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BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

Single-cell assay for transposase-accessible chromatin by sequencing (scATAC-seq) has emerged as a powerful tool for dissecting regulatory landscapes and cellular heterogeneity. However, an exploration of systemic biases among scATAC-seq technologies has remained absent. In this study, we benchmark the performance of eight scATAC-seq methods across 47 experiments using human peripheral blood mononuclear cells (PBMCs) as a reference sample and develop PUMATAC, a universal preprocessing pipeline, to handle the various sequencing data formats. Our analyses reveal significant differences in sequencing library complexity and tagmentation specificity, which impact cell-type annotation, genotype demultiplexing, peak calling, differential region accessibility and transcription factor motif enrichment. Our findings underscore the importance of sample extraction, method selection, data processing and total cost of experiments, offering valuable guidance for future research. Finally, our data and analysis pipeline encompasses 169,000 PBMC scATAC-seq profiles and a best practices code repository for scATAC-seq data analysis, which are freely available to extend this benchmarking effort to future protocols.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.

During the twentieth century, state health authorities in California recommended sterilization for over 20,000 individuals held in state institutions. Asian immigrants occupied a marginalized position in racial, gender, and class hierarchies in California at the height of its eugenic sterilization program. Scholars have documented the disproportionate sterilization of other racialized groups, but little research exists connecting the racist, gendered implementation of Asian immigration restriction to the racism and sexism inherent in eugenics. This study examines patterns of coercive sterilization in Asian immigrants in California, hypothesizing higher institutionalization and sterilization rates among Asian-born compared with other foreign- and US-born individuals. We used complete count census microdata from 1910 to 1940 and digitized sterilization recommendation forms from 1920 to 1945 to model relative institutionalization and sterilization rates of Asian-born, other foreign-born, and US-born populations, stratified by gender. Other foreign-born men and women had the highest institutionalization rates in all four census years. Sterilization rates were higher for Asian-born women compared with US-born [Incidence Rate Ratio (IRR) = 2.00 (95% CI: 1.61, 2.48)] and other foreign-born women (p

BACKGROUND: PSMA expression is influenced by hormonal status. We evaluated changes in PSA and whole-body 68Ga-PSMA-11 PET/CT (WB-PSMA PET) after initiation of androgen receptor signaling inhibitors (ARSi). METHODS: Prospectively enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) initiating ARSi underwent serial PSA measurements and WB-PSMA PET at baseline, 1-week, and 3-months post-ARSi. We correlated WB-PSMA PET metrics and PSA kinetics after ARSi to 1-year clinical outcome. RESULTS: Due to low enrollment rate, the study was closed before reaching the recruitment goal of 30 patients. Nine patients were enrolled. At 1-year, unfavorable outcome was documented in 6/9 (66%) patients. Nine/9 patients completed PSMA PET at 1-week, 5/9 at 3-months. Changes in PSA, PSMA-VOL, SUVmean and SUVmax were - 12%, + 5%, + 3%, and + 10% at 1-week, - 42%, - 16%, - 15% and - 17% at 3-months, respectively. CONCLUSIONS: Our prospective trial involving 9 mCRPC patients initiating ARSi did not show significant modulation of PSMA expression measured on WB-PSMA PET at 1-week. This study was registered on clinicaltrials.gov (NCT04279561).

BackgroundDevelopment of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life.ObjectiveTo assess the safety and efficacy of amubarvimab plus romlusevimab.DesignRandomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410).SettingNonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines.PatientsAdults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression.InterventionCombination of monoclonal antibodies amubarvimab plus romlusevimab or placebo.MeasurementsNasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death.ResultsEight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P

Small molecule inhibitors of glycosylation enzymes are valuable tools for dissecting glycan functions and potential drug candidates. Screening for inhibitors of glycosyltransferases are mainly performed by in vitro enzyme assays with difficulties moving candidates to cells and animals. Here, we circumvent this by employing a cell-based screening assay using glycoengineered cells expressing tailored reporter glycoproteins. We focused on GalNAc-type O-glycosylation and selected the GalNAc-T11 isoenzyme that selectively glycosylates endocytic low-density lipoprotein receptor (LDLR)-related proteins as targets. Our screen of a limited small molecule compound library did not identify selective inhibitors of GalNAc-T11, however, we identify two compounds that broadly inhibited Golgi-localized glycosylation processes. These compounds mediate the reversible fragmentation of the Golgi system without affecting secretion. We demonstrate how these inhibitors can be used to manipulate glycosylation in cells to induce expression of truncated O-glycans and augment binding of cancer-specific Tn-glycoprotein antibodies and to inhibit expression of heparan sulfate and binding and infection of SARS-CoV-2.

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new gland-associated immune niche has implications for respiratory health.

Edaphic specialization is considered to promote ecological differentiation among closely related species of Damburneya (Lauraceae) occurring in sympatry. However, little is known about the effects of soil and other key environmental factors like climate on the ecological niche and distributionof these tree species. Here, we assessed the role of climate and soil on niche divergence and potential distribution of four Damburneya species whose distributions span Central America and Mexico. We performed ecological niche modeling with MaxEnt using three sets of environmental data: climatic-only, edaphic-only, and a combination of both, to characterize species niches and suitable distribution areas. Niche overlap was quantified, and niche similarity was tested to assess niche differentiation among species. Climate and soil determined species’ potential distribution. While climatic niches were mostly similar, edaphic niches tended to differ. Warm and moist tropical forests with no water deficit and low seasonality in precipitation are the most suitable environments for the four species. This study supports previous reports of wide ecological plasticity of Damburneya salicifolia based on its distribution and leaf trait variation, as it occurred in drier environments with wider temperature and soil pH ranges than the other species. The observed patterns of niche similarity did not reflect the phylogenetic relationships between species, suggesting that the modeled niches do not necessarily reflect past evolutionary processes but rather the current environmental variation across the geographical ranges of the species. The results suggest that the studied species are similarly constrained by climate and toleratewide edaphic variation, supporting a potential role for soils on ecological divergence within the genus. On the other hand, performance and predictions varied between models built with different datasets. This research supports the utility of including climate and soil data in ecological niche models to comprehensively analyze the niche and distribution of plant species.

As the largest longitudinal study of adolescent brain development and behavior to date, the Adolescent Brain Cognitive Development (ABCD) Study® has provided immense opportunities for researchers across disciplines since its first data release in 2018. The size and scope of the study also present a number of hurdles, which range from becoming familiar with the study design and data structure to employing rigorous and reproducible analyses. The current paper is intended as a guide for researchers and reviewers working with ABCD data, highlighting the features of the data (and the strengths and limitations therein) as well as relevant analytical and methodological considerations. Additionally, we explore justice, equity, diversity, and inclusion efforts as they pertain to the ABCD Study and other large-scale datasets. In doing so, we hope to increase both accessibility of the ABCD Study and transparency within the field of developmental cognitive neuroscience.

BackgroundDried plasma spot specimens may be a viable alternative to traditional liquid plasma in field settings, but the diagnostic accuracy is not well understood.MethodsStandard databases (PubMed and Medline), conferences, and gray literature were searched until January 2019. The quality of evidence was evaluated using the Standards for Reporting Studies of Diagnostic Accuracy and Quality Assessment of Diagnostic Accuracy Studies-2 criteria. We used univariate and bivariate random effects models to determine misclassification, sensitivity, and specificity across multiple thresholds, overall and for each viral load technology, and to account for between-study variation.ResultsWe identified 23 studies for inclusion in the systematic review that compared the diagnostic accuracy of dried plasma spots with that of plasma. Primary data from 16 of the 23 studies were shared and included in the meta-analysis, representing 18 countries, totaling 1847 paired dried plasma spot:plasma data points. The mean bias of dried plasma spot specimens compared with that of plasma was 0.28 log10 copies/mL, whereas the difference in median viral load was 2.25 log10 copies/mL. More dried plasma spot values were undetectable compared with plasma values (43.6% vs. 29.8%). Analyzing all technologies together, the sensitivity and specificity of dried plasma spot specimens were >92% across all treatment failure thresholds compared and total misclassification

It is critical to understand how human modifications of Earths ecosystems are influencing ecosystem functioning, including net and gross community production (NCP and GCP, respectively) and community respiration (CR). These responses are often estimated by measuring oxygen production in the light (NCP) and consumption in the dark (CR), which can then be combined to estimate GCP. However, the method used to create dark conditions-either experimental darkening during the day or taking measurements at night-could result in different estimates of respiration and production, potentially affecting our ability to make integrative predictions. We tested this possibility by measuring oxygen concentrations under daytime ambient light conditions, in darkened tide pools during the day, and during nighttime low tides. We made measurements every 1-3 months over one year in southeastern Alaska. Daytime respiration rates were substantially higher than those measured at night, associated with higher temperature and oxygen levels during the day and leading to major differences in estimates of GCP calculated using daytime versus nighttime measurements. Our results highlight the potential importance of measuring respiration rates during both day and night to account for effects of temperature and oxygen-especially in shallow-water, constrained systems-with implications for understanding the impacts of global change on ecosystem metabolism.

We describe a case of prolonged COVID-19 caused by the SARS-CoV-2 Gamma variant in a fully vaccinated healthcare worker, 387 days after an infection caused by lineage B.1.1.33. Infections were confirmed by whole-genome sequencing and corroborated by the detection of neutralizing antibodies in convalescent serum samples. Considering the permanent exposure of this healthcare worker to SARS-CoV-2, the waning immunity after the first infection, the low efficacy of the inactivated vaccine at preventing COVID-19, the immune escape of the Gamma variant (VOC), and the burden of post-COVID syndrome, this individual would have benefited from an additional dose of a heterologous vaccine.

BackgroundHuman brain function declines with aging. In this sense, exercise-based interventions has a promising effect on brain plasticity for older adults. Serum brain-derived neurotrophic factor (BDNF) is a positive biomarker for brain neuroplasticity in healthy older adults also modified by exercise training. Selected features of the exercise prescription for improving brain health are missing; therefore, the aim of this study was to determine the effects of concurrent exercise training frequency on serum BDNF levels in healthy older adults.MethodsNineteen volunteers (age: 65 ± 4 year; body mass index: 28.0 ± 4.5 kg/m2) completed either a three times/week (3-t/w) (n = 8) or five times/week (5-t/w) (n = 11) concurrent exercise program. The exercise program lasted 11 weeks and all exercise sessions were performed for 50 min at moderate intensity. Serum BDNF, body composition, cardiovascular, and physical fitness variables were assessed before and after the exercise training program.ResultsRegardless of the group, the serum BDNF increased following the intervention (p < 0.001), and there were no significant group (p = 0.827) or interaction (p = 0.063) effects. The maximal oxygen consumption (VO2max) increased regardless of the group (p = 0.007), with a non-significant group (p = 0.722) or interaction (p = 0.223) effects. Upper- and lower-body strength increased in both groups (p = 0.003); however, there was no effect of the training frequency (p = 0.53). For the skeletal muscle mass, there was a trend in the interaction effect (p = 0.053). Finally, the body fat percentage was unchanged.ConclusionEleven weeks of combined exercise training increased serum BDNF levels in healthy older adults, a response independent of the training frequency. The overall fitness level improved similarly in both exercise groups. These data reveal that a minimal dosage of concurrent exercise enhance functional capacity and a brain health biomarker in older adults.

Brown adipose tissue (BAT) thermogenic activity is tightly regulated by cellular redox status, but the underlying molecular mechanisms are incompletely understood. Protein S-nitrosylation, the nitric-oxide-mediated cysteine thiol protein modification, plays important roles in cellular redox regulation. Here we show that diet-induced obesity (DIO) and acute cold exposure elevate BAT protein S-nitrosylation, including UCP1. This thermogenic-induced nitric oxide bioactivity is regulated by S-nitrosoglutathione reductase (GSNOR; alcohol dehydrogenase 5 [ADH5]), a denitrosylase that balances the intracellular nitroso-redox status. Loss of ADH5 in BAT impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction. Mechanistically, we demonstrate that Adh5 expression is induced by the transcription factor heat shock factor 1 (HSF1), and administration of an HSF1 activator to BAT of DIO mice increases Adh5 expression and significantly improves UCP1-mediated respiration. Together, these data indicate that ADH5 controls BAT nitroso-redox homeostasis to regulate adipose thermogenesis, which may be therapeutically targeted to improve metabolic health.

Domestication of horses fundamentally transformed long-range mobility and warfare1. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling2-4 at Botai, Central Asia around 3500 BC3. Other longstanding candidate regions for horse domestication, such as Iberia5 and Anatolia6, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association7 between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC8,9 driving the spread of Indo-European languages10. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture11,12.

The article ‘EGFR/Ras-induced CCL20 production modulates the tumour microenvironment’, written by Andreas Hippe, Stephan Alexander Braun, Péter Oláh, Peter Arne Gerber, Anne Schorr, Stephan Seeliger, Stephanie Holtz, Katharina Jannasch, Andor Pivarcsi, Bettina Buhren, Holger Schrumpf, Andreas Kislat, Erich Bünemann, Martin Steinhoff, Jens Fischer, Sérgio A. Lira, Petra Boukamp, Peter Hevezi, Nikolas Hendrik Stoecklein, Thomas Hoffmann, Frauke Alves, Jonathan Sleeman, Thomas Bauer, Jörg Klufa, Nicole Amberg, Maria Sibilia, Albert Zlotnik, Anja Müller- Homey and Bernhard Homey, was originally published electronically on the publisher’s internet portal on 30 June 2020 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 16 September 2021 to © The Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. Open Access funding enabled and organized by Projekt DEAL.

Introduction and hypothesisThis study aimed to report 3-year completed follow-up of the safety and efficacy of Macroplastique® (MPQ) in women with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD).MethodsThis is a retrospective analysis of all women who completed 3-year follow-up post-MPQ injection(s) at ten medical centers. We used the ROSE registry data report of Macroplastique® [Macroplastique® Real-time Observation of Safety and Effectiveness (ROSE) registry P040050/PAS001 on 2017]. Subjective incontinence outcome and adverse effects were assessed.ResultsThe study included all patients (n = 70) who completed 3-year follow-up after the last MPQ injection. Twenty-four of 70 (34%) patients had two injections; 21/70 (30%) patients reported Stamey grade 0 and 28/70 (40%) reported Stamey grade 1. The overall patient satisfaction was 68% who completed 3-year follow-up. The composite success rate (I-QoL, PGI-S, and Stamey grade improvement) was 51.4%. No serious adverse events (AE) were reported within the completed 3-year follow-up.ConclusionsMPQ was found to be safe and efficacious for the treatment of SUI secondary to ISD in women. The overall high satisfaction rate was sustained from baseline to 3 years post-injection. Most complications were minor and transient without sequelae.

Introduction and hypothesisThis study aimed to report 3-year completed follow-up of the safety and efficacy of Macroplastique® (MPQ) in women with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD).MethodsThis is a retrospective analysis of all women who completed 3-year follow-up post-MPQ injection(s) at ten medical centers. We used the ROSE registry data report of Macroplastique® [Macroplastique® Real-time Observation of Safety and Effectiveness (ROSE) registry P040050/PAS001 on 2017]. Subjective incontinence outcome and adverse effects were assessed.ResultsThe study included all patients (n = 70) who completed 3-year follow-up after the last MPQ injection. Twenty-four of 70 (34%) patients had two injections; 21/70 (30%) patients reported Stamey grade 0 and 28/70 (40%) reported Stamey grade 1. The overall patient satisfaction was 68% who completed 3-year follow-up. The composite success rate (I-QoL, PGI-S, and Stamey grade improvement) was 51.4%. No serious adverse events (AE) were reported within the completed 3-year follow-up.ConclusionsMPQ was found to be safe and efficacious for the treatment of SUI secondary to ISD in women. The overall high satisfaction rate was sustained from baseline to 3 years post-injection. Most complications were minor and transient without sequelae.

Different mating systems are expected to affect the extent and direction of hybridization. Due to the different levels of sexual conflict, the weak inbreeder/strong outbreeder (WISO) hypothesis predicts that gametes from self-incompatible (SI) species should outcompete gametes from self-compatible (SC) ones. However, other factors such as timing of selfing and unilateral incompatibilities may also play a role on the direction of hybridization. In addition, differential mating opportunities provided by different mating systems are also expected to affect the direction of introgression in hybrid zones involving outcrossers and selfers. Here, we explored these hypotheses with a unique case of recent hybridization between two mangrove killifish species with different mating systems, Kryptolebias ocellatus (obligately outcrossing) and K. hermaphroditus (predominantly self-fertilizing) in two hybrid zones in southeast Brazil. Hybridization rates were relatively high (~20%), representing the first example of natural hybridization between species with different mating systems in vertebrates. All F1 individuals were sired by the selfing species. Backcrossing was small, but mostly asymmetrical with the SI parental species, suggesting pattern commonly observed in plant hybrid zones with different mating systems. Our findings shed light on how contrasting mating systems may affect the direction and extent of gene flow between sympatric species, ultimately affecting the evolution and maintenance of hybrid zones.

Scientific communication is facilitated by a data-driven, scientifically sound taxonomy that considers the end-user's needs and established successful practice. In 2013, the Fusarium community voiced near unanimous support for a concept of Fusarium that represented a clade comprising all agriculturally and clinically important Fusarium species, including the F. solani species complex (FSSC). Subsequently, this concept was challenged in 2015 by one research group who proposed dividing the genus Fusarium into seven genera, including the FSSC described as members of the genus Neocosmospora, with subsequent justification in 2018 based on claims that the 2013 concept of Fusarium is polyphyletic. Here, we test this claim and provide a phylogeny based on exonic nucleotide sequences of 19 orthologous protein-coding genes that strongly support the monophyly of Fusarium including the FSSC. We reassert the practical and scientific argument in support of a genus Fusarium that includes the FSSC and several other basal lineages, consistent with the longstanding use of this name among plant pathologists, medical mycologists, quarantine officials, regulatory agencies, students, and researchers with a stake in its taxonomy. In recognition of this monophyly, 40 species described as genus Neocosmospora were recombined in genus Fusarium, and nine others were renamed Fusarium. Here the global Fusarium community voices strong support for the inclusion of the FSSC in Fusarium, as it remains the best scientific, nomenclatural, and practical taxonomic option available.

The prostate-specific membrane antigen (PSMA) has been targeted for PET imaging and radioligand therapy (RLT) in patients with prostate cancer. Xerostomia is a common side effect of RLT because of the high salivary gland uptake of PSMA radioligands. Here, we aimed to determine the impact of monosodium glutamate (MSG) administration on PSMA-radioligand biodistribution within healthy organs and tumor lesions by using 68Ga-PSMA-11 PET imaging. Methods: Sixteen men with prostate cancer were randomized (1:1) into oral ingestion and oral topical application ("swishing") arms. Each subject underwent 2 68Ga-PSMA-11 PET/CT scans within 14 d under baseline and MSG conditions. The salivary glands and whole-body tumor lesions were segmented using qPSMA software. We quantified tracer uptake via SUVmean and SUVmax and compared parameters within each patient. Results: For the oral ingestion arm, salivary gland SUVmean and SUVmax decreased on average from the control scan to the MSG scan by 45% ± 15% (P = 0.004) and 53% ± 11% (P < 0.001), respectively. Tumor lesion SUVmean and SUVmax also decreased by 38% (interquartile range, -67% to -33%) and -52% (interquartile range, -70% to -49%), respectively (P = 0.018). Swishing had no significant effect on 68Ga-PSMA-11 accumulation in normal organs or tumor lesions. Conclusion: Oral ingestion but not topical application of MSG reduced 68Ga-PSMA-11 uptake in salivary glands. Tumor uptake also declined; therefore, the clinical application of MSG is unlikely to be useful in the framework of RLT.

Scientific communication is facilitated by a data-driven, scientifically sound taxonomy that considers the end-user's needs and established successful practice. In 2013, the Fusarium community voiced near unanimous support for a concept of Fusarium that represented a clade comprising all agriculturally and clinically important Fusarium species, including the F. solani species complex (FSSC). Subsequently, this concept was challenged in 2015 by one research group who proposed dividing the genus Fusarium into seven genera, including the FSSC described as members of the genus Neocosmospora, with subsequent justification in 2018 based on claims that the 2013 concept of Fusarium is polyphyletic. Here, we test this claim and provide a phylogeny based on exonic nucleotide sequences of 19 orthologous protein-coding genes that strongly support the monophyly of Fusarium including the FSSC. We reassert the practical and scientific argument in support of a genus Fusarium that includes the FSSC and several other basal lineages, consistent with the longstanding use of this name among plant pathologists, medical mycologists, quarantine officials, regulatory agencies, students, and researchers with a stake in its taxonomy. In recognition of this monophyly, 40 species described as genus Neocosmospora were recombined in genus Fusarium, and nine others were renamed Fusarium. Here the global Fusarium community voices strong support for the inclusion of the FSSC in Fusarium, as it remains the best scientific, nomenclatural, and practical taxonomic option available.

HIV-negative individuals in serodiscordant partnerships experience reduced risk of HIV acquisition when their partners adhere to ART and achieve undetectable viral loads. Partnership support may encourage ART adherence, reducing viral load and the risk of HIV transmission. This study aims to determine whether HIV viral suppression is associated with partnership status and partnership support among 201 HIV positive (HIV+ individuals in serodiscordant partnerships and 100 HIV+ unpartnered individuals receiving care at Hospital Nossa Senhora da Conceição in Porto Alegre, Brazil between 2014 and 2016. Clinical data and patient-reported questionnaire data were assessed, and propensity scores were used to control for confounding variables in adjusted logistic regression models. Viral suppression did not significantly differ between HIV+ partnered (78.5% virally suppressed) and unpartnered (76.0% virally suppressed) individuals. Among individuals in partnerships, viral suppression was significantly associated with having a partner who attended monthly clinic visits (AOR 2.99; 95% CI 1.00-8.93). Instrumental social support-attending monthly visits-may improve the odds of viral suppression among HIV+ individuals in serodiscordant relationships.

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

In this contribution, we achieve the primary goal of the active galactic nucleus (AGN) STORM campaign by recovering velocity-delay maps for the prominent broad emission lines (Lyα, C iv, He ii, and Hβ) in the spectrum of NGC 5548. These are the most detailed velocity-delay maps ever obtained for an AGN, providing unprecedented information on the geometry, ionization structure, and kinematics of the broad-line region. Virial envelopes enclosing the emission-line responses show that the reverberating gas is bound to the black hole. A stratified ionization structure is evident. The He ii response inside 5-10 lt-day has a broad single-peaked velocity profile. The Lyα, C iv, and Hβ responses extend from inside 2 to outside 20 lt-day, with double peaks at ±2500 km s-1 in the 10-20 lt-day delay range. An incomplete ellipse in the velocity-delay plane is evident in Hβ. We interpret the maps in terms of a Keplerian disk with a well-defined outer rim at R = 20 lt-day. The far-side response is weaker than that from the near side. The line-center delay days gives the inclination i ≈ 45°. The inferred black hole mass is M BH ≈ 7 × 107 M o˙. In addition to reverberations, the fit residuals confirm that emission-line fluxes are depressed during the "BLR Holiday"identified in previous work. Moreover, a helical "Barber-Pole"pattern, with stripes moving from red to blue across the C iv and Lyα line profiles, suggests azimuthal structure rotating with a 2 yr period that may represent precession or orbital motion of inner-disk structures casting shadows on the emission-line region farther out.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

In this contribution, we achieve the primary goal of the active galactic nucleus (AGN) STORM campaign by recovering velocity-delay maps for the prominent broad emission lines (Lyα, C iv, He ii, and Hβ) in the spectrum of NGC 5548. These are the most detailed velocity-delay maps ever obtained for an AGN, providing unprecedented information on the geometry, ionization structure, and kinematics of the broad-line region. Virial envelopes enclosing the emission-line responses show that the reverberating gas is bound to the black hole. A stratified ionization structure is evident. The He ii response inside 5-10 lt-day has a broad single-peaked velocity profile. The Lyα, C iv, and Hβ responses extend from inside 2 to outside 20 lt-day, with double peaks at ±2500 km s-1 in the 10-20 lt-day delay range. An incomplete ellipse in the velocity-delay plane is evident in Hβ. We interpret the maps in terms of a Keplerian disk with a well-defined outer rim at R = 20 lt-day. The far-side response is weaker than that from the near side. The line-center delay days gives the inclination i ≈ 45°. The inferred black hole mass is M BH ≈ 7 × 107 M o˙. In addition to reverberations, the fit residuals confirm that emission-line fluxes are depressed during the "BLR Holiday"identified in previous work. Moreover, a helical "Barber-Pole"pattern, with stripes moving from red to blue across the C iv and Lyα line profiles, suggests azimuthal structure rotating with a 2 yr period that may represent precession or orbital motion of inner-disk structures casting shadows on the emission-line region farther out.

Children differ widely in their early language development, and this variability has important implications for later life outcomes. Parent language input is a strong experiential factor predicting the variability in children's early language skills. However, little is known about the brain or cognitive mechanisms that underlie the relationship. In addressing this gap, we used longitudinal data spanning 15 years to examine the role of early parental language input that children receive during preschool years in the development of brain structures that support language processing during school years. Using naturalistic parent-child interactions, we measured parental language input (amount and complexity) to children between the ages of 18 and 42 months (n = 23). We then assessed longitudinal changes in children's cortical thickness measured at five time points between 9 and 16 years of age. We focused on specific regions of interest (ROIs) that have been shown to play a role in language processing. Our results support the view that, even after accounting for important covariates such as parental intelligence quotient (IQ) and education, the amount and complexity of language input to a young child prior to school forecasts the rate of change in cortical thickness during the 7-year period from 5½ to 12½ years later. Examining the proximal correlates of change in brain and cognitive differences has the potential to inform targets for effective prevention and intervention strategies.

Background: Reversible etiologies of cognitive impairment are common and treatable, yet the majority of mild cognitive impairment (MCI) and dementia research in Latin America has focused on irreversible, neurodegenerative etiologies. Objective: We sought to determine if thyroid dysfunction and vitamin B12 and folate deficiencies are associated with cognitive disorders among older adults with memory complaints in Lima, Peru. Methods: This was a retrospective review of patients who presented for cognitive evaluations to a multidisciplinary neurology clinic in Lima, Peru from January 2014 to February 2020. We included individuals aged ≥60 years, native Spanish-speakers, with at least a primary school educational level and a complete clinical assessment. Patients had either subjective cognitive decline (SCD), MCI, or dementia. One-way ANOVA and multiple logistic regression analyses were performed. Results: We included 720 patients (330 SCD, 154 MCI, and 236 dementia); the dementia group was significantly older [mean age SCD 69.7 ± 4.1, dementia 72.4 ± 3.7 (p = 0.000)] and had lower folate levels than SCD patients. The MCI group had higher free T3 levels compared with SCD patients. Those with lower TSH had greater dementia risk (OR = 2.91, 95%CI: 1.15-6.86) but not MCI risk in unadjusted models. B12 deficiency or borderline B12 deficiency was present in 34% of the dementia group, yet no clear correlation was seen between neuropsychological test results and B12 levels in our study. There was no association between MCI or dementia and thyroid hormone, B12 nor folate levels in adjusted models. Conclusion: Our findings do not support an association between metabolic and endocrine disorders and cognitive impairment in older Peruvians from Lima despite a high prevalence of B12 deficiency. Future work may determine if cognitive decline is associated with metabolic or endocrine changes in Latin America.

Children differ widely in their early language development, and this variability has important implications for later life outcomes. Parent language input is a strong experiential factor predicting the variability in children's early language skills. However, little is known about the brain or cognitive mechanisms that underlie the relationship. In addressing this gap, we used longitudinal data spanning 15 years to examine the role of early parental language input that children receive during preschool years in the development of brain structures that support language processing during school years. Using naturalistic parent-child interactions, we measured parental language input (amount and complexity) to children between the ages of 18 and 42 months (n = 23). We then assessed longitudinal changes in children's cortical thickness measured at five time points between 9 and 16 years of age. We focused on specific regions of interest (ROIs) that have been shown to play a role in language processing. Our results support the view that, even after accounting for important covariates such as parental intelligence quotient (IQ) and education, the amount and complexity of language input to a young child prior to school forecasts the rate of change in cortical thickness during the 7-year period from 5½ to 12½ years later. Examining the proximal correlates of change in brain and cognitive differences has the potential to inform targets for effective prevention and intervention strategies.

Different mating systems are expected to affect the extent and direction of hybridization. Due to the different levels of sexual conflict, the weak inbreeder/strong outbreeder (WISO) hypothesis predicts that gametes from self-incompatible (SI) species should outcompete gametes from self-compatible (SC) ones. However, other factors such as timing of selfing and unilateral incompatibilities may also play a role on the direction of hybridization. In addition, differential mating opportunities provided by different mating systems are also expected to affect the direction of introgression in hybrid zones involving outcrossers and selfers. Here, we explored these hypotheses with a unique case of recent hybridization between two mangrove killifish species with different mating systems, Kryptolebias ocellatus (obligately outcrossing) and K. hermaphroditus (predominantly self-fertilizing) in two hybrid zones in southeast Brazil. Hybridization rates were relatively high (~20%), representing the first example of natural hybridization between species with different mating systems in vertebrates. All F1 individuals were sired by the selfing species. Backcrossing was small, but mostly asymmetrical with the SI parental species, suggesting pattern commonly observed in plant hybrid zones with different mating systems. Our findings shed light on how contrasting mating systems may affect the direction and extent of gene flow between sympatric species, ultimately affecting the evolution and maintenance of hybrid zones.

This article is to alert medical mycologists and infectious disease specialists of recent name changes of medically important species of the filamentous mold FusariumFusarium species can cause localized and life-threating infections in humans. Of the 70 Fusarium species that have been reported to cause infections, close to one-third are members of the Fusarium solani species complex (FSSC), and they collectively account for approximately two-thirds of all reported Fusarium infections. Many of these species were recently given scientific names for the first time by a research group in the Netherlands, but they were misplaced in the genus Neocosmospora In this paper, we present genetic arguments that strongly support inclusion of the FSSC in Fusarium There are potentially serious consequences associated with using the name Neocosmospora for Fusarium species because clinicians need to be aware that fusaria are broadly resistant to the spectrum of antifungals that are currently available.

We present geometric and dynamical modeling of the broad line region (BLR) for the multi-wavelength reverberation mapping campaign focused on NGC 5548 in 2014. The data set includes photometric and spectroscopic monitoring in the optical and ultraviolet, covering the Hβ, C iv, and Ly broad emission lines. We find an extended disk-like Hβ BLR with a mixture of near-circular and outflowing gas trajectories, while the C iv and Ly BLRs are much less extended and resemble shell-like structures. There is clear radial structure in the BLR, with C iv and Ly emission arising at smaller radii than the Hβ emission. Using the three lines, we make three independent black hole mass measurements, all of which are consistent. Combining these results gives a joint inference of . We examine the effect of using the V band instead of the UV continuum light curve on the results and find a size difference that is consistent with the measured UV-optical time lag, but the other structural and kinematic parameters remain unchanged, suggesting that the V band is a suitable proxy for the ionizing continuum when exploring the BLR structure and kinematics. Finally, we compare the Hβ results to similar models of data obtained in 2008 when the active galactic nucleus was at a lower luminosity state. We find that the size of the emitting region increased during this time period, but the geometry and black hole mass remained unchanged, which confirms that the BLR kinematics suitably gauge the gravitational field of the central black hole.

We present geometric and dynamical modeling of the broad line region (BLR) for the multi-wavelength reverberation mapping campaign focused on NGC 5548 in 2014. The data set includes photometric and spectroscopic monitoring in the optical and ultraviolet, covering the Hβ, C iv, and Ly broad emission lines. We find an extended disk-like Hβ BLR with a mixture of near-circular and outflowing gas trajectories, while the C iv and Ly BLRs are much less extended and resemble shell-like structures. There is clear radial structure in the BLR, with C iv and Ly emission arising at smaller radii than the Hβ emission. Using the three lines, we make three independent black hole mass measurements, all of which are consistent. Combining these results gives a joint inference of . We examine the effect of using the V band instead of the UV continuum light curve on the results and find a size difference that is consistent with the measured UV-optical time lag, but the other structural and kinematic parameters remain unchanged, suggesting that the V band is a suitable proxy for the ionizing continuum when exploring the BLR structure and kinematics. Finally, we compare the Hβ results to similar models of data obtained in 2008 when the active galactic nucleus was at a lower luminosity state. We find that the size of the emitting region increased during this time period, but the geometry and black hole mass remained unchanged, which confirms that the BLR kinematics suitably gauge the gravitational field of the central black hole.

This article is to alert medical mycologists and infectious disease specialists of recent name changes of medically important species of the filamentous mold Fusarium Fusarium species can cause localized and life-threating infections in humans. Of the 70 Fusarium species that have been reported to cause infections, close to one-third are members of the Fusarium solani species complex (FSSC), and they collectively account for approximately two-thirds of all reported Fusarium infections. Many of these species were recently given scientific names for the first time by a research group in the Netherlands, but they were misplaced in the genus Neocosmospora In this paper, we present genetic arguments that strongly support inclusion of the FSSC in Fusarium There are potentially serious consequences associated with using the name Neocosmospora for Fusarium species because clinicians need to be aware that fusaria are broadly resistant to the spectrum of antifungals that are currently available.

BackgroundThe activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.MethodsThe effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo.ResultsTumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system.ConclusionWe propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.

Ileal conduit-vaginal fistulas are a rare but challenging complication of urinary diversion. Here we identify risk factors and summarize the workup and conservative management strategies for this complication. We present two cases of elderly women with remote history of cancer who presented with persistent urinary leakage from the vagina several years after ileal conduit creation. Fistulas may be identified using dye or imaging with a loopogram and looposcopy. Correction of obstruction such as stomal stenosis or urinary diversion should be pursued to relieve pressure off the conduit. Minimally invasive management such as fulguration can result temporary relief; however, the recurrence rate is high.

Ileal conduit-vaginal fistulas are a rare but challenging complication of urinary diversion. Here we identify risk factors and summarize the workup and conservative management strategies for this complication. We present two cases of elderly women with remote history of cancer who presented with persistent urinary leakage from the vagina several years after ileal conduit creation. Fistulas may be identified using dye or imaging with a loopogram and looposcopy. Correction of obstruction such as stomal stenosis or urinary diversion should be pursued to relieve pressure off the conduit. Minimally invasive management such as fulguration can result temporary relief; however, the recurrence rate is high.

We present a case of a 14-year-old girl born without the left hemisphere due to prenatal left internal carotid occlusion. We combined longitudinal language and cognitive assessments with functional and structural neuroimaging data to situate the case within age-matched, typically developing children. Despite having had a delay in getting language off the ground during the preschool years, our case performed within the normal range on a variety of standardized language tests, and exceptionally well on phonology and word reading, during the elementary and middle school years. Moreover, her spatial, number, and reasoning skills also fell in the average to above-average range based on assessments during these time periods. Functional MRI data revealed activation in right fronto-temporal areas when listening to short stories, resembling the bilateral activation patterns in age-matched typically developing children. Diffusion MRI data showed significantly larger dorsal white matter association tracts (the direct and anterior segments of the arcuate fasciculus) connecting areas active during language processing in her remaining right hemisphere, compared to either hemisphere in control children. We hypothesize that these changes in functional and structural brain organization are the result of compensatory brain plasticity, manifesting in unusually large right dorsal tracts, and exceptional performance in phonology, speech repetition, and decoding. More specifically, we posit that our case's large white matter connections might have played a compensatory role by providing fast and reliable transfer of information between cortical areas for language in the right hemisphere.

Circumscribed storiform collagenoma is a rare benign tumor. It appears as an isolated skin lesion or as part of the clinical spectrum of Cowden syndrome. The pathogenesis is still controversial. Although its clinical expression is heterogeneous, it has a characteristic histological pattern. We describe a case of a solitary circumscribed storiform collagenoma not associated with Cowden syndrome.

ObjectivesHIV-1 heterosexual transmission among individuals on antiretroviral treatment (ART) with undetectable viremia is extremely rare. The aim of this study was to evaluate the risk of sexual HIV-1 transmission and other sexually transmitted infections (STIs) in HIV-1 serodifferent couples while the index partner is on ART.MethodsHIV transmission was evaluated in 200 HIV-1 heterosexual serodifferent couples in a stable relationship (≥3 months). All HIV-positive individuals had been on ART for ≥3 months and had been followed up for a median preceding time of 4.5 years (range 0.3-16 years) at the HIV couples clinic at Hospital Nossa Senhora da Conceição in Porto Alegre, Brazil. Following written informed consent, participants responded to demographic/behavioral questionnaires. Quantitative PCR for HIV RNA, T-cell subsets, and STI testing (syphilis, herpes, human papillomavirus, gonorrhea, and bacterial vaginosis) were performed. Self-collected vaginal swabs were obtained for quantitative HIV genital viral load testing.ResultsAmong 200 couples, 70% of index partners were female. Five seroconversions were observed; the HIV infection incidence was 2.5% (95% confidence interval 0.8% to 5.7%). Mean plasma viral load results were higher in HIV transmitters compared to non-transmitters (p=0.02). The presence of STIs was significantly greater in couples who seroconverted (60.0% vs. 13.3%; odds ratio 9.75, 95% confidence interval 1.55-61.2; p=0.023). The duration of undetectable HIV viremia and presence of STIs were associated with HIV transmission.ConclusionsUndetectable viremia was the main factor associated with non-transmissibility of HIV in this setting.

The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1β served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1β and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1β, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1β and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.

BackgroundAn undetectable serum HIV-1 load is key to effectiveness of antiretroviral (ARV) therapy, which depends on adherence to treatment. We evaluated factors possibly associated with ARV adherence and virologic response in HIV-infected heterosexual individuals.MethodsA cross-sectional study was conducted in 200 HIV-1 serodiscordant couples and 100 unpartnered individuals receiving ARV treatment at a tertiary hospital in southern Brazil. All subjects provided written informed consent, answered demographic/behavioral questionnaires through audio computer-assisted self-interviews (ACASI), and collected blood and vaginal samples for biological markers and assessment of sexually transmitted infections (STIs). HIV-negative partners were counseled and tested for HIV-1.ResultsThe study population mean age was 39.9 years, 53.6% were female, 62.5% were Caucasian, 52.6% had incomplete or complete elementary education, 63.1% resided in Porto Alegre. Demographic, behavioral and biological marker characteristics were similar between couples and single individuals. There was an association between adherence reported on ACASI and an undetectable serum viral load (P