Prior Bariatric Surgery is Associated with Improved Total Hip Arthroplasty Outcomes in Patients Who Have Obesity: A National Cohort Study with 6 Years of Follow-Up.

BACKGROUND: Obesity is a risk factor for end-stage hip osteoarthritis (OA). While total hip arthroplasty (THA) is commonly performed to reduce pain and improve function associated with OA, obesity has been associated with an increased risk of complications after THA. Although bariatric surgery may also be utilized to reduce weight, the impact of bariatric surgery on THA outcomes remains inadequately understood. METHODS: This retrospective cohort analysis utilized multicenter electronic medical record data ranging from 2003 to 2023. Patients who have obesity who underwent THA were stratified based on prior bariatric surgery. The final bariatric cohort comprised 451 patients after propensity score matching. Complication rates and revision risks were compared between cohorts at six, 24, and 72 months. Additional analysis stratified patients by interval between bariatric surgery and THA. RESULTS: At six-month follow-up, the bariatric cohort had significantly lower risks of surgical site infection (SSI), wound dehiscence, and deep vein thrombosis (DVT). At 24 months, the bariatric cohort had a lower risk of DVT. At 72 month follow-up, the bariatric cohort had reduced rates of revision, mortality, cardiac morbidity, and Clavien-Dindo grade IV complications. CONCLUSION: Obese patients who underwent bariatric surgery prior to THA experienced reduced medical complications at all time points and reduced rates of revision at 72 months relative to a matched cohort who did not undergo bariatric surgery.

Revolutionizing Healthcare: Qure.AI's Innovations in Medical Diagnosis and Treatment.

Qure.AI, a leading company in artificial intelligence (AI) applied to healthcare, has developed a suite of innovative solutions to revolutionize medical diagnosis and treatment. With a plethora of FDA-approved tools for clinical use, Qure.AI continually strives for innovation in integrating AI into healthcare systems. This article delves into the efficacy of Qure.AI's chest X-ray interpretation tool, "qXR," in medicine, drawing from a comprehensive review of clinical trials conducted by various institutions. Key applications of AI in healthcare include machine learning, deep learning, and natural language processing (NLP), all of which contribute to enhanced diagnostic accuracy, efficiency, and speed. Through the analysis of vast datasets, AI algorithms assist physicians in interpreting medical data and making informed decisions, thereby improving patient care outcomes. Illustrative examples highlight AI's impact on medical imaging, particularly in the diagnosis of conditions such as breast cancer, heart failure, and pulmonary nodules. AI can significantly reduce diagnostic errors and expedite the interpretation of medical images, leading to more timely interventions and treatments. Furthermore, AI-powered predictive analytics enable early detection of diseases and facilitate personalized treatment plans, thereby reducing healthcare costs and improving patient outcomes. The efficacy of AI in healthcare is underscored by its ability to complement traditional diagnostic methods, providing physicians with valuable insights and support in clinical decision-making. As AI continues to evolve, its role in patient care and medical research is poised to expand, promising further advancements in diagnostic accuracy and treatment efficacy.

Social Induction via a Social Behavioral Intervention on Changes in Metabolic Risk Factors: A Randomized Controlled Trial in Rural Appalachia, United States.

OBJECTIVE: To conduct a randomized controlled trial examining the effects of a social network intervention on health. PARTICIPANTS AND METHODS: The Microclinic Social Network Program randomized controlled trial (implemented from June 1, 2011, through December 31, 2014) delivered weekly social-health classroom interventions for 9 to 10 months vs standard of care. Longitudinal multilevel analyses examined end-of-trial and 6-month post-intervention outcomes. Social network effects were estimated via a novel social induction ratio. RESULTS: We randomized 494 participants, comprising 27 classroom clusters from five neighborhood cohorts. Compared with controls, the intervention showed decreased body weight -6.32 pounds (95% CI, -8.65 to -3.98; overall P<.001), waist circumference -1.21 inches (95% CI, -1.84 to -0.58; overall P<.001), hemoglobin A1c % change -1.60 (95% CI, -1.88 to -1.33; overall P<.001), mean arterial blood pressure -1.83 mm Hg (95% CI, -3.79 to 0.32; overall P<.01), borderline-increased high-density lipoprotein cholesterol 1.09 (95% CI, 0.01-2.17; P=.05; overall P=.01). At 6 months post-intervention, net improvements were: weight change 97% sustained (P<.001), waist circumference change 92% sustained (P<.001), hemoglobin A1c change 82.5% sustained (P<.001), high-density lipoprotein change 79% sustained (overall P=.01), and mean arterial blood pressure change greater than 100% sustained improvement of -4.21 mm Hg (P<.001). Mediation analysis found that diet and exercise did not substantially explain improvements. In the intent-to-treat analysis of social causal induction, the weight-change social induction ratio (SIR) was 1.80 for social-network weight change-meaning that social networks explained the greater weight loss in the intervention than controls. Furthermore, we observed an even stronger weight-loss SIR of 2.83 at 6 months post-intervention. CONCLUSION: Results show intervention effectiveness for improving health in resource-limited communities, with SIR demonstrating that social-network effects helped induce such improvements. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT01651065.

Thrombospondin-1 promotes fibro-adipogenic stromal expansion and contractile dysfunction of the diaphragm in obesity.

Pulmonary disorders impact 40% to 80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragmatic weakness. Increased intra-diaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs) - mesenchymal cells that differentiate into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated diaphragm remodeling and contractile dysfunction in DIO. We tested this by comparing the effects of dietary challenge on diaphragms of wild-type (WT) and Thbs1 knockout (Thbs1-/-) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGF ß-related expression signatures and augmentation of a Thy1-expressing sub-population previously linked to type 2 diabetes. Despite similar weight gain, Thbs1-/- mice were protected from these transcriptomic changes and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls, Thbs1-/- diaphragms maintained normal contractile force and motion after DIO challenge. These findings establish THBS1 as a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition and a potential therapeutic target in obesity-associated respiratory dysfunction.

A machine-learning regional clustering approach to understand ventilator-induced lung injury: a proof-of-concept experimental study.

BACKGROUND: The spatiotemporal progression and patterns of tissue deformation in ventilator-induced lung injury (VILI) remain understudied. Our aim was to identify lung clusters based on their regional mechanical behavior over space and time in lungs subjected to VILI using machine-learning techniques. RESULTS: Ten anesthetized pigs (27 ± 2 kg) were studied. Eight subjects were analyzed. End-inspiratory and end-expiratory lung computed tomography scans were performed at the beginning and after 12 h of one-hit VILI model. Regional image-based biomechanical analysis was used to determine end-expiratory aeration, tidal recruitment, and volumetric strain for both early and late stages. Clustering analysis was performed using principal component analysis and K-Means algorithms. We identified three different clusters of lung tissue: Stable, Recruitable Unstable, and Non-Recruitable Unstable. End-expiratory aeration, tidal recruitment, and volumetric strain were significantly different between clusters at early stage. At late stage, we found a step loss of end-expiratory aeration among clusters, lowest in Stable, followed by Unstable Recruitable, and highest in the Unstable Non-Recruitable cluster. Volumetric strain remaining unchanged in the Stable cluster, with slight increases in the Recruitable cluster, and strong reduction in the Unstable Non-Recruitable cluster. CONCLUSIONS: VILI is a regional and dynamic phenomenon. Using unbiased machine-learning techniques we can identify the coexistence of three functional lung tissue compartments with different spatiotemporal regional biomechanical behavior.

Palliative Pharmacotherapy for Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Cardiovascular disease exacts a heavy toll on health and quality of life and is the leading cause of death among people ≥65 years of age. Although medical, surgical, and device therapies can certainly prolong a life span, disease progression from chronic to advanced to end stage is temporally unpredictable, uncertain, and marked by worsening symptoms that result in recurrent hospitalizations and excessive health care use. Compared with other serious illnesses, medication management that incorporates a palliative approach is underused among individuals with cardiovascular disease. This scientific statement describes palliative pharmacotherapy inclusive of cardiovascular drugs and essential palliative medicines that work synergistically to control symptoms and enhance quality of life. We also summarize and clarify available evidence on the utility of guideline-directed and evidence-based medical therapies in individuals with end-stage heart failure, pulmonary arterial hypertension, coronary heart disease, and other cardiomyopathies while providing clinical considerations for de-escalating or deprescribing. Shared decision-making and goal-oriented care are emphasized and considered quintessential to the iterative process of patient-centered medication management across the spectrum of cardiovascular disease.

Abdominal Drains After Laparoscopic Sleeve Gastrectomy: Should They Be Used?

Purpose: Laparoscopic sleeve gastrectomy (LSG) is one of the most common surgical procedures worldwide for the treatment of morbid obesity. Blake-type drains are widely used in this procedure despite the lack of clear evidence regarding their benefits in the diagnosis and treatment of common postoperative complications such as gastric suture line leak (GSLL) and postoperative bleeding (PB). Materials and Methods: A retrospective descriptive study with prospective case registry was conducted, analyzing all patients who underwent LSG between January 2012 and December 2022 at a high-volume center. Our primary outcome was to evaluate the role of drains for diagnosis and treatment of GSLL and PB in LSG. Our secondary outcome was to determine drain related surgical site infection (DRSSI) rate. Results: A total of 335 LSG were performed in the studied period. In all patients one abdominal drain was placed during surgery. Six GSLL (1.79%) and 5 PB (1.49%) were recorded. Drain placement did not prove to ensure early diagnosis or conservative management of GSLL or PB after LSG. Furthermore, an incidence of DRSSI of 4.1% (14 patients) was found. Conclusion: In our study, no clear diagnostic or therapeutic benefits of the systematic use of drains for GSLL or PB in LSG was found; but drain use did show a considerable rate of DRSSI, which must be taken into consideration prior to considering drain systematic use. While no randomized prospective trials have been performed, the retrospective data does not support drain systematic use.

Comparative Effectiveness and Safety of Apixaban, Rivaroxaban, and Warfarin in Patients With Cirrhosis and Atrial Fibrillation : A Nationwide Cohort Study.

BACKGROUND: Apixaban, rivaroxaban, and warfarin have shown benefit for preventing major ischemic events, albeit with increased bleeding risk, among patients in the general population with atrial fibrillation (AF). However, data are scarce in patients with cirrhosis and AF. OBJECTIVE: To compare the effectiveness and safety of apixaban versus rivaroxaban and versus warfarin in patients with cirrhosis and AF. DESIGN: Population-based cohort study. SETTING: Two U.S. claims data sets (Medicare and Optum's de-identified Clinformatics Data Mart Database [2013 to 2022]). PARTICIPANTS: 1:1 propensity score (PS)-matched patients with cirrhosis and nonvalvular AF initiating use of apixaban, rivaroxaban, or warfarin. MEASUREMENTS: Primary outcomes included ischemic stroke or systemic embolism and major hemorrhage (intracranial hemorrhage or major gastrointestinal bleeding). Database-specific and pooled PS-matched rate differences (RDs) per 1000 person-years (PY) and Cox proportional hazard ratios (HRs) with 95% CIs were estimated, controlling for 104 preexposure covariates. RESULTS: Rivaroxaban initiators had significantly higher rates of major hemorrhagic events than apixaban initiators (RD, 33.1 per 1000 PY [95% CI, 12.9 to 53.2 per 1000 PY]; HR, 1.47 [CI, 1.11 to 1.94]) but no significant differences in rates of ischemic events or death. Consistently higher rates of major hemorrhage were found with rivaroxaban across subgroup and sensitivity analyses. Warfarin initiators also had significantly higher rates of major hemorrhage than apixaban initiators (RD, 26.1 per 1000 PY [CI, 6.8 to 45.3 per 1000 PY]; HR, 1.38 [CI, 1.03 to 1.84]), particularly hemorrhagic stroke (RD, 9.7 per 1000 PY [CI, 2.2 to 17.2 per 1000 PY]; HR, 2.85 [CI, 1.24 to 6.59]). LIMITATION: Nonrandomized treatment selection. CONCLUSION: Among patients with cirrhosis and nonvalvular AF, initiators of rivaroxaban versus apixaban had significantly higher rates of major hemorrhage and similar rates of ischemic events and death. Initiation of warfarin versus apixaban also contributed to significantly higher rates of major hemorrhagic events, including hemorrhagic stroke. PRIMARY FUNDING SOURCE: National Institutes of Health.

Patient-specific quality assurance of dynamically-collimated proton therapy treatment plans.

BACKGROUND: The dynamic collimation system (DCS) provides energy layer-specific collimation for pencil beam scanning (PBS) proton therapy using two pairs of orthogonal nickel trimmer blades. While excellent measurement-to-calculation agreement has been demonstrated for simple cube-shaped DCS-trimmed dose distributions, no comparison of measurement and dose calculation has been made for patient-specific treatment plans. PURPOSE: To validate a patient-specific quality assurance (PSQA) process for DCS-trimmed PBS treatment plans and evaluate the agreement between measured and calculated dose distributions. METHODS: Three intracranial patient cases were considered. Standard uncollimated PBS and DCS-collimated treatment plans were generated for each patient using the Astroid treatment planning system (TPS). Plans were recalculated in a water phantom and delivered at the Miami Cancer Institute (MCI) using an Ion Beam Applications (IBA) dedicated nozzle system and prototype DCS. Planar dose measurements were acquired at two depths within low-gradient regions of the target volume using an IBA MatriXX ion chamber array. RESULTS: Measured and calculated dose distributions were compared using 2D gamma analysis with 3%/3 mm criteria and low dose threshold of 10% of the maximum dose. Median gamma pass rates across all plans and measurement depths were 99.0% (PBS) and 98.3% (DCS), with a minimum gamma pass rate of 88.5% (PBS) and 91.2% (DCS). CONCLUSIONS: The PSQA process has been validated and experimentally verified for DCS-collimated PBS. Dosimetric agreement between the measured and calculated doses was demonstrated to be similar for DCS-collimated PBS to that achievable with noncollimated PBS.

Anatolian genetic ancestry in North Lebanese populations.

Lebanon's rich history as a cultural crossroad spanning millennia has significantly impacted the genetic composition of its population through successive waves of migration and conquests from surrounding regions. Within modern-day Lebanon, the Koura district stands out with its unique cultural foundations, primarily characterized by a notably high concentration of Greek Orthodox Christians compared to the rest of the country. This study investigates whether the prevalence of Greek Orthodoxy in Koura can be attributed to modern Greek heritage or continuous blending resulting from the ongoing influx of refugees and trade interactions with Greece and Anatolia. We analyzed both ancient and modern DNA data from various populations in the region which could have played a role in shaping the current population of Koura using our own and published data. Our findings indicate that the genetic influence stemming directly from modern Greek immigration into the area appears to be limited. While the historical presence of Greek colonies has left its mark on the region's past, the distinctive character of Koura seems to have been primarily shaped by cultural and political factors, displaying a stronger genetic connection mostly with Anatolia, with affinity to ancient but not modern Greeks.

Vitamin D Status and Cardiovascular Disease in College Athletes After SARS-CoV-2 Infection.

OBJECTIVE: To evaluate the association between vitamin D status and CV disease after COVID-19 in college athletes. DESIGN: Retrospective cohort study. SETTING: National College Athletic Association Division-I college athletes from a single academic institution. PATIENTS: A total of 157 athletes (60 female; median age: 20 years) from 9 sports with a positive SARS-CoV-2 test, cardiac magnetic resonance imaging (CMR), and vitamin D level. INDEPENDENT VARIABLES: Serum 25-hydroxyvitamin D level (primary); age, sex (regression models). MAIN OUTCOMES MEASURES: Differences in age, sex, race, ethnicity, myocarditis, pericarditis, and CMR metrics by vitamin D status were analyzed. Regression models were used to assess the relationship between vitamin D status and CMR metrics accounting for age and sex. RESULTS: Low vitamin D (LVD) was found in 33 (21.0%) of athletes, particularly Black males (P < 0.001). Athletes with LVD had higher biventricular and lower mid-ventricular extracellular volumes, but these differences were not significant when corrected for age and sex. Athletes with LVD had higher left ventricle (LV) mass (P < 0.001) and LV mass index (P = 0.001) independent of age and sex. Differences in global circumferential strain were noted but are likely clinically insignificant. Vitamin D status did not associate with myocarditis and pericarditis (P = 0.544). CONCLUSIONS: LVD is common in athletes, particularly in Black males. Although athletes with LVD had higher LV mass, cardiac function and tissue characterization did not differ by vitamin D status. Future studies are needed to determine if the differences in LV mass and LV mass index by vitamin D status are clinically significant. This study suggests that vitamin D status does not impact the development of myocarditis or pericarditis after COVID-19 infection.

Effectiveness of immune checkpoint inhibitor therapy on bone metastases in non-small-cell lung cancer.

Background: Bone metastases (BoMs) are prevalent in patients with metastatic non-small-cell lung cancer (NSCLC) however, there are limited data detailing how BoMs respond to immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the imaging response to ICIs of BoMs against visceral metastases and to evaluate the effect of BoMs on survival. Materials and methods: A retrospective, multicentre cohort study was conducted in patients with NSCLC treated with nivolumab or pembrolizumab in Alberta, Canada from 2015 to 2020. The primary endpoint was the real-world organ specific progression free survival (osPFS) of bone versus visceral metastases. Visceral metastases were categorized as adrenal, brain, liver, lung, lymph node, or other intra-abdominal lesions. The secondary outcome was overall survival (OS) amongst patients with and without BoMs. Results: A total of 573 patients were included of which all patients had visceral metastases and 243 patients (42.4%) had BoMs. High PD-L1 expression was identified in 268 patients (46.8%). No significant difference in osPFS was observed between bone, liver, and intra-abdominal metastases (p=0.20 and p=0.76, respectively), with all showing shorter osPFS than other disease sites. There was no difference in the osPFS of extra-thoracic sites of disease in patients with high PD-L1 expression. There was significant discordance between visceral disease response and bone disease response to ICI (p=0.047). The presence of BoMs was an independent poor prognostic factor for OS (HR 1.26, 95%CI: 1.05-1.53, p=0.01). Conclusion: Metastatic bone, liver, and intra-abdominal lesions demonstrated inferior clinical responses to ICI relative to other sites of disease. Additionally, the presence of bone and liver metastases were independent poor prognostic factors for overall survival. This real-world data suggests that BoMs respond poorly to ICI and may require treatment adjuncts for disease control.

Use of Decipher Prostate Biopsy Test in Patients with Favorable-risk Disease Undergoing Conservative Management or Radical Prostatectomy in the Surveillance, Epidemiology, and End Results Registry.

BACKGROUND AND OBJECTIVE: The extent of prostate cancer found on biopsy, as well as prostate cancer grade and genomic tests, can affect clinical decision-making. The impact of these factors on the initial management approach and subsequent patient outcomes for men with favorable-grade prostate cancer has not yet been determined on a population level. Our objective was to explore the association of Decipher 22-gene genomic classifier (GC) biopsy testing on the initial use of conservative management versus radical prostatectomy (RP) and to determine the independent effect of GC scores on RP pathologic outcomes. METHODS: A total of 87 140 patients diagnosed with grade group 1 and 2 prostate cancer between 2016 and 2018 from the Surveillance, Epidemiology, and End Results registry data were linked to GC testing results (2576 tested and 84 564 untested with a GC). The primary endpoints of interest were receipt of conservative management or RP, pathologic upgrading (pathologic grade group 3-5), upstaging (pathologic ≥T3b), and adverse pathologic features (pathologic upgrading, upstaging, or lymph node invasion). Multivariable logistic regressions quantified the association of variables with outcomes of interest. KEY FINDINGS AND LIMITATIONS: GC tested patients were more likely to have grade group 2 on biopsy (51% vs 46%, p < 0.001) and lower prostate-specific antigen (6.1 vs 6.3, p = 0.016). Conservative management increased from 37% to 39% and from 22% to 24% during 2016-2018 for the GC tested and untested populations, respectively. GC testing was significantly associated with increased odds of conservative management (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.9-2.4, p < 0.001). The distribution of biopsy GC risk was as follows: 45% low risk, 30% intermediate risk, and 25% high risk. In adjusted analyses, higher GC (per 0.1 increment) scores (OR 1.24, 95% CI 1.17-1.31, p < 0.001) and percent positive cores (1.07, 95% CI 1.02-1.12, p = 0.009) were significantly associated with the receipt of RP. A higher GC score was significantly associated with all adverse outcomes (pathologic upgrading [OR 1.29, 95% CI 1.12-1.49, p < 0.001], upstaging [OR 1.31, 95% CI 1.05-1.62, p = 0.020], and adverse pathology [OR 1.27, 95% CI 1.12-1.45, p < 0.001]). Limitations include observational biases associated with the retrospective study design. CONCLUSIONS AND CLINICAL IMPLICATIONS: Men who underwent GC testing were more likely to undergo conservative management. GC testing at biopsy is prognostic of adverse pathologic outcomes in a large population-based registry. PATIENT SUMMARY: In this population analysis of men with favorable-risk prostate cancer, those who underwent genomic testing at biopsy were more likely to undergo conservative management. Of men who initially underwent radical prostatectomy, higher genomic risk but not tumor volume was associated with adverse pathologic outcomes. The use of genomic testing at prostate biopsy improves risk stratification and may better inform treatment decisions than the use of tumor volume alone.

Partitioning the Genomic Components of Behavioral Disinhibition and Substance Use (Disorder) Using Genomic Structural Equation Modeling.

Externalizing behaviors encompass manifestations of risk-taking, self-regulation, aggression, sensation-/reward-seeking, and impulsivity. Externalizing research often includes substance use (SUB), substance use disorder (SUD), and other (non-SUB/SUD) "behavioral disinhibition" (BD) traits. Genome-wide and twin research have pointed to overlapping genetic architecture within and across SUB, SUD, and BD. We created single-factor measurement models-each describing SUB, SUD, or BD traits-based on mutually exclusive sets of European ancestry genome-wide association study (GWAS) statistics exploring externalizing variables. We then assessed the partitioning of genetic covariance among the three facets using correlated factors models and Cholesky decomposition. Even when the residuals for indicators relating to the same substance were correlated across the SUB and SUD factors, the two factors yielded a large correlation (rg = 0.803). BD correlated strongly with the SUD (rg = 0.774) and SUB (rg = 0.778) factors. In our initial decompositions, 33% of total BD variance remained after partialing out SUD and SUB. The majority of covariance between BD and SUB and between BD and SUD was shared across all factors, and, within these models, only a small fraction of the total variation in BD operated via an independent pathway with SUD or SUB outside of the other factor. When only nicotine/tobacco, cannabis, and alcohol were included for the SUB/SUD factors, their correlation increased to rg = 0.861; in corresponding decompositions, BD-specific variance decreased to 27%. Further research can better elucidate the properties of BD-specific variation by exploring its genetic/molecular correlates.

A colloidal model for the equilibrium assembly and liquid-liquid phase separation of the reflectin A1 protein.

Reflectin is an intrinsically disordered protein (IDP) known for its ability to modulate the biophotonic camouflage of cephalopods based on its assembly-induced osmotic properties. Its reversible self-assembly into discrete, size-controlled clusters and condensed droplets are known to depend sensitively on the net protein charge, making reflectin stimuli-responsive to pH, phosphorylation, and electric fields. Despite considerable efforts to characterize this behavior, the detailed physical mechanisms of reflectin's assembly are yet fully understood. Here, we pursue a coarse-grained molecular understanding of reflectin assembly using a combination of experiments and simulations. We hypothesize that reflectin assembly and phase behavior can be explained from a remarkably simple colloidal model whereby individual protein monomers effectively interact via a short-range attractive and long-range repulsive (SA-LR) pair potential. We parameterize a coarse-grained SA-LR interaction potential for reflectin A1 from small angle X-ray scattering measurements, and then extend it to a range of pH using Gouy-Chapman theory to model monomer-monomer electrostatic interactions. The pH-dependent SA-LR interaction is then used in molecular dynamics simulations of reflectin assembly, which successfully capture a number of qualitative features of reflectin, including pH-dependent formation of discrete-sized nanoclusters and liquid-liquid phase separation at high pH, resulting in a putative phase diagram for reflectin. Importantly, we find that at low pH, size-controlled reflectin clusters are equilibrium assemblies, which dynamically exchange protein monomers to maintain an equilibrium size distribution. These findings provide a mechanistic understanding of the equilibrium assembly of reflectin, and suggest that colloidal-scale models capture key driving forces and interactions to explain thermodynamic aspects of native reflectin behavior. Furthermore, the success of SA-LR interactions presented in this study demonstrates the potential of a colloidal interpretation of interactions and phenomena in a range of IDPs.

Oral Insulin Delay of Stage 3 Type 1 Diabetes Revisited in HLA DR4-DQ8 Participants in the TrialNet Oral Insulin Prevention Trial (TN07).

OBJECTIVE: To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As). RESEARCH AND METHODS: Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin. RESULTS: Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 × 10-6) and negatively associated with the HLA DR7-containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028). CONCLUSIONS: These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset.

Glial expression of a steroidogenic enzyme underlies natural variation in hitchhiking behavior.

Phoresy is an interspecies interaction that facilitates spatial dispersal by attaching to a more mobile species. Hitchhiking species have evolved specific traits for physical contact and successful phoresy, but the regulatory mechanisms involved in such traits and their evolution are largely unexplored. The nematode Caenorhabditis elegans displays a hitchhiking behavior known as nictation during its stress-induced developmental stage. Dauer-specific nictation behavior has an important role in natural C. elegans populations, which experience boom-and-bust population dynamics. In this study, we investigated the nictation behavior of 137 wild C. elegans strains sampled throughout the world. We identified species-wide natural variation in nictation and performed a genome-wide association mapping. We show that the variants in the promoter of nta-1, encoding a putative steroidogenic enzyme, underlie differences in nictation. This difference is due to the changes in nta-1 expression in glial cells, which implies that glial steroid metabolism regulates phoretic behavior. Population genetic analysis and geographic distribution patterns suggest that balancing selection maintained two nta-1 haplotypes that existed in ancestral C. elegans populations. Our findings contribute to further understanding of the molecular mechanism of species interaction and the maintenance of genetic diversity within natural populations.

Shredding artifacts: extracting brain activity in EEG from extreme artifacts during skateboarding using ASR and ICA.

Introduction: To understand brain function in natural real-world settings, it is crucial to acquire brain activity data in noisy environments with diverse artifacts. Electroencephalography (EEG), while susceptible to environmental and physiological artifacts, can be cleaned using advanced signal processing techniques like Artifact Subspace Reconstruction (ASR) and Independent Component Analysis (ICA). This study aims to demonstrate that ASR and ICA can effectively extract brain activity from the substantial artifacts occurring while skateboarding on a half-pipe ramp. Methods: A dual-task paradigm was used, where subjects were presented with auditory stimuli during skateboarding and rest conditions. The effectiveness of ASR and ICA in cleaning artifacts was evaluated using a support vector machine to classify the presence or absence of a sound stimulus in single-trial EEG data. The study evaluated the effectiveness of ASR and ICA in artifact cleaning using five different pipelines: (1) Minimal cleaning (bandpass filtering), (2) ASR only, (3) ICA only, (4) ICA followed by ASR (ICAASR), and (5) ASR preceding ICA (ASRICA). Three skateboarders participated in the experiment. Results: Results showed that all ICA-containing pipelines, especially ASRICA (69%, 68%, 63%), outperformed minimal cleaning (55%, 52%, 50%) in single-trial classification during skateboarding. The ASRICA pipeline performed significantly better than other pipelines containing ICA for two of the three subjects, with no other pipeline performing better than ASRICA. The superior performance of ASRICA likely results from ASR removing non-stationary artifacts, enhancing ICA decomposition. Evidenced by ASRICA identifying more brain components via ICLabel than ICA alone or ICAASR for all subjects. For the rest condition, with fewer artifacts, the ASRICA pipeline (71%, 82%, 75%) showed slight improvement over minimal cleaning (73%, 70%, 72%), performing significantly better for two subjects. Discussion: This study demonstrates that ASRICA can effectively clean artifacts to extract single-trial brain activity during skateboarding. These findings affirm the feasibility of recording brain activity during physically demanding tasks involving substantial body movement, laying the groundwork for future research into the neural processes governing complex and coordinated body movements.