Putative Association Research Articles

A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs

In vitro secondary pharmacology assays are an important tool for predicting clinical adverse drug reactions (ADRs) of investigational drugs. We created the Secondary Pharmacology Database (SPD) by testing 1958 drugs using 200 assays to validate target-ADR associations. Compared to public and subscription resources, 95% of all and 36% of active (AC50 < 1 µM) results are unique to SPD, with bias towards higher activity in public resources. Annotating drugs with free maximal plasma concentrations, we find 684 physiologically relevant unpublished off-target activities. Furthermore, 64% of putative ADRs linked to target activity in key literature reviews are not statistically significant in SPD. Systematic analysis of all target-ADR pairs identifies several putative associations supported by publications. Finally, candidate mechanisms for known ADRs are proposed based on SPD off-target activities. Here we present a freely-available resource for benchmarking ADR predictions, explaining phenotypic activity and investigating clinical properties of marketed drugs.

Discovering Venom-Derived Drug Candidates Using Differential Gene Expression.

Venoms are a diverse and complex group of natural toxins that have been adapted to treat many types of human disease, but rigorous computational approaches for discovering new therapeutic activities are scarce. We have designed and validated a new platform-named VenomSeq-to systematically identify putative associations between venoms and drugs/diseases via high-throughput transcriptomics and perturbational differential gene expression analysis. In this study, we describe the architecture of VenomSeq and its evaluation using the crude venoms from 25 diverse animal species and 9 purified teretoxin peptides. By integrating comparisons to public repositories of differential expression, associations between regulatory networks and disease, and existing knowledge of venom activity, we provide a number of new therapeutic hypotheses linking venoms to human diseases supported by multiple layers of preliminary evidence.

Systematic Screening of Associations between Medication Use and Risk of Neurodegenerative Diseases Using a Mendelian Randomization Approach.

Systematically assessing the causal associations between medications and neurodegenerative diseases is significant in identifying disease etiology and novel therapies. Here, we investigated the putative causal associations between 23 existing medication categories and major neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). A two-sample mendelian randomization (MR) approach was conducted. Estimates were calculated using the inverse-variance weighted (IVW) method as the main model. A sensitivity analysis and a pleiotropy analysis were performed to identify potential violations. Genetically predisposition to antihypertensives (OR = 0.809, 95% CI = 0.668-0.981, p = 0.031), thyroid preparations (OR = 0.948, 95% CI = 0.909-0.988, p = 0.011), and immunosuppressants (OR = 0.879, 95% CI = 0.789-0.979, p = 0.018) was associated with a decreased risk of AD. Genetic proxies for thyroid preparations (OR = 0.934, 95% CI = 0.884-0.988, p = 0.017), immunosuppressants (OR = 0.825, 95% CI = 0.699-0.973, p = 0.022), and glucocorticoids (OR = 0.862, 95% CI = 0.756-0.983, p = 0.027) were causally associated with a decreased risk of PD. Genetically determined antithrombotic agents (OR = 1.234, 95% CI = 1.042-1.461, p = 0.015), HMG CoA reductase inhibitors (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005), and salicylic acid and derivatives (OR = 1.294, 95% CI = 1.078-1.553, p = 0.006) were associated with an increased risk of ALS. We presented a systematic view concerning the causal associations between medications and NDs, which will promote the etiology discovery, drug repositioning and patient management for NDs.

How does land-use change alter soil microbial diversity, composition, and network in subtropical China?

Soil microbial communities play essential roles in degraded soil ecosystems. The “emergent trait” indices (e.g., microbial biomass C and N, and enzyme activity) and specific soil microbiota associations have been intensively studied, but the responses of soil microbial composition and network complexities to land-use changes remain unclear. Using amplicon sequencing of 16S rRNA genes and internal transcribed spacer (ITS) regions, we assessed the response ratio of soil microbial genomic diversity, community structure, and network parameters to primary evergreen broadleaved forest (control) conversion to conifer plantations, orchards, sloping tillage, and paddy fields. Agricultural lands had a higher soil bacterial and lower fungal diversity than primary forest. Overall, primary forest conversion reduced microbial network complexity, except in the sloping tillage. Moreover, land-use changes shifted the microbial community composition by either decreasing or increasing the relative abundance of dominant and putative keystone associations. The mean response ratio (indicator response percentage to primary forest conversion) of the microbial index to the land-use change varied depending on the soil microbial alpha diversity, network topological parameters, and dominant and putative keystone associations. Alterations in soil microbial diversity, composition, and network complexity were related to reduced soil resource availability following land-use change. Our study suggested that primary forest conversion to agricultural lands did not always negatively influences soil microbial diversity, composition, network complexity, and putative keystone associations. In addition, specific soil microbial associations showed highly sensitive to land-use change.

Increased Binding of von Willebrand Factor to Sub-Endothelial Collagen May Facilitate Thrombotic Events Complicating Bothrops lanceolatus Envenomation in Humans.

Consumption coagulopathy and hemorrhagic syndrome exacerbated by blood anticoagulability remain the most important causes of lethality associated with Bothrops snake envenomation. Bothrops venom also engages platelet aggregation on the injured endothelium via von Willebrand factor (vWF) interactions. Besides platelet aggregation, some Bothrops venom toxins may induce qualitative thrombopathy, which has been in part related to the inhibition of vWF activation. We tested whether B. lanceolatus venom impaired vWF to collagen(s) binding (vWF:CB) activity. Experiments were performed with B. lanceolatus crude venom, in the presence or absence of Bothrofav, a monospecific B. lanceolatus antivenom. Venom of B. lanceolatus fully inhibited vWF to collagen type I and III binding, suggesting venom interactions with the vWF A3 domain. In contrast, B. lanceolatus venom increased vWF to collagen type VI binding, suggesting the enhancement of vWF binding to collagen at the vWF A1 domain. Hence, B. lanceolatus venom exhibited contrasting in vitro effects in terms of the adhesive properties of vWF to collagen. On the other hand, the antivenom Bothrofav reversed the inhibitory effects of B. lanceolatus venom on vWF collagen binding activity. In light of the respective distribution of collagen type III and collagen type VI in perivascular connective tissue and the sub-endothelium, a putative association between an increase in vWF:CB activity for collagen type VI and the onset of thrombotic events in human B. lanceolatus envenomation might be considered.

Genetic evidence for the causal linkage between telomere length and aortic aneurysm risk: A Mendelian randomisation study.

Evidence of a clear causal relationship between telomere length and aortic aneurysms is limited by the potential for confounding or reverse causation effects. In this study, we used a Mendelian randomisation (MR) approach to investigate this putative causal association. In total, 118 telomere length-associated single-nucleotide polymorphisms, identified in 472,174 individuals of European ancestry, were used as the instrumental variables. Summary statistics for genome-wide association studies of aortic aneurysms were obtained from the FinnGen consortium. For the primary MR analyses, the inverse-variance weighted random-effects method was used and was supplemented with multivariable MR, weighted median and MR-Egger approaches. The MR-Egger intercept test, Cochran's Q test and 'leave-one-out' sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneity and stability of the genetic variants. Forward and reverse MR analyses were performed. All forward univariable MR analyses showed that longer telomere lengths decreased aortic aneurysm risks (total aortic aneurysms: OR = 0.80, 95% CI 0.67-0.96, p = .015; thoracic aortic aneurysms: OR = 0.82, 95% CI 0.68-0.98, p = .026; abdominal aortic aneurysms: OR = 0.525, 95% CI 0.398-0.69, p < .001), whereas all reverse MR analyses suggested the absence of aortic aneurysm liability on telomere length. The sensitivity analysis results were robust, and no evidence of horizontal pleiotropy was observed. Our results support a possible causal association between telomere length and aortic aneurysms, providing new insights into the involvement of telomere biology in this condition and offering a potential avenue for targeted therapeutic interventions.

Clonostachys rosea ‘omics profiling: identification of putative metabolite-gene associations mediating its in vitro antagonism against Fusarium graminearum

BackgroundClonostachys rosea is an established biocontrol agent. Selected strains have either mycoparasitic activity against known pathogens (e.g. Fusarium species) and/or plant growth promoting activity on various crops. Here we report outcomes from a comparative ‘omics analysis leveraging a temporal variation in the in vitro antagonistic activities of C. rosea strains ACM941 and 88–710, toward understanding the molecular mechanisms underpinning mycoparasitism.ResultsTranscriptomic data highlighted specialized metabolism and membrane transport related genes as being significantly upregulated in ACM941 compared to 88–710 at a time point when the ACM941 strain had higher in vitro antagonistic activity than 88–710. In addition, high molecular weight specialized metabolites were differentially secreted by ACM941, with accumulation patterns of some metabolites matching the growth inhibition differences displayed by the exometabolites of the two strains. In an attempt to identify statistically relevant relationships between upregulated genes and differentially secreted metabolites, transcript and metabolomic abundance data were associated using IntLIM (Integration through Linear Modeling). Of several testable candidate associations, a putative C. rosea epidithiodiketopiperazine (ETP) gene cluster was identified as a prime candidate based on both co-regulation analysis and transcriptomic-metabolomic data association.ConclusionsAlthough remaining to be validated functionally, these results suggest that a data integration approach may be useful for identification of potential biomarkers underlying functional divergence in C. rosea strains.

Cuproptosis engages in c-Myc-mediated breast cancer stemness

BackgroundIntra-tumoral heterogeneity (ITH) is a distinguished hallmark of cancer, and cancer stem cells (CSCs) contribute to this malignant characteristic. Therefore, it is of great significance to investigate and even target the regulatory factors driving intra-tumoral stemness. c-Myc is a vital oncogene frequently overexpressed or amplified in various cancer types, including breast cancer. Our previous study indicated its potential association with breast cancer stem cell (BCSC) biomarkers.MethodsIn this research, we performed immunohistochemical (IHC) staining on sixty breast cancer surgical specimens for c-Myc, CD44, CD24, CD133 and ALDH1A1. Then, we analyzed transcriptomic atlas of 1533 patients with breast cancer from public database.ResultsIHC staining indicated the positive correlation between c-Myc and BCSC phenotype. Then, we used bioinformatic analysis to interrogate transcriptomics data of 1533 breast cancer specimens and identified an intriguing link among c-Myc, cancer stemness and copper-induced cell death (also known as “cuproptosis”). We screened out cuproptosis-related characteristics that predicts poor clinical outcomes and found that the pro-tumoral cuproptosis-based features were putatively enriched in MYC-targets and showed a significantly positive correlation with cancer stemness.ConclusionIn addition to previous reports on its oncogenic roles, c-Myc showed significant correlation to stemness phenotype and copper-induced cell toxicity in breast cancer tissues. Moreover, transcriptomics data demonstrated that pro-tumoral cuproptosis biomarkers had putative positive association with cancer stemness. This research combined clinical samples with large-scale bioinformatic analysis, covered description and deduction, bridged classic oncogenic mechanisms to innovative opportunities, and inspired the development of copper-based nanomaterials in targeting highly heterogeneous tumors.

O-119 Time-lapse comprehensive portrait of cytoplasmic strings appearing during blastulation: prevalence and implications for embryo assessment.

Abstract Study question What are the prevalence and implications of cytoplasmic strings (Cyt-S) in preimplantation development after blastulation? Summary answer Cyt-S are common in human embryos and are associated with faster blastocyst development, larger expansion, and better morphological quality. What is known already Cyt-S are dynamic cellular projections connecting inner-cell-mass (ICM) and trophectoderm during blastocyst expansion. Their prevalence in human embryos in vitro has been estimated 44-93%. Currently, their role is unknown. Studies in animal models suggested they might be involved in ICM-to-trophectoderm communication or cell fate-related events. Nevertheless, comprehensive descriptions and clear definitions, evidence-based hypotheses about their function, and data about their clinical implications are lacking, limited or controversial. Here we leveraged time-lapse microscopy, artificial intelligence, and chromosomal testing to comprehensively portray these common features of blastulation and expansion processes. Study design, size, duration Observational study involving 124 PGT-A cycles in EmbryoScope (Vitrolife) with ≥1 blastocyst (N = 315) between May-2013 and November-2014. Timings from tSB to biopsy (t-biopsy, i.e., blastocyst full-expansion) in hours-post-insemination (hpi) and embryo area (including zona-pellucida in µm2) were automatically annotated through an AI-based software (CHLOE™, Fairtility). One senior embryologist annotated Cyt-S presence, number, timings, and type (thick cell-to-cell connections and/or threads), and blastocyst collapses (i.e., reduction of embryo area preventing the discrimination of ICM from trophectoderm). Participants/materials, setting, methods ICSI, continuous blastocyst culture (day 5-7) in time-lapse incubators, trophectoderm biopsy without zona-pellucida drilling on fully-expanded blastocysts, and qPCR to assess non-mosaic full-chromosome aneuploidies were all conducted. Blastocyst morphological quality was defined according to Gardner’s schemes as excellent (AA), good (AB,BA), average (BB,AC,CA) and poor (CC,BC,CB). Only vitrified-warmed euploid single-embryo-transfers were performed. Along with developmental timings, extent of expansion and morphological quality, we also assessed euploidy and live-birth rates in blastocysts with and without Cyt-S. Main results and the role of chance 94.4% of the patients (N = 117/124) had ≥1 embryo with Cyt-S (mean:2.2±1.6, range:0-9). 86% of all blastocysts analyzed (N = 271/315) had ≥1 Cyt-S (3.5±2.1, 1-13; duration of the longest Cyt-S: 5.8±3.4 hours, 0.5-20.9). Overall, we analyzed 937 Cyt-S detected at 117.3±11.8 hpi (85.7-160.5) and lasting 3.8±2.7 hours (0.2-20.9). The first Cyt-S of each embryo lasted longer (4.4±3.2 hours) compared to the following (≈3 hours or less). Cyt-S were mostly threads (N = 133/271, 54.2%) or thick cell-to-cell connections becoming threads (N = 382/937, 40.8%) than connections of constant diameter (N = 47/937, 5%). Of the 271 embryos with ≥1 Cyt-S, 71.9% showed these projections only during early expansion processes after tSB (N = 195; 3.0±1.6, 1-10), 7.7% only after collapses (N = 21; 2.6±1.5, 1-6), and 20.3% both in early expansion and after collapses (N = 55; 2.3±1.3 and 3.2±2.4, 1-11 respectively). Poor- versus excellent-quality blastocysts (N = 54/75, 72% versus N = 120/129, 93%, multivariate-OR=0.32, 95%CI 0.11-0.92, adjusted-p=0.03), t-biopsy (multivariate-OR=0.97, 95%CI 0.95-0.99, p = 0.05) and blastocyst area at t-biopsy (multivariate-OR=1.1, 95%CI 1.01-1.18, p = 0.02) were all associated with the prevalence of embryos with Cyt-S. Lastly, while euploidy rates were comparable between blastocysts with and without Cyt-S, an association instead was shown with live-birth-rates per vitrified-warmed euploid transfers (N = 34/77, 44.2% versus N = 0/10, 0%; p &amp;lt; 0.01), although these data are very preliminary. Limitations, reasons for caution Some Cyt-S after collapses might correspond to connections already present before these events. Larger datasets are required to confirm putative associations between Cyt-S and clinical outcomes. Only associations could be reported here, but not causations/consequences. Specific basic research studies are required to this end Wider implications of the findings Embryos with ≥1 Cyt-S were faster in reaching all blastocyst timings (tSB to t-biopsy) and to expand, achieved a larger area at t-biopsy and had a better morphology. These dynamic features of blastocyst expansion might be physiological and represent biomarkers of embryo quality. Nevertheless, their function is yet unknown Trial registration number not applicable

Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.

Maternal High-Fat Diet Results in Long-Term Sex-Specific Alterations to Metabolic and Gut Microbial Diurnal Oscillations in Adult Offspring.

Circadian rhythms profoundly impact metabolism and the gut microbiota. A maternal high-fat diet (HFD) exerts effects on the metabolic syndrome of adult offspring in a sex-specific manner, the underlying mechanisms, however, remain unclear. Female mice are fed an HFD and raise their offspring on a standard chow diet until 24 weeks. The glucose tolerance, insulin sensitivity, and diurnal rhythms of serum metabolic profiles are assessed in male and female adult offspring. Simultaneously, 16S rRNA is applied to characterize gut microbiota diurnal rhythms. The study finds that maternal HFD tends to deteriorate glucose tolerance and impairs insulin sensitivity in male offspring, but not female offspring, which can be associated with the circadian alterations of serum metabolic profiles in male offspring. As expected, maternal HFD sex-specifically alters diurnal rhythms of the gut microbiota, which exhibits putative associations with metabolic profiles in males. The presentstudy identifies the critical role of gut microbiota diurnal rhythms in triggering sex-biased metabolic diurnal rhythms in response to maternal HFD, at least in part. As early life may be a critical window for preventing metabolic diseases, these findings provide the basis for developing chronobiology applications targeting the gut microbiota to combat early metabolic alterations, especially in males.

Emergence of novel genomic regulatory regions associated with light-organ development in the bobtail squid

Light organs (LO) with symbiotic bioluminescent bacteria are hallmarks of many bobtail squid species. These organs possess structural and functional features to modulate light, analogous to those found in coleoid eyes. Previous studies identified four transcription factors and modulators (SIX, EYA, PAX6, DAC) associated with both eyes and light organ development, suggesting co-option of a highly conserved gene regulatory network. Using available topological, open chromatin, and transcriptomic data, we explore the regulatory landscape around the four transcription factors as well as genes associated with LO and shared LO/eye expression. This analysis revealed several closely associated and putatively co-regulated genes. Comparative genomic analyses identified distinct evolutionary origins of these putative regulatory associations, with the DAC locus showing a unique topological and evolutionarily recent organization. We discuss different scenarios of modifications to genome topology and how these changes may have contributed to the evolutionary emergence of the light organ.

Endogenous viral elements reveal associations between a non-retroviral RNA virus and symbiotic dinoflagellate genomes

Endogenous viral elements (EVEs) offer insight into the evolutionary histories and hosts of contemporary viruses. This study leveraged DNA metagenomics and genomics to detect and infer the host of a non-retroviral dinoflagellate-infecting +ssRNA virus (dinoRNAV) common in coral reefs. As part of the Tara Pacific Expedition, this study surveyed 269 newly sequenced cnidarians and their resident symbiotic dinoflagellates (Symbiodiniaceae), associated metabarcodes, and publicly available metagenomes, revealing 178 dinoRNAV EVEs, predominantly among hydrocoral-dinoflagellate metagenomes. Putative associations between Symbiodiniaceae and dinoRNAV EVEs were corroborated by the characterization of dinoRNAV-like sequences in 17 of 18 scaffold-scale and one chromosome-scale dinoflagellate genome assembly, flanked by characteristically cellular sequences and in proximity to retroelements, suggesting potential mechanisms of integration. EVEs were not detected in dinoflagellate-free (aposymbiotic) cnidarian genome assemblies, including stony corals, hydrocorals, jellyfish, or seawater. The pervasive nature of dinoRNAV EVEs within dinoflagellate genomes (especially Symbiodinium), as well as their inconsistent within-genome distribution and fragmented nature, suggest ancestral or recurrent integration of this virus with variable conservation. Broadly, these findings illustrate how +ssRNA viruses may obscure their genomes as members of nested symbioses, with implications for host evolution, exaptation, and immunity in the context of reef health and disease.

Birth order, sibship size, and risk of atopic dermatitis, food allergy, and atopy: A systematic review and meta‐analysis

AbstractBackgroundAtopic dermatitis and food allergy are two frequently concomitant manifestations of the presence of atopy. A substantial number of studies have been published on the association of birth order and sibship size (number of siblings) with atopic dermatitis, food allergy, and atopy. The present work is the first systematic synthesis of the existing literature on this topic.MethodsFifteen databases were searched. Screening, data extraction, and quality assessment were performed by independent pairs. Comparable numerical data were statistically synthesized using random‐effects robust variance estimation.ResultsIn total, 114 studies were included out of 8819 papers obtained from database searches. Birth order ≥2 versus 1 was associated with lower risk of ever atopic dermatitis (pooled risk ratio [RR] 0.91, 95% CI 0.84–0.98), current food allergy (RR 0.77, 95% CI 0.66–0.90), and positive skin prick test (SPT) to common aeroallergens (RR 0.86, 95% CI 0.77–0.97). Sibship size ≥2 versus 1 was associated with decreased risk of current atopic dermatitis (RR 0.90, 95% CI 0.83–0.98), ever atopic dermatitis (RR 0.92, 95% CI 0.86–0.97), and positive SPT to common aeroallergens (RR 0.88, 95% CI 0.83–0.92). No putative associations were seen regarding atopy assessed through allergen‐specific immunoglobulin E with common allergens.ConclusionThe presence of siblings and being second‐born or later may decrease the lifetime risk of atopic dermatitis and food allergy, albeit marginally. Similar association was seen with SPT sensitization. However, significant protection was not found for IgE sensitization.

ARTERIAL STIFFNESS IS A DETERMINANT OF THE WHITE-COAT EFFECT IN YOUNG SUBJECTS IN THE INITIAL STAGES OF HYPERTENSION

Objective: The white-coat effect (WCE) evaluated from the difference between office and ambulatory blood pressure (BP) is often pronounced in young hypertensive subjects chiefly in people with isolated systolic hypertension (ISHY). The WCE in this setting is considered to merely reflect the alarm reaction to doctor's visit and to be a benign phenomenon. However, the WCE might be amplified in subjects with stiffer arteries. The aim of this study was to investigate whether the WCE in the young is influenced by individual vascular characteristics and whether this putative association may differ according to hypertension subtype. Design and method: We examined 371 young-to middle age participants (mean age 31.1±8.7 years, 74.7% males). BP phenotypes were identified using ambulatory BP with a 24-hour BP cut-off of 130/80 mmHg. ISHY was present in 24.2 % of participants, isolated diastolic hypertension in 20.0%, systolic-diastolic hypertension in 30.1%, and normotension in 25.7%. Vascular stiffness was assessed by radial-carotid pulse wave velocity (PWV) and vascular compliance by radial tonometry. 24-hour urinary catecholamines were measured with HPLC in 101 participants. The association of WCE with arterial functional indexes was assessed with multivariable linear regression analysis controlling for ambulatory BP. Improvement in the models was expressed by the difference in the Akaike index(↗ AIC) Results: In the whole group, PWV was a significant predictors of the WCE with a ↗AIC of 9.9 (p = 0.001). In addition, a negative association was found between the WCE and large artery (p = 0.001) or small artery (p = 0.002) compliance. Twenty-four-hour urinary epinephrine and nor-epinephrine were totally unrelated to WCE. PWV was a significant predictor of the WCE also among the participants with ISHY with a ↗AIC of 8.2 (p = 0.002). This association was not present in the participants with isolated diastolic hypertension (p = 0.15) or systolic-diastolic hypertension (p = 0.28). Conclusions: These data indicate that arterial stiffness rather than sympatho-adrenergic activity is an important determinant of the surrogate measure of the WCE in young subjects in the initial stage of hypertension. This association was confirmed in the subgroup of participants with ISHY suggesting that in some individuals ISHY may not be a benign condition.

Differences in Telomere Length between Adolescent Females with Anorexia Nervosa Restricting Type and Anorexia Nervosa Binge-Purge Type.

Physiological and psychological distress may accelerate cellular aging, manifested by shortening of telomere length (TL). The present study focused on TL shortening in anorexia nervosa (AN), an illness combining physiological and psychological distress. For that purpose, we measured TL in 44 female adolescents with AN at admission to inpatient treatment, in a subset of 18 patients also at discharge, and in 22 controls. No differences in TL were found between patients with AN and controls. At admission, patients with AN-binge/purge type (AN-B/P; n = 18) showed shorter TL compared with patients with AN-restricting type (AN-R; n = 26). No change in TL was found from admission to discharge, despite an improvement in body mass index standard deviation score (BMI-SDS) following inpatient treatment. Older age was the only parameter assessed to be correlated with greater TL shortening. Several methodological changes have to be undertaken to better understand the putative association of shorter TL with B/P behaviors, including increasing the sample size and the assessment of the relevant pathological eating disorder (ED) and non-ED psychological correlates in the two AN subtypes.

Capturing species‐wide diversity of the gut microbiota and its relationship with genomic variation in the critically endangered kākāpō

AbstractGut microbiota play an essential role in host health with important implications for conservation management of threatened wildlife. While factors such as diet, medication and habitat are known to shape the microbiota, our understanding of the entirety of factors, including the complex role of host genomic background, remains incomplete. Our research on the interaction between the host genome and gut microbiota of the critically endangered kākāpō (Strigops habroptilus), a flightless parrot endemic to Aotearoa New Zealand, represents, to our knowledge, one of the most comprehensive studies of the gastrointestinal bacterial diversity and its relationship with host genomic diversity for virtually an entire threatened species. We conducted a 16S rRNA gene‐based analysis of faecal samples representing the gut microbiota for 84% of kākāpō. This survey was leveraged with exceptional metadata to tease apart the impact of host genomic diversity and factors including sex, age, diet, antibiotics, disease, habitat and sampling date on the kākāpō gut microbiota. We find evidence of a highly polygenic genomic architecture of the gut microbiota and identify putative associations between bacterial diversity and functional pathways related to intestinal homeostasis, inflammation, immunity and metabolism. This improved understanding of the kākāpō gut microbiota—and its relationship with host genomics—can directly benefit kākāpō conservation by providing new insights into the role of the gut microbiome in kākāpō health and disease mitigation. Overall, we anticipate that an integration of microbiome studies in conservation research and management will improve our understanding and realisation of the One Health concept.

Opening the black box: why do euploid blastocysts fail to implant? A systematic review and meta-analysis.

A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo implantation. Yet, its positive predictive value is not higher than 50-60%. This gap of knowledge on the causes of euploid blastocysts' reproductive failure is known as 'the black box of implantation'. Several embryonic, maternal, paternal, clinical, and IVF laboratory features were scrutinized for their putative association with reproductive success or implantation failure of euploid blastocysts. A systematic bibliographical search was conducted without temporal limits up to August 2021. The keywords were '(blastocyst OR day5 embryo OR day6 embryo OR day7 embryo) AND (euploid OR chromosomally normal OR preimplantation genetic testing) AND (implantation OR implantation failure OR miscarriage OR abortion OR live birth OR biochemical pregnancy OR recurrent implantation failure)'. Overall, 1608 items were identified and screened. We included all prospective or retrospective clinical studies and randomized-controlled-trials (RCTs) that assessed any feature associated with live-birth rates (LBR) and/or miscarriage rates (MR) among non-mosaic euploid blastocyst transfer after TE biopsy and PGT-A. In total, 41 reviews and 372 papers were selected, clustered according to a common focus, and thoroughly reviewed. The PRISMA guideline was followed, the PICO model was adopted, and ROBINS-I and ROB 2.0 scoring were used to assess putative bias. Bias across studies regarding the LBR was also assessed using visual inspection of funnel plots and the trim and fill method. Categorical data were combined with a pooled-OR. The random-effect model was used to conduct the meta-analysis. Between-study heterogeneity was addressed using I2. Whenever not suitable for the meta-analysis, the included studies were simply described for their results. The study protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42021275329). We included 372 original papers (335 retrospective studies, 30 prospective studies and 7 RCTs) and 41 reviews. However, most of the studies were retrospective, or characterized by small sample sizes, thus prone to bias, which reduces the quality of the evidence to low or very low. Reduced inner cell mass (7 studies, OR: 0.37, 95% CI: 0.27-0.52, I2 = 53%), or TE quality (9 studies, OR: 0.53, 95% CI: 0.43-0.67, I2 = 70%), overall blastocyst quality worse than Gardner's BB-grade (8 studies, OR: 0.40, 95% CI: 0.24-0.67, I2 = 83%), developmental delay (18 studies, OR: 0.56, 95% CI: 0.49-0.63, I2 = 47%), and (by qualitative analysis) some morphodynamic abnormalities pinpointed through time-lapse microscopy (abnormal cleavage patterns, spontaneous blastocyst collapse, longer time of morula formation I, time of blastulation (tB), and duration of blastulation) were all associated with poorer reproductive outcomes. Slightly lower LBR, even in the context of PGT-A, was reported among women ≥38 years (7 studies, OR: 0.87, 95% CI: 0.75-1.00, I2 = 31%), while obesity was associated with both lower LBR (2 studies, OR: 0.66, 95% CI: 0.55-0.79, I2 = 0%) and higher MR (2 studies, OR: 1.8, 95% CI: 1.08-2.99, I2 = 52%). The experience of previous repeated implantation failures (RIF) was also associated with lower LBR (3 studies, OR: 0.72, 95% CI: 0.55-0.93, I2 = 0%). By qualitative analysis, among hormonal assessments, only abnormal progesterone levels prior to transfer were associated with LBR and MR after PGT-A. Among the clinical protocols used, vitrified-warmed embryo transfer was more effective than fresh transfer (2 studies, OR: 1.56, 95% CI: 1.05-2.33, I2 = 23%) after PGT-A. Lastly, multiple vitrification-warming cycles (2 studies, OR: 0.41, 95% CI: 0.22-0.77, I2 = 50%) or (by qualitative analysis) a high number of cells biopsied may slightly reduce the LBR, while simultaneous zona-pellucida opening and TE biopsy allowed better results than the Day 3 hatching-based protocol (3 studies, OR: 1.41, 95% CI: 1.18-1.69, I2 = 0%). Embryo selection aims at shortening the time-to-pregnancy, while minimizing the reproductive risks. Knowing which features are associated with the reproductive competence of euploid blastocysts is therefore critical to define, implement, and validate safer and more efficient clinical workflows. Future research should be directed towards: (i) systematic investigations of the mechanisms involved in reproductive aging beyond de novo chromosomal abnormalities, and how lifestyle and nutrition may accelerate or exacerbate their consequences; (ii) improved evaluation of the uterine and blastocyst-endometrial dialogue, both of which represent black boxes themselves; (iii) standardization/automation of embryo assessment and IVF protocols; (iv) additional invasive or preferably non-invasive tools for embryo selection. Only by filling these gaps we may finally crack the riddle behind 'the black box of implantation'.

The Effect of Dehydroepiandrosterone Administration during Rehabilitation on White Matter Integrity Among Individuals With Polysubstance Use Disorder.

Individuals with polysubstance use disorder (pSUD) exhibit vulnerability to relapse even after prolonged abstinence, with rehabilitation efforts achieving limited success. Previous studies highlighted dehydroepiandrosterone (DHEA) as a putative therapeutic agent that may aid rehabilitation, potentially by impacting white matter (WM) properties. The current study tested, for the first time, the effect of DHEA administration during rehabilitation on WM integrity among pSUD individuals, while assessing its putative association with long-term relapse rates. Immediately after admission to rehabilitation, 30 pSUD individuals were assigned to receive either placebo or DHEA (100 mg) daily for 3 months, via a randomized double-blind counterbalanced design. Participants also provided blood samples to assess circulating DHEA levels at treatment initiation and completed a diffusion tensor imaging (DTI) scan approximately 1 month after treatment initiation. Clinical status was evaluated 16 months after treatment initiation. Thirty matched healthy controls also underwent a DTI scan without any intervention. DHEA administration was not associated with reduced relapse rates compared with placebo. Nevertheless, exploratory analysis revealed that DHEA was associated with successful rehabilitation among pSUD individuals with low circulating DHEA levels at treatment initiation. White matter integrity in the splenium corpus callosum (CC) was reduced in pSUD individuals compared with healthy controls, yet pSUD individuals receiving DHEA exhibited recovery of splenium CC WM integrity. DHEA administration during rehabilitation may restore WM integrity in the CC among pSUD individuals. Although DHEA was not associated with reduced relapse rates in here, its therapeutic efficacy may depend on circulating DHEA levels at treatment initiation.

Cataracts in Havanese: genome wide association study reveals two loci associated with posterior polar cataract

BackgroundCataract is considered an important health issue in Havanese, and studies indicate a breed predisposition. Possible consequences of cataracts include lens induced uveitis, reduced eyesight, and blindness in severe cases. Reducing the prevalence of cataracts could therefore improve health and welfare significantly. The most frequently diagnosed forms of cataract in Havanese are cortical- and anterior suture line cataract, but cases of posterior polar cataract are also regularly reported. Out of the three, posterior polar- and cortical cataracts are considered the most clinically relevant.ResultsWe performed a genome wide association study that included 57 controls and 27 + 23 + 7 cases of cortical-, anterior suture line- and posterior polar cataract, respectively. An association analysis using a mixed linear model, revealed two SNPs on CFA20 (BICF2S23632983, p = 7.2e-09) and CFA21 (BICF2G630640490, p = 3.3e-09), that were significantly associated with posterior polar cataract, both of which are linked to relevant candidate genes. The results suggest that the two variants are linked to alleles with large effects on posterior polar cataract formation, possibly in a dominant fashion, and identifies regions that should be subject to further sequencing.Promising regions on CFA4 and CF30 were also identified in the association analysis of cortical cataract. The top SNPs on each chromosome, chr4_12164500 (p = 4.3e-06) and chr30_28836339 (p = 5.6e-06), are located within, or in immediate proximity to, potential cataract candidate genes.The study shows that age at examination is strongly associated with sensitivity of cataract screening. Havanese in Norway are on average 3.4 years old when eye examinations are performed: an age where most dogs that are genetically at risk have not yet developed clinically observable changes. Increasing the average age of breeding animals could increase accuracy of selection, leading to improved health.ConclusionsThe study identified two loci, on CFA20 and CFA21, that were significantly associated with posterior polar cataract in Havanese. SNPs that showed putative association with cortical cataracts, were observed on CFA4 and CFA30. All the top SNPs are located in close proximity to cataract candidate genes. The study also show that sensitivity of cataract screening is highly dependent on age at examination.