Systems biology can unravel complex biology but has not been extensively applied to human newborns, a group highly vulnerable to a wide range of diseases. We optimized methods to extract ...transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from <1 ml of blood, a volume readily obtained from newborns. Indexing to baseline and applying innovative integrative computational methods reveals dramatic changes along a remarkably stable developmental trajectory over the first week of life. This is most evident in changes of interferon and complement pathways, as well as neutrophil-associated signaling. Validated across two independent cohorts of newborns from West Africa and Australasia, a robust and common trajectory emerges, suggesting a purposeful rather than random developmental path. Systems biology and innovative data integration can provide fresh insights into the molecular ontogeny of the first week of life, a dynamic developmental phase that is key for health and disease.
IMPORTANCE: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life. OBJECTIVE: To evaluate whether a ...hospital-initiated program that combined transition and long-term self-management support for patients hospitalized due to COPD and their family caregivers can improve outcomes. DESIGN, SETTING, AND PARTICIPANTS: Single-site randomized clinical trial conducted in Baltimore, Maryland, with 240 participants. Participants were patients hospitalized due to COPD, randomized to intervention or usual care, and followed up for 6 months after hospital discharge. Enrollment occurred from March 2015 to May 2016; follow-up ended in December 2016. INTERVENTIONS: The intervention (n = 120) involved a comprehensive 3-month program to help patients and their family caregivers with long-term self-management of COPD. It was delivered by nurses with special training on supporting patients with COPD using standardized tools. Usual care (n = 120) included transition support for 30 days after discharge to ensure adherence to discharge plan and connection to outpatient care. MAIN OUTCOMES AND MEASURES: The primary outcome was number of COPD-related acute care events (hospitalizations and emergency department visits) per participant at 6 months. The co-primary outcome was change in participants’ health-related quality of life measured by the St George’s Respiratory Questionnaire (SGRQ) at 6 months after discharge (score, 0 best to 100 worst; 4-point difference is clinically meaningful). RESULTS: Among 240 patients who were randomized (mean SD age, 64.9 9.8 years; 61.7% women), 203 (85%) completed the study. The mean (SD) baseline SGRQ score was 62.3 (18.8) in the intervention group and 63.6 (17.4) in the usual care group. The mean number of COPD-related acute care events per participant at 6 months was 1.40 (95% CI, 1.01-1.79) in the intervention group vs 0.72 (95% CI, 0.45-0.97) in the usual care group (difference, 0.68 95% CI, 0.22-1.15; P = .004). The mean change in participants’ SGRQ total score at 6 months was 2.81 in the intervention group and −2.69 in the usual care group (adjusted difference, 5.18 95% CI, −2.15 to 12.51; P = .11). During the study period, there were 15 deaths (intervention: 8; usual care: 7) and 339 hospitalizations (intervention: 202; usual care: 137). CONCLUSIONS AND RELEVANCE: In a single-site randomized clinical trial of patients hospitalized due to COPD, a 3-month program that combined transition and long-term self-management support resulted in significantly greater COPD-related hospitalizations and emergency department visits, without improvement in quality of life. Further research is needed to determine reasons for this unanticipated finding. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02036294
Bioactive glass scaffolds (70S30C; 70% SiO2 and 30% CaO) produced by a sol–gel foaming process are thought to be suitable matrices for bone tissue regeneration. Previous in vitro data showed bone ...matrix production and active remodelling in the presence of osteogenic cells. Here we report their ability to act as scaffolds for in vivo bone regeneration in a rat tibial defect model, but only when preconditioned. Pretreatment methods (dry, pre-wetted or preconditioned without blood) for the 70S30C scaffolds were compared against commercial synthetic bone grafts (NovaBone® and Actifuse®). Poor bone ingrowth was found for both dry and wetted sol–gel foams, associated with rapid increase in pH within the scaffolds. Bone ingrowth was quantified through histology and novel micro-CT image analysis. The percentage bone ingrowth into dry, wetted and preconditioned 70S30C scaffolds at 11weeks were 10±1%, 21±2% and 39±4%, respectively. Only the preconditioned sample showed above 60% material–bone contact, which was similar to that in NovaBone and Actifuse. Unlike the commercial products, preconditioned 70S30C scaffolds degraded and were replaced with new bone. The results suggest that bioactive glass compositions should be redesigned if sol–gel scaffolds are to be used without preconditioning to avoid excess calcium release.
OBJECTIVES:This analysis assessed the impact of undisclosed HIV infection and antiretroviral therapy (ART) on national estimates of diagnosed HIV and ART coverage in Kenya.
METHODS:HIV-positive dried ...blood spot samples from Kenyaʼs second AIDS Indicator Survey were tested for an antiretroviral biomarker by liquid chromatography-tandem mass spectrometry. Weighted estimates of diagnosed HIV and ART coverage based on self-report were compared with those corrected for undisclosed HIV infection and ART use based on antiretroviral test results. Multivariate analysis determined factors associated with undisclosed HIV infection and ART use among persons on ART.
RESULTS:The antiretroviral biomarker was detected in 42.5% confidence interval (CI) 37.4–47.7 of HIV-infected persons. Antiretroviral drugs were present in 90.7% (CI 86.1–95.2) of HIV-infected persons reporting HIV-positive status and receiving ART, 66.7% (CI 59.9–73.4) reporting HIV-positive status irrespective of ART use, 21.0% (CI 13.4–28.6) reporting HIV-negative status, and 19.3% (CI 9.0–29.5) reporting no previous HIV test. After correcting for undisclosed HIV infection and ART use, diagnosed HIV increased from 46.9 to 57.2% and ART coverage increased from 31.8 to 42.8%. Undisclosed HIV infection while on ART was associated with being aged 25–39 years and not visiting a health provider in the past year, while younger age and higher wealth were associated with undisclosed ART use.
CONCLUSION:Substantial levels of undisclosed HIV infection and ART use among persons on ART were observed, resulting in diagnosed HIV underestimated by approximately 112000 persons and ART coverage by approximately 131000 persons. Supplementing self-reported ART status with objective measures of ART use in national population-based serosurveys can improve monitoring of HIV diagnosis and treatment targets in countries.
BACKGROUND AND PURPOSE—We hypothesized that total marine n-3 polyunsaturated fatty acids (PUFA), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the diet and in adipose ...tissue (biomarkers of long-term intake and endogenous exposure) were inversely associated with the risk of ischemic stroke and its subtypes.
METHODS—The Diet, Cancer and Health cohort consisted of 57 053 participants aged 50 to 65 years at enrolment. All participants filled in a food frequency questionnaire and had an adipose tissue biopsy taken at baseline. Information on ischemic stroke during follow-up was obtained from The Danish National Patient Register, and all cases were validated. Cases and a random sample of 3203 subjects from the whole cohort had their fatty acid composition of adipose tissue determined by gas chromatography.
RESULTS—During 13.5 years of follow-up 1879 participants developed an ischemic stroke. Adipose tissue content of EPA was inversely associated with total ischemic stroke (hazard ratio HR, 0.74; 95% CI, 0.62–0.88) when comparing the highest with the lowest quartile. Also, lower rates of large artery atherosclerosis were seen with higher intakes of total marine n-3 PUFA (HR, 0.69; 95% CI, 0.50–0.95), EPA (HR, 0.66; 95% CI, 0.48–0.91) and DHA (HR, 0.72; 95% CI, 0.53–0.99), and higher adipose tissue content of EPA (HR, 0.52; 95% CI, 0.36–0.76). Higher rates of cardioembolism were seen with higher intakes of total marine n-3 PUFA (HR, 2.50; 95% CI, 1.38–4.53) and DHA (HR, 2.12; 95% CI, 1.21–3.69) as well as with higher adipose tissue content of total marine n-3 PUFA (HR, 2.63; 95% CI, 1.33–5.19) and DHA (HR, 2.00; 95% CI, 1.04–3.84). The EPA content in adipose tissue was inversely associated with small-vessel occlusion (HR, 0.69; 95% CI, 0.55–0.88).
CONCLUSIONS—EPA was associated with lower risks of most types of ischemic stroke, apart from cardioembolism, while inconsistent findings were observed for total marine n-3 PUFA and DHA.
IMPORTANCE: The Patent Foramen Ovale (PFO)–Associated Stroke Causal Likelihood classification system combines information regarding noncardiac patient features (vascular risk factors, infarct ...topography) and PFO features (shunt size and presence of atrial septal aneurysm ASA) to classify patients into 3 validated categories of responsiveness to treatment with PFO closure. However, the distinctive associations of shunt size and ASA, alone and in combination, have not been completely delineated. OBJECTIVE: To evaluate the association of PFO closure with stroke recurrence according to shunt size and/or the presence of an ASA. DESIGN, SETTING, AND PARTICIPANTS: Pooled individual patient data from 6 randomized clinical trials conducted from February 2000 to October 2017 that compared PFO closure with medical therapy. Patients in North America, Europe, Australia, Brazil, and South Korea with PFO-associated stroke were included. Analysis was completed in January 2022. EXPOSURES: Transcatheter PFO closure plus antithrombotic therapy vs antithrombotic therapy alone, stratified into 4 groups based on the combination of 2 features: small vs large PFO shunt size and the presence or absence of an ASA. MAIN OUTCOMES AND MEASURES: Recurrent ischemic stroke. RESULTS: A total of 121 recurrent ischemic strokes occurred in the pooled 3740 patients (mean SD age, 45 10 years; 1682 45% female) during a median (IQR) follow-up of 57 (23.7-63.8) months. Treatment with PFO closure was associated with reduced risk for recurrent ischemic stroke (adjusted hazard ratio aHR, 0.41 95% CI, 0.28-0.60; P < .001). The reduction in hazard for recurrent stroke was greater for patients with both a large shunt and an ASA (aHR, 0.15 95% CI, 0.06-0.35) than for large shunt without ASA (aHR, 0.27 95% CI, 0.14-0.56), small shunt with ASA (aHR, 0.36 95% CI, 0.17-0.78), and small shunt without ASA (aHR, 0.68 95% CI, 0.41-1.13) (interaction P = .02). At 2 years, the absolute risk reduction of recurrent stroke was greater (5.5% 95% CI, 2.7-8.3) in patients with large shunt and ASA than for patients in the other 3 categories (1.0% for all). CONCLUSIONS AND RELEVANCE: Patients with both a large shunt and an ASA showed a substantially greater beneficial association with PFO closure than patients with large shunt alone, patients with small shunt and ASA, and patients with neither large shunt nor ASA. These findings, combined with other patient features, may inform shared patient-clinician decision-making.
Regulatory T cells (Tregs) can potentially migrate to the B cell areas of secondary lymphoid tissues and suppress T cell-dependent B cell Ig response. T cell-dependent Ig response requires B cell ...stimulation by Th cells. It has been unknown whether Tregs can directly suppress B cells or whether they must suppress Th cells to suppress B cell response. We report here that Foxp3+ Tregs are found in T-B area borders and within germinal centers of human lymphoid tissues and can directly suppress B cell Ig response. Although Tregs can effectively suppress T cells, they can also directly suppress B cell response without the need to first suppress Th cells. The direct suppression of B cell Ig production by Tregs is accompanied by inhibition of Ig class switch recombination.
Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a ...well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50 µM, respectively. The cellular ATP content started to decrease at 20 µM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10 µM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial β-oxidation at 10 µM and amiodarone at 20 µM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of β-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo.
The Conwy estuary was evaluated for sediment quality. Microtox bioassay revealed 38 of 39 sites were non-toxic. Hg ranged from 0.001 to 0.153 μg kg−1, mean 0.026 mg kg−1, Σ16 PAH from 18 to ...1578 μg kg−1, mean 269 μg kg−1, Σ22 PAH, 18 to 1871 μg kg−1 mean to 312 μg kg−1, two sites had high perylene relative to ΣPAH. Σ22PAH correlated positively with TOC, clay and silt (R2 0.89, 0.92, 0.90) and negatively with sand. Multivariate statistics, delineated four spatial (site) and five variable (measurements) clusters. Spatial clustering relates to sediment grain size, in response to hydrodynamic processes in estuary; fine (clay to silt) sized sediments exhibit the highest Hg and PAH content, because these components partitioned into the fine fraction. Comparison to national and international environmental standards suggests Hg and PAH content of Conwy sediments are unlikely to harm ecology or transfer up into the human food chain.
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•Conwy sediments contain low amounts of polycyclic aromatic hydrocarbons and mercury.•PAH were strongly correlated to fine particle fraction (clay and silt) and TOC.•Principal component and cluster analyses delineate four pollution-sediment types.•Perylene hotspot was identified close to the castle and marina.
Abstract
Background
The COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary ...vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders.
Methods
The primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity.
Results
Of the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range IQR, 60–66), 86% were male, and median CD4+ T-cell count was 650/μL (IQR, 423–941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval CI, 24–46) to 4317 BAU/mL (95% CI, 3275–5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed.
Conclusions
An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination.
Clinical Trials Registration. EUCTR2021-001054-57-N.
An additional 100 µg mRNA-1273 vaccination substantially increased SARS-CoV-2 S1-specific binding antibody levels in people with HIV with a serological hyporesponse after a primary vaccination regimen. This response was observed regardless of the primary vaccination regimen or patient characteristics.
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