Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract.

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Plasma per- and polyfluoroalkyl substance mixtures during pregnancy and duration of breastfeeding in the New Hampshire birth cohort study.

BACKGROUND: Prior studies suggest that prenatal per- and polyfluoroalkyl substances (PFAS) exposures are associated with shorter breastfeeding duration. Studies assessing PFAS mixtures and populations in North America are sparse. METHODS: We quantified PFAS concentrations in maternal plasma collected during pregnancy in the New Hampshire Birth Cohort Study (2010-2017). Participants completed standardized breastfeeding surveys at regular intervals until weaning (n = 813). We estimated associations between mixtures of 5 PFAS and risk of stopping exclusive breastfeeding before 6 months or any breastfeeding before 12 months using probit Bayesian kernel machine regression. For individual PFAS, we calculated the relative risk and hazard ratio (HR) of stopping breastfeeding using modified Poisson regression and accelerated failure time models respectively. RESULTS: PFAS mixtures were associated with stopping exclusive breastfeeding before 6 months, primarily driven by perfluorooctanoate (PFOA). We observed statistically significant trends in the association of perfluorohexane sulfonate (PFHxS), PFOA, and perfluorononanoate (PFNA) (p-trends≤0.02) with stopping exclusive breastfeeding. Participants in the highest PFOA quartile had a 28% higher risk of stopping exclusive breastfeeding before 6 months compared to those in the lowest quartile (95% Confidence Interval: 1.04, 1.56). Similar trends were observed for PFHxS and PFNA with exclusive breastfeeding (p-trends≤0.05). PFAS were not associated with stopping any breastfeeding before 12 months. CONCLUSIONS: In this cohort, we observed that participants with greater overall plasma PFAS concentrations had greater risk of stopping exclusive breastfeeding before 6 months and associations were driven largely by PFOA. These findings further support the growing literature indicating that PFAS may be associated with shorter duration of breastfeeding.

Inflammatory Rhabdomyoblastic Tumor of the Posterior Pharyngeal Wall.

This case report describes a healthy man in his 40s who presented with a 1-year history of snoring, sleep apnea, dysphonia, and dysphagia owing to a large mass of the posterior pharynx and was diagnosed with an inflammatory rhabdomyoblastic tumor.

Firm-Level and Public-Sector Costs Make Small-Scale Maize Flour Fortification Challenging in Uganda.

BACKGROUND: Maize flour in Uganda is milled by hundreds of enterprises, mostly small- (5-20 metric tons [MT]/day) and micro-scale (<5 MT/day) mills or firms. A mandatory maize flour fortification program exists for medium-scale mills (>20 MT/day) and policymakers are considering including smaller-scale millers. OBJECTIVE: We estimated the private and public costs of maize flour fortification at different scales and explored their implications for extending the mandatory fortification to include smaller-scale mills. METHODS: We used secondary data on the structure of the maize flour market and primary data on milling and fortification costs to estimate mill and regulatory costs at 3 scales of flour production: micro, small, and medium. RESULTS: For micro-, small-, and medium-size operations, respectively, operational costs of fortification were US$13, US$9, and US$7 per metric ton (MT) of maize flour, which represented 20%, 16%, and 16% of annual operating costs, and the ratio of fortification equipment cost to mill equipment costs was higher for micro-scale mills (2.7) than for small- (0.38) and medium-scale (0.54) maize mills. Governmental regulatory costs rise if smaller-scale mills are included due to the increased number of facility inspections. CONCLUSIONS: Fortification and regulatory costs increase as production scale decreases. Up-front capital costs of fortification would be daunting for micro- and small-scale mills. Medium-scale mills, which supply social protection programs, might be able to manage fortification costs and other challenges. Decision-makers should consider all costs and cost burdens, and the realities of enforcement capabilities before expanding fortification programs to include smaller-scale operations.

Plain language titleCosts of Small-scale Maize Flour Fortification in UgandaPlain language summaryA study of the costs of adding vitamins and minerals by small-scale maize flour millers in Uganda was undertaken to understand if it would be commercially beneficial from a business and operations perspective for them to do so, and if requiring them to do so would impose additional cost burdens on government to ensure that fortification standards were met.Why was the study done?Maize flour is consumed by the majority of Uganda's population, especially the rural poor. If the flour were fortified, it would reduce vitamin and mineral deficiencies among those at risk. The most important constraint to market-wide fortification is the presence of many small-scale mills or firms that neither have the resources nor the technology to adopt and sustain the fortification process. To date, no study has been done to calculate the costs that small-scale mills would have to face to fortify flour, or what the cost implications for government would be for including smaller-scale mills in a national fortification program, including the costs of enforcing regulations.What did the researchers do?The researchers interviewed millers of several scales of operation to collect cost information on their operations and interviewed representatives of government regulatory bodies to estimate the costs of testing maize flour to ensure compliance with regulations. Researchers estimated the cost to the mills of adding fortification to their business models, and the impacts on the government costs (eg, testing additional samples, etc.) of including smaller-scale mills in the fortification program.What did the researchers find?The researchers looked at 3 different types of mills based on their capacity to mill maize flour­micro-scale firms milled less than 5 metric tons (MT) a day, small-scale firms milled 5 to 20 MT per day, and medium-scale firms milled over 20 MT a day. For micro-, small-, and medium-size firms, respectively, fortification increased operational costs by US$13, US$9, and US$7 per MT of maize flour, which represented 20%, 16%, and 16% of annual operating costs. Similarly, governmental regulatory costs rose if smaller-scale mills were included because of the increased number of facility inspections required since the current legislation requires mandatory annual inspections.What do the findings mean?Fortification and regulatory costs increase as the scale of production by the millers decreases. If fortification by small- and micro-scale mills were made mandatory, up-front costs of fortification equipment and materials would be daunting for micro- and small-scale millers. Ugandan medium-scale millers might manage fortification costs and other challenges, but only if the social protection programs they supplied were of sufficient volume and regularity.

Rare pelvic peritoneal defect causing small bowel obstruction in a young female with virgin abdomen.

This case report discusses a 46-year-old female with no prior surgical history who presented with severe abdominal pain and generalized tenderness. She was found to have a small bowel obstruction secondary to internal hernia caused by a rare congenital pelvic peritoneal defect in the Pouch of Douglas. She required diagnostic laparoscopy and repair of the pelvic peritoneal defect. Congenital peritoneal defect is an extremely rare cause of small bowel obstruction but should remain a possible differential diagnosis in patients with virgin abdomen presenting with acute abdominal pain.

Greenspace and Land Cover Diversity During Pregnancy in a Rural Region, and Associations With Birth Outcomes.

Beneficial effects on health outcomes have been observed from exposure to spaces with substantial green vegetation ("greenspace"). This includes studies of greenspace exposure on birth outcomes; however, these have been conducted largely in urban regions. We characterized residential exposure to greenspace and land cover diversity during pregnancy in rural northern New England, USA, investigating whether variation in greenspace or diversity related to newborn outcomes. Five landscape variables (greenspace land cover, land cover diversity, impervious surface area, tree canopy cover, and the Normalized Difference Vegetation Index) were aggregated within six circular zones of radii from 100 to 3,000 m around residential addresses, and distance to conservation land was measured, providing a total of 31 greenspace and diversity metrics. Four birth outcomes along with potentially confounding variables were obtained from 1,440 participants in the New Hampshire Birth Cohort Study. Higher greenspace land cover up to 3,000 m was associated with larger newborn head circumference, while impervious surface area (non-greenspace) had the opposite association. Further, birth length was positively associated with land cover diversity. These findings support beneficial health impacts of greenspace exposure observed in urban regions for certain health outcomes, such as newborn head circumference and length but not others such as birthweight and gestational age. Further our results indicate that larger radius buffer zones may be needed to characterize the rural landscape. Vegetation indices may not be interchangeable with other greenspace metrics such as land cover and impervious surface area in rural landscapes.

Successful Pregnancy After Cardiac Arrest in a Woman With Severe Coronary Vasospasm.

A 37-year-old gravida 5, para 3 woman presented with an unplanned pregnancy 6 weeks after experiencing a cardiac arrest caused by ventricular fibrillation from coronary vasospasm. She opted to continue the pregnancy with medical management despite ongoing chest pain and delivered a healthy female infant via vaginal delivery at 37 weeks.

Bacterial Modification of the Association Between Arsenic and Autism-Related Social Behavior Scores.

Arsenic is related to neurodevelopmental outcomes and is associated with the composition of the gut microbiome. Data on the modifying role of the microbiome are limited. We probed suggestive relationships between arsenic and social behaviors to quantify the modifying role of the infant gut microbiome. We followed children for whom arsenic concentrations were quantified in 6-week-old toenail clippings. Scores on the Social Responsiveness Scale (SRS-2), which measures autism-related social behaviors, were provided by caregivers when the child was approximately 3 years of age. Metagenomic sequencing was performed on infant stools collected at 6 weeks and 1 year of age. To evaluate modification by the top ten most abundant species and functional pathways, we modeled SRS-2 total T-scores as a function of arsenic concentrations, microbiome features dichotomized at their median, and an interaction between exposure and the microbiome, adjusting for other trace elements and sociodemographic characteristics. As compared to the standardized population (SRS-2 T-scores = 50), participants in our study had lower SRS-2 scores (n = 78, mean = 44, SD = 5).The relative abundances of several functional pathways identified in 6-week stool samples modified the arsenic-SRS-2 association, including the pathways of valine and isoleucine biosynthesis; we observed no association among those with high relative abundance of each pathway [ß = - 0.67 (95% CI - 1.46, 0.12)], and an adverse association [ß = 1.67 (95% CI 0.3, 3.04), pinteraction= 0.05] among infants with low relative abundance. Our findings indicate the infant gut microbiome may alter neurodevelopmental susceptibility to environmental exposures.

Prenatal exposure to metal mixtures and lung function in children from the New Hampshire birth cohort study.

Prenatal exposure to metals/metalloids, even at common US population levels, may pose risks to fetal health, and affect children's lung function. Yet, the combined effects of simultaneous prenatal exposures on children's lung function remain largely unexplored. This study analyzed 11 metals (As speciation, Cd, Co, Cu, Mo, Ni, Pb, Sb, Se, Sn, Zn) in maternal urine during weeks 24-28 of gestation and evaluated lung function, including forced vital capacity (FVC) and forced expiratory volume in the first second of expiration (FEV1), in 316 US mother-child pairs at around age 7. We used Bayesian Kernel Machine Regression (BKMR), weighted quantile sum regression (WQSR), and multiple linear regression to examine the association between metal mixture exposure and children's lung function, adjusting for maternal smoking, child age, sex, and height. In BKMR models assessing combined exposure effects, limited evidence of metal non-linearity or interactions was found. Nevertheless, Co, As species, and Pb showed a negative association, while Mo exhibited a positive association with children's FVC and FEV1, with other metals held constant at their medians. The weighted index, from WQSR analysis assessing the cumulative impact of all metals, highlighted prenatal Mo with the highest positive weight, and Co, As, and Sb with the most substantial negative weights on children's FVC and FEV1. Urinary Co and Pb were negatively associated with FVC (ß = -0.09, 95% confidence interval (CI) (-0.18; -0.01) and ß = -0.07, 95% CI (-0.13; 0.00), respectively). Co was also negatively associated with FEV1 (ß = -0.09, 95% CI (-0.18; 0.00). There was a negative association between As and FVC, and a positive association between Mo and both FVC and FEV1, though with wide confidence intervals. Our findings suggest that prenatal trace element exposures may impact children's lung function, emphasizing the importance of reducing toxic exposures and maintaining adequate nutrient levels.

Pathway-specific polygenic scores for Alzheimer's disease are associated with changes in brain structure in younger and older adults.

Genome-wide association studies have identified multiple Alzheimer's disease risk loci with small effect sizes. Polygenic risk scores, which aggregate these variants, are associated with grey matter structural changes. However, genome-wide scores do not allow mechanistic interpretations. The present study explored associations between disease pathway-specific scores and grey matter structure in younger and older adults. Data from two separate population cohorts were used as follows: the Avon Longitudinal Study of Parents and Children, mean age 19.8, and UK Biobank, mean age 64.4 (combined n = 18 689). Alzheimer's polygenic risk scores were computed using the largest genome-wide association study of clinically assessed Alzheimer's to date. Relationships between subcortical volumes and cortical thickness, pathway-specific scores and genome-wide scores were examined. Increased pathway-specific scores were associated with reduced cortical thickness in both the younger and older cohorts. For example, the reverse cholesterol transport pathway score showed evidence of association with lower left middle temporal cortex thickness in the younger Avon participants (P = 0.034; beta = -0.013, CI -0.025, -0.001) and in the older UK Biobank participants (P = 0.019; beta = -0.003, CI -0.005, -4.56 × 10-4). Pathway scores were associated with smaller subcortical volumes, such as smaller hippocampal volume, in UK Biobank older adults. There was also evidence of positive association between subcortical volumes in Avon younger adults. For example, the tau protein-binding pathway score was negatively associated with left hippocampal volume in UK Biobank (P = 8.35 × 10-05; beta = -11.392, CI -17.066, -5.718) and positively associated with hippocampal volume in the Avon study (P = 0.040; beta = 51.952, CI 2.445, 101.460). The immune response score had a distinct pattern of association, being only associated with reduced thickness in the right posterior cingulate in older and younger adults (P = 0.011; beta = -0.003, CI -0.005, -0.001 in UK Biobank; P = 0.034; beta = -0.016, CI -0.031, -0.001 in the Avon study). The immune response score was associated with smaller subcortical volumes in the older adults, but not younger adults. The disease pathway scores showed greater evidence of association with imaging phenotypes than the genome-wide score. This suggests that pathway-specific polygenic methods may allow progress towards a mechanistic understanding of structural changes linked to polygenic risk in pre-clinical Alzheimer's disease. Pathway-specific profiling could further define pathophysiology in individuals, moving towards precision medicine in Alzheimer's disease.

Menopause age, reproductive span and hormone therapy duration predict the volume of medial temporal lobe brain structures in postmenopausal women.

Medial temporal lobe (MTL) atrophy is correlated with risk and severity of Alzheimer disease (AD) pathology and cognitive decline. Increasing evidence suggest that oestrogens affect the aging of MTL structures. Here we investigate the relationship between reproductive hormone exposure, polygenic scores for AD risk and oestradiol concentration, MTL anatomy and cognitive performance in postmenopausal women. To this end, we used data from 10,924 female participants in the UK Biobank from whom brain MRI and genetic data were available. We fitted linear regression models to test whether the volume of structures comprising the MTL were predicted by a) timing related to menopause, b) the use and timing of hormone replacement therapy (HRT) and c) polygenic scores for AD risk and oestradiol concentration. Results showed that longer use of HRT was associated with larger parahippocampal volumes (2.53 mm3/year, p = 0.042). A later age of natural menopause, and a longer reproductive span, was associated with larger hippocampal (6.08 and 5.72 mm3/year, p = 0.0006 and 0.0005), parahippocampal (4.17 mm3 and 4.19 mm3/year, p = 0.00006 and 0.00001), amygdala (2.10 and 2.22 mm3/year, p = 0.028 and 0.01) and perirhinal cortical (2.56 and 2.95 mm3/year, p = 0.028 and 0.008) volumes. Superior prospective memory performance was associated with later age at natural menopause, and a longer reproductive span (ß = 0.05 and 0.05 respectively, p = 0.019 and 0.019). Polygenic scores for AD risk and for oestradiol concentration were not associated with MTL volume and did not interact with menopause-related factors to affect MTL structure. Our results suggest that HRT use did not have any detrimental effects on cognition or brain structure, whilst greater exposure to reproductive hormones across time is associated both with slightly larger volumes of specific MTL structures and marginally superior memory performance, independent of genetic risk for AD and genetic predisposition for higher oestradiol levels. However, the clinical utility of maintenance of oestrogens post-menopause for brain health and protection against cognitive decline is curtailed by the small effect sizes observed.

A novel STRN3::PRKD1 fusion in a cribriform adenocarcinoma of salivary gland with high-grade transformation.

Cribriform adenocarcinoma of salivary gland (CASG) is a rare form of salivary gland neoplasm that mostly arises from minor salivary glands. We report a case of CASG with high-grade transformation harboring a novel STRN3::PRKD1 fusion. A 59-year-old male presented with a palatal mass. Morphologically, the tumor consisted of two components: solid high-grade and glandular low-grade areas. The solid high-grade area comprised solid nests of high-grade carcinoma with central necrosis arranged in lobules delineated with prominent stromal septa. The glandular low-grade area comprised of cribriform and microcystic architecture in a hyalinized and hypocellular stroma. Immunophenotypically, the tumor was positive for S100 but negative for p40 and actin. However, due to the high-grade component, tissue was sent for salivary gland NGS fusion panel analysis to confirm the diagnosis. The current case illustrates high-grade transformation in CASG. Furthermore, identification of a STRN3::PRKD1 fusion expands the genetic spectrum of CASG.

Predictors of Breastfeeding Duration in the New Hampshire Birth Cohort Study.

INTRODUCTION: Breastfeeding has significant health benefits for infants and birthing persons, including reduced risk of chronic disease. The American Academy of Pediatrics recommends exclusively breastfeeding infants for 6 months and recently extended its recommendation for continuing to breastfeed with supplementation of solid foods from one to two years. Studies consistently identify lower breastfeeding rates among US infants, with regional and demographic variability. We examined breastfeeding in birthing person-infant pairs among healthy, term pregnancies enrolled in the New Hampshire Birth Cohort Study between 2010 and 2017 (n = 1176). METHODS: Birthing persons 18-45 years old were enrolled during prenatal care visits at ~ 24-28 weeks gestation and have been followed since enrollment. Breastfeeding status was obtained from postpartum questionnaires. Birthing person and infant health and sociodemographic information was abstracted from medical records and prenatal and postpartum questionnaires. We evaluated the effects of birthing person age, education, relationship status, pre-pregnancy body mass index, gestational weight gain (GWG), smoking and parity, and infant sex, ponderal index, gestational age and delivery mode on breastfeeding initiation and duration using modified Poisson and multivariable linear regression. RESULTS: Among healthy, term pregnancies, 96% of infants were breastfed at least once. Only 29% and 28% were exclusively breastfed at 6-months or received any breastmilk at 12-months, respectively. Higher birthing person age, education, and parity, being married, excessive GWG, and older gestational age at delivery were associated with better breastfeeding outcomes. Smoking, obesity, and cesarean delivery were negatively associated with breastfeeding outcomes. CONCLUSIONS: Given the public health importance of breastfeeding for infants and birthing persons, interventions are needed to support birthing persons to extend their breastfeeding duration.

Design and Selection of Heterodimerizing Helical Hairpins for Synthetic Biology.

Synthetic biology applications would benefit from protein modules of reduced complexity that function orthogonally to cellular components. As many subcellular processes depend on peptide-protein or protein-protein interactions, de novo designed polypeptides that can bring together other proteins controllably are particularly useful. Thanks to established sequence-to-structure relationships, helical bundles provide good starting points for such designs. Typically, however, such designs are tested in vitro and function in cells is not guaranteed. Here, we describe the design, characterization, and application of de novo helical hairpins that heterodimerize to form 4-helix bundles in cells. Starting from a rationally designed homodimer, we construct a library of helical hairpins and identify complementary pairs using bimolecular fluorescence complementation in E. coli. We characterize some of the pairs using biophysics and X-ray crystallography to confirm heterodimeric 4-helix bundles. Finally, we demonstrate the function of an exemplar pair in regulating transcription in both E. coli and mammalian cells.

What does heritability of Alzheimer's disease represent?

INTRODUCTION: Both late-onset Alzheimer's disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. METHODS: We compute heritability in five large independent cohorts (N = 7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. RESULTS: SNP-based heritability of late onset Alzheimer's disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD = 8%] on average when the APOE region is excluded and an additional 1% [SD = 3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. CONCLUSION: The heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes.

Metals and per- and polyfluoroalkyl substances mixtures and birth outcomes in the New Hampshire Birth Cohort Study: Beyond single-class mixture approaches.

We aimed to investigate the joint, class-specific, and individual impacts of (i) PFAS, (ii) toxic metals and metalloids (referred to collectively as "metals"), and (iii) essential elements on birth outcomes in a prospective pregnancy cohort using both established and recent mixture modeling approaches. Participants included 537 mother-child pairs from the New Hampshire Birth Cohort Study. Concentrations of 6 metals and 5 PFAS were measured in maternal toenail clippings and plasma, respectively. Birth weight, birth length, and head circumference at birth were abstracted from medical records. Joint, index-wise, and individual associations of the metals and PFAS concentrations with birth outcomes were evaluated using Bayesian Kernel Machine Regression (BKMR) and Bayesian Multiple Index Models (BMIM). After controlling for potential confounders, the metals-PFAS mixture was associated with a larger head circumference at birth, which was driven by manganese. When using BKMR, the difference in the head circumference z-score when changing manganese from its 25th to 75th percentiles while holding all other mixture components at their medians was 0.22 standard deviations (95% posterior credible interval [CI]: -0.02, 0.46). When using BMIM, the posterior mean of index weight estimates assigned to manganese for head circumference z-score was 0.72 (95% CI: 0, 0.99). Prenatal exposure to the metals-PFAS mixture was not associated with birth weight or birth length by either BKMR or BMIM. Using both traditional and new mixture modeling approaches, prenatal exposure to manganese was associated with a larger head circumference at birth after accounting for exposure to PFAS and multiple toxic and essential metals.

Early-life exposure to per- and polyfluoroalkyl substances and infant gut microbial composition.

Human milk is rich in essential nutrients and immune-activating compounds but is also a source of toxicants including per- and polyfluoroalkyl substances (PFAS). Evidence suggests that immune-related effects of PFAS may, in part, be due to alterations of the microbiome. We aimed to identify the association between milk PFAS exposure and the infant gut microbiome. Methods: PFAS [perfluorooctane sulfonic acid (PFOS) and perfluorooctanoate (PFOA)] were quantified in milk from ~6 weeks postpartum using high-performance liquid chromatography with tandem mass spectrometry. A molar sum (ΣPFAS) was calculated. Caregivers collected infant stool samples at 6 weeks (n = 116) and/or 1 year postpartum (n = 119). Stool DNA underwent metagenomic sequencing. We estimated the association of PFAS with diversity and relative abundances of species with linear regression. Single- and multi-PFAS models adjusted for potential confounders in complete case analyses and with imputed missing covariate data for 6-week and 1-year microbiomes separately. We assessed sensitive populations with stratification. Results: PFOS and PFOA were detected in 94% and 83% of milk samples, respectively. PFOS was associated with increased diversity at 6 weeks among infants fed exclusively human milk [ß = 0.24 per PFOS doubling, (95% CI = 0.03, 0.45), P = 0.03] and born to primiparous mothers [ß = 0.37 (0.06, 0.67), P = 0.02]. Estimates were strongest in multi-PFAS models and among complete cases. ΣPFAS was associated with Bacteroides vulgatus relative abundance at 1 year [(ß = -2.34% per doubling (-3.63, -1.05), FDR q = 0.099]. Conclusions: PFAS may increase infant gut microbiome diversity and alter the relative abundance of biologically relevant bacteria. Additional analyses may identify related health outcomes.

Umbilical cord blood immune cell profiles in relation to the infant gut microbiome.

During infancy, the interplay between the developing immune system and the microbiome is critical. We examined whether blood immune cell composition at birth in the umbilical cord (inferred by DNA methylation profiling) related to the early infant gut microbiome (assessed by 16S rRNA gene sequencing) among 73 infants in the New Hampshire Birth Cohort Study. We used generalized estimating equations and controlled for false discovery rate to select microbial taxa associated with immune cells. We found associations between the infant gut microbiome and immune cells, including a positive association between B cells and Enterobacter, a negative association between natural killer cells and Bifidobacterium, and a positive association between granulocytes and Bifidobacterium. Our findings give clues that immune profiles at the time of birth as measured in umbilical cord blood are associated with the development of the gut microbiome in early life.

Golgi apparatus, endoplasmic reticulum and mitochondrial function implicated in Alzheimer's disease through polygenic risk and RNA sequencing.

Polygenic risk scores (PRS) have been widely adopted as a tool for measuring common variant liability and they have been shown to predict lifetime risk of Alzheimer's disease (AD) development. However, the relationship between PRS and AD pathogenesis is largely unknown. To this end, we performed a differential gene-expression and associated disrupted biological pathway analyses of AD PRS vs. case/controls in human brain-derived cohort sample (cerebellum/temporal cortex; MayoRNAseq). The results highlighted already implicated mechanisms: immune and stress response, lipids, fatty acids and cholesterol metabolisms, endosome and cellular/neuronal death, being disrupted biological pathways in both case/controls and PRS, as well as previously less well characterised processes such as cellular structures, mitochondrial respiration and secretion. Despite heterogeneity in terms of differentially expressed genes in case/controls vs. PRS, there was a consensus of commonly disrupted biological mechanisms. Glia and microglia-related terms were also significantly disrupted, albeit not being the top disrupted Gene Ontology terms. GWAS implicated genes were significantly and in their majority, up-regulated in response to different PRS among the temporal cortex samples, suggesting potential common regulatory mechanisms. Tissue specificity in terms of disrupted biological pathways in temporal cortex vs. cerebellum was observed in relation to PRS, but limited tissue specificity when the datasets were analysed as case/controls. The largely common biological mechanisms between a case/control classification and in association with PRS suggests that PRS stratification can be used for studies where suitable case/control samples are not available or the selection of individuals with high and low PRS in clinical trials.

Characterising heart rhythm abnormalities associated with Xp22.31 deletion.

BACKGROUND: Genetic deletions at Xp22.31 are associated with the skin condition X linked ichthyosis (XLI), and with a substantially increased risk of atrial fibrillation/flutter (AF), in males. AF is associated with elevated thrombosis, heart failure, stroke and dementia risk. METHODS: Through: (a) examining deletion carriers with a diagnosis of AF in UK Biobank, (b) undertaking an online survey regarding abnormal heart rhythms (AHRs) in men/boys with XLI and female carriers of XLI-associated deletions and (c) screening for association between common genetic variants within Xp22.31 and idiopathic AF-related conditions in UK Biobank, we have investigated how AHRs manifest in deletion carriers, and have identified associated risk factors/comorbidities and candidate gene(s). Finally, we examined attitudes towards heart screening in deletion carriers. RESULTS: We show that AHRs may affect up to 35% of deletion carriers (compared with <20% of age-matched non-carriers), show no consistent pattern of onset but may be precipitated by stress, and typically resolve quickly and respond well to intervention. Gastrointestinal (GI) conditions and asthma/anaemia were the most strongly associated comorbidities in male and female deletion carriers with AHR, respectively. Genetic analysis indicated significant enrichment of common AF risk variants around STS (7 065 298-7 272 682 bp in GRCh37/hg19 genome build) in males, and of common GI disorder and asthma/anaemia risk variants around PNPLA4 (7 866 804-7 895 780 bp) in males and females, respectively. Deletion carriers were overwhelmingly in favour of cardiac screening implementation. CONCLUSION: Our data suggest AHRs are frequently associated with Xp22.31 deletion, and highlight subgroups of deletion carriers that may be prioritised for screening. Examining cardiac function further in deletion carriers, and in model systems lacking steroid sulfatase, may clarify AF pathophysiology.