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Abstract Germ granules are biomolecular condensates present in most animal germ cells. One function of germ granules is to help maintain germ cell totipotency by organizing mRNA regulatory machinery, including small RNA-based gene regulatory pathways. The C. elegans germ granule is compartmentalized into multiple subcompartments whose biological functions are largely unknown. Here, we identify an uncharted subcompartment of the C. elegans germ granule, which we term the E granule. The E granule is nonrandomly positioned within the germ granule. We identify five proteins that localize to the E granule, including the RNA-dependent RNA polymerase (RdRP) EGO-1, the Dicer-related helicase DRH-3, the Tudor domain-containing protein EKL-1, and two intrinsically disordered proteins, EGC-1 and ELLI-1. Localization of EGO-1 to the E granule enables synthesis of a specialized class of 22G RNAs, which derive exclusively from 5’ regions of a subset of germline-expressed mRNAs. Defects in E granule assembly elicit disordered production of endogenous siRNAs, which disturbs fertility and the RNAi response. Our results define a distinct subcompartment of the C. elegans germ granule and suggest that one function of germ granule compartmentalization is to facilitate the localized production of specialized classes of small regulatory RNAs.

Abstract Programmed DNA double-strand break (DSB) formation is a crucial feature of meiosis in most organisms. DSBs initiate recombination-mediated linking of homologous chromosomes, which enables correct chromosome segregation in meiosis. DSBs are generated on chromosome axes by heterooligomeric focal clusters of DSB-factors. Whereas DNA-driven protein condensation is thought to assemble the DSB-machinery, its targeting to chromosome axes is poorly understood. We uncover in mice that efficient biogenesis of DSB-machinery clusters requires seeding by axial IHO1 platforms. Both IHO1 phosphorylation and formation of axial IHO1 platforms are diminished by chemical inhibition of DBF4-dependent kinase (DDK), suggesting that DDK contributes to the control of the axial DSB-machinery. Furthermore, we show that axial IHO1 platforms are based on an interaction between IHO1 and the chromosomal axis component HORMAD1. IHO1-HORMAD1-mediated seeding of the DSB-machinery on axes ensures sufficiency of DSBs for efficient pairing of homologous chromosomes. Without IHO1-HORMAD1 interaction, residual DSBs depend on ANKRD31, which enhances both the seeding and the growth of DSB-machinery clusters. Thus, recombination initiation is ensured by complementary pathways that differentially support seeding and growth of DSB-machinery clusters, thereby synergistically enabling DSB-machinery condensation on chromosomal axes.

Diagnostic of transsexualism and gender incongruence are terms to describe individuals whose self-identity does not match their sex assignment at birth. A transgender woman is an individual assigned male at birth (AMAB) on the basis of the external or internal genitalia who identifies and lives as a woman. In recent decades, a significant increase in the number of transgender people has been reported. Although, its etiology is unknown, biological, anatomical, genetic, environmental and cultural factors have been suggested to contribute to gender variation. In XY animals, it has been shown that environmental endocrine disruptors, through their anti-androgenic activity, induce a female identity. In this work, we described four XY individuals who were exposed in utero to the xenoestrogen diethylstilbesterol (DES) and were part of the French HHORAGES cohort. They all reported a female transgender identity starting from childhood and adolescence. This high prevalence of male to female transgenderism (1.58%) in our cohort of 253 DES sons suggests that exposure to chemicals with xenoestrogen activity during fetal life may affect the male sex identity and behavior.

Abstract Background Resistance and balance training are important exercise interventions for older populations living with chronic diseases. Accurately measuring if an individual is adhering to exercises as prescribed is important to determine if lack of improvement in health outcomes is because of issues with adherence. Measuring adherence to resistance and balance exercises is limited by current methods that depend heavily on self-report and are often better at and tailored towards capturing aerobic training parameters (e.g., step count, minutes of moderate to vigorous physical activity). Adherence measures must meet users’ needs to be useful. Methods Using a Dillman tailored study design, we surveyed researchers who conduct exercise trials, clinicians who prescribe exercise for older adults, and older adults to determine: (1) how they are currently measuring adherence; (2) barriers and facilitators they have experienced to measurement; and (3) the information they would like collected about adherence (e.g., repetitions, sets, intensity, duration, frequency, quality). Surveys were disseminated internationally through professional networks, professional organizations, and social media. Participants completed an online survey between August 2021 and April 2022. Results Eighty-eight older adults, 149 clinicians, and 41 researchers responded to the surveys. Most clinicians and researchers were between the ages of 30 and 39 years, and 70.0% were female. Most older adults were aged 70–79 years, and 46.6% were female. Diaries and calendars (either analog or digital) were the most common current methods of collecting adherence data. Users would like information about the intensity and quality of exercises completed that are presented in clear, easy to use formats that are meaningful for older adults where all data can be tracked in one place. Most older adults did not measure adherence because they did not want to, while clinicians most frequently reported not having measurement tools for adherence. Time, resources, motivation, and health were also identified as barriers to recording adherence. Conclusions Our work provides information about current methods of measuring exercise adherence and suggestions to inform the design of future adherence measures. Future measures should comprehensively track adherence data in one place, including the intensity and quality of exercises.

Comprising nearly 300 described species, Eumerus Meigen, 1822, is one of the most speciose syrphid genera worldwide, and its taxonomic diversity is remarkable in the Mediterranean basin. The Eumerus barbarus (Coquebert, 1804) group consists of four species in the western Mediterranean. Although the phenotypic variability of this species group has been commented on in previous studies, it has never been contrasted with molecular data. In the present work, the morphological variation found in 300+ specimens of this species group from the western Mediterranean is explored and tested against the COI mitochondrial DNA (mtDNA). The highest phenotypic disparity was found in E. barbarus and Eumerus sulcitibius Rondani 1868. The integrative approach has not revealed cryptic diversity within the species E. barbarus but in E. sulcitibius. As a result, a new species close to E. sulcitibius was discovered, Eumerus sardus Aguado-Aranda, Ricarte & Hauser sp. n., from Sardinia, Italy. The new insular species is here described, illustrated, and discussed. A total of twenty-three haplotypes of COI mtDNA were identified amongst the analyzed Mediterranean specimens of E. barbarus, whereas two and five haplotypes were distinguished in the Iberian specimens of E. sulcitibius and Eumerus gibbosus van Steenis, Hauser & van Zuijen, 2017, respectively. Moreover, the first known barcodes of E. gibbosus and Eumerus schmideggeri van Steenis, Hauser & van Zuijen, 2017 were obtained, and the distribution ranges of all species are mapped. An updated dichotomous key to the males of the E. barbarus group from the western Mediterranean is provided.

Background The combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab for the treatment of locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN).Methods Patients with newly diagnosed, stage IVA–IVB SCCHN eligible for cisplatin-based chemotherapy received nivolumab (3 mg/kg every 2 weeks for a total of 17 doses) and ipilimumab (1 mg/kg every 6 weeks for a total of 6 doses) starting 2 weeks prior to radiotherapy. The primary endpoint was safety of definitive RIT. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the association of baseline programmed death-ligand 1 (PD-L1) expression as well as on-treatment changes in immune bias with treatment outcomes.Results Twenty-four patients were enrolled. With a median follow-up of 36.1 months, grade 3 or higher treatment-related adverse events were reported in 21 individuals (88%); 5 individuals developed in-field soft tissue ulceration during consolidation immunotherapy, resulting in one fatality. The 3-year PFS and OS rates were 74% (95% CI 58% to 94%) and 96% (95% CI 88% to 100%), respectively. PD-L1 combined positive score (CPS) did not correlate with death or disease progression. Decreases in extracellular vesicle PD-L1 within the concurrent RIT phase were associated with prolonged PFS (p=0.006). Also, interval decreases in circulating interleukin (IL)4, IL9, IL12, and IL17a during concurrent RIT were associated with subsequent ulceration.Conclusions Definitive RIT with nivolumab and ipilimumab has sufficient clinical activity to support further development. Early changes in circulating biomarkers appear able to predict treatment outcomes as well as ensuing in-field soft tissue ulceration.Trial registration number NCT03162731.

Numerical weather prediction (NWP) is a challenging task which involves working with micro and macro-scale spatio-temporal parameters susceptible to biases and accuracy problems. In recent years, machine learning has grown in popularity with the increasing demand in accurate weather predictions. In this study, we adopt a multimodel (ensemble) forecasting approach by collecting precipitation data from multiple NWP models of Canadian, American and European weather agencies in an effort to deploy an optimal machine learning-based weather model for real-time precipitation forecasting that will outperform the baseline. We considered 8 NWP models as inputs and combined them to create ensemble predictors using 5 different machine learning techniques along with a baseline model (mean of eight input NWP models). We demonstrate that machine learning approaches can improve upon the results of the individual NWP models. The best results were obtained by the neural-network variants with 17% improvement in the mean absolute error, 3% in the root mean squared error, 47% in the median absolute error, 5% in the maximum error, 70% in the relative bias, 41% in the false alarm ratio and 8% in the critical score index over the baseline. Neural networks also complied with the practicality constraints, with minutes of training time and near-real time prediction time.

The Lake Tahoe Basin of California and Nevada is a popular destination for visitors. As temperatures rise globally, visitation to this climatic refuge is likely to grow. Increased visitation contributes to increases in vehicle miles of travel (VMT), congestion, crashes, emissions, and deteriorating travel experiences at Lake Tahoe, while also contributing to friction between visitors and residents. Policymakers are exploring ways to mitigate these problems, but one key uncertainty to first address is exactly how many visitors are in the Tahoe Basin at a given time and how and where they travel while there. It is also unclear how visitation is influenced by heat in the nearby lower-elevation population centers during the summertime, which is when visitation is the highest. This study thus seeks to 1) quantify day and overnight visitors in the Tahoe Basin, 2) estimate VMT attributable to each group, and 3) model the influence of hot temperatures nearby on visitation and VMT within the Tahoe Basin. We use existing survey data, network GIS analysis, and publicly available weather data to model the relationship between particularly hot conditions and vehicle flow through two of the region’s primary entry points and estimate in-basin VMT attributable to travel through them. We evaluate several ways of defining “hot conditions” nearby and find that between 500 and 1,200 additional vehicles enter the basin at these two points alone, generating an additional in-basin daily VMT of about 12,000 to 33,000 when hot conditions exist. Quantifying the magnitude of the challenge enables managers to design and scale interventions to mitigate impacts.

Abstract Background Diabetes mellitus affects 13% of American adults. To address the complex care requirements necessary to avoid diabetes-related morbidity, the American Diabetes Association recommends utilization of multidisciplinary teams. Research shows pharmacists have a positive impact on multiple clinical diabetic outcomes. Methods Open-label randomized controlled trial with 1:1 assignment that took place in a single institution resident-run outpatient medicine clinic. Patients 18–75 years old with type 2 diabetes mellitus and most recent HbA1c ≥9% were randomized to standard of care (SOC) (continued with routine follow up with their primary provider) or to the SOC + pharmacist-managed diabetes clinic PMDC group (had an additional 6 visits with the pharmacist within 6 months from enrollment). Patients were followed for 12 months after enrollment. Data collected included HbA1c, lipid panel, statin use, blood pressure control, immunization status, and evidence of diabetic complications (retinopathy, nephropathy, neuropathy). Intention-to-treat and per-protocol analysis were performed. Results Forty-four patients were enrolled in the SOC + PMDC group and 42 patients in the SOC group. Average decrease in HbA1c for the intervention compared to the control group at 6 months was − 2.85% vs. -1.32%, (p = 0.0051). Additionally, the odds of achieving a goal HbA1c of ≤8% at 6 months was 3.15 (95% CI = 1.18, 8.42, p = 0.0222) in the intervention versus control group. There was no statistically significant difference in the remaining secondary outcomes measured. Conclusions Addition of pharmacist managed care for patients with type 2 diabetes mellitus is associated with significant improvements in HbA1c compared with standard of care alone. Missing data during follow up limited the power of secondary outcomes analyses. Trial registration ClinicalTrials.gov , ID: NCT03377127 ; first posted on 19/12/2017.

Seismic lines are cleared corridors for the location mapping of subsurface bitumen. After use, the lines can be left to regenerate naturally with varying success. Wildfires, another prominent disturbance in the Boreal region, are propagated by continuous fuel distribution (coarse/fine), meteorological variables (e.g., wind speed, temperature, and precipitation), and the moisture content of the fuel and soil. However, little is known about seismic lines and the potential risk and severity of wildfires. This work presents a case study of wildfire variables on two paired (seismic line and adjacent natural area) sites near Fort McMurray, Alberta, Canada. Wind speed was increased on seismic lines, and the dominant wind direction changed. Higher precipitation, air temperature, and soil moisture and reduced water table depths were observed on seismic lines. Coarse fuel distribution was not continuous on seismic lines; however, fine fuels were. Although the Fire Weather Index (FWI) indicated an enhanced wildfire potential on one line (NS orientation), peat smouldering and ignition models (Hcomb/Hign) showed increased smouldering potential on both seismic lines compared to adjacent natural areas. Future work should focus on expanding the diversity of seismic line characterization, working towards the landscape-scale modelling of these variables.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in humans in late 2019 and spread rapidly, becoming a global pandemic. A zoonotic spillover event from animal to human was identified as the presumed origin. Subsequently, reports began emerging regarding spillback events resulting in SARS-CoV-2 infections in multiple animal species. These events highlighted critical links between animal and human health while also raising concerns about the development of new reservoir hosts and potential viral mutations that could alter the virulence and transmission or evade immune responses. Characterizing susceptibility, prevalence, and transmission between animal species became a priority to help protect animal and human health. In this study, we coalesced a large team of investigators and community partners to surveil for SARS-CoV-2 in domestic and free-ranging animals around Ohio between May 2020 and August 2021. We focused on species with known or predicted susceptibility to SARS-CoV-2 infection, highly congregated or medically compromised animals (e.g., shelters, barns, veterinary hospitals), and animals that had frequent contact with humans (e.g., pets, agricultural animals, zoo animals, or animals in wildlife hospitals). This included free-ranging deer (n = 76 individuals), free-ranging mink (n = 57), multiple species of bats (n = 59), and other wildlife in addition to domestic cats (n = 275) and pigs (n = 184). In total, we tested 792 individual animals (34 species) via rRT-PCR for SARS-CoV-2 RNA. SARS-CoV-2 viral RNA was not detected in any of the tested animals despite a major peak in human SARS-CoV-2 cases that occurred in Ohio subsequent to the peak of animal samplings. Importantly, we did not test for SARS-CoV-2 antibodies in this study, which limited our ability to assess exposure. While the results of this study were negative, the surveillance effort was critical and remains key to understanding, predicting, and preventing the re-emergence of SARS-CoV-2 in humans or animals.

Summary: ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis after ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. After estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes, including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis.

Road Weather Information Systems (RWIS) provide real-time weather information at point locations and are often used to produce road weather forecasts and provide input for pavement forecast models. Compared to the prevalant street cameras, however, RWIS are sometimes limited in availability. Thus, extraction of road conditions data by computer vision can provide a complementary observational data source if it can be done quickly and on large scales. In this paper, we leverage state-of-the-art convolutional neural networks (CNN) in labeling images taken by street and highway cameras located across North America. The final training set included 47,000 images labeled with five classes: dry, wet, snow/ice, poor, and offline. The experiments tested different configurations of six CNNs. The EfficientNet-B4 framework was found to be most suitable to this problem, achieving validation accuracy of 90.6%, although EfficientNet-B0 achieved an accuracy of 90.3% with half the execution time. The classified images were then used to construct a map showing real-time road conditions at various camera locations. The proposed approach is presented in three parts: i) application pipeline, ii) description of the deep learning frameworks, iii) the dataset labeling process and the classification metrics.

Eumerus Meigen, 1822 is one of the largest Syrphidae genera in the Palaearctic Region, with the highest levels of taxonomic diversity found in the Eumerus tricolor species group. Despite its high diversity, the interspecific levels of morphological variability can be low. Additionally, some species may show certain levels of intraspecific variability. Hence, species delimitation may become challenging. In this work, we assessed the diversity of the E. tricolor group in the Iberian Peninsula through an integrative analysis of nomenclature, morphology and the 5′ (COI-5′) and 3′ (COI-3′) end regions of the Cytochrome c oxidase subunit I gene. Two new species, Eumerus ancylostylus Aguado-Aranda & Ricarte sp. n. and Eumerus petrarum Aguado-Aranda, Nedeljković & Ricarte sp. n., were described, and their intra- and interspecific variations discussed. In addition, the first barcodes of Iberian members of the E. tricolor group were obtained, and the distribution ranges of all species were mapped within the study area. The systematic position of the new species is discussed based on the resulting COI-based trees. The male genitalia of Eumerus hispanicus van der Goot, 1966 and Eumerus bayardi Séguy, 1961 were studied and illustrated. A lectotype was designated for Eumerus lateralis (Zetterstedt, 1819). An updated dichotomous key for all known European species of the E. tricolor group is provided. The egg of E. petrarum sp. n. is also described.

Abstract In the era of precision medicine, digital technologies and artificial intelligence, drug discovery and development face unprecedented opportunities for product and business model innovation, fundamentally changing the traditional approach of how drugs are discovered, developed and marketed. Critical to this transformation is the adoption of new technologies in the drug development process, catalyzing the transition from serendipity-driven to data-driven medicine. This paradigm shift comes with a need for both translation and precision, leading to a modern Translational Precision Medicine approach to drug discovery and development. Key components of Translational Precision Medicine are multi-omics profiling, digital biomarkers, model-based data integration, artificial intelligence, biomarker-guided trial designs and patient-centric companion diagnostics. In this review, we summarize and critically discuss the potential and challenges of Translational Precision Medicine from a cross-industry perspective.

CCR5 is a co-receptor for many transmitted HIV strains. Here, the authors show that biweekly injection of the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of a CCR5-tropic SHIV.

The Afrotropical representatives of the hover fly genus Mesembrius Rondani, 1857 (Diptera) are divided into two subgenera, namely Mesembrius s.s. and Vadonimyia Séguy, 1951 and, in this present work, the subgenus Mesembrius s.s. is revised. A total of 23 Mesembrius s.s. species are recognised for the Afrotropics. Known species are re-described and six species new to science are described: Mesembrius arcuatus sp. nov., M. copelandi sp. nov., M. longipilosus sp. nov., M. sulcus sp. nov., M. tibialis sp. nov. and M. vockerothi sp. nov. Mesembrius africanus (Verrall, 1898) is considered a junior synonym of M. senegalensis (Macquart, 1842), M. ctenifer Hull, 1941 a junior synonym of M. caffer (Loew, 1858), M. lagopus (Loew, 1869) a junior synonym of M. capensis (Macquart, 1842) and M. platytarsis Curran, 1929 a junior synonym of M. simplicipes Curran, 1929. The females of Mesembrius chapini Curran, 1939, M. rex Curran, 1927 and M. regulus (Hull, 1937) are described for the first time. Lectotypes are designated for Mesembrius caffer, M. capensis, M. cyanipennis (Bezzi, 1915), M. minor (Bezzi, 1915), M. senegalensis, M. strigilatus (Bezzi, 1912) and M. tarsatus (Bigot, 1883). Separate identification keys for males and females are presented. We obtained 236 DNA barcodes for 18 species. The relationships amongst the different Mesembrius species are briefly discussed, based on morphological and DNA barcode data.

Objective: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global pandemic. Emerging results indicate a dysregulated immune response. Given the role of CCR5 in immune cell migration and inflammation, we investigated the impact of CCR5 blockade via the CCR5-specific antibody leronlimab on clinical, immunological, and virological parameters in severe COVID-19 patients. Methods: In March 2020, 10 terminally ill, critical COVID-19 patients received two doses of leronlimab via individual emergency use indication. We analyzed changes in clinical presentation, immune cell populations, inflammation, as well as SARS-CoV-2 plasma viremia before and 14 days after treatment. Results: Over the 14-day study period, six patients survived, two were extubated, and one discharged. We observed complete CCR5 receptor occupancy in all donors by day 7. Compared with the baseline, we observed a concomitant statistically significant reduction in plasma IL-6, restoration of the CD4/CD8 ratio, and resolution of SARS-CoV2 plasma viremia (pVL). Furthermore, the increase in the CD8 percentage was inversely correlated with the reduction in pVL (r = −0.77, p = 0.0013). Conclusions: Our study design precludes clinical efficacy inferences but the results implicate CCR5 as a therapeutic target for COVID-19 and they form the basis for ongoing randomized clinical trials.

Synthetic aperture radar (SAR) focusing will be a fundamental step in the analysis of the radar sounding datasets collected by the Radar for Europa Assessment and Sounding: Ocean to Near-surface (REASON) instrument as part of NASA's upcoming Europa Clipper mission. Due to the flyby trajectory of the mission, REASON data acquisition will be distinct compared to other space-borne radar sounders, and therefore, require a tailored SAR focusing strategy. Here, we present a SAR focusing architecture based on the delay Doppler approach employed in US SHAllow RADar (SHARAD) data analysis with the following modifications for REASON data idiosyncrasies; an interpolation to a constant ground track interval to account for REASON's variable PRF; and an adaptive Doppler centroid estimation to account for the flyby geometry. The ability of our modified delay Doppler SAR focusing approach to focus space-borne datasets as well as its specific feasibility for REASON are demonstrated using both SHARAD and MARSIS datasets. In addition, we present a quantitative quality control framework based on pixel power probabilities and demonstrate how it can be leveraged to quantify the effects of SAR focusing and differentiate focused results generated with different processing parameters. Finally, we revisit and discuss the assumption of depth-independent SAR focusing implicit in the choice to construct a REASON SAR focusing approach based on the delay Doppler method and provide a comparison with depth-dependent SAR focusing for a simplified acquisition geometry.

Introduction The evaluation of the Victorian Healthy Homes Program (VHHP) will generate evidence about the efficacy and cost-effectiveness of home upgrades to improve thermal comfort, reduce energy use and produce health and economic benefits to vulnerable households in Victoria, Australia.Methods and analysis The VHHP evaluation will use a staggered, parallel group clustered randomised controlled trial to test the home energy intervention in 1000 households. All households will receive the intervention either before (intervention group) or after (control group) winter (defined as 22 June to 21 September). The trial spans three winters with differing numbers of households in each cohort. The primary outcome is the mean difference in indoor average daily temperature between intervention and control households during the winter period. Secondary outcomes include household energy consumption and residential energy efficiency, self-reported respiratory symptoms, health-related quality of life, healthcare utilisation, absences from school/work and self-reported conditions within the home. Linear and logistic regression will be used to analyse the primary and secondary outcomes, controlling for clustering of households by area and the possible confounders of year and timing of intervention, to compare the treatment and control groups over the winter period. Economic evaluation will include a cost-effectiveness and cost-benefit analysis.Ethics and dissemination Ethical approval was received from Victorian Department of Human Services Human Research Ethics Committee (reference number: 04/17), University of Technology Sydney Human Research Ethics Committee (reference number: ETH18-2273) and Australian Government Department of Veterans Affairs. Study results will be disseminated in a final report and peer-reviewed journals.Trial registration number ACTRN12618000160235.

The CCR5-specific antibody Leronlimab is being investigated as a novel immunotherapy that can suppress HIV replication with minimal side effects. Here we studied the virological and immunological consequences of Leronlimab in chronically CCR5-tropic HIV-1 infected humans (n = 5) on suppressive antiretroviral therapy (ART) and in ART-naïve acutely CCR5-tropic SHIV infected rhesus macaques (n = 4). All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350 mg or 700 mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes. In ART-naïve rhesus macaques acutely infected with CCR5-tropic SHIV, weekly SC injections of 50 mg/kg Leronlimab fully suppressed plasma viremia in half of the macaques. CCR5 receptor occupancy by Leronlimab occurred concomitant with rebound of CD4+ CCR5+ T-cells in peripheral blood, and full CCR5 receptor occupancy was found in multiple anatomical compartments. Our results demonstrate that weekly, self-administered Leronlimab was safe, well-tolerated, and efficacious for long-term virologic suppression and should be included in the arsenal of safe, easily administered, longer-acting antiretroviral treatments for people living with HIV-1. Trial Registration: ClinicalTrials.gov Identifiers: NCT02175680 and NCT02355184.

Abstract Background The benefit of combining aspirin and direct oral anticoagulants on the reduction of cardiovascular events in atrial fibrillation or flutter is not well studied. We aimed to assess whether concurrent aspirin and direct oral anticoagulant therapy for atrial fibrillation or flutter will result in less coronary, cerebrovascular and systemic ischemic events compared to direct oral anticoagulant therapy alone. Methods Retrospective study of adult patients between 18 and 100 years old who have nonvalvular atrial fibrillation or flutter and were started on a direct oral anticoagulant (apixaban, rivaroxaban, or dabigatran), between January 1, 2010 and September 1, 2015 within the Beaumont Health System. Exclusions were history of venous thromboembolic disease and use of other antiplatelet therapies such as P2Y12 inhibitors. Patients were classified into two groups based on concurrent aspirin use and observed for a minimum of 2 years. Primary outcome was major adverse cardiac events, defined as acute coronary syndromes, ischemic strokes, and embolic events. Secondary outcomes were bleeding and death. Results Six thousand four patients were in the final analysis, 57% males and 80% Caucasians, median age 71, interquartile range (63–80). The group exposed to aspirin contained 2908 subjects, and the group unexposed to aspirin contained 3096 subjects. After using propensity scores to balance the baseline characteristics in both groups, the analysis revealed higher rate of major adverse cardiac events in the exposed group compared to the unexposed group, (HR 2.11, 95% CI (1.74–2.56)) with a number needed to harm of 11 (95% CI [9–11]). The rate of bleeding was also higher in the exposed group, (HR 1.30, 95% CI (1.11–1.52)). The rate of death was not statistically different between the groups, (HR 0.87, 95% CI (0.61–1.25)). Conclusions In this observational analysis of patients with atrial fibrillation and flutter, the concomitant use of direct oral anticoagulants and aspirin was associated with an increased risk of both major adverse cardiac and bleeding events when compared to the use of direct oral anticoagulants alone. These findings underscore the potential harm of this combination therapy when used without a clear indication.

Abstract In 2015, Aotearoa New Zealand became a signatory to the Sendai Framework for Disaster Risk Reduction 2015–2030 (Sendai Framework), the Paris Climate Change Agreement (Paris Agreement), and the Sustainable Development Goals (SDGs). Since 2017 Aotearoa New Zealand has been undergoing governance reform to realign priorities and to improve the management of natural hazards and climate change. The aim of this article is to provide a review of how Aotearoa New Zealand is taking steps to improve consistency of planning across the legislative environment, thereby implementing its commitments to the Sendai Framework, the SDGs, and the Paris Agreement. It provides an overview of the national governance arrangements, with a focus on the key legislative tools; identifies how key terms are defined nationally; and provides an overview of the governance arrangements that contribute to the country’s international obligations. The discussion describes how obligations are applied, and considers two “disruptive and proactive” action examples. Four recommended actions are provided to further implement these international aspirations: (1) take into account these international agreements during the development and implementation of all legislation; (2) build awareness, capability, and capacity within central, regional, and local governments to support implementation; (3) actively evaluate the progress of implementing initiatives designed to reduce vulnerability and strengthen resilience; and (4) ensure that more weight and value are given to indigenous planning documents.

The species of the Neotropical hoverfly genus Peradon Reemer, 2013 are revised, based on morphological characters with aid of mitochondrial DNA barcodes. The resulting number of valid species is increased to 31, of which the following seven are described as new: P. ballux Reemer, sp. nov., P. brevis Reemer, sp. nov., P. costaricensis Reemer, sp. nov., P. notialus Reemer, sp. nov., P. palpator Reemer, sp. nov., P. pompiloides Reemer, sp. nov., and P. surinamensis Reemer, sp. nov. Two new synonymies are established: Microdon langi Curran, 1925, syn. nov. and Microdon flavomarginatum Curran, 1925, syn. nov. are both junior synonyms of Mulio bidens Fabricius, 1805. A neotype is designated for Microdon diaphanus Sack, 1921. This neotype, which has been reared from an ant nest, also represents the first case of a larval record for this genus. In some species, most notably in P. bidens (Fabricius) and P. normalis (Curran), discrete and distinct colour morphs are recognized, with strongly differing colouration of wings and abdomen.

Summary: Mechanisms driving the prolonged meiotic prophase I in mammals are poorly understood. RNA helicase YTHDC2 is critical for mitosis to meiosis transition. However, YTHDC2 is highly expressed in pachytene cells. Here we identify an essential role for YTHDC2 in meiotic progression. Specifically, YTHDC2 deficiency causes microtubule-dependent telomere clustering and apoptosis at the pachytene stage of prophase I. Depletion of YTHDC2 results in a massively dysregulated transcriptome in pachytene cells, with a tendency toward upregulation of genes normally expressed in mitotic germ cells and downregulation of meiotic transcripts. Dysregulation does not correlate with m6A status, and YTHDC2-bound mRNAs are enriched in genes upregulated in mutant germ cells, revealing that YTHDC2 primarily targets mRNAs for degradation. Furthermore, altered transcripts in mutant pachytene cells encode microtubule network proteins. Our results demonstrate that YTHDC2 regulates the pachytene stage by perpetuating a meiotic transcriptome and preventing microtubule network changes that could lead to telomere clustering.

CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes.

Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.

The Middle East species of Claraeola Aczél (Diptera, Pipunculidae) are revised based on morphological characteristics and sequence data from the mitochondrial COI barcoding gene, using a novel COI mini-barcode protocol. Four new Claraeola species are described: C. bousynterga Motamedinia & Skevington, sp. nov., C. heidiae Motamedinia & Skevington, sp. nov., C. khuzestanensis Motamedinia & Skevington, sp. nov., and C. mantisphalliga Motamedinia & Skevington, sp. nov. Eudorylas thekkadiensis Kapoor, Grewal & Sharma, 1987 is transferred to Claraeola, C. thekkadiensis (comb. nov.). Diagnoses, illustrations, an identification key, and a distributional map are given for the Middle East species.

We investigate Open Educational Resources (OER) in post-secondary Calculus with face-to-face instruction using web-based homework in a side-by-side comparison with Closed (Proprietary) Educational Resources (CER). Statistical analyses using multilinear regression models are developed to demonstrate several significant effects, to within a probability of 5%. Our first finding is that students’ pretest scores and access dates to online homework were both significant factors in predicting first exam scores. While pretest scores were similar between the groups, students in the OER group accessed the online homework earlier in the semester, which contributed to higher first exam scores. Second, homework scores were significantly higher in the CER group, which was a significant measure of final exam scores. In understanding this result, we cite student comments suggesting the proprietary CER homework system had more resources providing help on problems. However, the differences in final course grades were not significant. We conclude from our study that the OER materials are effective, but recommend that care is taken to ensure the free materials provide a quality experience.

Meiotic recombination density is increased on shorter chromosomes. Here the authors show that recombination initiation continues near all chromosome ends long after interstitial regions become quiescent in a process that proportionally benefits short chromosomes.

Piwi-interacting RNAs (piRNAs) play critical roles in protecting germline genome integrity and promoting normal spermiogenic differentiation. In mammals, there are two populations of piRNAs: pre-pachytene and pachytene. Transposon-rich pre-pachytene piRNAs are expressed in fetal and perinatal germ cells and are required for retrotransposon silencing, whereas transposon-poor pachytene piRNAs are expressed in spermatocytes and round spermatids and regulate mRNA transcript levels. MOV10L1, a germ cell-specific RNA helicase, is essential for the production of both populations of piRNAs. Although the requirement of the RNA helicase domain located in the MOV10L1 C-terminal region for piRNA biogenesis is well known, its large N-terminal region remains mysterious. Here we report a novel Mov10l1 mutation, named yama, in the Mov10l1 N-terminal region. The yama mutation results in a single amino acid substitution V229E. The yama mutation causes meiotic arrest, de-repression of transposable elements, and male sterility because of defects in pre-pachytene piRNA biogenesis. Moreover, restricting the Mov10l1 mutation effects to later stages in germ cell development by combining with a postnatal conditional deletion of a complementing wild-type allele causes absence of pachytene piRNAs, accumulation of piRNA precursors, polar conglomeration of piRNA pathway proteins in spermatocytes, and spermiogenic arrest. Mechanistically, the V229E substitution in MOV10L1 reduces its interaction with PLD6, an endonuclease that generates the 5' ends of piRNA intermediates. Our results uncover an important role for the MOV10L1-PLD6 interaction in piRNA biogenesis throughout male germ cell development.

Adaptive oscillators (AOs) are nonlinear oscillators with plastic states that encode information. Here, an analog implementation of a four-state adaptive oscillator, including design, fabrication, and verification through hardware measurement, is presented. The result is an oscillator that can learn the frequency and amplitude of an external stimulus over a large range. Notably, the adaptive oscillator learns parameters of external stimuli through its ability to completely synchronize without using any pre- or post-processing methods. Previously, Hopf oscillators have been built as two-state (a regular Hopf oscillator) and three-state (a Hopf oscillator with adaptive frequency) systems via VLSI and FPGA designs. Building on these important implementations, a continuous-time, analog circuit implementation of a Hopf oscillator with adaptive frequency and amplitude is achieved. The hardware measurements and SPICE simulation show good agreement. To demonstrate some of its functionality, the circuit's response to several complex waveforms, including the response of a square wave, a sawtooth wave, strain gauge data of an impact of a nonlinear beam, and audio data of a noisy microphone recording, are reported. By learning both the frequency and amplitude, this circuit could be used to enhance applications of AOs for robotic gait, clock oscillators, analog frequency analyzers, and energy harvesting.

Occupant behaviour plays a significant role in shaping the dynamics of energy consumption in buildings, but the complex nature of occupant behaviour has hindered a deeper understanding of its influence. A meta-analysis was conducted on 65 published studies that used data-driven quantitative assessments to assess energy-related occupant behaviour using the Knowledge Discovery and Data Mining (KDD) framework. Hierarchical clustering was utilised to categorise different modelling techniques based on the intended outcomes of the model and the types of parameters used in various models. This study will assist researchers in selecting the most appropriate parameters and methods under various data constraints and research questions. The research revealed two distinct model categories being used to study occupant behaviour-driven energy consumption, namely (i) occupancy status models and (ii) energy-related behaviour models. Multiple studies have identified limitations on data collection and privacy concerns as constraints of modelling occupant behaviour in residential buildings. The “regression model” and its variants were found to be the preferred model types for research that models “energy-related behaviour”, and “classification models” were found to be preferable for modelling “occupancy” status. There were only limited instances of data-driven studies that modelled occupant behaviour in low-income households, and there is a need to generate region-specific models to accurately model energy-related behaviour.

Background: Point-of-care ultrasound (POCUS) implemented through task shifting to nontraditional users has potential as a diagnostic adjuvant to enhance acute obstetrical care in resource-constrained environments with limited access to physician providers. Objective: This study evaluated acute obstetrical needs and the potential role for POCUS programming in the North East region of Haiti. Methods: Data was collected on all women presenting to the obstetrical departments of two Ministry of Public Health and Population (MSPP)-affiliated public hospitals in the North East region of Haiti: Fort Liberté Hospital and Centre Medicosocial de Ouanaminthe. Data was obtained via retrospective review of hospital records from January 1 through March 31, 2016. Trained personnel gathered data on demographics, obstetrical history, diagnoses, clinical care and outcomes using a standardized tool. Diagnoses a priori, defined as those diagnoses whose detection could be assisted with POCUS, included multi-gestations, non-vertex presentation, cephalopelvic disproportion, placental abruption, placenta previa, spontaneous abortions, retained products and ectopic pregnancy. Results: Data were collected from 589 patients during the study period. Median maternal age was 26 years and median gestational age was 38 weeks. The most common reason for seeking care was pelvic pain (85.2%). Sixty-seven (11.5%) women were transferred to other facilities for higher-level care. Among cases not transferred, post-partum hemorrhage, infant mortality and maternal mortality occurred in 2.4%, 3.0% and 0.6% of cases, respectively. There were 69 cases with diagnoses that could have benefited from POCUS use. Between sites, significantly more cases had the potential for improved diagnostics with POCUS at Fort Liberté Hospital (19.8%) than Centre Medicosocial de Ouanaminthe (8.2%) (p < 0.001). Conclusion: Acute obstetrical care is common and POCUS has the potential to impact the care of obstetrical patients in the North East region of Haiti. Future programs evaluating the feasibility of task shifting and the sustainable impacts of acute obstetric POCUS in Haiti will be important.

Species of the distinctive and cosmopolitan genus Dasydorylas Skevington, 2001 in the Middle East are revised. Seven species are documented, and three new species, Dasydorylas dactylos sp. nov., D. forcipus sp. nov. and D. parazardouei sp. nov., are described, and one synonym, D. derafshani Motamedinia & Kehlmaier, 2017, syn. nov. is proposed, based on sequence information from the mitochondrial COI barcoding gene and morphological parameters. Diagnoses, illustrations and distributional data are provided for all studied species. Descriptions of new species as well as an identification key to all known species in the Middle East are also provided.

Homologous recombination ensures genome integrity during meiotic recombination. Here the authors reveal that factors SWS1 and SWSAP1 are critical for meiotic homologues recombination, particularly in promoting assembly of RAD51 and DMC1 on early recombination intermediates.

Abstract Introduction Single intra-articular (IA) injections of poly(lactic-co-glycolic acid) (PLGA) microsphere-based triamcinolone acetonide extended-release (TA–ER; formerly FX006) demonstrated sustained, clinically relevant benefits in patients with knee osteoarthritis. The local effects of TA–ER were assessed in normal canine knees in three nonclinical studies. Methods Knees were evaluated for up to 6 weeks or 9 months after a single injection of TA–ER (2.1/6.25/18.75 mg TA), or TA crystalline suspension (TAcs, 18.75 mg TA), and for up to 6 months after three injections (every 1 or 3 months) of TA–ER (6.25/18.75 mg TA) or TAcs (18.75 mg). Vehicle-diluent, blank microspheres, and untreated knees were used as controls. Plasma and synovial fluid (SF) TA concentrations and standard histopathological assessment of the synovium were conducted. Articular cartilage morphology was assessed via modified Mankin scoring. Results Plasma and SF concentrations indicated prolonged dose-dependent TA joint residency with TA–ER compared with TAcs. Effects in articular cartilage were dose- and time-dependent and consistent with known effects of corticosteroids in the normal knee. Loss of Safranin O staining occurred, indicative of a reduction in cartilage matrix proteoglycan, and recovered in a similar manner for TA–ER and TAcs across all studies. Structural lesions were infrequent and generally comparable in severity between TA–ER and TAcs but slightly higher in incidence for TA–ER. Focal/multifocal foreign-body responses (FBR) to PLGA were observed in the superficial layer of the synovium, peaking after 4–6 weeks, with significant recovery or complete resolution by month 6. Conclusions These findings suggest that the effects of IA injections of TA–ER on cartilage are predominantly transient, and comparable to those observed with TAcs in the normal canine knee joint. These mild effects in the normal joint differ from the beneficial effects observed with TA–ER and other corticosteroids in disease models. The synovial FBR to PLGA microspheres was focal and transient. Funding Flexion Therapeutics, Inc. Plain Language Summary Plain language summary available for this article.

Abstract Background Millions of Americans are currently living with diabetes and approximately 1.5 million cases are being diagnosed each year. Diabetes is now the seventh leading cause of death in the United States. In addition, the economic burden of the disease has resulted in billions of dollars in health care costs. In spite of these investments, the United States lags behind other developed countries on diabetes life expectancy and disease-related deaths. The purpose of this study is to assess the impact of a pharmacist-managed diabetes clinic (PMDC) model on diabetes core measures. Our hypothesis is that a PMDC would have a significant positive impact on the diabetes measures and will result in higher-quality care at a lower price. Methods This study is a randomized, open-label, controlled, parallel-group trial which will be conducted in the outpatient clinic at Beaumont Hospital, Royal Oak, Michigan. Patients will be randomly assigned to one of two groups: standard of care (SOC) or standard of care plus PMDC (SOC + PMDC). Included in the study will be patients older than 18 years of age with a diagnosis of type 2 diabetes mellitus and a hemoglobin A1c ≥ 9%, who are established with a primary care resident and who have not been seen in the PMDC within the last 3 months. The primary outcome is the change in hemoglobin A1c, measured at 6 and 12 months. Secondary outcomes include the impact on all diabetes core measures, patient quality of life, harms, and cost impact related to the intervention. Discussion If the results of this trial are consistent with the previous retrospective analysis that a pharmacy clinic has a significant impact in controlling hemoglobin A1c levels as well as other diabetes core measures to improve clinical outcomes, it will constitute a scaffold for a future multicenter, randomized controlled trial. In addition, these results may influence future diabetes guidelines, leading to the inclusion of a PMDC as the standard of care. The impact of these results on the economic burden, life expectancy, and diabetes-related deaths are needed and have yet to be studied. Trial registration ClinicalTrials.gov, ID: NCT03377127. Protocol version: registered on 10 February 2018; version #1.

Antimicrobial resistance (AMR) is a global concern, pertaining not only to human health but also to the health of industry and the environment. AMR research has traditionally focused on genetic exchange mechanisms and abiotic environmental constraints, leaving important aspects of microbial ecology unresolved. The genetic and ecological aspects of AMR, however, not only contribute separately to the problem but also are interrelated. For example, mutualistic associations among microbes such as biofilms can both serve as a barrier to antibiotic penetration and a breeding ground for horizontal exchange of antimicrobial resistance genes (ARGs). In this review, we elucidate how species interactions promote and impede the establishment, maintenance, and spread of ARGs and indicate how management initiatives might benefit from leveraging the principles and tools of community ecology to better understand and manipulate the processes underlying AMR.

ATR kinase is required for meiosis in non-mammalian model organisms. Here the authors demonstrate, using a tissue-specific knockout approach, that ATR is also essential for male meiosis in mouse, regulating meiotic recombination and synapsis.

ATR kinase is required for meiosis in non-mammalian model organisms. Here the authors demonstrate, using a hypomorphic Atr mutation and chemical inhibition, that ATR is also essential for male meiosis in mouse, regulating meiotic recombination and synapsis.

A great number of studies published on long-term ocean warming and increased acidification have forecasted changes in regional biodiversity preempted by aquatic invasive species (AIS). The present paper is focused on invasive Tubastraea coccinea (TC), an azooxanthellate AIS coral thriving in regions of the Gulf of Mexico, which has shown an ability to invade altered habitats, including endemic Indo-Pacific T. coccinea (TCP) populations. To determine if invasive TC are more stress resistant than endemic Indo-Pacific T. coccinea (TCP), authors measured tissue loss and heat shock protein 70 (HSP70) expression, using a full factorial design, post exposure to changes in pH (7.5 and 8.1) and heat stress (31 °C and 34 °C). Overall, the mean time required for TCP to reach 50% tissue loss (LD50) was less than observed for TC by a factor of 0.45 (p < 0.0003). Increasing temperature was found to be a significant main effect (p = 0.004), decreasing the LD50 by a factor of 0.58. Increasing acidity to pH 7.5 from 8.1 did not change the sensitivity of TC to temperature; however, TCP displayed increased sensitivity at 31 °C. Increases in the relative density of HSP70 (TC) were seen at all treatment levels. Hence, TC appears more robust compared to TCP and may emerge as a new dominant coral displacing endemic populations as a consequence of climate change.

Geodesign is a participatory planning approach in which stakeholders use geographic information systems to develop and vet alternative design scenarios in a collaborative and iterative process. This study is based on a 2019 geodesign workshop in which 17 participants from industry, government, university, and non-profit sectors worked together to design an initial network of hydrogen refueling stations in the Hartford, Connecticut, metropolitan area. The workshop involved identifying relevant location factors, rapid prototyping of station network designs, and developing consensus on a final design. The geodesign platform, which was designed specifically for facility location problems, enables breakout groups to add or delete stations with a simple point-and-click operation, view and overlay different map layers, compute performance metrics, and compare their designs to those of other groups. By using these sources of information and their own expert local knowledge, participants recommended six locations for hydrogen refueling stations over two distinct phases of station installation. We quantitatively and qualitatively compared workshop recommendations to solutions of three optimal station location models that have been used to recommend station locations, which minimize travel times from stations to population and traffic or maximize trips that can be refueled on origin–destination routes. In a post-workshop survey, participants rated the workshop highly for facilitating mutual understanding and information sharing among stakeholders. To our knowledge, this workshop represents the first application of geodesign for hydrogen refueling station infrastructure planning.

Objective: The present study evaluates the concurrent and predictive validity of the Seguin Form Board Test (SFBT) as an intelligence tool for children in low- and middle-income countries. Methods: In a cohort of normal children, followed up in South India, two cross-sectional analyses were done at 3 and 7 years of age on 95 children. The SFBT and Vineland Social Maturity Scale (VSMS) were done at 3 years of age and Malin’s Intelligence Scale for Indian Children (MISIC) and the VSMS were done at 7 years of age, and the results were compared for concurrent and predictive validity for the SFBT. Results: Intelligence quotient and social quotient had positive correlations at 3 years of age, indicating fair concurrent validity. The SFBT done at around 3 years of age had good positive correlation with MISIC at 7 years of age, indicating good predictive validity. Conclusion: This study shows the utility of the SFBT as a community-based intelligence tool with acceptable concurrent and predictive validity.