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.

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.

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.

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.

Development of Aptamers for RNase Inactivation in Xtract-Free™ Sample Collection and Transport Medium.

There is a significant need to develop new environmentally friendly, extraction-free sample collection mediums that can effectively preserve and protect genetic material for point-of-care and/or self-collection, home-collection, and mail-back testing. Systematic evolution of ligands by exponential enrichment (SELEX) was used to create anti-ribonuclease (RNase) deoxyribonucleic acid (DNA) aptamers against purified RNase A conjugated to paramagnetic carboxylated beads. Following eight rounds of SELEX carried out under various stringency conditions, e.g., selection using Xtract-Free™ (XF) specimen collection medium and elevated ambient temperature of 28 °C, a panel of five aptamers was chosen following bioinformatic analysis using next-generation sequencing. The efficacy of aptamer inactivation of RNase was assessed by monitoring ribonucleic acid (RNA) integrity via fluorometric and real-time RT-PCR analysis. Inclusion of aptamers in reaction incubations resulted in an 8800- to 11,200-fold reduction in RNase activity, i.e., digestion of viral RNA compared to control. Thus, anti-RNase aptamers integrated into XF collection medium as well as other commercial reagents and kits have great potential for ensuring quality intact RNA for subsequent genomic analyses.

Sequential Infection with Influenza A Virus Followed by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Leads to More Severe Disease and Encephalitis in a Mouse Model of COVID-19.

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly influenza viruses, is a global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected with influenza A virus (IAV) followed by SARS-CoV-2 and the host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 alone. The sequentially infected mice showed reduced SARS-CoV-2 RNA synthesis, yet exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to the singly infected or control mice. Sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz Tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis, albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by IAV inhibits SARS-CoV-2. Interestingly, infection with an attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest coinfection ('twinfection') is deleterious and mitigation steps should be instituted as part of the comprehensive public health and management strategy of COVID-19.

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.

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome.

Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest multi-brain-region bulk transcriptional datasets for the rhesus macaque and characterized sex-biased gene expression patterns to investigate the translatability of this species for sex-biased neurological conditions. We identify patterns similar to those in humans, which are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and support the rhesus macaque model for the translational study of these conditions.

Correction: Electron microscope loading and in situ nanoindentation of water ice at cryogenic temperatures.

[This corrects the article DOI: 10.1371/journal.pone.0281703.].

Lessons Learned from Remote Assessment of Mother-Infant Interactions Among Women with Postpartum Depression.

Purpose: The COVID-19 pandemic posed challenges to measuring mother-infant interactions, a critical outcome for many interventions to support mothers with postpartum depression symptoms and their new infants. The current study describes the process and lessons learned from implementing a remote assessment of mother-infant interactions during the pandemic. Description: At the onset of the COVID-19 pandemic, we pivoted from in-person to using two different strategies to remotely assess mother-infant interactions: (1) participants independently recorded and uploaded videos of free-play with their child; and (2) research team conducted a live-video recording of the free-play. Assessment: We found initial barriers including technical and video quality issues but overall, a remote option could increase enrollment and retention rates in a sample of postpartum women across various racial/ethnic groups and economic levels. Conclusion: Our experiences in conducting remote assessments with postpartum women add to growing evidence for the feasibility and validity of remote visits. This showed how our methods can be implemented in future research and in practice with postpartum mothers and their infants.

How cytoskeletal crosstalk makes cells move: Bridging cell-free and cell studies.

Cell migration is a fundamental process for life and is highly dependent on the dynamical and mechanical properties of the cytoskeleton. Intensive physical and biochemical crosstalk among actin, microtubules, and intermediate filaments ensures their coordination to facilitate and enable migration. In this review, we discuss the different mechanical aspects that govern cell migration and provide, for each mechanical aspect, a novel perspective by juxtaposing two complementary approaches to the biophysical study of cytoskeletal crosstalk: live-cell studies (often referred to as top-down studies) and cell-free studies (often referred to as bottom-up studies). We summarize the main findings from both experimental approaches, and we provide our perspective on bridging the two perspectives to address the open questions of how cytoskeletal crosstalk governs cell migration and makes cells move.

Localization of the greater occipital nerve through palpation of bony landmarks: A cadaveric study.

OBJECTIVE: to provide anatomic confirmation that standard methods which practitioners skilled in palpation use, can reliably identify the most likely site of emergence of the greater occipital nerve in most patients. The location and frequency of subcutaneous emergence of the greater occipital nerve and occipital artery with respect to the external occipital protuberance-mastoid line are reported. METHODS: The external occipital protuberance and the mastoid processes were identified by palpation bilaterally on 57 body donors and the medial trisection point of a line connecting these bony landmarks was identified. A 4 cm circular dissection guide divided into 4 quadrants was centered on the trisection point and used to guide the removal of a circle of skin. The in-situ location of the nerve and artery were exposed by deep dissection within the circle. The frequency of the emergence and occurrence of the nerve and artery by quadrant were analyzed. RESULTS: In 114 total dissections the greater occipital nerve was found to emerge within the circle 96 times (84%) and the occipital artery 100 times (88%). The nerve (90%) and artery (81%) emerged from the two inferior quadrants most of the time with no difference noted between male and female donors. The greater occipital nerve and occipital artery were found to emerge together most commonly in inferior lateral quadrant. Branches of the nerve and artery traveled together most frequently through the two lateral quadrants. CONCLUSION: This study confirmed that the medial trisection point of the external occipital protuberance-mastoid line can be located via palpation and reliably used to pinpoint the subcutaneous emergence of the greater occipital nerve and occipital artery in most individuals. When relying on palpation alone to identify the trisection point in the clinic, infusion of nerve block inferior and lateral to this point is most likely to bathe the greater occipital nerve in anesthetic.

Dietary supplement use among military personnel: international patterns and motivations for use.

Dietary supplements, products that contain one or more dietary ingredients, or their components, typically in a concentrated form, are often consumed for purported health and performance benefits. The frequency, forms and motivations for dietary supplement use may differ between civilian and military populations. The objective of this manuscript is to review patterns and trends in dietary supplement use in military personnel from the USA, France, the UK and Slovenia. Main findings indicate that dietary supplement use may be higher in military personnel as compared with civilian populations. Factors motivating dietary supplement use in military personnel include physical and cognitive performance, recovery, and the maintenance of body weight and composition, whereas civilian populations tend to be motivated by health and wellness. Commonly used dietary supplements in military populations, such as proteins and amino acids, may be associated with performance, body weight management and body composition. The relationship between dietary supplement use and the frequency and severity of adverse events, along with the potential benefits of dietary supplements, has not been carefully assessed in military populations and should be the focus of future studies.

Evaluation of a novel university-based testing platform to increase access to SARS-CoV-2 testing during the COVID-19 pandemic in a cohort study.

OBJECTIVE: We aimed to evaluate the feasibility and utility of an unsupervised testing mechanism, in which participants pick up a swab kit, self-test (unsupervised) and return the kit to an on-campus drop box, as compared with supervised self-testing at staffed locations. DESIGN: University SARS-CoV-2 testing cohort. SETTING: Husky Coronavirus Testing provided voluntary SARS-CoV-2 testing at a university in Seattle, USA. OUTCOME MEASURES: We computed descriptive statistics to describe the characteristics of the study sample. Adjusted logistic regression implemented via generalised estimating equations was used to estimate the odds of a self-swab being conducted through unsupervised versus supervised testing mechanisms by participant characteristics, including year of study enrolment, pre-Omicron versus post-Omicron time period, age, sex, race, ethnicity, affiliation and symptom status. RESULTS: From September 2021 to July 2022, we received 92 499 supervised and 26 800 unsupervised self-swabs. Among swabs received by the laboratory, the overall error rate for supervised versus unsupervised swabs was 0.3% vs 4%, although this declined to 2% for unsupervised swabs by the spring of the academic year. Results were returned for 92 407 supervised (5% positive) and 25 836 unsupervised (4%) swabs from 26 359 participants. The majority were students (79%), 61% were female and most identified as white (49%) or Asian (34%). The use of unsupervised testing increased during the Omicron wave when testing demand was high and stayed constant in spring 2022 even when testing demand fell. We estimated the odds of using unsupervised versus supervised testing to be significantly greater among those <25 years of age (p<0.001), for Hispanic versus non-Hispanic individuals (OR 1.2, 95% CI 1.0 to 1.3, p=0.01) and lower among individuals symptomatic versus asymptomatic or presymptomatic (0.9, 95% CI 0.8 to 0.9, p<0.001). CONCLUSIONS: Unsupervised swab collection permitted increased testing when demand was high, allowed for access to a broader proportion of the university community and was not associated with a substantial increase in testing errors.