Urinary metabolomics reveals potential biomarkers for early detection of pregnancy in Mithun (Bos frontalis) cows.

The present study investigated the urinary metabolic profiles of early pregnant and non-pregnant Mithun to identify potential pregnancy detection biomarkers. Urine samples were collected on days 0, 10, 18, 35 and 45 of gestation from pregnant (n = 6) and on days 0, 10 and 18 from non-pregnant (n = 6) Mithun. Urinary metabolites were assessed using proton nuclear magnetic resonance (1H NMR) spectroscopy and identified 270 metabolites. Statistical analyses demonstrated pronounced distinctions in metabolite profiles between pregnant and non-pregnant samples. Twenty-five metabolites that could discriminate between pregnant and non-pregnant Mithun based on Variable Importance in Projection (VIP) scores >1 were identified. Upon further examination of six metabolites (kynurenine, kynurenate, 3-hydroxykynurenine, quinolinate, tyrosine and leucine) identified with high VIP scores, ROC curve analyses demonstrated their significant predictive potential, with AUC values ranging between 0.50 and 0.85. Additionally, a combined panel of top 25 metabolites yielded an AUC value of 0.85. Pathway analysis identified seven potential metabolic pathway modulations during early gestation, with particular emphasis on phenylalanine, tyrosine and tryptophan biosynthesis, tryptophan pathway and pathways involved in the metabolism of various amino acids. In conclusion, kynurenine, kynurenate, 3-hydroxykynurenine, quinolinate, tyrosine, and leucine show promise as non-invasive urinary biomarkers for early pregnancy detection in Mithun. SIGNIFICANCE: This study presents the first report on the metabolic profile of urine from early pregnant and non-pregnant Mithun (Bos frontalis). The metabolites like kynurenine and its derivatives (kynurenate, 3-hydroxykynurenine and quinolinate), tyrosine and leucine were documented signature urinary metabolites associated with early pregnancy in Mithun. The identified combination of metabolites holds promise as predictive biomarkers for non-invasive urinary-based early pregnancy diagnostics in Mithun. In addition, this study identified changes in metabolic pathways that involve phenylalanine, tyrosine, tryptophan and related amino acids and biomarkers identified were either precursors or products within these metabolic pathways.

Care-seeking for difficulties conceiving in sub-Saharan Africa: findings from population-based surveys in eight geographies.

STUDY QUESTION: What is the nature of women's care-seeking for difficulties conceiving in sub-Saharan Africa (SSA), including the correlates of seeking biomedical infertility care at a health facility? SUMMARY ANSWER: Care-seeking for difficulties getting pregnant was low, much of which involved traditional or religious sources of care, with evidence of sociodemographic disparities in receipt of biomedical care. WHAT IS KNOWN ALREADY: Nearly all research on infertility care-seeking patterns in SSA is limited to clinic-based studies among the minority of people in these settings who obtain facility-based services. In the absence of population-based data on infertility care-seeking, we are unable to determine the demand for services and disparities in the use of more effective biomedical sources of care. STUDY DESIGN, SIZE, DURATION: We used cross-sectional, population-based data from the Performance Monitoring for Action (PMA) female survey in eight geographies in SSA, including nationally representative data from Burkina Faso, Côte d'Ivoire, Kenya, and Uganda and regionally representative data from two provinces in the Democratic Republic of the Congo (DRC) (Kinshasa and Kongo Central) and two states in Nigeria (Kano and Lagos). We employed a multi-stage cluster random sampling design with probability proportional to size selection of clusters within each geography to produce representative samples of women aged 15-49. Samples ranged from 1144 in Kano, Nigeria, to 9489 in Kenya. PMA collected these data between November 2021 and December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: We restricted the sample to women who had ever had sex, with analytic samples ranging from 854 in Kano to 8,059 in Kenya, then conducted descriptive and bivariable analyses to examine characteristics of those who sought care for difficulties getting pregnant. Among those who reported seeking care, we conducted bivariable and multivariable logistic regression analyses to determine factors associated with receipt of biomedical services from a health facility. All analyses were conducted separately by geography. MAIN RESULTS AND THE ROLE OF CHANCE: Our study found low levels of care-seeking for difficulties getting pregnant among sexually active women in eight geographies in SSA, ranging from 3.7% (Kenya) to 15.3% (Côte d'Ivoire). Of this, 51.8% (Burkina Faso) to 86.7% (Kinshasa) involved receipt of biomedical services in health facilities. While many factors were consistently associated with infertility care-seeking from any source across geographies, factors associated with receipt of biomedical care specifically were less pronounced. This may be a result of the highly limited sources of infertility services in SSA; thus, even privileged groups may struggle to obtain effective treatment for difficulties getting pregnant. However, we did observe disparities in biomedical care-seeking in our bivariable results in several geographies, with the wealthiest women, those with more education, and those residing in urban areas generally more likely to have sought biomedical care for difficulties getting pregnant. LIMITATIONS, REASONS FOR CAUTION: Our data lacked details on the nature of the services received and outcomes, and we do not have information on reasons why women chose the sources they did. Small samples of women who sought care limited our power to detect significant differences in care-seeking by women's characteristics in several geographies. WIDER IMPLICATIONS OF THE FINDINGS: Infertility and access to appropriate treatment are issues of reproductive health and human rights. While our results do not indicate to what extent use of non-biomedical sources of care is driven by preferences, cost, or lack of accessible services, it is clear from our results and existing literature that more needs to be done to ensure access to affordable, quality, cost-effective infertility services in SSA. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Bill & Melinda Gates Foundation (INV009639) and the National Institute of Child Health and Human Development (K01HD107172). The funders were not involved in the study design, analyses, manuscript writing, or the decision to publish. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Domitiuslusitanicus (Araneae, Nesticidae) - an umbrella species for the conservation of troglobionts in the Estremenho Karst Massif, Portugal.

Background: Domitiuslusitanicus (Fage, 1931) is a troglobiont spider, endemic from caves in the largest karst massif in Portugal, the Estremenho. It was the first described cave-adapted species from Portugal, but the male of the species was only described in 1988. New information: Over the last two decades, the knowledge on the distribution of D.lusitanicus increased significantly. We assess the conservation status of D.lusitanicus, providing new information on its extent of occurrence and the anthropogenic threats and present a IUCN Red List profile. D.lusitanicus faces various anthropogenic threats, such as habitat loss, agriculture, pollution and tourism impacts. Despite a large part of its distribution is included in a Natural Park, it expands outside of the areas deemed for protection in the Natura 2000 network. This species has the widest spread distribution of all troglobionts in the Estremenho Massif; therefore, it may be used as an umbrella species for the protection of other cave-adapted species of invertebrates of the massif.

Optimization of pyrazolopyridine 4-carboxamides with potent antimalarial activity for which resistance is associated with the P. falciparum transporter ABCI3.

Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7'-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.

Is it possible that menopause is associated with telomere length? Findings of an integrative review.

OBJECTIVE: Knowing the important repercussions of menopause for women's health and that female longevity can be better understood through studies based on aging biomarkers, studies on the relationship between menopause and telomere shortening may help to better understand this stage of life. This study aimed to analyze what research has been produced regarding the relationship between menopause and telomere length. METHODS: This integrative literature review included searches in PubMed, CINAHL, LILACS, Web of Science and Scopus databases. Four studies were selected for the final sample. RESULTS: The findings of these studies indicate that older age for menopause and longer reproductive life (difference between age at menopause and menarche) are associated with longer telomeres, that is, with longevity. CONCLUSION: The relationship between menopause and telomere length is uncertain. The small number of studies included in this review, and the fact that the results indicate that the relationship between menopause and telomere length may be dependent on the stage of the menopause and race/ethnicity, suggest that additional research focusing on these variables should be carried out.

Temporary omission of oral anticoagulation in atrial fibrillation patients undergoing percutaneous coronary intervention: rationale and design of the WOEST-3 randomised trial.

The optimal antithrombotic management of atrial fibrillation (AF) patients who require oral anticoagulation (OAC) undergoing percutaneous coronary intervention (PCI) remains unclear. Current guidelines recommend dual antithrombotic therapy (DAT; OAC plus P2Y12 inhibitor - preferably clopidogrel) after a short course of triple antithrombotic therapy (TAT; DAT plus aspirin). Although DAT reduces bleeding risk compared to TAT, this is counterbalanced by an increase in ischaemic events. Aspirin provides early ischaemic benefit, but TAT is associated with an increased haemorrhagic burden; therefore, we propose a 30-day dual antiplatelet therapy (DAPT; aspirin plus P2Y12 inhibitor) strategy post-PCI, temporarily omitting OAC. The study aims to compare bleeding and ischaemic risk between a 30-day DAPT strategy following PCI and a guideline-directed therapy in AF patients requiring OAC. WOEST-3 (ClinicalTrials.gov: NCT04436978) is an investigator-initiated, international, open-label, randomised controlled trial (RCT). AF patients requiring OAC who have undergone successful PCI will be randomised within 72 hours after PCI to guideline-directed therapy (edoxaban plus P2Y12 inhibitor plus limited duration of aspirin) or a 30-day DAPT strategy (P2Y12 inhibitor plus aspirin, immediately discontinuing OAC) followed by DAT (edoxaban plus P2Y12 inhibitor). With a sample size of 2,000 patients, this trial is powered to assess both superiority for major or clinically relevant non-major bleeding and non-inferiority for a composite of all-cause death, myocardial infarction, stroke, systemic embolism or stent thrombosis. In summary, the WOEST-3 trial is the first RCT temporarily omitting OAC in AF patients, comparing a 30-day DAPT strategy with guideline-directed therapy post-PCI to reduce bleeding events without hampering efficacy.

Impact of symptom duration and mechanical circulatory support on prognosis in cardiogenic shock complicating acute myocardial infarction.

BACKGROUND: Mortality rates in patients with cardiogenic shock complicating acute myocardial infarction (AMICS) remain high despite advancements in AMI care. Our study aimed to investigate the impact of prehospital symptom duration on the prognosis of AMICS patients and those receiving mechanical circulatory support (MCS). METHODS AND RESULTS: We conducted a retrospective cohort study with data registered in the Netherlands Heart Registration. A total of 1,363 patients with AMICS who underwent percutaneous coronary intervention between 2017 and 2021 were included. Patients presenting after out-of-hospital cardiac arrest were excluded. Most patients were male (68%), with a median age of 69 years (IQR 61-77), predominantly presenting with ST-elevation myocardial infarction (86%). The overall 30-day mortality was 32%. Longer prehospital symptom duration was associated with a higher 30-day mortality with the following rates: < 3 h, 26%; 3-6 h, 29%; 6-24 h, 36%; ≥ 24 h, 46%; p < 0.001. In a subpopulation of AMICS patients with MCS (n = 332, 24%), symptom duration of > 24 h was associated with significantly higher mortality compared to symptom duration of < 24 h (59% vs 45%, p = 0.029). Multivariate analysis identified > 24 h symptom duration, age and in-hospital cardiac arrest as predictors of 30-day mortality in MCS patients. CONCLUSION: Prolonged prehospital symptom duration was associated with significantly increased 30-day mortality in patients presenting with AMICS. In AMICS patients treated with MCS, a symptom duration of > 24 h was an independent predictor of poor survival. These results emphasise the critical role of early recognition and intervention in the prognosis of AMICS patients.

Deciphering molecular regulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) signalling networks in Oryza genus amid environmental stress.

The Oryza genus, containing Oryza sativa L., is quintessential to sustain global food security. This genus has a lot of sophisticated molecular mechanisms to cope with environmental stress, particularly during vulnerable stages like flowering. Recent studies have found key involvements and genetic modifications that increase resilience to stress, including exogenous application of melatonin, allantoin, and trehalose as well as OsSAPK3 and OsAAI1 in the genetic realm. Due to climate change and anthropogenic reasons, there is a rise in sea level which raises a concern of salinity stress. It is tackled through osmotic adjustment and ion homeostasis, mediated by genes like P5CS, P5CR, GSH1, GSH2, and SPS, and ion transporters like NHX, NKT, and SKC, respectively. Oxidative damage is reduced by a complex action of antioxidants, scavenging RONS. A complex action of genes mediates cold stress with studies highlighting the roles of OsWRKY71, microRNA2871b, OsDOF1, and OsICE1. There is a need to research the mechanism of action of proteins like OsRbohA in ROS control and the action of regulatory genes in stress response. This is highly relevant due to the changing climate which will raise a lot of environmental changes that will adversely affect production and global food security if certain countermeasures are not taken. Overall, this study aims to unravel the molecular intricacies of ROS and RNS signaling networks in Oryza plants under stress conditions, with the ultimate goal of informing strategies for enhancing stress tolerance and crop performance in this important agricultural genus.

Distribution and bioaccumulation status of polycyclic aromatic hydrocarbons (PAHs) in Veraval coastal waters using copepods as bio-indicators.

The study investigates the pollution characteristics of 16 priority PAHs, accumulated in copepods from a major fishing harbour and its adjacent coastal waters of Veraval, west coast of India. The total PAH accumulation is in the range of 922.16-27,807.49 ng g-1 dw, with the mean concentration of 5776.59 ng g-1 dw. High concentrations of PAHs were present in the copepod samples from inside the harbour. Notably, there was no significant correlation between the lipid content of copepods and the accumulation of PAHs. The molecular diagnostic ratio method (MDR) indicates that the PAH sources are petrogenic in origin, while principal component analysis (PCA) points to petroleum, coal combustion and vehicular emission sources. Total cancerous PAHs (C-PAHs) in the study area dominate by 40% of the total PAHs identified; moreover, the bioaccumulation factor (BAF) is very high in the offshore area, which is also a fishing ground. The global relevance and magnitude of the present study in the Veraval, one of the prime seafood exporting hubs in India, should be dealt with utmost avidity as the accumulation status of PAHs in the zooplankton has never been explored in the Indian coastal waters. Moreover, the current study gives the foremost data on the bioaccumulation status of PAHs in copepods from the tropical waters of India.

Structural Elucidation of a Metagenomic Urethanase and Its Engineering Towards Enhanced Hydrolysis Profiles.

While plastics like polyethylene terephthalate can already be degraded efficiently by the activity of hydrolases, other synthetic polymers like polyurethanes (PUs) and polyamides (PAs) largely resist biodegradation. In this study, we solved the first crystal structure of the metagenomic urethanase UMG-SP-1, identified highly flexible loop regions to comprise active site residues, and targeted a total of 20 potential hot spots by site-saturation mutagenesis. Engineering campaigns yielded variants with single mutations, exhibiting almost 3- and 8-fold improved activity against highly stable N-aryl urethane and amide bonds, respectively. Furthermore, we demonstrated the release of the corresponding monomers from a thermoplastic polyester-PU and a PA (nylon 6) by the activity of a single, metagenome-derived urethanase after short incubation times. Thereby, we expanded the hydrolysis profile of UMG-SP-1 beyond the reported low-molecular weight carbamates. Together, these findings promise advanced strategies for the bio-based degradation and recycling of plastic materials and waste, aiding efforts to establish a circular economy for synthetic polymers.

Search for Baryon Number Violation in Top Quark Production and Decay Using Proton-Proton Collisions at sqrt[s]=13 TeV.

A search is presented for baryon number violating interactions in top quark production and decay. The analysis uses data from proton-proton collisions at a center-of-mass energy of 13 TeV, collected with the CMS detector at the LHC with an integrated luminosity of 138 fb^{-1}. Candidate events are selected by requiring two oppositely charged leptons (electrons or muons) and exactly one jet identified as originating from a bottom quark. Multivariate discriminants are used to separate the signal from the background. No significant deviation from the standard model prediction is observed. Upper limits are placed on the strength of baryon number violating couplings. For the first time the production of single top quarks via baryon number violating interactions is studied. This allows the search to set the most stringent constraints to date on the branching fraction of the top quark decay to a lepton, an up-type quark (u or c), and a down-type quark (d, s, or b). The results improve the previous bounds by 3 to 6 orders of magnitude based on the fermion flavor combination of the baryon number violating interactions.

Patient Perception of Cough in Interstitial Lung Disease; Impact of Cough Hypersensitivity.

INTRODUCTION: Cough is common in interstitial lung disease (ILD) and is associated with disease progression, yet its mechanisms are understudied. We investigated cough hypersensitivity features and impact in ILD. METHODS: Participants with ILD and cough (n = 195) completed a multiple choice and free text questionnaire on cough sensations/triggers and impacts. RESULTS: The majority of participants were male (54%), aged > 65 (64%), with idiopathic pulmonary fibrosis (IPF, 75%). Common cough triggers were body position (74%), physical activity (72%), and talking (62%). Common laryngeal sensations were globus (43%), and itch/tickle (42%). Cough impacted everyday life in 55%, and all activities in 31%, causing exhaustion (59%), social embarrassment (70%), urinary incontinence (46% females), and syncope/pre-syncope (12%). The total number of cough-provoking sensations/triggers correlated with impacts; ρ = 0.73, p < 0.001. CONCLUSION: Cough hypersensitivity symptoms are prevalent in ILD and detrimentally affect quality of life. Further studies investigating mechanisms of cough hypersensitivity and targeted pharmacotherapy are warranted.

The impact of primary health care on AIDS incidence and mortality: A cohort study of 3.4 million Brazilians.

BACKGROUND: Primary Health Care (PHC) is essential for effective, efficient, and more equitable health systems for all people, including those living with HIV/AIDS. This study evaluated the impact of the exposure to one of the largest community-based PHC programs in the world, the Brazilian Family Health Strategy (FHS), on AIDS incidence and mortality. METHODS AND FINDINGS: A retrospective cohort study carried out in Brazil from January 1, 2007 to December 31, 2015. We conducted an impact evaluation using a cohort of 3,435,068 ≥13 years low-income individuals who were members of the 100 Million Brazilians Cohort, linked to AIDS diagnoses and deaths registries. We evaluated the impact of FHS on AIDS incidence and mortality and compared outcomes between residents of municipalities with low or no FHS coverage (unexposed) with those in municipalities with 100% FHS coverage (exposed). We used multivariable Poisson regressions adjusted for all relevant municipal and individual-level demographic, socioeconomic, and contextual variables, and weighted with inverse probability of treatment weighting (IPTW). We also estimated the FHS impact by sex and age and performed a wide range of sensitivity and triangulation analyses; 100% FHS coverage was associated with lower AIDS incidence (rate ratio [RR]: 0.76, 95% CI: 0.68 to 0.84) and mortality (RR: 0.68, 95%CI: 0.56 to 0.82). FHS impact was similar between men and women, but was larger in people aged ≥35 years old both for incidence (RR: 0.62, 95% CI: 0.53 to 0.72) and mortality (RR: 0.56, 95% CI: 0.43 to 0.72). The absence of important confounding variables (e.g., sexual behavior) is a key limitation of this study. CONCLUSIONS: AIDS should be an avoidable outcome for most people living with HIV today and our study shows that FHS coverage could significantly reduce AIDS incidence and mortality among low-income populations in Brazil. Universal access to comprehensive healthcare through community-based PHC programs should be promoted to achieve the Sustainable Development Goals of ending AIDS by 2030.

Higher risk of incident diabetes among patients with primary hyperparathyroidism.

OBJECTIVES: There is relatively scarce data regarding the association between primary hyperparathyroidism (PHPT) and incident diabetes in large population-based longitudinal studies. We aimed to evaluate the risk of incident diabetes in individuals with and without PHPT and investigate the association between serum calcium concentrations and the risk of incident diabetes in patients with PHPT. METHODS: We included 2749 PHPT patients and 13,745 age, sex and index year matched non-PHPT individuals during 2000-2019. We used Cox regression models to compare the risk of incident diabetes in individuals with and without PHPT, and the risk of incident diabetes in PHPT patients with serum calcium concentration above and below the median value. The association between serum calcium concentrations and the risk of incident diabetes was examined by restricted cubic spline analyses in patients with PHPT. RESULTS: During a median follow-up time of 5.17 years (IQR 2.17, 9.58), 433 patients (15.75%) with PHPT and 2110 individuals (15.35%) without PHPT developed diabetes, respectively. Patients with PHPT had a higher incidence rate of diabetes compared to non-PHPT individuals (27.60 [95% CI 25.00, 30.30] vs. 23.90 [95% CI 22.80, 24.90] per 1000 person-years, log-rank test p = .007]. Crude Cox regression model showed PHPT was associated with a 15% higher risk of incident diabetes (HR 1.15, 95%CI 1.04, 1.28). In patients with PHPT, a 44% higher risk of incident diabetes was found in patients with serum calcium concentrations above the median value (2.63 mmol/L), compared to those below the median value (HR 1.44, 95%CI 1.08, 1.90). Restricted cubic spline analyses confirmed a positive linear association between serum calcium concentrations and the risk of incident diabetes in those with PHPT (p-value for nonlinear = .751) CONCLUSIONS: Patients with PHPT had a higher risk of incident diabetes compared to non-PHPT individuals. A positive linear association was found between serum calcium concentrations and the risk of incident diabetes in patients with PHPT.

ToxinPred 3.0: An improved method for predicting the toxicity of peptides.

Toxicity emerges as a prominent challenge in the design of therapeutic peptides, causing the failure of numerous peptides during clinical trials. In 2013, our group developed ToxinPred, a computational method that has been extensively adopted by the scientific community for predicting peptide toxicity. In this paper, we propose a refined variant of ToxinPred that showcases improved reliability and accuracy in predicting peptide toxicity. Initially, we utilized a similarity/alignment-based approach employing BLAST to predict toxic peptides, which yielded satisfactory accuracy; however, the method suffered from inadequate coverage. Subsequently, we employed a motif-based approach using MERCI software to uncover specific patterns or motifs that are exclusively observed in toxic peptides. The search for these motifs in peptides allowed us to predict toxic peptides with a high level of specificity with poor sensitivity. To overcome the coverage limitations, we developed alignment-free methods using machine/deep learning techniques to balance sensitivity and specificity of prediction. Deep learning model (ANN - LSTM with fixed sequence length) developed using one-hot encoding achieved a maximum AUROC of 0.93 with MCC of 0.71 on an independent dataset. Machine learning model (extra tree) developed using compositional features of peptides achieved a maximum AUROC of 0.95 with MCC of 0.78. We also developed large language models and achieved maximum AUC of 0.93 using ESM2-t33. Finally, we developed hybrid or ensemble methods combining two or more methods to enhance performance. Our specific hybrid method, which combines a motif-based approach with a machine learning-based model, achieved a maximum AUROC of 0.98 with MCC 0.81 on an independent dataset. In this study, all models were trained and tested on 80 % of data using five-fold cross-validation and evaluated on the remaining 20 % of data called independent dataset. The evaluation of all methods on an independent dataset revealed that the method proposed in this study exhibited better performance than existing methods. To cater to the needs of the scientific community, we have developed a standalone software, pip package and web-based server ToxinPred3 (https://github.com/raghavagps/toxinpred3 and https://webs.iiitd.edu.in/raghava/toxinpred3/).

Rare Pathogenic Variants Identified in Whole Exome Sequencing of Monozygotic Twins With Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a childhood-onset complex neurodevelopmental disorder characterized by problems with communication and social interaction and restricted, repetitive, stereotyped behavior. The prevalence of ASD is one in 36 children. The genetic architecture of ASD is complex in spite of its high heritability. To identify the potential candidate genes of ASD, we carried out a comprehensive genetic study of monozygotic (MZ) twins concordant or discordant for ASD. METHODS: Five MZ twins and their parents were recruited for the study. Four of the twins were concordant, whereas one was discordant for ASD. Whole exome sequencing was conducted for the twins and their parents. The exome DNA was enriched using Twist Human Customized Core Exome Kit, and paired-end sequencing was performed on HiSeq system. RESULTS: We identified several rare and pathogenic variants (homozygous recessive, compound heterozygous, de novo) in ASD-affected individuals. CONCLUSION: We report novel variants in individuals diagnosed with ASD. Several of these genes are involved in brain-related functions and not previously reported in ASD. Intriguingly, some of the variants were observed in the genes involved in sensory perception (auditory [MYO15A, PLEC, CDH23, UBR3, GPSM2], olfactory [OR9K2], gustatory [TAS2R31], and visual [CDH23, UBR3]). This is the first comprehensive genetic study of MZ twins in an Indian population. Further validation is required to determine whether these variants are associated with ASD.

Search for Narrow Trijet Resonances in Proton-Proton Collisions at sqrt[s]=13 TeV.

The first search for singly produced narrow resonances decaying to three well-separated hadronic jets is presented. The search uses proton-proton collision data corresponding to an integrated luminosity of 138 fb^{-1} at sqrt[s]=13 TeV, collected at the CERN LHC. No significant deviations from the background predictions are observed between 1.75 and 9.00 TeV. The results provide the first mass limits on a right-handed boson Z_{R} decaying to three gluons and on an excited quark decaying via a vector boson to three quarks, as well as updated limits on a Kaluza-Klein gluon decaying via a radion to three gluons.

Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies.

BACKGROUND: Converging evidence suggests that markers of Alzheimer's disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aß+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aß-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aß+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aß+ underwent tau PET imaging in A4 (n=350). Aß- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aß- and A4 Aß+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer's Disease.

BACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool. OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals. SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study. INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention. MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL. RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)). CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.

Longitudinal Trajectories of the Cognitive Function Index in the A4 Study.

BACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period. OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study. DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally. SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States. PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab. MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (<46.1 CL, 46.1 to 77.2 CL, >77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined. RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile. CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.