Advancements in prokaryotic systematics and the role of Bergey's International Society for Microbial Systematicsin addressing challenges in the meta-data era.

Prokaryotes are ubiquitous in the biosphere, important for human health and drive diverse biological and environmental processes. Systematics of prokaryotes, whose origins can be traced to the discovery of microorganisms in the 17th century, has transitioned from a phenotype-based classification to a more comprehensive polyphasic taxonomy and eventually to the current genome-based taxonomic approach. This transition aligns with a foundational shift from studies focused on phenotypic traits that have limited comparative value to those using genome sequences. In this context, Bergey's Manual of Systematics of Archaea and Bacteria (BMSAB) and Bergey's International Society for Microbial Systematics (BISMiS) play a pivotal role in guiding prokaryotic systematics. This review focuses on the historical development of prokaryotic systematics with a focus on the roles of BMSAB and BISMiS. We also explore significant contributions and achievements by microbiologists, highlight the latest progress in the field and anticipate challenges and opportunities within prokaryotic systematics. Additionally, we outline five focal points of BISMiS that are aimed at addressing these challenges. In conclusion, our collaborative effort seeks to enhance ongoing advancements in prokaryotic systematics, ensuring its continued relevance and innovative characters in the contemporary landscape of genomics and bioinformatics.

Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption.

SLC30A10 deficiency is a disease of severe manganese excess attributed to loss of SLC30A10-dependent manganese excretion via the gastrointestinal tract. Patients develop dystonia, cirrhosis, and polycythemia. They are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here we explore the latter observation. Intriguingly, manganese absorption is increased in Slc30a10-deficient mice despite manganese excess. Studies of multiple mouse models indicate that increased dietary manganese absorption reflects two processes: loss of manganese export from enterocytes into the gastrointestinal tract lumen by SLC30A10, and increased absorption of dietary manganese by iron transporters SLC11A2 (DMT1) and SLC40A1 (ferroportin). Our work demonstrates that aberrant absorption contributes prominently to SLC30A10 deficiency and expands our understanding of biological interactions between iron and manganese. Based on these results, we propose a reconsideration of the role of iron transporters in manganese homeostasis is warranted.

Use of Computer Navigation for Optimal Acetabular Cup Placement in Revision Total Hip Arthroplasty: Case Reports and Surgical Techniques.

Background: The outcomes of revision total hip arthroplasty (rTHA) have become increasingly important as their volume increases. Computer navigation, a reliable method to improve component positioning during primary total hip arthroplasty (THA), is not well studied in the rTHA setting. Given that dislocation rates following rTHA are significantly higher than those of primary THA, component positioning becomes paramount in these cases. Methods: Here, we present two case reports and surgical techniques, one of a 77-year-old man undergoing rTHA for recurrent hip instability following primary THA, and one of a 61-year-old woman undergoing rTHA for severe iliopsoas bursitis who was at increased risk for instability and dislocation given her history of large segment spinal fusion. Results: Both patients achieved optimal acetabular component positioning after rTHA with imageless computer navigation. Conclusions: The use of imageless computer navigation in rTHA provides accurate and reproducible component positioning during acetabular rTHA.

A Narrative Review of Ultrasound-Guided and Landmark-based Percutaneous Cryoneurolysis for the Management of Acute and Chronic Pain.

PURPOSE OF REVIEW: Cryoneurolysis refers to the process of reversibly ablating peripheral nerves with extremely cold temperatures to provide analgesia for weeks to months. With ultrasound-guidance or landmark-based techniques, it is an effective modality for managing both acute and chronic pain. In this review, we summarize the reported literature behind its potential applications and efficacy. RECENT FINDINGS: Here, we summarize several studies (from case reports to clinical trials) describing the use of ultrasound-guided and landmark-based cryoneurolysis for acute and chronic pain. Acute pain indications included pain related to knee arthroplasty, limb amputations, mastectomies, shoulder surgery, rib fractures, and burn. Chronic pain indications included chronic knee pain (due to osteoarthritis), shoulder pain, painful neuropathies, postmastectomy pain syndrome, phantom limb pain, facial pain/headaches, foot/ankle pain, inguinal pain, and sacroiliac joint pain. For both acute and chronic pain indications, more high quality randomized controlled clinical trials are needed to definitively assess the efficacy of cryoneurolysis versus other standard therapies for a multitude of pain conditions.

Machine learning identifies prognostic subtypes of the tumor microenvironment of NSCLC.

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, and ten baseline patient characteristics. Prognostic subregions of the biomarker space are delineated for each method using synthetic patient data augmentation and compared between models for overall survival concordance. A total of 423 NSCLC patients (46% female; median age [inter quantile range]: 67 [60-73]) treated with definite surgical resection were included in the study. And 219 (52%) patients experienced events during the observation period consisting of a maximum follow-up of 10 years and median follow up 78 months. The random survival forest (RSF) achieved the highest predictive accuracy, with a C-index of 0.84. The resultant biomarker subtypes demonstrate that patients with high PD-L1 expression combined with low CD3 counts experience higher risk of death within five-years of surgical resection.

The Role of Family Support in Moderating Mental Health Outcomes for LGBTQ+ Youth in Primary Care.

Importance: Lesbian, gay, bisexual, transgender, queer, and/or questioning (LGBTQ+) youth face worse mental health outcomes than non-LGBTQ+ peers. Family support may mitigate this, but sparse evidence demonstrates this in clinical settings. Objectives: To compare depression and suicide risk between LGBTQ+ and non-LGBTQ+ youth in primary care settings and to investigate whether family support mitigates these negative mental health outcomes. Design, Setting, and Participants: This cross-sectional study uses data from well care visits completed by adolescents aged 13 to 19 years from February 2022 through May 2023, including the Patient Health Questionnaire-9 Modified for Teens (PHQ-9-M) and the Adolescent Health Questionnaire (AHQ; an electronic screener assessing identity, behaviors, and guardian support), at 32 urban or suburban care clinics in Pennsylvania and New Jersey. Exposures: The primary exposure was self-reported LGBTQ+ status. Family support moderators included parental discussion of adolescent strengths and listening to feelings. Race and ethnicity (determined via parent or guardian report at visit check-in), sex, payer, language, age, and geography were covariates. Main Outcomes and Measures: PHQ-9-M-derived mental health outcomes, including total score, recent suicidal ideation, and past suicide attempt. Results: The sample included 60 626 adolescents; among them, 9936 (16.4%) were LGBTQ+, 15 387 (25.5%) were Black, and 30 296 (50.0%) were assigned female sex at birth. LGBTQ+ youth, compared with non-LGBTQ+ youth, had significantly higher median (IQR) PHQ-9-M scores (5 [2-9] vs 1 [0-3]; P < .001) and prevalence of suicidal ideation (1568 [15.8%] vs 1723 [3.4%]; P < .001). Fewer LGBTQ+ youth endorsed parental support than non-LGBTQ+ youth (discussion of strengths, 8535 [85.9%] vs 47 003 [92.7%]; P < .001; and listening to feelings, 7930 [79.8%] vs 47 177 [93.1%]; P < .001). In linear regression adjusted for demographic characteristics and parental discussion of strengths, LGBTQ+ status was associated with a higher PHQ-9-M score (mean difference, 3.3 points; 95% CI, 3.2-3.3 points). In logistic regression, LGBTQ+ youth had increased adjusted odds of suicidal ideation (adjusted odds ratio, 4.3; 95% CI, 4.0-4.7) and prior suicide attempt (adjusted odds ratio, 4.4; 95% CI, 4.0-4.7). Parental support significantly moderated the association of LGBTQ+ status with PHQ-9-M score and suicidal ideation, with greater protection against these outcomes for LGBTQ+ vs non-LGBTQ+ youth. Conclusions and Relevance: Compared with non-LGBTQ+ youth, LGBTQ+ youth at primary care visits had more depressive symptoms and higher odds of suicidal ideation and prior suicide attempt. Youth-reported parental support was protective against these outcomes, suggesting potential benefits of family support-focused interventions to mitigate mental health inequities for LGBTQ+ youth.

Cultivation of novel Atribacterota from oil well provides new insight into their diversity, ecology, and evolution in anoxic, carbon-rich environments.

BACKGROUND: The Atribacterota are widely distributed in the subsurface biosphere. Recently, the first Atribacterota isolate was described and the number of Atribacterota genome sequences retrieved from environmental samples has increased significantly; however, their diversity, physiology, ecology, and evolution remain poorly understood. RESULTS: We report the isolation of the second member of Atribacterota, Thermatribacter velox gen. nov., sp. nov., within a new family Thermatribacteraceae fam. nov., and the short-term laboratory cultivation of a member of the JS1 lineage, Phoenicimicrobium oleiphilum HX-OS.bin.34TS, both from a terrestrial oil reservoir. Physiological and metatranscriptomics analyses showed that Thermatribacter velox B11T and Phoenicimicrobium oleiphilum HX-OS.bin.34TS ferment sugars and n-alkanes, respectively, producing H2, CO2, and acetate as common products. Comparative genomics showed that all members of the Atribacterota lack a complete Wood-Ljungdahl Pathway (WLP), but that the Reductive Glycine Pathway (RGP) is widespread, indicating that the RGP, rather than WLP, is a central hub in Atribacterota metabolism. Ancestral character state reconstructions and phylogenetic analyses showed that key genes encoding the RGP (fdhA, fhs, folD, glyA, gcvT, gcvPAB, pdhD) and other central functions were gained independently in the two classes, Atribacteria (OP9) and Phoenicimicrobiia (JS1), after which they were inherited vertically; these genes included fumarate-adding enzymes (faeA; Phoenicimicrobiia only), the CODH/ACS complex (acsABCDE), and diverse hydrogenases (NiFe group 3b, 4b and FeFe group A3, C). Finally, we present genome-resolved community metabolic models showing the central roles of Atribacteria (OP9) and Phoenicimicrobiia (JS1) in acetate- and hydrocarbon-rich environments. CONCLUSION: Our findings expand the knowledge of the diversity, physiology, ecology, and evolution of the phylum Atribacterota. This study is a starting point for promoting more incisive studies of their syntrophic biology and may guide the rational design of strategies to cultivate them in the laboratory. Video Abstract.

Exposure to metal mixtures and telomere length in Bangladeshi children.

Telomere length is associated with chronic diseases and in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length, we investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. In single exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (µg/g) were associated with a -0.21 (95%CI: -0.032, -0.010; p=0.0005) and -0.017 (95%CI: -0.029, -0.004; p=0.006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend <0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females, compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.

Volumetric Analysis: Effect on Diagnosis and Management of Indeterminate Solid Pulmonary Nodules in Routine Clinical Practice.

OBJECTIVE: To evaluate the effect of volumetric analysis on the diagnosis and management of indeterminate solid pulmonary nodules in routine clinical practice. METHODS: This was a retrospective study with 107 computed tomography (CT) cases of solid pulmonary nodules (range, 6-15 mm), 57 pathology-proven malignancies (lung cancer, n = 34; metastasis, n = 23), and 50 benign nodules. Nodules were evaluated on a total of 309 CT scans (average number of CTs/nodule, 2.9 [range, 2-7]). CT scans were from multiple institutions with variable technique. Nine radiologists (attendings, n = 3; fellows, n = 3; residents, n = 3) were asked their level of suspicion for malignancy (low/moderate or high) and management recommendation (no follow-up, CT follow-up, or care escalation) for baseline and follow-up studies first without and then with volumetric analysis data. Effect of volumetry on diagnosis and management was assessed by generalized linear and logistic regression models. RESULTS: Volumetric analysis improved sensitivity (P = 0.009) and allowed earlier recognition (P < 0.05) of malignant nodules. Attending radiologists showed higher sensitivity in recognition of malignant nodules (P = 0.03) and recommendation of care escalation (P < 0.001) compared with trainees. Volumetric analysis altered management of high suspicion nodules only in the fellow group (P = 0.008). κ Statistics for suspicion for malignancy and recommended management were fair to substantial (0.38-0.66) and fair to moderate (0.33-0.50). Volumetric analysis improved interobserver variability for identification of nodule malignancy from 0.52 to 0.66 (P = 0.004) only on the second follow-up study. CONCLUSIONS: Volumetric analysis of indeterminate solid pulmonary nodules in routine clinical practice can result in improved sensitivity and earlier identification of malignant nodules. The effect of volumetric analysis on management recommendations is variable and influenced by reader experience.

Prevalence of reducing carbohydrate intake and fasted training in elite endurance athletes and association with bone injury.

There are conflicting reports both within the lay media and scientific literature regarding the use and benefit of dietary practices that aim to reduce CHO intake in endurance athletes. This study aimed to determine the prevalence of intentional reduction of CHO intake and fasted training in elite endurance-based athletes using a semi-quantitative questionnaire. Bone is a nutritionally modulated tissue; therefore, this study also aimed to explore if these dietary practices are potentially associated with bone injury incidence. The reported reduction of CHO intake was prevalent (28%) with the primary motivation being maintenance or manipulation of body composition. However, discrepancies in athletes' awareness of CHO intake were identified providing a potential avenue of intervention especially within applied practice. The use of fasted training was more prevalent (38%) with athletes using this practice for both body composition manipulation and promoting a desired adaptive response. Forty-four per cent of participants had suffered a radiographically confirmed bone injury at some point in their career. There was no association between reduction in CHO intake and bone injury incidence; however, the incidence of bone injury was 1.61 times higher in those who currently use fasted training compared to those who have never used it or who have used it in the past. Although a direct causal link between these dietary practices and the incidence of bone injury cannot be drawn, it provides robust justification for future investigations of the potential mechanisms that could explain this finding.

Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis.

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual ("visual2"), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients-both affective and non-affective-exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged the visual2 and somatomotor network connections and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p=2e-10, Hedges' g=1.05). This "somato-visual" biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, or anxiety. It had moderate test-retest reliability (ICC=.61) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC=.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.

Predictors of Toxic Metal/Metalloid Exposures Among Mexican Americans in Starr County, Texas.

BACKGROUND: Arsenic, cadmium, and lead are toxic elements that widely contaminate our environment. These toxicants are associated with acute and chronic health problems, and evidence suggests that minority communities, including Hispanic/Latino Americans, are disproportionately exposed. Few studies have assessed culturally specific predictors of exposure to understand the potential drivers of racial/ethnic exposure disparities. OBJECTIVE: We sought to evaluate acculturation measures as predictors of metal/metalloid (hereafter "metal") concentrations among Mexican American adults to illuminate potential exposure sources that may be targeted for interventions. METHODS: As part of a longitudinal cohort, 510 adults, aged 35 to 69 years, underwent baseline interview, physical examination, and urine sample collection. Self-reported acculturation was assessed across various domains using the Short Acculturation Scale for Hispanics (SASH). Multivariable linear regression was used to assess associations between acculturation and urinary concentrations of arsenic, cadmium, and lead. Ordinal logistic regression was utilized to assess associations between acculturation and a metal mixture score. Lastly, best subset selection was used to build a prediction model for each toxic metal with a combination of the acculturation predictors. RESULTS: After adjustment, immigration factors were positively associated with arsenic and lead concentrations. For lead alone, English language and American media and food preferences were associated with lower levels. Immigration and parental heritage from Mexico were positively associated with the metal mixture, while preferences for English language, media, and food were negatively associated. CONCLUSION: Acculturation-related predictors of exposure provide information about potential sources of toxic metals, including international travel, foods, and consumer products. The findings in this research study provide information to empower future efforts to identify and address specific acculturation-associated toxicant exposures in order to promote health equity through clinical guidance, patient education, and public policy.

Cytoskeleton-associated gelsolin responds to the midgut distention process in saline meal-fed Aedes aegypti and affects arbovirus dissemination from the midgut.

The mosquito, Aedes aegypti, is the principal vector for several arboviruses. The mosquito midgut is the initial tissue that gets infected with an arbovirus acquired along with a blood meal from a vertebrate host. Blood meal ingestion leads to midgut tissue distention thereby increasing the pore size of the surrounding basal lamina. This allows newly synthesized virions to exit the midgut by traversing the distended basal lamina to infect secondary tissues of the mosquito. We conducted a quantitative label-free proteomic time course analysis with saline meal-fed Ae. aegypti females to identify host factors involved in midgut tissue distention. Around 2000 proteins were detected during each of the seven sampling time points and 164 of those were uniquely expressed. Forty-five of 97 differentially expressed proteins were upregulated during the 96-h time course and most of those were involved in cytoskeleton modulation, metabolic activity, and vesicle/vacuole formation. The F-actin-modulating Ae. aegypti (Aa)-gelsolin was selected for further functional studies. Stable knockout of Aa-gelsolin resulted in a mosquito line, which showed distorted actin filaments in midgut-associated tissues likely due to diminished F-actin processing by gelsolin. Zika virus dissemination from the midgut of these mosquitoes was diminished and delayed. The loss of Aa-gelsolin function was associated with an increased induction of apoptosis in midgut tissue indicating an involvement of Aa-gelsolin in apoptotic signaling in mosquitoes. Here, we used proteomics to discover a novel host factor, Aa-gelsolin, which affects the midgut escape barrier for arboviruses in mosquitoes and apoptotic signaling in the midgut.

CDK9 inhibition by dinaciclib is a therapeutic vulnerability in epithelioid hemangioendothelioma.

PURPOSE: There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ-CAMTA1 (TC) fusion gene. Here, we aimed to understand the regulation of TC using pharmacological tools and identify vulnerabilities that can potentially be exploited for the treatment of EHE. EXPERIMENTAL DESIGN: TC is a transcriptional co-regulator; we hypothesized that compounds that reduce TC nuclear levels, either through translocation of TC to the cytoplasm, or through degradation, would render TC less oncogenic. TC localization was monitored using immunofluorescence (IF) in an EHE tumor cell line. Two target-selective libraries were used to identify small molecules that reduce TC localization in the nucleus. The ability of the shortlisted hits to affect cell viability, apoptosis, and tumorigenesis was also evaluated. RESULTS: Basal TC remained 'immobile' in the nucleus; administration of cyclin-dependent kinase inhibitors (CDKi) such as CGP60474 and dinaciclib mobilized TC. 'Mobile' TC shuttled between the nucleus and cytoplasm; however, it was eventually degraded through proteasomes. This dramatically suppressed the levels of TC-regulated transcripts and cell viability, promoted apoptosis, and reduced the area of metastatic lesions in the allograft model of EHE. We specifically identified that the inhibition of CDK9, a transcriptional CDK, destabilizes TC. CONCLUSIONS: The CDK inhibitor dinaciclib exhibited anti-tumorigenic properties both in vitro and in vivo in EHE models. Dinaciclib has been rigorously tested in clinical trials and displayed an acceptable toxicity profile. Therefore, there is a potential therapeutic window for repurposing dinaciclib for the treatment of EHE.

15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

PURPOSE: Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier. MATERIALS AND METHODS: This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS). RESULTS: 15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter. CONCLUSION: In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

An Integrated Optogenetic and Bioelectronic Platform for Regulating Cardiomyocyte Function.

Bioelectronic medicine is emerging as a powerful approach for restoring lost endogenous functions and addressing life-altering maladies such as cardiac disorders. Systems that incorporate both modulation of cellular function and recording capabilities can enhance the utility of these approaches and their customization to the needs of each patient. Here is report an integrated optogenetic and bioelectronic platform for stable and long-term stimulation and monitoring of cardiomyocyte function in vitro. Optical inputs are achieved through the expression of a photoactivatable adenylyl cyclase, that when irradiated with blue light causes a dose-dependent and time-limited increase in the secondary messenger cyclic adenosine monophosphate with subsequent rise in autonomous cardiomyocyte beating rate. Bioelectronic readouts are obtained through a multi-electrode array that measures real-time electrophysiological responses at 32 spatially-distinct locations. Irradiation at 27 µW mm-2 results in a 14% elevation of the beating rate within 20-25 min, which remains stable for at least 2 h. The beating rate can be cycled through "on" and "off" light states, and its magnitude is a monotonic function of irradiation intensity. The integrated platform can be extended to stretchable and flexible substrates, and can open new avenues in bioelectronic medicine, including closed-loop systems for cardiac regulation and intervention, for example, in the context of arrythmias.

The Survival Benefit of Re-abstinence After Harmful Alcohol Use Following Early Liver Transplant for Severe Alcohol-Associated Hepatitis: A Multi-Center ACCELERATE Study.

BACKGROUND AND AIMS: Early (i.e. without mandated period of abstinence) liver transplant (LT) for alcohol-associated hepatitis (AH) is the fastest growing indication for LT in the US and Europe. Harmful alcohol use post-LT is associated with poor outcomes but the distinction of establishing abstinence after return to drinking (i.e. re-abstinence) is understudied. This study aims to characterize the survival outcomes of achieving re-abstinence after post-LT harmful alcohol use. METHODS: We analyzed early LT recipients from 12 US LT centers between 2006-2021. Post-LT alcohol use was characterized as harmful using criteria of "binge" (>5 [men] or >4 [women] drinks in < 24 hours) or "frequent" (>4 days in one week) by interview or phosphatidylethanol >20ng/mL. Re-abstinence was defined as >12 consecutive months without harmful alcohol use following harmful alcohol use. RESULTS: Among 347 LT recipients (64% male, median age 43, median MELD-Na 38) with median post-LT follow-up of 2.2 years (IQI 1.1 - 3.6), 276 (80%) recipients had no evidence of harmful alcohol use, 35 (10%) recipients had re-abstinence, and 36 (10%) recipients had continued harmful alcohol use without re-abstinence. Five-year predicted survival, adjusted for age, sex, MELD-Na score, was lowest among LT recipients with continued harmful alcohol use (77%), but similar among those with no harmful use (93%) and re-abstinence (94%). CONCLUSIONS: Achieving re-abstinence after post-LT harmful alcohol use is associated with similar five-year post-LT survival compared to those without evidence of post-LT harmful alcohol use. Our findings highlight the importance of early detection and treatment of post-LT alcohol use.

The Mineralocorticoid Receptors in diabetic kidney disease.

Diabetes mellitus is one of the leading causes of chronic kidney disease and its progression to end-stage kidney disease. Diabetic kidney disease (DKD) is characterized by glomerular hypertrophy, hyperfiltration, inflammation and the onset of albuminuria, together with a progressive reduction in glomerular filtration rate. This progression is further accompanied by tubulointerstitial inflammation and fibrosis. Factors such as genetic predisposition, epigenetic modifications, metabolic derangements, hemodynamic alterations, inflammation, and inappropriate renin-angiotensin-aldosterone system (RAAS) activity contribute to the onset and progression of DKD. In this context, decades of work have focused on glycemic and blood pressure reduction strategies, especially targeting the RAAS to slow disease progression. While much of the work has focused on targeting angiotensin II, emerging data support that the mineralocorticoid receptor (MR) is integral in the development and progression of DKD. Molecular mechanisms linked to the underlying pathophysiological changes derived from MR activation include vascular endothelial, as well as epithelial cell responses, to oxidative stress and inflammation. These responses lead to alterations in the microcirculatory environment, the abnormal release of extracellular vesicles, gut dysbiosis, epithelial-mesenchymal transition, and kidney fibrosis. Herein we present recent experimental and clinical evidence on the MR in DKD onset and progress along with new MR based strategies for the treatment and prevention of DKD.

Outcomes of Patients Undergoing the Kawashima Procedure at an Early Age: A Single Center Experience.

BACKGROUND: Previous reports have demonstrated the safety and efficacy of performing early Kawashima procedure (KP). Despite this, more recent studies have shown that the average age at the time of operation remains greater than one year of age. We report our experience with performing KP at an earlier age than previously reported. METHODS: A retrospective review was completed of patients undergoing KP at a single center (January 2000 to June 2020). Clinical outcomes were examined. RESULTS: Initial palliation was performed in 11 out of 12 patients. Age and weight at time of KP were 8.25 months (6.4-9.7) and 7.7 kg (6.5-8.6). Intensive care unit stay was 3.16 days (1-12), overall length of stay was 9.5 days (3-22). There was one unplanned reoperation, and no mortality in the cohort. Discharge oxygen saturation was 88% (80%-98%). Seven patients developed pulmonary arteriovenous malformations (PAVMs) with six proceeding to hepatic vein incorporation (HVI). Interval time to development of PAVMs was 42.3 months (16-121). Four of the 12 patients were left with antegrade pulmonary blood flow (PBF) and three (75%) remain without PAVMs. Median follow-up was 10 years (1.5-22) with 11 of 12 (91.67%) survival for the cohort. CONCLUSIONS: The KP can be done at a younger age than previously reported with adequate early and late results. Most patients will go on to develop PAVMs and require HVI but leaving patients with some antegrade PBF is likely protective but will need further investigation to show definitive benefit.