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The ongoing outbreaks of mpox highlight the urgent need for a rapid and low-cost diagnostic test to accurately detect and control this emerging disease. We estimated the analytical sensitivity using viral culture of the monkeypox virus clade IIb lineage B1 and clinical diagnostic performance of 3 antigen detection rapid diagnostic tests (Ag-RDT) by using skin swab samples and upper-respiratory swab samples from mpox patients in the Democratic Republic of the Congo and the United Kingdom. The analytical limit of detection was 1.0 × 10 plaque-forming units/mL, fulfilling World Health Organization recommendations. Specificity of the 3 Ag-RDTs was 100%, but sensitivity was estimated at 0.00%-15.79% using skin samples and 0.00% using respiratory samples. None of the 3 Ag-RDTs reached the World Health Organization's target clinical sensitivity, and we do not recommend them as diagnostic or screening tools for suspected mpox cases. Accurate Ag-RDTs for mpox diagnosis remain urgently needed.

Antibiotics have been key to the treatment of bacterial infections since their introduction, but the increasing levels of antimicrobial resistance is a concern. Patients with serious respiratory conditions, such as those often encountered within critical care units like ventilator-associated pneumonia (VAP), are most under threat as a result of increasing resistance, especially due to the patients’ critical condition. Despite a better understanding of increasing resistance, other effects of treatment with antibiotics on bacterial phenotypes remain poorly understood, and it is therefore important and timely to identify and study key traits that bacteria present because of adaptation to antimicrobial treatment. In this study, a clinical strain of Pseudomonas aeruginosa was exposed to antibiotics that are commonly prescribed to treat VAP patients, and tested its ability to grow and form biofilms through in vitro testing under a number of experimental conditions, including co-infection and limited growth media. Whole genome sequencing data was collected to identify genetic mutations correlated to such growth. The findings included in this thesis indicates that the P. aeruginosa clinical strain was able to adapt to all antibiotics prescribed, including the Ceftazidime/Avibactam combination. Further analysis of growth and biofilm formation patterns included as part of study indicate that the adapted bacteria differ in growth patterns and biofilm formation in contrast to the un-adapted Parent. Further evidence is needed, however, to clarify whether these differences are indeed as a result of adaptation to antibiotics. Subsequent whole genome sequencing detected SNPs in several genes of interest, including the OprD domain. Future studies should continue to analyse the genetic expression of adapted strains through transcriptomics, and incorporate methods that are more applicable to patient lung environments.

Machines powered by artificial intelligence increasingly mediate our social, cultural, economic and political interactions. Understanding the behaviour of artificial intelligence systems is essential to our ability to control their actions, reap their benefits and minimize their harms. Here we argue that this necessitates a broad scientific research agenda to study machine behaviour that incorporates and expands upon the discipline of computer science and includes insights from across the sciences. We first outline a set of questions that are fundamental to this emerging field and then explore the technical, legal and institutional constraints on the study of machine behaviour. Understanding the behaviour of the machines powered by artificial intelligence that increasingly mediate our social, cultural, economic and political interactions is essential to our ability to control the actions of these intelligent machines, reap their benefits and minimize their harms.

Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn’s disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2 . Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency ( NOD2 ) and effect ( TNFSF15 ). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS. Genome-wide association analyses across individuals of East Asian and European ancestries identify new risk loci for inflammatory bowel diseases. A polygenic risk score derived from the combined datasets shows improved prediction accuracy.

The range of the mosquito Aedes aegypti continues to expand, putting more than two billion people at risk of arboviral infection. The sterile insect technique (SIT) has been used to successfully combat agricultural pests at large scale, but not mosquitoes, mainly because of challenges with consistent production and distribution of high-quality male mosquitoes. We describe automated processes to rear and release millions of competitive, sterile male Wolbachia- infected mosquitoes, and use of these males in a large-scale suppression trial in Fresno County, California. In 2018, we released 14.4 million males across three replicate neighborhoods encompassing 293 hectares. At peak mosquito season, the number of female mosquitoes was 95.5% lower (95% CI, 93.6–96.9) in release areas compared to non-release areas, with the most geographically isolated neighborhood reaching a 99% reduction. This work demonstrates the high efficacy of mosquito SIT in an area ninefold larger than in previous similar trials, supporting the potential of this approach in public health and nuisance-mosquito eradication programs. Mosquitoes are nearly eradicated in three suburbs of California using accurately sorted sterile male mosquitoes.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn’s disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C , we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation. Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn’s disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

Background: Adherence to treatment is critical for successful treatment outcomes. Although factors influencing antiretroviral therapy (ART) adherence vary, young adults are less likely to adhere owing to psychosocial issues such as stigma, ART-related side effects, and a lack of access to treatment. The Call for Life Uganda (CFLU) mobile health (mHealth) tool is a mobile phone–based technology that provides text messages or interactive voice response functionalities through a web interface and offers 4 modules of support. Objective: This study aims to describe the acceptability and feasibility of a mobile phone support tool to promote adherence to ART among young adults in a randomized controlled trial. Methods: An exploratory qualitative design with a phenomenological approach at 2 study sites was used. A total of 17 purposively selected young adults with HIV infection who had used the mHealth tool CFLU from 2 clinics were included. In total, 11 in-depth interviews and 1 focus group discussion were conducted to examine the following topics: experience with the CFLU tool (benefits and challenges), components of the tool, the efficiency of the system (level of comfort, ease, or difficulty in using the system), how CFLU resolved adherence challenges, and suggestions to improve CFLU. Participants belonged to 4 categories of interest: young adults on ART for the prevention of mother-to-child transmission, young adults switching to or on the second-line ART, positive partners in an HIV-discordant relationship, and young adults initiating the first-line ART. All young adults had 12 months of daily experience using the tool. Data were analyzed using NVivo version 11 software (QSR International Limited) based on a thematic approach. Results: The CFLU mHealth tool was perceived as an acceptable intervention; young adults reported improvement in medication adherence, strengthened clinician-patient relationships, and increased health knowledge from health tips. Appointment reminders and symptom reporting were singled out as beneficial and helped to address the problems of forgetfulness and stigma-related issues. HIV-related stigma was reported by a few young people. Participants requested extra support for scaling up CFLU to make it more youth friendly. Improving the tool to reduce technical issues, including network outages and a period of software failure, was suggested. They suggested that in addition to digital solutions, other support, including the promotion of peer support meetings and the establishment of a designated space and staff members for youth, was also important. Conclusions: This mHealth tool was an acceptable and feasible strategy for improving ART adherence and retention among young adults in resource-limited settings. Trial Registration: ClinicalTrials.gov NCT02953080; https://clinicaltrials.gov/ct2/show/NCT02953080

The taxonomy of sculpins (Cottus, Cottidae) remains one of the last major unresolved puzzles in the systematics of North American freshwater fishes. We used molecular approaches to identify candidate taxa and their distribution across western North America. We crowd-sourced the collection of specimens (n = 8272) via outreach to biologists in the western United States and Canada. From that collection, we sequenced—at up to 2 mitochondrial and 2 nuclear genes—a subset (n = 4009) of specimens from most basins in the western United States, added sequences from public sequence databases, and applied an array of species delimitation and specimen identification methods to assess phylogenetic and spatial patterns of diversity. Species delimitation methods, primarily relying on a conservative interpretation of the phylogenetic species concept, were broadly concordant and indicated that 43 candidate species were present. Some named taxa were unsupported, whereas others, if recognized, would violate the phylogenetic species concept. Specimen assignment was largely unambiguous and geographic distributions were consistent with phylogeographic patterns in other taxa. Our work establishes a benchmark for understanding the diversity of sculpin in western North America and suggests new species hypotheses both there and in eastern North America. La taxonomía de los sculpins (Cottus, Cottidae) sigue siendo uno de los últimos grandes rompecabezas sin resolver en la sistemática de los peces de agua dulce de Norteamérica. Utilizamos métodos moleculares para identificar los taxones candidatos y su distribución en el oeste de Norteamérica. Recolectamos especímenes (n = 8272) a través de una campaña de divulgación entre biólogos del oeste de Estados Unidos y Canadá. A partir de esa colección, secuenciamos hasta 2 genes mitocondriales y 2 nucleares de un subconjunto (n = 4009) de especímenes, pertenecientes a la mayoría de las cuencas del oeste de Estados Unidos. Adicionalmente, añadimos secuencias de bases de datos de secuencias públicas y aplicamos una serie de métodos de delimitación de especies e identificación de especímenes para evaluar los patrones filogenéticos y espaciales de diversidad. Los métodos de delimitación de especies basados principalmente en una interpretación conservadora del concepto filogenético de especie, fueron ampliamente concordantes e indicaron la presencia de 43 especies candidatas. Algunos de los taxones nombrados no estaban respaldados, mientras que otros, de ser reconocidos, violarían el concepto filogenético de especie. La asignación de especímenes fue en gran medida inequívoca y las distribuciones geográficas fueron coherentes con los patrones filogeográficos de otros taxones. Nuestro trabajo establece un punto de referencia para entender la diversidad de peces Cottus en el oeste de Norteamérica y sugiere nuevas hipótesis de especies tanto allí como en el este de Norteamérica.

Aims Abnormal serum free light chain (FLC) ratios are diagnostically important in almost all plasma cell disorders. However, absolute increases in polyclonal FLC levels are often discarded as inconsequential. Here we report an association between increased combined polyclonal FLC (cFLC: FLCκ plus FLCλ) concentrations and mortality. Methods 723 patients sent for 30 routine haematological assessments were enrolled. Patients with a confirmed monoclonal gammopathy were removed. The remaining 527 patients were followed up for up to 4.5 years. Statistical analysis was performed using SPSS (V.19). Results During follow-up, there were 99 deaths (18.8%). Kaplan-Meier survival analysis revealed 29% of these deaths occurred within the first 100 days (N=29). Multivariate analysis identified only cFLC >65 mg/l, albumin <33 g/l and  estimated glomerular filtration rate <30 ml/min/1.73 m2 to be independently associated with mortality within 100 days and 4.5 years with, cFLC having the highest HR of 7.1. A simple risk stratification model based only on albumin and cFLC identified 86% mortality within 100 days and 62% over 4.5 years. Conclusions Elevated cFLC is significantly associated with increased mortality and with albumin can be used to identify patients at risk of mortality at 4.5 years with high-risk patients detected within 100 days.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.