconversion on day 28 and sustainable IgG antibody titres by day 365. Avidity and neutralisation functions of the anti-rVSVΔG-ZEBOV-GP antibodies peaked at day 28 and were maintained by day 365., Interpretation: The replication and shedding do not affect the favourable risk-benefit balance of the rVSVΔG-ZEBOV-GP in children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Clinical competency committees (CCCs) rely on narrative evaluations to assess resident competency. Despite the emphasis on these evaluations, their utility is frequently hindered by lack of sufficient detail for use by CCCs. Prior resources have sought to improve specificity of comments and use of evaluations by residents but not their utility for CCCs in assessing trainee performance., Methods: We developed a 1-hour faculty development workshop focused on a newly devised framework for Department of Medicine faculty supervising internal medicine residents. The what/why/when/where/how framework highlighted key features of useful narrative evaluations: behaviors of strength and growth, contextualized observations, improvement over time, and actionable next steps. Workshop sessions were implemented at a large multisite internal medicine residency program. We assessed the workshop by measuring attendee confidence and skill in writing narrative evaluations useful for CCCs. Skill was assessed through a rubric adapted from literature on the utility of narrative evaluations., Results: Fifty-four participants started the presurvey, and 33 completed the workshop, for a response rate of 61%. Participant confidence improved pre-, post-, and 3 months postworkshop. Total utility scores improved in mock evaluations from 12.4 to 15.5 and in real evaluations from 13.7 to 15.0, but only some subcomponent scores improved, with fewer improving in the real evaluations., Discussion: A short workshop focusing on our framework improves confidence and utility of narrative evaluations of internal medicine residents for use by CCCs. Next steps should include developing more challenging components of narrative evaluations for continued improvement in trainee performance and faculty assessment., (© 2024 Sekar et al.)

SARS-CoV-2 is the pathogen responsible for the most recent global pandemic, which has claimed hundreds of thousands of victims worldwide. Despite remarkable efforts to develop an effective vaccine, concerns have been raised about the actual protection against novel variants. Thus, researchers are eager to identify alternative strategies to fight against this pathogen. Like other opportunistic entities, a key step in the SARS-CoV-2 lifecycle is the maturation of the envelope glycoprotein at the RARR685↓ motif by the cellular enzyme Furin. Inhibition of this cleavage greatly affects viral propagation, thus representing an ideal drug target to contain infection. Importantly, no Furin-escape variants have ever been detected, suggesting that the pathogen cannot replace this protease by any means. Here, we designed a novel fluorogenic SARS-CoV-2-derived substrate to screen commercially available and custom-made libraries of small molecules for the identification of new Furin inhibitors. We found that a peptide substrate mimicking the cleavage site of the envelope glycoprotein of the Omicron variant (QTQTKSHRRAR-AMC) is a superior tool for screening Furin activity when compared to the commercially available Pyr-RTKR-AMC substrate. Using this setting, we identified promising novel compounds able to modulate Furin activity in vitro and suitable for interfering with SARS-CoV-2 maturation. In particular, we showed that 3-((5-((5-bromothiophen-2-yl)methylene)-4-oxo-4,5 dihydrothiazol-2-yl)(3-chloro-4-methylphenyl)amino)propanoic acid ( P3 , IC 50 = 35 μM) may represent an attractive chemical scaffold for the development of more effective antiviral drugs via a mechanism of action that possibly implies the targeting of Furin secondary sites (exosites) rather than its canonical catalytic pocket. Overall, a SARS-CoV-2-derived peptide was investigated as a new substrate for in vitro high-throughput screening (HTS) of Furin inhibitors and allowed the identification of compound P3 as a promising hit with an innovative chemical scaffold. Given the key role of Furin in infection and the lack of any Food and Drug Administration (FDA)-approved Furin inhibitor, P3 represents an interesting antiviral candidate.

Importance: Youths with type 2 diabetes are at higher risk for complications compared with peers with type 1 diabetes, though few studies have evaluated differences in access to specialty care., Objective: To compare claims with diabetes specialists for youths with type 1 vs type 2 diabetes and the association between specialist claims with multidisciplinary and acute care utilization., Design, Setting, and Participants: This cross-sectional study used Optum Clinformatics Data Mart commercial claims. Individuals included in the study were youths younger than 19 years with type 1 or 2 diabetes as determined by a validated algorithm and prescription claims. Data were collected for youths with at least 80% enrollment in a commercial health plan from December 1, 2018, to December 31, 2019. Statistical analysis was performed from September 2022 to January 2024., Main Outcomes and Measures: The primary outcome was the number of ambulatory claims from an endocrine and/or diabetes physician or advanced practice clinician associated with a diabetes diagnosis code; secondary outcomes included multidisciplinary and acute care claims., Results: Claims were analyzed for 4772 youths (mean [SD] age, 13.6 [3.7] years; 4300 [90.1%] type 1 diabetes; 472 [9.9%] type 2 diabetes; 2465 [51.7%] male; 128 [2.7%] Asian, 303 [6.4] Black or African American, 429 [9.0%] Hispanic or Latino, 3366 [70.5%] non-Hispanic White, and 546 [11.4%] unknown race and ethnicity). Specialist claims were lower in type 2 compared with type 1 diabetes (incidence rate ratio [IRR], 0.61 [95% CI, 0.52-0.72]; P < .001) in propensity score-weighted analyses. The presence of a comorbidity was associated with increased specialist claims for type 1 diabetes (IRR, 1.07 [95% CI, 1.03-1.10]) and decreased claims for type 2 diabetes (IRR, 0.77 [95% CI, 0.67-0.87]). Pooling diagnosis groups and adjusted for covariates, each additional specialist claim was associated with increased odds of a claim with a diabetes care and education specialist (odds ratio [OR], 1.31 [95% CI, 1.25-1.36]), dietitian (OR, 1.14 [95% CI, 1.09-1.19]), and behavioral health clinician (OR, 1.16 [95% CI, 1.12-1.20]). For acute care claims, each additional specialist claim was associated with increased odds of admission (OR, 1.17 [95% CI, 1.11-1.24]) but not for emergency claims (OR, 1.03 [95% CI, 0.98-1.82])., Conclusions and Relevance: This cross-sectional study found that youths with type 2 diabetes were significantly less likely to have specialist claims despite insurance coverage, indicating other barriers to care, which may include medical complexity. Access to diabetes specialists influences engagement with multidisciplinary services. The association between increasing ambulatory clinician services and admissions suggests high utilization by a subgroup of patients at greater risk for poor outcomes.

Problem: Physicians in training are responsible for leading clinical teams, coordinating interdisciplinary management, navigating conflict, and supervising and giving feedback to junior learners. Giving feedback and resolving conflict are key leadership skills for internal medicine (IM) residents, many of whom desire additional training. Although these skills are integral to successful leadership for physicians in training, residents receive little explicit education and existing curricula have not established best practices for skill acquisition., Approach: Study authors designed a pilot longitudinal, skills-based curriculum to teach first- through third-year IM residents at the University of Pittsburgh how to give formative feedback and engage in conflict resolution. From February to May 2021, authors delivered a series of interactive lectures utilizing frameworks, workplace-based scenarios, skills practice, and discussion. Skills transfer was evaluated with novel pre- and postcurriculum objective structured clinical examinations (OSCEs) wherein participants played the role of senior resident. Each OSCE involved 2 feedback and 2 conflict resolution stations. OSCE performances were evaluated using an author-created checklist with a 1-4 rating scale. The exposure group comprised post-OSCE participants who attended the curriculum. Data were analyzed using a mixed effects regression model., Outcomes: Thirty-six residents participated in curriculum evaluation, and 23 were included in postcurriculum data analysis. Within feedback, the skill "explores feedback content" significantly improved for exposure group participants (precurriculum median, 2.64; postcurriculum, 3.24; P < .05). For conflict resolution, among the exposure group, the skill "identifies a common goal, value, or purpose" significantly improved (pre, 3.10; post, 3.62; P < .05)., Next Steps: This curriculum and evaluation can serve as a stepping stone for further evidence-based leadership frameworks, curricula, and evaluations developed specifically for physicians within their unique leadership roles. The feedback and conflict resolution frameworks used in this curriculum can be applied to various medical specialties, with specialty-relevant scenario adaptations for interactive skills practice., (Copyright © 2023 the Association of American Medical Colleges.)

Adults with obesity experience high rates of disability and rapid functional decline. Identifying movement dysfunction early can direct intervention and disrupt disability development; however, subtle changes in movement are difficult to detect with the naked eye. This study evaluated how a portable, inertial measurement unit (IMU)-based motion capture system compares to a laboratory-based optokinetic motion capture (OMC) system for evaluating gait kinematics in adults with obesity. Ten adults with obesity performed overground walking while equipped with the OMC and IMU systems. Fifteen gait cycles for each participant were extracted for the 150 total cycles analyzed. Kinematics were compared between OMC and IMU across the gait cycles (coefficient of multiple correlations), at clinically significant time points (interclass correlations), and over clinically relevant ranges (Bland-Altman plots). Sagittal plane kinematics were most similar between systems, especially at the knee. Sagittal plane joint angles at clinically meaningful timepoints were poorly associated except for ankle dorsiflexion at heel strike (ρ = 0.38) and minimum angle (ρ = 0.83). All motions except for ankle dorsiflexion and hip abduction had >5° difference between systems across the range of angles measured. While IMU-based motion capture shows promise for detecting subtle gait changes in adults with obesity, more work is needed before this method can replace traditional OMC. Future work should explore standardization procedures to improve consistency of IMU motion capture performance.

Background: A previously reported study examined the treatment of primary care patients with at least moderate severity depressive or anxiety symptoms via an evidence-based computerized cognitive behavioral therapy (CCBT) program (Beating the Blues) and an online health community (OHC) that included a moderated internet support group. The 2 treatment arms proved to be equally successful at 6-month follow-up., Objective: Although highly promising, e-mental health treatment programs have encountered high rates of noninitiation, poor adherence, and discontinuation. Identifying ways to counter these tendencies is critical for their success. To further explore these issues, this study identified the primary care patient characteristics that increased the chances patients would not initiate the use of an intervention, (ie, not try it even once), initiate use, and go on to discontinue or continue to use an intervention., Methods: The study had 3 arms: one received access to CCBT (n=301); another received CCBT plus OHC (n=302), which included a moderated internet support group; and the third received usual care (n=101). Participants in the 2 active intervention arms of the study were grouped together for analyses of CCBT use (n=603) because both arms had access to CCBT, and there were no differences in outcomes between the 2 arms. Analyses of OHC use were based on 302 participants who were randomized to that arm., Results: Several baseline patient characteristics were associated with failure to initiate the use of CCBT, including having worse physical health (measured by the Short Form Health Survey Physical Components Score, P=.01), more interference from pain (by the Patient-Reported Outcomes Measurement Information System Pain Interference score, P=.048), less formal education (P=.02), and being African American or another US minority group (P=.006). Characteristics associated with failure to initiate use of the OHC were better mental health (by the Short Form Health Survey Mental Components Score, P=.04), lower use of the internet (P=.005), and less formal education (P=.001). Those who initiated the use of the CCBT program but went on to complete less of the program had less formal education (P=.01) and lower severity of anxiety symptoms (P=.03)., Conclusions: This study found that several patient characteristics predicted whether a patient was likely to not initiate use or discontinue the use of CCBT or OHC. These findings have clear implications for actionable areas that can be targeted during initial and ongoing engagement activities designed to increase patient buy-in, as well as increase subsequent use and the resulting success of eHealth programs., Trial Registration: ClinicalTrials.gov NCT01482806; https://clinicaltrials.gov/study/NCT01482806., (©Armando J Rotondi, Bea Herbeck Belnap, Scott Rothenberger, Robert Feldman, Barbara Hanusa, Bruce L Rollman. Originally published in JMIR Mental Health (https://mental.jmir.org), 17.01.2024.)

Epilepsy affects 1% of the US population. Healthcare disparities are well-studied among adults with epilepsy but less so among children. We examined whether children with epilepsy (1) have lower income than or (2) utilize the emergency department (ED) differently from children without epilepsy, and (3) if income moderates ED utilization. Data from the 2016-2019 National Survey of Children's Health were used to identify children with active "epilepsy or seizure disorder". Children with versus without epilepsy were compared. Income and ED visits were modeled with logistic and Poisson regressions. This analysis included 131,326 children; 835 were diagnosed with epilepsy. Estimated population prevalence of epilepsy was 0.6%. Children from higher-income-households were less likely to have epilepsy (aOR: 0.7). Children with epilepsy were more likely to visit EDs (aOR = 10.2), see healthcare professionals (aOR: 2.7), and receive care from specialists (aOR: 10.3). Income moderated the relationship between having epilepsy and ED visits. 7.7% of children with epilepsy did not receive needed healthcare. Some barriers were acquiring appointments (aOR: 3.9) and transportation (aOR: 4.7). In conclusion, children with epilepsy were more likely than children without epilepsy to live in lower-income-households, visit EDs, see healthcare professionals, and not receive needed healthcare. Barrier-specific policy interventions may improve medical access for children with epilepsy., (© 2023. The Author(s).)

Objectives: To report 5-year persistence and avidity of antibodies produced by the live-attenuated recombinant vesicular stomatitis virus (rVSV) expressing the Zaire Ebolavirus (ZEBOV) glycoprotein (GP), known as rVSV-ZEBOV (Ervebo®)., Methods: Healthy adults vaccinated with 300,000 or 10-50 million plaque-forming units of rVSV-ZEBOV in the WHO-coordinated trials of 2014-2015 were followed for up to 4 (Lambaréné, Gabon) and 5 (Geneva, Switzerland) years. We report seropositivity rates, geometric mean titres (GMTs), and population distribution of ZEBOV-GP ELISA IgG antibodies, neutralizing antibodies (pseudovirus and live-virus neutralization) and antibody avidity; the primary outcome was ZEBOV-GP ELISA IgG GMTs at 4 or 5 years compared with 1 year (Y1) after immunization., Results: Among the 168 eligible vaccinees (Geneva: 97 and Lambaréné: 71) enrolled 1 year post-immunization, 146 (87%) remained enrolled at 4 years (Geneva: n = 88, Lambaréné: n = 58), and 84 (87%, Geneva) at 5 years post-vaccination. ZEBOV-GP ELISA IgG GMTs plateaued, with no declining trend from 1 year through the last time point assessed (1147.8 [95% CI 874.3-1507.0] at Y1 versus 1548.1 [95% CI 1136.6-2108.5] at Y5 in Geneva volunteers receiving ≥10 million plaque-forming units of rVSV-ZEBOV), their avidity matching that of ZEBOV convalescents. Live-virus neutralizing antibodies were detected for shorter periods and in fewer vaccinees (53/95 [56%] at Y1 versus 35/84 [42%] at Y5 in Geneva volunteers, all dose levels)., Discussion: Titres at Y1 emerged as a correlate of antibody persistence at Y5. The findings of persistent ZEBOV-GP ELISA IgG titres yet shorter-lasting, lower titres of live-virus neutralizing antibodies suggest the contribution of antibody-mediated protective mechanisms other than neutralization. Long-term clinical efficacy of rVSV-ZEBOV, however, requires further study., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: Anterior cruciate ligament (ACL) injury is common within the US military and represents a significant loss to readiness. Since recent changes to operational tempo, there has not been an analysis of ACL injury risk. The aim of this retrospective cohort study was to evaluate military occupation, sex, rank and branch of service on ACL injury risk in the US military from 2006 to 2018., Methods: The Defense Medical Epidemiology Database was queried for the number of US tactical athletes with International Classification of Diseases diagnosis codes 717.83 (old disruption of ACL), 844.2 (sprain of knee cruciate ligament), M23.61 (other spontaneous disruption of ACL) and S83.51 (sprain of ACL of knee) on their initial encounter. Relative risk and χ 2 statistics were calculated to assess sex and military occupation effects on ACL injury. A multivariable negative binomial regression model evaluated changes in ACL injury incidence with respect to sex, branch of service and rank., Results: The study period displayed a significant decrease in the ACL injury rate at 0.18 cases per 1000 person-years or relative decrease of 4.08% each year (p<0.001) after averaging over the main and interactive effects of sex, rank and branch of service. The interaction effect of time with sex indicated a steeper decline in the incidence in men as compared with women. The risk of ACL injury by sex was modified by rank. The incidence among military personnel varied by occupation., Conclusion: Despite the decline among tactical athletes over time, rates of ACL injury remain much higher than the general US population. Sex, rank, branch of service and military occupation were found to be risk factors for ACL injury. It is critical for policy makers to understand the salient risk factors for ACL injury to guide proactive measures to prevent injury., Competing Interests: Competing interests: ADA, AJM and JJF are military service members or employees of the US Government. This work was prepared as part of their official duties., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

When infecting humans, Andes orthohantavirus (ANDV) may cause a severe disease called hantavirus cardiopulmonary syndrome (HCPS). Following non-specific symptoms, the infection may progress to a syndrome of hemorrhagic fever combined with hyper-acute cardiopulmonary failure. The case fatality rate ranges between 25-40%, depending on the outbreak. In this study, we present the follow-up of a male patient who recovered from HCPS six years ago. We demonstrate that the ANDV genome persists within the reproductive tract for at least 71 months. Genome sequence analysis early and late after infection reveals a low number of mutations (two single nucleotide variants and one deletion), suggesting limited replication activity. We can exclude the integration of the viral genome into the host genome, since the treatment of the specimen with RNAse led to a loss of signal. We demonstrate a long-lasting, strong neutralizing antibody response using pseudovirions expressing the ANDV glycoprotein. Taken together, our results show that ANDV has the potential for sexual transmission.

Background: Population health management approaches can help target diabetes resources like Diabetes Self-Management Education and Support (DSMES) to individuals at the highest risk of complications and poor outcomes. Little is known about patient characteristics associated with DSMES receipt since widespread uptake of telemedicine for diabetes care in 2020., Methods: In this retrospective cohort study, we used electronic medical record (EMR) data to assess patterns of DSMES delivery from May 2020 to May 2022 among adults who used telemedicine for type 2 diabetes (T2D) endocrinology care in a large integrated health system. Multilevel regression models were used to evaluate the association of key patient characteristics with DSMES receipt., Results: Of 3530 patients in the overall cohort, 401 patients (11%) received DSMES. In adjusted multivariable logistic regression, higher baseline HbA1c (odds ratios [OR] 3.10 [95% confidence interval 2.22-4.33] for HbA1c ≥9% vs <7%), insulin regimen complexity (OR 3.53 [2.59-4.80] for multiple daily injections vs no insulin), and number of noninsulin medications (OR 1.17 [1.05-1.30] per 1 additional medication) were significantly associated with receipt of DSMES, whereas rurality and area-level deprivation of patient residence were not., Conclusions: Diabetes Self-Management Education and Support remains underutilized in this cohort of adults using telemedicine to access endocrinology care for T2D. Factors contributing to clinical complexity increased the odds of receiving DSMES. These results support a potential population health management approach using EMR data, which could target DSMES resources to those at higher risk of poor outcomes. This risk-stratified approach may be even more effective now that more people can access DSMES via telemedicine in addition to in-person care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: The latest guidelines continue to recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). Despite this, overall use of these 2 drug classes has been suboptimal., Objective: To assess the association of high out-of-pocket (OOP) costs and the initiation of an SGLT2 inhibitor or GLP-1 RA among adults with T2D and established CVD who are treated with metformin-treated., Design, Setting, and Participants: This retrospective cohort study used 2017 to 2021 data from the Optum deidentified Clinformatics Data Mart Database. Each individual in the cohort was categorized into quartiles of OOP costs for a 1-month supply of SGLT2 inhibitor and GLP-1 RA based on their health plan assignment. Data were analyzed from April 2021 to October 2022., Exposures: OOP cost for SGLT2 inhibitors and GLP-1 RA., Main Outcomes and Measures: The primary outcome was treatment intensification, defined as a new dispensing (ie, initiation) of either an SGLT2 inhibitor or GLP-1 RA, among patients with T2D previously treated with metformin monotherapy. For each drug class separately, Cox proportional hazards models were used to adjust for demographic, clinical, plan, clinician, and laboratory characteristics to estimate the hazard ratios of treatment intensification comparing the highest vs the lowest quartile of OOP costs., Results: Our cohort included 80 807 adult patients (mean [SD] age, 72 [9.5] years, 45 129 [55.8%] male; 71 128 [88%] were insured with Medicare Advantage) with T2D and established CVD on metformin monotherapy. Patients were followed for a median (IQR) of 1080 days (528 to 1337). The mean (SD) of OOP costs in the highest vs lowest quartile was $118 [32] vs $25 [12] for GLP-1 RA, and $91 [25] vs $23 [9] for SGLT2 inhibitors. Compared with patients in plans with the lowest quartile (Q1) of OOP costs, patients in plans with the highest quartile (Q4) of costs were less likely to initiate a GLP-1 RA (adjusted HR, 0.87 [95% CI, 0.78 to 0.97]) or an SGLT2 inhibitor (adjusted HR, 0.80 [95% CI, 0.73 to 0.88]). The median (IQR) number of days to initiating a GLP-1 RA was 481 (207-820) days in Q1 and 556 (237-917) days in Q4 of OOP costs and 520 (193-876) days in Q1 vs 685 (309-1017) days in Q4 for SGLT2 inhibitors., Conclusions and Relevance: In this cohort study of more than 80 000 older adults with T2D and established CVD covered by Medicare Advantage and commercial plans, those in the highest quartile of OOP cost were 13% and 20% less likely to initiate a GLP-1 RA or SGLT2 inhibitor, respectively, when compared with those in the lowest quartile of OOP costs.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiological agent responsible for the worldwide pandemic and has now claimed millions of lives. The virus combines several unusual characteristics and an extraordinary ability to spread among humans. In particular, the dependence of the maturation of the envelope glycoprotein S from Furin enables the invasion and replication of the virus virtually within the entire body, since this cellular protease is ubiquitously expressed. Here, we analyzed the naturally occurring variation of the amino acids sequence around the cleavage site of S. We found that the virus grossly mutates preferentially at P positions, resulting in single residue replacements that associate with gain-of-function phenotypes in specific conditions. Interestingly, some combinations of amino acids are absent, despite the evidence supporting some cleavability of the respective synthetic surrogates. In any case, the polybasic signature is maintained and, as a consequence, Furin dependence is preserved. Thus, no escape variants to Furin are observed in the population. Overall, the SARS-CoV-2 system per se represents an outstanding example of the evolution of substrate-enzyme interaction, demonstrating a fast-tracked optimization of a protein stretch towards the Furin catalytic pocket. Ultimately, these data disclose important information for the development of drugs targeting Furin and Furin-dependent pathogens.

Objective: Using continuous glucose monitoring (CGM), we examined patterns in glycemia during school hours for children with type 1 diabetes, exploring differences between school and non-school time., Methods: We conducted a retrospective analysis of CGM metrics in children 7-12 years (n=217, diabetes duration 3.5±2.5 years, hemoglobin A1c 7.5±0.8%). Metrics were obtained for weekday school hours (8 AM to 3 PM) during four weeks in fall 2019. Two comparison settings included weekend (fall 2019) and weekday (spring 2020) data when children had transitioned to virtual school due to COVID-19. We used multilevel mixed models to examine factors associated with time in range (TIR) and compare glycemia between in-school, weekends, and virtual school., Results: Though CGM metrics were clinically similar across settings, TIR was statistically higher, and time above range (TAR), mean glucose, and standard deviation (SD) lower, for weekends and virtual school (p<0.001). Hour and setting exhibited a significant interaction for several metrics (p<0.001). TIR in-school improved from a mean of 40.9% at the start of the school day to 58.0% later in school, with a corresponding decrease in TAR. TIR decreased on weekends (60.8 to 50.7%) and virtual school (62.2 to 47.8%) during the same interval. Mean glucose exhibited a similar pattern, though there was little change in SD. Younger age (p=0.006), lower hemoglobin A1c (p<0.001), and insulin pump use (p=0.02) were associated with higher TIR in-school., Conclusion: Although TIR was higher for weekends and virtual school, glycemic metrics improve while in-school, possibly related to beneficial school day routines., Competing Interests: Conflict of Interest disclosure: The authors have no significant conflicts of interest to disclose.

Proprotein Convertases (PCs) are serine endoproteases that regulate the homeostasis of protein substrates in the cell. The PCs family counts 9 members-PC1/3, PC2, PC4, PACE4, PC5/6, PC7, Furin, SKI-1/S1P, and PCSK9. The first seven PCs are known as Basic Proprotein Convertases due to their propensity to cleave after polybasic clusters. SKI-1/S1P requires the additional presence of hydrophobic residues for processing, whereas PCSK9 is catalytically dead after autoactivation and exerts its functions using mechanisms alternative to direct cleavage. All PCs traffic through the canonical secretory pathway, reaching different compartments where the various substrates reside. Despite PCs members do not share the same subcellular localization, most of the cellular organelles count one or more Proprotein Convertases, including ER, Golgi stack, endosomes, secretory granules, and plasma membranes. The widespread expression of these enzymes at the systemic level speaks for their importance in the homeostasis of a large number of biological functions. Among others, PCs cleave precursors of hormones and growth factors and activate receptors and transcription factors. Notably, dysregulation of the enzymatic activity of Proprotein Convertases is associated to major human pathologies, such as cardiovascular diseases, cancer, diabetes, infections, inflammation, autoimmunity diseases, and Parkinson. In the current COVID-19 pandemic, Furin has further attracted the attention as a key player for conferring high pathogenicity to SARS-CoV-2. Here, we review the Proprotein Convertases family and their most important substrates along the secretory pathway. Knowledge about the complex functions of PCs is important to identify potential drug strategies targeting this class of enzymes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: The inclusion of non-English-speaking (NES) participants in pediatric research is an essential step to improving health equity for these populations. Although some studies have shown lack of progress in NES research participation in the past decade, few have examined NES inclusivity in pediatric research or details about the practices that researchers have used to communicate with NES participants., Objective: To assess how frequently NES families were included in pediatric research, how rates of inclusion changed over time, what languages were included, and methodological details about oral and written communication with NES participants., Evidence Review: In this review, all original investigation articles published in JAMA Pediatrics, Pediatrics, and The Journal of Pediatrics between January 2012 and November 2021 were screened. Eligible articles, which included those based in the US and with human participants, were reviewed to determine whether they included or excluded NES participants or whether or not there was specific mention of language. A second-round review was conducted on the subset of articles that included NES participants to determine methodological details (eg, languages included, type of study, region where the study was located, and oral and written communication practices with NES participants)., Findings: Of the 8142 articles screened, 5008 (62%) met inclusion criteria; of these, 469 (9%) included NES participants. The most common language was Spanish (350 [75%]); 145 articles (31%) reported non-English or other language without specification. A total of 230 articles (49%) reported the number of NES participants, and 61 (13%) specified the methods used to determine whether participants preferred a language other than English. In all, 101 (22%) and 136 (29%) articles specified how oral and written communication occurred with NES participants, respectively., Conclusions and Relevance: This review of 3 pediatric journals provides preliminary evidence suggesting exclusion of NES communities from pediatric research from 2012 to 2021 and highlights an opportunity to provide more methodological detail about communication with NES participants. Best practices for improving inclusivity of NES participants are needed to guide researchers toward improved methods and more relevant results.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19)., (© 2022. The Author(s).)

Background: Newer glucose-lowering drugs, including sodium glucose co-transporter 2 inhibitors (SGLT2i) and GLP-1 agonists, have a key role in the pharmacologic management of type 2 diabetes. No studies have measured primary nonadherence for these two drug classes, defined as when a medication is prescribed for a patient but ultimately not dispensed to them., Objective: To describe the incidence and predictors of primary nonadherence to SGLT2i (canagliflozin, empagliflozin) or GLP-1 agonists (dulaglutide, liraglutide, semaglutide) using a dataset that links electronic prescribing with health insurance claims., Design and Participants: A retrospective cohort design using data of adult patients from a large health system who had at least one prescription order for a SGLT2i or GLP-1 agonist between 2012 and 2019. We used mixed-effects multivariable logistic regression to determine associations between sociodemographic, clinical, and provider variables and primary nonadherence., Main Measures: Primary medication nonadherence, defined as no dispensed claim within 30 days of an electronic prescription order for any drug within each medication class., Key Results: The cohort included 5146 patients newly prescribed a SGLT2i or GLP-1 agonist. The overall incidence of 30-day primary medication nonadherence was 31.8% (1637/5146). This incidence rate was 29.8% (n = 726) and 33.6% (n = 911) among those initiating a GLP-1 agonist and SGLT2i, respectively. Age ≥ 65 (aOR 1.37 (95% CI 1.09 to 1.72)), Black race vs White (aOR 1.29 (95% CI 1.02 to 1.62)), diabetic nephropathy (aOR 1.31 (95% CI 1.02 to 1.68)), and hyperlipidemia (aOR 1.18 (95% CI 1.01 to 1.39)) were associated with a higher odds of primary nonadherence. Female sex (aOR 0.86 (95% CI 0.75 to 0.99)), peripheral artery disease (aOR 0.73 (95% CI 0.56 to 0.94)), and having the index prescription ordered by an endocrinologist vs a primary care provider (aOR 0.76 (95% CI 0.61 to 0.95)) were associated with lower odds of primary nonadherence., Conclusions: One third of patients prescribed SGLT2i or GLP-1 agonists in this sample did not fill their prescription within 30 days. Black race, male sex, older age, having greater baseline comorbidities, and having a primary care provider vs endocrinologist prescribe the index drug were associated with higher odds of primary nonadherence. Interventions targeting medication adherence for these newer drugs must consider primary nonadherence as a barrier to optimal clinical care., (© 2022. The Author(s) under exclusive licence to Society of General Internal Medicine.)

Designed ankyrin repeat proteins (DARPins) are engineered proteins comprising consensus designed ankyrin repeats as scaffold. Tightly packed repeats form a continuous hydrophobic core and a large groove-like solvent-accessible surface that creates a binding surface. DARPin domains recognizing a target of interest with high specificity and affinity can be generated using a synthetic combinatorial library and in vitro selection methods. They can be linked together in a single molecule to build multispecific and multifunctional proteins without affecting expression or function. The modular architecture of DARPins offers unprecedented possibilities of design and opens avenues for innovative antiviral strategies.

Gait analysis can identify injury-risk markers indiscernible to the naked eye. Inertial measurement unit (IMU)-based motion capture circumvents optokinetic motion capture (OMC) clinical implementation barriers with its portability, increased affordability, and decreased computational burden. We compared an IMU system to a robust OMC marker set for gait analysis. 10 healthy adults walked at self-selected speeds equipped with Noraxon MyoMotion IMUs and a 24-marker, 5-cluster marker-set in view of 14 OMC cameras. A single calibration was applied. IMU system and OMC calculated joint angles were compared. A single calibration performed similarly to previously reported repeated calibration. IMU and OMC agreement was best in the sagittal plane with IMU axis-mixing affecting off-sagittal plane agreement. System differences were greater than 5° for most motions. Measurement system bias showed at the ankle and knee, however differences varied across participants. IMU kinematics should be interpreted with caution; consistency and accuracy must improve before IMUs can replace OMC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Early-stage cancer diagnosis is critical for higher survival rates. Because early cancers can be difficult to detect, our focus is on the identification of cancer risk markers such as pleiotropic genes involved in the etiology of both craniofacial conditions and cancers. In this study we aimed to test if our previously detected association between ERN1 rs196929 marker and oral health outcomes would be detected in individuals diagnosed with cancer as well as in a subpopulation of individuals who also had one or more teeth missing due to dental caries, periodontal disease, or periapical lesions. We genotyped a total of 1,671 subjects and selected a subset of 1,421 subjects for stratified analysis of cancer types; three hundred and twelve self-reported a diagnosis of various cancer types and 1,109 reported never receiving a diagnosis of cancer. Our results showed a statistically significant association between the rs196929 in ERN1, and cancer overall in both the additive and dominant models (OR = 1.37, 95% C.I. 1.06-1.79, p = 0.014). When we stratified the analysis for each cancer type, our results show that the rs196929 ERN1 variant is associated with skin cancer (OR = 2.07, 95% C.I. 1.27-3.37, p = 0.003) and breast cancer (OR = 1.83, 95% C.I. 1.13-2.99, p = 0.013) in the subset of patients that had tooth loss. An additional nominal association between the rs196929 in ERN1 and male's reproductive system cancers (OR = 1.96, 95% C.I. 1.07-3.59, p = 0.028) was identified. We hope that our study helps guide future genetic studies on these cancers and this specific genetic variant as well as drive attention to the potential for oral health outcomes to serve as indicators for cancer risk. The early identification of genetic markers and/or oral conditions that indicate increased cancer risk could positively impact cancer outcomes and survival rates with timely implementation of preventive and diagnostic measures. In conclusion, our results suggest that the genetic variant in ERN1 (rs196929) is associated with increased risk of skin and breast cancers., (© 2022. The Author(s).)

Background: Newer intravenous lipid emulsions (ILEs), such as fish oil-based intravenous lipid emulsions (FO-ILEs) and soybean oil, medium-chain triglycerides, olive oil, and fish oil-based intravenous lipid emulsions (SMOF-ILEs), provide alternatives to soybean oil-based intravenous lipid emulsions (SO-ILEs). We explored current ILE practice patterns among intestinal rehabilitation and transplant centers., Methods: A survey was developed addressing ILE availability, ILE preference in clinical scenarios, and factors influencing ILE choice. This survey was reviewed locally and by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Intestinal Rehabilitation Special Interest Group, the Intestinal Rehabilitation and Transplant Association scientific committee, and the American Society of Parenteral and Enteral Nutrition pediatric intestinal failure section research committee. We recruited providers nationally and internationally from centers with and without intestinal transplant programs., Results: We included 34 complete responses, 29 from the United States. Sixteen centers performed intestinal transplants. All centers had access to SMOF-ILEs, 85% had access to FO-ILEs, and 91% had access to SO-ILEs. In new patients, 85% use SMOF-ILEs as the first choice ILE. In those with new intestinal failure-associated liver disease (IFALD), FO-ILE was preferred to SMOF-ILE (56% vs 38%). In those developing IFALD on SMOF-ILE, 65% switched to FO-ILE, whereas 24% remained on SMOF-ILE., Conclusions: Centers have routine access to alternative ILEs, and these are quickly replacing SO-ILEs in all circumstances. Future work should focus on how this shift in practice affects outcomes to provide decision support in specific clinical scenarios., (© 2022 American Society for Parenteral and Enteral Nutrition.)

Background: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency., Methods: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity., Results: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW., Conclusions: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The drug supply chain is global and at risk of disruption and subsequent drug shortages, especially during unanticipated events., Objective: Our objective was to determine the impact of coronavirus disease 2019 (COVID-19) on drug purchases overall, by class, and for specific countries., Methods: A cross-sectional time series analysis of country-level drug purchase data from August 2014 to August 2020 from IQVIA MIDAS was conducted. Standardized units per 100 population and percentage increase in units purchased were assessed from 68 countries and jurisdictions in March 2020 (when the World Health Organization declared COVID-19 a pandemic). Analyses were compared by United Nations development status and drug class. Autoregressive integrated moving average models tested the significance of changes in purchasing trends., Results: Before COVID-19, standardized medication units per 100 population ranged from 3990 to 4760 monthly. In March 2020, there was a global 15% increase in units of drugs purchased to 5309.3 units per 100 population compared with the previous year; the increase was greater in developed countries (18.5%; P < 0.001) than in developing countries (12.8%; P < 0.0001). After the increase in March 2020, there was a correction in the global purchase rate decreasing by 4.7% (April to August 2020 rate, 21,334.6/100 population; P < 0.001). Globally, we observed high purchasing rates and large changes for respiratory medicines such as inhalers and systemic adrenergic drugs (March 2020 rate, 892.7/100 population; change from 2019, 28.5%; P < 0.001). Purchases for topical dermatologic products also increased substantially (42.2%), although at lower absolute rates (610.0/100 population in March 2020; P < 0.0001). Interestingly, purchases for systemic anti-infective agents (including antiviral drugs) increased in developing countries (11.3%; P < 0.001), but decreased in developed countries (1.0%; P = 0.06)., Conclusion: We observed evidence of global drug stockpiling in the early months of the COVID-19 pandemic, especially among developed countries. Actions toward equitable distribution of medicines through a resilient drug supply chain should be taken to increase global response to future unanticipated events, such as pandemics., (Copyright © 2022 American Pharmacists Association®. All rights reserved.)

Objectives: Hospital discharge is a challenging time for residents, requiring the completion of many tasks to ensure safe transitions for patients. Despite recognition of the importance of hospital discharge planning, formal curricula are lacking. We sought to improve medicine residents' comfort and skills with discharge planning and enhance the quality of care by introducing a standardized approach to discharge on the medicine wards., Methods: The intervention included a didactic, a bedside rounds component, and a discharge checklist. Interns were surveyed at the end of rotations to measure confidence, attitudes, and frequency of completing discharge planning tasks. Results were compared with a control group of experienced interns from the previous academic year. Clinical outcomes included hospital readmission and emergency department return rates and patient satisfaction scores in discharge-related domains., Results: Study interns reported similar confidence to control group interns with discharge planning and endorsed completing four of five discharge tasks more frequently than control interns. There were no differences in clinical outcomes., Conclusions: We did not identify changes in clinical outcomes, although this finding likely reflects the multifactorial nature of hospital readmissions. Interns exposed to the curriculum early in the academic year had a higher reported frequency of completing key discharge tasks and similar confidence around discharge, when compared with end-of-the-year interns. These improvements suggest that the curriculum led to a change in culture surrounding discharge planning and perhaps accelerated learning of skills associated with discharge best practices.