Discordant Pairs Research Articles

Aetiology of neonatal jaundice in apparently well late-preterm and term neonates at a mission hospital, Southwestern Nigeria

Background: The knowledge of the aetiology for neonatal jaundice is important in the early detection and effective management of infants with or at risk of severe jaundice before hospital discharge. This study assessed the aetiological factors of neonatal jaundice among apparently well late preterm and termnewborns to ensure timely intervention where these risk factors exist.Method: This was a cross sectional study involving 174 apparently well neonates at a tertiary mission hospital. Detailed history, physical examination, relevant haematological and biochemical tests were undertaken. Significant jaundice was defined as serum bilirubin greater than 2 standard deviations above the postnatal age and weight dependent treatment concentration.Results: Of the 844 neonates admitted into the neonatal care unit, 174 (20.6%) had significant jaundice. Median age at presentation was 3 days (95% CI of median 3-4days). The mean ±SD gestation age and birth weight of the neonates at recruitment were 38.1±1.6 weeks and 3.1± 0.5kg respectively. Males were 108 (62.4%; M: F.1.6.1). The mean ±SD total serum bilirubin was 13.9±4.7mg/dl. Significant jaundice was more common with maternal-baby concordant paired blood group of AA, O-O compared with discordant materno-baby group pairs. Of the known causes of significant neonatal jaundice, G6PD deficiency (57-38.5%) ranked topmost. Half (87-50.0%) of the causes of significant jaundice were unidentified.Conclusion : G6PD deficiency remains the leading aetiology for significant neonatal jaundice. G6PD screening should be mandated before hospital discharge, compatible mother-baby blood group pairs do not rule the risk for significant jaundice; further research is required to elucidate other inherent unidentified aetiologies.

Childhood trauma and borderline personality disorder traits: A discordant twin study.

A discordant twin design was utilized to examine the potentially causal effects of childhood trauma (CT; i.e., emotional abuse, physical abuse, sexual abuse, and witnessing violence) on borderline personality disorder traits (BPD traits) in early adulthood. The participants were 2,808 twins between 17 and 23 years from the Oslo University Adolescent and Young Adult Twin Project. BPD traits were assessed by the Structured Interview for DSM-IV Personality (SIDP-IV), and CT was assessed using the Childhood Trauma Interview (CTI). BPD traits (h² = .50) and CT (h² = .33-.69) were both found to be moderately heritable. Small but statistically significant associations between CT and BPD traits were found in the total sample. After controlling for shared environmental and genetic factors in the discordant twin pairs, the analyses showed little to no evidence for causal effects of CT on BPD traits. The results indicated that the associations between CT and BPD traits stem from common genetic influences. These findings are inconsistent with the widely held assumption that CT causes the development of BPD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers

Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers

Weighted McNemar's test for the comparison of two screening tests in the presence of verification bias.

Statistical methods have been well-developed for comparing two binary screening tests in the presence of verification bias. However, the complexity of existing methods and the computational difficulty in implementing them have restricted their use. A simple and easily implemented statistical method is therefore needed. In this paper, we propose a weighted McNemar's test statistic for comparing two sensitivities(specificities). The proposed test statistics are intuitive and simple to compute, only involving some minor modification of a McNemar's test statistic using the estimated verification probabilities for discordant pairs. Simulations demonstrate that the proposed weighted McNemar's test statistics preserve type I error as well as or better than the existing statistics. Furthermore, unlike the existing methods, the proposed weighted McNemar's test statistics can still be applied even when none of the accordant pairs are verified.

Concordant pairs in ratios with rank at least two and the distribution of $\theta$-congruent numbers

Let $k$ and $\ell$ be distinct nonzero integers. We show that in every congruence class modulo an integer $m>1$, there exist infinitely many integers $n$ such that the Mordell-Weil rank over $\mathbf{Q}$ of the elliptic curve $E(kn,\ell n) : y^{2} = x(x+kn)(x+\ell n)$ is at least two. We also find that for sufficiently large $T$, the number of square-free integers $n$ with $|n| \leq T$ for which the elliptic curve $E(kn, \ell n)$ has rank at least two is at least $\mathcal{O}(T^{2/7})$.

Noise-rearing precludes the behavioral benefits of multisensory integration.

Concordant visual-auditory stimuli enhance the responses of individual superior colliculus (SC) neurons. This neuronal capacity for "multisensory integration" is not innate: it is acquired only after substantial cross-modal (e.g. auditory-visual) experience.Masking transient auditory cues by raising animals inomnidirectional sound ("noise-rearing") precludes their ability to obtain this experience and the ability of the SC to construct a normal multisensory (auditory-visual) transform. SC responses to combinations of concordant visual-auditory stimuli are depressed, rather than enhanced. The present experiments examined the behavioral consequence of this rearing condition in a simple detection/localization task. In the first experiment, the auditory component of the concordant cross-modal pair was novel, and only the visual stimulus was a target. In the second experiment, both component stimuli were targets. Noise-reared animals failed to show multisensory performance benefits in either experiment. These results reveal a close parallel between behavior and single neuron physiology in the multisensory deficits that are induced when noise disrupts early visual-auditory experience.

Work incapacity and psychiatric patient care following attempted suicide - a cohort study of 65 097 Swedish twins.

Research is scarce on the role of familial factors and previous psychiatric care on the association between suicide attempt and future work incapacity as well as deterioration in mental health. We aimed to investigate the associations between suicide attempt and sickness absence, disability pension and psychiatric patient care and to study the influence of previous psychiatric care and familial factors (genetics and shared environment) on the associations. The study included 65 097 twins living in Sweden on 31st of December 2006, aged 19-60 years. The twins were followed 2007-2013 regarding sickness absence, disability pension, inpatient care or specialized outpatient care for a mental diagnosis. Cox regression models were performed for the whole sample, and conditional models for discordant twin pairs. The analyses were also stratified by psychiatric care before 2007. We found that suicide attempt predicted sickness absence, disability pension, and future mental diagnosis among the whole sample. The discordant twin pair analyses showed that the association between suicide attempt and sickness absence or disability pension was influenced by familial factors. Stratified analyses of individuals with or without psychiatric care before 2007 showed that previous psychiatric care had some impact on the associations. A suicide attempt is a risk factor for work incapacity and psychiatric patient care. Familial factors and previous psychiatric care play a role in the associations between attempting suicide and work incapacity as well as psychiatric patient care. These factors are important when developing measures preventing work incapacity among those with a suicide attempt.

Cancer in twin pairs discordant for smoking: The Nordic Twin Study of Cancer.

The discordant twin pair study design is powerful to control for familial confounding. We employed this approach to investigate the associations of smoking with several cancers. The NorTwinCan study combines data from the Danish, Finnish, Norwegian and Swedish twin and cancer registries. Follow‐up started when smoking status was determined and ended at cancer diagnosis confirmed by information in the cancer registry, death or end of follow‐up. We classified the participants as never (n = 59 093), former (n = 21 168) or current (n = 47 314) smokers. We pooled data from twin pairs where one co‐twin was diagnosed with any of the following tobacco‐related cancers: esophagus, kidney, larynx, liver, oral cavity, pancreas, pharynx or urinary bladder, while their co‐twin had none of those. Lung cancer was included in further analysis. We used Cox regression allowing for pair‐specific baseline functions to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). For tobacco‐related cancer sites, we recorded 7379 cases during median 27 years of follow‐up. The analyses based on individual twins showed that former (HR 1.31, 95% CI: 1.17‐1.48) and current (HR 2.14 [1.95‐2.34]) smokers are at increased risk to develop one of cancers listed above, compared to never smokers. Among 109 monozygotic twin pairs discordant for cancer and smoking, the HR was 1.85 (95% CI: 1.15‐2.98) among current smokers and 1.69 (1.00‐2.87) among former smokers when compared to their never smoking co‐twin. Thus, associations of smoking with several cancers were replicated for discordant identical twin pairs. Analyses based on genetically informative data provide evidence consistent with smoking causing multiple cancers.

Investigation of the reliability of semi-automatic annotation by the Geri time-lapse system

Research questionWhat is the reliability of Geri® Assess 2.0 software time-lapse technology for annotating kinetic events and identifying abnormal phenotypes in preimplantation human embryos? DesignEmbryos were annotated using Assess 2.0 for the appearance and fading of pronuclei, and for progression to the 2-, 3-, 4-, 5- and 6-cell stages and to three blastocyst stages. Identification of reverse cleavage and direct cleavage phenotypes was also recorded. Manual annotation was undertaken after these events in a blinded fashion. Embryo scores were compared between Assess 2.0 and manual annotation. ResultsA total of 513 oocytes from 34 women were included. Detection rates for Assess 2.0 versus manual annotation among the 10 kinetic events and including direct cleavage and reverse cleavage ranged between 0% and 94.4%. The percentage of discordant pairs was significantly different for all 12 events analysed (P-value range 0.036 to <0.0001). The sensitivity of Assess 2.0 ranged from 68.2% to 94.4% and specificity ranged from 63.8% to 97.3%. Assess 2.0 called for verification by the embryologist for at least one event in 55.2% of oocytes assessed. Of the 297 embryos scored by manual annotation, Assess 2.0 assigned the same score for only 125 (42.1%), although after manual corrections, concordance with manual annotation scores was raised to 66.0%. ConclusionsThe results reveal striking differences between Assess 2.0 and manual annotation for kinetic annotations. Failure of Assess 2.0 to detect direct cleavage events and the low detection rate of reverse cleavage are further limitations. These collective findings highlight the importance of validating time-lapse annotation software before clinical implementation. Manual verification of Assess 2.0 outputs remains essential for accurate data interpretation.

TC-hunter: identification of the insertion site of a transgenic gene within the host genome

BackgroundTransgenic animal models are crucial for the study of gene function and disease, and are widely utilized in basic biological research, agriculture and pharma industries. Since the current methods for generating transgenic animals result in the random integration of the transgene under study, the phenotype may be compromised due to disruption of known genes or regulatory regions. Unfortunately, most of the tools that predict transgene insertion sites from high-throughput data are not publicly available or not properly maintained.ResultsWe implemented TC-hunter, Transgene-Construct hunter, an open tool that identifies transgene insertion sites and provides simple reports and visualization aids. It relies on common tools used in the analysis of high-throughput data and makes use of chimeric reads and discordant read pairs to identify and support the transgenic insertion site. To demonstrate its applicability, we applied TC-hunter to four transgenic mice samples harboring the human PPM1D gene, a model used in the study of malignant tumor development. We identified the transgenic insertion site in each sample and experimentally validated them with Touchdown-polymerase chain reaction followed by Sanger sequencing.ConclusionsTC-hunter is an accessible bioinformatics tool that can automatically identify transgene insertion sites from DNA sequencing data with high sensitivity (98%) and precision (92.45%). TC-hunter is a valuable tool that can aid in evaluating any potential phenotypic complications due to the random integration of the transgene and can be accessed at https://github.com/bcfgothenburg/SSF.

Linkage analysis identifies novel genetic modifiers of microbiome traits in families with inflammatory bowel disease

ABSTRACT Dysbiosis of the gut microbiome is a hallmark of inflammatory bowel disease (IBD) and both, IBD risk and microbiome composition, have been found to be associated with genetic variation. Using data from families of IBD patients, we examined the association between genetic and microbiome similarity in a specific IBD context, followed by a genome-wide quantitative trait locus (QTL) linkage analysis of various microbiome traits using the same data. SNP genotypes as well as gut microbiome and phenotype data were obtained from the Kiel IBD family cohort (IBD-KC). The IBD-KC is an ongoing prospective study in Germany currently comprising 256 families with 455 IBD patients and 575 first- and second-degree relatives. Initially focusing upon known IBD risk loci, we noted a statistically significant (FDR<0.05) association between genetic similarity at SNP rs11741861 and overall microbiome dissimilarity among pairs of relatives discordant for IBD. In a genome-wide QTL analysis, 12 chromosomal regions were found to be linked to the abundance of one of seven microbial genera, namely Barnesiella (chromosome 4, region spanning 10.34 cM), Clostridium_XIVa (chr4, 3.86 cM; chr14, two regions spanning 7.05 and 13.02 cM respectively), Pseudoflavonifractor (chr7, 12.80 cM) Parasutterella (chr14, 8.26 cM), Ruminococcus (chr16, two overlapping regions spanning 8.01 and 16.87 cM, respectively), Roseburia (chr19, 7.99 cM), and Odoribacter (chr22, three regions spanning 0.89, 5.57 and 1.71 cM, respectively), as well as the Shannon index of α diversity (chr3, 1.47 cM). Our study thus shows that, in families of IBD patients, pairwise genetic similarity for at least one IBD risk locus is associated with overall microbiome dissimilarity among discordant pairs of relatives, and that hitherto unknown genetic modifiers of microbiome traits are located in at least 12 human genomic regions.

Factors Influencing HIV Status Disclosure to Partners Among Antiretroviral Therapy Clients in the Upper East Region, Ghana.

In Ghana, HIV status disclosure to partners is voluntary. This study sought to determine the factors associated with HIV status disclosure to partners among antiretroviral therapy (ART) clients in the Upper East Region. A matched case-control study (1:1) was carried out in nine ART sites in the Upper East region in which 100 ART sexually active clients who had not disclosed their status to their partners were compared with 100 ART sexually ART clients who had disclosed their status to their partners. To each of the 200 study participants, a structured questionnaire was administered to elicit relevant responses. Discordant pair analysis was done with Mantel-Haenszel matched test to determine associations between variables. The study found persons with informal education more likely to disclose HIV status, whereas persons living apart or not having children with a partner were less likely to disclose their status to their sexual partners. On the other hand, active involvement or participation in ART-related services were more likely going to impact HIV status disclosure. Early initiation of ART, while adherence to ART services and the use of treatment monitors were less associated with disclosure. Active participation in ART related services such as prompt initiation of ART following diagnosis, adherence promotion, and treatment monitoring should be encouraged to promote HIV status disclosure among sexual partners.

Abstract TP119: Celecoxib In Aneurysmal Subarachnoid Hemorrhage: A Single Center Experience

Introduction: Inflammation may play a central role in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Prostaglandins are inflammatory mediators that are elevated in aSAH and are synthesized by cyclooxygenase-2 (Cox-2). Celecoxib is a selective Cox-2 inhibitor with anti-inflammatory effects and good central nervous system penetration. In a mouse model of SAH, Cox-2 gene expression was found to be up-regulated in brain endothelial cells and celecoxib was found to limit Cox-2 up-regulation. We sought to evaluate the safety of celecoxib in patients with aSAH for future clinical studies. Methods: We used a matched case-control study to evaluate safety of celecoxib in aSAH patients. Our prospectively collected aSAH database (N=230) was retrospectively reviewed from 1/2010 - 2/2020. Celecoxib cases (N=13) and controls (N=217) were matched by closest Euclidean distance based on age and Glasgow Coma Scale (Figure 1). Each case was matched with 4 controls to maximize power based on closest Euclidean distance. Baseline characteristics for cases and controls were compared using a t-test or signed rank test for pairs. Categorical variables were compared using McNemar’s test for discordant pairs. A p value ≤.05 was considered significant for all univariate testing. Results are listed in Table 1. Discussion: No adverse events were associated with celecoxib use. At our center, celecoxib was primarily used in high grade aSAH for fever or headache. Maximum and mean temperature are statistically higher in the celecoxib group, consistent with the treatment indication. There were no differences in vasospasm prevalence, although our analysis is limited by sample size. Given the favorable safety profile, ease of drug availability, and plausible mechanism of therapeutic effect, celecoxib warrants further study in aSAH.

Evidence of gene-gene interaction in hidradenitis suppurativa: a nationwide registry study of Danish twins.

Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease that, apart from rare causative loss-of-function mutations, has a widely unknown genetic aetiology. To estimate the relative importance of genetic and environmental factors underlying susceptibility to HS. Via the Danish Twin Registry and the Danish National Patient Registry we pulled together information on zygosity with that of HS status. Cases of HS were identified by the International Classification of Diseases (ICD)-8 (705·91) and ICD-10 (L73·2). Heritability was assessed by the classic biometric model and the possibility of gene-gene interaction via the multilocus modelling approach. Among 100 044 registered twins, we found 170 twins (from 163 pairs) diagnosed with HS. The seven concordant pairs were all monozygotic. Monozygotic twins had a case-wise concordance rate of 28% [95% confidence interval (CI) 7-49], corresponding to a familial risk of 73 (95% CI 13-133) times that of the background population. The biometrical modelling suggested a heritability of 0·80 (95% CI 0·67-0·93), and the multilocus index estimate was 230 (95% CI 60-400). This is highly indicative of gene-gene interactions, with the possibility of up to six interacting loci. This twin study was substantially larger and employed a more valid phenotype than previous studies. Genetics account for the majority of HS susceptibility, and HS is most likely caused by gene-gene interactions rather than monogenetic mutations or solely additive genetic factors. New approaches aimed at assessing potential interactions at a single-nucleotide polymorphism (SNP)-SNP level should be implemented in future HS genome-wide association studies.

Regularizing the Deepsurv Network Using Projection Loss for Medical Risk Assessment

State-of-the-art deep survival prediction approaches expand network parameters to accommodate performance over a fine discretization of output time. For medical applications where data are limited, the regression-based Deepsurv approach is more advantageous because its continuous output design limits unnecessary network parameters. Despite the practical advantage, the typical network lacks control over the feature distribution causing the network to be more prone to noisy information and occasional poor prediction performance. We propose a novel projection loss as a regularizing objective to improve the time-to-event Deepsurv model. The loss formulation maximizes the lower bound of the multiple-correlation coefficient between the network’s features and the desired hazard value. Reducing the loss also theoretically lowers the upper bound on the likelihood of discordant pair and improves C-index performance. We observe superior performances and robustness of regularized Deepsurv over many state-of-the-art approaches in our experiments with five public medical datasets and two cross-cohort validation tasks.

Comparison of outcomes between pessary use and surgery for symptomatic pelvic organ prolapse: A prospective self-controlled study.

PurposeWe compared the degree of pelvic floor symptom improvement between pessary use and prolapse surgery.Materials and MethodsPessary-naïve women who elected prolapse surgery were enrolled and used a pessary preoperatively (for ≥7 days and ≤30 days). Pelvic floor symptoms were assessed at baseline, after pessary use, and at 3 months postoperatively. The primary outcome was concordance in the degree of symptoms improvement between pessary use and surgery, as assessed by Patient Global Impression of Improvement (PGI-I). Secondary outcomes were related to prolapse specific symptoms on validated questionnaires (POPDI-6, PFIQ-7). The McNemar test was used for comparisons of discordant pairs for comparisons of the PGI-I ratings after pessary use and surgery.ResultsSixty-one participants were enrolled (March 2016 through April 2019) and 58 patients used a pessary. Mean±standard deviation age was 60.7±10.7 years; 24.1% had prior hysterectomy, and 13.8% had prior prolapse surgery. While both treatments demonstrated symptomatic improvement, concordance in the degree of overall improvement on the PGI-I score was poor (n=40); responses significantly favored more improvement postoperatively (p<0.001). Pessary use and surgery were associated with significant improvements in prolapse symptoms from baseline on POPDI-6 (both p<0.001) and POPIQ-7 (pessary, p=0.002; surgery, p<0.001). The degree of improvement was larger postoperatively compared to post-pessary use on POPDI-6 (p<0.001) and PFIQ-7 (p=0.004).ConclusionsBoth pessary use and surgery significantly improved pelvic floor symptoms from baseline. However, concordance in degrees of improvement between these treatments was poor, with more favorable outcomes after surgery for prolapse symptoms.

1164. Acquisition of Methicillin-Susceptible Staphylococcus aureus in the Neonatal Intensive Care Unit: Molecular Comparison of Relatedness of Isolates

BackgroundIn the NICU MSSA infections occur frequently and cause morbidity and mortality. Colonization is a risk factor for infection. Optimal infection prevention strategies await a more complete understanding of acquisition and transmission. To investigate possible transmission, we studied whether newly MSSA colonized infants share a strain with another contemporaneously colonized infant.MethodsThis is a prospective observational study in a level IV NICU from April through November 2019. Infants had weekly MSSA nasal surveillance cultures. Isolates from newly MSSA colonized infants and other infants colonized with MSSA during the same/previous week were subjected to staphylococcal protein A (spa) typing; most pairs with a concordant (CC) spa type were analyzed by whole genome sequencing (WGS; Illumina MiSeq). Pairs of isolates with a CC spa type and < 25 single nucleotide polymorphism differences on WGS were considered closely related (CC pairs). A control group consisted of pairs of isolates from a newly colonized infant with one randomly chosen colonized infant with a discordant (DC) spa type during the same/previous week. The medical records were reviewed for staff member (SM) and room assignment. Fischer’s exact test was used to compare proportions.ResultsIsolates from 60/68 consecutive newly MSSA colonized infants and 111/133 comparison infants were available for spa typing. Of these 60 infants, 23 (38 %) had a CC spa type with another infant colonized during the same/previous week. Of 18 isolate pairs from infants with a CC spa type that were subjected to WGS, 12 (67%) pairs of isolates were closely related. 7/12 (58 %) of CC pairs had a SM in common compared to 2/13 (15 %) in the DC pair groups, p=0.04. 2/12 (17 %) of CC pairs shared a room compared to 2/13 (15 %) pairs in the DC group, p=1.0.ConclusionAmong newly MSSA colonized infants at least 25% are colonized with an isolate closely related to that of another colonized infant indicating likely infant to infant transmission. WGS is more discriminatory than spa typing for MSSA. Given the lack of commonality of room assignment and the commonality of SM assignment, a possible role of healthcare personnel in MSSA transmission should be further investigated.Disclosures Anne-Catrin Uhlemann, MD, PhD, Merck (Grant/Research Support)

Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing

Machado-Joseph disease (MJD/SCA3) is a neurodegenerative polyglutamine disorder exhibiting a wide spectrum of phenotypes. The abnormal size of the (CAG)n at ATXN3 explains ~55% of the age at onset variance, suggesting the involvement of other factors, namely genetic modifiers, whose identification remains limited. Our aim was to find novel genetic modifiers, analyse their epistatic effects and identify disease-modifying pathways contributing to MJD variable expressivity. We performed whole-exome sequencing in a discovery sample of four age at onset concordant and four discordant first-degree relative pairs of Azorean patients, to identify candidate variants which genotypes differed for each discordant pair but were shared in each concordant pair. Variants identified by this approach were then tested in an independent multi-origin cohort of 282 MJD patients. Whole-exome sequencing identified 233 candidate variants, from which 82 variants in 53 genes were prioritized for downstream analysis. Eighteen disease-modifying pathways were identified; two of the most enriched pathways were relevant for the nervous system, namely the neuregulin signaling and the agrin interactions at neuromuscular junction. Variants at PARD3, NFKB1, CHD5, ACTG1, CFAP57, DLGAP2, ITGB1, DIDO1 and CERS4 modulate age at onset in MJD, with those identified in CFAP57, ACTG1 and DIDO1 showing consistent effects across cohorts of different geographical origins. Network analyses of the nine novel MJD modifiers highlighted several important molecular interactions, including genes/proteins previously related with MJD pathogenesis, namely between ACTG1/APOE and VCP/ITGB1. We describe novel pathways, modifiers, and their interaction partners, providing a broad molecular portrait of age at onset modulation to be further exploited as new disease-modifying targets for MJD and related diseases.

Fecal Microbiome and Metabolome Differ in Healthy and Food-Allergic Twins

In this study, the authors characterize fecal microbiomes to identify bacterial taxa and their products that may influence the expression of food allergies in children and adults.Participants included a cohort of 18 twin pairs across a broad age range, 13 of which were discordant twin pairs (one sibling had a food allergy and the other was healthy) and 5 of which were concordant twin pairs (both siblings had a food allergy).First, fecal samples were collected from the twin pairs who lived in the same household, in which they equally avoided the foods to which the affected twin was found to be allergic. 16S ribosomal RNA gene amplicon sequencing was performed on the fecal samples from the 12 discordant twin pairs and 5 concordant twin pairs, and the microbial composition between the twin pairs was compared. For each twin pair, the authors compared the relative abundance of operational taxonomic units (OTUs) and then calculated an OTU correlation score. Next, liquid chromatography-tandem mass spectrometry was used to measure the abundance of metabolic compounds in the same set of fecal samples. Finally, the authors compared the microbial taxa and their metabolites and correlated the data sets to identify any bacterial species or metabolites that may be mechanistically related to health.The healthy and allergic twins exhibited distinct fecal microbial profiles. A bacterial signature of 64 OTUs distinguished healthy from allergic twins; the OTUs enriched in the healthy twins were largely taxa from the Clostridia class. Healthy and allergic twins also exhibit differential enrichment in fecal metabolic pathways, most notably with the enrichment of diacylglycerol in healthy twins. Next, there was a significant association between healthy twins and Phascolarctobacterium faecium and Ruminococcus bromii. These are species from a taxon not previously associated with protection against allergies.Twin pairs exhibited significant differences in their fecal microbiomes and metabolomes through adulthood, suggesting that the gut microbiota may play a protective role in patients with food allergies beyond the infant stage.With this study, the authors are one of the first to offer unique insight into the fecal microbiome and metabolome in allergic and nonallergic patients. By identifying bacterial species and metabolites that may be mechanistically related to health, it may be possible in the future to integrate live microbiome-modulating biotherapies into the treatment of food allergies. Oral immunotherapy, which typically achieves only short-term desensitization and often is accompanied by gastrointestinal symptoms, can potentially be targeted with biotherapeutics to ultimately improve its efficacy and safety. Further investigation is warranted to determine if or how the identified metabolites contribute to protection against allergies.

The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites

White to brown/beige adipocytes conversion is a possible therapeutic strategy to tackle the current obesity epidemics. While mitochondria are key for energy dissipation in brown fat, it is unknown if they can drive adipocyte browning. Here, we show that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning. In two cohorts of patients with obesity, including weight discordant monozygotic twin pairs, adipose tissue OPA1 levels are reduced. In the mouse, Opa1 overexpression favours white adipose tissue expandability as well as browning, ultimately improving glucose tolerance and insulin sensitivity. Transcriptomics and metabolomics analyses identify the Jumanji family chromatin remodelling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning. Mechanistically, the higher cyclic adenosine monophosphate (cAMP) levels in Opa1 pre-adipocytes activate cAMP-responsive element binding protein (CREB), which transcribes urea cycle enzymes. Flux analyses in pre-adipocytes indicate that Opa1-dependent fumarate accumulation depends on the urea cycle. Conversely, adipocyte-specific Opa1 deletion curtails urea cycle and beige differentiation of pre-adipocytes, and is rescued by fumarate supplementation. Thus, the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning.