Prescription medications with actionable pharmacogenomic recommendations in Veterans Health Administration patients.

Aim: To evaluate the prevalence of medications with actionable pharmacogenomic (PGx) safety and efficacy recommendations in patients receiving care from the Veterans Health Administration. Materials & methods: Outpatient prescription data from 2011 to 2021 and any documented adverse drug reactions (ADRs) were reviewed for those who received PGx testing at one Veterans Administration location between November 2019 and October 2021. Results: Among the reviewed prescriptions, 381 (32.8%) were associated with an actionable recommendation based on the Clinical Pharmacogenetics Implementation Consortium (CPIC) prescribing guidelines, with 205 (17.7%) for efficacy concerns and 176 (15.2%) for safety concerns. Among those with a documented ADR for a PGx-impacted medication, 39.1% had PGx results that aligned with CPIC recommendations. Conclusion: Medications with actionable PGx recommendations for safety and efficacy concerns are received with similar frequency, and most patients who have undergone PGx testing at the Phoenix Veterans Administration have received medications that may be impacted by PGx testing.

Modulation of the Activity of the Insulin-Degrading Enzyme by Aß Peptides.

The insulin-degrading enzyme (IDE) is an evolutionarily conserved protease implicated in the degradation of insulin and amyloidogenic peptides. Most of the biochemical and biophysical characterization of IDE's catalytic activity has been conducted using solutions containing a single substrate, i.e., insulin or Aß(1-40). IDE's activity toward a particular substrate, however, is likely to be influenced by the presence of other substrates. Here, we show by a kinetic assay based on insulin's helical circular dichroic signal and MALDI TOF mass spectrometry that Aß peptides modulate IDE's activity toward insulin in opposing ways. Aß(1-40) enhances IDE-dependent degradation of insulin, whereas Aß(pyroE3-42), the most pathogenic pyroglutamate-modified Aß peptide in AD, inhibits IDE's activity. Intriguingly, Aß(pyroE3-42) also inhibits IDE's ability to degrade Aß(1-40). Together, our results implicate Aß peptides in the abnormal catabolism of IDE's key substrates.

The epidemiology of Shiga toxin-producing Escherichia coli O26:H11 (clonal complex 29) in England, 2014-2021.

OBJECTIVES: We aimed to describe the genomic epidemiology of the foodborne gastrointestinal pathogen, Shiga toxin-producing Escherichia coli (STEC) serotype O26:H11 belonging to clonal complex 29 (CC29) in England. METHODS: Between 01 January 2014 and 31 December 2021, 834 human isolates belonging to CC29 were sequenced at the UK Health Security Agency, and the genomic data was integrated with epidemiological data. RESULTS: Diagnoses of STEC O26:H11 in England have increased each year from 19 in 2014 to 144 in 2021. Most isolates had the Shiga toxin subtype profiles stx1a (47%), stx1a,stx2a (n = 24%) or stx2a (n = 28%). Most cases were female (57%), and the highest proportion of cases belonged to the 0-5 age group (38%). Clinical symptoms included diarrhoea (93%), blood-stained stool (48%), and abdominal pain (74%). Haemolytic Uraemic Syndrome (HUS) was diagnosed in 40/459 (9%) cases and three children died. All isolates causing STEC-HUS had stx2a either alone (n = 33) or in combination with stx1a (n = 7). CONCLUSIONS: STEC O26:H11 are a clinically significant, emerging threat to public health in England. Determining the true incidence and prevalence is challenging due to inconsistent national surveillance strategies. Improved diagnostics and surveillance algorithms are required to monitor the true burden, detect outbreaks and to implement effective interventions.

Forgotten but not gone: Yersinia infections in England, 1975 to 2020.

BackgroundYersiniosis is one of the most common food-borne zoonoses in Europe, but there are large variations in the reported incidence between different countries.AimWe aimed to describe the trends and epidemiology of laboratory-confirmed Yersinia infections in England and estimate the average annual number of undiagnosed Yersinia enterocolitica cases, accounting for under-ascertainment.MethodsWe analysed national surveillance data on Yersinia cases reported by laboratories in England between 1975 and 2020 and enhanced surveillance questionnaires from patients diagnosed in a laboratory that has implemented routine Yersinia testing of diarrhoeic samples since 2016.ResultsThe highest incidence of Yersinia infections in England (1.4 cases per 100,000 population) was recorded in 1988 and 1989, with Y. enterocolitica being the predominant species. The reported incidence of Yersinia infections declined during the 1990s and remained low until 2016. Following introduction of commercial PCR at a single laboratory in the South East, the annual incidence increased markedly (13.6 cases per 100,000 population in the catchment area between 2017 and 2020). There were notable changes in age and seasonal distribution of cases over time. The majority of infections were not linked to foreign travel and one in five patients was admitted to hospital. We estimate that around 7,500 Y. enterocolitica infections may be undiagnosed in England annually.ConclusionsFindings suggest a considerable number of undiagnosed yersiniosis cases in England, with possibly important changes in the epidemiology. The apparently low incidence of yersiniosis in England is probably due to limited laboratory testing.

Reforestation success can be enhanced by improving tree planting methods.

Successful cost-effective reforestation plantings depend substantially on maximising sapling survival from the time of planting, yet in reforestation programs remarkably little attention is given to management of saplings at the planting stage and to planting methods used. Critical determinants of sapling survival include their vigour and condition when planted, the wetness of the soil into which saplings are planted, the trauma of transplant shock from nursery to natural field soils, and the method and care taken during planting. While some determinants are outside planters' control, careful management of specific elements associated with outplanting can significantly lessen transplanting shock and improve survival rates. Results from three reforestation experiments designed to examine cost-effective planting methods in the Australian wet tropics provided the opportunity to examine the effects of specific planting treatments, including (1) watering regime prior to planting, (2) method of planting and planter technique, and (3) site preparation and maintenance, on sapling survival and establishment. Focusing on sapling root moisture and physical protection during planting improved sapling survival by at least 10% (>91% versus 81%) at 4 months. Survival rates of saplings under different planting treatments were reflected in longer-term survival of trees at 18-20 months, differing from a low of 52% up to 76-88%. This survival effect was evident more than 6 years after planting. Watering saplings immediately prior to planting, careful planting using a forester's planting spade in moist soil and suppressing grass competition using appropriate herbicides were critical to improved plant survival.

A high-mass X-ray binary descended from an ultra-stripped supernova.

Ultra-stripped supernovae are different from other terminal explosions of massive stars, as they show little or no ejecta from the actual supernova event1,2. They are thought to occur in massive binary systems after the exploding star has lost its surface through interactions with its companion2. Such supernovae produce little to no kick, leading to the formation of a neutron star without loss of the binary companion, which itself may also evolve into another neutron star2. Here we show that a recently discovered high-mass X-ray binary, CPD -29 2176 (CD -29 5159; SGR 0755-2933)3-6, has an evolutionary history that shows the neutron star component formed during an ultra-stripped supernova. The binary has orbital elements that are similar both in period and in eccentricity to 1 of 14 Be X-ray binaries that have known orbital periods and eccentricities7. The identification of the progenitors systems for ultra-stripped supernovae is necessary as their evolution pathways lead to the formation of binary neutron star systems. Binary neutron stars, such as the system that produced the kilonova GW170817 that was observed with both electromagnetic and gravitational energy8, are known to produce a large quantity of heavy elements9,10.

Evaluation of Submental Blood Collection in Mice ( Mus musculus).

The submental route is an option for nonterminal and serial blood collection in mice. This study compared the submental route to the maxillary route (also referred to as the submandibular route). The study used male CD1 and C57BL/6 strains of mice in 2 age groups: 8 and 19 wk. To simulate repeated toxicokinetic blood collection, blood was collected from each mouse at 1 and 24-h on Study Day 1, and at 1, 4 and 24 h on Study Day 16. Food consumption, body weights, and clinical observations were assessed daily. No apparent differences were found between the 2 blood collection sites in terms of either food consumption or body weight. Mice bled via the submental route showed fewer adverse clinical effects than did mice bled via the maxillary route. Clinical pathology showed no differences between the 2 methods. In addition, 7 trained technicians, who were inexperienced with the 2 bleeding methods prior to these evaluations, were surveyed to gain insights into expectations and overall experience of using the 2 routes. All 7 technicians preferred the submental route to the maxillary route. Furthermore, the average time needed to become proficient in submental blood collection (1.6 d) was less than that required to become proficient in maxillary blood collection (2.6 d). The qualitative aspects of this study, combined with fewer adverse clinical events, suggest ways to improve both animal and staff welfare. Our findings suggest that the submental route is safe, effective, and easier than the maxillary route for nonterminal serial blood collection in mice.

Informing antimicrobial stewardship with explainable AI.

The accuracy and flexibility of artificial intelligence (AI) systems often comes at the cost of a decreased ability to offer an intuitive explanation of their predictions. This hinders trust and discourage adoption of AI in healthcare, exacerbated by concerns over liabilities and risks to patients' health in case of misdiagnosis. Providing an explanation for a model's prediction is possible due to recent advances in the field of interpretable machine learning. We considered a data set of hospital admissions linked to records of antibiotic prescriptions and susceptibilities of bacterial isolates. An appropriately trained gradient boosted decision tree algorithm, supplemented by a Shapley explanation model, predicts the likely antimicrobial drug resistance, with the odds of resistance informed by characteristics of the patient, admission data, and historical drug treatments and culture test results. Applying this AI-based system, we found that it substantially reduces the risk of mismatched treatment compared with the observed prescriptions. The Shapley values provide an intuitive association between observations/data and outcomes; the associations identified are broadly consistent with expectations based on prior knowledge from health specialists. The results, and the ability to attribute confidence and explanations, support the wider adoption of AI in healthcare.

Cluster detection with random neighbourhood covering: Application to invasive Group A Streptococcal disease.

The rapid detection of outbreaks is a key step in the effective control and containment of infectious diseases. In particular, the identification of cases which might be epidemiologically linked is crucial in directing outbreak-containment efforts and shaping the intervention of public health authorities. Often this requires the detection of clusters of cases whose numbers exceed those expected by a background of sporadic cases. Quantifying exceedances rapidly is particularly challenging when only few cases are typically reported in a precise location and time. To address such important public health concerns, we present a general method which can detect spatio-temporal deviations from a Poisson point process and estimate the odds of an isolate being part of a cluster. This method can be applied to diseases where detailed geographical information is available. In addition, we propose an approach to explicitly take account of delays in microbial typing. As a case study, we considered invasive group A Streptococcus infection events as recorded and typed by Public Health England from 2015 to 2020.

Exchange Broadening Underlies the Enhancement of IDE-Dependent Degradation of Insulin by Anionic Membranes.

Insulin-degrading enzyme (IDE) is an evolutionarily conserved ubiquitous zinc metalloprotease implicated in the efficient degradation of insulin monomer. However, IDE also degrades monomers of amyloidogenic peptides associated with disease, complicating the development of IDE inhibitors. In this work, we investigated the effects of the lipid composition of membranes on the IDE-dependent degradation of insulin. Kinetic analysis based on chromatography and insulin's helical circular dichroic signal showed that the presence of anionic lipids in membranes enhances IDE's activity toward insulin. Using NMR spectroscopy, we discovered that exchange broadening underlies the enhancement of IDE's activity. These findings, together with the adverse effects of anionic membranes in the self-assembly of IDE's amyloidogenic substrates, suggest that the lipid composition of membranes is a key determinant of IDE's ability to balance the levels of its physiologically and pathologically relevant substrates and achieve proteostasis.

Non-opioid analgesics and post-operative pain following transoral robotic surgery for oropharyngeal cancer.

OBJECTIVE: To investigate associations between multimodal analgesia and post-operative pain among patients undergoing transoral robotic surgery for oropharyngeal squamous cell carcinoma. METHODS: Records of patients who underwent surgery from 5 September 2012 to 30 November 2016 were abstracted. Associations were assessed using multivariable analysis. RESULTS: A total of 216 patients (mean age of 59.1 years, 89.4 per cent male) underwent transoral robotic surgery (92.6 per cent were human papilloma virus positive, 87.5 per cent had stage T1-T2 tumours, and 82.9 per cent had stage N0-N1 nodes). Gabapentin (n = 86) was not associated with a reduction in severe pain. Ibuprofen (n = 72) was administered less often in patients with severe pain. Gabapentin was not associated with increased post-operative sedation (p = 0.624) and ibuprofen was not associated with increased bleeding (p = 0.221). Post-operative opioid usage was not associated with surgical duration, pharyngotomy, bilateral neck dissections, tumour stage, tumour size, subsite or gabapentin. CONCLUSION: Scheduled low-dose gabapentin was not associated with improved pain control or increased respiratory depression. Ibuprofen was not associated with an increased risk of bleeding and may be under-utilised.

Cost-effectiveness of testing for latent tuberculosis infection in people with HIV.

OBJECTIVE: The aim of this study was to estimate the cost-effectiveness of screening strategies for predicting LTBI that progresses to active tuberculosis (TB) in people with HIV. DESIGN: We developed a decision-analytical model that constituted a decision tree covering diagnosis of LTBI and a Markov model covering progression to active TB. The model represents the lifetime experience following testing for LTBI, and discounting costs, and benefits at 3.5% per annum in line with UK standards. We undertook probabilistic and one-way sensitivity analyses. SETTING: UK National Health Service and Personal Social Service perspective in a primary care setting. PARTICIPANTS: Hypothetical cohort of adults recently diagnosed with HIV. INTERVENTIONS: Interferon-gamma release assays and tuberculin skin test. MAIN OUTCOME MEASURE: Cost per quality-adjusted life year (QALY). RESULTS: All strategies except T-SPOT.TB were cost-effective at identifying LTBI, with the QFT-GIT-negative followed by TST5mm strategy being the most costly and effective. Results indicated that there was little preference between strategies at a willingness-to-pay threshold of £20 000. At thresholds above £40 000 per QALY, there was a clear preference for the QFT-GIT-negative followed by TST5mm, with a probability of 0.41 of being cost-effective. Results showed that specificity for QFT-GIT and TST5mm were the main drivers of the economic model. CONCLUSION: Screening for LTBI has important public health and clinical benefits. Most of the strategies are cost-effective. These results should be interpreted with caution because of the paucity of studies included in the meta-analysis of test accuracy studies. Additional high-quality primary studies are needed to have a definitive answer about, which strategy is the most effective.

Differential Effects of Polyphenols on Insulin Proteolysis by the Insulin-Degrading Enzyme.

The insulin-degrading enzyme (IDE) possesses a strong ability to degrade insulin and Aß42 that has been linked to the neurodegeneration in Alzheimer's disease (AD). Given this, an attractive IDE-centric strategy for the development of therapeutics for AD is to boost IDE's activity for the clearance of Aß42 without offsetting insulin proteostasis. Recently, we showed that resveratrol enhances IDE's activity toward Aß42. In this work, we used a combination of chromatographic and spectroscopic techniques to investigate the effects of resveratrol on IDE's activity toward insulin. For comparison, we also studied epigallocatechin-3-gallate (EGCG). Our results show that the two polyphenols affect the IDE-dependent degradation of insulin in different ways: EGCG inhibits IDE while resveratrol has no effect. These findings suggest that polyphenols provide a path for developing therapeutic strategies that can selectively target IDE substrate specificity.

Intrinsic properties of primary hippocampal neurons contribute to PIP2 depletion during nsEP-induced physiological response.

High-energy, short-duration electric pulses (EPs) are known to be effective in neuromodulation, but the biological mechanisms underlying this effect remain unclear. Recently, we discovered that nanosecond electric pulses (nsEPs) could initiate the phosphatidylinositol4,5-bisphosphate (PIP2) depletion in non-excitable cells identical to agonist-induced activation of the Gq11 coupled receptors. PIP2 is the precursor for multiple intracellular second messengers critically involved in the regulation of intracellular Ca2+ homeostasis and plasma membrane (PM) ion channels responsible for the control of neuronal excitability. In this paper we demonstrate a novel finding that five day in vitro (DIV5) primary hippocampal neurons (PHNs) undergo significantly higher PIP2 depletion after 7.5 kV/cm 600 ns EP exposure than DIV1 PHNs and day 1-5 (D1-D5) non-excitable Chinese hamster ovarian cells with muscarinic receptor 1 (CHO-hM1). Despite the age of development, the stronger 15 kV/cm 600 ns or longer 7.5 kV/cm 12 µs EP initiated profound PIP2 depletion in all cells studied, outlining damage of the cellular PM and electroporation. Therefore, the intrinsic properties of PHNs in concert with nanoporation explain the stronger neuronal response to nsEP at lower intensity exposures. PIP2 reduction in neurons could be a primary biological mechanism responsible for the stimulation or inhibition of neuronal tissues.

Contrasting factors associated with COVID-19-related ICU admission and death outcomes in hospitalised patients by means of Shapley values.

Identification of those at greatest risk of death due to the substantial threat of COVID-19 can benefit from novel approaches to epidemiology that leverage large datasets and complex machine-learning models, provide data-driven intelligence, and guide decisions such as intensive-care unit admission (ICUA). The objective of this study is two-fold, one substantive and one methodological: substantively to evaluate the association of demographic and health records with two related, yet different, outcomes of severe COVID-19 (viz., death and ICUA); methodologically to compare interpretations based on logistic regression and on gradient-boosted decision tree (GBDT) predictions interpreted by means of the Shapley impacts of covariates. Very different association of some factors, e.g., obesity and chronic respiratory diseases, with death and ICUA may guide review of practice. Shapley explanation of GBDTs identified varying effects of some factors among patients, thus emphasising the importance of individual patient assessment. The results of this study are also relevant for the evaluation of complex automated clinical decision systems, which should optimise prediction scores whilst remaining interpretable to clinicians and mitigating potential biases.

Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data.

BACKGROUND: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. METHODS: In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. FINDINGS: 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27-0·37]) and 82% at 8 weeks (0·18 [0·14-0·23]) following the week in which significant changes in population movements were recorded. INTERPRETATION: The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. FUNDING: Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).

Validation of a new fluidic device for mechanical stimulation and characterization of microspheres: A first step towards cartilage characterization.

Articular cartilage is made of chondrocytes surrounded by their extracellular matrix that can both sense and respond to various mechanical stimuli. One of the most widely used in vitro model to study cartilage growth is the model of mesenchymal stromal cells-derived cartilage micropellet. However, mechanical stimulation of micropellets has never been reported probably because of their small size and imperfect round shape. The objective of the study was to develop an original custom-made device allowing both the mechanical stimulation and characterization of cartilage micropellets. The fluidic-based device was designed for the concomitant stimulation or characterization of six microspheres placed into the conical wells of a tank. In the present study, the device was validated using alginate-, collagen- and crosslinked collagen-based microspheres. Different types and ranges of pressure signals (square, sinusoidal and constant) were applied. The mechanical properties of microspheres were equivalent to those determined by a conventional compression test. Accuracy, repeatability and reproducibility of all types of pressure signals were demonstrated even though square signals were less accurate and sinusoidal signals were less reproducible than the others. The interest of this new device lies in the reliability to mechanically stimulate and characterize microspheres with diameters in the range of 900 to 1500 µm. Mechanical stimulation can be performed on six microspheres in parallel allowing the mechanical and molecular characterization of the same group of cartilage micropellets. The device will be useful to evaluate the growth of cartilage micropellets under mechanical stimuli.