Systematic comparison of ranking aggregation methods for gene lists in experimental results

MOTIVATION: A common experimental output in biomedical science is a list of genes implicated in a given biological process or disease. The gene lists resulting from a group of studies answering the same, or similar, questions can be combined by ranking aggregation methods to find a consensus or a more reliable answer. Evaluating a ranking aggregation method on a specific type of data before using it is required to support the reliability since the property of a dataset can influence the performance of an algorithm. Such evaluation on gene lists is usually based on a simulated database because of the lack of a known truth for real data. However, simulated datasets tend to be too small compared to experimental data and neglect key features, including heterogeneity of quality, relevance and the inclusion of unranked lists. RESULTS: In this study, a group of existing methods and their variations that are suitable for meta-analysis of gene lists are compared using simulated and real data. Simulated data were used to explore the performance of the aggregation methods as a function of emulating the common scenarios of real genomic data, with various heterogeneity of quality, noise level and a mix of unranked and ranked data using 20 000 possible entities. In addition to the evaluation with simulated data, a comparison using real genomic data on the SARS-CoV-2 virus, cancer (non-small cell lung cancer) and bacteria (macrophage apoptosis) was performed. We summarize the results of our evaluation in a simple flowchart to select a ranking aggregation method, and in an automated implementation using the meta-analysis by information content algorithm to infer heterogeneity of data quality across input datasets. AVAILABILITY AND IMPLEMENTATION: The code for simulated data generation and running edited version of algorithms: https://github.com/baillielab/comparison_of_RA_methods. Code to perform an optimal selection of methods based on the results of this review, using the MAIC algorithm to infer the characteristics of an input dataset, can be downloaded here: https://github.com/baillielab/maic. An online service for running MAIC: https://baillielab.net/maic. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

A robust COVID-19 mortality prediction calculator based on Lymphocyte count, Urea, C-Reactive Protein, Age and Sex (LUCAS) with chest x-rays

There have been numerous risk tools developed to enable triaging of SARS-CoV-2 positive patients with diverse levels of complexity. Here we presented a simplified risk-tool based on minimal parameters and chest X-ray (CXR) image data that predicts the survival of adult SARS-CoV-2 positive patients at hospital admission. We analysed the NCCID database of patient blood variables and CXR images from 19 hospitals across the UK using multivariable logistic regression. The initial dataset was non-randomly split between development and internal validation dataset with 1434 and 310 SARS-CoV-2 positive patients, respectively. External validation of the final model was conducted on 741 Accident and Emergency (A&E) admissions with suspected SARS-CoV-2 infection from a separate NHS Trust. The LUCAS mortality score included five strongest predictors (Lymphocyte count, Urea, C-reactive protein, Age, Sex), which are available at any point of care with rapid turnaround of results. Our simple multivariable logistic model showed high discrimination for fatal outcome with the area under the receiving operating characteristics curve (AUC-ROC) in development cohort 0.765 (95% confidence interval (CI): 0.738–0.790), in internal validation cohort 0.744 (CI: 0.673–0.808), and in external validation cohort 0.752 (CI: 0.713–0.787). The discriminatory power of LUCAS increased slightly when including the CXR image data. LUCAS can be used to obtain valid predictions of mortality in patients within 60 days of SARS-CoV-2 RT-PCR results into low, moderate, high, or very high risk of fatality

Demographics and Outcomes of Initial Phase of COVID-19 Medicines Delivery Units Across 4 UK Centers During Peak B1.1.529 Omicron Epidemic: A Service Evaluation

BACKGROUND: COVID-19 medicines delivery units (CMDU) were established in late December 2021 to deliver early antiviral therapy to patients classified as at risk with the aim of preventing hospitalization. METHODS: We performed a service evaluation at 4 CMDUs in England. We assessed demographics and triage outcomes of CMDU referral, uptake of antiviral therapy, and the rate of subsequent hospitalizations within 2 weeks of CMDU referral. RESULTS: Over a 3-week period, 4788 patients were referred and 3989 were ultimately assessed by a CMDU. Overall, 832 of the patients referred (17%) were judged eligible for treatment and 628 (13%) were ultimately prescribed an antiviral agent. The overall rate of admission within 14 days was 1%. Patients who were admitted were significantly older than those who did not require hospitalization. Of patients prescribed molnupiravir and sotrovimab, 1.8% and 3.2%, respectively, were admitted. CONCLUSIONS: There was a high volume of referrals to CMDU service during the initial surge of the Omicron wave in the United Kingdom. A minority of patients were judged to be eligible for therapy. In a highly vaccinated population, the overall hospitalization rate was low

Opsonic phagocytosis in chronic obstructive pulmonary disease is enhanced by Nrf2 agonists

Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AM) in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms and clinical consequences remain incompletely defined. Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences and potential for therapeutic manipulation of these defects. Methods: We isolated alveolar macrophages (AM) and monocyte-derived macrophages (MDM) from a cohort of COPD patients and controls within the MRC COPD-MAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features. Measurements and Main Results: COPD AM and MDM have impaired phagocytosis of S. pneumoniae. COPD AM have a selective defect in uptake of opsonized bacteria, despite the presence of anti-pneumococcal antibodies in bronchoalveolar lavage, not observed in MDM or healthy donor’s AM. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria and health related quality of life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AM was not reduced. COPD AM have reduced transcriptional responses to opsonized bacteria, including cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2-regualted genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and Compound) reverse defects in phagocytosis of S. pneumoniae and non-type able Haemophilus influenzae by COPD. Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AM, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists

The therapeutic potential of epigenetic manipulation during infectious diseases.

Epigenetic modifications are increasingly recognized as playing an important role in the pathogenesis of infectious diseases. They represent a critical mechanism regulating transcriptional profiles in the immune system that contributes to the cell-type and stimulus specificity of the transcriptional response. Recent data highlight how epigenetic changes impact macrophage functional responses and polarization, influencing the innate immune system through macrophage tolerance and training. In this review we will explore how post-translational modifications of histone tails influence immune function to specific infectious diseases. We will describe how these may influence outcome, highlighting examples derived from responses to acute bacterial pathogens, models of sepsis, maintenance of viral latency and HIV infection. We will discuss how emerging classes of pharmacological agents, developed for use in oncology and other settings, have been applied to models of infectious diseases and their potential to modulate key aspects of the immune response to bacterial infection and HIV therapy

Methodological approaches for studying the microbial ecology of drinking water distribution systems

The study of the microbial ecology of drinking water distribution systems (DWDS) has traditionally been based on culturing organisms from bulk water samples. The development and application of molecular methods has supplied new tools for examining the microbial diversity and activity of environmental samples, yielding new insights into the microbial community and its diversity within these engineered ecosystems. In this review, the currently available methods and emerging approaches for characterising microbial communities, including both planktonic and biofilm ways of life, are critically evaluated. The study of biofilms is considered particularly important as it plays a critical role in the processes and interactions occurring at the pipe wall and bulk water interface. The advantages, limitations and usefulness of methods that can be used to detect and assess microbial abundance, community composition and function are discussed in a DWDS context. This review will assist hydraulic engineers and microbial ecologists in choosing the most appropriate tools to assess drinking water microbiology and related aspects

Clinical features and management of individuals admitted to hospital with monkeypox and associated complications across the UK: a retrospective cohort study.

BACKGROUND The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. METHODS In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. FINDINGS 156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30-44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm (IQR 349-828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2-9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. INTERPRETATION Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital