Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae.

Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen, Klebsiella pneumoniae (KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36.

Improved Interpretability of Brain-Behavior CCA With Domain-Driven Dimension Reduction.

Canonical Correlation Analysis (CCA) has been widely applied to study correlations between neuroimaging data and behavioral data. Practical use of CCA typically requires dimensionality reduction with, for example, Principal Components Analysis (PCA), however, this can result in CCA components that are difficult to interpret. In this paper, we introduce a Domain-driven Dimension Reduction (DDR) method, reducing the dimensionality of the original datasets and combining human knowledge of the structure of the variables studied.

Senescence: An Identity Crisis Originating from Deep Within the Nucleus.

Cellular senescence is implicated in a wide range of physiological and pathological conditions throughout an organism's entire lifetime. In particular, it has become evident that senescence plays a causative role in aging and age-associated disorders. This is not due simply to the loss of function of senescent cells.

Germline allelic expression of genes at 17q22 locus associates with risk of breast cancer.

Introduction: Translation of genome-wide association study (GWAS) findings into preventive approaches is challenged by the identification of the causal risk variants and the understanding of the biological mechanisms by which they act. We present using allelic expression (AE) ratios to perform quantitative case-control analysis as a novel approach to identify risk associations, causal regulatory variants, and target genes.

Methods: Using the breast cancer (BC) risk locus 17q22 to validate this approach, we measured AE ratios in normal breast tissue samples from controls and cases, as well as from unmatched blood samples.

Ancient DNA reveals five streams of migration into Micronesia and matrilocality in early Pacific seafarers.

Micronesia began to be peopled earlier than other parts of Remote Oceania, but the origins of its inhabitants remain unclear. We generated genome-wide data from 164 ancient and 112 modern individuals. Analysis reveals five migratory streams into Micronesia.

Systemic and Oligo-Acquired Resistance to PD-(L)1 Blockade in Lung Cancer.

Purpose: Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood.

Experimental Design: All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR ≤ 3 lesions of disease progression) or systemic (sAR).

Low Use of Guideline-recommended Cardiorenal Protective Antihyperglycemic Agents in Primary Care: A Cross-sectional Study of Adults With Type 2 Diabetes.

Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown cardiorenal benefits independent of their glucose-lowering effects among persons living with type 2 diabetes mellitus (T2DM). In this study, we describe the proportion of persons with T2DM eligible to receive and currently receiving these agents based on their risk criteria for cardiorenal events.

Methods: This study was a cross-sectional analysis of primary care electronic medical records, in southern Alberta, of persons with T2DM who had at least 1 encounter with their primary care provider between December 31, 2018, to December 31, 2020.

Causal inference on neuroimaging data with Mendelian randomisation.

While population-scale neuroimaging studies offer the promise of discovery and characterisation of subtle risk factors, massive sample sizes increase the power for both meaningful associations and those attributable to confounds. This motivates the need for causal modelling of observational data that goes beyond statements of association and towards deeper understanding of complex relationships between individual traits and phenotypes, clinical biomarkers, genetic variation, and brain-related measures of health. Mendelian randomisation (MR) presents a way to obtain causal inference on the basis of genetic data and explicit assumptions about the relationship between genetic variables, exposure and outcome.

Niche-specific genome degradation and convergent evolution shaping adaptation during severe infections.

During severe infections, moves from its colonising sites to blood and tissues and is exposed to new selective pressures, thus, potentially driving adaptive evolution. Previous studies have shown the key role of the locus in pathoadaptation; however, a more comprehensive characterisation of genetic signatures of bacterial adaptation may enable prediction of clinical outcomes and reveal new targets for treatment and prevention of these infections. Here, we measured adaptation using within-host evolution analysis of 2590 .

Mating pair stabilization mediates bacterial conjugation species specificity.

Bacterial conjugation mediates contact-dependent transfer of DNA from donor to recipient bacteria, thus facilitating the spread of virulence and resistance plasmids. Here we describe how variants of the plasmid-encoded donor outer membrane (OM) protein TraN cooperate with distinct OM receptors in recipients to mediate mating pair stabilization and efficient DNA transfer. We show that TraN from the plasmid pKpQIL (Klebsiella pneumoniae) interacts with OmpK36, plasmids from R100-1 (Shigella flexneri) and pSLT (Salmonella Typhimurium) interact with OmpW, and the prototypical F plasmid (Escherichia coli) interacts with OmpA.

Comparative performance of the EuroQol EQ-5D-5L and the CDC healthy days measures in assessing population health.

Objectives: To examine the comparative performance of EuroQol EQ-5D-5L and Center for Disease Control Healthy Days measures in assessing population health.

Methods: Using data from 2014 Alberta Community Health Survey, a cross-sectional population-based survey (N = 7559), conducted in Alberta, Canada, we examined construct validity of the measures as indicators of population health. Differences in EQ-5D-5L index score, visual analogue scale (EQ-VAS), and CDC unhealthy days index across socio-demographic subgroups were tested by Mann-Whitney and Kruskal-Wallis tests using known-groups approach.

Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial.

Background: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8.

Mendelian imputation of parental genotypes improves estimates of direct genetic effects.

Effects estimated by genome-wide association studies (GWASs) include effects of alleles in an individual on that individual (direct genetic effects), indirect genetic effects (for example, effects of alleles in parents on offspring through the environment) and bias from confounding. Within-family genetic variation is random, enabling unbiased estimation of direct genetic effects when parents are genotyped. However, parental genotypes are often missing.

Centrosome function is critical during terminal erythroid differentiation.

Red blood cells are produced by terminal erythroid differentiation, which involves the dramatic morphological transformation of erythroblasts into enucleated reticulocytes. Microtubules are important for enucleation, but it is not known if the centrosome, a key microtubule-organizing center, is required as well. Mice lacking the conserved centrosome component, CDK5RAP2, are likely to have defective erythroid differentiation because they develop macrocytic anemia.

Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant.

PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor-positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.

Can Researchers Assess the Suitability of Datasets to Answer Their Research Questions, with Access to Metadata Only?

Health research increasingly requires effective ways to identify existing datasets and assess their suitability for research. We sought to test whether researchers could use an existing metadata catalogue to assess the suitability of datasets for addressing specified research questions. Five datasets were described in the National Institute for Health Research Health Informatics Collaborative metadata catalogue, and for each dataset five associated research questions were formulated, some of which were answerable with the dataset while others were not.

Genetically predicted vitamin K levels and risk of osteoarthritis: Mendelian randomization study.

Objective: Osteoarthritis (OA) is a progressive disease for which there is no disease modifying therapy. Vitamin K levels and vitamin K antagonism have been associated with risk and progression of OA which may have direct implications for clinical management, but these observational findings are susceptible to confounding. We aimed to estimate the causal association between vitamin K and OA risk using Mendelian randomisation (MR).

Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study.

Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression.

Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa and understand the genetic factors associated with such progression.

Design, Setting, And Participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG) consortium from the UK, Canada, Germany, Australia, and France.

A framework for reconstructing SARS-CoV-2 transmission dynamics using excess mortality data.

The transmission dynamics and burden of SARS-CoV-2 in many regions of the world is still largely unknown due to the scarcity of epidemiological analyses and lack of testing to assess the prevalence of disease. In this work, we develop a quantitative framework based on excess mortality data to reconstruct SARS-CoV-2 transmission dynamics and assess the level of underreporting in infections and deaths. Using weekly all-cause mortality data from Iran, we are able to show a strong agreement between our attack rate estimates and seroprevalence measurements in each province and find significant heterogeneity in the level of exposure across the country with 11 provinces reaching near 100% attack rates.