Search

Recent research highlights the significant impact of the gut microbiota on health and disease. Thalassemia, a hereditary blood disorder, requires regular blood transfusions, leading to an accumulation of iron in the body. Such changes could potentially alter the intestinal microbiota, thereby increasing the susceptibility of thalassemic patients to infection. In this study, we analyzed the fecal microbiota of 70 non-transfusion-dependent (NTDT) β-thalassemia/HbE patients and 30 healthy controls. Our findings indicate that iron chelation intervention had no detectable effect on the microbiome profile of thalassemic patients. However, the cross-sectional analysis revealed that the bacterial diversity and community structure in patients were significantly less diverse and distinct compared to those of healthy subjects. Using reference frames, we were also able to demonstrate that bacterial taxa that are known to produce short chain fatty acids, from the genera Alistipes, Coprococcus, and Oscillospira, and those from the family Ruminococcaceae, were less prevalent in the patients. In contrast, bacterial taxa associated with an unhealthy gut, including the genus Clostridium and those from the families Fusobacteriaceae, Enterobacteriaceae, and Peptostrptococcaceae, were more prevalent in patients and found to be correlated with higher levels of ferritin. Collectively, these changes in the microbiota could be regarded as markers of raised ferritin levels, and therefore, awareness should be exercised as they could interfere, albeit indirectly, with the treatment of the co-morbidities of thalassemia.

BACKGROUND: Pre-diagnostic disturbances in the microbiome-derived metabolome have been associated with an increased risk of diabetes in non-pregnant populations. However, the roles of microbiome-derived metabolites, the end-products of microbial metabolism, in gestational diabetes (GDM) remain understudied. We examined the prospective association of microbiome-derived metabolites in early to mid-pregnancy with GDM risk in a diverse population. METHODS: We conducted a prospective discovery and validation study, including a case-control sample of 91 GDM and 180 non-GDM individuals within the multi-racial/ethnic The Pregnancy Environment and Lifestyle Study (PETALS) as the discovery set, a random sample from the PETALS (42 GDM, 372 non-GDM) as validation set 1, and a case-control sample (35 GDM, 70 non-GDM) from the Gestational Weight Gain and Optimal Wellness randomized controlled trial as validation set 2. We measured untargeted fasting serum metabolomics at gestational weeks (GW) 10-13 and 16-19 by gas chromatography/time-of-flight mass spectrometry (TOF-MS), liquid chromatography (LC)/quadrupole TOF-MS, and hydrophilic interaction LC/quadrupole TOF-MS. GDM was diagnosed using the 3-h, 100-g oral glucose tolerance test according to the Carpenter-Coustan criteria around GW 24-28. RESULTS: Among 1362 annotated compounds, we identified 140 of gut microbiome metabolism origin. Multivariate enrichment analysis illustrated that carbocyclic acids and branched-chain amino acid clusters at GW 10-13 and the unsaturated fatty acids cluster at GW 16-19 were positively associated with GDM risk (FDR

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

PurposeHigh consumption of fruits and vegetables decrease the risk of bladder cancer (BC). The evidence of specific fruits and vegetables and the BC risk is still limited.MethodsFruit and vegetable consumptions in relation to BC risk was examined by pooling individual participant data from case-control studies. Unconditional logistic regression was used to estimate study-specific odds ratio's (ORs) with 95% confidence intervals (CIs) and combined using a random-effects model for intakes of total fruits, total vegetables, and subgroups of fruits and vegetables.ResultsA total of 11 case-control studies were included, comprising 5637 BC cases and 10,504 controls. Overall, participants with the highest intakes versus the lowest intakes of fruits in total (OR 0.79; 95% CI 0.68-0.91), citrus fruits (OR 0.81; 95% CI 0.65-0.98), pome fruits (OR 0.76; 95% CI 0.65-0.87), and tropical fruits (OR 0.84; 95% CI 0.73-0.94) reduced the BC risk. Greater consumption of vegetables in total, and specifically shoot vegetables, was associated with decreased BC risk (OR 0.82; 95% CI 0.68-0.96 and OR 0.87; 95% CI 0.78-0.96, respectively). Substantial heterogeneity was observed for the associations between citrus fruits and total vegetables and BC risk.ConclusionThis comprehensive study provides compelling evidence that the consumption of fruits overall, citrus fruits, pome fruits and tropical fruits reduce the BC risk. Besides, evidence was found for an inverse association between total vegetables and shoot vegetables intake.

Anorexia nervosa (AN) is associated with food restriction and significantly low body weight, but the neurobiology of food avoidance in AN is unknown. Animal research suggests that food avoidance can be triggered by conditioned fear that engages the anterior cingulate and nucleus accumbens. We hypothesized that the neural activation during food avoidance in AN could be modeled based on aversive goal value processing. Nineteen females with AN and thirty healthy controls matched for age underwent functional magnetic resonance brain imaging while conducting a food avoidance task. During active control free-bid and computer-generated forced-bid trials, participants bid money to avoid eating food items. Brain activation was parametrically modulated with the trial-by-trial placed bids. During free-bid trials, the AN group engaged the caudate nucleus, nucleus accumbens, ventral anterior cingulate, and inferior and medial orbitofrontal cortex more than the control group. High- versus low-bid trials in the AN group were associated with higher caudate nucleus response. Emotion dysregulation and intolerance of uncertainty scores were inversely associated with nucleus accumbens free-bid trial brain response in AN. This study supports the idea that food avoidance behavior in AN involves aversive goal value computation in the nucleus accumbens, caudate nucleus, anterior cingulate, and orbitofrontal cortex.

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

BackgroundPrenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.MethodsWe evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.ResultsNone of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.ConclusionsThis large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.ImpactGenetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Exposure to toxic heavy metals has been associated with the development of attention-deficit/hyperactivity disorder (ADHD). However, fewer studies have examined the associations between abnormal levels of essential trace metals and ADHD, and none have done so using saliva. We investigated whether salivary metals were associated with ADHD in adolescents aged 12 from the Family Life Project (FLP) using a nested case-control study design that included 110 adolescents who met diagnostic criteria for inattentive (ADHD-I), hyperactive-impulsive (ADHD-H), or combined type ADHD (ADHD-C) (cases) and 173 children who did not (controls). We used inductively coupled plasma optical emission spectrophotometry to measure chromium, copper, manganese, and zinc in saliva samples. We employed logistic regression models to examine associations between quartile levels of individual metals and ADHD outcomes by subtype. Salivary copper levels were significantly associated with increased odds of any ADHD diagnosis (OR = 3.31, 95% CI: 1.08-10.12; p = 0.04) and with increased odds of ADHD-C diagnosis (OR = 8.44, 95% CI: 1.58-45.12; p = 0.01). Salivary zinc levels were significantly associated with increased odds of ADHD-C diagnosis (OR = 4.06, 95% CI: 1.21-13.69; p = 0.02). Salivary manganese levels were also significantly associated with increased odds of ADHD-C diagnosis (OR = 5.43, 95% CI: 1.08-27.27, p = 0.04). This is the first study using saliva to assess metal exposure and provide a potential link between salivary levels of copper, manganese, and zinc and ADHD diagnoses in adolescents. Public health interventions focused on metal exposures might reduce ADHD incidence in low-income, minority communities.

OBJECTIVES: Eating disorders (EDs) typically emerge during adolescence. Parental bonding has a lasting impact on a childs mental health during those developmentally critical years. There remains uncertainty over whether parental bonding is a risk factor for developing or maintaining specifically EDs or, rather, general psychopathology and the associated underlying brain function. METHODS: Forty-one young adult healthy control individuals (HC, 26.6 ± 3.5 years) and 46 individuals with EDs (25 with anorexia nervosa, AN, 22.8 ± 6.4 years, and 21 with bulimia nervosa, BN, 23.5 ± 4.2 years) completed the parental bonding instrument (PBI), assessments for anxiety, depression, and ED behaviors, and underwent a conditioning paradigm during brain imaging. RESULTS: In both groups, perceived parental care and overprotection were correlated with state and trait anxiety and interpersonal alienation, and in HC only, with body dissatisfaction and drive for thinness. Individuals with an ED reported lower self-perceived parental care, but higher overprotection compared to the HC group. Nucleus accumbens (NAc) response was related to bonding measures in both groups and right NAc response mediated the relationship between maternal care and trait anxiety in HC. CONCLUSIONS: Perceived parental bonding is associated with general psychopathology, including elevated anxiety and interpersonal difficulties across HC and ED groups. Lower perceived parental care and higher overprotection could predispose healthy individuals to develop problems with body shape or weight; however, other, maybe biological factors may determine whether a person will develop an ED. The link between perceived parental bonding, NAc valence processing and anxiety implicates dopaminergic circuits that should be studied further. LEVEL OF EVIDENCE: Level III: Case-control analytic study.

A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.

PURPOSE: Gastric cancer (GC) is among the leading causes of cancer mortality worldwide. The objective of this study was to investigate the association between dietary fiber intake and GC. METHODS: We pooled data from 11 population or hospital-based case-control studies included in the Stomach Cancer Pooling (StoP) Project, for a total of 4865 histologically confirmed cases and 10,626 controls. Intake of dietary fibers and other dietary factors was collected using food frequency questionnaires. We calculated the odds ratios (OR) and 95% confidence intervals (CI) of the association between dietary fiber intake and GC by using a multivariable logistic regression model adjusted for study site, sex, age, caloric intake, smoking, fruit and vegetable intake, and socioeconomic status. We conducted stratified analyses by these factors, as well as GC anatomical site and histological type. RESULTS: The OR of GC for an increase of one quartile of fiber intake was 0.91 (95% CI: 0.85, 0.97), that for the highest compared to the lowest quartile of dietary fiber intake was 0.72 (95% CI: 0.59, 0.88). Results were similar irrespective of anatomical site and histological type. CONCLUSION: Our analysis supports the hypothesis that dietary fiber intake may exert a protective effect on GC.

OBJECTIVES: Adipose tissue has been associated with knee osteoarthritis (KOA) pathogenesis, but the longitudinal changes in adipose tissue with KOA progression have not been carefully evaluated. This study aimed to determine if longitudinal changes of systemic and local adipose tissue is associated with radiographic progression of KOA. METHODS: This case-control study used data from the Osteoarthritis Initiative (OAI) and included 315 cases (all the right knees with a minimum of Kellgren-Lawrence score (KL) of 0 and an increase of ≥ 1 KL from baseline to 48 months) and 315 controls matched by age, sex, race, and baseline KL. Cross sectional area of IPFP (IPFP CSA) and subcutaneous adipose tissue around the distal thigh (SCATthigh) were measured using MRI images at baseline and 24 months. Conditional logistic regression models were fitted to estimate associations of obesity markers, IPFP CSA, and SCATthigh with radiographic KOA progression. Mediation analysis was used to assess whether IPFP CSA or SCATthigh mediates the relationships between baseline BMI and radiographic KOA progression. RESULTS: 24-month changes of IPFP CSA (ΔIPFP CSA) and SCATthigh (ΔSCATthigh) were significantly greater in cases compared to controls, whereas Δ BMI and Δ abdominal circumference were similar in both groups during follow-up. Adjusted ORs for radiographic KOA progression were 9.299, 95% CI (5.357-16.141) per 1 SD increase of Δ IPFP CSA and 1.646, 95% CI (1.288-2.103) per 1 SD increase of Δ SCATthigh. ΔIPFP CSA mediated the association between baseline BMI and radiographic KOA progression (87%). CONCLUSIONS: Subjects with radiographic progression of KOA, had significant increases in IPFP CSA and subcutaneous adipose tissue while BMI and abdominal circumference remained stable. Additional studies are needed to confirm these associations.

BACKGROUND/AIMS: While DNA methylation and gastric microbiome are each associated with gastric cancer (GC), their combined role in predicting GC remains unclear. This study investigated the potential of a combined DNA methylation and gastric microbiome signature to predict Helicobacter pylori-negative GC. METHODS: In this case-control study, we conducted quantitative methylation-specific polymerase chain reaction to measure the methylation levels of DKK3, SFRP1, EMX1, NKX6-1, MIR124-3, and TWIST1 in the gastric mucosa from 75 H. pylori-negative patients, including chronic gastritis (CG), intestinal metaplasia (IM), and GC. A combined analysis of DNA methylation and gastric microbiome, using 16S rRNA gene sequencing, was performed in 30 of 75 patients. RESULTS: The methylation levels of DKK3, SFRP1, EMX1, MIR124-3, and TWIST1 were significantly higher in patients with GC than in controls (all q

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Patients with degenerative cervical myelopathy (DCM) experience structural and functional brain reorganization. However, few studies have investigated the influence of sex on cerebral alterations. The present study investigates the role of sex on brain functional connectivity (FC) and global network topology in DCM and healthy controls (HCs). The resting-state functional MRI data was acquired for 100 patients (58 males vs. 42 females). ROI-to-ROI FC and network topological features were characterized for each patient and HC. Group differences in FC and network topological features were examined. Compared to healthy counterparts, DCM males exhibited higher FC between vision-related brain regions, and cerebellum, brainstem, and thalamus, but lower FC between the intracalcarine cortex and frontal and somatosensory cortices, while DCM females demonstrated higher FC between the thalamus and cerebellar and sensorimotor regions, but lower FC between sensorimotor and visual regions. DCM males displayed higher FC within the cerebellum and between the posterior cingulate cortex (PCC) and vision-related regions, while DCM females displayed higher FC between frontal regions and the PCC, cerebellum, and visual regions. Additionally, DCM males displayed significantly greater intra-network connectivity and efficiency compared to healthy counterparts. Results from the present study imply sex-specific supraspinal functional alterations occur in patients with DCM.

BACKGROUND: Endometriosis is considered as a systemic disease with the presence of proinflammatory cytokines in the circulation, which drives hypercoagulable state of endometriosis. Currently, endometriosis is classified into four stages: I (minimal), II (mild), III (moderate) and IV (severe). The aim of this study is to investigate the correlations between inflammatory markers and coagulation factors in patients diagnosed of endometriosis with stage IV. METHODS: This retrospective case-control study included 171 endometriosis patients with stage IV and 184 controls. Continuous data were expressed by mean ± standard deviation. Mann-Whitney U and χ2 tests were used to compare the medians and frequencies among the groups. Spearman analysis was conducted to determine the correlation among the measured parameters. The diagnostic values of the parameters differentiating endometriomas were tested by receiver operating characteristic (ROC) curve. RESULTS: The time of activated partial thromboplastin time (APTT) was decreased and the concentration of fibrinogen (FIB) and neutrophil-to-lymphocyte ratio (NLR) were increased in women of endometriosis with stage IV. The APTT were negatively correlated with NLR while the concentrations of FIB were positively correlated with NLR. The ROC analysis showed that the Area under the curve (AUC) of FIB was 0.766 (95% confidence interval:0.717-0.814) with sensitivity and specificity reaching 86.5 and 60.9%, respectively. The AUC of CA125 and CA199 was 0.638 (95% confidence interval: 0.578-0.697), 0.71 (95% confidence interval: 0.656-0.763) with sensitivity and specificity reaching 40.9 and 91.8%, 80.7 and 56.5% respectively. The combination of these factors showed the highest AUC of 0.895 (0.862-0.927) with sensitivity of 88.9% and specificity of 77.7%. CONCLUSION: In the present study, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV. Moreover, the coagulation factors combined with CA125 and CA199 were more reliable for identifying the endometriosis with stage IV.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

BACKGROUND: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS: Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

ObjectiveHIV treatment regimen during pregnancy was associated with preterm delivery (PTD) in the PROMISE 1077 BF trial. Systemic inflammation among pregnant women with HIV could help explain differences in PTD by treatment regimen. We assessed associations between inflammation, treatment regimen, and PTD.Design/methodsA nested 1 : 1 case-control study ( N  = 362) was conducted within a multicountry randomized trial comparing three HIV regimens in pregnant women: zidovudine alone, or combination antiretroviral therapy (ART) with lopinavir/ritonavir and either zidovudine or tenofovir. Cases were women with PTD (

BACKGROUND: Asymptomatic SARS-CoV-2 infection in children is highly prevalent but its acute and chronic implications have been minimally described. METHODS: In this controlled case-ascertained household transmission study, we recruited asymptomatic children

BACKGROUND: Numerous studies have linked fine particulate matter (PM2.5) to increased cardiovascular mortality. Less is known how the PM2.5-cardiovascular mortality association varies by use of cardiovascular medications. This study sought to quantify effect modification by statin use status on the associations between long-term exposure to PM2.5 and mortality from any cardiovascular cause, coronary heart disease (CHD), and stroke. METHODS: In this nested case-control study, we followed 1.2 million community-dwelling adults aged ≥66 years who lived in Ontario, Canada from 2000 through 2018. Cases were patients who died from the three causes. Each case was individually matched to up to 30 randomly selected controls using incidence density sampling. Conditional logistic regression models were used to estimate odds ratios (ORs) for the associations between PM2.5 and mortality. We evaluated the presence of effect modification considering both multiplicative (ratio of ORs) and additive scales (the relative excess risk due to interaction, RERI). RESULTS: Exposure to PM2.5 increased the risks for cardiovascular, CHD, and stroke mortality. For all three causes of death, compared with statin users, stronger PM2.5-mortality associations were observed among non-users [e.g. for cardiovascular mortality corresponding to each interquartile range increase in PM2.5, OR = 1.042 (95% CI, 1.032-1.053) vs OR = 1.009 (95% CI, 0.996-1.022) in users, ratio of ORs = 1.033 (95% CI, 1.019-1.047), RERI = 0.039 (95% CI, 0.025-0.050)]. Among users, partially adherent users exhibited a higher risk of PM2.5-associated mortality than fully adherent users. CONCLUSIONS: The associations of chronic exposure to PM2.5 with cardiovascular and CHD mortality were stronger among statin non-users compared to users.

UNLABELLED: Long-term physical functioning trajectories following distal forearm fracture are unknown. We found that women with versus those without distal forearm fracture were more likely to experience a 5-year decline in physical functioning, independent of initial physical functioning level. This association was most evident among women 80 years and older. INTRODUCTION: Physical functioning trajectory following lower arm or wrist fracture is not well understood. PURPOSE: This study is to evaluate physical functioning trajectory before vs. after lower arm or wrist fracture, stratified by age. METHODS: We performed a nested case-control study of prospective data from the Womens Health Initiative Study (n = 2097 cases with lower arm or wrist fracture, 20,970 controls). Self-reported fractures and the physical functioning subscale of the RAND 36-item Short-Form Health Survey were assessed annually. We examined three physical functioning trajectory groups: stable, improving, and declining. RESULTS: Mean (SD) number of physical functioning measurements was 5.2 (1.5) for cases and 5.0 (1.4) for controls. Declining physical functioning was observed among 20.4% of cases and 16.0% of controls. Compared to women without lower arm or wrist fracture, women with lower arm or wrist fracture were 33% more likely to experience declining physical functioning (adjusted odds ratio [aOR] 1.33 95% confidence interval [CI] 1.19-1.49, reference group stable or improving physical functioning trajectory). Associations varied by age: age ≥ 80 years aOR 1.56 (95% CI 1.29-1.88); age 70-79 years aOR 1.29 (95% CI 1.09-1.52); age

BackgroundMaternal solvent exposure has been suspected to increase offspring cancer risk. The study aimed to evaluate the associations between maternal residential exposure to solvents from industrial pollution during pregnancy and childhood cancer.MethodsThe present study included 15,744 cancer cases (aged 0-19 years at diagnosis) identified from California Cancer Registry and 283,141 controls randomly selected from California Birth Registry (20:1 frequency-matched by birth year: 1998-2016). We examined industrial releases of tetrachloroethylene and 1,1,1-trichloroethane within 3 km of the birth address, while we used a 5 km buffer for carbon disulfide. We calculated the total exposure from all linked Toxic Release Inventory sites during each index pregnancy and assigned "ever/never" and "high/low exposed/unexposed" exposure, using median values. We performed quadratic decay models to estimate cancer risks associated with maternal solvent exposure in pregnancy.Results1,1,1-Trichloroethane was associated with rhabdomyosarcoma (adjusted Odds Ratio (aOR): 1.96; 95% Confidence Interval (CI): 1.16, 3.32) in the "ever exposed" group. Ever exposure to carbon disulfide was associated with increased risks of medulloblastoma (OR = 1.85, 95% CI 1.01, 3.40) and ependymoma (OR = 1.63, 95% CI 0.97, 2.74).ConclusionsOverall, our findings suggested maternal residential exposure to solvents from industrial sources might be associated with elevated childhood cancer risks.

BackgroundS100A8 is a melanoma biomarker expressed in the melanoma-associated epidermal keratinocytes, but its diagnostic utility has not been compared with other biomarkers, including PRAME.ObjectivesTo compare the utility of S100A8 and PRAME immunohistochemistry (IHC) in the differential diagnosis of melanoma and naevi in a case-control study.MethodsA previously described cohort of 209 melanomas (case samples) and naevi (control samples) dual-immunostained for S100A8 and PRAME were included. For S100A8, previously reported scores indicating the proportion of tumour-associated epidermis stained (0 = indeterminate; 1 = 0-4%; 2 = 5-25%; 3 = 26-50%; 4 = 51-75%; 5 = > 75%) were utilized. PRAME IHC was reviewed by at least two reviewers and a consensus score assigned, with score indicating the proportion of tumour stained (0 = indeterminate; 1 = 0%; 2 = 1-50%; 3 = > 50%). A positive test was defined as > 50% staining.ResultsThe area under the receiver operating characteristic curves for S100A8 (0.833) and PRAME (0.874) were not significantly different from each other (P = 0.22). The diagnostic sensitivity and specificity were 42.4% [95% confidence interval (CI) 32.6-52.8%] and 98.2% (95% CI 93.6-99.8%) for S100A8, and 79.8% (95% CI 70.5-87.2%) and 87.3% (95% CI 79.6-92.9%) for PRAME, respectively. A combined test requiring both S100A8 and PRAME IHC positivity had a sensitivity of 39.4% (95% CI 29.7-49.7%) and specificity of 99.1% (95% CI 95.0-100.0%).ConclusionsS100A8 and PRAME have utility in the diagnostic workup of melanoma, with S100A8 being more specific and PRAME being more sensitive when using this threshold. Our findings suggest that these two immunohistochemical markers may favourably complement one another to improve the detection of melanoma.

Disordered eating behavior differs between the restricting subtype (AN-R) and the binging and purging subtype (AN-BP) of anorexia nervosa (AN). Yet, little is known about how these differences impact fatty acid (FA) dysregulation in AN. To address this question, we analyzed 26 FAs and 7 FA lipogenic enzymes (4 desaturases and 3 elongases) in 96 women: 25 AN-R, 25 AN-BP, and 46 healthy control women. Our goal was to assess subtype-specific patterns. Lauric acid was significantly higher in AN-BP than in AN-R at the fasting timepoint (p = 0.038) and displayed significantly different postprandial changes 2 h after eating. AN-R displayed significantly higher levels of n-3 alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, and n-6 linoleic acid and gamma-linolenic acid compared to controls. AN-BP showed elevated EPA and saturated lauric acid compared to controls. Higher EPA was associated with elevated anxiety in AN-R (p = 0.035) but was linked to lower anxiety in AN-BP (p = 0.043). These findings suggest distinct disordered eating behaviors in AN subtypes contribute to lipid dysregulation and eating disorder comorbidities. A personalized dietary intervention may improve lipid dysregulation and enhance treatment effectiveness for AN.

The genetic influence on human vocal pitch in tonal and non-tonal languages remains largely unknown. In tonal languages, such as Mandarin Chinese, pitch changes differentiate word meanings, whereas in non-tonal languages, such as Icelandic, pitch is used to convey intonation. We addressed this question by searching for genetic associations with interindividual variation in median pitch in a Chinese major depression case-control cohort and compared our results with a genome-wide association study from Iceland. The same genetic variant, rs11046212-T in an intron of the ABCC9 gene, was one of the most strongly associated loci with median pitch in both samples. Our meta-analysis revealed four genome-wide significant hits, including two novel associations. The discovery of genetic variants influencing vocal pitch across both tonal and non-tonal languages suggests the possibility of a common genetic contribution to the human vocal system shared in two distinct populations with languages that differ in tonality (Icelandic and Mandarin).

Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

BACKGROUND: Previous studies suggest that dietary vitamin C is inversely associated with gastric cancer (GC), but most of them did not consider intake of fruit and vegetables. Thus, we aimed to evaluate this association within the Stomach cancer Pooling (StoP) Project, a consortium of epidemiological studies on GC. METHODS: Fourteen case-control studies were included in the analysis (5362 cases, 11,497 controls). We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the association between dietary intake of vitamin C and GC, adjusted for relevant confounders and for intake of fruit and vegetables. The dose-response relationship was evaluated using mixed-effects logistic models with second-order fractional polynomials. RESULTS: Individuals in the highest quartile of dietary vitamin C intake had reduced odds of GC compared with those in the lowest quartile (OR: 0.64; 95% CI: 0.58, 0.72). Additional adjustment for fruit and vegetables intake led to an OR of 0.85 (95% CI: 0.73, 0.98). A significant inverse association was observed for noncardia GC, as well as for both intestinal and diffuse types of the disease. The results of the dose-response analysis showed decreasing ORs of GC up to 150-200 mg/day of vitamin C (OR: 0.54; 95% CI: 0.41, 0.71), whereas ORs for higher intakes were close to 1.0. CONCLUSIONS: The findings of our pooled study suggest that vitamin C is inversely associated with GC, with a potentially beneficial effect also for intakes above the currently recommended daily intake (90 mg for men and 75 mg for women).

BACKGROUND: In Madagascar, the districts of Antsirabe II, Faratsiho and Antsiranana I have relatively low malaria incidence rates and have been selected by the National Malaria Control Programme for pilot elimination strategies. The districts have residual transmission despite increasing coverage and quality of malaria services. This study sought to identify priority subpopulations at highest risk for malaria and collect information on intervention preferences and methods that will inform subnational tailoring of malaria service delivery. METHODS: This mixed methods study employed (i) a quantitative malaria risk factor assessment in Antsirabe II and Faratsiho comprising a test-negative frequency matched case-control study and a qualitative risk factor assessment in Antsiranana I; and (ii) a qualitative formative assessment in all three districts. For the case-control study, a mixed effects logistic regression was used with age, sex and district included as fixed effects and health facility included as a random effect. The qualitative risk factor assessment used semi-structured interview guides and key informant interviews. For the qualitative formative assessment in the three districts, a summary report was generated following semi-structured interviews and focus group discussions with high-risk populations (HRPs) and stakeholders. RESULTS: In Antsirabe II and Faratsiho districts, rice agriculture workers, outdoor/manual workers, particularly miners, and those with jobs that required travel or overnight stays, especially itinerant vendors, had higher odds of malaria infection compared to other (non-rice) agricultural workers. In Antsiranana I, respondents identified non-rice farmers, mobile vendors, and students as HRPs. Risk factors among these groups included overnight stays and travel patterns combined with a lack of malaria prevention tools. HRPs reported treatment cost and distance to the health facility as barriers to care and expressed interest in presumptive treatment and involvement of gatekeepers or people who have influence over intervention access or participation. CONCLUSIONS: The study results illustrate the value of in-depth assessments of risk behaviours, access to services and prevention tools, surveillance and prevention strategies, and the involvement of gatekeepers in shaping subnational tailoring to reach previously unreached populations and address residual transmission in elimination settings.

IntroductionThe Vietnamese Smell Identification Test (VSIT) has been validated in determining olfactory dysfunction in the Vietnamese population; however, its value in diagnosing Parkinson's disease (PD) has not been established.MethodsThis case-control study was conducted at University Medical Center HCMC, Ho Chi Minh City, Vietnam. The study sample included non-demented PD patients and healthy controls (HC) who were gender- and age-matched. All participants were evaluated for odor identification ability using the VSIT and the Brief Smell Identification Test (BSIT).ResultsA total of 218 HCs and 218 PD patients participated in the study. The median VSIT and BSIT scores were significantly different between PD and HC groups (VSIT, 5 (3) vs. 9 (2), P  0.05).ConclusionThe VSIT can be a valuable ancillary tool for supporting the diagnosis of PD in Vietnam. Olfactory dysfunction in PD was unrelated to the disease duration and severity. The VSIT can be applied to improve the accuracy of clinical PD diagnosis.

OBJECTIVES: Hepatitis B virus (HBV) infection remains a global health problem. Risk factors for HBV infection are usually assessed in prevalent rather than incident infections. To identify demographic and behavioral risks associated with incident HBV among South African blood donors. METHODS: A case-control study was performed between November 2014 and January 2018. Cases were blood donors testing positive for HBV DNA with or without hepatitis B surface antigen but negative for antibody to hepatitis B core antigen. Participants completed an audio computer-assisted structured interview on exposures during the previous 6 months. Sex-specific multivariable logistic regression yielded independent associations between risks and HBV infection. RESULTS: 56 females and 37 males with incident HBV were compared to 438 female and 439 male controls, respectively. For females, risk factors were accepting money or goods for sex, using agents to prepare ones anus prior to anal sex, penetrating injury, non-Black race, and lower educational status. Men reporting homosexual or bisexual orientation or sex with other men, previous injury, referral for HBV testing, or lack of medical insurance were at increased risk. For both sexes, having more than two male sexual partners increased risk. CONCLUSIONS: Sexual behaviors predominated over parenteral exposures as risks for incident HBV in both female and male blood donors.

BACKGROUND: Exposures associated with mpox infection remain imperfectly understood. METHODS: We conducted a case-control study enrolling participants who received molecular tests for mpox/orthopoxvirus in California from November 2022 through June 2023. We collected data on behaviors during a 21-day risk period before symptom onset or testing among mpox case patients and test-negative controls. RESULTS: Thirteen of 54 case patients (24.1%) and 5 of 117 controls (4.3%) reported sexual exposure to individuals they identified as potential mpox case patients (index contacts; odds ratio [OR], 7.7 [95% confidence interval (CI), 2.5-19.3] relative to individuals who did not report exposure to potential mpox case patients). Among these participants, 10 of 13 case patients (76.9%) and 2 of 5 controls (40.0%) reported that their index contacts were not experiencing symptoms visible to participants during sex (OR, 14.9 [95% CI, 3.6-101.8]). Only 3 of 54 case patients (5.6%) reported exposure to symptomatic index contacts. Case patients reported more anal/vaginal sex partners than did controls (adjusted OR, 2.2 [95% CI, 1.0-4.8] for 2-3 partners and 3.8 [1.7-8.8] for ≥4 partners). Male case patients with penile lesions more commonly reported insertive anal/vaginal sex than those without penile lesions (adjusted OR, 9.3 [95% CI, 1.6-54.8]). Case patients with anorectal lesions more commonly reported receptive anal sex than those without anorectal lesions (adjusted OR, 14.4 [95% CI, 1.0-207.3]). CONCLUSIONS: Sexual exposure to contacts known or suspected to have experienced mpox was associated with increased risk of infection, often when index contacts lacked apparent symptoms. Exposure to more sex partners, including those whom participants did not identify as index contacts, was associated with increased risk of infection in a site-specific manner. While participants assessment of symptoms in partners may be imperfect, these findings suggest that individuals without visibly prominent mpox symptoms transmit infection.

Objective: the aim of this study was to identify plasma metabolomic markers of Dietary Approaches to Stop Hypertension (DASH) dietary patterns in pregnant women. Methods: This study included 186 women who had both dietary intake and metabolome measured from a nested case-control study within the NICHD Fetal Growth Studies-Singletons cohort (FGS). Dietary intakes were ascertained at 8-13 gestational weeks (GW) using the Food Frequency Questionnaire (FFQ) and DASH scores were calculated based on eight food and nutrient components. Fasting plasma samples were collected at 15-26 GW and untargeted metabolomic profiling was performed. Multivariable linear regression models were used to examine the association of individual metabolites with the DASH score. Least absolute shrinkage and selection operator (LASSO) regression was used to select a panel of metabolites jointly associated with the DASH score. Results: Of the total 460 known metabolites, 92 were individually associated with DASH score in linear regressions, 25 were selected as a panel by LASSO regressions, and 18 were identified by both methods. Among the top 18 metabolites, there were 11 lipids and lipid-like molecules (i.e., TG (49:1), TG (52:2), PC (31:0), PC (35:3), PC (36:4) C, PC (36:5) B, PC (38:4) B, PC (42:6), SM (d32:0), gamma-tocopherol, and dodecanoic acid), 5 organic acids and derivatives (i.e., asparagine, beta-alanine, glycine, taurine, and hydroxycarbamate), 1 organic oxygen compound (i.e., xylitol), and 1 organoheterocyclic compound (i.e., maleimide). Conclusions: our study identified plasma metabolomic markers for DASH dietary patterns in pregnant women, with most of being lipids and lipid-like molecules.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

INTRODUCTION: We aimed to investigate the impact of reduced contact prenatal care necessitated by the COVID-19 pandemic on meeting standards of care and perinatal outcomes. METHODS: This was a retrospective case-control study of patients in low-risk obstetrics clinic at a tertiary care county facility serving solely publicly insured patients comparing reduced in-person prenatal care (R) over 12 weeks with a control group (C) receiving traditional prenatal care who delivered prior. RESULTS: Total 90 patients in reduced contact (R) cohort were matched with controls (C). There were similar rates of standard prenatal care metrics between groups. Gestational age (GA) of anatomy ultrasound was later in R (p = 0.017). Triage visits and missed appointments were similar, though total number of visits (in-person and telehealth) was higher in R (p = 0.043). R group had higher GA at delivery (p = 0.001). Composite neonatal morbidity and length of stay were lower in R (p = 0.017, p = 0.048). Maternal and neonatal outcomes did not otherwise differ between groups. Using Kotelchuck Adequacy of Prenatal Care Utilization index, R had higher rates of adequate prenatal care (45.6% R vs. 24.4% C, p = 0.005). DISCUSSION: Our study demonstrates the non-inferiority of a hybrid, reduced schedule prenatal schedule to traditional prenatal scheduling. In a reduced contact prenatal care model, more patients met criteria for adequate prenatal care, likely due to higher attendance of telehealth visits. These findings raise the question of revising the prenatal care model to mitigate disparities in disadvantaged populations.

BackgroundCocaine is an illegal recreational drug used worldwide, yet little is known about whether cocaine inhalation (smoking/snorting) increases the risk of head and neck cancer (HNC).MethodsThe analyses were conducted by pooling data from three case-control studies with 1639 cases and 2506 controls from the International Head and Neck Cancer Epidemiology Consortium. Epidemiologic data, including cocaine use histories, were obtained in face-to-face interviews. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using hierarchical logistic regression models.ResultsControlling for cumulative tobacco and alcohol use, we observed a weak positive association between cocaine use and HNC (ORever vs. never  = 1.35, 95% CI: 0.96, 1.90). In stratified analysis, while we did not detect associations among never tobacco or alcohol users due to the limited sample size, the association with cocaine use was observed among tobacco users and alcohol drinkers. ORs for ever and high cumulative use (>18 times) versus never use were 1.40 (95% CI: 0.98, 2.00) and 1.66 (95% CI: 1.03, 2.69) among tobacco users, and 1.34 (95% CI: 0.93, 1.92) and 1.59 (95% CI: 1.00, 2.51) among alcohol drinkers, respectively.ConclusionIn this pooled analysis, we observed a weak positive association between cocaine inhalation and HNC risk. Our findings provide preliminary evidence of the potential carcinogenic effect of cocaine on HNC. Because of study limitations, including limited number of cocaine users, confounding, and heterogeneity across studies, future investigations will require larger studies with more detailed information on cocaine use history.

In pre-disposed individuals, a reprogramming of the hepatic lipid metabolism may support liver cancer initiation. We conducted a high-resolution mass spectrometry based untargeted lipidomics analysis of pre-diagnostic serum samples from a nested case-control study (219 liver cancer cases and 219 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Out of 462 annotated lipids, 158 (34.2%) were associated with liver cancer risk in a conditional logistic regression analysis at a false discovery rate (FDR)

BackgroundPostoperative delirium is prevalent in older adults and has been shown to increase the risk of long-term cognitive decline. Plasma biomarkers to identify the risk for postoperative delirium and the risk of Alzheimer's disease and related dementias are needed.MethodsThis biomarker discovery case-control study aimed to identify plasma biomarkers associated with postoperative delirium. Patients aged ≥65 years undergoing major elective noncardiac surgery were recruited. The preoperative plasma proteome was interrogated with SOMAmer-based technology targeting 1433 biomarkers.ResultsIn 40 patients (20 with vs. 20 without postoperative delirium), a preoperative panel of 12 biomarkers discriminated patients with postoperative delirium with an accuracy of 97.5%. The final model of five biomarkers delivered a leave-one-out cross-validation accuracy of 80%. Represented biological pathways included lysosomal and immune response functions.ConclusionIn older patients who have undergone major surgery, plasma SOMAmer proteomics may provide a relatively non-invasive benchmark to identify biomarkers associated with postoperative delirium.

BackgroundSystematically recorded smoking data are not always available in vital statistics records, and even when available it can underestimate true smoking rates.ObjectiveTo develop a prediction model for maternal tobacco smoking in late pregnancy based on birth certificate information using a combination of self- or provider-reported smoking and biomarkers (smoking metabolites) in neonatal blood spots as the alloyed gold standard.MethodsWe designed a case-control study where childhood cancer cases were identified from the California Cancer Registry and controls were from the California birth rolls between 1983 and 2011 who were cancer-free by the age of six. In this analysis, we included 894 control participants and performed high-resolution metabolomics analyses in their neonatal dried blood spots, where we extracted cotinine [mass-to-charge ratio (m/z) = 177.1023] and hydroxycotinine (m/z = 193.0973). Potential predictors of smoking were selected from California birth certificates. Logistic regression with stepwise backward selection was used to build a prediction model. Model performance was evaluated in a training sample, a bootstrapped sample, and an external validation sample.ResultsOut of seven predictor variables entered into the logistic model, five were selected by the stepwise procedure: maternal race/ethnicity, maternal education, child's birth year, parity, and child's birth weight. We calculated an overall discrimination accuracy of 0.72 and an area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval [CI] 0.77, 0.84) in the training set. Similar accuracies were achieved in the internal (AUC 0.81, 95% CI 0.77, 0.84) and external (AUC 0.69, 95% CI 0.64, 0.74) validation sets.ConclusionsThis easy-to-apply model may benefit future birth registry-based studies when there is missing maternal smoking information; however, some smoking status misclassification remains a concern when only variables from the birth certificate are used to predict maternal smoking.

BACKGROUND: A major challenge to malaria elimination is identifying and targeting populations that are harbouring residual infections and contributing to persistent transmission. In many near-elimination settings in Southeast Asia, it is known that forest-goers are at higher risk for malaria infection, but detailed information on their behaviours and exposures is not available. METHODS: In Aceh Province, Indonesia, a near-elimination setting where a growing proportion of malaria is due to Plasmodium knowlesi, a case-control study was conducted to identify risk factors for symptomatic malaria, characteristics of forest-goers, and key intervention points. From April 2017 to September 2018, cases and controls were recruited and enrolled in a 1:3 ratio. Cases had confirmed malaria infection by rapid diagnostic test or microscopy detected at a health facility (HF). Gender-matched controls were recruited from passive case detection among individuals with suspected malaria who tested negative at a health facility (HF controls), and community-matched controls were recruited among those testing negative during active case detection. Multivariable logistic regression (unconditional for HF controls and conditional for community controls) was used to identify risk factors for symptomatic malaria infection. RESULTS: There were 45 cases, of which 27 were P. knowlesi, 17 were Plasmodium vivax, and one was not determined. For controls, 509 and 599 participants were recruited from health facilities and the community, respectively. Forest exposures were associated with high odds of malaria; in particular, working and sleeping in the forest (HF controls: adjusted odds ratio (aOR) 21.66, 95% CI 5.09-92.26; community controls: aOR 16.78, 95% CI 2.19-128.7) and having a second residence in the forest (aOR 6.29, 95% CI 2.29-17.31 and 13.53, 95% CI 2.10-87.12). Male forest-goers were a diverse population employed in a variety of occupations including logging, farming, and mining, sleeping in settings, such as huts, tents, and barracks, and working in a wide range of group sizes. Reported use of protective measures, such as nets, hammock nets, mosquito coils, and repellents was low among forest-goers and interventions at forest residences were absent. CONCLUSIONS: Second residences in the forest and gaps in use of protective measures point to key malaria interventions to improve coverage in forest-going populations at risk for P. knowlesi and P. vivax in Aceh, Indonesia. Intensified strategies tailored to specific sub-populations will be essential to achieve elimination.

BACKGROUND: In low- and middle-income countries countries, millions of deaths occur annually from household air pollution (HAP), pulmonary tuberculosis (PTB), and HIV-infection. However, it is unknown whether HAP influences PTB risk among people living with HIV-infection. METHODS: We conducted a case-control study among 1,277 HIV-infected adults in Bukavu, eastern Democratic Republic of Congo (February 2018 - March 2019). Cases had current or recent (3h/day and ≥2 times/day and ≥5 days/week were more likely to have PTB (aOR 1·36; 95%CI 1·06-1·75) than those spending less time in the kitchen. Time-weighted average 24h personal CO exposure was related dose-dependently with the likelihood of having PTB, with aOR 4·64 (95%CI 1·1-20·7) for the highest quintile [12·3-76·2 ppm] compared to the lowest quintile [0·1-1·9 ppm]. CONCLUSION: Time spent cooking and personal CO exposure were independently associated with increased risk of PTB among people living with HIV. Considering the high burden of TB-HIV coinfection in the region, effective interventions are required to decrease HAP exposure caused by cooking with biomass among people living with HIV, especially women.

BackgroundTobacco smoke adversely affects the prognosis of adult cancers including myeloid leukemia, but less is known in children.MethodsWe evaluated whether pre- and postnatal exposures to tobacco smoke decrease 5-year survival of 1,235 childhood acute lymphoblastic leukemia (ALL) and 188 childhood acute myeloid leukemia (AML) cases derived from a population-based case-control study in California. Cases were diagnosed between 1995 and 2015 (median follow-up time of 13.2 years overall). We obtained data on tobacco smoking (before conception, during pregnancy, after birth), parental education and income, clinical features, and vital status through 2020. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for mortality associated with smoking, adjusting for sociodemographic characteristics and risk group (ALL only).ResultsAbout 23% of mothers and 39% of fathers reported smoking and 130 children with ALL and 52 with AML died within 5 years. For AML, increased risks of death were observed among children whose fathers smoked before conception compared with nonsmoking fathers [HR = 1.41; 95% confidence interval (CI), 0.95-3.44 and 3.47; 95% CI, 1.37-8.81, respectively for

PurposeTo compare baseline levels of exploratory biomarkers in the vitreous fluid of patients with primary retinal detachment who subsequently develop proliferative vitreoretinopathy (PVR) versus those who do not.MethodsIn this exploratory case-control study, we evaluated the baseline protein biomarker levels from a biobank containing the vitreous fluid of patients who had undergone primary pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment. Undiluted samples were collected at the time of PPV and stored at -80°C. Samples from 13 patients who developed PVR within 6 months (PVR group) and 13 age- and gender-matched controls who did not develop PVR (control group) were included. Protein abundance levels were evaluated using a proximity extension assay, and a confirmatory enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of vimentin.ResultsBaseline vimentin (Normalized Protein eXpression [NPX], 8.6 vs. 6.4, P < 0.0001) and heme oxygenase 1 (NPX 8.9 vs. 7.0, P < 0.001) levels were found to be elevated in vitreous fluid of patients who subsequently developed PVR compared to those who did not. Confirmatory analysis using ELISA demonstrated mean vimentin concentrations of 7254 vs. 2727 ng/mL in the PVR versus control groups (P = 0.0152). The odds ratio for developing PVR was 14 (confidence interval, 1.4-168; P = 0.03), assuming a baseline vimentin threshold of 7500 ng/mL.ConclusionsVimentin is an intermediate filament protein expressed by retinal glial cells, and our data combined with prior evidence suggest that it may serve as an early vitreous biomarker for subsequent PVR formation and reactive gliosis. Furthermore, we found, for the first time, elevated baseline levels of heme oxygenase 1, a measurable indicator of oxidative stress.Translational relevanceOur positive findings could impact clinical care for retinal detachment patients by facilitating risk stratification for targeted interventions or closer monitoring in those at the highest risk of developing PVR.

PurposeTo assess whether transcutaneous retrobulbar amphotericin B injections (TRAMB) reduce exenteration rate without increasing mortality in rhino-orbital-cerebral mucormycosis (ROCM).MethodsIn this retrospective case-control study, 46 patients (51 eyes) with biopsy-proven ROCM were evaluated at 9 tertiary care institutions from 1998 to 2021. Patients were stratified by radiographic evidence of local orbital versus extensive involvement at presentation. Extensive involvement was defined by MRI or CT evidence of abnormal or loss of contrast enhancement of the orbital apex with or without cavernous sinus, bilateral orbital, or intracranial extension. Cases (+TRAMB) received TRAMB as adjunctive therapy while controls (-TRAMB) did not. Patient survival, globe survival, and vision/motility loss were compared between +TRAMB and -TRAMB groups. A generalized linear mixed effects model including demographic and clinical covariates was used to evaluate the impact of TRAMB on orbital exenteration and disease-specific mortality.ResultsAmong eyes with local orbital involvement, exenteration was significantly lower in the +TRAMB group (1/8) versus -TRAMB (8/14) (p = 0.04). No significant difference in mortality was observed between the ±TRAMB groups. Among eyes with extensive involvement, there was no significant difference in exenteration or mortality rates between the ±TRAMB groups. Across all eyes, the number of TRAMB injections correlated with a statistically significant decreased rate of exenteration (p = 0.048); there was no correlation with mortality.ConclusionsPatients with ROCM with local orbital involvement treated with adjunctive TRAMB demonstrated a lower exenteration rate and no increased risk of mortality. For extensive involvement, adjunctive TRAMB does not improve or worsen these outcomes.

IntroductionKawasaki disease (KD) is a pediatric vasculitis that can result in coronary artery aneurysm (CAA) formation, which is a dangerous complication. Treatment with intravenous immunoglobulin (IVIg) significantly decreases the risk of CAA, possibly through competitive binding to Fc-gamma receptors (FcγRs), which reduces the binding of pathological immune complexes. However, ~20% of children have recrudescence of fever and have an increased risk of CAA. Therefore, we aimed to identify genetic markers at the FCGR2/3 locus associated with susceptibility to KD, IVIg resistance, or CAA.Materials and methodsWe investigated the association of single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) at the FCGR2/3 locus with KD susceptibility, IVIg resistance, and CAA risk using a family-based test (KD susceptibility) and case-control analyses (IVIg resistance and CAA risk) in different cohorts, adding up to a total of 1,167 KD cases. We performed a meta-analysis on IVIg resistance and CAA risk including all cohorts supplemented by previous studies identified through a systematic search.ResultsFCGR2A-p.166His was confirmed to be strongly associated with KD susceptibility (Z = 3.17, p = 0.0015). In case-control analyses, all of the investigated genetic variations at the FCGR2/3 locus were generally not associated with IVIg resistance or with CAA risk, apart from a possible association in a Polish cohort for the FCGR3B-NA2 haplotype (OR = 2.15, 95% CI = 1.15-4.01, p = 0.02). Meta-analyses of all available cohorts revealed no significant associations of the FCGR2/3 locus with IVIg resistance or CAA risk.DiscussionFCGR2/3 polymorphisms are associated with susceptibility to KD but not with IVIg resistance and CAA formation. Currently known genetic variations at the FCGR2/3 locus are not useful in prediction models for IVIg resistance or CAA risk.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition that often persists into adulthood. Underlying alterations in brain connectivity have been identified but some relevant connections, such as the middle, superior, and inferior cerebellar peduncles (MCP, SCP, and ICP, respectively), have remained largely unexplored; thus, we sought to investigate whether the cerebellar peduncles contribute to ADHD pathophysiology among adults. METHODS: We applied diffusion-weighted spherical deconvolution tractography to dissect the cerebellar peduncles of male adults with ADHD (including those who did or did not respond to methylphenidate, based on at least 30% symptom improvement at 2 months) and controls. We investigated differences in tract metrics between controls and the whole ADHD sample and between controls and treatment-response groups using sensitivity analyses. Finally, we analyzed the association between the tract metrics and cliniconeuropsychological profiles. RESULTS: We included 60 participants with ADHD (including 42 treatment responders and 18 nonresponders) and 20 control participants. In the whole ADHD sample, MCP fractional anisotropy (FA; t 78 = 3.24, p = 0.002) and hindrance modulated orientational anisotropy (HMOA; t 78 = 3.01, p = 0.004) were reduced, and radial diffusivity (RD) in the right ICP was increased (t 78 = -2.84, p = 0.006), compared with controls. Although case-control differences in MCP FA and HMOA, which reflect white-matter microstructural organization, were driven by both treatment response groups, only responders significantly differed from controls in right ICP RD, which relates to myelination (t 60 = 3.14, p = 0.003). Hindrance modulated orientational anisotropy of the MCP was significantly positively associated with hyperactivity measures. LIMITATIONS: This study included only male adults with ADHD. Further research needs to investigate potential sex- and development-related differences. CONCLUSION: These results support the role of the cerebellar networks, especially of the MCP, in adult ADHD pathophysiology and should encourage further investigation. CLINICAL TRIAL REGISTRATION: NCT03709940.

BACKGROUND: Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. OBJECTIVES: To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. ANIMALS: Dogs with pCKD (n = 36) and healthy controls (n = 20). METHODS: Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. RESULTS: Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P

Post-traumatic stress disorder (PTSD) may be a risk factor for Parkinsons disease (PD). We examined the relation between PTSD and PD in a cohort of 158,122 Veterans who had any Veterans Health Administration (VHA) or Medicare health care utilization between 10/1/1999- 2/17/2021. Using a nested case-control design we matched 10 controls to each Veteran with PD by sex, race, and rank. In conditional logistic regression models adjusted for camp and smoking, a PTSD diagnosis was significantly associated with PD (OR = 1.35; p = 0.0002); odds were higher if PTSD was coded before PD (OR = 1.53, p

Rheumatoid arthritis (RA) management leans toward achieving remission or low disease activity. In this study, we conducted single-cell RNA sequencing (scRNA-Seq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 patients with RA and 18 matched controls, accounting for age, sex, race, and ethnicity), to identify disease-relevant cell subsets and cell type-specific signatures associated with disease activity. Our analysis revealed 18 distinct PBMC subsets, including an IFN-induced transmembrane 3-overexpressing (IFITM3-overexpressing) IFN-activated monocyte subset. We observed an increase in CD4+ T effector memory cells in patients with moderate-high disease activity (DAS28-CRP ≥ 3.2) and a decrease in nonclassical monocytes in patients with low disease activity or remission (DAS28-CRP < 3.2). Pseudobulk analysis by cell type identified 168 differentially expressed genes between RA and matched controls, with a downregulation of proinflammatory genes in the γδ T cell subset, alteration of genes associated with RA predisposition in the IFN-activated subset, and nonclassical monocytes. Additionally, we identified a gene signature associated with moderate-high disease activity, characterized by upregulation of proinflammatory genes such as TNF, JUN, EGR1, IFIT2, MAFB, and G0S2 and downregulation of genes including HLA-DQB1, HLA-DRB5, and TNFSF13B. Notably, cell-cell communication analysis revealed an upregulation of signaling pathways, including VISTA, in both moderate-high and remission-low disease activity contexts. Our findings provide valuable insights into the systemic cellular and molecular mechanisms underlying RA disease activity.