Strong Evidence Of Association Research Articles

Head injury and 25-year risk of dementia.

Head injury is associated with significant morbidity and mortality. Long-term associations of head injury with dementia in community-based populations are less clear. Prospective cohort study of 14,376 participants (mean age 54 years at baseline, 56% female, 27% Black, 24% with head injury) enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. Head injury was defined using self-report and International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) codes. Dementia was defined using cognitive assessments, informant interviews, and ICD-9/10 and death certificate codes. Head injury was associated with risk of dementia (hazard ratio [HR]=1.44, 95% confidence interval [CI]=1.3-1.57), with evidence of dose-response (1 head injury: HR=1.25, 95% CI=1.13-1.39, 2+ head injuries: HR=2.14, 95% CI=1.86-2.46). There was evidence for stronger associations among female participants (HR=1.69, 95% CI=1.51-1.90) versus male participants (HR=1.15, 95% CI=1.00-1.32), P-for-interaction<.001, and among White participants (HR=1.55, 95% CI=1.40-1.72) versus Black participants (HR=1.22, 95% CI=1.02-1.45), P-for-interaction=.008. In this community-based cohort with 25-year follow-up, head injury was associated with increased dementia risk in a dose-dependent manner, with stronger associations among female participants and White participants.

Identification of cutaneous fungi and mites in adult atopic dermatitis: analysis by targeted 18S rRNA amplicon sequencing

BackgroundAtopic dermatitis (AD) patients have an altered skin bacterial community, with an abundance of Staphylococcus aureus associated with flares, highlighting that microbial organisms may be important for disease exacerbation. Despite strong evidence of association between bacterial skin colonisation and AD, very limited knowledge regarding the eukaryotic microbial community, including fungi and ectoparasites, in AD exists. In this study, we compared the skin and nasal eukaryotic microbial community between adult AD patients (n = 55) and non-AD healthy controls (n = 45) using targeted 18S rRNA amplicon sequencing. Analysis was based on the presence or absence of eukaryotic microorganisms.ResultsThe cutaneous composition of the eukaryotic microbial community and the alpha-diversity differed significantly between AD patients and non-AD individuals, with increased species richness on AD skin. Alpha-diversity and beta-diversity were similar on lesional and non-lesional skin of patients. The ectoparasite Demodex folliculorum and the yeast Geotrichum candidum were significantly more prevalent on the skin of AD patients. The prevalence of D. folliculorum on lesional skin was greater among patients recently treated with topical corticosteroid. Malassezia was one of the most frequently detected genera at all sites, with M. globosa and M. restricta being the most prevalent. M. restricta was under represented in the anterior nares of AD patients as compared to the non-AD control population.ConclusionSignificant differences in the eukaryotic microbial communities were found between AD patients and non-AD individuals, with the most striking finding being the significantly overrepresentation of D. folliculorum on AD skin. Whether D. folliculorum can contribute to skin inflammation in AD needs further investigation.

Pain, eating behavior, and weight outcomes in adolescent girls.

In adults, pain is prospectively associated with overweight/obesity and concurrently associated with dysregulated eating, with evidence for stronger associations in women than men. This study aimed to evaluate whether similar associations among pain response, BMI, and loss of control (LOC) eating are also evident in adolescent girls. Girls (n = 202) completed the cold pressor test (CPT) at age 10, and BMI and LOC eating were assessed annually from ages 10-16 years. Generalized linear models were used to test associations between pain tolerance (total immersion time) and threshold (latency to highest pain rating), and changes in BMI and LOC eating. Lower pain tolerance and threshold at age 10 were associated with increases in LOC eating from age 10 to 16 (tolerance: B < -.01, SE < .01, p = .005; threshold: B = -.03, SE = .01, p = .0118). No significant associations were observed between pain tolerance/threshold and increasing BMI. Pain responsivity in childhood is associated with increases in dysregulated eating from childhood to adolescence. These findings provide support for the early development of an interface between pain and eating behaviors.

Porcine Circovirus 3 Detection in Aborted Fetuses and Stillborn Piglets from Swine Reproductive Failure Cases.

Porcine circovirus 3 (PCV-3) has been widely detected in healthy and diseased pigs; among different pathologic conditions, the strongest evidence of association comes from reproductive disease cases. However, simple viral detection does not imply the causality of the clinical conditions. Detection of PCV-3 within lesions may provide stronger evidence of causality. Thus, this study aimed to assess the frequency of PCV-3 detection in tissues from fetuses/stillborn piglets in cases of reproductive problems in domestic swine, as well as the histopathologic assessment of fetal tissues. Fetuses or stillborn piglets from 53 cases of reproductive failure were collected and analyzed by PCV-3 qPCR. The presence of porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus 2 (PCV-2), and porcine parvovirus 1 (PPV1) was also checked. PCV-3 qPCR positive samples with a high viral load were tested by PCV-3 in situ hybridization (ISH), sequenced, and phylogenetically analyzed. PCV-3 DNA was detected in 18/53 (33.9%) reproductive failure cases and in 16 of them PCV-3 was the only pathogen found. PCV-2 DNA was found in 5/53 (9.4%), PRRSV RNA in 4/53 (7.5%) and PPV1 was not detected. Four out of the six PCV-3 qPCR-positive cases with Ct value <30 were positive when tested by ISH. In these samples, PCV-3 was detected within mild histopathologic lesions, such as arteritis and periarteritis in multiple tissues. The present work emphasizes the need to include PCV-3 as a potential causative agent of reproductive failure in swine.

Abstract PO003: CD38 in the advanced prostate cancer

Abstract Background: CD38, an ecto-enzyme involved in adenosine synthesis, is implicated in tumor immune evasion. Its expression and role in the prostate tumor microenvironment (TME) has not been fully elucidated. Main objectives: To determine whether CD38 is associated with prostate cancer (PC) immune evasion, to characterize CD38 expression on PC epithelial cells and tumor infiltrating immune cells (TIICs) as tumors progress from castration-sensitive PC (CSPC) to metastatic castration-resistant PC (mCRPC), and to determine the association between CD38+ TIICs and survival. Methods: Data from 159 mCRPC transcriptomes from the Stand Up To Cancer/Prostate Cancer Foundation cohort were analyzed for associations between CD38 and 200 cell signaling pathways, an adenosine signature and T cell exhaustion signatures. CD38 protein expression on tumor epithelial cells and TIICs was scored using validated immunohistochemistry (IHC) assays on 51 treatment-naïve CSPC biopsies and matching, same-patient mCRPC biopsies obtained between 2016-2018 from men treated at The Royal Marsden Hospital. To characterize CD38+ TIICs, CD38 co-expression with immune cell surface markers for T cells (CD3), B cells (CD19, CD20, CD138, CD79a), and myeloid cells (CD11b, CD15, CD33) was determined by dual-color IHC or multiplex immunofluorescence. The change in CD38+ TIICs density from CSPC to mCRCP was assessed by negative binomial regression and the associations between CD38+ TIIC density and survival were studied using Kaplan-Meier methods, Cox regression and the log-rank test. Results: Unbiased transcriptome analyses showed that CD38 mRNA expression in mCRPC was associated with upregulated immune signaling pathways, with the ten pathways showing the strongest evidence of association (all P &amp;lt; 1 × 10^-10) with CD38 mRNA expression all being immunomodulatory. CD38 expression was associated with IL-23 signaling (P &amp;lt; 1 × 10^-10), a myeloid suppressor cell-derived mediator of endocrine resistance, as well as immunosuppressive adenosine signaling (P &amp;lt; 1 × 10^-8) and T cell exhaustion signatures (P &amp;lt; 1 × 10^-10). CD38 protein was largely absent from tumor epithelial cells (7.7%). CD38 was expressed by phenotypically diverse TIICs. CD38+ TIICs co-expressed myeloid cell surface markers (CD33, CD15), B cell surface markers (CD19, CD20, CD79a, CD138), and the T cell surface marker (CD3). CD38+ TIIC density increased as tumors progressed from CSPC to CRPC (negative binomial regression, P = 0.03). CSPC and CRPC with higher CD38+ TIIC density (dichotomized based on the median; &amp;gt; 1.5 cells/mm^2) were associated with shorter overall survival from the time of PC diagnosis (hazard ratio [HR]: 1.89; 95% CI: 1.02-3.50) and the time of mCRPC biopsy (HR: 2.14; 95% CI: 1.15-4.00), respectively. Conclusion: CD38 is expressed by diverse TIICs in the prostate TME and was associated with potential mechanisms of immune evasion. CD38 expression may serve as a potential prognostic biomarker and therapeutic target in PC aimed at overcoming PC immunoresistance. Citation Format: Christina Guo, Mateus Crespo, Bora Gurel, David Dolling, Jan Rekowski, Adam Sharp, Antonella Petremolo, Semini Sumanasuriya, Daniel N. Rodrigues, Ana Ferreira, Rita Pereira, Ines Figueiredo, Niven Mehra, Maryou B.K. Lambros, Antje Neeb, Veronica Gil, Leon Terstappen, Andrea Alimonti, Charles G. Drake, Wei Yuan, Johann S. de Bono. CD38 in the advanced prostate cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO003.

Biochemical, carcass and meat quality alterations associated with different degree of lung lesions in slaughtered pigs

This study examined the relationship between lung lesion severity and presence of antibodies of various respiratory pathogens, and the effects of lung lesion severity on growth performance, biochemical indicators, total aerobe counts, and carcass and meat quality indicators in total of 240 slaughter pigs originating from two farms with similar rearing conditions. Lung lesion severity was calculated based on the degree of pneumonia and pleurisy in slaughtered pigs. Two-step cluster analysis was used to place individual pigs to four clusters according to pneumonia and pleurisy scores: no lung lesions (cluster 1); mild lung lesions (cluster 2); moderate lung lesions (cluster 3); and severe lung lesions (cluster 4). ANOVA and post hoc pairwise comparisons using Tukey’s test were performed to assess the differences between clusters in examined variables. Multivariate linear regression analysis was run to identify associations between lung lesions and examined variables.There was a strong evidence of association between the absence of lung lesions and increased albumin, sodium and chloride levels, daily weight gain, live weight, hot carcass weight, cold carcass weight, loin thickness and carcass lean content, and decreased haptoglobin, CK and LDH levels. Also, pigs without lung lesions produced the highest percentage of red, firm and nonexudative pork. Pigs having severe lung lesions had the highest percentage of simultaneously seropositive samples to SIV, PRRSV, PCV-2, PRCV, APP and M. hyopneumoniae. There was a strong evidence of association between the presence of severe lung lesions and decreased lactate, glucose, sodium, chloride and albumine levels, daily weight gain, live weight, hot carcass weight, cold carcass weight, loin thickness and carcass lean content, and increased CK, LDH and haptoglobin levels. There was a strong evidence of association between the presence of severe lung lesions in slaughered pigs and increased meat pH and sensory colour scores, and decreased drip, thawing and cooking losses and L* and b* values, which led to the highest occurrence of moderate DFD and DFD pork. There was a strong evidence of association between the presence of mild lung lesions in slaughtered pigs and decreased meat pH and sensory colour scores, and increased drip, thawing and cooking losses, L* and b* values, which led to the highest occurrence of moderate PSE and PSE pork.In conclusion, the presence of lung lesions, irrespective of severity, was significantly associated with alterations in the biochemical indicators, growth performance and carcass and meat quality in slaughtered pigs.

Geographic variability in lingcod Ophiodon elongatus life history and demography along the US West Coast: oceanographic drivers and management implications

Understanding the environmental and anthropogenic drivers of spatial patterns in life history variation for exploited fish populations is important when making management decisions and designating stock boundaries. These considerations are especially germane for stocks that are overfished or recently rebuilt, such as lingcodOphiodon elongatus, a commercially and recreationally valuable species of groundfish along the West Coast of North America. Between 2015 and 2017, we collected 2189 lingcod from 24 port locations, spanning 28° of latitude from southeast Alaska (60°N) to southern California (32°N), to investigate latitudinal patterns in size- and age-structure, growth, timing of maturity, condition, and mortality, as well as to identify biologically relevant population breakpoints along the coast. We found strong latitudinal patterns in these life history and demographic traits consistent with Bergmann’s rule: lingcod from colder, northern waters were larger-at-age, lived longer, matured at larger sizes, and had lower natural mortality rates than lingcod from warmer, southern waters. Female lingcod were larger-at-age, lived longer, and matured at larger sizes compared to males within each examined region. In addition, we found evidence for strong associations between lingcod life history traits and the oceanographic variables of sea surface temperature and chlorophylla. Cluster analysis using life history traits indicated that central Oregon is a biologically relevant breakpoint for lingcod along the US West Coast. This breakpoint based on life history traits, in conjunction with a recently identified population genetic breakpoint between central and northern California, highlights the need for future lingcod stock assessments to consider multiple sources of information to best inform management of this trans-boundary stock.

The influence of adult hip shape genetic variants on adolescent hip shape: Findings from a population-based DXA study.

ObjectiveHip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape.MethodsHip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2.ResultsComplete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta −0.05, p = 9.9 × 10−8; age 18: −0.05, p = 3.3 × 10−6) and HSM5 (age 14: beta −0.07, p = 1.6 × 10−4; age 18: −0.1, p = 2.7 × 10−6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 × 10−5; age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: −0.06, p = 0.001; age 18: −0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture.ConclusionIn conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.

Paraoxonase single nucleotide variants show associations with polycystic ovary syndrome: a meta-analysis

BackgroundEtiology of polycystic ovary syndrome (PCOS) is attributed to genetic and environmental factors. One environmental factor is oxidative stress. Paraoxonase 1 (PON1) is an antioxidant high-density lipoprotein-associated enzyme encoded by the PON1 gene. The PON1 gene has been implicated in the risk for PCOS, the influence of which appears to come from single nucleotide variants (SNVs) at multiple genetic loci. However, association study reports have been inconsistent which compels a meta-analysis to obtain more precise estimates.MethodsFrom 12 publications, extracted genotype data were used in two genetic procedures. First, linkage disequilibrium (LD) was used to group eight PON SNVs into three: LD1, LD2 and LD3. Second, frequencies of the variant (var), wild-type (wt) and heterozygous (het) genotypes were used for genetic modeling (allele-genotype for LD1 and standard for LD2 and LD3). Risk associations were expressed in terms of pooled odds ratios (ORs), 95% confidence intervals (CIs) and Pa-values. Evidence was considered strong when significance was high (Pa < 0.0001) and heterogeneity absent (I2 = 0%). Pooled effects were subjected to modifier (power), subgroup (Asian/Caucasian), outlier, sensitivity and publication bias treatments. Multiple comparisons were Bonferroni-corrected.ResultsThis meta-analysis generated 11 significant outcomes, five in LD1, six in LD2 and none in LD3. All six LD2 outcomes did not survive the Bonferroni-correction but two of the five in LD1 did. These two core LD1 findings conferred greater odds of PCOS to the var allele in the highly significant (Pa < 0.0001) overall (OR 1.44, 95% CI 1.24–1.67) and Asian (OR 1.41, 95% CI 1.20–1.65) outcomes. Of these two core outcomes, the Asian effect was homogeneous (I2 = 0%) but not the overall (I2 = 29%).ConclusionsOf the eight PON SNVs examined, two (rs854560 and rs662) were associated with PCOS risk. These 1.4-fold increased risk effects rendered Asians susceptible to PCOS. High statistical power, high significance, zero to low-level heterogeneity, robustness and lack of bias in the core outcomes underpinned the strong evidence for association.

Prediction of stillbirth: an umbrella review of evaluation of prognostic variables.

Stillbirth accounts for over 2million deaths a year worldwide and rates remains stubbornly high. Multivariable prediction models may be key to individualised monitoring, intervention or early birth in pregnancy to prevent stillbirth. To collate and evaluate systematic reviews of factors associated with stillbirth in order to identify variables relevant to prediction model development. MEDLINE, Embase, DARE and Cochrane Library databases and reference lists were searched up to November 2019. We included systematic reviews of association of individual variables with stillbirth without language restriction. Abstract screening and data extraction were conducted in duplicate. Methodological quality was assessed using AMSTAR and QUIPS criteria. The evidence supporting association with each variable was graded. The search identified 1198 citations. Sixty-nine systematic reviews reporting 64 variables were included. The most frequently reported were maternal age (n=5), body mass index (n=6) and maternal diabetes (n=5). Uterine artery Doppler appeared to have the best performance of any single test for stillbirth. The strongest evidence of association was for nulliparity and pre-existing hypertension. We have identified variables relevant to the development of prediction models for stillbirth. Age, parity and prior adverse pregnancy outcomes had a more convincing association than the best performing tests, which were PAPP-A, PlGF and UtAD. The evidence was limited by high heterogeneity and lack of data on intervention bias. Review shows key predictors for use in developing models predicting stillbirth include age, prior pregnancy outcome and PAPP-A, PLGF and Uterine artery Doppler.

A predictive Bayesian network that risk stratifies patients undergoing Barrett's surveillance for personalized risk of developing malignancy.

BackgroundBarrett’s esophagus is strongly associated with esophageal adenocarcinoma. Considering costs and risks associated with invasive surveillance endoscopies better methods of risk stratification are required to assist decision-making and move toward more personalised tailoring of Barrett’s surveillance.MethodsA Bayesian network was created by synthesizing data from published studies analysing risk factors for developing adenocarcinoma in Barrett’s oesophagus through a two-stage weighting process.ResultsData was synthesized from 114 studies (n = 394,827) to create the Bayesian network, which was validated against a prospectively maintained institutional database (n = 571). Version 1 contained 10 variables (dysplasia, gender, age, Barrett’s segment length, statin use, proton pump inhibitor use, BMI, smoking, aspirin and NSAID use) and achieved AUC of 0.61. Version 2 contained 4 variables with the strongest evidence of association with the development of adenocarcinoma in Barrett’s (dysplasia, gender, age, Barrett’s segment length) and achieved an AUC 0.90.ConclusionThis Bayesian network is unique in the way it utilizes published data to translate the existing empirical evidence surrounding the risk of developing adenocarcinoma in Barrett’s esophagus to make personalized risk predictions. Further work is required but this tool marks a vital step towards delivering a more personalized approach to Barrett’s surveillance.

Maternal haemoglobin in pregnancy and offspring childhood weight and height trajectories: analysis of a prospective birth cohort study

Background: Both anaemia and high haemoglobin in pregnancy are associated with adverse pregnancy outcomes including foetal growth restriction. The objective of this study was to investigate the associations between maternal haemoglobin in pregnancy and trajectories of length/height and weight from birth through childhood. Methods: Data from 7,597 singleton pregnancies in the Avon Longitudinal Study of Parents and Children (ALSPAC), an ongoing, prospective, UK population-based pregnancy cohort study were used. We examined associations between maternal haemoglobin (overall pregnancy and trimester specific) and offspring length and weight at birth, as well as trajectories of height and weight gain from birth to age 10 years derived from multilevel models. Results: Mean pregnancy haemoglobin was 11.61 g/dL (SD 1.12). For each 1g/dL higher mean overall pregnancy haemoglobin, offspring were on average -0.30 cm shorter (95%CI: -0.35, -0.24, p &lt;0.001), and -97.7 g lighter (95%CI: -110.42, -84.93, p &lt;0.001) at birth when adjusting for potential confounders. Trimester specific inverse associations with birth length and weight were strongest for third trimester haemoglobin. There was evidence of a positive association between maternal haemoglobin levels and offspring height gain up to the age of one year and no strong evidence of associations between pregnancy haemoglobin and childhood weight gain. Conclusions: In high income countries, higher maternal haemoglobin in pregnancy may be a concern, as well as anaemia. Further studies are needed to define ‘high’ haemoglobin in pregnancy and whether monitoring of women with high pregnancy haemoglobin is warranted.

Mood-Stabilizing Antiepileptic Treatment Response in Bipolar Disorder: A Genome-Wide Association Study.

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED‐MSs). To identify genetic polymorphisms that contribute to the variability in AED‐MS response, we performed a discovery genome‐wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED‐MS valproate/divalproex and/or lamotrigine. AED‐MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome‐wide significant single‐nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E‐09) and SLC35F3 (rs114872993, P = 3.2E‐08) genes. We also identified two genes with statistically significant gene‐level associations: ABCC1 (P = 6.7E‐07; top SNP rs875740, P = 2.0E‐6), and DISP1 (P = 8.9E‐07; top SNP rs34701716, P = 8.9E‐07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ‐aminobutyric acidergic (GABAergic) neurons, which are targets of AED‐MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED‐MS treatment response, and may facilitate precision medicine in BD.

Werner Syndrome Protein Expression in Breast Cancer

IntroductionWerner protein (WRN) plays an important role in DNA repair, replication, transcription, and consequently genomic stability via its DNA-helicase and exonuclease activity. Loss of function of WRN is associated with Werner syndrome (WS), which is characterized by premature aging and cancer predisposition. Malignancies that are commonly linked to WS are thyroid carcinoma, melanoma, breast cancer, meningioma, and soft tissue and bone sarcomas. Currently, the clinicopathologic significance of WRN in breast cancer is largely unknown. Patients and MethodsWe investigated the clinicopathologic and prognostic significance of WRN protein expression in a cohort of clinically annotated series of sporadic (n = 1650) and BRCA-mutated (n = 75) invasive breast cancers. We correlated WRN protein expression to clinicopathologic characteristics, DNA repair protein expression, and survival outcomes. ResultsThere is strong evidence of association between low nuclear and cytoplasmic WRN co-expression and low levels of KU70/KU80, DNA-PK, DNA Pol-B, CKD18, cytoplasmic RECQL4, and nuclear BLM protein expression (adjusted P-values < .05). Tumors with low nuclear or cytoplasmic WRN expression have worse overall breast cancer-specific survival (BCSS) (adjusted P-values < .05). In topoisomerase I overexpressed tumors, low WRN nuclear expression was associated with poor BCSS (P-value < .05). In BRCA-mutated tumors, low WRN cytoplasmic expression conferred shortest BCSS (P < .05). ConclusionsLow WRN protein expression is associated with poor BCSS in patients with breast cancer. This can be used to optimize the risk stratification for personalized treatment.

Genome-wide associations of human gut microbiome variation and implications for causal inference analyses.

Recent population-based1–4 and clinical studies5 have identified a range of factors associated with human gut microbiome variation. Murine quantitative trait loci6, human twin studies7 and microbiome genome-wide association studies (mGWAS)1,3,8–12 have provided evidence for genetic contributions to microbiome composition. Despite this, there is still poor overlap in genetic association across human studies. Using appropriate taxon-specific models along with support from independent cohorts, we show association between human host genotype and gut microbiome variation. We also suggest that interpretation of applied analyses using genetic associations is complicated by the likely overlap between genetic contributions and heritable components of host environment. Using fecal derived 16S rRNA gene sequences and host genotype data from the Flemish Gut Flora Project (FGFP, n=2223) and two German cohorts (FoCus, n=950, PopGen n=717), we identify genetic associations involving multiple microbial traits (MTs). Two of these associations achieved a study-level p-value threshold of 1.57×10−10; an association between Ruminococcus and rs150018970 near RAPGEF1 on chromosome 9, and between Coprococcus and rs561177583 within LINC01787 on chromosome 1. Exploratory analysis was undertaken using 11 other genome-wide associations with strong evidence for association (p-value < 2.5×10−08) and a previously reported signal of association between rs4988235 (MCM6/LCT) and Bifidobacterium. Across these 14 SNPs there was evidence of signal overlap with other GWAS including those for age at menarche and cardiometabolic traits. Mendelian randomization (MR) analysis was able to estimate associations between MTs and disease (including Bifidobacterium and body composition), however in the absence of clear microbiome driven effects, caution is needed in interpretation. Overall, this work marks a growing catalog of genetic associations which will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis.

Neurocognitive functioning in MDR-TB patients with and without HIV in KwaZulu-Natal, South Africa.

Optimising medication adherence is one of the essential factors in reversing the tide of a TB-HIV syndemic in sub-Saharan Africa, especially South Africa. Impairment in key neurocognitive domains may impair patients' ability to maintain adherence to treatment, but the level of cognition and its relationship to HIV status has not been examined in individuals with drug-resistant TB. We therefore investigated performance on several key neurocognitive domains in relationship to HIV status in a multidrug-resistant tuberculosis patients (MDR-TB) sample. We enrolled microbiologically confirmed MDR-TB inpatients at a TB-specialist referral hospital in KwaZulu-Natal province, South Africa. We collected cross-sectional data on sociodemographic, clinical and neurocognitive function (e.g. attention, memory, executive functioning, language fluency, visual-spatial, eye-hand coordination). For the primary analysis, we excluded participants with major depressive episode/substance use disorder (MDE/SUD). We fitted adjusted Poisson regression models to explore the association between HIV and neurocognitive function. We enrolled 200 people with MDR-TB; 33 had MDE/SUD, and data of 167 were analysed (151 HIV+, 16 HIV-). The mean age of participants was 34.2years; the majority were female (83%), and 53% had not completed secondary school. There was evidence of impaired neurocognitive functioning across all domains in both HIV+/- study participants. Based on the regression analyses, individuals with co-infection (MDR-TB/HIV+), as well as those who had longer duration of hospital stays experienced significantly lower cognitive performance in several domains. Poor cognitive performance was significantly related to older age and lower educational attainment. The presence of major depression or substance use disorders did not influence the significance of the findings. Adults with MDR-TB have significant neurocognitive impairment, especially if HIV positive. An integrated approach is necessary in the management of MDR-TB as cognitive health influences the ability to adhere to chronic treatment, clinical outcomes and functionality.

A cross-disorder PRS-pheWAS of 5 major psychiatric disorders in UK Biobank.

Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 330,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package. There was evidence after multiple testing (p<2.55x10-06) for associations of PRSs with 294 outcomes, most of them attributed to associations of PRSMDD (n = 167) and PRSSCZ (n = 157) with mental health factors. Among others, we found strong evidence of association of higher PRSADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]: -1.25,-0.92] and a history of physical maltreatment; PRSASD with 0.01% lower erythrocyte distribution width [95%CI: -0.013,-0.007]; PRSSCZ with 0.95 lower odds of playing computer games [95%CI:0.95,0.96]; PRSMDD with a 0.12 points higher neuroticism score [95%CI:0.111,0.135] and PRSBP with 1.03 higher odds of having a university degree [95%CI:1.02,1.03]. We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis.

Relationship between Fundamental Movement Skills and Physical Activity in Preschool-Aged Children: A Systematic Review.

Preschool-aged children are in a critical period of developing fundamental movement skills (FMS). FMS have a close link with physical activity (PA). This study aimed to systematically review the associations between FMS and PA in preschool-aged children. Searching Cochrane Library, Web of Science, PubMed, ScienceDirect, and EBSCO (including SPORTDiscus, ERIC, and Academic Search Premier) was utilized to conduct a systematic review of the available literature. Studies were included if they examined associations between FMS and PA among typically developing children aged 3–6 years, published between January 2000 and April 2020. A total of 26 studies met the inclusion criteria, including 24 cross-sectional studies and two cohort studies. There was a strong level of evidence to support low to moderate associations between moderate to vigorous physical activity and components of FMS, specifically, the total FMS (r = 0.11–0.48, R2 = 16%–19%) and object control skill (r = 0.16–0.46, β = 0.28–0.49, R2 = 10.4%–16.9%). Similar associations were also found between the total physical activity and components of FMS, specifically, the total FMS (r = 0.10–0.45, R2 = 16%), locomotor skills (r = 0.14–0.46, R2 = 21.3%), and objective control skills (r = 0.16–0.44, β = 0.47, R2 = 19.2%). There was strong evidence that there is no significant association between light physical activity and FMS, specifically, total FMS and locomotor skills. The associations, including “stability skills–PA” and “locomotor skills–moderate to vigorous PA”, were uncertain due to insufficient evidence. Our findings provide strong evidence of associations between specific FMS components and a specific PA intensity. Future studies should consider using a longitudinal study design in order to explore the causal relationship between specific-intensity PA and the FMS subdomain.

From Polygenic Scores to Precision Medicine in Alzheimer's Disease: A Systematic Review.

Background:Late-onset Alzheimer’s disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual’s risk alleles, have been used to draw inferences about the pathological processes underpinning AD.Objective:This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration.Methods:We searched the literature from July 2008–July 2018 following PRISMA guidelines.Results:57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes.Conclusion:PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity.

The Association Between Preeclampsia and Childhood Development and Behavioural Outcomes.

To examine the associations between preeclampsia and longitudinal child developmental and behavioural outcomes using data from a nationally representative study of children living in Ireland. We used maternal-reported data from the Growing Up in Ireland longitudinal study of children. Data on preeclampsia and preeclampsia + small for gestational age (SGA) were collected when children were 9-months old. Data on child development and behavioural outcomes were collected at 9-months using the Ages and Stages Questionnaire (ASQ), and at 3years, 5years and 7-8years using the Strengths and Difficulties Questionnaire (SDQ). Multivariate logistic regression analysis was used to examine the association between preeclampsia exposure and failure of ASQ domains, and abnormal SDQ domains. Linear spline multilevel models were used to examine the association between preeclampsia and preeclampsia + SGA and repeated measures of SDQ. All models controlled for several perinatal and sociodemographic factors. A total of 10,692 children were included in the study at baseline, representing a weighted total of 70,791. Multivariate logistic regression suggested that preeclampsia was not associated with failing any ASQ domain. Preeclampsia was associated with abnormal SDQ cut-off of emotional (≥ 5) and hyperactivity (≥ 7) domains at age 5years only. In the linear spline model, mean SDQ score was higher at each time point in exposed groups. While we did not find strong evidence of associations between preeclampsia and child developmental and behavioural outcomes overall, some associations between preeclampsia-exposure and subtle behavioural issues did persist. Further research is needed to replicate these findings, and determine the clinical significance of changes in SDQ scores.