The Association Between Pre-Pregnancy and First-Trimester Hair Cortisol and Preterm Birth: A Causal Inference Model.

Background Adverse life events and chronic psychological distress before and during pregnancy have frequently been associated with preterm birth (PTB) but the biological underpinnings remain unclear. We investigated the association between corticosteroid levels in pre-pregnancy and first-trimester hair and the risk of PTB. Methods We followed 1,808 pregnant women from a prospective pre-birth cohort study in Lima, Perú. Hair samples were taken at the end of the first pregnancy trimester. The two most proximal 3cm segments to the scalp (representing pre-pregnancy and first-trimester) were analyzed to obtain hair cortisol and cortisone concentrations (HCC and HCNC). PTB was defined as birth < 37 completed gestational weeks. We constructed four generalized propensity scores for pre-pregnancy and first-trimester HCC and HCNC to create corresponding inverse probability weights before fitting marginal structural models for estimating the effect of HCC and HCNC on PTB risk. Results Pre-pregnancy Log HCC was not independently associated with PTB risk (RR = 0.97; 95%CI: 0.79, 1.19). In contrast, one SD increase from the mean first-trimester Log HCC was independently associated with a 37% (95%CI: 1.11, 1.69) increased risk of PTB. Although imprecise, pre-pregnancy Log HCNC was negatively associated with PTB risk (RR = 0.84; 95%CI: 0.58, 1.20), whereas the association between first-trimester Log HCNC and PTB risk was positive (RR = 1.20; 95%CI: 0.87, 1.65). Conclusions Our findings show that chronic corticosteroid levels in early pregnancy are causally linked to PTB risk in pregnant Peruvian women. This finding contributes to understanding the biological underpinnings of PTB better to enhance PTB prevention.

First Decade of Supportive Services for Veteran Families Program and Homelessness, 2012-2022.

As homelessness remains an urgent public health crisis in the United States, specific programs in the US Department of Veterans Affairs (VA) system may serve as a roadmap for addressing it. We examine lessons learned from the first decade (2012-2022) of the Supportive Services for Veteran Families (SSVF) program, a cornerstone in the VA continuum of homeless services aimed at both preventing homelessness among those at risk and providing rapid rehousing for veterans and their families who are currently experiencing homelessness. Drawing on information from annual reports and other relevant literature, we have identified 3 themes of SSVF that emerged as features to comprehensively deliver support for homeless veterans and their families: (1) responsiveness and flexibility, (2) coordination and integration, and (3) social resource engagement. Using these strategies, SSVF reached nearly three quarters of a million veterans and their families in its first decade, thereby becoming one of the VA's most substantial programmatic efforts designed to address homelessness. We discuss how each feature might apply to addressing homelessness in the general population as well as future research directions. (Am J Public Health. 2024;114(6):610-618. https://doi.org/10.2105/AJPH.2024.307625).

Saturn's F ring is intermittently shepherded by Prometheus.

One of the stranger planetary rings is Saturn's narrow, clumpy F ring, lying just outside the main rings, in a region disturbed by chaotic orbital dynamics. We show that the F ring has a stable "true core" that dominates its mass and is confined into discontinuous short arcs of particles larger than a few millimeters in radius. The more obvious micron-size particles seen in images, outlining and obscuring the true core, contribute only a small fraction of its mass. We found that these arcs of large particles orbit Saturn in a specific corotational resonance with the nearby 100-kilometer diameter ringmoon Prometheus, which stabilizes the F ring material and allows it to persist within the disturbed region for decades or longer. Toward the end of the observing period, a small chaotic glitch in the orbit of Prometheus temporarily disrupted the confinement, but the arcs seem to be able to adapt.

A rapid host-protein test for differentiating bacterial from viral infection: Apollo diagnostic accuracy study.

Objectives: To determine the diagnostic accuracy of a rapid host-protein test for differentiating bacterial from viral infections in patients who presented to the emergency department (ED) or urgent care center (UCC). Methods: This was a prospective multicenter, blinded study. MeMed BV (MMBV), a test based on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-inducible protein-10 (IP-10), and C-reactive protein (CRP), was measured using a rapid measurement platform. Patients were enrolled from 9 EDs and 3 UCCs in the United States and Israel. Patients >3 months of age presenting with fever and clinical suspicion of acute infection were considered eligible. MMBV results were not provided to the treating clinician. MMBV results (bacterial/viral/equivocal) were compared against a reference standard method for classification of infection etiology determined by expert panel adjudication. Experts were blinded to MMBV results. They were provided with comprehensive patient data, including laboratory, microbiological, radiological and follow-up. Results: Of 563 adults and children enrolled, 476 comprised the study population (314 adults, 162 children). The predominant clinical syndrome was respiratory tract infection (60.5% upper, 11.3% lower). MMBV demonstrated sensitivity of 90.0% (95% confidence interval [CI]: 80.3-99.7), specificity of 92.8% (90.0%-95.5%), and negative predictive value of 98.8% (96.8%-99.6%) for bacterial infections. Only 7.2% of cases yielded equivocal MMBV scores. Area under the curve for MMBV was 0.95 (0.90-0.99). Conclusions: MMBV had a high sensitivity and specificity relative to reference standard for differentiating bacterial from viral infections. Future implementation of MMBV for patients with suspected acute infections could potentially aid with appropriate antibiotic decision-making.

Neutrophil percentages in bronchoalveolar lavage fluid: Implications for diagnosing bacterial pneumonia in patients with immunocompromise and neutropenia.

Background: Pneumonia is the leading cause of infectious deaths and the most common infection identified in ICU patients. Assessment of bronchoalveolar lavage fluid (BALF) cellularity can aid in pneumonia diagnosis. Low percentages (<50%) of BALF neutrophils have a high negative predictive value for bacterial pneumonia in a general medical ICU population, but unclear operating characteristics in patients with immunocompromise and neutropenia remain unknown. Methods: We analyzed a large cohort of BALF specimens obtained for routine care for suspected pneumonia in mechanically ventilated patients and enrolled in the single-center Successful Clinical Response In Pneumonia Therapy (SCRIPT) study. BALF neutrophils were reported as a percentage of leukocytes by the clinical laboratory. The etiology of each episode of suspected pneumonia was adjudicated by a committee of critical care physicians using a predefined protocol. Immunocompromise was defined using predetermined criteria by the study research team. Neutropenia was defined here as a peripheral ANC <1500 cells/µl. Data are expressed as median [Quartile (Q) 1, Q3] and compared using the Mann-Whitney U test. Results: 688 mechanically ventilated patients with suspected pneumonia were included. 409 (59.4%) were male; median age was 62 [51,71]. 461 patients (67.0%) were immunocompetent, 149 (21.7%) were immunocompromised without neutropenia and 78 (11.3%) were neutropenic at some point during their admission. A total of 1746 BALs were performed. Fifty-seven BALs were obtained on a day where the patient's ANC<1500. Amongst pneumonia episodes classified as bacterial, no difference was found amongst BALF percent neutrophils taken patients who were immunocompetent and those who were immunocompromised but not neutropenic on day of sampling: 84.0% [69.0, 93.0] vs 87.0% [68.3, 93.0], p = 0.878 (Figure 1B). However, BALF percent neutrophils were significantly lower in patients neutropenic on day of sampling, with median BALF percent neutrophils of only 65.0% [22.3, 70.5] (p=0.016 compared with immunocompromised group, p=0.0096 compared with immunocompetent group). Conclusion: Among patients with bacterial pneumonia, BALF neutrophil percentage was not significantly decreased by a spectrum of immunocompromise. However, the subset of patients who were acutely neutropenic at the time of BAL sampling had significantly lower BALF % neutrophils. A traditional approach using BALF<50% to suggest against bacterial pneumonia may be inaccurate in this particular population.

Glucose Regulation of ß-Cell KATP Channels: It Is Time for a New Model!

An agreed-upon consensus model of glucose-stimulated insulin secretion from healthy ß-cells is essential for understanding diabetes pathophysiology. Since the discovery of the KATP channel in 1984, an oxidative phosphorylation (OxPhos)-driven rise in ATP has been assumed to close KATP channels to initiate insulin secretion. This model lacks any evidence, genetic or otherwise, that mitochondria possess the bioenergetics to raise the ATP/ADP ratio to the triggering threshold, and conflicts with genetic evidence demonstrating that OxPhos is dispensable for insulin secretion. It also conflates the stoichiometric yield of OxPhos with thermodynamics, and overestimates OxPhos by failing to account for established features of ß-cell metabolism, such as leak, anaplerosis, cataplerosis, and NADPH production that subtract from the efficiency of mitochondrial ATP production. We have proposed an alternative model, based on the spatial and bioenergetic specializations of ß-cell metabolism, in which glycolysis initiates insulin secretion. The evidence for this model includes that 1) glycolysis has high control strength over insulin secretion; 2) glycolysis is active at the correct time to explain KATP channel closure; 3) plasma membrane-associated glycolytic enzymes control KATP channels; 4) pyruvate kinase has favorable bioenergetics, relative to OxPhos, for raising ATP/ADP; and 5) OxPhos stalls before membrane depolarization and increases after. Although several key experiments remain to evaluate this model, the 1984 model is based purely on circumstantial evidence and must be rescued by causal, mechanistic experiments if it is to endure.

Double Electrode Experiments Reveal the Processes Occurring at PEDOT-Coated Neural Electrode Arrays.

Neural electrodes have recently been developed with surface modifications of conductive polymers, in particular poly(3,4-ethylenedioxythiophene) (PEDOT), and extensively studied for their roles in recording and stimulation, aiming to improve their biocompatibility. In this work, the implications for the design of practical neural sensors are clarified, and systematic procedures for their preparation are reported. In particular, this study introduces the use of in vitro double electrode experiments to mimic the responses of neural electrodes with a focus on signal-recording electrodes modified with PEDOT. Specifically, potential steps on one unmodified electrode in an array are used to identify the responses for PEDOT doped with different anions and compared with that of a bare platinum (Pt) electrode. The response is shown to be related to the rearrangement of ions in solution near the detector electrode resulting from the potential step, with a current transient seen at the detector electrode. A rapid response for PEDOT doped with chloride (ca. 0.04 s) ions was observed and attributed to the fast movement of chloride ions in and out of the polymer film. In contrast, PEDOT doped with poly(styrenesulfonate) (PSS) responds much slower (ca. 2.2 s), and the essential immobility of polyanion constrains the direction of current flow.

Incorporating solvent effects in DFT: insights from cation exchange in faujasites.

Zeolites are versatile materials renowned for their extra-framework cation exchange capabilities, with applications spanning diverse fields, including nuclear waste treatment. While detailed experimental characterization offers valuable insight, density functional theory (DFT) proves particularly adept at investigating ion exchange in zeolites, owing to its atomic and electronic resolution. However, the prevalent occurrence of zeolitic ion exchange in aqueous environments poses a challenge to conventional DFT modeling, traditionally conducted in a vacuum. This study seeks to enhance zeolite modeling by systematically evaluating predictive differences across varying degrees of aqueous solvent inclusion. Specifically focusing on monovalent cation exchange in Na-X zeolites, we explore diverse modeling approaches. These range from simple dehydrated systems (representing bare reference states in vacuum) to more sophisticated models that incorporate aqueous solvent effects through explicit water molecules and/or a dielectric medium. Through comparative analysis of DFT and semi-empirical DFT approaches, along with their validation against experimental results, our findings underscore the necessity to concurrently consider explicit and implicit solvent effects for accurate prediction of zeolitic ionic exchange.

Mapping the Single-cell Differentiation Landscape of Osteosarcoma.

PURPOSE: The genetic intratumoral heterogeneity observed in human osteosarcomas (OS) poses challenges for drug development and the study of cell fate, plasticity, and differentiation, processes linked to tumor grade, cell metastasis, and survival. EXPERIMENTAL DESIGN: To pinpoint errors in OS differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directsMSCs toward adipogenic and osteoblastic fates. Incorporating pre-existing chondrocyte data, we applied trajectory analysis and non-negative matrix factorization (NMF) to generate the first human mesenchymal differentiation atlas. RESULTS: This 'roadmap' served as a reference to delineate the cellular composition of morphologically complex OS tumors and quantify each cell's lineage commitment. Projecting a bulk RNA-seq OS dataset onto this roadmap unveiled a correlation between a stem-like transcriptomic phenotype and poorer survival outcomes. CONCLUSIONS: Our study quantifies OS differentiation and lineage, a prerequisite to better understanding lineage-specific differentiation bottlenecks that might someday be targeted therapeutically.

Rapid and sustained improvements in itch and quality of life with upadacitinib plus topical corticosteroids in adults and adolescents with atopic dermatitis: 52-week outcomes from the phase 3 AD Up study.

Purpose: Atopic dermatitis (AD) adversely impacts quality of life (QoL). We evaluated the effect of upadacitinib, an oral selective Janus kinase inhibitor approved for moderate-to-severe AD, plus topical corticosteroids (+TCS) on patient-reported outcomes (PROs) over 52 weeks.Materials and methods: In the phase 3 AD Up study (NCT03568318), adults and adolescents with moderate-to-severe AD were randomized 1:1:1 to once-daily upadacitinib 15 mg, 30 mg, or placebo + TCS. Itch, skin pain/symptoms, sleep, QoL, daily activities, emotional state, mental health, and patient impressions of disease severity/improvement/treatment satisfaction were assessed.Results: This analysis included 901 patients. Within 1-2 weeks, PRO improvements were greater with both upadacitinib doses than with placebo (p <.05). Improvements increased through weeks 4-8; rates were generally maintained through week 52. At week 52, the proportion of patients with clinically meaningful improvements in itch (Worst Pruritus Numerical Rating Scale improvement ≥4), skin pain (AD Symptom Scale Skin Pain improvement ≥4), sleep (AD Impact Scale [ADerm-IS] Sleep improvement ≥12), daily activities (ADerm-IS Daily Activities improvement ≥14), and emotional state (ADerm-IS Emotional State improvement ≥11) ranged from 62.1%-77.7% with upadacitinib 15 mg + TCS and 71.3%-83.6% with upadacitinib 30 mg + TCS.Conclusions: Upadacitinib + TCS results in rapid, sustained improvements in burdensome AD symptoms and QoL.

TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.

Contribution of vaccination to improved survival and health: modelling 50 years of the Expanded Programme on Immunization.

BACKGROUND: WHO, as requested by its member states, launched the Expanded Programme on Immunization (EPI) in 1974 to make life-saving vaccines available to all globally. To mark the 50-year anniversary of EPI, we sought to quantify the public health impact of vaccination globally since the programme's inception. METHODS: In this modelling study, we used a suite of mathematical and statistical models to estimate the global and regional public health impact of 50 years of vaccination against 14 pathogens in EPI. For the modelled pathogens, we considered coverage of all routine and supplementary vaccines delivered since 1974 and estimated the mortality and morbidity averted for each age cohort relative to a hypothetical scenario of no historical vaccination. We then used these modelled outcomes to estimate the contribution of vaccination to globally declining infant and child mortality rates over this period. FINDINGS: Since 1974, vaccination has averted 154 million deaths, including 146 million among children younger than 5 years of whom 101 million were infants younger than 1 year. For every death averted, 66 years of full health were gained on average, translating to 10·2 billion years of full health gained. We estimate that vaccination has accounted for 40% of the observed decline in global infant mortality, 52% in the African region. In 2024, a child younger than 10 years is 40% more likely to survive to their next birthday relative to a hypothetical scenario of no historical vaccination. Increased survival probability is observed even well into late adulthood. INTERPRETATION: Since 1974 substantial gains in childhood survival have occurred in every global region. We estimate that EPI has provided the single greatest contribution to improved infant survival over the past 50 years. In the context of strengthening primary health care, our results show that equitable universal access to immunisation remains crucial to sustain health gains and continue to save future lives from preventable infectious mortality. FUNDING: WHO.

Religious/spiritual struggles and whole person functioning among Colombian university students: Longitudinal evidence of mutual influence.

This prospective study examined the primary, secondary and complex conceptual models of religious/spiritual struggles with 18 indicators of whole person functioning across five domains: psychological well-being, psychological distress, social well-being, physical well-being and character. We used three waves of longitudinal data (Wave 1: August/September 2021, Wave 2: October/November 2021, Wave 3: February 2022) from Colombian university students (N = 2878, Mage = 20.88 ± 4.05 years). Adjusting for covariates assessed in Wave 1, our primary analysis applied the analytic templates for outcome-wide and lagged exposure-wide designs to estimate two sets of lagged linear regression models. Religious/spiritual struggles in Wave 2 were associated with a small-to-medium-sized decline in subsequent functioning on 17/18 indicators in Wave 3, and worse functioning on 16/18 indicators in Wave 2 was associated with very small-to-medium-sized increases in subsequent religious/spiritual struggles in Wave 3. The results provided evidence in favour of the complex conceptual model for 16/18 indicators of whole person functioning. Our findings extend existing evidence on the reciprocal association between religious/spiritual struggles and individual functioning to a wide range of indicators, reinforcing the need for practitioners to consider the dynamic interplay between religious/spiritual struggles and individual functioning as they work with younger populations.

Vegetable omega-3 and omega-6 fatty acids differentially modulate the antiviral and antibacterial immune responses of Atlantic salmon.

The immunomodulatory effects of omega-3 and omega-6 fatty acids are a crucial subject of investigation for sustainable fish aquaculture, as fish oil is increasingly replaced by terrestrial vegetable oils in aquafeeds. Unlike previous research focusing on fish oil replacement with vegetable alternatives, our study explored how the omega-6 to omega-3 polyunsaturated fatty acid (PUFA) ratio in low-fish oil aquafeeds influences Atlantic salmon's antiviral and antibacterial immune responses. Atlantic salmon were fed aquafeeds rich in soy oil (high in omega-6) or linseed oil (high in omega-3) for 12 weeks and then challenged with bacterial (formalin-killed Aeromonas salmonicida) or viral-like (polyriboinosinic polyribocytidylic acid) antigens. The head kidneys of salmon fed high dietary omega-3 levels exhibited a more anti-inflammatory fatty acid profile and a restrained induction of pro-inflammatory and neutrophil-related genes during the immune challenges. The high-omega-3 diet also promoted a higher expression of genes associated with the interferon-mediated signaling pathway, potentially enhancing antiviral immunity. This research highlights the capacity of vegetable oils with different omega-6 to omega-3 PUFA ratios to modulate specific components of fish immune responses, offering insights for future research on the intricate lipid nutrition-immunity interplay and the development of novel sustainable low-fish oil clinical aquaculture feeds.

Transcriptomic analyses to summarize gene expression patterns that occur during leaf initiation of Chinese cabbage.

In Chinese cabbage, rosette leaves expose their adaxial side to the light converting light energy into chemical energy, acting as a source for the growth of the leafy head. In the leafy head, the outer heading leaves expose their abaxial side to the light while the inner leaves are shielded from the light and have become a sink organ of the growing Chinese cabbage plant. Interestingly, variation in several ad/abaxial polarity genes is associated with the typical leafy head morphotype. The initiation of leaf primordia and the establishment of leaf ad/abaxial polarity are essential steps in the initiation of marginal meristem activity leading to leaf formation. Understanding the molecular genetic mechanisms of leaf primordia formation, polar differentiation, and leaf expansion is thus relevant to understand leafy head formation. As Brassica's are mesa-hexaploids, many genes have multiple paralogues, complicating analysis of the genetic regulation of leaf development. In this study, we used laser dissection of Chinese cabbage leaf primordia and the shoot apical meristem (SAM) to compare gene expression profiles between both adaxial and abaxial sides and the SAM aiming to capture transcriptome changes underlying leaf primordia development. We highlight genes with roles in hormone pathways and transcription factors. We also assessed gene expression gradients along expanded leaf blades from the same plants to analyze regulatory links between SAM, leaf primordia and the expanding rosette leaf. The catalogue of differentially expressed genes provides insights in gene expression patterns involved in leaf development and form a starting point to unravel leafy head formation.

SARS-CoV-2 infection exacerbates the cellular pathology of Parkinson's disease in human dopaminergic neurons and a mouse model.

While an association between Parkinson's disease (PD) and viral infections has been recognized, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on PD progression remains unclear. Here, we demonstrate that SARS-CoV-2 infection heightens the risk of PD using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons and a human angiotensin-converting enzyme 2 (hACE2) transgenic (Tg) mouse model. Our findings reveal that SARS-CoV-2 infection exacerbates PD susceptibility and cellular toxicity in DA neurons pre-treated with human preformed fibrils (hPFFs). Additionally, nasally delivered SARS-CoV-2 infects DA neurons in hACE2 Tg mice, aggravating the damage initiated by hPFFs. Mice infected with SARS-CoV-2 display persisting neuroinflammation even after the virus is no longer detectable in the brain. A comprehensive analysis suggests that the inflammatory response mediated by astrocytes and microglia could contribute to increased PD susceptibility associated with SARS-CoV-2. These findings advance our understanding of the potential long-term effects of SARS-CoV-2 infection on the progression of PD.