Trends in Bundled Outpatient Behavioral Health Services in VA-Direct Versus VA-Purchased Care.

The Veterans Health Administration (VA) increasingly purchases community-based care (CC) to improve healthcare access, including behavioral health. In 2018, VA introduced standardized episodes of care (SEOCs) to guide authorization and purchase of CC services for specific indications in a defined timeframe without bundling payment. In this retrospective cross-sectional study, we describe trends in VA and CC behavioral healthcare utilization using the VA Outpatient Psychiatry SEOC definition. Counts of Outpatient Psychiatry SEOC-allowable service and procedure codes during fiscal years 2016-2019 were organized according to four SEOC-defined service types (evaluation and management, laboratory services, psychiatry services, transitional care) and measured as percentages of all included codes. Trends comparing behavioral healthcare utilization between Veterans using any CC versus VA only were analyzed using a linear mixed effects model. We identified nearly 3 million Veterans who registered 60 million qualifying service and procedure codes, with overall utilization increasing 77.8% in CC versus 5.2% in VA. Veterans receiving any CC comprised 3.9% of the cohort and 4.7% of all utilization. When examining service type as a percent of all Outpatient Psychiatry SEOC-allowable care among Veterans using CC, psychiatry services increased 12.2%, while transitional care decreased 8.8%. In regression analysis, shifts in service type utilization reflected descriptive results but with attenuated effect sizes. In sum, Outpatient Psychiatry SEOC-allowable service utilization grew, and service type composition changed, significantly more in CC than in VA. The role of SEOCs and their incentives may be important when evaluating future behavioral healthcare quality and value in bundled services.

Neurosteroid [3α,5α]3-hydroxypregnan-20-one inhibition of chemokine monocyte chemoattractant protein-1 in alcohol-preferring rat brain neurons, microglia, and astroglia.

BACKGROUND: Neuroimmune dysfunction in alcohol use disorder (AUD) is associated with activation of myeloid differentiation primary response 88 (MyD88)-dependent Toll-like receptors (TLR) resulting in overexpression of the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). MCP-1 overexpression in the brain is linked to anxiety, higher alcohol intake, neuronal death, and activation of microglia observed in AUD. The neurosteroid [3α,5α][3-hydroxypregnan-20-one (3α,5α-THP) has been reported as an inhibitor of MyD88-dependent TLR activation and MCP-1 overexpression in mouse and human macrophages and the brain of alcohol-preferring (P) rats. METHODS: We investigated how 3α,5α-THP regulates MCP-1 expression at the cellular level in P rat nucleus accumbens (NAc) and central amygdala (CeA). We focused on neurons, microglia, and astrocytes, examining the individual voxel density of MCP-1, neuronal marker NeuN, microglial marker IBA1, astrocytic marker GFAP, and their shared voxel density, defined as intersection. Ethanol-naïve male and female P rats were perfused 1 h after IP injections of 15 mg/kg of 3α,5α-THP, or vehicle. The NAc and CeA were imaged using confocal microscopy following double-immunofluorescence staining for MCP-1 with NeuN, IBA1, and GFAP, respectively. RESULTS: MCP-1 intersected with NeuN predominantly and IBA1/GFAP negligibly. 3α,5α-THP reduced MCP-1 expression in NeuN-labeled cells by 38.27 ± 28.09% in male and 56.11 ± 21.46% in female NAc, also 37.99 ± 19.53% in male and 54.96 ± 30.58% in female CeA. In females, 3α,5α-THP reduced the MCP-1 within IBA1 and GFAP-labeled voxels in the NAc and CeA. Conversely, in males, 3α,5α-THP did not significantly alter the MCP-1 within IBA1 in NAc or with GFAP in the CeA. Furthermore, 3α,5α-THP decreased levels of IBA1 in both regions and sexes with no impact on GFAP or NeuN levels. Secondary analysis performed on data normalized to % control values indicated that no significant sex differences were present. CONCLUSIONS: These data suggest that 3α,5α-THP inhibits neuronal MCP-1 expression and decreases the proliferation of microglia in P rats. These results increase our understanding of potential mechanisms for 3α,5α-THP modulation of ethanol consumption.

Age-dependent changes in skin features and perceived facial appearance in women of five ethnic groups.

OBJECTIVE: Research documents effects of skin features on assessments of age, health and attractiveness of female faces. Ethnic variation also has been reported for the impact of age-related changes in skin features on face assessments. Here, we investigate women's self-ratings across age cohorts and ethnic groups and discrepancies with (non-expert) assessor ratings of facial appearance together with age-dependent changes in skin features. METHODS: Faces of women 20-65 years from five ethnic groups (each n = 36) were imaged. Participants provided self-ratings of age, health and attractiveness, and were judged on these attributes by members of the same ethnic group (each n = 120). Digital image analysis was used to quantify skin gloss, tone evenness, wrinkling and sagging. Age-dependent changes in ratings and skin features within and between ethnic groups were assessed by comparing information from 10-year cohorts. We also tested whether menopausal status could be predicted by self-ratings, assessor ratings and image-based skin features. RESULTS: Women of all ethnic groups judged themselves younger and higher in attractiveness and health compared to third-party assessors, with the largest discrepancies for age in French women and for attractiveness and health in South African women. In Indian and South African women, specular gloss and skin tone evenness were lower compared to other participants, and sagging was higher in Indian, Japanese and South African women compared to Chinese and French women. Women's menopausal status could be predicted from assessor ratings and image-based skin features but not from self-ratings. CONCLUSION: There are differences between women's self-ratings and assessor ratings of facial appearance. These discrepancies vary with female age and ethnicity. Age and ethnicity effects also are evident in age-dependent changes in skin features within and across ethnic groups, which together with assessor (but not self-) ratings of facial appearance predict menopausal status.

OBJECTIF: l'étude documente les effets des caractéristiques de la peau sur les évaluations de l'âge, de la santé et de l'attractivité des visages féminins. Des variations ethniques ont également été rapportées en ce qui concerne l'impact des changements liés à l'âge dans les caractéristiques de la peau sur les évaluations du visage. Ici, nous étudions les auto­évaluations des femmes à travers les cohortes d'âge et les groupes ethniques et les divergences avec les évaluations (non expertes) de l'apparence du visage ainsi que les changements des caractéristiques de la peau dépendant de l'âge. MÉTHODES: les visages des femmes âgées de 20 à 65 ans issues de cinq groupes ethniques (chacun n = 36) ont été examinés par imagerie. Les participantes ont fourni des auto­évaluations de leur âge, de leur santé et de leur attractivité, et ont été jugées sur ces attributs par les membres du même groupe ethnique (chacun n = 120). L'analyse d'images numériques a été utilisée pour quantifier la luminosité de la peau, l'uniformité du teint, les rides et le relâchement cutané. Les changements dépendants de l'âge dans les évaluations et les caractéristiques de la peau au sein et entre les groupes ethniques ont été évalués en comparant les informations provenant de cohortes sur 10 ans. Nous avons également évalué si le statut ménopausique pouvait être prédit par les auto­évaluations, les évaluations de l'évaluateur et les caractéristiques de la peau basées sur l'imagerie. RÉSULTATS: les femmes de tous les groupes ethniques se sont jugées plus jeunes et plus performantes en termes d'attractivité et de santé par rapport aux évaluateurs tiers, les plus grandes discordances concernant l'âge chez les femmes françaises et l'attractivité et la santé chez les femmes sud­africaines. Chez les femmes indiennes et sud­africaines, la luminosité spéculaire et l'uniformité du teint de la peau étaient inférieures à celles des autres participantes, et le relâchement cutané était plus élevé chez les femmes indiennes, japonaises et sud­africaines que chez les femmes chinoises et françaises. Le statut ménopausique des femmes pouvait être prédit à partir des évaluations de l'évaluateur et des caractéristiques cutanées basées sur l'imagerie, mais pas à partir des auto­évaluations. CONCLUSION: il existe des différences entre les auto­évaluations des femmes et les évaluations de l'apparence faciale par l'évaluateur. Ces divergences varient en fonction de l'âge et de l'origine ethnique des femmes. Les effets sur l'âge et l'origine ethnique sont également évidents dans les changements dépendants de l'âge des caractéristiques de la peau au sein et entre les groupes ethniques, qui, avec les évaluations de l'évaluateur (mais pas de l'auto­évaluation) de l'apparence du visage, prédisent le statut ménopausique.

Interneuron-Selective HCN Channel Knockdown in Prelimbic Cortex of Female Rats Mimics Effects of Chronic Ethanol Exposure.

Our laboratory has previously shown that chronic ethanol exposure elicits enhanced working memory performance in female, but not male, adult Sprague-Dawley rats, indicative of a fundamental sex difference in cortical plasticity. Recent studies have furthermore revealed that females display markedly reduced HCN-mediated channel activity in inhibitory Martinotti interneurons after chronic ethanol exposure that is similarly not observed in males. From these observations we hypothesized that alcohol elicits facilitated working memory performance via down-regulation of these channels' activity specifically within interneurons. To test this hypothesis, we employed a Pol-II compatible shRNA expression system to elicit targeted knockdown of HCN channel activity in these cells, and measured performance on a delayed Non-Match-to-Sample (NMS) T-maze test to gauge effects on working memory performance. A significant baseline enhancement of working memory performance with HCN channel knockdown was observed, indicative of a critical role for interneuron-expressed HCNs in maintaining optimal cortical network activity during cognitively-demanding tasks. Consistent with previous observations, ethanol exposure resulted in enhanced NMS T-maze performance, however elevated working memory performance was observed in both scram- and hcn-shRNA infected groups after alcohol administration. We therefore conclude that interneuron-expressed HCN channels, despite representing a minor population of total cortical HCN expression, contribute substantially to maintaining working memory processes. Downregulated HCN channel activity, though, does not alone appear sufficient to manifest alcohol-induced enhancement of working memory performance observed in female rats during acute withdrawal.

Neurosteroid [3α,5α]-3-Hydroxy-pregnan-20-one Enhances the CX3CL1-CX3CR1 Pathway in the Brain of Alcohol-Preferring Rats with Sex-Specificity.

This study investigates the impact of allopregnanolone ([3α,5α]3-hydroxypregnan-20-one or 3α,5α-tetrahydroprogesterone (3α,5α-THP); 10 mg/kg, IP) on fractalkine/CX3-C motif chemokine ligand 1 (CX3CL1) levels, associated signaling components, and markers for microglial and astrocytic cells in the nucleus accumbens (NAc) of male and female alcohol-preferring (P) rats. Previous research suggested that 3α,5α-THP enhances anti-inflammatory interleukin-10 (IL-10) cytokine production in the brains of male P rats, with no similar effect observed in females. This study reveals that 3α,5α-THP elevates CX3CL1 levels by 16% in the NAc of female P rats, with no significant changes observed in males. The increase in CX3CL1 levels induced by 3α,5α-THP was observed in females across multiple brain regions, including the NAc, amygdala, hypothalamus, and midbrain, while no significant effect was noted in males. Additionally, female P rats treated with 3α,5α-THP exhibited notable increases in CX3CL1 receptor (CX3CR1; 48%) and transforming growth factor-beta 1 (TGF-ß1; 24%) levels, along with heightened activation (phosphorylation) of signal transducer and activator of transcription 1 (STAT1; 85%) in the NAc. Conversely, no similar alterations were observed in male P rats. Furthermore, 3α,5α-THP decreased glial fibrillary acidic protein (GFAP) levels by 19% in both female and male P rat NAc, without affecting microglial markers ionized calcium-binding adaptor molecule 1 (IBA1) and transmembrane protein 119 (TMEM119). These findings indicate that 3α,5α-THP enhances the CX3CL1/CX3CR1 pathway in the female P rat brain but not in males, primarily influencing astrocyte reactivity, with no observed effect on microglial activation.

Minimally Invasive Mitral Valve Surgery Using a Cold Fibrillatory Cardiac Arrest Technique in Patients With Prior Cardiac Surgery.

OBJECTIVE: Minimally invasive mitral valve surgery (mini-MVS) is typically reserved for patients who have not undergone open cardiac surgery. In the reoperative setting, using intrapericardial dissection for crossclamping the aorta through a minimally invasive approach can be difficult and, at times, risky. Cold fibrillatory cardiac arrest (CFCA) with systemic cardiopulmonary bypass without cross-clamping is a well-described technique; however, data about its safety for patients who undergo reoperative mini-MVS are limited. METHODS: Data for 34 patients who underwent reoperative mini-MVS with CFCA from March 2017 to March 2022 were reviewed retrospectively. A mini right thoracotomy (n = 30) or robotic (n = 4) approach was used. Systemic hypothermia was induced to a target temperature of 25 °C. RESULTS: Patient mean (SD) age was 64.5 (9.6) years, and 15 of 34 (44.1%) patients were women. Of those 34 patients, 23 (67.6%) had severe regurgitation, and 11 (32.4%) had severe stenosis. Before mini-MVS, 28 patients had undergone valve surgery, and 8 had undergone coronary artery bypass graft surgery. The mitral valve was repaired in 5 of 34 (14.7%) and replaced in 29 of 34 (85.3%) patients. No difference was observed in preoperative and postoperative left ventricular function (P = .82). In 1 patient, kidney failure developed that necessitated dialysis. No postoperative stroke or mortality at 30 days occurred. CONCLUSION: Mini-MVS with CFCA is well tolerated in patients with prior cardiac surgery. Myocardial function was not impaired, nor was the risk of stroke increased in this cohort, indicating that CFCA is a safe alternative in this high-risk population.

Activation of a GPCR, ORL1 receptor: A novel therapy to prevent heart failure progression.

Purpose: The number of ischemic heart failure (HF) patients is growing dramatically worldwide. However, there are at present no preventive treatments for HF. Our previous study showed that Gata4 overexpression improved cardiac function after myocardial infarction in the rat heart. We also found that Gata4 overexpression significantly increased a Pnoc gene expression, an endogenous ligand for cell membrane receptor, ORL1. We hypothesized that an activation of ORL1 receptor would suppress HF in a rat ischemic heart model. Method: Adult Sprague Dawley rats (8 weeks old, 6 males and 6 females) underwent left anterior descending coronary artery ligation. Three weeks later, normal saline or MCOPPB (ORL1 activator, 2.5mg/kg/day) intraperitoneal injection was started, and continued 5 days a week, for 3 months. Echocardiography was performed six times, pre-operative, 3 days after coronary artery ligation, pre-MCOPPB or saline injection, and 1, 2, and 3 months after saline or MCOPPB injection started. Animals were euthanized after 3 months follow up and the heart was harvested for histological analysis. Results: ORL1 activator, MCOPPB, significantly improved cardiac function after myocardial infarction in rat (Ejection fraction, MCOPPB vs saline at euthanasia, 67 ± 3 vs 43 ± 2, p < 0.001). MCOPPB also decreased fibrosis and induced angiogenesis. Conclusion: ORL1 activator, MCOPPB, may be a novel treatment for preventing HF progression.

Safety of Early Discharge After Coronary Artery Bypass Grafting: A Nationwide Readmissions Analysis.

BACKGROUND: We determined the safety of early discharge after coronary artery bypass grafting (CABG) in patients with uncomplicated postoperative courses and compared outcomes with routine discharge in a national cohort. We identified preoperative factors associated with readmission after early discharge after CABG. METHODS: The Nationwide Readmissions Database was queried to identify patients undergoing CABG from January 2016 to December 2018. Patients were stratified based on length of stay (LOS) as early (≤4 days) vs routine (5-10 days) discharge. Patients were excluded with hospital courses indicative of complicated stays (emergent procedures, LOS >10 days, discharge to extended care facility or with home health, index hospitalization mortality). Propensity score matching was performed to compare outcomes between cohorts. Multivariable logistic regression models were used to identify factors associated with readmission after early discharge. RESULTS: During the study period, 91,861 patients underwent CABG with an uncomplicated postoperative course (∼20% of CABG population). Of these, 31% (28,790 of 91,861) were discharged early, and 69% (63,071 of 91,861) were routinely discharged. After propensity score matching, patients discharged early had lower readmission rates at 30 days, 90 days, and up to 1 year (P < .001 for all). The index hospitalization cost was lower with early discharge ($26,676 vs $32,859; P < .001). Early discharge was associated with a lower incidence of nosocomial infection at the index hospitalization (0.17% vs 0.81%, P < .001) and readmission from infection (14.5% vs 18%, P = .016). CONCLUSIONS: Early discharge after uncomplicated CABG can be considered in a highly selective patient population. Early-discharge patients are readmitted less frequently than matched routine-discharge patients, with a lower incidence of readmission from infection. Appropriate postdischarge processes to facilitate early discharge after CABG should be further pursued.

Synergistic Photoenzymatic Catalysis Enables Synthesis of a-Tertiary Amino Acids Using Threonine Aldolases.

a-Tertiary amino acids are essential components of drugs and agrochemicals, yet traditional syntheses are step-intensive and provide access to a limited range of structures with varying levels of enantioselectivity. Here, we report the α-alkylation of unprotected alanine and glycine by pyridinium salts using pyridoxal (PLP)-dependent threonine aldolases with a Rose Bengal photoredox catalyst. The strategy efficiently prepares various a-tertiary amino acids in a single chemical step as a single enantiomer. UV-vis spectroscopy studies reveal a ternary interaction between the pyridinium salt, protein, and photocatalyst, which we hypothesize is responsible for localizing radical formation to the active site. This method highlights the opportunity for combining photoredox catalysts with enzymes to reveal new catalytic functions for known enzymes.

Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Psychological distress, wellbeing and resilience: modelling adolescent mental health profiles during the COVID-19 pandemic.

There has been concern about adolescent mental health during the pandemic. The current study examined adolescent mental health during the initial phase of the COVID-19 pandemic in the UK. Using indicator of psychological distress, wellbeing and resilience, latent profile analysis was used to identify homogeneous mental health groups among young people aged 13-24 (N = 1971). Multinomial logistic regression was then used to examine which sociodemographic and psychosocial variables predicted latent class membership. Four classes were found. The largest class (Class 1, 37.2%) was characterised by moderate symptomology and moderate wellbeing. Class 2 (34.2%) was characterised by low symptomology and high wellbeing, while Class 3 (25.4%) was characterised by moderate symptomology and high wellbeing. Finally, Class 4 was the smallest (3.2%) and was characterised by high symptomology and low wellbeing. Compared to the low symptomology, high wellbeing class, all other classes were associated with less social engagement with friends, poorer family functioning, greater somatic symptoms, and a less positive model of self. A number of unique associations between the classes and predictor variables were identified. Although around two-thirds of adolescents reported moderate-to-high symptomology, most of these individuals also reported concurrent moderate-to-high levels of wellbeing, reflecting resilience. Furthermore, these findings demonstrate how a more comprehensive picture of mental health can be gained through adopting a dual-continua conceptualisation of mental health that incorporates both pathology and well-being. In this way, at-risk youth can be identified and interventions and resources targeted appropriately.

Associations between 2D:4D from direct and radiographic measurements with handgrip strength in young adult Tuvans.

BACKGROUND: Digit ratio (2D:4D) - the relative lengths of the index and ring finger - is sexually dimorphic (male < female), possibly because of the sex-differentiated impact of prenatal androgenization on fetal development in the 1st trimester. The sex difference remains stable with age and has been reported in children, adolescents, and adults from industrialized and non-industrialized societies. Handgrip strength (HGS) also is sexually dimorphic (males > females) and correlates negatively with 2D:4D. AIMS: To examine in a sample of young adult Tuvans from Siberia (Russian Federation): i) the association between 2D:4D measured directly from the palms with 2D:4D measured from radiographic images of the same individuals and ii) the associations between 2D:4D and HGS in Tuvan men and women. STUDY DESIGN AND SUBJECTS: The study was cross-sectional. Participants were Tuvans (n = 185; 80 men; mean age = 21.02 years). 2D:4D was measured with a caliper from the ventral surface of the palm (both hands) and from radiographic images (left hand). HGS of both hands was measured with a digital hand dynamometer. Body height and weight were measured with an anthropometer and a body composition scale. RESULTS: 2D:4D ratios and anthropometric measures (including HGS) were sexually dimorphic. Men had lower 2D:4D and higher HGS than women. Direct measures of 2D:4D correlated positively with 2D:4D measured from radiographs. Body mass index (BMI) was a significant predictor of HGS for both sexes. Male right 2D:4D and female right and left 2D:4D correlated negatively with HGS after controlling for the influence of BMI. There were no associations with radiographic measurements of 2D:4D. CONCLUSION: Our findings provide evidence of sexual dimorphism in 2D:4D among young adult Tuvans. Together with previous research on Tuvan children and adolescents, these findings provide clear evidence of 2D:4D sexual dimorphism in pre- and postpubertal Tuvans. The small negative association between 2D:4D and HGS corresponds to similar reports across populations, suggesting that 2D:4D is a weak correlate of muscular fitness.

From Ground-State to Excited-State Activation Modes: Flavin-Dependent "Ene"-Reductases Catalyzed Non-natural Radical Reactions.

Enzymes are desired catalysts for chemical synthesis, because they can be engineered to provide unparalleled levels of efficiency and selectivity. Yet, despite the astonishing array of reactions catalyzed by natural enzymes, many reactivity patterns found in small molecule catalysts have no counterpart in the living world. With a detailed understanding of the mechanisms utilized by small molecule catalysts, we can identify existing enzymes with the potential to catalyze reactions that are currently unknown in nature. Over the past eight years, our group has demonstrated that flavin-dependent "ene"-reductases (EREDs) can catalyze various radical-mediated reactions with unparalleled levels of selectivity, solving long-standing challenges in asymmetric synthesis.This Account presents our development of EREDs as general catalysts for asymmetric radical reactions. While we have developed multiple mechanisms for generating radicals within protein active sites, this account will focus on examples where flavin mononucleotide hydroquinone (FMNhq) serves as an electron transfer radical initiator. While our initial mechanistic hypotheses were rooted in electron-transfer-based radical initiation mechanisms commonly used by synthetic organic chemists, we ultimately uncovered emergent mechanisms of radical initiation that are unique to the protein active site. We will begin by covering intramolecular reactions and discussing how the protein activates the substrate for reduction by altering the redox-potential of alkyl halides and templating the charge transfer complex between the substrate and flavin-cofactor. Protein engineering has been used to modify the fundamental photophysics of these reactions, highlighting the opportunity to tune these systems further by using directed evolution. This section highlights the range of coupling partners and radical termination mechanisms available to intramolecular reactions.The next section will focus on intermolecular reactions and the role of enzyme-templated ternary charge transfer complexes among the cofactor, alkyl halide, and coupling partner in gating electron transfer to ensure that it only occurs when both substrates are bound within the protein active site. We will highlight the synthetic applications available to this activation mode, including olefin hydroalkylation, carbohydroxylation, arene functionalization, and nitronate alkylation. This section also discusses how the protein can favor mechanistic steps that are elusive in solution for the asymmetric reductive coupling of alkyl halides and nitroalkanes. We are aware of several recent EREDs-catalyzed photoenzymatic transformations from other groups. We will discuss results from these papers in the context of understanding the nuances of radical initiation with various substrates.These biocatalytic asymmetric radical reactions often complement the state-of-the-art small-molecule-catalyzed reactions, making EREDs a valuable addition to a chemist's synthetic toolbox. Moreover, the underlying principles studied with these systems are potentially operative with other cofactor-dependent proteins, opening the door to different types of enzyme-catalyzed radical reactions. We anticipate that this Account will serve as a guide and inspire broad interest in repurposing existing enzymes to access new transformations.

Fidelity in Academic Global Surgery and Research: Incorporating Trustworthiness in the Development of Research Partnerships, Infrastructure, and Policy.

Academic global surgery consists of collaborative partnerships that address surgical inequities through research, training, education, advocacy, and diplomacy. It has been characterized by increased scholastic production through global surgery publications, dedicated global surgery sessions within scientific conferences, global surgery-specific research grants, database development to support global surgery research, global surgery research fellowships, and global surgery-based academic promotion paradigms. The increased emphasis on global surgery research has been accompanied by multiple ethical challenges. This article reviews critical ethical dilemmas presented by global surgery research efforts and proposes interventions on the partnership, infrastructural, and policy levels to enhance fidelity within research partnerships.

cis,cis,cis-Di-chlorido-bis-(N4,N4-di-methyl-pyridin-4-amine-κN1)bis-(dimethyl sulfoxide-κS)ruthenium(II).

The structure of the title compound, [RuCl2(C7H10N2)2(C2H6OS)2], has monoclinic (P21/n) symmetry. The Ru-N distances of the coordination compound are influenced by the trans chloride or di-methyl-sulfoxide-κS ligands. The mol-ecular structure exhibits disorder for two of the terminal methyl groups of a dimethyl sulfoxide ligand.

Asymmetric Synthesis of α-Chloroamides via Photoenzymatic Hydroalkylation of Olefins.

Photoenzymatic intermolecular hydroalkylations of olefins are highly enantioselective for chiral centers formed during radical termination but poorly selective for centers set in the C-C bond-forming event. Here, we report the evolution of a flavin-dependent "ene"-reductase to catalyze the coupling of α,α-dichloroamides with alkenes to afford α-chloroamides in good yield with excellent chemo- and stereoselectivity. These products can serve as linchpins in the synthesis of pharmaceutically valuable motifs. Mechanistic studies indicate that radical formation occurs by exciting a charge-transfer complex templated by the protein. Precise control over the orientation of molecules within the charge-transfer complex potentially accounts for the observed stereoselectivity. The work expands the types of motifs that can be prepared using photoenzymatic catalysis.

Regiodivergent Radical Termination for Intermolecular Biocatalytic C-C Bond Formation.

Radical hydrofunctionalizations of electronically unbiased dienes are challenging to render regioselective, because the products are nearly identical in energy. Here, we report two engineered FMN-dependent "ene"-reductases (EREDs) that catalyze regiodivergent hydroalkylations of cyclic and linear dienes. While previous studies focused exclusively on the stereoselectivity of alkene hydroalkylation, this work highlights that EREDs can control the regioselectivity of hydrogen atom transfer, providing a method for selectively preparing constitutional isomers that would be challenging to prepare using traditional synthetic methods. Engineering the ERED from Gluconabacter sp. (GluER) furnished a variant that favors the γ,δ-unsaturated ketone, while an engineered variant from a commercial ERED panel favors the δ,ε-unsaturated ketone. The effect of beneficial mutations has been investigated using substrate docking studies and the mechanism probed by isotope labeling experiments. A variety of α-bromo ketones can be coupled with cyclic and linear dienes. These interesting building blocks can also be further modified to generate difficult-to-access heterocyclic compounds.

A Qualitative, Small-Sample Study of Employment Challenges for People with Disabilities in Saudi Arabia.

Many people live with disabilities and many countries worldwide are acting to provide people with disabilities opportunities to find and sustain gainful employment. Notwithstanding, people with disabilities still do not have the same access to employment as their counterparts without disabilities. Although some research has investigated these issues in Western countries, very little research has investigated these issues in the Middle East, in general, and in Saudi Arabia, in particular. The aim of the present study is to gain an initial understanding of the employment experiences of people with disabilities and prospective employers of people with disabilities in Saudi Arabia. We identify several potential obstacles preventing people with disabilities from securing and maintaining gainful employment in Saudi Arabia. We secured qualitative data from semi-structured interviews with five prospective employers and five individuals with disabilities in Saudi Arabia. We focused on identifying barriers to employment. The impact of demographic factors such as age, gender, and education on employment opportunities was also examined. The results suggest several practical conclusions and recommendations relating to improving and enhancing opportunities for employment for people with disabilities in Saudi Arabia.

Outcomes after bioprosthetic versus mechanical mitral valve replacement for infective endocarditis in the United States.

Objective: In patients who underwent mitral valve replacement for infectious endocarditis, we evaluated the association of prosthesis choice with readmission rates and causes (the primary outcomes), as well as with in-hospital mortality, cost, and length of stay (the secondary outcomes). Methods: Patients with infectious endocarditis who underwent isolated mitral valve replacement from January 2016 to December 2018 were identified in the United States Nationwide Readmissions Database and stratified by valve type. Propensity score matching was used to compare adjusted outcomes. Results: A weighted total of 4206 patients with infectious endocarditis underwent bioprosthetic mitral valve replacement (n = 3132) and mechanical mitral valve replacement (n = 1074) during the study period. Patients in the bioprosthetic mitral valve replacement group were older than those in the mechanical mitral valve replacement group (median 57 vs 46 y, P < .001). After propensity matching, the bioprosthetic mitral valve replacement group (n = 1068) had similar in-hospital mortality, length of stay, and costs compared with the mechanical mitral valve replacement group (n = 1056). Overall, 90-day readmission rates were high (28.9%) and comparable for bioprosthetic mitral valve replacement (30.5%) and mechanical mitral valve replacement (27.5%, P = .4). Likewise, there was no difference in readmissions over a calendar year by prosthesis type. Readmissions for infection and bleeding were common for both bioprosthetic mitral valve replacement and mechanical mitral valve replacement groups. Conclusions: Outcomes and readmission rates were similar for mechanical mitral valve replacement and bioprosthetic mitral valve replacement in infectious endocarditis, suggesting that valve choice should not be determined by endocarditis status. Additionally, strategies to mitigate readmission for infection and bleeding are needed for both groups.