Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than DNMT3A (non- DNMT3A CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes. Methods: In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulating Tet2 -CHIP compared to controls transplanted wild-type bone marrow. Results: Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m 2 , and 24% had CHIP. Upon meta-analysis, non- DNMT3A CHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR ≥ 30 ml/min/1.73m (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non- DNMT3A CHIP carriers, relative to non-carriers (ß -0.61 ± 0.31 ml/min/1.73m 2 , p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. In a dietary adenine mouse model of CKD, Tet2 -CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. Conclusion: Non- DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.

Stereospecific Phosphination and Thioetherification of Organoboronic Esters.

Alkyllithium-activated organoboronic esters are found to undergo stereospecific phosphination with copper chloride and chlorophosphines. They also react with thiolsulfonate electrophiles under copper catalysis. These reactions enable stereospecific phosphination and thiolation of organoboronic esters, which are further applied in preparation of chiral ligands and biologically active molecules.

Safety and Outcome of Admission to Step-Down Level of Care in Patients with Low-Risk Spontaneous Intracerebral Hemorrhage: A Systematic Review and Meta-analysis.

Spontaneous intracerebral hemorrhage (ICH) is the most devastating type of stroke, and it is associated with high morbidity and mortality. Patients with a spontaneous ICH are routinely admitted to an intensive care unit (ICU). However, an ICU is a valuable and limited resource, and not all patients may require this level of care. The authors conducted a systematic review and meta-analysis evaluating the safety and outcome of admission to a step-down level of care or stroke unit (SU) compared to intensive care in adult patients with low-risk spontaneous ICH. PubMed, Embase, and the Cochrane Library were searched for randomized clinical trials and observational cohort studies. The Mantel-Haenszel method or inverse variance, as applicable, was applied to calculate an overall effect estimate for each outcome by combining the specific risk ratio (RR) or standardized mean difference. Risk of bias was analyzed using the Newcastle-Ottawa Scale. The protocol was registered in PROSPERO (CRD42023481915). The primary outcome examined was in-hospital mortality. Secondary outcomes were unfavorable short-term outcome, length of hospital stay, and (re)admission to the ICU. Five retrospective cohort studies involving 1347 patients were included in the qualitative analysis. Two of the studies had severity-matched groups. The definition of low-risk ICH was heterogeneous among the studies. Admission to an SU was associated with a similar rate of mortality compared to admission to an ICU (1.4% vs. 0.6%; RR 1.66; 95% confidence interval [CI] 0.24-11.41; P = 0.61), a similar rate of unfavorable short-term outcome (14.6% vs. 19.2%; RR 0.77; 95% CI 0.43-1.36; P = 0.36), and a significantly shorter mean length of stay (standardized mean difference - 0.87 days; 95% CI - 1.15 to - 0.60; P < 0.01). Risk of bias was low to moderate for each outcome. The available literature suggests that a select subgroup of patients with ICH may be safely admitted to the SU without affecting short-term outcome, potentially saving in-hospital resources and reducing length of stay. Further studies are needed to identify specific and reliable characteristics of this subgroup of patients.

Epigenetic scores derived in saliva are associated with gestational age at birth.

BACKGROUND: Epigenetic scores (EpiScores), reflecting DNA methylation (DNAm)-based surrogates for complex traits, have been developed for multiple circulating proteins. EpiScores for pro-inflammatory proteins, such as C-reactive protein (DNAm CRP), are associated with brain health and cognition in adults and with inflammatory comorbidities of preterm birth in neonates. Social disadvantage can become embedded in child development through inflammation, and deprivation is overrepresented in preterm infants. We tested the hypotheses that preterm birth and socioeconomic status (SES) are associated with alterations in a set of EpiScores enriched for inflammation-associated proteins. RESULTS: In total, 104 protein EpiScores were derived from saliva samples of 332 neonates born at gestational age (GA) 22.14 to 42.14 weeks. Saliva sampling was between 36.57 and 47.14 weeks. Forty-three (41%) EpiScores were associated with low GA at birth (standardised estimates |0.14 to 0.88|, Bonferroni-adjusted p-value < 8.3 × 10-3). These included EpiScores for chemokines, growth factors, proteins involved in neurogenesis and vascular development, cell membrane proteins and receptors, and other immune proteins. Three EpiScores were associated with SES, or the interaction between birth GA and SES: afamin, intercellular adhesion molecule 5, and hepatocyte growth factor-like protein (standardised estimates |0.06 to 0.13|, Bonferroni-adjusted p-value < 8.3 × 10-3). In a preterm subgroup (n = 217, median [range] GA 29.29 weeks [22.14 to 33.0 weeks]), SES-EpiScore associations did not remain statistically significant after adjustment for sepsis, bronchopulmonary dysplasia, necrotising enterocolitis, and histological chorioamnionitis. CONCLUSIONS: Low birth GA is substantially associated with a set of EpiScores. The set was enriched for inflammatory proteins, providing new insights into immune dysregulation in preterm infants. SES had fewer associations with EpiScores; these tended to have small effect sizes and were not statistically significant after adjusting for inflammatory comorbidities. This suggests that inflammation is unlikely to be the primary axis through which SES becomes embedded in the development of preterm infants in the neonatal period.

Brain 3T magnetic resonance imaging in neonates: features and incidental findings from a research cohort enriched for preterm birth.

BACKGROUND AND OBJECTIVES: The survival rate and patterns of brain injury after very preterm birth are evolving with changes in clinical practices. Additionally, incidental findings can present legal, ethical and practical considerations. Here, we report MRI features and incidental findings from a large, contemporary research cohort of very preterm infants and term controls. METHODS: 288 infants had 3T MRI at term-equivalent age: 187 infants born <32 weeks without major parenchymal lesions, and 101 term-born controls. T1-weighted, T2-weighted and susceptibility-weighted imaging were used to classify white and grey matter injury according to a structured system, and incidental findings described. RESULTS: Preterm infants: 34 (18%) had white matter injury and 4 (2%) had grey matter injury. 51 (27%) infants had evidence of intracranial haemorrhage and 34 (18%) had punctate white matter lesions (PWMLs). Incidental findings were detected in 12 (6%) preterm infants. Term infants: no term infants had white or grey matter injury. Incidental findings were detected in 35 (35%); these included intracranial haemorrhage in 22 (22%), periventricular pseudocysts in 5 (5%) and PWMLs in 4 (4%) infants. From the whole cohort, 10 (3%) infants required referral to specialist services. CONCLUSIONS: One-fifth of very preterm infants without major parenchymal lesions have white or grey matter abnormalities at term-equivalent age. Incidental findings are seen in 6% of preterm and 35% of term infants. Overall, 3% of infants undergoing MRI for research require follow-up due to incidental findings. These data should help inform consent procedures for research and assist service planning for centres using 3T neonatal brain MRI for clinical purposes.

Inhibition of prefrontal cortex parvalbumin interneurons mitigates behavioral and physiological sequelae of chronic stress in male mice.

Chronic stress leads to hypofunction of the medial prefrontal cortex (mPFC), mechanisms of which remain to be determined. Enhanced activation of GABAergic of parvalbumin (PV) expressing interneurons (INs) is thought to play a role in stress-induced prefrontal inhibition. In this study, we tested whether chemogenetic inhibition of mPFC PV INs after chronic stress can rescue chronic stress-related behavioral and physiological phenotypes. Mice underwent 2 weeks of chronic variable stress (CVS) followed by a battery of behavioral tests known to be affected by chronic stress exposure, e.g. an open field (OF), novel object recognition (NOR), tail suspension test (TST), sucrose preference test (SPT), and light dark (LD) box. Inhibitory DREADDs were actuated by 3 mg/kg CNO administered 30 min prior to each behavioral test. CVS caused hyperactivity in the OF, reduced sucrose preference in the SPT (indicative of enhanced anhedonia), and increased anxiety-like behavior in the LD box. Inhibition of PV IN after stress mitigated these effects. In addition, CVS also resulted in reduced thymus weight and body weight loss, which were also mitigated by PV IN inhibition. Our results indicate that chronic stress leads to plastic changes in PV INs that may be mitigated by chemogenetic inhibition. Our findings implicate cortical GABAergic INs as a therapeutic target in stress-related diseases.

Motor vehicle collision characteristics and hospitalization outcomes associated with mild traumatic brain injury and concomitant whiplash injury.

OBJECTIVE: Few large studies have investigated the factors and outcomes related to concomitant injuries occurring alongside mild traumatic brain injury (mTBI) after motor vehicle collisions (MVCs). Thus, the objective of this study was to assess whether MVC characteristics predict which patients with mTBI will have concomitant whiplash injury, and whether concomitant whiplash injury affects care utilization for these patients. METHODS: This retrospective cohort study included 22,213 patients with mTBI after MVC identified from the American College of Surgeons Trauma Quality Programs dataset. A hierarchical logistic regression model was constructed to investigate patient and MVC factors associated with concomitant whiplash injury. Propensity score matching on whiplash status, in conjunction with a multivariable logistic regression model, assessed if concomitant whiplash affected odds of hospitalization. In the subgroup of patients who were hospitalized, associations with hospital length of stay (LOS) and discharge disposition were investigated. RESULTS: The median (IQR) age was 34 (24-51) years, with a median Glasgow Coma Scale score at presentation of 15 (15-15). Patients with concomitant whiplash were older (median 36 years vs 34 years, p = 0.03) and had higher rates of hospitalization (75% vs 64%, p < 0.001). In the hierarchical model for associations with concomitant whiplash injury, patients with blood alcohol content (BAC) greater than the federal driving limit had lower odds of concomitant whiplash (OR 0.63, 95% CI 0.49-0.81) along with those who had airbag deployment (OR 0.80, 95% CI 0.68-0.95), but seatbelt use was associated with greater odds (OR 1.41, 95% CI 1.16-1.71). After matching, concomitant whiplash was independently associated with increased odds of hospitalization (OR 1.67, 95% CI 1.40-1.99) while seatbelt use was associated with decreased odds (OR 0.88, 95% CI 0.81-0.95). Among hospitalized patients, concomitant whiplash was not associated with hospital LOS or discharge disposition. CONCLUSIONS: MVC characteristics such as alcohol consumption and airbag deployment were protective toward development of concomitant whiplash for mTBI patients, while seatbelt use was associated with higher risk. Concomitant whiplash increases the odds of hospitalization for mTBI patients but does not affect hospital LOS or discharge disposition, while seatbelt use is associated with lower rates of hospitalization and a more favorable hospital course. These findings provide context to injury patterns and care provision after a common mechanism of injury.

Chronic Kidney Disease Stage and Cardiovascular and Mortality Events Among Older Adults: The SPRINT Trial.

Rationale & Objective: The risk implications of the Kidney Disease: Improving Global Outcomes (KDIGO) chronic kidney disease classification in older adults are controversial. We evaluated the risk of adverse outcomes in this population across categories of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). Study Design: Prospective cohort. Settings & Participants: In total, 2,509 participants aged ≥75 years in the Systolic Blood Pressure Intervention Trial (SPRINT). Exposure: KDIGO eGFR and UACR categories. We combined KDIGO categories G1 and G2, G3b and G4, as well as A2 and A3. Outcomes: Primary SPRINT outcome (composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes), and all-cause death. Analytical Approach: Multivariable Cox proportional hazard models. Results: Mean age was 79.8 years, and 37.4% were female. The mean eGFR was 64.0 mL/min/1.73 m2, and the median UACR was 13.1 mg/g. In multivariable Cox proportional hazard analysis, compared with participants with eGFR ≥ 60 mL/min/1.73 m2 and UACR < 30 mg/g, there was no statistically significant difference in the risk of the primary outcome among participants with eGFR 45-59 or 15-44 mL/min/1.73 m2 and UACR < 30 mg/g. However, those with eGFR 45-59 or 15-44 mL/min/1.73 m2 and UACR ≥ 30 mg/g had higher risk of the primary outcome (HR [95% CI], 1.97 [1.27-3.04] and 3.32 [2.23-4.93], respectively). The risk for all-cause death was higher for each category of abnormal eGFR and UACR, with the highest risk observed among those with eGFR 15-44 mL/min/1.73 m2 and UACR ≥ 30 mg/g (3.34 [2.05-5.44]). Limitations: Individuals with diabetes and urine protein >1 g/day were excluded from SPRINT. Conclusion: Among older adults SPRINT participants, low eGFR without albuminuria was associated with higher mortality but not with increased risk of cardiovascular events. Additional studies are needed to evaluate an adapted chronic kidney disease stage-based risk stratification for older adults.

Using data from participants in the SPRINT trial, we evaluated the association of chronic kidney disease stage with adverse clinical outcomes among adults older than 75 years without diabetes. We found that low level of kidney function determined by a low estimated glomerular filtration rate with moderately or severely increased urine albumin excretion was associated with increased risk for cardiovascular events and all-cause mortality. However, low estimated glomerular filtration rate with normal or mildly increased urinary albumin excretion was not consistently associated with these adverse outcomes. This finding supports the need for additional studies to evaluate an age-adapted classification of chronic kidney disease to improve risk stratification among older adults.

Preliminary field validity of ActiGraph-based energy expenditure estimation in wheelchair users with spinal cord injury.

STUDY DESIGN: Cross-sectional validation study. OBJECTIVES: To develop a raw acceleration signal-based random forest (RF) model for predicting total energy expenditure (TEE) in manual wheelchair users (MWUs) and evaluate the preliminary field validity of this new model, along with four existing models published in prior literature, using the Doubly Labeled Water (DLW) method. SETTING: General community and research institution in Pittsburgh, USA. METHODS: A total of 78 participants' data from two previous studies were used to develop the new RF model. A seven-day cross-sectional study was conducted to collect participants' free-living physical activity and TEE data, resting metabolic rate, demographics, and anthropometrics. Ten MWUs with spinal cord injury (SCI) completed the study, with seven participants having valid data for evaluating the preliminary field validity of the five models. RESULTS: The RF model achieved a mean absolute error (MAE) of 0.59 ± 0.60 kcal/min and a mean absolute percentage error (MAPE) of 23.6% ± 24.3% on the validation set. For preliminary field validation, the five assessed models yielded MAE from 136 kcal/day to 1141 kcal/day and MAPE from 6.1% to 50.2%. The model developed by Nightingale et al. in 2015 achieved the best performance (MAE: 136 ± 96 kcal/day, MAPE: 6.1% ± 4.7%), while the RF model achieved comparable performance (MAE: 167 ± 99 kcal/day, MAPE: 7.4% ± 5.1%). CONCLUSIONS: Two existing models and our newly developed RF model showed good preliminary field validity for assessing TEE in MWUs with SCI and the potential to detect lifestyle change in this population. Future large-scale field validation studies and model iteration are recommended.

Effectiveness of HIV self-testing when offered within assisted partner services in Western Kenya (APS-HIVST Study): a cluster randomized controlled trial.

INTRODUCTION: Assisted partner services (APS) is an effective strategy for increasing HIV testing, new diagnosis, and linkage to care among sexual partners of people living with HIV (PLWH). APS can be resource intensive as it requires community tracing to locate each partner named and offer them testing. There is limited evidence for the effectiveness of offering HIV self-testing (HIVST) as an option for partner testing within APS. METHODS: We conducted a cluster randomized controlled trial comparing provider-delivered HIV testing (Standard APS) versus offering partners the option of provider-delivered testing or HIVST (APS+HIVST) at 24 health facilities in Western Kenya. Facilities were randomized 1:1 and we conducted intent-to-treat analyses using Poisson generalized linear mixed models to estimate intervention impact on HIV testing, new HIV diagnoses, and linkage to care. All models accounted for clustering at the clinic level and new diagnoses and linkage models were adjusted for individual-level age, sex, and income a priori. RESULTS: From March to December 2021, 755 index clients received APS and named 5054 unique partners. Among these, 1408 partners reporting a prior HIV diagnosis were not eligible for HIV testing and were excluded from analyses. Of the remaining 3646 partners, 96.9% were successfully contacted for APS and tested for HIV: 2111 (97.9%) of 2157 in the APS+HIVST arm and 1422 (95.5%) of 1489 in the Standard APS arm. In the APS+HIVST arm, 84.6% (1785/2111) tested via HIVST and 15.4% (326/2111) received provider-delivered testing. Overall, 16.7% of the 3533 who tested were newly diagnosed with HIV (APS+HIVST = 357/2111 [16.9%]; Standard APS = 232/1422 [16.3%]). Of the 589 partners who were newly diagnosed, 90.7% were linked to care (APS+HIVST = 309/357 [86.6%]; Standard APS = 225/232 [97.0%]). There were no significant differences between the two arms in HIV testing (relative risk [RR]: 1.02, 95% CI: 0.96-1.10), new HIV diagnoses (adjusted RR [aRR]: 1.03, 95% CI: 0.76-1.39) or linkage to care (aRR: 0.88, 95% CI: 0.74-1.06). CONCLUSIONS: There were no differences between APS+HIVST and Standard APS, demonstrating that integrating HIVST into APS continues to be an effective strategy for identifying PLWH by successfully reaching and HIV testing >95% of elicited partners, newly diagnosing with HIV one in six of those tested, >90% of whom were linked to care. CLINICAL TRIAL NUMBER: NCT04774835.

Expectations of How Acute Cannabis Use Affects Gambling Experiences and Behaviors.

Emerging research shows that many individuals commonly consume cannabis while gambling. However, individuals' expectations for how cannabis consumption will impact their gambling behavior remain unknown. Participants who gambled weekly (N = 472) were recruited from Amazon Mechanical Turk and completed assessments of gambling behaviors, cannabis consumption, and expectations about the influence of cannabis on gambling. Almost all participants (94%) screened positive for problem gambling. Over half of participants (55%) reported lifetime cannabis consumption, and almost all those participants (99%) reported gambling under the influence of cannabis (GUIC) in the past month. Most participants agreed with positive expectations of gambling; they expected that they would feel calmer when under the influence of cannabis (61.4%), that gambling would be more enjoyable (61.0%), and that their gambling skills would increase when GUIC (60.6%). At the same time, most participants also agreed with negative expectations of GUIC. They expected cannabis use would make them more careless (56.4%), more anxious (54.8%), and less able to concentrate (53.7%) while gambling. Negative cannabis expectancies were significantly associated with the severity of cannabis consumption. Both positive and negative cannabis expectancies were significantly associated with gambling problems and time spent gambling under the influence of cannabis. These findings indicate that expectations may influence the decision to consume cannabis and gamble simultaneously. This study contributes to the need for addressing cannabis expectations during treatment of gambling problems.

Primary Renal Lymphoma: A Rare Cause of Bilateral Renal Enlargement and Acute Renal Failure in a Patient With Rheumatoid Arthritis.

Primary renal lymphoma (PRL) is a rare non-Hodgkin's lymphoma (NHL) involving the kidneys without evidence of extra-renal involvement. We describe a 66-year-old female who presented with bilateral pleural effusions, and acute renal failure and was diagnosed with primary renal diffuse large B-cell lymphoma (DLBCL). She presented with shortness of breath due to bilateral pleural effusions and acute renal failure. Computed tomography (CT) of the chest reported bilateral pleural effusions. Thoracocentesis and subsequent fluid analysis reported non-malignant effusion. Her kidney function worsened during her hospital stay, requiring dialysis. Nonspecific findings such as bilateral renal enlargement on imaging prompted a renal biopsy. Histopathology reported mixed tubulointerstitial atypical lymphocytic CD 20 and BCL-6 positive cell infiltrates, confirming non-Hodgkin diffuse large B-cell lymphoma. Whole-body positron emission tomography/CT (PET/CT) and brain magnetic resonance imaging (MRI) ruled out the involvement of any other organs or lymph nodes, confirming our diagnosis of PRL. She was treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Her kidney function recovered fully and remained normal at the one-year follow-up. We highlight the importance of recognizing PRL as an underlying cause of renal failure and its association with autoimmune diseases. Prompt investigation with timely diagnosis and treatment can result in improved morbidity and mortality in these patients.

Radar for Europa Assessment and Sounding: Ocean to Near-Surface (REASON).

The Radar for Europa Assessment and Sounding: Ocean to Near-surface (REASON) is a dual-frequency ice-penetrating radar (9 and 60 MHz) onboard the Europa Clipper mission. REASON is designed to probe Europa from exosphere to subsurface ocean, contributing the third dimension to observations of this enigmatic world. The hypotheses REASON will test are that (1) the ice shell of Europa hosts liquid water, (2) the ice shell overlies an ocean and is subject to tidal flexing, and (3) the exosphere, near-surface, ice shell, and ocean participate in material exchange essential to the habitability of this moon. REASON will investigate processes governing this material exchange by characterizing the distribution of putative non-ice material (e.g., brines, salts) in the subsurface, searching for an ice-ocean interface, characterizing the ice shell's global structure, and constraining the amplitude of Europa's radial tidal deformations. REASON will accomplish these science objectives using a combination of radar measurement techniques including altimetry, reflectometry, sounding, interferometry, plasma characterization, and ranging. Building on a rich heritage from Earth, the moon, and Mars, REASON will be the first ice-penetrating radar to explore the outer solar system. Because these radars are untested for the icy worlds in the outer solar system, a novel approach to measurement quality assessment was developed to represent uncertainties in key properties of Europa that affect REASON performance and ensure robustness across a range of plausible parameters suggested for the icy moon. REASON will shed light on a never-before-seen dimension of Europa and - in concert with other instruments on Europa Clipper - help to investigate whether Europa is a habitable world.

IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques.

The regulation of inflammatory responses and pulmonary disease during SARS-CoV-2 infection is incompletely understood. Here we examine the roles of the prototypic pro- and anti-inflammatory cytokines IFNγ and IL-10 using the rhesus macaque model of mild COVID-19. We find that IFNγ drives the development of 18fluorodeoxyglucose (FDG)-avid lesions in the lungs as measured by PET/CT imaging but is not required for suppression of viral replication. In contrast, IL-10 limits the duration of acute pulmonary lesions, serum markers of inflammation and the magnitude of virus-specific T cell expansion but does not impair viral clearance. We also show that IL-10 induces the subsequent differentiation of virus-specific effector T cells into CD69+CD103+ tissue resident memory cells (Trm) in the airways and maintains Trm cells in nasal mucosal surfaces, highlighting an unexpected role for IL-10 in promoting airway memory T cells during SARS-CoV-2 infection of macaques.

Admixture Mapping of Chronic Kidney Disease and Risk Factors in Hispanic/Latino Individuals From Central America Country of Origin.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in Central America, and genetic factors may contribute to CKD risk. To understand the influences of genetic admixture on CKD susceptibility, we conducted an admixture mapping screening of CKD traits and risk factors in US Hispanic and Latino individuals from Central America country of origin. METHODS: We analyzed 1023 participants of HCHS/SOL (Hispanic Community Health Study/Study of Latinos) who reported 4 grandparents originating from the same Central America country. Ancestry admixture findings were validated on 8191 African Americans from WHI (Women's Health Initiative), 3141 American Indians from SHS (Strong Heart Study), and over 1.1 million European individuals from a multistudy meta-analysis. RESULTS: We identified 3 novel genomic regions for albuminuria (chromosome 14q24.2), CKD (chromosome 6q25.3), and type 2 diabetes (chromosome 3q22.2). The 14q24.2 locus driven by a Native American ancestry had a protective effect on albuminuria and consisted of 2 nearby regions spanning the RGS6 gene. Variants at this locus were validated in American Indians. The 6q25.3 African ancestry-derived locus, encompassing the ARID1B gene, was associated with increased risk for CKD and replicated in African Americans through admixture mapping. The European ancestry type 2 diabetes locus at 3q22.2, encompassing the EPHB1 and KY genes, was validated in European individuals through variant association. CONCLUSIONS: US Hispanic/Latino populations are culturally and genetically diverse. This study focusing on Central America grandparent country of origin provides new loci discovery and insights into the ancestry-of-origin influences on CKD and risk factors in US Hispanic and Latino individuals.

Location of Shoulder Glenoid Labral Tears: A Study of 1763 Consecutive Patients.

BACKGROUND: Anterior shoulder labral tearing has historically been considered the most common location of shoulder labral pathology. Recently, smaller studies have reported that posterior labral involvement may be more common than previously recognized. PURPOSE: To examine the location of surgically repaired labral tears by a single surgeon over a consecutive 23-year period. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 1763 consecutive patients who underwent arthroscopic or open shoulder labral repair by a single seniorsports medicine fellowship-trained orthopaedic surgeon between April 2000 and April 2023 were retrospectively reviewed. Current Procedural Terminology codes were used to identify patients, which included 29806, 29807, 29822, and 29823. Exclusion criteria included isolated shoulder manipulation or glenohumeral joint or labral debridement that did not include repair. Intraoperative glenoid labral tears observed were categorized into 7 broad categories: (1) anterior labral tears, (2) posterior labral tears, (3) superior labral anterior posterior (SLAP) type II tears (A, B, or C), (4) SLAP type V tears, (5) SLAP type VIII tears, or (6) circumferential labral tears (combined SLAP, anterior, and posterior labral tear). Shoulders diagnosed with multiple tear patterns (ie, anterior and posterior) were also noted. RESULTS: During the 23-year period, 1763 patients underwent arthroscopic or open labral repair; they included 1295 male and 468 female patients, ranging in age from 12 to 70 years, with a mean age of 23.2 years and median age of 19 years. Overall, 28.4% of tears involved the anterior labrum, 64.9% involved the posterior labrum, and 59.6% involved the superior labrum. Regarding isolated tears, 9.3% were isolated anterior labral tears, 19.7% were isolated posterior labral tears, 11.5% involved the anterior and posterior labrum, 22.2% were isolated superior (SLAP type II-IV) tears, 3.63% were isolated SLAP type V tears, 29.8% were isolated SLAP type VIII tears, and 4.1% were circumferential tears. CONCLUSION: Posterior shoulder labral tearing was more common than anterior tearing in a large consecutive series of 1763 patients who underwent surgical repair. This highlights the importance of posterior labral pathology, which sometimes may be overlooked because of more vague complaints, with pain and loss of function being the most common.

Computable species descriptions and nanopublications: applying ontology-based technologies to dung beetles (Coleoptera, Scarabaeinae).

Background: Taxonomy has long struggled with analysing vast amounts of phenotypic data due to computational and accessibility challenges. Ontology-based technologies provide a framework for modelling semantic phenotypes that are understandable by computers and compliant with FAIR principles. In this paper, we explore the use of Phenoscript, an emerging language designed for creating semantic phenotypes, to produce computable species descriptions. Our case study centers on the application of this approach to dung beetles (Coleoptera, Scarabaeinae). New information: We illustrate the effectiveness of Phenoscript for creating semantic phenotypes. We also demonstrate the ability of the Phenospy python package to automatically translate Phenoscript descriptions into natural language (NL), which eliminates the need for writing traditional NL descriptions. We introduce a computational pipeline that streamlines the generation of semantic descriptions and their conversion to NL. To demonstrate the power of the semantic approach, we apply simple semantic queries to the generated phenotypic descriptions. This paper addresses the current challenges in crafting semantic species descriptions and outlines the path towards future improvements. Furthermore, we discuss the promising integration of semantic phenotypes and nanopublications, as emerging methods for sharing scientific information. Overall, our study highlights the pivotal role of ontology-based technologies in modernising taxonomy and aligning it with the evolving landscape of big data analysis and FAIR principles.

CpG island turnover events predict evolutionary changes in enhancer activity.

BACKGROUND: Genetic changes that modify the function of transcriptional enhancers have been linked to the evolution of biological diversity across species. Multiple studies have focused on the role of nucleotide substitutions, transposition, and insertions and deletions in altering enhancer function. CpG islands (CGIs) have recently been shown to influence enhancer activity, and here we test how their turnover across species contributes to enhancer evolution. RESULTS: We integrate maps of CGIs and enhancer activity-associated histone modifications obtained from multiple tissues in nine mammalian species and find that CGI content in enhancers is strongly associated with increased histone modification levels. CGIs show widespread turnover across species and species-specific CGIs are strongly enriched for enhancers exhibiting species-specific activity across all tissues and species. Genes associated with enhancers with species-specific CGIs show concordant biases in their expression, supporting that CGI turnover contributes to gene regulatory innovation. Our results also implicate CGI turnover in the evolution of Human Gain Enhancers (HGEs), which show increased activity in human embryonic development and may have contributed to the evolution of uniquely human traits. Using a humanized mouse model, we show that a highly conserved HGE with a large CGI absent from the mouse ortholog shows increased activity at the human CGI in the humanized mouse diencephalon. CONCLUSIONS: Collectively, our results point to CGI turnover as a mechanism driving gene regulatory changes potentially underlying trait evolution in mammals.

Nasal cathelicidin is expressed in early life and is increased during mild, but not severe respiratory syncytial virus infection.

Respiratory syncytial virus is the major cause of acute lower respiratory tract infections in young children, causing extensive mortality and morbidity globally, with limited therapeutic or preventative options. Cathelicidins are innate immune antimicrobial host defence peptides and have antiviral activity against RSV. However, upper respiratory tract cathelicidin expression and the relationship with host and environment factors in early life, are unknown. Infant cohorts were analysed to characterise early life nasal cathelicidin levels, revealing low expression levels in the first week of life, with increased levels at 9 months which are comparable to 2-year-olds and healthy adults. No impact of prematurity on nasal cathelicidin expression was observed, nor were there effects of sex or birth mode, however, nasal cathelicidin expression was lower in the first week-of-life in winter births. Nasal cathelicidin levels were positively associated with specific inflammatory markers and demonstrated to be associated with microbial community composition. Importantly, levels of nasal cathelicidin expression were elevated in infants with mild RSV infection, but, in contrast, were not upregulated in infants hospitalised with severe RSV infection. These data suggest important relationships between nasal cathelicidin, upper airway microbiota, inflammation, and immunity against RSV infection, with interventional potential.