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Abstract Background Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

Abstract This study was to determine whether extracellular vesicles (EVs) derived from insulin-producing cells (IPCs) can modulate naïve mesenchymal stromal cells (MSCs) to become insulin-secreting. MSCs were isolated from human adipose tissue. The cells were then differentiated to generate IPCs by achemical-based induction protocol. EVs were retrieved from the conditioned media of undifferentiated (naïve) MSCs (uneducated EVs) and from that of MSC-derived IPCs (educated EVs) by sequential ultracentrifugation. The obtained EVs were co-cultured with naïve MSCs.The cocultured cells were evaluated by immunofluorescence, flow cytometry, C-peptide nanogold silver-enhanced immunostaining, relative gene expression and their response to a glucose challenge.Immunostaining for naïve MSCs cocultured with educated EVs was positive for insulin, C-peptide, and GAD65. By flow cytometry, the median percentages of insulin-andC-peptide-positive cells were 16.1% and 14.2% respectively. C-peptide nanogoldimmunostaining providedevidence for the intrinsic synthesis of C-peptide. These cells released increasing amounts of insulin and C-peptide in response to increasing glucose concentrations. Gene expression of relevant pancreatic endocrine genes, except for insulin, was modest. In contrast, the results of naïve MSCs co-cultured with uneducated exosomes were negative for insulin, C-peptide, and GAD65. These findings suggest that this approach may overcome the limitations of cell therapy.

Abstract Triple-negative breast cancer (TNBC) is often treated with neoadjuvant systemic therapy (NAST). We investigated if radiomic models based on multiparametric Magnetic Resonance Imaging (MRI) obtained early during NAST predict pathologic complete response (pCR). We included 163 patients with stage I-III TNBC with multiparametric MRI at baseline and after 2 (C2) and 4 cycles of NAST. Seventy-eight patients (48%) had pCR, and 85 (52%) had non-pCR. Thirty-six multivariate models combining radiomic features from dynamic contrast-enhanced MRI and diffusion-weighted imaging had an area under the receiver operating characteristics curve (AUC) > 0.7. The top-performing model combined 35 radiomic features of relative difference between C2 and baseline; had an AUC = 0.905 in the training and AUC = 0.802 in the testing set. There was high inter-reader agreement and very similar AUC values of the pCR prediction models for the 2 readers. Our data supports multiparametric MRI-based radiomic models for early prediction of NAST response in TNBC.

Genetic selection for feed efficiency is possible in Holstein dairy cattle. However, measuring individual cow feed intake is expensive, which limits available phenotypes, resulting in lower prediction accuracy of breeding values than desired. New indicator trait phenotypes for feed efficiency could help improve breeding value accuracies if they can be measured widely across dairy herds. The objective of this study was to identify milk metabolites associated with feed intake and efficiency traits that may serve as new indicator traits. Metabolites were obtained from three sources and two distinct groups of cows. Gas chromatography mass spectrometry (GC-MS), and liquid chromatography mass spectrometry (LC-MS) assays were conducted on a subset of 39 cows identified based on their extreme residual feed intake (RFI; top and bottom 15%). Routinely collected on-farm milk testing data were evaluated on a second, larger subset of 357 cows. Statistical models were created to evaluate if metabolites: 1) provided novel feed efficiency information; 2) served as proxies for body weight traits not routinely collected on farms; and 3) were associated with breeding values for feed efficiency traits, including: predicted transmitting abilities (PTA) for feed saved (FS), RFI and body weight composite (BWC). Ontology enrichment analysis was used to identify enriched pathways from the contrast of extreme RFI cows by GC-MS and LC-MS. The false discovery rate (FDR, reported as q-values) and Hommel corrections were used as multiple testing corrections. Partial least squares discriminate analysis confirmed animals could be classified as high or low feed efficiency groups. A total of 33 GC-MS metabolites, 10 LC-MS ontology pathways (both q

Abstract Background COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study’s objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. Methods This cohort study identified children aged 5–17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. Results There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36–40%]) and hospital/ED–diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56–65%]). VE estimates were lowest among children 5–11 years and during the Omicron-variant era. Conclusions Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED–diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. Registration The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf ).

Abstract Background Breast density is an important risk factor for breast cancer complemented by a higher risk of cancers being missed during screening of dense breasts due to reduced sensitivity of mammography. Automated, deep learning-based prediction of breast density could provide subject-specific risk assessment and flag difficult cases during screening. However, there is a lack of evidence for generalisability across imaging techniques and, importantly, across race. Methods This study used a large, racially diverse dataset with 69,697 mammographic studies comprising 451,642 individual images from 23,057 female participants. A deep learning model was developed for four-class BI-RADS density prediction. A comprehensive performance evaluation assessed the generalisability across two imaging techniques, full-field digital mammography (FFDM) and two-dimensional synthetic (2DS) mammography. A detailed subgroup performance and bias analysis assessed the generalisability across participants’ race. Results Here we show that a model trained on FFDM-only achieves a 4-class BI-RADS classification accuracy of 80.5% (79.7–81.4) on FFDM and 79.4% (78.5–80.2) on unseen 2DS data. When trained on both FFDM and 2DS images, the performance increases to 82.3% (81.4–83.0) and 82.3% (81.3–83.1). Racial subgroup analysis shows unbiased performance across Black, White, and Asian participants, despite a separate analysis confirming that race can be predicted from the images with a high accuracy of 86.7% (86.0–87.4). Conclusions Deep learning-based breast density prediction generalises across imaging techniques and race. No substantial disparities are found for any subgroup, including races that were never seen during model development, suggesting that density predictions are unbiased.

ABSTRACT Most of Earth’s trees rely on critical soil nutrients that ectomycorrhizal fungi (EcMF) liberate and provide, and all of Earth’s land plants associate with bacteria that help them survive in nature. Yet, our understanding of how the presence of EcMF modifies soil bacterial communities, soil food webs, and root chemistry requires direct experimental evidence to comprehend the effects that EcMF may generate in the belowground plant microbiome. To this end, we grew Pinus muricata plants in soils that were either inoculated with EcMF and native forest bacterial communities or only native bacterial communities. We then profiled the soil bacterial communities, applied metabolomics and lipidomics, and linked omics data sets to understand how the presence of EcMF modifies belowground biogeochemistry, bacterial community structure, and their functional potential. We found that the presence of EcMF (i) enriches soil bacteria linked to enhanced plant growth in nature, (ii) alters the quantity and composition of lipid and non-lipid soil metabolites, and (iii) modifies plant root chemistry toward pathogen suppression, enzymatic conservation, and reactive oxygen species scavenging. Using this multi-omic approach, we therefore show that this widespread fungal symbiosis may be a common factor for structuring soil food webs.IMPORTANCEUnderstanding how soil microbes interact with one another and their host plant will help us combat the negative effects that climate change has on terrestrial ecosystems. Unfortunately, we lack a clear understanding of how the presence of ectomycorrhizal fungi (EcMF)—one of the most dominant soil microbial groups on Earth—shapes belowground organic resources and the composition of bacterial communities. To address this knowledge gap, we profiled lipid and non-lipid metabolites in soils and plant roots, characterized soil bacterial communities, and compared soils amended either with or without EcMF. Our results show that the presence of EcMF changes soil organic resource availability, impacts the proliferation of different bacterial communities (in terms of both type and potential function), and primes plant root chemistry for pathogen suppression and energy conservation. Our findings therefore provide much-needed insight into how two of the most dominant soil microbial groups interact with one another and with their host plant.

Background: Inadequate pain control after lung transplantation increases perioperative complications. Standard opioid-based regimens are associated with adverse effects and epidural catheters that reduce opioid use are limited by contraindications and technical challenges. We report the use of intercostal nerve cryoablation to enhance perioperative pain control as part of an opioid-sparing protocol for lung transplant recipients (LTR). Methods: We conducted a retrospective cohort study of LTRs from January 1, 2016 to December 31, 2021, before (precryo) and after (postcryo) initiation of an opioid-sparing protocol utilizing intraoperative intercostal nerve cryoablation. The precryo cohort included consecutive patients treated with opioids and selective use of epidural catheters. The postcryo cohort received intercostal nerve cryoablation at levels 3 to 7, scheduled acetaminophen, gabapentin, and tramadol. Additional opioids or epidural catheters were used for breakthrough pain. Results: In total, 49 precryo and 40 postcryo patients were analyzed. Baseline demographics were similar aside from a shift to performing more bilateral lung transplants in the postcryo cohort (57% vs 95%, p

Abstract Introduction Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common and preventable event in patients with chronic obstructive pulmonary disease (COPD). Data regarding the impact of AECOPD on short- and long-term renal outcomes are lacking. Methods We included all COPD patients who were followed at Queen Mary Hospital (QMH) in year 2015 and reviewed their clinical/renal outcomes in subsequent five years. Relationships between AECOPD and adverse renal outcomes were evaluated. Results 371 COPD patients were included. 169 patients had hospitalized AECOPD in past one year (HAE group) while 202 patients did not (non-HAE group). 285 patients (76.8%) had renal progression/death and 102 (27.5%) patients developed acute kidney injury (AKI). HAE group showed a more rapid eGFR decline than non-HAE group (-4.64 mL/min/1.73m2/year vs. -2.40 mL/min/1.73m2/year, p = 0.025). HAE group had significantly higher risk for renal progression/death at 5 years [adjusted OR (aOR) 2.380 (95% CI = 1.144–4.954), p = 0.020]. The frequency of hospitalized AECOPD in past 3 years, any AECOPD in past 3 years, hospitalized AECOPD in past 3 years were also predictive of renal progression/death at 5 years [aOR were 1.176 (95% CI = 1.038– 1.331), 2.998 (95% CI = 1.438–6.250) and 2.887 (95% CI = 1.409–5.917) respectively; p = 0.011, 0.003 and 0.004]. HAE group also showed significantly higher risk of AKI [adjusted HR (aHR) 2.430; 95% CI = 1.306–4.519, p = 0.005]. Conclusions AECOPD, in particular HAE, was associated with increased risk of renal progression/death and AKI. Prevention of AECOPD, especially HAE, may potentially improve short- and long-term renal outcomes in COPD patients.

Abstract To curb HIV infection rate in Tanzania, antiretroviral therapy (ART) has been scaled up since 2006, and in 2019, the country shifted to regimen including dolutegravir as a default first line. We assessed the success of ART and the contribution of HIV drug resistance (HIVDR) to unsuppressed viral loads. Between February and May 2023 a cross-sectional survey with random sampling was conducted in the six clinics in an urban cohort in Dar es Salaam. Patients with unsuppresed viral loads (local criteria viral load (VL) ≥ 1000 copies/mL) were tested for HIVDR mutations using the WHO adapted protocol for plasma samples. Mutations were interpreted using the Stanford HIVDR database. In total 600 individuals participated in this survey, the majority were female (76.83%), mean age ( $$\pm$$ ± standard deviation) was 44.0 ( $$\pm$$ ± 11.6) years. The median duration on ART (interquartile range) was 6.5 (3.9–10.2) years. Approximately 99% were receiving tenofovir + lamivudine + dolutegravir as a fixed dose combination. VL testing was successful in 99.67% (598/600) of survey patients and only 33 had VL ≥ 1000 copies/mL, resulting in a viral suppression level of 94.48% (565/598, 95% CI 92.34–96.17%). For 23 samples, protease and reverse transcriptase (RT) genotyping were successful, with 13 sequences containing RT inhibitor surveillance drug resistance mutations (SDRMs) (56.5%). No SDRM against protease inhibitors were detected. Thirty samples were successfully genotyped for integrase with 3 sequences (10.08%) containing integrase strand transfer inhibitor (INSTI) SDRMs. In samples successfully genotyped in the three genetic regions, 68.18% (16/22) had a genotypic susceptibility score (GSS) ≥ 2.5 for the concurrent regimen, implying factors beyond drug resistance caused the unsuppressed viral load. For five patients, GSS indicated that HIVDR may have caused the unsuppressed viral load. All three patients with INSTI resistance mutations were highly resistant to dolutegravir and accumulated nucleoside and non-nucleoside RT inhibitor HIVDR mutations. Although in this cohort the last 95 UNAIDS target was almost achieved, HIVDR mutations, including INSTIs resistance mutations were detected in HIV-positive individuals taking ART for at least one year. We recommend the design and implementation of high-impact interventions to prevent the increase of HIVDR, failure of dolutegravir and address the non-resistance factors in the study area.

Abstract Bacteriophages are abundant in soils. However, the majority are uncharacterized, and their hosts are unknown. Here, we apply high-throughput chromosome conformation capture (Hi–C) to directly capture phage-host relationships. Some hosts have high centralities in bacterial community co-occurrence networks, suggesting phage infections have an important impact on the soil bacterial community interactions. We observe increased average viral copies per host (VPH) and decreased viral transcriptional activity following a two-week soil-drying incubation, indicating an increase in lysogenic infections. Soil drying also alters the observed phage host range. A significant negative correlation between VPH and host abundance prior to drying indicates more lytic infections result in more host death and inversely influence host abundance. This study provides empirical evidence of phage-mediated bacterial population dynamics in soil by directly capturing specific phage-host interactions.

Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disorder that represents a major global public health concern. Traditionally, AD is diagnosed using cerebrospinal fluid biomarker analysis or brain imaging modalities. Recently, less burdensome, more widely available blood biomarker (BBM) assays for amyloid-beta (Aβ42/40) and phosphorylated-tau concentrations have been found to accurately identify the presence/absence of brain amyloid plaques and tau tangles and have helped to streamline AD diagnosis. However, few BBMs have been rigorously analytically validated. Herein, we report the analytical validation of a novel liquid chromatography–tandem mass spectrometry (LC-MS/MS) multiplex method for quantifying plasma phosphorylated-tau217 (p-tau217) and non-phosphorylated-tau217 (np-tau217) peptide concentrations. We combined the p-tau217/np-tau217 concentrations ratio (%p-tau217) and the previously validated LC-MS/MS multiplex assay for plasma Aβ42/40 into a new multianalyte assay with algorithmic analysis (MAAA; PrecivityAD2™ test) that identifies brain amyloid status based on brain amyloid positron emission tomography. We found (a) the %p-tau217 assay is precise, accurate, sensitive, and linear over a wide analytical measurement range, and free from carryover and interference; (b) the pre-analytical specimen collection, processing, storage, and shipping conditions that maintain plasma tau peptide stability; and (c) using the measured analytical imprecision for plasma Aβ42/40 and p-tau217/np-tau217 levels in a worst-case scenario model, the PrecivityAD2 test algorithm for amyloid pathology classification changed for only 3.5% of participants from brain amyloid positive to negative, or from negative to positive. The plasma sample preparation and LC-MS/MS methods underlying the PrecivityAD2 test are suitable for use in the clinical laboratory and valid for the test’s intended purpose: to aid in the diagnostic evaluation of individuals aged 55 and older with signs or symptoms of mild cognitive impairment or dementia.

Complete blood counts (CBCs) measure the abundance of individual immune cells, red blood cells, and related measures such as platelets in circulating blood. These measures can indicate the health status of an animal; thus, baseline circulating levels in a healthy animal may be related to the productive life, resilience, and production efficiency of cattle. The objective of this study is to determine the heritability of CBC traits and identify genomic regions that are associated with CBC measurements in lactating Holstein dairy cattle. The heritability of CBCs was estimated using a Bayes C0 model. The study population consisted of 388 cows with genotypes at roughly 75,000 markers and 16 different CBC phenotypes taken at one to three time points (n = 33, 131, and 224 for 1, 2, and 3 time points, respectively). Heritabilities ranged from 0.00 ± 0.00 (red cell distribution width) to 0.68 ± 0.06 (lymphocytes). A total of 96 different 1-Mb windows were identified that explained more than 1% of the genetic variance for at least one CBC trait, with 10 windows explaining more than 1% of the genetic variance for two or more traits. Multiple genes in the identified regions have functions related to immune response, cell differentiation, anemia, and disease. Positional candidate genes include RAD52 motif-containing protein 1 (RDM1), which is correlated with the degree of immune infiltration of immune cells, and C-X-C motif chemokine ligand 12 (CXCL12), which is critically involved in neutrophil bone marrow storage and release regulation and enhances neutrophil migration. Since animal health directly impacts feed intake, understanding the genetics of CBCs may be useful in identifying more disease-resilient and feed-efficient dairy cattle. Identification of genes responsible for variation in CBCs will also help identify the variability in how dairy cattle defend against illness and injury.

The renin–angiotensin system (RAS) is a complex homeostatic entity with multiorgan systemic and local effects. Traditionally, RAS works in conjunction with the kidney to control effective arterial circulation, systemic vascular resistance, and electrolyte balance. However, chronic hepatic injury and resulting splanchnic dilation may disrupt this delicate balance. The role of RAS in liver disease, however, is even more extensive, modulating hepatic fibrosis and portal hypertension. Recognition of an alternative RAS pathway in the past few decades has changed our understanding of RAS in liver disease, and the concept of opposing vs. “rebalanced” forces is an ongoing focus of research. Whether RAS inhibition is beneficial in patients with chronic liver disease appears to be context-dependent, but further study is needed to optimize clinical management and reduce organ-specific morbidity and mortality. This review presents the current understanding of RAS in liver disease, acknowledges areas of uncertainty, and describes potential areas of future investigation.

Alzheimer's disease (AD) is characterized by cognitive and memory impairments and neuropathological abnormalities. AD has no cure, inadequate treatment options, and a limited understanding of possible prevention measures. Previous studies have demonstrated that AD model mice that received a diet high in the essential nutrient choline had reduced amyloidosis, cholinergic deficits, and gliosis, and increased neurogenesis. In this study, we investigated the lifelong effects of perinatal choline supplementation on behavior, cognitive function, and amyloidosis in AppNL-G-F AD model mice. Pregnant and lactating mice were given a diet containing either 1.1 g/kg (control) or 5 g/kg (supplemented) of choline chloride until weaning and subsequently, all offspring received the control diet throughout their life. At 3, 6, 9, and 12 months of age, animals were behaviorally tested in the Open Field Test, Elevated Plus Maze, Barnes Maze, and in a contextual fear conditioning paradigm. Immunohistochemical analysis of Aβ42 was also conducted on the brains of these mice. AppNL-G-F mice displayed hippocampal-dependent spatial learning deficits starting at 3-months-old that persisted until 12-months-old. These spatial learning deficits were fully prevented by perinatal choline supplementation at young ages (3 and 6 months) but not in older mice (12 months). AppNL-G-F mice also had impaired fearful learning and memory at 9- and 12-months-old that were diminished by choline supplementation. Perinatal choline supplementation reduced Aβ42 deposition in the amygdala, cortex, and hippocampus of AppNL-G-F mice. Together, these results demonstrate that perinatal choline supplementation is capable of preventing cognitive deficits and dampening amyloidosis in AppNL-G-F mice and suggest that ensuring adequate choline consumption during early life may be a valuable method to prevent or reduce AD dementia and neuropathology.

Background: Monovalent booster/additional doses of COVID-19 vaccines were first authorized in August 2021 in the United States. We evaluated the real-world effectiveness of receipt of a monovalent booster/additional dose of COVID-19 vaccine compared with receiving a primary vaccine series without a booster/additional dose. Methods: Cohorts of individuals receiving a COVID-19 booster/additional dose after receipt of a complete primary vaccine series were identified in 2 administrative insurance claims databases (Optum, CVS Health) supplemented with state immunization information system data between August 2021 and March 2022. Individuals with a complete primary series but without a booster/additional dose were one-to-one matched to boosted individuals on calendar date, geography, and clinical factors. COVID-19 diagnoses were identified in any medical setting, or specifically in hospitals/emergency departments (EDs). Propensity score-weighted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated with Cox proportional hazards models; vaccine effectiveness (VE) was estimated as 1 minus the HR by vaccine brand overall and within subgroups of variant-specific eras, immunocompromised status, and homologous/heterologous booster status. Results: Across both data sources, we identified 752,165 matched pairs for BNT162b2, 410,501 for mRNA-1273, and 11,398 for JNJ-7836735. For any medically diagnosed COVID-19, meta-analyzed VE estimates for BNT162b2, mRNA-1273, and JNJ-7836735, respectively, were: BNT162b2, 54% (95% CI, 53%-56%); mRNA-1273, 58% (95% CI, 56%-59%); JNJ-7836735, 34% (95% CI, 23%-44%). For hospital/ED-diagnosed COVID-19, VE estimates ranged from 70% to 76%. VE was generally lower during the Omicron era than the Delta era and for immunocompromised individuals. There was little difference observed by homologous or heterologous booster status. Conclusion: The original, monovalent booster/additional doses were reasonably effective in real-world use among the populations for which they were indicated during the study period. Additional studies may be informative in the future as new variants emerge and new vaccines become available.Registration: The study protocol was publicly posted on the BEST Initiative website (https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf).

This study sought to determine the perceived benefits of the Residential Care Transition Module (RCTM), a novel multi-component, psychoeducational/psychosocial, telehealth intervention for caregivers of cognitively impaired relatives living in residential long-term care (RLTC). Few support programs exist for these caregivers. Determining the intervention’s mechanisms of benefit will provide actionable clinical and research information regarding which key features aspects RLTC and public health agencies should offer their families. We conducted semi-structured interviews with 30 purposively selected participants randomly assigned to receive the RCTM. Additionally, an open-ended survey question solicited feedback at 4 (n = 90), 8 (n = 79), and 12 months (n = 77). Available qualitative data were analyzed for thematic content. Participants endorsed 9 mechanisms of benefit. Six mechanisms were related to RCTM content: education dementia progression and dementia behavior management, personalized resource provision, strategies for communication and engagement with the care recipient (CR) and others, management of multiple roles, and relaxation exercises. Three mechanisms were related to coaching: emotional support, knowledgeability, and being a neutral third party. Common benefits attributed to RCTM included improvement in mood, caregiving confidence, and communication and interactions with CR and others. Using qualitative data and analyses, we discovered the most valued aspects of the RCTM intervention. These mechanisms of benefit have not been described in the literature. Notably, we were unable to detect mechanisms of benefit in a separate analysis utilizing quantitative data. Findings emphasize the importance of including qualitative measures in intervention research and selecting quantitative measures that reflect the intervention’s real effects, if any.

BackgroundMedication adherence is vital in the treatment of patients with chronic illness who require long-term medication therapies to maintain optimal health. Medication adherence, a complex and widespread problem, has been difficult to solve. Additionally, lower-income, medically underserved communities have been found to have higher rates of inadequate adherence to oral medications. Even so, this population has been underrepresented in studies using mobile medication adherence app interventions. Federally qualified health centers provide care for medically underserved populations, defined as communities and populations where there is a demonstrable unmet need for health services. These centers have been reporting an increase in a more complex chronic disease population. Including medically underserved individuals in mobile health studies provides opportunities to support this disproportionately affected group, work toward reducing health disparities in access to health care, and understand barriers to mobile health uptake. ObjectiveThe aim of this preliminary efficacy study was to evaluate the effects and feasibility of a commercially available medication adherence app, Medisafe, in a medically underserved adult population with various chronic illnesses seeking care in a federally qualified health center. MethodsParticipants in this single-arm pre-post intervention preliminary efficacy study (N=10) completed a baseline survey, used the app for 2 weeks, and completed an end-of-study survey. The primary outcome measures were medication adherence and medication self-efficacy. Feedback on the use of the app was also gathered. ResultsA statistically significant median increase of 8 points on the self-efficacy for adherence to medications scale was observed (P=.03, Cohen d=0.69). Though not significant, the adherence to refills and medications scale demonstrated a median change of 2.5 points in the direction of increased medication adherence (P=.21, Cohen d=0.41). Feedback about the app was positive. ConclusionsUse of the Medisafe app is a viable option to improve medication self-efficacy and medication adherence in medically underserved patients in an outpatient setting with a variety of chronic illnesses.

Abstract Background Recent advancements in additive manufacturing have made 3D design a desirable skill in combating the historically slow development of biomedical products. Due to the broad applicability of additive manufacturing to biomedical engineering, 3D design and 3D printing are attractive educational tools for biomedical engineering students. However, due to the multidisciplinary nature of biomedical engineering, finding a suitable spot in the curriculum to teach students basic and application-based skills for 3D manufacturing is difficult. Furthermore, prior training in fundamental 3D design skills may be needed to support the use of application-based supplementary content. Results We designed a SolidWorks Simulations toolkit to complement a sophomore (2nd-year)-level Biomechanics course and distributed this assignment to students with and without prior training in 3D design delivered in an introductory biomedical engineering course. Using short videos, example-based problem solving, and step-by-step tutorials, students completed this as an extra-credit assignment and completed a survey gauging student opinion on SolidWorks and 3D design, confidence in each target skill, and the effectiveness of assignment delivery. The compilation of survey responses suggests that the assignment effectively increased positive responses in student opinion on interest in and likeliness to use SolidWorks in both groups. However, confidence in the target assignment skills was higher in the trained group and fewer problems occurred in operating SolidWorks for trained students. Further, analyzing the distribution of student grades with respect to survey responses suggests that responses had no relationship with initial class grade. Conclusion These data collectively indicate that prior training provided to the students had a positive impact on the effectiveness of the assignment although increases in student opinion on the utility of 3D design were observed in both trained and untrained students. Our work has generated and identified a useful educational supplement to enrich existing biomedical engineering course materials with practical skills.

Aging is often accompanied by health events that may disrupt older adults’ desires to age in place. Understanding older adults’ perceptions of planning for their aging process was a priority to identify how planning behaviors occur. Our study explored how people perceive the concept of planning for aging and frailty, and identified the facilitators and barriers involved in the planning process. Using conventional qualitative content analysis, we used the data from semi-structured interviews of twenty community-dwelling older adults aged 50–80 years old. Demographic information was obtained, followed by the participant interviews. Seventeen code categories surfaced including six categories in the perception domain (i.e., internal, external, and future-oriented), seven categories in the facilitators domain (i.e., internal, external, and systems), and four categories in the barriers domain (i.e., internal, and systems). The emergent categories included understanding one’s perception of planning through a holistic lens, the importance of experiences with self/others as facilitators, and the physical/cognitive/emotional factors that serve as barriers within a larger sphere of societal influence. Planning for aging and frailty is an innovative concept that normalizes the aging process and promotes planning through an awareness of aging across the life-course domains. Future research is warranted for intervention development to help older adults recognize and actively plan for aging and to address the barriers involved.

Abstract Background Microbiomes contribute to multiple ecosystem services by transforming organic matter in the soil. Extreme shifts in the environment, such as drying-rewetting cycles during drought, can impact the microbial metabolism of organic matter by altering microbial physiology and function. These physiological responses are mediated in part by lipids that are responsible for regulating interactions between cells and the environment. Despite this critical role in regulating the microbial response to stress, little is known about microbial lipids and metabolites in the soil or how they influence phenotypes that are expressed under drying-rewetting cycles. To address this knowledge gap, we conducted a soil incubation experiment to simulate soil drying during a summer drought of an arid grassland, then measured the response of the soil lipidome and metabolome during the first 3 h after wet-up. Results Reduced nutrient access during soil drying incurred a replacement of membrane phospholipids, resulting in a diminished abundance of multiple phosphorus-rich membrane lipids. The hot and dry conditions increased the prevalence of sphingolipids and lipids containing long-chain polyunsaturated fatty acids, both of which are associated with heat and osmotic stress-mitigating properties in fungi. This novel finding suggests that lipids commonly present in eukaryotes such as fungi may play a significant role in supporting community resilience displayed by arid land soil microbiomes during drought. As early as 10 min after rewetting dry soil, distinct changes were observed in several lipids that had bacterial signatures including a rapid increase in the abundance of glycerophospholipids with saturated and short fatty acid chains, prototypical of bacterial membrane lipids. Polar metabolites including disaccharides, nucleic acids, organic acids, inositols, and amino acids also increased in abundance upon rewetting. This rapid metabolic reactivation and growth after rewetting coincided with an increase in the relative abundance of firmicutes, suggesting that members of this phylum were positively impacted by rewetting. Conclusions Our study revealed specific changes in lipids and metabolites that are indicative of stress adaptation, substrate use, and cellular recovery during soil drying and subsequent rewetting. The drought-induced nutrient limitation was reflected in the lipidome and polar metabolome, both of which rapidly shifted (within hours) upon rewet. Reduced nutrient access in dry soil caused the replacement of glycerophospholipids with phosphorus-free lipids and impeded resource-expensive osmolyte accumulation. Elevated levels of ceramides and lipids with long-chain polyunsaturated fatty acids in dry soil suggest that lipids likely play an important role in the drought tolerance of microbial taxa capable of synthesizing these lipids. An increasing abundance of bacterial glycerophospholipids and triacylglycerols with fatty acids typical of bacteria and polar metabolites suggest a metabolic recovery in representative bacteria once the environmental conditions are conducive for growth. These results underscore the importance of the soil lipidome as a robust indicator of microbial community responses, especially at the short time scales of cell-environment reactions. Video Abstract

Abstract Background Stable isotope probing (SIP) approaches are a critical tool in microbiome research to determine associations between species and substrates, as well as the activity of species. The application of these approaches ranges from studying microbial communities important for global biogeochemical cycling to host-microbiota interactions in the intestinal tract. Current SIP approaches, such as DNA-SIP or nanoSIMS allow to analyze incorporation of stable isotopes with high coverage of taxa in a community and at the single cell level, respectively, however they are limited in terms of sensitivity, resolution or throughput. Results Here, we present an ultra-sensitive, high-throughput protein-based stable isotope probing approach (Protein-SIP), which cuts cost for labeled substrates by 50–99% as compared to other SIP and Protein-SIP approaches and thus enables isotope labeling experiments on much larger scales and with higher replication. The approach allows for the determination of isotope incorporation into microbiome members with species level resolution using standard metaproteomics liquid chromatography-tandem mass spectrometry (LC–MS/MS) measurements. At the core of the approach are new algorithms to analyze the data, which have been implemented in an open-source software ( https://sourceforge.net/projects/calis-p/ ). We demonstrate sensitivity, precision and accuracy using bacterial cultures and mock communities with different labeling schemes. Furthermore, we benchmark our approach against two existing Protein-SIP approaches and show that in the low labeling range used our approach is the most sensitive and accurate. Finally, we measure translational activity using 18O heavy water labeling in a 63-species community derived from human fecal samples grown on media simulating two different diets. Activity could be quantified on average for 27 species per sample, with 9 species showing significantly higher activity on a high protein diet, as compared to a high fiber diet. Surprisingly, among the species with increased activity on high protein were several Bacteroides species known as fiber consumers. Apparently, protein supply is a critical consideration when assessing growth of intestinal microbes on fiber, including fiber-based prebiotics. Conclusions We demonstrate that our Protein-SIP approach allows for the ultra-sensitive (0.01 to 10% label) detection of stable isotopes of elements found in proteins, using standard metaproteomics data.

Abstract Background Erdheim-Chester disease (ECD) is a rare histiocytic disorder recently recognized as a neoplasm due to the discovery of activating MAPK pathway mutations. Hepatic involvement by ECD is extremely rare. Case presentation We describe a case of a 64-year-old male who presented with pruritis, weight loss, and cholestatic liver function tests. Magnetic resonance imaging of the abdomen showed beaded appearance of the intrahepatic biliary tree. A liver biopsy was suggestive of primary or secondary sclerosing cholangitis. Computerized tomography (CT) of the abdomen showed perinephric and periaortic soft tissue stranding suggestive of ECD. 18F-fluorodeoxyglucose positron emission/computerized tomography scan showed a mediastinal hilar mass which turned out to be follicular lymphoma. Histopathology of molluscum-like skin lesions showed CD68 + , Factor XIIIa + , and CD1a-foamy histiocytes with multiple giant cells suggestive of ECD. The patient developed recurrent episodes of ascending cholangitis and his hyperbilirubinemia continued to worsen despite stenting of a common hepatic duct stricture found on endoscopic retrograde cholangiopancreatography. Conclusions The absence of associated inflammatory bowel disease and anti-neutrophil cytoplasmic antibody, as well as the rapidity of disease progression, makes us consider the possibility of hepatic involvement by ECD or an overlap syndrome. We want to highlight that negative histopathology should not delay the diagnosis of ECD as effective and potentially lifesaving therapies with BRAF or MEK pathway inhibitors are now available for these patients.

Background: This secondary analysis of data from a randomized controlled trial (RCT) investigated how the maternal gut, breast milk, and infant gut microbiomes may contribute to the effects of a relaxation intervention, which reduced maternal stress and promoted infant weight gain. Methods: An RCT was undertaken in healthy Chinese primiparous mother–infant pairs (340/7–376/7gestation weeks). Mothers were randomly allocated to either the intervention group (IG, listening to relaxation meditation) or the control group (CG). Outcomes were the differences in microbiome composition and the diversity in the maternal gut, breast milk, and infant gut at 1 (baseline) and 8 weeks (post-intervention) between IG and CG, assessed using 16S rRNA gene amplicon sequencing of fecal and breastmilk samples. Results: In total, 38 mother–infant pairs were included in this analysis (IG = 19, CG = 19). The overall microbiome community structure in the maternal gut was significantly different between the IG and CG at 1 week, with the difference being more significant at 8 weeks (Bray–Curtis distance R2 = 0.04 vs. R2 = 0.13). Post-intervention, a significantly lower α-diversity was observed in IG breast milk (observed features: CG = 295 vs. IG = 255, p = 0.032); the Bifidobacterium genera presented a higher relative abundance. A significantly higher α-diversity was observed in IG infant gut (observed features: CG = 73 vs. IG = 113, p < 0.001). Conclusions: The findings were consistent with the hypothesis that the microbiome might mediate observed relaxation intervention effects via gut–brain axis and entero-mammary pathways; but confirmation is required.

People are increasingly encouraged to reduce animal food consumption and shift towards plant-based diets; however, the implications for children’s health are unclear. In this narrative review of research in high-income settings, we summarize evidence on the increasing consumption of plant-based diets in children and update an earlier systematic review regarding their associations with children’s health outcomes. The evidence indicates that vegan, but not vegetarian, diets can restrict growth relative to omnivorous children and increase the risk of being stunted and underweight, although the percentage affected is relatively small. Bone mineral content is reduced in vegetarian and, in particular, vegan children, compared to omnivores. Both vegetarian and vegan children who do not use vitamin B12 supplements manifest with B12 deficiency; however, supplementation rectifies this problem. Both vegetarians and vegans have lower concentrations of 25(OH)D if unsupplemented, and lower body iron stores, but usually have normal iron metabolism markers. Both groups are at risk of iodine deficiency, and this might affect thyroid health. Children consuming a vegan diet have a more favorable lipid profile than omnivorous children; however, the results for a vegetarian diet are inconsistent and vary by outcome. Based on the same scientific evidence, national and international dietary recommendations are heterogeneous, with some countries supporting plant-based diets among infants, children, and adolescents, and others discouraging them. We offer a research roadmap, highlighting what is needed to provide adequate evidence to harmonize dietary recommendations for plant-based diets in children. A number of measures should urgently be introduced at international and national levels to improve the safety of their use in children.

ABSTRACT Despite the promise of the gut microbiome to predict human health, few studies expose the molecular-scale processes underpinning such forecasts. We mined over 200,000 gut-derived genomes from cultivated and uncultivated microbial lineages to inventory the gut microorganisms and their gene content that control trimethylamine-induced cardiovascular disease. We assigned an atherosclerotic profile to the 6,341 microbial genomes that encoded metabolisms associated with heart disease, creating the Methylated Amine Gene Inventory of Catabolism database (MAGICdb). From microbiome gene expression data sets, we demonstrate that MAGICdb enhanced the recovery of disease-relevant genes and identified the most active microorganisms, unveiling future therapeutic targets. From the feces of healthy and diseased subjects, we show that MAGICdb predicted cardiovascular disease status as effectively as traditional lipid blood tests. This functional microbiome catalog is a public, exploitable resource, designed to enable a new era of microbiota-based therapeutics and diagnostics. IMPORTANCE One of the most-cited examples of the gut microbiome modulating human disease is the microbial metabolism of quaternary amines from protein-rich foods. By-products of this microbial processing promote atherosclerotic heart disease, a leading cause of human mortality globally. Our research addresses current knowledge gaps in our understanding of this microbial metabolism by holistically inventorying the microorganisms and expressed genes catalyzing critical atherosclerosis-promoting and -ameliorating reactions in the human gut. This led to the creation of an open-access resource, the Methylated Amine Gene Inventory of Catabolism database, the first systematic inventory of gut methylated amine metabolism. More importantly, using this resource we deliver here, we show for the first time that these gut microbial genes can predict human disease, paving the way for microbiota-inspired diagnostics and interventions.

Introduction: This study evaluated patient preference of physician attire both before and after the coronavirus disease 2019 (COVID-19) global pandemic began. The primary outcome was patient preference of physician attire in 2017 compared to 2022 survey cohorts. Methods: An observational cross-sectional study performed at a single-site academic institution in the United States using patient survey materials. In total, 339 patients were included in the study, 161 from 2017 and 178 from 2022. Key Points: There was a statistically significant decrease in patient preference for formal attire in the clinical settings of primary care, hospital, and overall. Male patient preference for formal attire declined in primary care, emergency room, and overall; whereas female patient preference for formal attire declined in the hospital setting. For all genders, the odds ratio was statistically significantly lower in the settings of primary care clinic, hospital, and overall clinical settings. Conclusions: Patient preference for physicians wearing formal attire has decreased significantly since the COVID-19 global pandemic began.

The forelimbs of hominoid primates (apes) are decidedly more flexible than those of monkeys, especially at the shoulder, elbow and wrist joints. It is tempting to link the greater mobility of these joints to the functional demands of vertical climbing and below-branch suspension, but field-based kinematic studies have found few differences between chimpanzees and monkeys when comparing forelimb excursion angles during vertical ascent (upclimbing). There is, however, a strong theoretical argument for focusing instead on vertical descent (downclimbing), which motivated us to quantify the effects of climbing directionality on the forelimb kinematics of wild chimpanzees (Pan troglodytes) and sooty mangabeys (Cercocebus atys). We found that the shoulders and elbows of chimpanzees and sooty mangabeys subtended larger joint angles during bouts of downclimbing, and that the magnitude of this difference was greatest among chimpanzees. Our results cast new light on the functional importance of downclimbing, while also burnishing functional hypotheses that emphasize the role of vertical climbing during the evolution of apes, including the human lineage.

Anemia is a common complication of chronic kidney disease (CKD) and is associated with increased mortality and reduced health-related quality of life. Anemia is characterized by a decrease in hemoglobin, the iron-rich protein that the body uses for oxygen transport. Iron is required to produce hemoglobin, and disruptions in the iron homeostasis can lead to iron-deficiency anemia. Management of anemia in individuals with CKD is typically performed by a team of physicians, nurse practitioners, physician assistants, or registered nurses. Throughout the care continuum, the management can be enhanced by multidisciplinary care, and individuals with CKD can benefit from the involvement of other specialties, with dietitians/nutritionists playing an important role. However, a key area of unmet clinical need is how to assess and address iron-deficiency anemia. This review aims to provide an overview of iron-deficiency anemia in CKD and how this may be diagnosed and managed by the entire kidney care team, such as describing the mechanisms underlying iron homeostasis, the complications of iron-deficiency anemia, and the current challenges associated with its diagnosis and treatment in CKD. Opportunities for each multidisciplinary team member to add value to the care of individuals with CKD and iron-deficiency anemia are also described.

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Neoadjuvant systemic therapy (NAST) followed by surgery are currently standard of care for TNBC with 50-60% of patients achieving pathologic complete response (pCR). We investigated ability of deep learning (DL) on dynamic contrast enhanced (DCE) MRI and diffusion weighted imaging acquired early during NAST to predict TNBC patients’ pCR status in the breast. During the development phase using the images of 130 TNBC patients, the DL model achieved areas under the receiver operating characteristic curves (AUCs) of 0.97 ± 0.04 and 0.82 ± 0.10 for the training and the validation, respectively. The model achieved an AUC of 0.86 ± 0.03 when evaluated in the independent testing group of 32 patients. In an additional prospective blinded testing group of 48 patients, the model achieved an AUC of 0.83 ± 0.02. These results demonstrated that DL based on multiparametric MRI can potentially differentiate TNBC patients with pCR or non-pCR in the breast early during NAST.

Abstract Background Little is known about the incidence of clinical events and treatment patterns among older adults with dementia-related psychosis. Given that dementia-related psychosis comprises various dementia types, this study describes the incidence of clinical events and treatment patterns by dementia type after patients with dementia are diagnosed with psychosis. Methods Adults aged ≥ 65 years with dementia and newly diagnosed with psychosis were identified in US Medicare claims during 2013–2018. Baseline characteristics were evaluated at the time of the psychosis diagnosis. After the initial psychosis diagnosis, incidence rates (IRs) of clinical events (e.g., falls/fractures, infections, healthcare utilization), mortality, and patterns of antipsychotic treatment were described for each dementia type (Alzheimer’s disease [AD], Parkinson’s disease dementia [PDD], dementia with Lewy bodies [DLB], frontotemporal dementia [FTD], vascular dementia [VD], and unspecified dementia). Daily mean cumulative counts were estimated to describe the incidence of recurrent events over time. Mortality was described using Kaplan–Meier survival curves. Results We identified 484,520 patients with dementia-related psychosis: mean age, 84 years (standard deviation, 7.8); female, 66%. At the time of psychosis diagnosis, the most prevalent type of dementia was unspecified dementia (56%), followed by AD (31%), VD (12%), PDD (10%), DLB (3%), and FTD (

The deep sea (below 200 m depth) is the largest carbon sink on Earth. It hosts abundant biodiversity that underpins the carbon cycle and provides provisioning, supporting, regulating and cultural ecosystem services. There is growing attention to climate-regulating ocean ecosystem services from the scientific, business and political sectors. In this essay we synthesize the unique biophysical, socioeconomic and governance characteristics of the deep sea to critically assess opportunities for deep-sea blue carbon to mitigate climate change. Deep-sea blue carbon consists of carbon fluxes and storage including carbon transferred from the atmosphere by the inorganic and organic carbon pumps to deep water, carbon sequestered in the skeletons and bodies of deep-sea organisms, carbon buried within sediments or captured in carbonate rock. However, mitigating climate change through deep-sea blue carbon enhancement suffers from lack of scientific knowledge and verification, technological limitations, potential environmental impacts, a lack of cooperation and collaboration, and underdeveloped governance. Together, these issues suggest that deep-sea climate change mitigation is limited. Thus, we suggest that a strong focus on blue carbon is too limited a framework for managing the deep sea to contribute to international goals, including the Sustainable Development Goals (SDGs), the Paris Agreement and the post-2020 Biodiversity Goals. Instead, the deep sea can be viewed as a more holistic nature-based solution, including many ecosystem services and biodiversity in addition to climate. Environmental impact assessments (EIAs), area-based management, pollution reduction, moratoria, carbon accounting and fisheries management are tools in international treaties that could help realize benefits from deep-sea, nature-based solutions.

Background Mechanical thrombectomy has been shown to be effective in patients with acute ischemic stroke secondary to large‐vessel occlusion and small to moderate infarct volume. However, there are no randomized clinical trials for large‐core infarct volume comparing mechanical thrombectomy to medical therapy in the population selected based solely on noncontrast computed tomography brain scan. The TESLA (Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke) randomized clinical trial is designed to address this clinical question. Methods The TESLA trial aim is to demonstrate the efficacy (3‐month and 1‐year disability following stroke) and safety of intraarterial mechanical thrombectomy in patients with large‐volume infarction assessed with a noncontrast computed tomography scan. The TESLA trial design is a prospective, randomized controlled, multicenter, open‐label, assessor‐blinded anterior circulation acute ischemic stroke trial with adaptive enrichment design, enrolling up to 300 patients. Patients with anterior circulation large‐vessel occlusion who meet the imaging and clinical eligibility criteria with a large‐core infarction on the basis of noncontrast computed tomography Alberta Stroke Program Early CT Score (2–5) adjudicated by a site investigator will be randomized in a 1:1 ratio to undergo intraarterial thrombectomy or best medical management up to 24 hours from last known well. Results The primary efficacy outcome is utility‐weighted modified Rankin Scale (mRS) score distribution at 90 days between the groups. The results will be based on an intention‐to‐treat analysis that will examine the Bayesian posterior probability that, adjusted for Alberta Stroke Program Early CT Score, patients with large‐core infarct volume treated with intra‐arterial thrombectomy have higher expected utility‐weighted mRS than those treated with best medical management alone. The primary safety outcome is the 90‐day death rate. Key secondary outcomes are dichotomized mRS 0 to 2 and 0 to 3 outcomes, ordinal mRS scores, and quality of life (EuroQol 5 Dimension 5 Level survey) at 90 days and 1 year, utility‐weighted mRS at 1 year, hemicraniectomy rate, and rate of 24‐hour symptomatic intracranial hemorrhage in both groups. Conclusion TESLA is a pragmatic trial, designed to address the unanswered question of the efficacy and safety of intra‐arterial thrombectomy in patients with large infarcts diagnosed by the site investigator only on noncontrast computed tomography scan secondary to anterior circulation large‐vessel occlusion up to 24 hours from stroke symptoms onset.