Cross-Phenotype GWAS Supports Shared Genetic Susceptibility to Systemic Sclerosis and Primary Biliary Cholangitis.

Objective: An increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype GWAS meta-analysis. Methods: We performed cross-phenotype GWAS meta-analysis and colocalization analysis for SSc and PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, colocalization analyses with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci. Results: We detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 × 10-6). In the cross-phenotype GWAS meta-analysis, we identified 44 non-HLA loci that reached genome-wide significance (p < 5 × 10-8). Evidence of shared causal variants between SSc and PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3, and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function. Conclusion: Our study supports a strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders.

Molecular patterns and mechanisms of tumorigenesis in HPV-associated and HPV-independent sinonasal squamous cell carcinoma.

Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly described due to its rare nature. A subset of SNSCC are associated with the human papillomavirus (HPV); however, it is unknown whether HPV is a driver of HPV-associated SNSCC tumorigenesis or merely a neutral bystander. We hypothesized that performing the first large high-throughput sequencing study of SNSCC would reveal molecular mechanisms of tumorigenesis driving HPV-associated and HPV-independent SNSCC and identify targetable pathways. High-throughput sequencing was performed on 64 patients with HPV-associated and HPV-independent sinonasal carcinomas. Mutation annotation, viral integration, copy number, and pathway-based analyses were performed. Analysis of HPV-associated SNSCC revealed similar mutational patterns observed in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations and the presence of known hotspot mutations in PI3K and FGFR3. Further similarities included enrichment of APOBEC mutational signature, viral integration at known hotspot locations, and frequent mutations in epigenetic regulators. HPV-associated SNSCC-specific recurrent mutations were also identified including KMT2C , UBXN11 , AP3S1 , MT-ND4 , and MT-ND5 . Mutations in KMT2D and FGFR3 were associated with decreased overall survival. We developed the first known HPV-associated SNSCC cell line and combinatorial small molecule inhibition of YAP/TAZ and PI3K pathways synergistically inhibited tumor cell clonogenicity. In conclusion, HPV-associated SNSCC and HPV-independent SNSCC are driven by molecularly distinct mechanisms of tumorigenesis. Combinatorial blockade of YAP/TAZ and vertical inhibition of the PI3K pathway may be useful in targeting HPV-associated SNSCC whereas targeting MYC and horizontal inhibition of RAS/PI3K pathways for HPV-independent SNSCC. One Sentence Summary: This study solidifies HPV as a driver of HPV-associated SNSCC tumorigenesis, identifies molecular mechanisms distinguishing HPV-associated and HPV-independent SNSCC, and elucidates YAP/TAZ and PI3K blockade as key targets for HPV-associated SNSCC.

Deep brain stimulation in Latin America in comparison with the US and Europe in a real-world population: indications, demographics, techniques, technology, and adverse events.

OBJECTIVE: The aim of this study was to provide geographic comparisons of deep brain stimulation (DBS) procedures in Latin America with the US and Europe regarding primary indications, demographic information, clinical and device-related adverse events, technology used, and patient outcomes using the Medtronic Product Surveillance Registry data as of July 31, 2021. METHODS: Two thousand nine hundred twelve patients were enrolled in the registry (2782 received DBS and 1580 are currently active). Fourteen countries contributed 44,100 years of device experience to the registry. DBS centers in Latin America are located in Colombia (n = 3), Argentina (n = 1), Brazil (n = 1), and Mexico (n = 1). Fisher's exact test was used to compare the difference in proportions of categorical variables between regions. The Wilcoxon signed-rank test was used for the EQ-5D index score change from baseline to follow-up. RESULTS: The most common indication for DBS was Parkinson's disease across all regions. In Latin America, dystonia was the second most common indication, compared to essential tremor in other regions. There was a striking finding with respect to age-patients were an average of 10 years younger at DBS implantation in Latin America. This difference was most likely due to the greater number of patients with dystonia receiving the device implants. The intraoperative techniques were quite similar, showing the same level of quality and covering the main principles of the surgeries with some variations in the brand of frames, planning software, and microrecording systems. Rechargeable batteries were significantly more common in Latin America (72.37%) than in the US (6.44%) and Europe (9.9%). Staging of the DBS procedure differed, with only 11.84% in Latin America staging the procedure compared with 97.58% and 34.86% in the US and Europe, respectively. The EQ-5D score showed significant improvements in all regions during the first 6-12 months (p < 0.0001). However, the 24-month follow-up only showed an improvement in the scale for Latin America (p < 0.0001). CONCLUSIONS: DBS was performed in Latin America with similar indications, techniques, and technology as in the US and Europe. Important differences were found, with Latin America implementing more regular use of rechargeable devices, including younger patients at the time of surgery, and showing more sustained quality of life improvements at 24 months of follow-up. The authors hypothesize that these disparities stem from differences in resources among regions. However, more studies are needed to standardize DBS practice across the world to improve patients' quality of life and provide high-quality care.

Ultradense Array of On-Chip Sensors for High-Throughput Electrochemical Analyses.

High-throughput sensors are valuable tools for enabling massive, fast, and accurate diagnostics. To yield this type of electrochemical device in a simple and low-cost way, high-density arrays of vertical gold thin-film microelectrode-based sensors are demonstrated, leading to the rapid and serial interrogation of dozens of samples (10 µL droplets). Based on 16 working ultramicroelectrodes (UMEs) and 3 quasi-reference electrodes (QREs), a total of 48 sensors were engineered in a 3D crossbar arrangement that devised a low number of conductive lines. By exploiting this design, a compact chip (75 × 35 mm) can enable performing 16 sequential analyses without intersensor interferences by dropping one sample per UME finger. In practice, the electrical connection to the sensors was achieved by simply switching the contact among WE adjacent fingers. Importantly, a short analysis time was ensured by interrogating the UMEs with chronoamperometry or square wave voltammetry using a low-cost and hand-held one-channel potentiostat. As a proof of concept, the detection of Staphylococcus aureus in 15 samples was performed within 14 min (20 min incubation and 225 s reading). Additionally, the implementation of peptide-tethered immunosensors in these chips allowed the screening of COVID-19 from patient serum samples with 100% accuracy. Our experiments also revealed that dispensing additional droplets on the array (in certain patterns) results in the overestimation of the faradaic current signals, a phenomenon referred to as crosstalk. To address this interference, a set of analyses was conducted to design a corrective strategy that boosted the testing capacity by allowing using all on-chip sensors to address subsequent analyses (i.e., 48 samples simultaneously dispensed on the chip). This strategy only required grounding the unused rows of QRE and can be broadly adopted to develop high-throughput UME-based sensors. In practice, we could analyze 48 droplets (with [Fe(CN)6]4-) within ∼8 min using amperometry.

Design of PEG-based hydrogels as soft ionic conductors.

Conductive hydrogels have gained interest in biomedical applications and soft electronics. To tackle the challenge of ionic hydrogels falling short of desired mechanical properties in previous studies, our investigation aimed to understand the pivotal structural factors that impact the conductivity and mechanical behavior of polyethylene glycol (PEG)-based hydrogels with ionic conductivity. Polyether urethane diacrylamide (PEUDAm), a functionalized long-chain macromer based on PEG, was used to synthesize hydrogels with ionic conductivity conferred by incorporating ions into the liquid phase of hydrogel. The impact of salt concentration, water content, temperature, and gel formation on both mechanical properties and conductivity was characterized to establish parameters for tuning hydrogel properties. To further expand the range of conductivity available in these ionic hydrogels, 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) was incorporated as a single copolymer network or double network configuration. As expected, conductivity in these ionic gels was primarily driven by ion diffusivity and charge density, which was dependent on hydrogel network formation and swelling. Copolymer network structure had minimal effect on the conductivity which was primarily driven by counter-ion equilibrium; however, the mechanical properties and equilibrium swelling was strongly dependent on network structure. The structure-property relationships elucidated here enables the rationale design of this new double network hydrogel to achieve target properties for a broad range of applications.

Implicit and Explicit Sequence Learning in Adults With Developmental Language Disorder.

PURPOSE: Developmental language disorder (DLD) is a neurodevelopmental disorder that impacts approximately 7% of the population and is characterized by unexplained deficits in expressive and/or receptive components of language. A common procedural learning task, serial reaction time (SRT), has been used to develop models of the basis of DLD. However, paradigms involve differing levels of implicit and explicit learning during this task, muddying interpretations of the data. Here, we tested adults with DLD on implicit and explicit SRT tasks to better understand implicit and explicit procedural learning in this population. We hypothesized that adults with DLD would demonstrate reduced learning on only the implicit SRT task, as alternate explicit neural mechanisms could lead to equivalent performance on the explicit task. METHOD: Fifty participants (25 with DLD and 25 with typical language) completed implicit and explicit SRT tasks, measuring their ability to learn visually presented 10-element sequences. Group differences were evaluated on sequence learning, error rates, and explicit recall of the sequence after learning. RESULTS: Sequence learning was the same between the groups on both tasks. However, individuals with DLD showed increased errors and significantly worse recall of the explicitly learned sequence. CONCLUSIONS: Results suggest that sequence learning may be intact in this population, while aspects of explicit learning and motoric responses are impaired. Results are interpreted in light of a neurobiological model of DLD. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26210651.

Catalysis of an SN2 pathway by geometric preorganization.

Bimolecular nucleophilic substitution (SN2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry1. Despite the importance of SN2 pathways in synthesis, catalytic control of ionic SN2 pathways is rare and notably uncommon even in biocatalysis2,3, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the SN2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity4. Here we show that a small-molecule (646 Da) hydrogen-bond-donor (HBD) catalyst accelerates the SN2 step of an enantioselective Michaelis-Arbuzov reaction by recapitulating the geometric preorganization principle employed by enzymes. Mechanistic and computational investigations reveal that the HBD diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the SN2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations. This work constitutes, to our knowledge, the first demonstration of catalytic enantiocontrol of the phosphonium dealkylation step, establishing a new platform for the synthesis of P-stereogenic compounds.

Association of Global Ultraviolet Radiation With the Incidence of Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: Inflammation is a key pathomechanism for growth and rupture of intracranial aneurysms. Anti-inflammatory mechanisms may reduce rupture of intracranial aneurysms and the incidence of aneurysmal subarachnoid hemorrhage (SAH). Ultraviolet (UV) radiation from sunlight exposure induces systemic anti-inflammatory responses through immunosuppressive mechanisms. We studied whether SAH incidence is associated with UV radiation. METHODS: Global SAH incidence, time trends, and regional differences from 32 countries were linked to UV radiation data from the Tropospheric Emission Monitoring Internet Service. Odds between low vs high UV exposure and SAH incidence were calculated. Correlation analysis was performed using R (R 4.1.2). RESULTS: SAH incidences ranged from 1.3 to 27 per 100 000 patient-years (p-y) and UV index from 1.76 to 11.27. The correlation coefficient (rho) between SAH incidence and UV index was -0.48 (P = .012). SAH incidence was highest in Japan (13.7-27.9 p-y) with an UV index 6.28. UV index was highest in Chile 11.27 with a lower SAH incidence (3.8-4.8 p-y). The lowest UV index 1.76 was seen in Iceland with higher SAH incidence (9.8 p-y).Within Europe, regions with higher UV indices reported lower SAH incidences (Northwest Europe: SAH incidence p-y 8.61/UV index 2.85; Southeast Europe: SAH incidence p-y 7.37/UV index 4.65) with a significant inverse correlation (rho = -0.68, P = .004) and not a significant correlation between non-European countries (rho = -0.43, P = .19). Low exposure of UV radiation in global regions predicted higher than median incidences of SAH with an odds ratio 5.13 (95% CIs 1.02-31.5). CONCLUSION: The incidence of SAH is inversely associated with UV radiation. Further studies should assess the actual UV exposure in relation to SAH incidence and potential biological explanations for the relation we found.

Differences in Cortical Surface Area in Developmental Language Disorder.

Approximately 7% of children have developmental language disorder (DLD), a neurodevelopmental condition associated with persistent language learning difficulties without a known cause. Our understanding of the neurobiological basis of DLD is limited. Here, we used FreeSurfer to investigate cortical surface area and thickness in a large cohort of 156 children and adolescents aged 10-16 years with a range of language abilities, including 54 with DLD, 28 with a history of speech-language difficulties who did not meet criteria for DLD, and 74 age-matched controls with typical language development (TD). We also examined cortical asymmetries in DLD using an automated surface-based technique. Relative to the TD group, those with DLD showed smaller surface area bilaterally in the inferior frontal gyrus extending to the anterior insula, in the posterior temporal and ventral occipito-temporal cortex, and in portions of the anterior cingulate and superior frontal cortex. Analysis of the whole cohort using a language proficiency factor revealed that language ability correlated positively with surface area in similar regions. There were no differences in cortical thickness, nor in asymmetry of these cortical metrics between TD and DLD. This study highlights the importance of distinguishing between surface area and cortical thickness in investigating the brain basis of neurodevelopmental disorders and suggests the development of cortical surface area to be of importance to DLD. Future longitudinal studies are required to understand the developmental trajectory of these cortical differences in DLD and how they relate to language maturation.

Relationship between Simulated Fire Suppression Activities and Acute Cardiac and Respiratory Events in Firefighters.

Cardiac deaths account for the largest share of on-duty firefighter deaths. To help ensure duty fitness and minimize injury risk, many fire departments require the passing of an annual physical ability test, consisting of a battery of simulated fire suppression activities (sFSAs). The purpose of the study was to determine the relationship of sFSA performance to acute cardiac and respiratory events (ACREs) and the effect that estimated VO2max has on sFSA performance. The study was retrospective. As part of an annual physical ability test, five timed sFSAs were performed, summed for a composite time, and categorized into three performance levels (fast, moderate, and slow). Estimated VO2max was determined using the Forestry Step Test. A significant (p = 0.023) linear trend was observed with higher sFSA performance times being associated with a higher proportion of firefighters going on to suffer an ACRE. The estimated VO2max was significantly (p < 0.001) higher in the fast group compared to the slow group. There was not a significant (p = 0.70) difference in estimated VO2max between the moderate and slow groups. Estimated VO2max performance and sFSA performance were significantly correlated, with rs(488) = -0.272 and p < 0.001. Poorer sFSA performance was found to be associated with a higher proportion of ACREs. The results suggest that sFSA performance may be a valid indicator of ACRE injury risk and aerobic capacity.

Can money buy control of Congress?

Can a political party spend enough across electoral campaigns to garner a majority within the U.S. Congress? Prior research on campaign spending minimizes the importance of campaign heterogeneity and fails to aggregate effects across campaigns, rendering it unable to address this question. Instead, we tackle the question with a system-level analysis of campaign expenditures. First, using a flexible machine learning approach, we show that spending has substantial and nonlinear marginal effects on outcomes at the level of the campaign. Second, by aggregating these effects to the entire U.S. Congress, we show that large seat swings that change congressional control have, in the past, been possible for expenditure levels consonant with those presently observed after having removed the most extreme levels. However, this possibility appears to have faded over the past decade. Our approach also allows us to illustrate the often significant effects that eliminating campaign spending could have.

Deconstructing synthetic biology across scales: a conceptual approach for training synthetic biologists.

Synthetic biology allows us to reuse, repurpose, and reconfigure biological systems to address society's most pressing challenges. Developing biotechnologies in this way requires integrating concepts across disciplines, posing challenges to educating students with diverse expertise. We created a framework for synthetic biology training that deconstructs biotechnologies across scales-molecular, circuit/network, cell/cell-free systems, biological communities, and societal-giving students a holistic toolkit to integrate cross-disciplinary concepts towards responsible innovation of successful biotechnologies. We present this framework, lessons learned, and inclusive teaching materials to allow its adaption to train the next generation of synthetic biologists.

Cancer Cell Small Molecule Secretome Induces the Immune Checkpoint NKG2A and Dysfunction of Human CD8+ T Cells.

PD-1 blockade has been approved for head and neck squamous cell carcinoma (HNSCC) patients. However, many HNSCC patients do not respond to this treatment, and other tumor microenvironmental factors may promote resistance to PD-1 blockade. We previously identified increased expression of the inhibitory receptor NKG2A on CD8+ T cells in HNSCC tumors compared with T cells in matching PBMC samples. Mechanisms that promote NKG2A expression and the role of NKG2A on human T cells in the tumor microenvironment, however, are uncertain. In this study, we show that tumor-conditioned media (TCM) of HNSCC cancer cell lines or ascites fluid from colorectal carcinoma patients is sufficient to induce the expression of NKG2A and other inhibitory receptors on activated CD8+ T cells isolated from PBMCs of healthy donors. Boiling or small molecular mass cutoff filtering did not eliminate the effect of TCM, suggesting that a small molecule promotes NKG2A. T cell activation in TCM decreased the basal and maximal mitochondrial respiration to metabolically restrain CD8+ T cells. Functionally, T cell activation in TCM reduced CD8+ T cell cytotoxicity as shown by lower production of cytokines, granzyme B, and perforin. Furthermore, TCM prevented CD8+ T cells from killing cancer cells in response to an anti-CD19/anti-CD3 bispecific T cell engager. Thus, a small secreted molecule from HNSCC cells can induce NKG2A expression and promote T cell dysfunction. Our findings may lead to targets for novel cancer therapies or biomarkers for NKG2A blockade response and provide a model to study T cell dysfunction and impaired metabolism.

Environmental and ecological factors affecting tick infestation in wild birds of the Americas.

The Americas hold the greatest bird diversity worldwide. Likewise, ectoparasite diversity is remarkable, including ticks of the Argasidae and Ixodidae families - commonly associated with birds. Considering that ticks have potential health implications for humans, animals, and ecosystems, we conducted a systematic review to evaluate the effects of bioclimatic, geographic variables, and bird species richness on tick infestation on wild birds across the Americas. We identified 72 articles that met our inclusion criteria and provided data on tick prevalence in wild birds. Using Generalized Additive Models, we assessed the effect of environmental factors, such as habitat type, climatic conditions, bird species richness, and geographic location, on tick infestation. Our findings show that most bird infestation case studies involved immature ticks, such as larvae or nymphs, while adult ticks represented only 13% of case studies. We found birds infested by ticks of the genera Amblyomma (68%), Ixodes (22%), Haemaphysalis (5%), Dermacentor (1%), and Rhipicephalus (0.8%) in twelve countries across the Americas. Our findings revealed that temperature variation and bird species richness were negatively associated with tick infestation, which also varied with geographic location, increasing in mid-latitudes but declining in extreme latitudes. Our results highlight the importance of understanding how environmental and bird community factors influence tick infestation in wild birds across the Americas and the dynamics of tick-borne diseases and their impact on biodiversity.

Avian haemosporidians of the genera Plasmodium and Haemoproteus from resident and Neotropical migrant birds in Colombia.

Avian haemosporidians of the genera Plasmodium and Haemoproteus are a group of widely distributed blood parasites that can negatively affect the fitness of their hosts. Colombia contains the greatest diversity of birds on the planet, but knowledge about the associations between haemosporidian and its avifauna is scarce and fragmented. We collected blood samples from 255 birds (203 residents and 52 neotropical migrants) belonging to 27 families and 108 species. The study was conducted in six localities in the inter-Andean valleys of the Cauca and Magdalena rivers. Parasites of the genera Plasmodium and Haemoproteus were identified in the samples by morphological and molecular analysis of a fragment of the mitochondrial gene cyt b. Among the samples, 9.3% (n = 24) were positive for Plasmodium or Haemoproteus. Co-infection with Plasmodium and Haemoproteus was found in Red-eyed Vireo. Seventeen haemosporidian lineages were identified, five of which were reported for the first time in resident birds (Common Ground Dove, Checker-throated Stipplethroat, Tropical Kingbird, Pale-breasted Thrush, and Ruddy-breasted Seedeater) and one in the Summer Tanager (neotropical migrant). The research results confirm the wide diversity of haemosporidian present in tropical lowlands and the possible role of neotropical migratory birds in dissemination on haemosporidian along their migratory routes.

Psychedelic 25H-NBOMe attenuates post-sepsis depression in rats.

Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the efficacy of 25H-NBOMe, a phenethylamine, in alleviating these symptoms, potentially offering an innovative treatment for post-sepsis depression. Wistar rats, weighing between 250-300 g, were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis. Depressive-like behaviors were assessed using the forced swim test (FST) on either day 7 or 14 post-surgery, to establish the presence of depressive symptoms. The impact of 25H-NBOMe treatment was then evaluated, focusing on the head-twitch response (HTR), performance in the FST, and GFAP expression in the prefrontal cortex. Treatment with 25H-NBOMe resulted in significant behavioral changes, demonstrated by decreased immobility and increased swimming times in the FST, along with a rise in the HTR. These outcomes indicate a reduction in depressive-like symptoms post-sepsis and the psychoactive effects of the compound. Furthermore, a notable decrease in GFAP expression in the study highlights the compound's impact on mitigating sepsis-induced astrogliosis. This study demonstrates the effectiveness of 25H-NBOMe, a psychedelic in the phenethylamine class, in treating post-sepsis depression and reducing astrogliosis. However, the psychedelic nature of 25H-NBOMe calls for further investigation into similar compounds with less psychoactive impact, crucial for advancing treatment options for neuropsychiatric symptoms following sepsis.

Ultra-Early and Short-Term Tranexamic Acid Treatment in Patients With Good- and Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: The results of the ULTRA trial showed that ultra-early and short-term treatment with tranexamic acid (TXA) does not improve clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Possibly, the lack of a beneficial effect in all patients with aSAH is masked by antagonistic effects of TXA in certain subgroups. In this post hoc subgroup analysis, we investigated the effect of TXA on clinical outcome in patients with good-grade and poor-grade aSAH. METHODS: The ULTRA trial was a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment. Participants received ultra-early and short-term TXA in addition to usual care or usual care only. This post hoc subgroup analysis included only ULTRA participants with confirmed aSAH and available World Federation of Neurosurgical Societies (WFNS) grade on admission. Patients were categorized into those with good-grade (WFNS 1-3) and poor-grade (WFNS 4-5) aSAH. The primary outcome was clinical outcome assessed by the modified Rankin scale (mRS). Odds ratios (ORs) and adjusted ORs (aORs) with 95% CIs were calculated using ordinal regression analyses. Analyses were performed using the as-treated principle. In all patients with aSAH, no significant effect modification of TXA on clinical outcome was observed for admission WFNS grade (p = 0.10). RESULTS: Of the 812 ULTRA participants, 473 patients had (58%; N = 232 TXA, N = 241 usual care) good-grade and 339 (42%; N = 162 TXA, N = 176 usual care) patients had poor-grade aSAH. In patients with good-grade aSAH, the TXA group had worse clinical outcomes (OR: 0.67, 95% CI 0.48-0.94, aOR 0.68, 95% CI 0.48-0.94) compared with the usual care group. In patients with poor-grade aSAH, clinical outcomes were comparable between treatment groups (OR: 1.04, 95% CI 0.70-1.55, aOR 1.05, 95% CI 0.70-1.56). DISCUSSION: This post hoc subgroup analysis provides another important argument against the use of TXA treatment in patients with aSAH, by showing worse clinical outcomes in patients with good-grade aSAH treated with TXA and no clinical benefit of TXA in patients with poor-grade aSAH, compared with patients treated with usual care. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid, given for <24 hours within the first 24 hours, does not improve the 6-month outcome in good-grade or poor initial-grade aneurysmal SAH.

Widespread Horizontal Gene Transfer Among Animal Viruses.

The initial objective of this study was to shed light on the evolution of small DNA tumor viruses by analyzing de novo assemblies of publicly available deep sequencing datasets. The survey generated a searchable database of contig snapshots representing more than 100,000 Sequence Read Archive records. Using modern structure-aware search tools, we iteratively broadened the search to include an increasingly wide range of other virus families. The analysis revealed a surprisingly diverse range of chimeras involving different virus groups. In some instances, genes resembling known DNA-replication modules or known virion protein operons were paired with unrecognizable sequences that structural predictions suggest may represent previously unknown replicases and novel virion architectures. Discrete clades of an emerging group called adintoviruses were discovered in datasets representing humans and other primates. As a proof of concept, we show that the contig database is also useful for discovering RNA viruses and candidate archaeal phages. The ancillary searches revealed additional examples of chimerization between different virus groups. The observations support a gene-centric taxonomic framework that should be useful for future virus-hunting efforts.

The lysosomal trafficking regulator "LYST": an 80-year traffic jam.

Lysosomes and lysosome related organelles (LROs) are dynamic organelles at the intersection of various pathways involved in maintaining cellular hemostasis and regulating cellular functions. Vesicle trafficking of lysosomes and LROs are critical to maintain their functions. The lysosomal trafficking regulator (LYST) is an elusive protein important for the regulation of membrane dynamics and intracellular trafficking of lysosomes and LROs. Mutations to the LYST gene result in Chédiak-Higashi syndrome, an autosomal recessive immunodeficiency characterized by defective granule exocytosis, cytotoxicity, etc. Despite eight decades passing since its initial discovery, a comprehensive understanding of LYST's function in cellular biology remains unresolved. Accumulating evidence suggests that dysregulation of LYST function also manifests in other disease states. Here, we review the available literature to consolidate available scientific endeavors in relation to LYST and discuss its relevance for immunomodulatory therapies, regenerative medicine and cancer applications.

Measuring algorithmic bias to analyze the reliability of AI tools that predict depression risk using smartphone sensed-behavioral data.

AI tools intend to transform mental healthcare by providing remote estimates of depression risk using behavioral data collected by sensors embedded in smartphones. While these tools accurately predict elevated symptoms in small, homogenous populations, recent studies show that these tools are less accurate in larger, more diverse populations. In this work, we show that accuracy is reduced because sensed-behaviors are unreliable predictors of depression across individuals; specifically the sensed-behaviors that predict depression risk are inconsistent across demographic and socioeconomic subgroups. We first identified subgroups where a developed AI tool underperformed by measuring algorithmic bias, where subgroups with depression were incorrectly predicted to be at lower risk than healthier subgroups. We then found inconsistencies between sensed-behaviors predictive of depression across these subgroups. Our findings suggest that researchers developing AI tools predicting mental health from behavior should think critically about the generalizability of these tools, and consider tailored solutions for targeted populations.