Search

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

IntroductionAlthough dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.MethodsWe applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43.ResultsFinal included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility.DiscussionA novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.HighlightsLatent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

PURPOSE: Left ventricular (LV) fibrosis has a key role in arrhythmogenesis in patients with mitral valve prolapse (MVP). Cardiac magnetic resonance identifies LV fibrosis by using late gadolinium enhancement (LGE) technique. LGE assessment and quantification in patients with MVP lacks of standardization protocols. METHODS: 66 MVP patients with normal systolic function and without significant regurgitation were enrolled. Semi-automated gray-scale thresholding techniques using full width at half maximum (FWHM) and 2, 3 and 5 standard deviation (SD) above the remote myocardium were used and compared with the visual assessment, considered as the gold standard. RESULTS: LGE was identified in 41 MVP patients (62%) and quantified. The mean quantity of LGE visually assessed was 2.40 ± 1.07% or 1.40 ± 0.82 g. With FWHM, LGE resulted 3.56 ± 1.23% or 1.99 ± 1.13 g. Using thresholding, the mean LGE quantity was 9.2 ± 3.1% or 4.82 ± 2.28 g for 2-SD, 5.72 ± 1.75% or 3.06 ± 1.47 g for 3-SD and 2.36 ± 0.99% or 1.29 ± 0.79 g for 5-SD. The 5-SD measurement in percentage demonstrated a good correlation with LGE quantification visually assessed (2.40 ± 1.07 vs. 2.363 ± 0.9909, p = 0.543). When compared with the gold standard, the 5-SD threshold quantification, both in percentage and in grams, revealed the least intra-observer (respectively, ICC: 0.976 and 0.966) and inter-observer variability (respectively ICC: 0.948 and 0.935). CONCLUSION: The 5-SD gray-scale threshold technique in percentage revealed the best correlation with the visual assessment and an optimal reproducibility in MVP patient.

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folates role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense, including the recurrent p.Val44Met in 7/17 individuals, or in-frame, all affecting conserved residues located in transmembrane regions of the protein. In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis, requiring blood transfusions in some. We modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca2+ transients generated under hypo-osmotic stimulation. Ectopic expression of the p.Val44Met and p.Gly580Cys variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a recognizable clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early-onset epilepsy associated with hematological abnormalities in most individuals.

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P

Individuals of admixed ancestries (for example, African Americans) inherit a mosaic of ancestry segments (local ancestry) originating from multiple continental ancestral populations. This offers the unique opportunity of investigating the similarity of genetic effects on traits across ancestries within the same population. Here we introduce an approach to estimate correlation of causal genetic effects (radmix) across local ancestries and analyze 38 complex traits in African-European admixed individuals (N = 53,001) to observe very high correlations (meta-analysis radmix = 0.95, 95% credible interval 0.93-0.97), much higher than correlation of causal effects across continental ancestries. We replicate our results using regression-based methods from marginal genome-wide association study summary statistics. We also report realistic scenarios where regression-based methods yield inflated heterogeneity-by-ancestry due to ancestry-specific tagging of causal effects, and/or polygenicity. Our results motivate genetic analyses that assume minimal heterogeneity in causal effects by ancestry, with implications for the inclusion of ancestry-diverse individuals in studies.

Background and objectivesBRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.MethodsThrough a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.ResultsWe included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.DiscussionBRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.

BackgroundPrevious studies have demonstrated low first-time donor return rates (DRR) following catastrophic events. Little is known, however, about the influence of demographic factors on the DRR of first-time donors during the COVID-19 pandemic, including the unique motivation of COVID-19 convalescent plasma (CCP) donors as compared to non-CCP donors.Study design and methodsThirteen blood collection organizations submitted deidentified data from first-time CCP and non-CCP donors returning for regular (non-CCP) donations during the pandemic. DRR was calculated as frequencies. Demographic factors associated with returning donors: race/ethnicity, gender, and generation (Gen Z: 19-24, Millennial: 25-40, Gen X: 41-56, and Boomer: ≥57 years old), within the CCP and non-CCP first-time cohorts were compared using chi-square test at p

BackgroundIn 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern.MethodsINTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile.FindingsWe enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose.InterpretationCOVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority.FundingNone.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

BACKGROUND: Accurate kinetic modeling of 18F-fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET) data requires accurate knowledge of the available tracer concentration in the plasma during the scan time, known as the arterial input function (AIF). The gold standard method to derive the AIF requires collection of serial arterial blood samples, but the introduction of long axial field of view (LAFOV) PET systems enables the use of non-invasive image-derived input functions (IDIFs) from large blood pools such as the aorta without any need for bed movement. However, such protocols require a prolonged dynamic PET acquisition, which is impractical in a busy clinical setting. Population-based input functions (PBIFs) have previously shown potential in accurate Patlak analysis of [18F]-FDG datasets and can enable the use of shortened dynamic imaging protocols. Here, we exploit the high sensitivity and temporal resolution of a LAFOV PET system and explore the use of PBIF with abbreviated protocols in [18F]-FDG total body kinetic modeling. METHODS: Dynamic PET data were acquired in 24 oncological subjects for 65 min following the administration of [18F]-FDG. IDIFs were extracted from the descending thoracic aorta, and a PBIF was generated from 16 datasets. Five different scaled PBIFs (sPBIFs) were generated by scaling the PBIF with the AUC of IDIF curve tails using various portions of image data (35-65, 40-65, 45-65, 50-65, and 55-65 min post-injection). The sPBIFs were compared with the IDIFs using the AUCs and Patlak Ki estimates in tumor lesions and cerebral gray matter. Patlak plot start time (t*) was also varied to evaluate the performance of shorter acquisitions on the accuracy of Patlak Ki estimates. Patlak Ki estimates with IDIF and t* = 35 min were used as reference, and mean bias and precision (standard deviation of bias) were calculated to assess the relative performance of different sPBIFs. A comparison of parametric images generated using IDIF and sPBIFs was also performed. RESULTS: There was no statistically significant difference between AUCs of the IDIF and sPBIFs (Wilcoxon test: P > 0.05). Excellent agreement was shown between Patlak Ki estimates obtained using sPBIF and IDIF. Using the sPBIF55-65 with the Patlak model, 20 min of PET data (i.e., 45 to 65 min post-injection) achieved  0.99 and peak signal-to-noise ratio > 55 dB. CONCLUSION: We demonstrate the feasibility of performing accurate [18F]-FDG Patlak analysis using sPBIFs with only 20 min of PET data from a LAFOV PET scanner.

BackgroundAlthough Black/African American older adults bear significant inequities in prevalence, incidence, and outcomes of Alzheimer's disease and related dementias, they are profoundly under-included in Alzheimer's Disease research. Community-Engaged Research (e.g., equitable community/science partnerships) is an evidence-based approach for improving engagement of underrepresented populations into Alzheimer's Disease research, but has lacked scalability to the national level. As internet use among older adults from underrepresented populations continues to grow, internet-based research shows promise as a feasible, valid approach to engagement and longitudinal assessment. The Community Engaged Digital Alzheimer's Research (CEDAR) study utilizes a community-engaged research approach to increase the engagement and research participation of Black/African American adults in the Brain Health Registry (BHR) and Alzheimer Disease clinical research.ObjectivesTo describe the methods and evaluate the feasibility of the CEDAR culturally-informed digital platform within BHR.DesignAll Black/African American participants in BHR were invited to enroll in CEDAR and to consider serving on a newly convened Community-Scientific Partnership Board to guide the study. The community board guided the development a culturally-informed cadre of engagement materials and strategies to increase research participation. Engagement strategies included incentives for study task completion, culturally-informed communications (e.g., landing page, emails and social media), resources about brain health, and video and written testimonials by CEDAR participants.SettingBHR, an Internet-based registry and cohort.ParticipantsBHR participants self-identifying as Black/African American were invited to enroll. All participants who signed an online informed consent document were enrolled.MeasurementsWe report the number of participants invited, enrolled, completed tasks, and volunteered to join the community board. We compared the demographics, cognitive profile, and baseline BHR task completion rates between CEDAR participants and all those invited to join the study.ResultsOf 3738 invited, 349 (9.34%) enrolled in CEDAR. 134 (37% of CEDAR participants) volunteered to join the community board, of which 19 were selected for the community board. Compared to those invited, the CEDAR cohort had a higher percentage of female participants (84.5%) and a lower percentage of participants who identify as belonging to more than one ethnocultural group (21.8%). Compared to those did not enroll in CEDAR, those enrolled in CEDAR had a higher percentage of participants completing all BHR tasks (22%) and a higher percentage of participants completing at least one cognitive test (76%). Those enrolled in CEDAR also had a higher percentage of participants having an enrolled study partner (18%).ConclusionsA culturally-informed Community-Engaged Research approach, including a remotely-convened community board, to engagement of Black/African American participants in an online research registry is feasible. This approach can be adapted for use in various clinical studies and other settings. Future studies will evaluate the effectiveness of the engagement strategies.

BackgroundFailure of Alzheimer's disease and related diseases (ADRD) research studies to include and engage Black participants is a major issue, which limits the impact and generalizability of research findings. Little is known about participation of Black adults in online ADRD-related research registries.ObjectivesAs part of the Community Engaged Digital Alzheimer's Research (CEDAR) Study, this study aims to increase our understanding of facilitators and barriers of Black adults to participating in ADRD-related online registries, as well as to understand their preferences for communication channels.Design, setting, participants, measurementsWe invited all Black participants enrolled in the Brain Health Registry (BHR) to complete a cross-sectional online survey. The survey consisted of rating scales and open-text questions asking about their attitudes towards brain health research, reasons for joining and continuing to participate in BHR, difficulties with participating, and preferences for modes of contact and website usage.ResultsOf all invited Black BHR participants (N=3,636), 198 (5.5%) completed the survey. The mean age was 58.4 (SD=11.3), mean years of education were 16.3 (SD=2.4), and 85.5% identified as female. Reported facilitators for joining and continuing to participate in BHR were personal interest (e.g., learning more about own brain health) and altruism (e.g., helping research). Among additional registry features which could encourage return, receiving feedback or scores about BHR tasks was rated the highest. Of those who found BHR participation difficult (21%), the most frequent reason was time burden. The most preferred way of receiving study information was via email. Participants reported that the websites that they used the most were YouTube and Facebook.DiscussionThe results of our study can inform the development of culturally-responsive registry features and engagement efforts to improve inclusion and participation of Black adults in online ADRD research. Providing participants with feedback about their registry performance and reducing the number of registry tasks are among the recommended strategies.

Background and purposeClinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation.MethodLogistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number.ResultsFrom March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p

PURPOSE: Attenuation correction is a critically important step in data correction in positron emission tomography (PET) image formation. The current standard method involves conversion of Hounsfield units from a computed tomography (CT) image to construct attenuation maps (µ-maps) at 511 keV. In this work, the increased sensitivity of long axial field-of-view (LAFOV) PET scanners was exploited to develop and evaluate a deep learning (DL) and joint reconstruction-based method to generate µ-maps utilizing background radiation from lutetium-based (LSO) scintillators. METHODS: Data from 18 subjects were used to train convolutional neural networks to enhance initial µ-maps generated using joint activity and attenuation reconstruction algorithm (MLACF) with transmission data from LSO background radiation acquired before and after the administration of 18F-fluorodeoxyglucose (18F-FDG) (µ-mapMLACF-PRE and µ-mapMLACF-POST respectively). The deep learning-enhanced µ-maps (µ-mapDL-MLACF-PRE and µ-mapDL-MLACF-POST) were compared against MLACF-derived and CT-based maps (µ-mapCT). The performance of the method was also evaluated by assessing PET images reconstructed using each µ-map and computing volume-of-interest based standard uptake value measurements and percentage relative mean error (rME) and relative mean absolute error (rMAE) relative to CT-based method. RESULTS: No statistically significant difference was observed in rME values for µ-mapDL-MLACF-PRE and µ-mapDL-MLACF-POST both in fat-based and water-based soft tissue as well as bones, suggesting that presence of the radiopharmaceutical activity in the body had negligible effects on the resulting µ-maps. The rMAE values µ-mapDL-MLACF-POST were reduced by a factor of 3.3 in average compared to the rMAE of µ-mapMLACF-POST. Similarly, the average rMAE values of PET images reconstructed using µ-mapDL-MLACF-POST (PETDL-MLACF-POST) were 2.6 times smaller than the average rMAE values of PET images reconstructed using µ-mapMLACF-POST. The mean absolute errors in SUV values of PETDL-MLACF-POST compared to PETCT were less than 5% in healthy organs, less than 7% in brain grey matter and 4.3% for all tumours combined. CONCLUSION: We describe a deep learning-based method to accurately generate µ-maps from PET emission data and LSO background radiation, enabling CT-free attenuation and scatter correction in LAFOV PET scanners.

The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu ) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research.

ObjectiveTo assess the impact of the Urology Collaborative Online Video Didactic (COViD) lecture series series on resident knowledge as a supplement to resident education during the coronavirus disease 2019 pandemic.MethodsOne hundred thirty-nine urology residents were voluntarily recruited from 8 institutions. A 20-question test, based on 5 COViD lectures, was administered before and after watching the lectures. Pre- and posttest scores (percent correct) and score changes (posttest minus pretest score) were assessed considering demographic data and number of lectures watched. Multiple linear regression determined predictors of improved scores.ResultsOf residents recruited, 95 and 71 took the pre- and posttests. Median number of lectures watched was 3. There was an overall increase in correct scores from pretest to posttest (45% vs 57%, P < .01). Watching any lectures vs none led to higher posttest scores (60% vs 44%, P < .01) and score changes (+16% vs +1%, P < .01). There was an increase in baseline pretest scores by post-graduate year (PGY) (P < .01); however there were no significant differences in posttest or score changes by PGY. When accounting for lectures watched, PGY, and time between lecture and posttest, being a PGY6 (P = .01) and watching 3-5 lectures (P < .01) had higher overall correct posttest scores. Watching 3-5 lectures led to greater score changes (P < .001-.04). Over 65% of residents stated the COViD lectures had a large or very large impact on their education.ConclusionsCOViD lectures improved overall correct posttest scores and increased knowledge base for all resident levels. Furthermore, lectures largely impacted resident education during the coronavirus disease 2019 pandemic.

BackgroundThe effect of COVID-19 in pregnancy on maternal outcomes and its association with preeclampsia and gestational diabetes mellitus have been reported; however, a detailed understanding of the effects of maternal positivity, delivery mode, and perinatal practices on fetal and neonatal outcomes is urgently needed.ObjectiveTo evaluate the impact of COVID-19 on fetal and neonatal outcomes and the role of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission.Study designIn this cohort study that took place from March 2020 to March 2021, involving 43 institutions in 18 countries, 2 unmatched, consecutive, unexposed women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy was determined by laboratory confirmation and/or radiological pulmonary findings or ≥2 predefined COVID-19 symptoms. The outcome measures were indices of neonatal and perinatal morbidity and mortality, neonatal positivity and its correlation with mode of delivery, breastfeeding, and hospital neonatal care practices.ResultsA total of 586 neonates born to women with COVID-19 diagnosis and 1535 neonates born to women without COVID-19 diagnosis were enrolled. Women with COVID-19 diagnosis had a higher rate of cesarean delivery (52.8% vs 38.5% for those without COVID-19 diagnosis, P14 days). Among neonates born to mothers with COVID-19 diagnosis, birth via cesarean delivery was a risk factor for testing positive for COVID-19 (odds ratio, 2.4; 95% confidence interval, 1.2-4.7), even when severity of maternal conditions was considered and after multivariable logistic analysis. In the subgroup of neonates born to women with COVID-19 diagnosis, the outcomes worsened when the neonate also tested positive, with higher rates of neonatal intensive care unit admission, fever, gastrointestinal and respiratory symptoms, and death, even after adjusting for prematurity. Breastfeeding by mothers with COVID-19 diagnosis and hospital neonatal care practices, including immediate skin-to-skin contact and rooming-in, were not associated with an increased risk of newborn positivity.ConclusionIn this multinational cohort study, COVID-19 in pregnancy was associated with increased maternal and neonatal complications. Cesarean delivery was significantly associated with newborn COVID-19 diagnosis. Vaginal delivery should be considered the safest mode of delivery if obstetrical and health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding were not risk factors for newborn COVID-19 diagnosis, thus well-established best practices can be continued among women with COVID-19 diagnosis.

Transcriptome-wide association studies (TWASs) are a powerful approach to identify genes whose expression is associated with complex disease risk. However, non-causal genes can exhibit association signals due to confounding by linkage disequilibrium (LD) patterns and eQTL pleiotropy at genomic risk regions, which necessitates fine-mapping of TWAS signals. Here, we present MA-FOCUS, a multi-ancestry framework for the improved identification of genes underlying traits of interest. We demonstrate that by leveraging differences in ancestry-specific patterns of LD and eQTL signals, MA-FOCUS consistently outperforms single-ancestry fine-mapping approaches with equivalent total sample sizes across multiple metrics. We perform TWASs for 15 blood traits using genome-wide summary statistics (average nEA = 511 k, nAA = 13 k) and lymphoblastoid cell line eQTL data from cohorts of primarily European and African continental ancestries. We recapitulate evidence demonstrating shared genetic architectures for eQTL and blood traits between the two ancestry groups and observe that gene-level effects correlate 20% more strongly across ancestries than SNP-level effects. Lastly, we perform fine-mapping using MA-FOCUS and find evidence that genes at TWAS risk regions are more likely to be shared across ancestries than they are to be ancestry specific. Using multiple lines of evidence to validate our findings, we find that gene sets produced by MA-FOCUS are more enriched in hematopoietic categories than alternative approaches (p = 2.36 × 10-15). Our work demonstrates that including and appropriately accounting for genetic diversity can drive more profound insights into the genetic architecture of complex traits.

BackgroundThe use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.MethodsWe conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.ResultsThe use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P

PURPOSE: Kinetic parameters from dynamic 18F-fluorodeoxyglucose (FDG) imaging offer complementary insights to the study of disease compared to static clinical imaging. However, dynamic imaging protocols are cumbersome due to the long acquisition time. Long axial field-of-view (LAFOV) PET scanners (> 70 cm) have two advantages for dynamic imaging over clinical PET scanners with a standard axial field-of-view (SAFOV; 16-30 cm). The large axial coverage enables multi-organ dynamic imaging in a single bed position, and the high sensitivity may enable clinically routine abbreviated dynamic imaging protocols. METHODS: In this work, we studied two abbreviated protocols using data from a 65-min dynamic 18F-FDG scan: (A) dynamic imaging immediately post-injection (p.i.) for variable durations, and (B) dynamic imaging immediately p.i. for variable durations plus a 1-h p.i. (5-min-long) datapoint. Nine cancer patients were imaged on the Biograph Vision Quadra (Siemens Healthineers). Time-activity curves over the lesions (N = 39) were fitted using the Patlak graphical analysis and a 2-tissue-compartment (2C, k4 = 0) model for variable scan durations (5-60 min). Kinetic parameters from the complete dataset served as the reference. Lesions from all cancers were grouped into low, medium, and high flux groups, and bias and precision of Ki (Patlak) and Ki, K1, k2, and k3 (2C) were calculated for each group. RESULTS: Using only early dynamic data with the 2C (or Patlak) model, accurate quantification of Ki required at least 50 (or 55) min of dynamic data for low flux lesions, at least 30 (or 40) min for medium flux lesions, and at least 15 (or 20) min for high flux lesions to achieve both 10% bias and precision. The addition of the final (5-min) datapoint allowed for accurate quantification of Ki with a bias and precision of 10% using only 10-15 min of early dynamic data for either model. CONCLUSION: Dynamic imaging for 10-15 min immediately p.i. followed by a 5-min scan at 1-h p.i can accurately and precisely quantify 18F-FDG on a long axial FOV scanner, potentially allowing for more widespread use of dynamic 18F-FDG imaging.

BackgroundYoung adults and other working-age adults with cancer are at risk for cancer-related financial toxicity (FT), including material hardships, depletion of coping resources, and psychological burden. This study compares FT domains in young adults (18-39 years old) (YAs), other working-age adults (40-64 years old), and older adults (≥65 years old) receiving cancer care.MethodsA total of 311 adults were surveyed using the multi-domain Economic Strain and Resilience in Cancer instrument measuring FT (0-10 score indicating least to greatest FT; score ≥5 severe FT). Participants were receiving ambulatory care from March-September 2019. Associations of age with overall FT and material hardship, coping resource depletion, and psychological burden FT domains were tested using Kruskal-Wallis and χ2 tests and multivariable generalized linear models with gamma distribution.ResultsYAs (median age, 31.5 years) comprised 9.6% of the sample; other working-age adults comprised 56.9%. Overall, material, coping, and psychological FT scores were worse in younger age adults versus older adults (P

BackgroundAmong nonpregnant individuals, diabetes mellitus and high body mass index increase the risk of COVID-19 and its severity.ObjectiveThis study aimed to determine whether diabetes mellitus and high body mass index are risk factors for COVID-19 in pregnancy and whether gestational diabetes mellitus is associated with COVID-19 diagnosis.Study designINTERCOVID was a multinational study conducted between March 2020 and February 2021 in 43 institutions from 18 countries, enrolling 2184 pregnant women aged ≥18 years; a total of 2071 women were included in the analyses. For each woman diagnosed with COVID-19, 2 nondiagnosed women delivering or initiating antenatal care at the same institution were also enrolled. The main exposures were preexisting diabetes mellitus, high body mass index (overweight or obesity was defined as a body mass index ≥25 kg/m2), and gestational diabetes mellitus in pregnancy. The main outcome was a confirmed diagnosis of COVID-19 based on a real-time polymerase chain reaction test, antigen test, antibody test, radiological pulmonary findings, or ≥2 predefined COVID-19 symptoms at any time during pregnancy or delivery. Relationships of exposures and COVID-19 diagnosis were assessed using generalized linear models with a Poisson distribution and log link function, with robust standard errors to account for model misspecification. Furthermore, we conducted sensitivity analyses: (1) restricted to those with a real-time polymerase chain reaction test or an antigen test in the last week of pregnancy, (2) restricted to those with a real-time polymerase chain reaction test or an antigen test during the entire pregnancy, (3) generating values for missing data using multiple imputation, and (4) analyses controlling for month of enrollment. In addition, among women who were diagnosed with COVID-19, we examined whether having gestational diabetes mellitus, diabetes mellitus, or high body mass index increased the risk of having symptomatic vs asymptomatic COVID-19.ResultsCOVID-19 was associated with preexisting diabetes mellitus (risk ratio, 1.94; 95% confidence interval, 1.55-2.42), overweight or obesity (risk ratio, 1.20; 95% confidence interval, 1.06-1.37), and gestational diabetes mellitus (risk ratio, 1.21; 95% confidence interval, 0.99-1.46). The gestational diabetes mellitus association was specifically among women requiring insulin, whether they were of normal weight (risk ratio, 1.79; 95% confidence interval, 1.06-3.01) or overweight or obese (risk ratio, 1.77; 95% confidence interval, 1.28-2.45). A somewhat stronger association with COVID-19 diagnosis was observed among women with preexisting diabetes mellitus, whether they were of normal weight (risk ratio, 1.93; 95% confidence interval, 1.18-3.17) or overweight or obese (risk ratio, 2.32; 95% confidence interval, 1.82-2.97). When the sample was restricted to those with a real-time polymerase chain reaction test or an antigen test in the week before delivery or during the entire pregnancy, including missing variables using imputation or controlling for month of enrollment, the observed associations were comparable.ConclusionDiabetes mellitus and overweight or obesity were risk factors for COVID-19 diagnosis in pregnancy, and insulin-dependent gestational diabetes mellitus was associated with the disease. Therefore, it is essential that women with these comorbidities are vaccinated.

BackgroundExperimental evidence indicates that exposure to certain pollutants is associated with liver damage. Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industry and consumer products and bioaccumulate in food webs and human tissues, such as the liver.ObjectiveThe objective of this study was to conduct a systematic review of the literature and meta-analysis evaluating PFAS exposure and evidence of liver injury from rodent and epidemiological studies.MethodsPubMed and Embase were searched for all studies from earliest available indexing year through 1 December 2021 using keywords corresponding to PFAS exposure and liver injury. For data synthesis, results were limited to studies in humans and rodents assessing the following indicators of liver injury: serum alanine aminotransferase (ALT), nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or steatosis. For human studies, at least three observational studies per PFAS were used to conduct a weighted z-score meta-analysis to determine the direction and significance of associations. For rodent studies, data were synthesized to qualitatively summarize the direction and significance of effect.ResultsOur search yielded 85 rodent studies and 24 epidemiological studies, primarily of people from the United States. Studies focused primarily on legacy PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid. Meta-analyses of human studies revealed that higher ALT levels were associated with exposure to PFOA (z-score= 6.20, p

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Background and purposeSome studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS.MethodsData were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity.ResultsIn all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009).ConclusionsEven if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.

We conducted a systematic review and meta-analysis of the associations between prenatal exposure to persistent organic pollutants (POPs) and childhood obesity. We focused on organochlorines (dichlorodiphenyltrichloroethane [DDT], dichlorodiphenyldichloroethylene [DDE], hexachlorobenzene [HCB], and polychlorinated biphenyls [PCBs]), perfluoroalkyl and polyfluoroalkyl substances (PFAS), and polybrominated diphenyl ethers (PBDEs) that are the POPs more widely studied in environmental birth cohorts so far. We search two databases (PubMed and Embase) through July/09/2021 and identified 33 studies reporting associations with prenatal organochlorine exposure, 21 studies reporting associations with prenatal PFAS, and five studies reporting associations with prenatal PBDEs. We conducted a qualitative review. Additionally, we performed random-effects meta-analyses of POP exposures, with data estimates from at least three prospective studies, and BMI-z. Prenatal DDE and HCB levels were associated with higher BMI z-score in childhood (beta: 0.12, 95% CI: 0.03, 0.21; I2 : 28.1% per study-specific log increase of DDE and beta: 0.31, 95% CI: 0.09, 0.53; I2 : 31.9% per study-specific log increase of HCB). No significant associations between PCB-153, PFOA, PFOS, or pentaPBDEs with childhood BMI were found in meta-analyses. In individual studies, there was inconclusive evidence that POP levels were positively associated with other obesity indicators (e.g., waist circumference).

BackgroundIt is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors.ObjectiveThis study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality.Study designThis was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions.ResultsWe enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios.ConclusionCOVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P

BackgroundOlder adults commonly face challenges in understanding, obtaining, administering, and monitoring medication regimens after hospitalization. These difficulties can lead to avoidable morbidity, mortality, and hospital readmissions. Pharmacist-led peri-discharge interventions can reduce adverse drug events, but few large randomized trials have examined their effectiveness in reducing readmissions. Demonstrating reductions in 30-day readmissions can make a financial case for implementing pharmacist-led programs across hospitals.Methods/designThe PHARMacist Discharge Care, or the PHARM-DC intervention, includes medication reconciliation at admission and discharge, medication review, increased communication with caregivers, providers, and retail pharmacies, and patient education and counseling during and after discharge. The intervention is being implemented in two large hospitals: Cedars-Sinai Medical Center and the Brigham and Women's Hospital. To evaluate the intervention, we are using a pragmatic, randomized clinical trial design with randomization at the patient level. The primary outcome is utilization within 30 days of hospital discharge, including unforeseen emergency department visits, observation stays, and readmissions. Randomizing 9776 patients will achieve 80% power to detect an absolute reduction of 2.5% from an estimated baseline rate of 27.5%. Qualitative analysis will use interviews with key stakeholders to study barriers to and facilitators of implementing PHARM-DC. A cost-effectiveness analysis using a time-and-motion study to estimate time spent on the intervention will highlight the potential cost savings per readmission.DiscussionIf this trial demonstrates a business case for the PHARM-DC intervention, with few barriers to implementation, hospitals may be much more likely to adopt pharmacist-led peri-discharge medication management programs.Trial registrationClinicalTrials.gov Identifier: NCT04071951.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

ObjectiveTo capture the perspective of prospective urology applicants experiencing unique challenges in the context of COVID-19.MethodsA voluntary, anonymous survey was distributed online, assessing the impact of COVID-19 on a large sample of US medical students planning to apply to urology residencies. Themes of (1) specialty discernment, (2) alterations to medical education, and (3) the residency application process were explored.ResultsA total of 238 medical students, 87% third and fourth years, responded to the survey. While 85% indicated that the pandemic had not deterred their specialty choice, they noted substantial impacts on education, including 82% reporting decreased exposure to urology. Nearly half of students reported changes to required rotations and 35% reported changes to urology-specific rotations at their home institutions. Students shared concerns about suspending in-person experiences, including the impact on letters of recommendation (68% "very concerned) and program choice (73% "very concerned"). Looking to the possibility of virtual interactions, students identified the importance of small group and one-on-one communication with residents (83% "very important") and opportunities to learn about hospital facilities (72% "very important").ConclusionDespite the impacts of COVID-19 on medical education, prospective urology applicants appear to remain confident in their specialty choice. Students' biggest concerns involve disruption of away rotations, including impacts on obtaining letters of recommendation and choosing a residency program.

BackgroundAdvances in untargeted metabolomic technologies have great potential for insight into adverse metabolic effects underlying exposure to environmental chemicals. However, important challenges need to be addressed, including how biological response corresponds to the environmental chemical burden in different target tissues.AimWe performed a pilot study using state-of-the-art ultra-high-resolution mass spectrometry (UHRMS) to characterize the burden of lipophilic persistent organic pollutants (POPs) in metabolic tissues and associated alterations in the plasma metabolome.MethodsWe studied 11 adolescents with severe obesity at the time of bariatric surgery. We measured 18 POPs that can act as endocrine and metabolic disruptors (i.e. 2 dioxins, 11 organochlorine compounds [OCs] and 5 polybrominated diphenyl ethers [PBDEs]) in visceral and subcutaneous abdominal adipose tissue (vAT and sAT), and liver samples using gas chromatography with UHRMS. Biological pathways were evaluated by measuring the plasma metabolome using high-resolution metabolomics. Network and pathway enrichment analysis assessed correlations between the tissue-specific burden of three frequently detected POPs (i.e. p,p'-dichlorodiphenyldichloroethene [DDE], hexachlorobenzene [HCB] and PBDE-47) and plasma metabolic pathways.ResultsConcentrations of 4 OCs and 3 PBDEs were quantifiable in at least one metabolic tissue for > 80% of participants. All POPs had the highest median concentrations in adipose tissue, especially sAT, except for PBDE-154, which had comparable average concentrations across all tissues. Pathway analysis showed high correlations between tissue-specific POPs and metabolic alterations in pathways of amino acid metabolism, lipid and fatty acid metabolism, and carbohydrate metabolism.ConclusionsMost of the measured POPs appear to accumulate preferentially in adipose tissue compared to liver. Findings of plasma metabolic pathways potentially associated with tissue-specific POPs concentrations merit further investigation in larger populations.

BackgroundSubstantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States.ObjectiveWe sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations.MethodsGenotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses.ResultsWe found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene-environment or gene-gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability.ConclusionThese findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

BackgroundBody mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.MethodsTo improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR

Latinos represent

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Single germline or somatic activating mutations of mammalian target of rapamycin (mTOR) pathway genes are emerging as a major cause of type II focal cortical dysplasia (FCD), hemimegalencephaly (HME) and tuberous sclerosis complex (TSC). A double-hit mechanism, based on a primary germline mutation in one allele and a secondary somatic hit affecting the other allele of the same gene in a small number of cells, has been documented in some patients with TSC or FCD. In a patient with HME, severe intellectual disability, intractable seizures and hypochromic skin patches, we identified the ribosomal protein S6 (RPS6) p.R232H variant, present as somatic mosaicism at ~15.1% in dysplastic brain tissue and ~11% in blood, and the MTOR p.S2215F variant, detected as ~8.8% mosaicism in brain tissue, but not in blood. Overexpressing the two variants independently in animal models, we demonstrated that MTOR p.S2215F caused neuronal migration delay and cytomegaly, while RPS6 p.R232H prompted increased cell proliferation. Double mutants exhibited a more severe phenotype, with increased proliferation and migration defects at embryonic stage and, at postnatal stage, cytomegalic cells exhibiting eccentric nuclei and binucleation, which are typical features of balloon cells. These findings suggest a synergistic effect of the two variants. This study indicates that, in addition to single activating mutations and double-hit inactivating mutations in mTOR pathway genes, severe forms of cortical dysplasia can also result from activating mutations affecting different genes in this pathway. RPS6 is a potential novel disease-related gene.

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Alu retroelements, whose retrotransposition requires prior transcription by RNA polymerase III to generate Alu RNAs, represent the most numerous non-coding RNA (ncRNA) gene family in the human genome. Alu transcription is generally kept to extremely low levels by tight epigenetic silencing, but it has been reported to increase under different types of cell perturbation, such as viral infection and cancer. Alu RNAs, being able to act as gene expression modulators, may be directly involved in the mechanisms determining cellular behavior in such perturbed states. To directly address the regulatory potential of Alu RNAs, we generated IMR90 fibroblasts and HeLa cell lines stably overexpressing two slightly different Alu RNAs, and analyzed genome-wide the expression changes of protein-coding genes through RNA-sequencing. Among the genes that were upregulated or downregulated in response to Alu overexpression in IMR90, but not in HeLa cells, we found a highly significant enrichment of pathways involved in cell cycle progression and mitotic entry. Accordingly, Alu overexpression was found to promote transition from G1 to S phase, as revealed by flow cytometry. Therefore, increased Alu RNA may contribute to sustained cell proliferation, which is an important factor of cancer development and progression.

BackgroundAsthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.ObjectiveWe sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.MethodsWe leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups.ResultsWe identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

BackgroundGenome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.ResultsHere, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.ConclusionsOur approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

Infertility affects ~7% of couples of reproductive age with little change in incidence in the last two decades. ART, as well as other interventions, have made major strides in correcting this condition. However, and in spite of advancements in the field, the age of the female partner remains a main factor for a successful outcome. A better understanding of the final stages of gamete maturation yielding an egg that can sustain embryo development and a pregnancy to term remains a major area for improvement in the field. This review will summarize the major cellular and molecular events unfolding at the oocyte-to-embryo transition. We will provide an update on the most important processes/pathways currently understood as the basis of developmental competence, including the molecular processes involved in mRNA storage, its recruitment to the translational machinery, and its degradation. We will discuss the hypothesis that the translational programme of maternal mRNAs plays a key role in establishing developmental competence. These regulations are essential to assemble the machinery that is used to establish a totipotent zygote. This hypothesis further supports the view that embryogenesis begins during oogenesis. A better understanding of the events required for developmental competence will guide the development of novel strategies to monitor and improve the success rate of IVF. Using this information, it will be possible to develop new biomarkers that may be used to better predict oocyte quality and in selection of the best egg for IVF.

Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.