Plasma proteomic associations with genetics and health in the UK Biobank.

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.

A Brucella effector modulates the Arf6-Rab8a GTPase cascade to promote intravacuolar replication.

Remodeling of host cellular membrane transport pathways is a common pathogenic trait of many intracellular microbes that is essential to their intravacuolar life cycle and proliferation. The bacterium Brucella abortus generates a host endoplasmic reticulum-derived vacuole (rBCV) that supports its intracellular growth, via VirB Type IV secretion system-mediated delivery of effector proteins, whose functions and mode of action are mostly unknown. Here, we show that the effector BspF specifically promotes Brucella replication within rBCVs by interfering with vesicular transport between the trans-Golgi network (TGN) and recycling endocytic compartment. BspF targeted the recycling endosome, inhibited retrograde traffic to the TGN, and interacted with the Arf6 GTPase-activating Protein (GAP) ACAP1 to dysregulate Arf6-/Rab8a-dependent transport within the recycling endosome, which resulted in accretion of TGN-associated vesicles by rBCVs and enhanced bacterial growth. Altogether, these findings provide mechanistic insight into bacterial modulation of membrane transport used to promote their own proliferation within intracellular vacuoles.

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

Trauma-focused therapy retention among military sexual trauma survivors: relationship with veterans' sexual or gender minority identification.

Military servicemembers identifying as sexual and gender minorities (SGM) are at increased risk for military sexual trauma (MST) exposure and Post-traumatic Stress Disorder (PTSD). Although evidence-based treatments can reduce symptoms of PTSD, treatment attrition is concerning. Unfortunately, evaluations of such approaches with veterans identifying as SGM are currently restricted to case studies offering limited information regarding treatment completion. Both historic and current contextual factors related to military and mental health practices may uniquely influence minority veterans' treatment engagement in veteran healthcare settings. We explored associations between SGM identification and treatment of MST-focused therapy completion patterns (finishing the full protocol [FP] or receiving minimally adequate care [MAC; defined as attending eight or more sessions]). Veterans (N = 271, 12.5% SGM) enrolled in individual Prolonged Exposure or Cognitive Processing Therapies at a Midwestern veterans hospital system. Those identifying as SGM were more likely than non-identifying peers to complete FP treatment and, even when attrition occurred, they were retained longer. For MAC, the SGM group was as likely as non-SGM peers to be retained. This research suggests SGM veterans represent a notable minority of those seeking treatment in association with MST and do not appear at greater risk for discontinuation from trauma-focused treatment.

Breakfast Quality of Preschool-aged Canadian Children.

Purpose: To investigate the breakfast quality of preschool-aged children through a comparison of their energy and nutrient intakes at breakfast to published benchmarks for a balanced breakfast.Methods: Dietary data were collected for 163 children aged 3-5 years enrolled in the Guelph Family Health Study using one parent-reported online 24-hour recall and analyzed for energy and nutrient intakes. Breakfast quality was assessed by tallying the frequency of participants whose nutrient and energy intakes at their breakfast meal met the recommendations for a balanced breakfast established by the International Breakfast Research Initiative (IRBI).Results: Almost all participants (98%) consumed breakfast, and most participants (82.5%) met the energy IRBI recommendation. However, the majority of participants did not meet the IRBI recommendations for breakfast intakes of most macronutrients and micronutrients. In particular, fewer than 25% of participants met the IRBI recommendations for breakfast intakes of dietary fibre, niacin, folate, vitamin C, calcium, potassium and zinc.Conclusions: Almost all preschool-aged children in this study consumed breakfast, but the nutritional quality of their breakfast did not meet recommendations for most nutrients. These results can inform nutrition education and intervention programs for children that aim to improve the nutritional quality of breakfast.

Self-advocates with Down syndrome research the lived experiences of COVID-19 lockdowns in Aotearoa New Zealand.

BACKGROUND: Individuals with Down syndrome are particularly vulnerable to COVID-19 because they are recognised as significantly immunocompromised. Yet their voices regarding their lived experiences of pandemic lockdowns have not been sought or heard. AIM: This study aims to describe the lived experiences of people with Down syndrome during the pandemic lockdowns in Aotearoa New Zealand to add evidence in order to inform systemic advocacy. METHOD: A mixed-methods approach positioned within an inclusive research paradigm was used, in which a group of self-advocates with Down syndrome co-designed a structured interview schedule and conducted 40 face-to-face interviews. Key themes were identified by using content analysis. RESULTS: Despite the difficulties associated with lockdowns and participants not receiving their usual supports and having to make significant adjustments, they remained positive, adapted well, and demonstrated a high level of resilience and adaptability. CONCLUSIONS: The findings add to the limited research on the lived experiences of people with Down syndrome during pandemic lockdowns. This research has given them a voice to contribute to policy, government initiatives, and service providers; particularly on issues around support during lockdown and staying connected with others.

Engaging men in maternal, infant and young child nutrition in rural Tanzania: Outcomes from a cluster randomized control trial and qualitative study.

There is growing recognition that engaging men in maternal, infant and young child nutrition (MIYCN) interventions can benefit child health and disrupt harmful gender norms. We conducted a cluster-randomized controlled trial in Tanzania, which engaged men and women in behaviour change via mobile messaging (short message service [SMS]) and traditional interpersonal communication (IPC), separately and in combination. Here, we evaluate intervention effects on individual-level men's MIYCN knowledge and discuss barriers to male engagement. Eligible clusters were dispensary catchment areas with >3000 residents. Forty clusters were stratified by population size and randomly allocated to the four study arms, with 10 clusters per arm. Data on knowledge and intervention exposure were collected from 1394 men through baseline and endline surveys (March-April 2018 and July-September 2019). A process evaluation conducted partway through the 15-18-month intervention period included focus group discussions and interviews. Data were analysed for key trends and themes using Stata and ATLAS.ti software. Male participants in the short message service + interpersonal communication (SMS + IPC) group reported higher exposure to IPC discussions than IPC-only men (43.8% and 21.9%, respectively). Knowledge scores increased significantly across all three intervention groups, with the greatest impact in the SMS + IPC group. Qualitative findings indicated that the main barriers to male participation were a lack of interest in health/nutrition and perceptions that these topics were a woman's responsibility. Other challenges included meeting logistics, prioritizing income-earning activities and insufficient efforts to engage men. The use of a combined approach fusing IPC with SMS is promising, yet countering gender norms and encouraging stronger male engagement may require additional strategies.

Sodium nitrite suicide and social media influence.

ABSTRACT: This article addresses the increase in suicide rates in the US, emphasizing the emergence of sodium nitrite ingestion as a method of self-harm, particularly among adolescents and young adults influenced by social media. Given the rising incidence of sodium nitrite-related suicide attempts, healthcare providers must remain vigilant and prepared to respond effectively.

Addressing nurses' prolonged grief due to the COVID-19 pandemic.

ABSTRACT: The COVID-19 pandemic resulted in physical and emotional tolls on healthcare workers and caregivers, which have caused prolonged grief disorder and persistent complex bereavement disorder. Highlighting key learnings from healthcare workers' experiences during the pandemic, this article outlines self-care strategies to help nurses better prepare for future healthcare emergencies.

Helping children and adolescents who lost a caregiver during the COVID-19 pandemic.

ABSTRACT: Between March 2020 and June of 2021, 140,000 children under 18 in the US lost a caregiver. Due to this sudden loss, their lives have been drastically impacted. This article presents interventions for this population's unique and stressful emotional trauma.

Misregulation of cell adhesion molecules in the Ciona neural tube closure mutant bugeye.

Neural tube closure (NTC) is a complex multi-step morphogenetic process that transforms the flat neural plate found on the surface of the post-gastrulation embryo into the hollow and subsurface central nervous system (CNS). Errors in this process underlie some of the most prevalent human birth defects, and occur in about 1 out of every 1000 births. Previously, we discovered a mutant in the basal chordate Ciona savignyi (named bugeye) that revealed a novel role for a T-Type Calcium Channel (Cav3) in this process. Moreover, the requirement for CAV3s in Xenopus NTC suggests a conserved function among the chordates. Loss of CAV3 leads to defects restricted to anterior NTC, with the brain apparently fully developed, but protruding from the head. Here we report first on a new Cav3 mutant in the related species C. robusta. RNAseq analysis of both C. robusta and C. savignyi bugeye mutants reveals misregulation of a number of transcripts including ones that are involved in cell-cell recognition and adhesion. Two in particular, Selectin and Fibronectin leucine-rich repeat transmembrane, which are aberrantly upregulated in the mutant, are expressed in the closing neural tube, and when disrupted by CRISPR gene editing lead to the open brain phenotype displayed in bugeye mutants. We speculate that these molecules play a transient role in tissue separation and adhesion during NTC and failure to downregulate them leads to an open neural tube.

Open innovation: the key to advancing brain health.

With the exponential growth in investment attention to brain health-solutions spanning brain wellness to mental health to neurological disorders-tech giants, payers, and biotechnology companies have been making forays into this field to identify technology solutions and pharmaceutical amplifiers. So far, their investments have had mixed results. The concept of open innovation (OI) was first coined by Henry Chesbrough to describe the paradigm by which enterprises allow free flow of ideas, products, and services from the outside to the inside and vice versa in order to remain competitive, particularly in rapidly evolving fields where there is abundant, relevant knowledge outside the traditional walls of the enterprise. In this article, we advocate for further exploration and advancement of OI in brain health.

Change in posttraumatic stress disorder-related thoughts during treatment: Do thoughts drive change when pills are involved?

Posttraumatic negative thoughts about one's self and the world are related to posttraumatic stress disorder (PTSD) symptom severity and change in cognitive behavioral treatment (CBT), but little is known about this association when CBT is delivered with medication. The current study presents a planned comparison of changes in negative posttraumatic thoughts during (a) prolonged exposure (PE) plus pill placebo (PE+PLB), (b) sertraline plus enhanced medication management (SERT+EMM), and (c) PE plus sertraline (PE+SERT) as part of a randomized clinical trial in a sample of 176 veterans. Lagged regression modeling revealed that change in posttraumatic negative thoughts was associated with PTSD symptom change in the conditions in which participants received sertraline, ds = 0.14-0.25, ps = 0.04-.001). However, contrary to previous research, the models that started with symptom change were also statistically significant, d = 0.23, p < .001, for the lagged effect of symptoms on negative thoughts about self in the SERT+EMM condition, indicating a bidirectional association between such thoughts and PTSD symptoms. In the PE+PLB condition, no significant association between posttraumatic thoughts and PTSD symptoms emerged in either direction. These results suggest that the previously demonstrated role of change in posttraumatic thoughts leading to PTSD symptom reduction in PE may be altered when combined with pill administration, either active or placebo.

Maternal Fructose Intake, Programmed Mitochondrial Function and Predisposition to Adult Disease.

Fructose consumption is now recognised as a major risk factor in the development of metabolic diseases, such as hyperlipidaemia, diabetes, non-alcoholic fatty liver disease and obesity. In addition to environmental, social, and genetic factors, an unfavourable intrauterine environment is now also recognised as an important factor in the progression of, or susceptibility to, metabolic disease during adulthood. Developmental trajectory in the short term, in response to nutrient restriction or excessive nutrient availability, may promote adaptation that serves to maintain organ functionality necessary for immediate survival and foetal development. Consequently, this may lead to decreased function of organ systems when presented with an unfavourable neonatal, adolescent and/or adult nutritional environment. These early events may exacerbate susceptibility to later-life disease since sub-optimal maternal nutrition increases the risk of non-communicable diseases (NCDs) in future generations. Earlier dietary interventions, implemented in pregnant mothers or those considering pregnancy, may have added benefit. Although, the mechanisms by which maternal diets high in fructose and the vertical transmission of maternal metabolic phenotype may lead to the predisposition to adult disease are poorly understood. In this review, we will discuss the potential contribution of excessive fructose intake during pregnancy and how this may lead to developmental reprogramming of mitochondrial function and predisposition to metabolic disease in offspring.

Maternal Fructose Intake Causes Developmental Reprogramming of Hepatic Mitochondrial Catalytic Activity and Lipid Metabolism in Weanling and Young Adult Offspring.

Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of ß-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.

Backpack health reduces data-sharing barriers between the medical community and individuals with rare diseases.

Technology has changed the way we approach medical care: health data is constantly being generated, medical discoveries are progressing more rapidly, and individuals are more connected across the world than ever before. Backpack Health is a global personal health record platform that harnesses the power of technology to connect users to their primary health data sources, the medical community, and researchers. By syncing with existing patient portals, health data can be stored on the Backpack Health platform and easily accessed and controlled by users in one connected interface. Individuals manage and collate their current and past conditions, genetic test results, symptoms, medications, procedures, labs, and other health data. Users are empowered to disseminate their information to clinicians, researchers, foundations, and pharmaceutical and biotechnology companies they connect with through the Backpack Health application. Here, we describe how two rare disease advocacy groups, The Marfan Foundation and Project Alive, utilize Backpack Health to connect with their target populations. Through secure transfer of pseudonymized data, groups can query their members to improve understanding of clinical features and to facilitate meaningful research. Responses to the groups' surveys show strong member engagement with high completion rates and increases in new Backpack Health users when surveys are deployed. Data from these surveys have been published and used to better inform clinical outcomes for treatment trials. By connecting users directly to the foundations, clinicians, researchers, and industry partners working on their condition, Backpack Health is instrumental in fast-tracking medical discoveries and treatment for rare diseases.

Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia.

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+ Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.

Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

Full inversion tillage during pasture renewal to increase soil carbon storage: New Zealand as a case study.

As soils under permanent pasture and grasslands have large topsoil carbon (C) stocks, the scope to sequester additional C may be limited. However, because C in pasture/grassland soils declines with depth, there may be potential to sequester additional C in the subsoil. Data from 247 continuous pasture sites in New Zealand (representing five major soil Orders and ~80% of the grassland area) showed that, on average, the 0.15-0.30 m layer contained 25-34 t ha-1 less C than the top 0.15 m. High-production grazed pastures require periodic renewal (re-seeding) every 7-14 years to maintain productivity. Our objective was to assess whether a one-time pasture renewal, involving full inversion tillage (FIT) to a depth of 0.30 m, has potential to increase C storage by burying C-rich topsoil and bringing low-C subsoil to the surface where C inputs from pasture production are greatest. Data from the 247 pasture sites were used to model changes in C stocks following FIT pasture renewal by predicting (1) the C accumulation in the new 0-0.15 m layer and (2) the decomposition of buried-C in the new 0.15-0.30 m layer. In the 20 years following FIT pasture renewal, soil C was predicted to increase by an average of 7.3-10.3 (Sedimentary soils) and 9.6-12.7 t C ha-1 (Allophanic soils), depending on the assumptions applied. Adoption of FIT for pasture renewal across all suitable soils (2.0-2.6 M ha) in New Zealand was predicted to sequester ~20-36 Mt C, sufficient to offset 9.6-17.5% of the country's cumulative greenhouse gas emissions from agriculture over 20 years at the current rate of emissions. Given that grasslands account for ~70% of global agricultural land, FIT renewal of pastures or grassland could offer a significant opportunity to sequester soil C and offset greenhouse gas emissions.

Brain Health Living Labs.

We call on geriatric brain health care providers, executives and entrepreneurs to embrace our Brain Health Living Lab model-a user-centered, iterative ecosystem, integrating concurrent clinical care, research and innovation processes.