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Background: Antimicrobial resistance (AMR) in Enterobacterales is a global health threat. Capacity for individual-level surveillance remains limited in many countries, whilst population-level surveillance approaches could inform empiric antibiotic treatment guidelines. Methods: In this exploratory study, a novel approach to population-level prediction of AMR in Enterobacterales clinical isolates using metagenomic (Illumina) profiling of pooled DNA extracts from human faecal samples was developed and tested. Taxonomic and AMR gene profiles were used to derive taxonomy-adjusted population-level AMR metrics. Bayesian modelling, and model comparison based on cross-validation, were used to evaluate the capacity of each metric to predict the number of resistant Enterobacterales invasive infections at a population-level, using available bloodstream/cerebrospinal fluid infection data. Findings: Population metagenomes comprised samples from 177, 157, and 156 individuals in Kenya, the UK, and Cambodia, respectively, collected between September 2014 and April 2016. Clinical data from independent populations included 910, 3356 and 197 bacterial isolates from blood/cerebrospinal fluid infections in Kenya, the UK and Cambodia, respectively (samples collected between January 2010 and May 2017). Enterobacterales were common colonisers and pathogens, and faecal taxonomic/AMR gene distributions and proportions of antimicrobial-resistant Enterobacterales infections differed by setting. A model including terms reflecting the metagenomic abundance of the commonest clinical Enterobacterales species, and of AMR genes known to either increase the minimum inhibitory concentration (MIC) or confer clinically-relevant resistance, had a higher predictive performance in determining population-level resistance in clinical Enterobacterales isolates compared to models considering only AMR gene information, only taxonomic information, or an intercept-only baseline model (difference in expected log predictive density compared to best model, estimated using leave-one-out cross-validation: intercept-only model = -223 [95% credible interval (CI): -330,-116]; model considering only AMR gene information = -186 [95% CI: -281,-91]; model considering only taxonomic information = -151 [95% CI: -232,-69]). Interpretation: Whilst our findings are exploratory and require validation, intermittent metagenomics of pooled samples could represent an effective approach for AMR surveillance and to predict population-level AMR in clinical isolates, complementary to ongoing development of laboratory infrastructures processing individual samples.

Staphylococcus epidermidis is carried asymptomatically by virtually all humans but is also a major cause of nosocomial infection. Here, the authors study 141 isolates from healthy carriage and 274 isolates from clinical infections, and identify genes and genetic elements associated with pathogenicity.

Repo-Man is a chromosome-binding subunit of protein phosphatase 1 to regulate mitosis. Here, de Castro and colleagues show that Repo-Man also regulates heterochromatin during interphase, and regulates gene repression and chromatin organization.

β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.