Outcomes of Blood Flow Restriction Training After ACL Reconstruction in NCAA Division I Athletes.

Background: Blood flow restriction training (BFRT) is a safe and potentially effective adjunctive therapeutic modality for postoperative rehabilitation related to various knee pathologies. However, there is a paucity of literature surrounding BFRT in high-performance athletes after anterior cruciate ligament reconstruction (ACLR). Purpose: To (1) compare the overall time to return to sports (RTS) in a cohort of National Collegiate Athletic Association (NCAA) Division I athletes who underwent a standardized rehabilitation program either with or without BFRT after ACLR and (2) identify a postoperative time interval for which BFRT has the maximum therapeutic benefit. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 55 student-athletes who underwent ACLR between 2000 and 2023 while participating in NCAA Division I sports at a single institution were included in this study. Athletes were allocated to 1 of 2 groups based on whether they participated in a standardized postoperative rehabilitation program augmented with BFRT (BFRT group; n = 22) or completed the standardized protocol alone (non-BFRT group [control]; n = 33). Our primary outcome measure was time to RTS. The secondary outcome measure was handheld dynamometry quadriceps strength testing at various postoperative time points, converted to a limb symmetry index (LSI). Quadriceps strength was not tested between the BFRT and non-BFRT groups because of the limited amount of data on the control group. Results: The mean age at the date of surgery was 18.59 ± 1.10 years for the BFRT group and 19.45 ± 1.30 years for the non-BFRT group (P = .011), and the mean RTS time was 409 ± 134 days from surgery for the BFRT group and 332 ± 100 days for the non-BFRT cohort (P = .047). For the BFRT group, the mean quadriceps strength LSI increased by 0.67% (95% CI, 0.53%-0.81%) for every week of rehabilitation, and there was a significantly positive rate of change in quadriceps strength in weeks 13-16 compared with weeks 9-12 (ΔLSI, 8.22%; P < .001). Conclusion: In elite NCAA Division I athletes, a statistically significant delay was observed in RTS with BFRT compared with standardized physical therapy alone after undergoing ACLR. There also appeared to be an early window during the rehabilitation period where BFRT had a beneficial impact on quadriceps strength.

Lower FIB-4 threshold in patients with diabetes improves diagnostic accuracy of the test in a Hispanic population.

Background: Non-invasive tests (NITs) can be used to estimate the severity of fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) but their diagnostic accuracy is variable. Hispanic patients are at increased risk of NAFLD and diabetes. We evaluate the diagnostic performance of the fibrosis index based on 4 factors (FIB-4) in a population of Hispanic patients who underwent vibration-controlled transient elastography (VCTE). Methods: A total of 1,524 patients underwent VCTE at University of California, Los Angeles from July 18, 2019 to June 7, 2022. Ultimately 110 patients were identified as Hispanic, with confirmed NAFLD. Sensitivity, specificity, positive predictive value and negative predictive value of FIB-4 threshold ≥1.3 were calculated. Logistic regression models were used to determine updated thresholds for patients with and without diabetes based on Youden's index. Results: Of the 110 patients, the majority (65%) were female. Prevalence of diabetes was higher in the group with clinically significant fibrosis (76% vs. 36%, P<0.001). Using a FIB-4 threshold ≥1.3 to predict clinically significant fibrosis (F2-F4 on VCTE), area under the receiver operating characteristic (AUROC) was 0.74. By incorporating diabetes status, AUROC was 0.81 when employing a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes. Conclusions: Using a FIB-4 threshold of ≥1.0 in patients with diabetes and ≥1.5 in patients without diabetes improves the diagnostic performance of the test. The new FIB-4 including diabetes status will lead to improved screening in patients who are at risk of clinically significant fibrosis.

A novel dance intervention program for children and adolescents with developmental disabilities: a pilot randomized control trial.

BACKGROUND: Organized physical activity programs have been shown to provide wide benefits to participants, though there are relatively few studies examining the impact of these programs for individuals with developmental disabilities. This pilot study was conducted to determine the feasibility and impact of an undergraduate-led dance intervention program for children and adolescents with developmental disabilities. We evaluated the impact of the dance program on motor ability and social skills. METHODS: The study design was a waitlist control clinical trial in which participants were randomized to active and control groups. Eligible participants included male and female children and adolescents between the ages of 4 and 17 years with neurodevelopmental disabilities. The Motor Assessment Battery for Children Checklist and the Social Responsiveness Scale were used to assess change in motor and social skills, respectively. After gathering baseline data, the active group completed 1 h of online dance classes per week for 10 weeks, while the control group entered a 10-week waiting period. All participants then returned for a follow-up visit. Pre- and post-intervention data were analyzed using linear mixed-effects modeling adjusting for age and class attendance with subject random intercept. RESULTS: We recruited and randomized 43 participants with neurodevelopmental disabilities (mean age = 8.63, SD = 2.98), of which 30 participated in dance classes. The attendance rate was 82.6% for the active group and 61.7% for the control group. The active group demonstrated a significant improvement in motor skills in an unpredictable environment, as indicated on the Motor Assessment Battery for Children Checklist (n = 21, p = 0.05). We also observed positive trends in social skills that did not reach significance. CONCLUSIONS: Our results indicate that it is feasible to develop and implement a fully digital dance intervention program for individuals with developmental disabilities. Further, we find that change in motor skills can be detected after just 10 h of low-intensity participation. However, a lack of significant change in social skills coupled with limitations in study implementation suggests further research is needed to determine the full impact of this dance program. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: Protocol ID 20-001680-AM-00005, registered 17/2/2021 - Retrospectively Registered, https://clinicaltrials.gov/study/NCT04762290 .

The association between population health management tools and clinician burnout in the United States VA primary care patient-centered medical home.

BACKGROUND: Technological burden and medical complexity are significant drivers of clinician burnout. Electronic health record(EHR)-based population health management tools can be used to identify high-risk patient populations and implement prophylactic health practices. Their impact on clinician burnout, however, is not well understood. Our objective was to assess the relationship between ratings of EHR-based population health management tools and clinician burnout. METHODS: We conducted cross-sectional analyses of 2018 national Veterans Health Administration(VA) primary care personnel survey, administered as an online survey to all VA primary care personnel (n = 4257, response rate = 17.7%), using bivariate and multivariate logistic regressions. Our analytical sample included providers (medical doctors, nurse practitioners, physicians' assistants) and nurses (registered nurses, licensed practical nurses). The outcomes included two items measuring high burnout. Primary predictors included importance ratings of 10 population health management tools (eg. VA risk prediction algorithm, recent hospitalizations and emergency department visits, etc.). RESULTS: High ratings of 9 tools were associated with lower odds of high burnout, independent of covariates including VA tenure, team role, gender, ethnicity, staffing, and training. For example, clinicians who rated the risk prediction algorithm as important were less likely to report high burnout levels than those who did not use or did not know about the tool (OR 0.73; CI 0.61-0.87), and they were less likely to report frequent burnout (once per week or more) (OR 0.71; CI 0.60-0.84). CONCLUSIONS: Burned-out clinicians may not consider the EHR-based tools important and may not be using them to perform care management. Tools that create additional technological burden may need adaptation to become more accessible, more intuitive, and less burdensome to use. Finding ways to improve the use of tools that streamline the work of population health management and/or result in less workload due to patients with poorly managed chronic conditions may alleviate burnout. More research is needed to understand the causal directional of the association between burnout and ratings of population health management tools.

Trends in Income Inequities in Cardiovascular Health Among US Adults, 1988-2018.

BACKGROUND: Mean cardiovascular health has improved over the past several decades in the United States, but it is unclear whether the benefit is shared equitably. This study examined 30-year trends in cardiovascular health using a suite of income equity metrics to provide a comprehensive picture of cardiovascular income equity. METHODS: The study evaluated data from the 1988-2018 National Health and Nutrition Examination Survey. Survey groupings were stratified by poverty-to-income ratio (PIR) category, and the mean predicted 10-year risk of a major cardiovascular event or death based on the pooled cohort equations (PCE) was calculated (10-year PCE risk). Equity metrics including the relative and absolute concentration indices and the achievement index-metrics that assess both the prevalence and the distribution of a health measure across different socioeconomic categories-were calculated. RESULTS: A total of 26 633 participants aged 40 to 75 years were included (mean age, 53.0-55.5 years; women, 51.9%-53.0%). From 1988-1994 to 2015-2018, the mean 10-year PCE risk improved from 7.8% to 6.4% (P<0.05). The improvement was limited to the 2 highest income categories (10-year PCE risk for PIR 5: 7.7%-5.1%, P<0.05; PIR 3-4.99: 7.6%-6.1%, P<0.05). The 10-year PCE risk for the lowest income category (PIR <1) did not significantly change (8.1%-8.7%). In 1988-1994, the 10-year PCE risk for PIR <1 was 6% higher than PIR 5; by 2015-2018, this relative inequity increased to 70% (P<0.05). When using metrics that account for all income categories, the achievement index improved (8.0%-7.1%, P<0.05); however, the achievement index was consistently higher than the mean 10-year PCE risk, indicating the poor persistently had a greater share of adverse health. CONCLUSIONS: In this serial cross-sectional survey of US adults spanning 30 years, the population's mean 10-year PCE risk improved, but the improvement was not felt equally across the income spectrum.

Impact of COVID-19 Pandemic on Sex and Racial Disparities in Chest Pain Presentation and Management Through the Emergency Department.

Background: Sex and racial disparities in the presentation and management of chest pain persist, however, the impact of coronavirus disease 2019 (COVID-19) on these disparities have not been studied. We sought to determine whether the COVID-19 pandemic contributed to pre-existing sex and racial disparities in the presentation, management, and outcomes of patients presenting to the emergency department (ED) with chest pain. Methods: We conducted an observational cohort study with retrospective data collection of patients between January 1, 2016, and May 1, 2022. This was a single study conducted at a quaternary academic medical center of all patients who presented to the ED with a complaint of chest pain or chest pain equivalent symptoms. Patient were further segregated into different groups based on sex (male, female), race, ethnicity (Asian, Black, Hispanic, White, and other), and age (18 - 40, 41 - 65, > 65). We compared diagnostic evaluations, treatment decisions, and outcomes during prespecified time points before, during, and after the COVID-19 pandemic. Results: This study included 95,764 chest pain encounters. Total chest pain presentations to the ED fell about 38% during the early pandemic months. Females presented significantly less than males during initial COVID-19 (48% vs. 52%, P < 0.001) and Asian females were least likely to present. There was an increase in the total number of troponins and echocardiograms ordered during peak COVID-19 across both sexes, but females were still less likely to have these tests ordered across all timepoints. The number of coronary angiograms did not increase during peak COVID-19, and females were less likely to undergo coronary angiogram during all timepoints. Finally, females with chest pain were less likely to be diagnosed with acute myocardial infarction (AMI) during all timepoints, while in-hospital deaths were similar between males and females during all timepoints. Conclusions: During COVID-19, females, especially Asian females, were less likely to present to the ED for chest pain. Non-White patients were less likely to present to the ED compared to White patients prior to and during the pandemic. Disparities in management and outcomes of chest pain encounters remained similar to pre-COVID-19, with females receiving less cardiac workup and AMI diagnoses than males, but in-hospital mortality remaining similar between groups and timepoints.

Marrow Fat-Cortical Bone Relationship in ß-Thalassemia: A Study Using MRI.

BACKGROUND: Growing evidence suggests that marrow adipocytes play an active role in the regulation of bone metabolism and hematopoiesis. However, research on the relationship between bone and fat in the context of hematological diseases, particularly ß-thalassemia, remains limited. PURPOSE: To investigate the relationship between marrow fat and cortical bone thickness in ß-thalassemia and to identify key determinants influencing these variables. STUDY TYPE: Prospective. SUBJECTS: Thirty-five subjects in four subject groups of increasing disease severity: 6 healthy control (25.0 ± 5.3 years, 2 male), 4 ß-thalassemia minor, 13 intermedia, and 12 major (29.1 ± 6.4 years, 15 male). FIELD STRENGTH/SEQUENCE: 3.0 T, 3D fast low angle shot sequence and T1-weighted turbo spin echo. ASSESSMENT: Analyses on proton density fat fraction (PDFF) and R2* values in femur subregions (femoral head, greater trochanter, intertrochanteric, diaphysis, distal) and cortical thickness (CBI) of the subjects' left femur. Clinical data such as age, sex, body mass index (BMI), and disease severity were also included. STATISTICAL TESTS: One-way analysis of variance (ANOVA), mixed ANOVA, Pearson correlation and multiple regression. P-values <0.05 were considered significant. RESULTS: Bone marrow PDFF significantly varied between the femur subregions, F(2.89,89.63) = 44.185 and disease severity, F(1,3) = 12.357. A significant interaction between subject groups and femur subregions on bone marrow PDFF was observed, F(8.67,89.63) = 3.723. Notably, a moderate positive correlation was observed between PDFF and CBI (r = 0.33-0.45). Multiple regression models for both PDFF (R2 = 0.476, F(13,151) = 10.547) and CBI (R2 = 0.477, F(13,151) = 10.580) were significant. Significant predictors for PDFF were disease severity (ßTMi = 0.36, ßTMa = 0.17), CBI (ß = 0.24), R2* (ß = -0.32), and height (ß = -0.29) while for CBI, the significant determinants were sex (ß = -0.27), BMI (ß = 0.55), disease severity (ßTMi = 2.15), and PDFF (ß = 0.25). DATA CONCLUSION: This study revealed a positive correlation between bone marrow fat fraction and cortical bone thickness in ß-thalassemia with varying disease severity, potentially indicating a complex interplay between bone health and marrow composition. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Head rotation and the perception of eyelid height and contour.

PURPOSE: Effective visual perceptual processing is one of the many components of surgical competence. Human face identification is most efficient when viewed upright. However, it is not yet clear how this perception sensitivity impacts eyelid symmetry. This study investigates surgeons' and laypeople's accuracy and efficiency in perceiving eyelid asymmetry from different spatial perspectives. METHODS: A prospective psychometric experiment was conducted where oculoplastic surgeons were recruited from the American Society of Ophthalmic Plastic and Reconstructive Surgery and the Brazilian Oculoplastic Surgery Society, and control participants were recruited via crowdsourcing (Amazon's Mechanical Turk). Standard illustrations of the human face with varying degrees of eyelid abnormality, laterality, gender and rotation were presented to participants who were asked to judge whether the eyelids were symmetric or asymmetric. RESULTS: The survey was completed by 75 oculoplastic surgeons (49.33% male; mean age of 46.9±10.7) and 192 lay individuals (54.6% male; mean age 34.6±11.3 years). Among oculoplastic surgeons, deviation from upright was significantly associated with increased reaction time and decreased proportion correct (OR per 45° for peak 0.68, 95% CI 0.60 to 0.77, p<0.001; OR per 45° for ptosis 0.52, 95% CI 0.32 to 0.87, p=0.012; OR per 180° for aggregate responses 0.56, 95% CI 0.51 to 0.61, p<0.001). Oculoplastic surgeons demonstrated increasing accuracy and decreasing reaction time with additional trials for both peak and ptosis. CONCLUSION: Oculoplastic surgeons perceive eyelid asymmetries more accurately and can better compensate for inverted sensory information. However, accuracy increases and reaction time decreases with additional trials, suggesting trainability and potential for improvement in inversion disability.

Sexist, Racist, and Homophobic Violence against Paramedics in a Single Canadian Site.

Violence against paramedics is widely recognized as a serious, but underreported, problem. While injurious physical attacks on paramedics are generally reported, non-physical violence is less likely to be documented. Verbal abuse can be very distressing, particularly if the harassment targets personal or cultural identities, such as race, ethnicity, gender, or sexual orientation. Leveraging a novel, point-of-event reporting process, our objective was to estimate the prevalence of harassment on identity grounds against paramedics in a single paramedic service in Ontario, Canada, and assess its potentially differential impact on emotional distress. In an analysis of 502 reports filed between 1 February 2021 and 28 February 2022, two paramedic supervisors independently coded the free-text narrative descriptions of violent encounters for themes suggestive of sexism, racism, and homophobia. We achieved high inter-rater agreement across the dimensions (k = 0.73-0.83), and after resolving discrepant cases, we found that one in four violent reports documented abuse on at least one of the identity grounds. In these cases, paramedics were 60% more likely to indicate being emotionally distressed than for other forms of violence. Our findings offer unique insight into the type of vitriol paramedics experience over the course of their work and its potential for psychological harm.

Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.

Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an APOA5 mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.

Utility of Adult-Based Discoid Lateral Meniscus Diagnostic Criteria in a Pediatric Population.

Background: Commonly cited discoid lateral meniscus (DLM) imaging definitions are based on adult magnetic resonance imaging (MRI) measurements. This pathology commonly presents in pediatric populations; however, whether accepted adult measurements reliably apply to children and adolescents is unknown. Purpose/Hypothesis: This purposes of the study were to determine (1) the utility of applying adult-accepted MRI definitions of DLM to pediatric patients, (2) whether sex differences affect the applicability of the criteria, and (3) whether MRI magnet strength and/or tear presence affect MRI measurements for diagnosing DLM in pediatric patients. It was hypothesized that MRI criteria for DLM would be similar in adults and pediatric patients. Study Design: Case series; Level of evidence, 4. Methods: A total of 100 consecutive MRIs from pediatric patients with DLM were evaluated, with 91 scans included. Two study authors independently reviewed the MRIs, evaluating meniscal height and width on sagittal and coronal images, "bow tie signs" on sagittal images, tibial sagittal and coronal width, and tear presence. For analysis, MRI magnet strength was dichotomized into high (>1.5 T) and low (<1.5 T) groups. Results: The mean age of the patients at MRI evaluation was 12.3 ± 3.4 years; 51% of the patients were male, and 56% of the scans were of left knees. Included patients with DLM showed a mean of 3.68 bow tie signs, a sagittal total anterior to posterior meniscal width/tibial width ratio of 73%, a coronal meniscal width/tibial width ratio of 30%, and a coronal, transverse width of the lateral meniscus at the midportion of the meniscal body of 20.6 ± 7.7 mm. The MRI tesla strength of the images included in this study ranged from 0.3 to 3. It was determined that high- versus low-resolution MRI scans did not affect the inter- or intraobserver reliability of the MRI measurments (P > .05). However, several measurements showed improved intraclass correlation coefficients with increased tesla strength. Conclusion: This study confirms that pediatric patients with DLM, diagnosed by board-certified pediatric sports medicine orthopaedic surgeons, have measurements on MRI consistent with adult DLM diagnostic criteria. This finding held true regardless of sex or MRI tesla strength. Pediatric patients with DLM had >3 bow tie signs, >70% sagittal tibial plateau coverage, >14 mm coronal width, and >20% coronal tibial plateau coverage on MRI.

Multilevel perceptions of the virtual delivery of the University of California Diabetes Prevention Program on RE-AIM domains due to COVID-19 mandates.

Background: The University of California's Diabetes Prevention Program (UC DPP) Initiative was implemented across all 10 UC campuses in 2018. The COVID-19 pandemic and accompanying mandates required swift changes to program delivery, including pivoting from in-person to virtual delivery (i.e., Zoom). Our goal was to assess multilevel constituent perceptions of the use of a virtual platform to deliver UC DPP due to COVID-19 mandates. Methods: We conducted qualitative interviews with 68 UC DPP participants, coordinators, and leaders to examine the use of virtual platform delivery on the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) of UC DPP. Transcripts were analyzed using rapid qualitative analysis and emergent themes were categorized using domains corresponding to RE-AIM framework. Results: Among UC DPP participants (n = 42), virtual delivery primarily impacted perceptions of UC DPP effectiveness and implementation. Some participants perceived program effectiveness to be negatively impacted, given their preference for in-person sessions, which they felt provided more engagement, peer support, and accountability. Implementation challenges included problems with virtual format (e.g., "Zoom fatigue"); however, several benefits were also noted (e.g., increased flexibility, maintenance of DPP connections during campus closures). UC DPP coordinators (n = 18) perceived virtual delivery as positively impacting UC DPP reach, since virtual platforms provided access for some who could not participate in-person, and negatively impacting effectiveness due to reduced engagement and lower peer support. UC leaders (n = 8) perceived that use of the virtual format had a positive impact on reach (e.g., increased availability, accessibility) and negatively impacted effectiveness (e.g., less intensive interactions on a virtual platform). Across constituent levels, the use of a virtual platform had little to no impact on perceptions of adoption and maintenance of UC DPP. Conclusion: Perceptions of the reach, effectiveness, and implementation of UC DPP using a virtual platform varied across constituents, although all groups noted a potential negative impact on overall program effectiveness. Unanticipated program adaptations, including virtual delivery, present potential benefits as well as perceived drawbacks, primarily across the effectiveness domain. Understanding differential constituent perceptions of the impact of virtual delivery can help maximize RE-AIM and inform future UC DPP delivery strategies.

The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Mitoquinone mesylate as post-exposure prophylaxis against SARS-CoV-2 infection in humans: an exploratory single center pragmatic open label non-randomized pilot clinical trial with matched controls.

BACKGROUND: An ongoing important need exists to rapidly develop novel therapeutics for COVID-19 that will retain antiviral efficacy in the setting of rapidly evolving SARS-CoV-2 variants and potential future development of resistance of SARS-COV-2 to remdesivir and protease inhibitors. To date, there is no FDA-approved treatment for post-exposure prophylaxis against SAR-CoV-2. We have shown that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has antiviral activity against SARS-CoV-2 in vitro and in SARS-CoV-2 infected K18-hACE2 mice. METHODS: In this exploratory, pragmatic open label clinical trial (ClinicalTrials.gov identifier NCT05381454), we studied whether Mito-MES is an effective post-exposure prophylaxis treatment in people who had high-grade unmasked exposures to SARS-CoV-2 within 5 days prior to study entry. Participants were enrolled in real-world setting in Los Angeles, United States between May 1 and December 1, 2022 and were assigned to either mito-MES 20 mg daily for 14 days (n = 40) or no mito-MES (controls) (n = 40). The primary endpoint was development of SARS-CoV-2 infection based on 4 COVID-19 diagnostic tests [rapid antigen tests (RATs) or PCR] performed during the study period (14 days post exposure). FINDINGS: Out of 40 (23 females; 57.5%) study participants who took Mito-MES, 12 (30%) developed SARS-CoV-2 infection compared to 30 of the 40 controls (75%) (difference -45.0%, 95% confidence intervals (CI): -64.5%, -25.5%). Out of 40 (19 females; 47.5%) study participants in the control group, 30 (75.0%) had at least one positive COVID-19 diagnostic test and 23 (57.5%) were symptomatic. With regards to key secondary outcomes, among symptomatic SARS-CoV-2 infections, the median duration of viral symptoms was lower in the Mito-MES group (median 3.0, 95% CI 2.75, 3.25) compared to the control group (median 5.0, 95% CI 4.0, 7.0). None of the study participants was hospitalized or required oxygen therapy. Mito-MES was well tolerated and no serious side effect was reported in any study participant. INTERPRETATION: This work describes antiviral activity of mito-MES in humans. Mito-MES was well tolerated in our study population and attenuated transmission of SARS-CoV-2 infection. Given established safety of Mito-MES in humans, our results suggest that randomized control clinical trials of Mito-MES as post-exposure prophylaxis against SARS-CoV-2 infection are warranted. FUNDING: This work was supported in part by National Institutes of Health grant R01AG059501 (TK), National Institutes of Health grant R01AG059502 04S1 (TK), NIH/National Center for Advancing Translational Sciences (NCATS) UCLA CTSI Grant Number UL1TR001881 and California HIV/AIDS Research Program grant OS17-LA-002 (TK).

Assessing molecular doping efficiency in organic semiconductors with reactive Monte Carlo.

The addition of molecular dopants into organic semiconductors (OSCs) is a ubiquitous augmentation strategy to enhance the electrical conductivity of OSCs. Although the importance of optimizing OSC-dopant interactions is well-recognized, chemically generalizable structure-function relationships are difficult to extract due to the sensitivity and dependence of doping efficiency on chemistry, processing conditions, and morphology. Computational modeling for an integrated OSC-dopant design is an attractive approach to systematically isolate fundamental relationships, but requires the challenging simultaneous treatment of molecular reactivity and morphology evolution. We present the first computational study to couple molecular reactivity with morphology evolution in a molecularly doped OSC. Reactive Monte Carlo is employed to examine the evolution of OSC-dopant morphologies and doping efficiency with respect to dielectric, the thermodynamic driving for the doping reaction, and dopant aggregation. We observe that for well-mixed systems with experimentally relevant dielectric constants, doping efficiency is near unity with a very weak dependence on the ionization potential and electron affinity of OSC and dopant, respectively. At experimental dielectric constants, reaction-induced aggregation is observed, corresponding to the well-known insolubility of solution-doped materials. Simulations are qualitatively consistent with a number of experimental studies showing a decrease of doping efficiency with increasing dopant concentration. Finally, we observe that the aggregation of dopants lowers doping efficiency and thus presents a rational design strategy for maximizing doping efficiency in molecularly doped OSCs. This work represents an important first step toward the systematic integration of molecular reactivity and morphology evolution into the characterization of multi-scale structure-function relationships in molecularly doped OSCs.

Validation of Distinct Bladder Pain Phenotypes Utilizing the MAPP Research Network Cohort.

INTRODUCTION AND HYPOTHESIS: As interstitial cystitis/bladder pain syndrome (IC/BPS) likely represents multiple pathophysiologies, we sought to validate three clinical phenotypes of IC/BPS patients in a large, multi-center cohort using unsupervised machine learning (ML) analysis. METHODS: Using the female Genitourinary Pain Index and O'Leary-Sant Indices, k-means unsupervised clustering was utilized to define symptomatic phenotypes in 130 premenopausal IC/BPS participants recruited through the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network. Patient-reported symptoms were directly compared between MAPP ML-derived phenotypic clusters to previously defined phenotypes from a single center (SC) cohort. RESULTS: Unsupervised ML categorized IC/BPS participants into three phenotypes with distinct pain and urinary symptom patterns: myofascial pain, non-urologic pelvic pain, and bladder-specific pain. Defining characteristics included presence of myofascial pain or trigger points on examination for myofascial pain patients (p = 0.003) and bladder pain/burning for bladder-specific pain patients (p < 0.001). The three phenotypes were derived using only 11 features (fGUPI subscales and ICSI/ICPI items), in contrast to 49 items required previously. Despite substantial reduction in classification features, unsupervised ML independently generated similar symptomatic clusters in the MAPP cohort with equivalent symptomatic patterns and physical examination findings as the SC cohort. CONCLUSIONS: The reproducible identification of IC/BPS phenotypes, distinguishing bladder-specific pain from myofascial and genital pain, using independent ML analysis of a multicenter database suggests these phenotypes reflect true pathophysiologic differences in IC/BPS patients.

Health and Well-Being at the Transition to Adulthood Among Individuals With Disabilities: An Analysis of the Panel Study of Income Dynamics.

PURPOSE: To describe positive mental health, or "flourishing," and self-reported health trajectories among transition-aged young adults (TAYA) with developmental/learning and physical disabilities over a 12-year period, utilizing a population-based sample. METHODS: This study features a secondary analysis of national data from the Panel Study of Income Dynamics Transition to Adulthood Supplement. The analytic sample included all TAYA with (n = 487) and without (n = 810) disabilities, including developmental/learning disabilities (DD/LD), attention deficit hyperactivity disorder (ADHD), and speech, hearing, and vision impairments who participated in 2017 Transition to Adulthood Supplement data collection (n = 1,297; M age = 24.5, standard deviation = 2.40). We utilized linear mixed modeling to retrospectively describe flourishing and self-reported health trajectories across 12 years among TAYA with and without disabilities between ages 18 to 28, adjusting for demographic and developmental characteristics. RESULTS: Relative to TAYA without disabilities, TAYA with speech [0.10, 0.85] and vision impairments [0.10, 0.92], DD/LD [0.38, 1.11], and ADHD [0.27, 0.97] demonstrated lower flourishing. TAYA with speech [0.07, 0.36] and vision impairments [0.08, 0.38], DD/LD [0.15, 0.411], and ADHD [0.14, 0.93] reported lower health. Relative to TAYA with other disabilities, TAYA with ADHD [0.14, 0.93] and DD/LD [0.01, 0.29] reported lower flourishing and health, respectively. Interaction effects and descriptive analyses revealed distinct patterns of change for TAYA with ADHD. DISCUSSION: TAYA with disabilities report lower flourishing and health, relative to TAYA without disabilities. TAYA with specific disabilities differ in their flourishing and health trajectories. Findings can inform the development of interventions for TAYA with disabilities.

Changes in surgical mortality during COVID-19 pandemic by patients' race, ethnicity and socioeconomic status among US older adults: a quasi-experimental event study model.

OBJECTIVES: To examine changes in the 30-day surgical mortality rate after common surgical procedures during the COVID-19 pandemic and investigate whether its impact varies by urgency of surgery or patient race, ethnicity and socioeconomic status. DESIGN: We used a quasi-experimental event study design to examine the effect of the COVID-19 pandemic on surgical mortality rate, using patients who received the same procedure in the prepandemic years (2016-2019) as the control, adjusting for patient characteristics and hospital fixed effects (effectively comparing patients treated at the same hospital). We conducted stratified analyses by procedure urgency, patient race, ethnicity and socioeconomic status (dual-Medicaid status and median household income). SETTING: Acute care hospitals in the USA. PARTICIPANTS: Medicare fee-for-service beneficiaries aged 65-99 years who underwent one of 14 common surgical procedures from 1 January 2016 to 31 December 2020. MAIN OUTCOME MEASURES: 30-day postoperative mortality rate. RESULTS: Our sample included 3 620 689 patients. Surgical mortality was higher during the pandemic, with peak mortality observed in April 2020 (adjusted risk difference (aRD) +0.95 percentage points (pp); 95% CI +0.76 to +1.26 pp; p<0.001) and mortality remained elevated through 2020. The effect of the pandemic on mortality was larger for non-elective (vs elective) procedures (April 2020: aRD +0.44 pp (+0.16 to +0.72 pp); p=0.002 for elective; aRD +1.65 pp (+1.00, +2.30 pp); p<0.001 for non-elective). We found no evidence that the pandemic mortality varied by patients' race and ethnicity (p for interaction=0.29), or socioeconomic status (p for interaction=0.49). CONCLUSIONS: 30-day surgical mortality during the COVID-19 pandemic peaked in April 2020 and remained elevated until the end of the year. The influence of the pandemic on surgical mortality did not vary by patient race and ethnicity or socioeconomic status, indicating that once patients were able to access care and undergo surgery, surgical mortality was similar across groups.

Intra-Abdominal Hemorrhage Triggering Inappropriate Therapy From a Subcutaneous Defibrillator.

The SMART Pass filter (Boston Scientific) aims to reduce inappropriate shocks (IASs) from subcutaneous implantable cardioverter-defibrillators by filtering out low-frequency signals such as T waves. However, this filter is deactivated in the presence of diminished R-wave sensing. We describe a case of IAS in the setting of extensive intra-abdominal hemorrhage.

Distilling coarse-grained representations of molecular electronic structure with continuously gated message passing.

Bottom-up methods for coarse-grained (CG) molecular modeling are critically needed to establish rigorous links between atomistic reference data and reduced molecular representations. For a target molecule, the ideal reduced CG representation is a function of both the conformational ensemble of the system and the target physical observable(s) to be reproduced at the CG resolution. However, there is an absence of algorithms for selecting CG representations of molecules from which complex properties, including molecular electronic structure, can be accurately modeled. We introduce continuously gated message passing (CGMP), a graph neural network (GNN) method for atomically decomposing molecular electronic structure sampled over conformational ensembles. CGMP integrates 3D-invariant GNNs and a novel gated message passing system to continuously reduce the atomic degrees of freedom accessible for electronic predictions, resulting in a one-shot importance ranking of atoms contributing to a target molecular property. Moreover, CGMP provides the first approach by which to quantify the degeneracy of "good" CG representations conditioned on specific prediction targets, facilitating the development of more transferable CG representations. We further show how CGMP can be used to highlight multiatom correlations, illuminating a path to developing CG electronic Hamiltonians in terms of interpretable collective variables for arbitrarily complex molecules.