Timely Hip Surgery Access in Children With Cerebral Palsy: Unaffected by Social Disadvantage at a Large Urban Safety Net Hospital.

BACKGROUND: Socioeconomic disadvantage has been shown to limit timely access to pediatric orthopaedic care and can result in poor surgical outcomes. Insurance coverage has often served as a proxy for socioeconomic status; however, area deprivation index (ADI) and child opportunity index (COI) are more comprehensive measures of social determinants of health (SDOH). The treatment of hip displacement in children with cerebral palsy (CP) requires early radiographic identification and continuous surveillance, which may be impacted by SDOH. This study seeks to evaluate the influence of insurance, ADI, and COI on preoperative Reimer migration percentage and need for pelvic osteotomy during varus derotation osteotomy (VDRO) in children with CP. METHODS: This retrospective cohort study examined 219 patients with CP who underwent VDRO surgery for hip subluxation or dislocation at a tertiary referral center (135 male, mean age 7.9 y, SD: 2.9, range: 2.4 to 17.2; 17 GMFCS II, 21 GMFCS III, 89 GMFCS IV, 92 GMFCS V) from 2004 to 2022. Imaging and clinical documentation for patients with CP and hip displacement, age <18 years with ≥1 year of follow-up, treated with VDRO were reviewed. GMFCS level, preoperative Reimer migration percentages (MP), surgical details, and demographic and socioeconomic data were collected, and addresses were used to determine ADI (2018 version) and COI (2.0 database). The relationship of ADI, COI, and insurance type to preoperative Reimer MP of the more displaced hip and the need for pelvic osteotomy were analyzed with linear regressions and logistic regressions. RESULTS: The mean preoperative Reimer MP was 64.4% (SD: 25.0, range: 0 to 100). As expected, patients functioning at higher GMFCS levels presented with greater Reimer MPs. The average Reimer MP was 34.0 for GMFCS II, 44.2 for GMFCS III, 64.6 for GMFCS IV, and 74.5 for GMFCS V (P<0.01). The mean ADI state decile (1 to 10 scale) and COI (1 to 100 scale) for the cohort were 5.6 (SD: 2.2, range: 1 to 10) and 37.2 (SD: 28.1, range: 4 to 100), respectively. ADI (P=0.77), COI (P=0.30), and insurance type (P=0.78) were not related to preoperative Reimer MP. However, patients with lower ADIs (OR 0.83, 95% CI [0.70, 0.99], P=0.04) and higher COIs (OR 1.01, 95% CI [1.00, 1.03], P=0.03) underwent pelvic osteotomies at a higher rate. CONCLUSIONS: ADI, COI, and insurance type were not related to preoperative Reimer MP. Interestingly, greater social disadvantage was associated with a lower frequency of pelvic osteotomy at the time of VDRO. Our data demonstrate that at our institution, greater social disadvantage does not result in limited access to timely orthopaedic care for children with CP. This is likely due to adequate governmental insurance coverage for children with neuromuscular disorders in this state and the active involvement of pediatric orthopaedic surgeons in government-sponsored clinics, including ongoing hip screening programs for children with CP. These results provide hope that healthcare disparities can potentially be mitigated.

Real-world Decision-making Process for Stereotactic Body Radiotherapy Versus Minimally Invasive Surgery in Early-stage Lung Cancer Patients.

OBJECTIVE: To generate a prediction model for selection of treatment modality for early-stage non-small cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: Stereotactic body radiotherapy (SBRT) and minimally invasive surgery (MIS) are used in the local treatment of early-stage NSCLC. However, selection of patients for either SBRT or MIS remains challenging, due to the multitude of factors influencing the decision-making process. METHODS: We analyzed 1291 patients with clinical stage I NSCLC treated with intended MIS or SBRT from January 2020 to July 2023. A prediction model for selection for SBRT was created based on multivariable logistic regression analysis. The receiver operating characteristic curve analysis stratified the cohort into 3 treatment-related risk categories. Post-procedural outcomes, recurrence and overall survival (OS) were investigated to assess the performance of the model. RESULTS: In total, 1116 patients underwent MIS and 175 SBRT. The prediction model included age, performance status, previous pulmonary resection, MSK-Frailty score, FEV1 and DLCO, and demonstrated an area-under-the-curve of 0.908 (95%CI, 0.876-0.938). Based on the probability scores (n=1197), patients were stratified into a low-risk (MIS, n=970 and SBRT, n=28), intermediate-risk (MIS, n=96 and SBRT, n=53) and high-risk category (MIS, n=10 and SBRT, n=40). Treatment modality was not associated with OS (HR of SBRT, 1.67 [95%CI: 0.80-3.48]; P=0.20). CONCLUSION: Clinical expertise can be translated into a robust predictive model, guiding the selection of stage I NSCLC patients for MIS versus SBRT and effectively categorizing them into three distinct risk groups. Patients in the intermediate category could benefit most from multidisciplinary evaluation.

An Organic Mineral Adhesive Bone Graft: A Preclinical Study.

The development of a successful bone grafting technology with cohesive and adhesive properties has been an elusive goal for dental and orthopedic researchers. Tetracalcium phosphate combined with phosphoserine (TTCP-PS) is a synthetic, injectable, cohesive, self-setting, mineral-organic wet-field adhesive. The objective of this study was to evaluate four formulations of TTCP-PS in comparison to the conventional grafting materials, Bioglass and deproteinized cancellous bovine bone with a bioresorbable collagen membrane in standardized defects created in the angle of the rat mandible. Microcomputed tomography and histomorphometry were utilized to evaluate bone replacement with each of these materials after in vivo residence of either 4 or 12 weeks. The results of this study demonstrate that specific TTCP-PS formulations can form bone comparable to conventional materials in an osteopromotive mechanism but with the advantage of having cohesive and adhesive properties.

Development of a vocational rehabilitation intervention to support return-to-work and well-being following major trauma: a person-based approach.

OBJECTIVES: Major trauma centres (MTCs) save lives but rehabilitation to support return-to-work (RTW) is lacking. This paper describes development of a vocational rehabilitation intervention (the ROWTATE intervention) to support RTW following traumatic injury. DESIGN: Sequential and iterative person-based approach in four stages-Stage 1: review of evidence about the efficacy and mechanisms of RTW interventions; Stage 2: interviews (n=38) and focus groups (n=25) with trauma survivors and service providers in five UK MTCs to identify the issues, and challenges faced postinjury; Stage 3: codesign workshops (n=43) with trauma stakeholders in MTCs to conceptually test and identify intervention delivery barriers/enablers; Stage 4: meetings (n=7) with intervention development working group (IDWG) to: (1) generate guiding principles, (2) identify key intervention features (process, components, mechanisms) to address unmet rehabilitation needs; (3) generate a logic model and programme theory to illustrate how the intervention works; and (4) develop a training package to support delivery. RESULTS: Trauma survivors described unmet needs relating to early advice about RTW; psychological support; pain management; hidden disabilities (eg, fatigue); estimating recovery; and community, amputee and musculoskeletal rehabilitation. Mechanisms of effective interventions identified in the review included early intervention, colocation, employer engagement, case coordination and work accommodations. Intervention features identified by IDWG members (n=13) from stages 1 and 2 were use of stepped-care approaches by occupational therapists (OTs) and clinical psychologists (CPs), OT/CP formulation for complex cases, assessment of mental health problems, individually tailored rehabilitation including vocational goal setting, cross-sector coordination/communication, employer engagement, phased RTW, education/advice for family/employers, exploration of work alternatives, ongoing review of physical and mental health needs, work stability monitoring. Conceptual testing ratified the logic model. Geography and long waiting lists were identified as potential delivery barriers. CONCLUSIONS: Real-world testing of the intervention is underway in a randomised controlled trial.

Single-cell transcriptomic atlas of enteroendocrine cells along the murine gastrointestinal tract.

BACKGROUND: Enteroendocrine cells (EECs) produce over 20 gut hormones which contribute to intestinal physiology, nutrient metabolism and the regulation of food intake. The objective of this study was to generate a comprehensive transcriptomic map of mouse EECs from the stomach to the rectum. METHODS: EECs were purified by flow-cytometry from the stomach, upper small intestine, lower small intestine, caecum and large intestine of NeuroD1-Cre mice, and analysed by single cell RNA sequencing. Regional datasets were analysed bioinformatically and combined into a large cluster map. Findings were validated by L-cell calcium imaging and measurements of CCK secretion in vitro. RESULTS: 20,006 EECs across the full gastrointestinal tract could be subdivided based on their full transcriptome into 10 major clusters, each exhibiting a different pattern of gut hormone expression. EECs from the stomach were largely distinct from those found more distally, even when expressing the same hormone. Cell clustering was also observed when performed only using genes related to GPCR cell signalling, revealing GPCRs predominating in different EEC populations. Mc4r was expressed in 55% of Cck-expressing cells in the upper small intestine, where MC4R agonism was found to stimulate CCK release in primary cultures. Many individual EECs expressed more than one hormone as well as machinery for activation by multiple nutrients, which was supported by the finding that the majority of L-cells exhibited calcium responses to multiple stimuli. CONCLUSIONS: This comprehensive transcriptomic map of mouse EECs reveals patterns of GPCR and hormone co-expression that should be helpful in predicting the effects of nutritional and pharmacological stimuli on EECs from different regions of the gut. The finding that MC4R agonism stimulates CCK secretion adds to our understanding of the melanocortin system.

Assessing Jealousy: Factor Analyses, Measurement Invariance, Nomological Validity, and Longitudinal APIM Analyses of the Multidimensional Jealousy Scale.

The Multidimensional Jealousy Scale is the standard instrument to assess cognitive, emotional, and behavioral jealousy. We examined competing factor models and external correlations with broad and narrow traits. Across two studies, we analyzed four samples (Ntotal = 2,117). Confirmatory factor analysis supported the measurement model of three correlated factors in comparison to unidimensional, second-order, and bifactor models. Thus, speaking against the use of a total score. Furthermore, we found measurement invariance between romantic partners. We extended the Multidimensional Jealousy Scale (MJS)' nomological net to personality pathology and replicated prior findings of associations with broad and narrow traits. Study 2 examined longitudinal data (5- to 9-month lag) from couples. Actor-Partner Interdependence Model analyses showed that the MJS predicts facets of relationship satisfaction in actors and partners. We discuss potential avenues for revising the MJS (e.g., heteronormative item wordings).

Multifaceted effects of microplastics on soil-plant systems: Exploring the role of particle type and plant species.

Microplastics have emerged as a global environmental concern, yet their impact on terrestrial environments, particularly agricultural soils, remains underexplored. Agricultural soils, due to intensive farming, may serve as significant sinks for microplastics. This study investigated the effects of different types of microplastics-polyester microfibers, polyethylene terephthalate microfragments, and polystyrene microspheres-on soil properties and radish growth, while a complementary experiment examined the impact of polyester microfibers on the growth of lettuce and Chinese cabbage. Through both horizontal and vertical comparisons, this research comprehensively evaluated the interactions between microplastic particles and plant species in soil-plant systems. The results showed that polyester microfibers significantly affected soil bulk density, with effects varying based on planting conditions (p < 0.01). Polyethylene terephthalate microfragments and polystyrene microspheres reduced the proportion of small soil macroaggregates under radish cultivation (p < 0.01). Additionally, polystyrene microspheres significantly altered the total organic carbon stock in radish-growing soil, potentially affecting the microclimate (p < 0.01). Interestingly, polyester microfibers promoted lettuce seed germination and significantly enhanced the root biomass of Chinese cabbage (p < 0.05). Overall, the environmental effects of microplastic exposure varied depending on the type of particle and plant species, suggesting that microplastics are not always harmful to soil-plant systems and may even offer benefits in certain scenarios. Given the crucial role of soil-plant systems in terrestrial ecosystems, and their direct connection to food safety, human health, and global change, further research should explore both the positive and negative impacts of microplastics on agricultural practices.

The Triple E project: a factorial randomised controlled trial to enhance engagement with eHealth approaches to improve health risk behaviours among adolescents.

BACKGROUND: Digital, or eHealth, interventions are highly promising approaches to help adolescents improve their health behaviours and reduce their risk of chronic disease. However, they often have low uptake and retention. There is also a paucity of high-quality research into the predictors of eHealth engagement, and a lack of studies that have systematically evaluated existing engagement strategies in adolescent populations. This paper describes the protocol for a randomised controlled trial which primarily aims to assess the effectiveness of different strategies in increasing engagement with a healthy lifestyles app, Health4Life. Associations between the engagement strategies and improvements in adolescent health behaviours (healthy eating, physical activity, sleep, recreational screen time, smoking, alcohol use) will also be examined, along with potential predictors of adolescents' intentions to use health apps and their use of the Health4Life app. METHODS: The current study will aim to recruit 336 adolescent and parent/guardian dyads (total sample N = 672) primarily through Australia wide online advertising. All adolescent participants will have access to the Health4Life app (a multiple health behaviour change, self-monitoring mobile app). The trial will employ a 24 factorial design, where participants will be randomly allocated to receive 1 of 16 different combinations of the four engagement strategies to be evaluated: text messages, access to a health coach, access to additional gamified app content, and provision of parent/guardian information resources. Adolescents and parents/guardians will both complete consent processes, baseline assessments, and a follow-up assessment after 3 months. All participants will also be invited to complete a qualitative interview shortly after follow-up. The primary outcome, app engagement, will be assessed via an App Engagement Index (Ei) using data collected in the Health4Life app and the Mobile App Rating Scale - User version. DISCUSSION: This research will contribute significantly to building our understanding of the types of strategies that are most effective in increasing adolescents' engagement with health apps and which factors may predict adolescents' use of health apps. TRIAL REGISTRATION: The trial is registered at the Australian New Zealand Clinical Trials Registry (ACTRN12623000399695). Date registered: 19/04/2023.

Experience-dependent serotonergic signaling in glia regulates targeted synapse elimination.

The optimization of brain circuit connectivity based on initial environmental input occurs during critical periods characterized by sensory experience-dependent, temporally restricted, and transiently reversible synapse elimination. This precise, targeted synaptic pruning mechanism is mediated by glial phagocytosis. Serotonin signaling has prominent, foundational roles in the brain, but functions in glia, or in experience-dependent brain circuit synaptic connectivity remodeling, have been relatively unknown. Here, we discover that serotonergic signaling between glia is essential for olfactory experience-dependent synaptic glomerulus pruning restricted to a well-defined Drosophila critical period. We find that experience-dependent serotonin signaling is restricted to the critical period, with both (1) serotonin production and (2) 5-HT2A receptors specifically in glia, but not neurons, absolutely required for targeted synaptic glomerulus pruning. We discover that glial 5-HT2A receptor signaling limits the experience-dependent synaptic connectivity pruning in the critical period and that conditional reexpression of 5-HT2A receptors within adult glia reestablishes "critical period-like" experience-dependent synaptic glomerulus pruning at maturity. These results reveal an essential requirement for glial serotonergic signaling mediated by 5-HT2A receptors for experience-dependent synapse elimination.

Whole-exome sequencing reveals the genetic causes and modifiers of moyamoya syndrome.

Moyamoya vasculopathy secondary to various genetic disorders is classified as moyamoya syndrome (MMS). Recent studies indicate MMS occurs due to a combination of genetic modifiers and causative mutations for the primary genetic disorders. We performed whole-exome sequencing (WES) in 13 patients with various genetic disorders who developed MMS. WES successfully revealed the genetic diagnoses of neurofibromatosis type 1 (NF-1), Down syndrome, multisystemic smooth muscle dysfunction syndrome, Noonan syndrome, and alpha thalassemia. The previously reported modifier genes, RNF213 and MRVI1, were confirmed in the NF-1 and Down syndrome cases. Further analysis revealed rare hypomorphic variants in the causative genes of the primary disorders underlying MMS, such as Alagille syndrome and Rasopathies, conferred susceptibility to MMS. Genes involved in the development of pulmonary arterial hypertension (PAH), such as ABCC8 and BMPR2, were also identified as potential modifiers. The rare variants in the MMS and PAH genes were significantly enriched in the eight Japanese patients with MMS compared with the 104 Japanese individuals from the 1000 Genomes Project. Disease genes associated with the arterial occlusive conditions represented by those of Rasopathies and PAH may provide novel diagnostic markers and future therapeutic targets for MMS as well as moyamoya disease with an unknown cause.

Impact of Oral Hygiene Practices in Reducing Cardiometabolic Risk, Incidence, and Mortality: A Systematic Review.

Cardiometabolic diseases share many modifiable risk factors. However, periodontitis, a chronic inflammatory condition of the gums, is a risk factor that is rarely publicized. This systematic review aims to evaluate the impact of oral hygiene practices on the risk, incidence, and/or mortality rate of cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD). Searches were conducted using MEDLINE, Embase, Scopus, and CINHAL. Randomized controlled trials (RCTs), quasi-RCTs, and observational studies were included. Eligible studies reported on associations of toothbrushing, interdental cleaning, mouthwash, or toothpaste use, either alone or in combination with CVD, CKD, and/or T2DM outcomes in adults ≥ 18 years. Fifty-five studies were included. Cochrane's risk of bias tool and the Newcastle-Ottawa Scale were used for quality assessment. Data synthesis is narratively presented. Toothbrushing and interdental cleaning were associated with lower risk of developing T2DM or hypertension HR 0.54 [p < 0.001] and a lower mortality risk in those with CVD HR = 0.25 [p = 0.03]. Mouthwash use reportedly increased the risk of developing hypertension and diabetes by 85% and 55%, respectively. This review highlights how simple oral hygiene practices can reduce cardiometabolic risk. Non-dental clinicians could integrate the findings into chronic disease health promotion.

Structural Plasticity as a Driver of the Maturation of Pro-Interleukin-18.

Dynamics are often critical for biomolecular function. Herein we explore the role of motion in driving the maturation process of pro-IL-18, a potent pro-inflammatory cytokine that is cleaved by caspases-1 and -4 to generate the mature form of the protein. An NMR dynamics study of pro-IL-18, probing time scales over 12 orders of magnitude and focusing on 1H, 13C, and 15N spin probes along the protein backbone and amino-acid side chains, reveals a plastic structure, with millisecond time scale dynamics occurring in a pair of ß-strands, ß1 and ß*, that show large structural variations in a comparison of caspase-free and bound pro-IL-18 states. Fits of the relaxation data to a three-site model of exchange showed that the ground state secondary structure is maintained in the excited conformers, with the side chain of I48 that undergoes a buried-to-exposed conformational change in the caspase-free to -bound transition of pro-IL-18, sampling a more extensive range of torsion angles in one of the excited states characterized, suggesting partial unpacking in this region. Hydrogen exchange measurements establish the occurrence of an additional process, whereby strands ß1 and ß* locally unfold. Our data are consistent with a hierarchy of dynamic events that likely prime pro-IL-18 for facile caspase binding.

Effects of Creatine Supplementation on the Performance, Physiological Response, and Body Composition Among Swimmers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Although recent studies have increasingly focused on examining the potential benefits of creatine supplementation to improve performance in swimming events, the impact of creatine supplementation on swimming performance remains a topic of debate and controversy. A comprehensive meta-analytical review was undertaken to evaluate the effects of creatine supplementation on the performance, physiological response, and body composition among swimmers. METHODS: The research methodology adhered strictly to the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A comprehensive search was conducted across six databases (Cochrane Library, Web of Science, Scopus, Embase, PubMed, and SPORTDiscus) until March 23, 2024. Eligible studies that investigated the impact of creatine supplementation on swimming time, physiological parameters, and body composition in swimmers were included. For the meta-analysis, a random-effects model was employed to determine the collective effect and assess variations across distinct subgroups defined by swimming time, physiological metrics, and body composition. Meta-regression analysis was conducted on datasets comprising ten or more studies. Standardized mean differences (SMD) along with their corresponding 95% confidence intervals (CI) were calculated. To evaluate the methodological rigor of the included studies, the Physiotherapy Evidence Database (PEDro) scale was utilized. RESULTS: The systematic review included seventeen studies with a total of 361 subjects. No significant differences were observed in the overall effect during single sprint swimming (SMD: -0.05, 95% CI: -0.26, 0.15; p = 0.61), repeated interval swimming (SMD: -0.11; 95% CI: -0.46, 0.25; p = 0.56), physiological response (SMD: 0.04, 95% CI: -0.16, 0.23; p = 0.71), and body composition (SMD: 0.18; 95% CI: -0.05, 0.41; p = 0.12) between creatine and placebo groups. CONCLUSIONS: Creatine supplementation exhibited ineffectiveness in enhancing the performance, physiological response, and body composition among swimmers.

Four Years in, What Are the Research Priorities for Long COVID? A Research Priority-Setting Partnership Between People With Lived Experience, Carers, Clinicians and Researchers.

INTRODUCTION: Long COVID is a life-limiting condition that affects 65 million people worldwide. It devastates lives with uncertain illness trajectories, and yet, there are many research uncertainties as there is a lack of understanding of its causes, effective treatments and management plans. We set out to identify current research priorities for people with Long COVID, carers, healthcare professionals and researchers. METHODS: A systematic literature review and previous Long COVID priority-setting exercises identified three broad under-researched areas of Long COVID research within the fields of Public Health and Health Services Research: symptoms; managing day-to-day life; and the emotional impact of Long COVID. We disseminated an elicitation survey that asked for research questions in these areas; responses were analysed and summarised into 42 research questions. A survey was then disseminated, asking respondents to prioritise these 42 questions. Workshops were held with people with Long COVID, carers, healthcare professionals and researchers to analyse responses and agree the top 10 priorities. RESULTS: The top priorities in order were pharmacological treatment of Long COVID; understanding the pathophysiology; nonpharmacological symptom management; improving public and professional understanding of Long COVID; understanding of the long-term risks of Long COVID; improving financial and social supports; improving understanding of postviral syndromes; diagnostics; service redesign/pathways; and the well-being of children with Long COVID. CONCLUSION: Four years into the pandemic, there is an emphasis on the need for research on treatment, understanding and support for people living with Long COVID. PATIENT AND PUBLIC CONTRIBUTION: People with Long COVID and carers were involved in the study design, survey design, dissemination, data analysis, interpretation and reviewing and editing the manuscript.

Defining precancer: a grand challenge for the cancer community.

The term 'precancer' typically refers to an early stage of neoplastic development that is distinguishable from normal tissue owing to molecular and phenotypic alterations, resulting in abnormal cells that are at least partially self-sustaining and function outside of normal cellular cues that constrain cell proliferation and survival. Although such cells are often histologically distinct from both the corresponding normal and invasive cancer cells of the same tissue origin, defining precancer remains a challenge for both the research and clinical communities. Once sufficient molecular and phenotypic changes have occurred in the precancer, the tissue is identified as a 'cancer' by a histopathologist. While even diagnosing cancer can at times be challenging, the determination of invasive cancer is generally less ambiguous and suggests a high likelihood of and potential for metastatic disease. The 'hallmarks of cancer' set out the fundamental organizing principles of malignant transformation but exactly how many of these hallmarks and in what configuration they define precancer has not been clearly and consistently determined. In this Expert Recommendation, we provide a starting point for a conceptual framework for defining precancer, which is based on molecular, pathological, clinical and epidemiological criteria, with the goal of advancing our understanding of the initial changes that occur and opportunities to intervene at the earliest possible time point.

Identification of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease Subgroups by Machine Learning Implementation in Electronic Health Records.

Rationale: Acute exacerbations of COPD (AECOPD) are heterogeneous. Machine learning (ML) has previously been used to dissect some of the heterogeneity in COPD. The widespread adoption of electronic health records (EHRs) has led to the rapid accumulation of large amounts of patient data as part of routine clinical care. However, it is unclear whether the implementation of ML in EHR-derived data has the potential to identify subgroups of AECOPD. Objectives: Determine whether ML implementation using EHR data from severe AECOPD requiring hospitalization identifies relevant subgroups. Methods: This study used two retrospective cohorts of patients with AECOPD (non-COVID-19 and COVID-19) treated at Yale-New Haven Hospital (YNHHS). K-means clustering was used to identify patient subgroups. Measurements and main results: We identified three subgroups in the non-COVID cohort (n=1,736). Each subgroup had distinct clinical characteristics. The reference subgroup was the largest (n=904), followed by cardio-renal (n = 548) and eosinophilic (n=284). The eosinophilic subgroup had milder severity of AECOPD, including a shorter hospital stay (p<0.01). The cardio-renal subgroup had the highest mortality during (5%) and in the year after hospitalization (30%). Validation of the severe AECOPD classifier in the COVID-19 cohort recapitulated the characteristics seen in the non-COVID cohort. AECOPD subgroups in the COVID-19 cohort had different IL-1 beta, IL-2R, and IL-8 levels (FDR ≤ 0.05. These specific leukocyte and cytokine profiles resulted in inflammatory differences between the AECOPD subgroups based on C-reactive protein levels. Conclusions: Incorporating ML with EHR-data allows the identification of specific clinical and biological subgroups for severe AECOPD.

Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions.

Importance: The feasibility of implementing genome sequencing as an adjunct to traditional newborn screening (NBS) in newborns of different racial and ethnic groups is not well understood. Objective: To report interim results of acceptability, feasibility, and outcomes of an ongoing genomic NBS study in a diverse population in New York City within the context of the New York State Department of Health Newborn Screening Program. Design, Setting, and Participants: The Genomic Uniform-screening Against Rare Disease in All Newborns (GUARDIAN) study was a multisite, single-group, prospective, observational investigation of supplemental newborn genome screening with a planned enrollment of 100 000 participants. Parent-reported race and ethnicity were recorded at the time of recruitment. Results of the first 4000 newborns enrolled in 6 New York City hospitals between September 2022 and July 2023 are reported here as part of a prespecified interim analysis. Exposure: Sequencing of 156 early-onset genetic conditions with established interventions selected by the investigators were screened in all participants and 99 neurodevelopmental disorders associated with seizures were optional. Main Outcomes and Measures: The primary outcome was screen-positive rate. Additional outcomes included enrollment rate and successful completion of sequencing. Results: Over 11 months, 5555 families were approached and 4000 (72.0%) consented to participate. Enrolled participants reflected a diverse group by parent-reported race (American Indian or Alaska Native, 0.5%; Asian, 16.5%; Black, 25.1%; Native Hawaiian or Other Pacific Islander, 0.1%; White, 44.7%; 2 or more races, 13.0%) and ethnicity (Hispanic, 44.0%; not Hispanic, 56.0%). The majority of families consented to screening of both groups of conditions (both groups, 90.6%; disorders with established interventions only, 9.4%). Testing was successfully completed for 99.6% of cases. The screen-positive rate was 3.7%, including treatable conditions that are not currently included in NBS. Conclusions and Relevance: These interim findings demonstrate the feasibility of targeted interpretation of a predefined set of genes from genome sequencing in a population of different racial and ethnic groups. DNA sequencing offers an additional method to improve screening for conditions already included in NBS and to add those that cannot be readily screened because there is no biomarker currently detectable in dried blood spots. Additional studies are required to understand if these findings are generalizable to populations of different racial and ethnic groups and whether introduction of sequencing leads to changes in management and improved health outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT05990179.

Hepatic steatosis estimated by VCTE-derived CAP scores was associated with lower risks of liver-related events and all-cause mortality in patients with chronic liver disease.

INTRODUCTION: The Controlled Attenuated Parameter (CAP) score derived from vibration-controlled transient elastography (VCTE, i.e. Fibroscan®) is a well-validated marker of hepatic steatosis. It is unclear if CAP scores are associated with risks of liver-related outcomes or all-cause mortality. METHODS: In this retrospective cohort study, we identified 7,587 U.S. Veterans (2,689 with cured hepatitis C [HCV], 1,523 with alcohol-associated liver disease [ALD], 3,375 with metabolic dysfunction-associated steatotic liver disease [MASLD]) who underwent VCTE between 5/2015-12/2021. We followed patients for new hepatic decompensation, hepatocellular carcinoma (HCC), and death from the VCTE date until 1/1/2022. Multivariable Cox-proportional hazards regression was used to assess for the associations between CAP measurements and clinical outcomes, adjusting for age, sex, race/ethnicity, body mass index, Charlson Comorbidity Index, diabetes, liver disease etiology, liver stiffness measurements, and FIB-4, and was reported separately by disease etiology and advanced fibrosis status. RESULTS: Over a median follow-up time of ∼1.9 years, hepatic steatosis (grades 1-3 vs. 0) was associated with a lower risk of death (aHR 0.70, 95% CI: 0.57-0.85). Among patients with MASLD, hepatic steatosis was associated with a lower risk of decompensation (aHR 0.54, 95% CI: 0.32-0.90) and death (aHR 0.52, 95% CI: 0.37-0.73). These associations persisted in subgroup analyses of patients with advanced fibrosis and without cirrhosis. DISCUSSION: Among patients who underwent VCTE in clinical practice, the presence of substantial hepatic steatosis estimated by the CAP score was associated with lower all-cause mortality among all patients and lower risk of decompensation and death among those with MASLD.

Decoding the magnetic bit positioning error in a ferrimagnetic racetrack.

Current-driven motion of magnetic domain walls is one of the key technologies for developing storage class memory devices. Extensive studies have revealed a variety of material systems that exhibit high-speed and/or lower power propagation of the domain walls driven by electric current. However, few studies have assessed the reliability of the operations of the memory technology. Here, we decode the errors associated with writing and shifting domain walls using nanosecond current pulses in a ~5-micrometer-wide wire composed of a Pt/GdFeCo bilayer. We find that writing a domain wall at the edge of the wire causes a bit positioning error of ~0.3 micrometers, whereas the shifting process induces an error of ~0.1 micrometers per a 2-nanosecond-long current pulse. The error correlation among successive shifting is negligible when the current drive is sufficiently large. These features allow reliable operation of highly packed domain walls in a ferrimagnetic racetrack.

SPOT: spatial proteomics through on-site tissue-protein-labeling.

BACKGROUND: Spatial proteomics seeks to understand the spatial organization of proteins in tissues or at different subcellular localization in their native environment. However, capturing the spatial organization of proteins is challenging. Here, we present an innovative approach termed Spatial Proteomics through On-site Tissue-protein-labeling (SPOT), which combines the direct labeling of tissue proteins in situ on a slide and quantitative mass spectrometry for the profiling of spatially-resolved proteomics. MATERIALS AND METHODS: Efficacy of direct TMT labeling was investigated using seven types of sagittal mouse brain slides, including frozen tissues without staining, formalin-fixed paraffin-embedded (FFPE) tissues without staining, deparaffinized FFPE tissues, deparaffinized and decrosslinked FFPE tissues, and tissues with hematoxylin & eosin (H&E) staining, hematoxylin (H) staining, eosin (E) staining. The ability of SPOT to profile proteomes at a spatial resolution was further evaluated on a horizontal mouse brain slide with direct TMT labeling at eight different mouse brain regions. Finally, SPOT was applied to human prostate cancer tissues as well as a tissue microarray (TMA), where TMT tags were meticulously applied to confined regions based on the pathological annotations. After on-site direct tissue-protein-labeling, tissues were scraped off the slides and subject to standard TMT-based quantitative proteomics analysis. RESULTS: Tissue proteins on different types of mouse brain slides could be directly labeled with TMT tags. Moreover, the versatility of our direct-labeling approach extended to discerning specific mouse brain regions based on quantitative outcomes. The SPOT was further applied on both frozen tissues on slides and FFPE tissues on TMAs from prostate cancer tissues, where a distinct proteomic profile was observed among the regions with different Gleason scores. CONCLUSIONS: SPOT is a robust and versatile technique that allows comprehensive profiling of spatially-resolved proteomics across diverse types of tissue slides to advance our understanding of intricate molecular landscapes.