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Abstract Background Despite the growing interest in the use of human genomic data for drug target identification and validation, the extent to which the spectrum of human disease has been addressed by genome-wide association studies (GWAS), or by drug development, and the degree to which these efforts overlap remain unclear. Methods In this study we harmonize and integrate different data sources to create a sample space of all the human drug targets and diseases and identify points of convergence or divergence of GWAS and drug development efforts. Results We show that only 612 of 11,158 diseases listed in Human Disease Ontology have an approved drug treatment in at least one region of the world. Of the 1414 diseases that are the subject of preclinical or clinical phase drug development, only 666 have been investigated in GWAS. Conversely, of the 1914 human diseases that have been the subject of GWAS, 1121 have yet to be investigated in drug development. Conclusions We produce target-disease indication lists to help the pharmaceutical industry to prioritize future drug development efforts based on genetic evidence, academia to prioritize future GWAS for diseases without effective treatments, and both sectors to harness genetic evidence to expand the indications for licensed drugs or to identify repurposing opportunities for clinical candidates that failed in their originally intended indication.

Abstract The impact of preterm babies’ admission at the Neonatal Intensive Care (NICU) on the mental health of mothers is a global challenge. However, the prevalence and predictors of Common Mental Disorders (CMDs) among this population remain underexplored. This study assessed the predictors of CMDs among mothers of preterm infants in the NICUs in the Upper East Region of Ghana. A cross-sectional study was conducted, targeting mothers of preterm babies in two hospitals in the Upper East Region. The Self-Report Questionnaire (SRQ-20) was used to collect data from 375 mothers of preterm babies admitted to the NICUs. Statistical analyses were done using SPSS version 20. The study found a prevalence of 40.9% for CMDs among mothers of preterm babies admitted to the two NICUs. The predictors of CMDs were unemployment (aOR 2.925, 95% CI 1.465, 5.840), lower levels of education (aOR 5.582, 95% CI 1.316, 23.670), antenatal anxiety (aOR 3.606, 95% CI 1.870, 6.952), and assisted delivery (aOR 2.144, 95% CI 1.083, 4.246). Conversely, urban residence (aOR 0.390, 95% CI 0.200, 0.760), age range between 25 and 31 (aOR 0.238, 95% CI 0.060, 0.953), and having a supportive partner (aOR 0.095, 95% CI 0.015, 0.593) emerged as protective factors. This study emphasizes the imperative of addressing maternal mental health within the NICU setting for preterm births.

Abstract The study of muscle mass as an imaging-derived phenotype (IDP) may yield new insights into determining the normal and pathologic variations in muscle mass in the population. This can be done by determining 3D abdominal muscle mass from 12 distinct abdominal muscle regions and groups using computed tomography (CT) in a racially diverse medical biobank. To develop a fully automatic technique for assessment of CT abdominal muscle IDPs and preliminarily determine abdominal muscle IDP variations with age and sex in a clinically and racially diverse medical biobank. This retrospective study was conducted using the Penn Medicine BioBank (PMBB), a research protocol that recruits adult participants during outpatient visits at hospitals in the Penn Medicine network. We developed a deep residual U-Net (ResUNet) to segment 12 abdominal muscle groups including the left and right psoas, quadratus lumborum, erector spinae, gluteus medius, rectus abdominis, and lateral abdominals. 110 CT studies were randomly selected for training, validation, and testing. 44 of the 110 CT studies were selected to enrich the dataset with representative cases of intra-abdominal and abdominal wall pathology. The studies were divided into non-overlapping training, validation and testing sets. Model performance was evaluated using the Sørensen–Dice coefficient. Volumes of individual muscle groups were plotted to distribution curves. To investigate associations between muscle IDPs, age, and sex, deep learning model segmentations were performed on a larger abdominal CT dataset from PMBB consisting of 295 studies. Multivariable models were used to determine relationships between muscle mass, age and sex. The model's performance (Dice scores) on the test data was the following: psoas: 0.85 ± 0.12, quadratus lumborum: 0.72 ± 0.14, erector spinae: 0.92 ± 0.07, gluteus medius: 0.90 ± 0.08, rectus abdominis: 0.85 ± 0.08, lateral abdominals: 0.85 ± 0.09. The average Dice score across all muscle groups was 0.86 ± 0.11. Average total muscle mass for females was 2041 ± 560.7 g with a high of 2256 ± 560.1 g (41–50 year old cohort) and a change of − 0.96 g/year, declining to an average mass of 1579 ± 408.8 g (81–100 year old cohort). Average total muscle mass for males was 3086 ± 769.1 g with a high of 3385 ± 819.3 g (51–60 year old cohort) and a change of − 1.73 g/year, declining to an average mass of 2629 ± 536.7 g (81–100 year old cohort). Quadratus lumborum was most highly correlated with age for both sexes (correlation coefficient of − 0.5). Gluteus medius mass in females was positively correlated with age with a coefficient of 0.22. These preliminary findings show that our CNN can automate detailed abdominal muscle volume measurement. Unlike prior efforts, this technique provides 3D muscle segmentations of individual muscles. This technique will dramatically impact sarcopenia diagnosis and research, elucidating its clinical and public health implications. Our results suggest a peak age range for muscle mass and an expected rate of decline, both of which vary between genders. Future goals are to investigate genetic variants for sarcopenia and malnutrition, while describing genotype–phenotype associations of muscle mass in healthy humans using imaging-derived phenotypes. It is feasible to obtain 3D abdominal muscle IDPs with high accuracy from patients in a medical biobank using fully automated machine learning methods. Abdominal muscle IDPs showed significant variations in lean mass by age and sex. In the future, this tool can be leveraged to perform a genome-wide association study across the medical biobank and determine genetic variants associated with early or accelerated muscle wasting.

ObjectivesTo identify factors to optimize long-term non-invasive ventilation (LT-NIV) use by exploring the experience of children using LT-NIV and their parents.Study design and methodsA qualitative framework analysis method was used. Children aged 8–12 years who used LT-NIV for at least 3-months and their parents/guardians were approached to participate. Thematic analysis of data derived from focus group interviews, conducted separately for children and parents, was performed. Findings were coded and grouped into identified themes.ResultsData analysis identified four themes: (1) “The double-edged sword,” which identified benefits and challenges of LT-NIV use; (2) “Feeling different,” where children and parents described fears, frustrations, and concerns including emotional and social implications, and physical changes; (3) “It's not just about the mask,” highlighted the influence of equipment issues, including the mask interface, headgear, tubing and humidity, and their impact on tolerance and use of LT-NIV; and (4) “Through the eyes of experience—children and parents as experts for change,” which captured ideas for the functional and aesthetic improvement of the equipment including the need for pediatric specific technology.ConclusionsLT-NIV use has two sides; it helps to improve lives though requires an investment of time and commitment to ensure success. Investing in pediatric-specific equipment needs to be a priority as do alliances between healthcare providers, children who use LT-NIV, and their families. Future technology development and studies of adherence need to consider the experiences of children and their families to reduce the challenges and support optimal use of LT-NIV.

Introduction The postnatal period often presents significant psychological and social distress for mothers, a burden that is potentially heightened by having a preterm baby. Mothers of preterm babies face various psychosocial challenges that need to be explored. While some studies have explored the experiences of mothers of preterm babies, there is a need for more context-specific research to inform targeted interventions, especially in resource-constrained settings like northern Ghana. This study aimed to explore the psychosocial experiences of mothers of preterm babies admitted to the neonatal intensive care unit (NICU) of the Upper East Regional Hospital, Ghana.Methods This descriptive phenomenological study was conducted in the NICU of the Upper East Regional Hospital in Ghana. Thirteen mothers of preterm babies were purposively sampled and interviewed using a semi-structured interview guide. The interviews were transcribed verbatim and analysed using Colaizzi’s descriptive phenomenological method.Results Three themes emerged namely, mothers’ emotional experience, challenges encountered at the NICU and coping strategies. The mothers expressed a range of emotions, from indifference to profound sadness, disbelief, fear and worry, on realising their babies were preterm. Challenges within the NICU were financial constraints and poor NICU facilities while coping strategies included reliance on God, self-reliance and support from family and nurses.Conclusion Mothers of preterm babies in the NICU experience significant emotional distress and face numerous challenges. Comprehensive support programmes that address financial, emotional and practical needs are essential to improve outcomes for both mothers and their preterm babies.

BackgroundInternalizing disorders (IDs), primarily depression and anxiety, are highly prevalent among adolescents receiving community-based treatment for substance use disorders (SUDs). For such clients, interventions that do not holistically address both SUDs and IDs are less effective. ObjectiveThis pilot treatment development study aims to develop and test a modular treatment protocol for addressing cooccurring IDs among adolescents (aged 13 to 18 years) enrolled in routine care for substance use problems: Family Support Protocol for Adolescent Internalizing Disorders (Fam-AID). As an adjunctive protocol, Fam-AID will not require clinicians to markedly alter existing base practices for SUD. It will be anchored by 3 evidence-based foundations for treating cooccurring adolescent IDs: family engagement techniques, transdiagnostic individual cognitive behavioral therapy techniques, and family psychoeducation and safety planning. MethodsThis quasi-experimental study will proceed in 2 stages. The pilot stage will use rapid-cycle prototyping methods in collaboration with end-user stakeholders to draft protocol delivery and fidelity guidelines adapted from existing resources, solicit provider and client input on protocol content and delivery via cognitive interviewing, and pilot prototype components on 4 to 6 cases. The second stage will be an interrupted time series study for 60 comorbid SUD+ID cases across 2 sites serving diverse adolescents: 30 will receive treatment as usual (TAU); following clinician training in the protocol, 30 new cases will receive TAU enhanced by Fam-AID. For aim 1, the focus is on evaluating the acceptability of the Fam-AID protocol through therapist and client interviews as well as assessing fidelity benchmarks using therapist- and observer-reported protocol fidelity data. For aim 2, the plan is to compare the effects of TAU only cases versus TAU+Fam-AID cases on family treatment attendance and on adolescent ID and substance use symptoms, with measurements taken at baseline and at 3-month and 6-month follow-ups. ResultsStudy recruitment will begin in April 2025. ConclusionsWe anticipate that Fam-AID will contain 5 treatment modules that can be delivered in any sequence to meet client needs: family engagement of primary supports in treatment planning and services; relational reframing of family constraints, resiliencies, and social capital connected to the adolescent’s ID symptoms; functional analysis of the adolescent’s ID symptoms and related behaviors; cognitive behavioral therapy to address the adolescent’s ID symptoms and functional needs, featuring 3 core techniques (emotion acceptance, emotional exposure, and behavioral activation) to address negative affect and emotional dysregulation; and family psychoeducation and safety planning focused on education about comorbid SUD+ID and prevention of adolescent self-harm. If the abovementioned modules are found to be feasible and effective, Fam-AID will offer a set of pragmatic interventions to SUD clinicians for treating cooccurring IDs in adolescent clients. Trial RegistrationClinicalTrials.gov NCT06413979; https://www.clinicaltrials.gov/study/NCT06413979 International Registered Report Identifier (IRRID)PRR1-10.2196/64332

Abstract A significant number of pregnancies are lost in the first trimester and 1–2% are ectopic pregnancies (EPs). Early pregnancy loss in general can cause significant morbidity with bleeding or infection, while EPs are the leading cause of maternal mortality in the first trimester. Symptoms of pregnancy loss and EP are very similar (including pain and bleeding); however, these symptoms are also common in live normally sited pregnancies (LNSP). To date, no biomarkers have been identified to differentiate LNSP from pregnancies that will not progress beyond early gestation (non-viable or EPs), defined together as combined adverse outcomes (CAO). In this study, we present a novel machine learning pipeline to create prediction models that identify a composite biomarker to differentiate LNSP from CAO in symptomatic women. This prospective cohort study included 370 participants. A single blood sample was prospectively collected from participants on first emergency presentation prior to final clinical diagnosis of pregnancy outcome: LNSP, miscarriage, pregnancy of unknown location (PUL) or tubal EP (tEP). Miscarriage, PUL and tEP were grouped together into a CAO group. Human chorionic gonadotrophin β (β-hCG) and progesterone concentrations were measured in plasma. Serum samples were subjected to untargeted metabolomic profiling. The cohort was randomly split into train and validation data sets, with the train data set subjected to variable selection. Nine metabolite signals were identified as key discriminators of LNSP versus CAO. Random forest models were constructed using stable metabolite signals alone, or in combination with plasma hormone concentrations and demographic data. When comparing LNSP with CAO, a model with stable metabolite signals only demonstrated a modest predictive accuracy (0.68), which was comparable to a model of β-hCG and progesterone (0.71). The best model for LNSP prediction comprised stable metabolite signals and hormone concentrations (accuracy = 0.79). In conclusion, serum metabolite levels and biochemical markers from a single blood sample possess modest predictive utility in differentiating LNSP from CAO pregnancies upon first presentation, which is improved by variable selection and combination using machine learning. A diagnostic test to confirm LNSP and thus exclude pregnancies affecting maternal morbidity and potentially life-threatening outcomes would be invaluable in emergency situations.

Background Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by rises in plasma cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. Methods In a multicentre prospective randomised open-label blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent plasma high-sensitivity cardiac troponin concentration monitoring and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Randomised controlled trial – patients at high risk of cardiotoxicity (plasma cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomised to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary end point was 6-month change in left ventricular ejection fraction. Prognostic cohort study – in low-risk non-randomised patients with plasma cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (± 2%). Results Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomised to cardioprotection (n = 29) or standard care (n = 28) had mean left ventricular ejection fractions of 65.7 ± 6.6% and 64.9 ± 5.9%, respectively, at 6 months. Twenty patients (68.9%) were adherent to cardioprotection therapy at 6 months. Adverse events were more commonly reported in the cardioprotection group, with 71.4% of patients having at least one adverse event compared with 12.7% non-randomised and 10.3% standard care patients. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean percentage-point difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was –0.4% (95% confidence interval –3.59 to 2.85%; p = 0.82). In low-risk non-randomised patients, baseline and 6-month left ventricular ejection fractions were 69.3 ± 5.7% and 66.4 ± 6.3%, respectively (estimated mean difference 2.9%, 95% confidence interval 1.45 to 4.28%; p = 0.92, not equivalent). The main secondary objective of demonstrating zero percentage-point change with equivalence of ± 2% was not met. Conclusions Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment plasma cardiac troponin I concentrations. Low-risk non-randomised patients had similar modest declines in left ventricular ejection fraction, suggesting that the clinical utility of routine cardiac troponin monitoring remains undefined. The modest short-term declines in left ventricular ejection fraction suggest that early cardioprotection therapy has a limited role in patients receiving anthracycline-based chemotherapy. Limitations Treatment effect might have been influenced by several patients stopping cardioprotection treatment within 2 months of randomisation. Across all groups, reduction in left ventricular ejection fraction was lower than expected and patients with high-risk cardiac troponin I concentrations did not exhibit a greater fall in left ventricular ejection fraction than low-risk patients. These factors, together with the trial being powered to detect a 5-percentage-point change in left ventricular ejection fraction, mean that a small treatment effect was not excluded. Future work Future work should aim to understand the transition from small changes in cardiac function, 6 months after completion of anthracycline chemotherapy, to the late development of heart failure in this population. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information. Plain language summary The improved survival for patients with cancer is in part down to chemotherapy drugs called anthracyclines. This medication can cause the unwanted side effect of heart muscle pump injury in a minority of patients. Cancer survivors have increased rates of heart problems, including heart muscle pump failure. Research questions The Cardiac CARE trial tested whether tablet medications called angiotensin receptor blockers and B-blockers, taken together (cardioprotection therapy), can prevent heart muscle injury related to chemotherapy. Doctors treat heart pump failure using these medications. We examined whether a blood test called high sensitivity cardiac troponin I can detect very slight heart muscle injury and predict future problems with heart pump failure. What we did In the trial, only patients with increased levels of the troponin blood test marker were treated with cardioprotection therapy. Breast and blood cancer patients receiving anthracycline treatment were approached to take part. After giving consent they had a detailed scan of their heart prior to starting and 6 months after completing anthracycline chemotherapy. Patients receiving anthracycline had blood taken routinely 2 or 3 days before each treatment. Cardiac troponin levels were measured in these blood samples, and patients with an increased level were allocated at random to treatment with cardioprotection therapy or to normal care. Research findings We found no evidence that cardioprotection therapy prevented decline in heart function in anthracycline-treated patients with elevated cardiac troponin levels. Patients with no increased troponin level had a similar decline in heart function. It was reassuring that the reduction in heart muscle function following anthracycline chemotherapy was small. We believe the results show that cardioprotection therapy is not effective and may not be required for most patients. Scientific summary Background Anthracycline chemotherapy has been shown to reduce the chances of cancer recurrence and death in individuals diagnosed with breast cancer and non-Hodgkin lymphoma. Anthracyclines can also cause damage to the heart muscle, potentially leading to left ventricular systolic dysfunction and cardiac failure. As cancer survival rates improve, there is growing concern about the long-term impact of chemotherapy-related cardiac toxicity. Previous studies have revealed that approximately 5% of patients treated with high doses of anthracycline experience cardiac failure, with the prevalence rising to 10% among those aged > 65 years. The progression from initial heart muscle injury during chemotherapy to the development of left ventricular systolic dysfunction and subsequent clinical heart failure remains poorly understood. Thankfully, the severity and incidence of cardiotoxicity have decreased with the implementation of modern chemotherapy protocols that use lower cumulative doses of anthracycline. To mitigate the risk of systolic dysfunction in patients receiving anthracyclines, recent clinical trials have investigated the use of medications commonly employed in heart failure treatment. A recent meta-analysis of 17 trials involving patients receiving anthracycline-based chemotherapy and randomised to neurohormonal blockade showed a mean 4-percentage-point higher left ventricular ejection fraction (LVEF) in the blockade group, along with a non-significant trend towards fewer clinical events. However, the studies in this meta-analysis have their limitations. First, therapy was prescribed to all patients, resulting in significant overtreatment as most patients do not develop cardiotoxicity. Second, the medications used targeted either the renin-angiotensin system or the sympathetic nervous system (B-adrenoreceptor blocker), even though the strongest evidence supports combined therapy with these medications for the treatment of left ventricular systolic dysfunction. With modern advancements in cancer care, lower rates of cardiotoxicity are being achieved. Consequently, future trials should focus on interventions for patients who are at the highest risk of developing cardiotoxicity. Addressing the limitations of previous studies, the Cardiac CARE trial (registered as EudraCT 2017-000896-99 and ISRCTN24439460) aimed to select patients who demonstrated the most evidence of anthracycline-induced myocardial injury and randomise them into a combination treatment of candesartan and carvedilol. Objectives The primary goals of the Cardiac CARE trial were twofold: first, to investigate whether high-sensitivity plasma cardiac troponin I (cTnI) monitoring can identify patients who are at risk of developing left ventricular systolic dysfunction after undergoing anthracycline chemotherapy, and, second, to determine if cTnI-guided treatment with candesartan and carvedilol can prevent the development of left systolic ventricular dysfunction. By achieving these objectives, Cardiac CARE trial findings would have immediate practical implications for clinical practice by testing a straightforward monitoring and intervention pathway that could easily be implemented within cancer treatment centres. The primary end point of the study was to measure the change in left ventricular ejection fraction using cardiac magnetic resonance imaging conducted 6 months after the final dose of anthracycline chemotherapy. The first secondary end point and main secondary objective were to establish the specificity of high-sensitivity cardiac troponin I (hs-cTnI) monitoring for cardiotoxicity by assessing the change in left ventricular ejection fraction in the low-risk non-randomised group. Additional secondary end points included evaluating hs-cTnI concentrations, conducting further cardiac magnetic resonance imaging measurements to assess the efficacy of candesartan and carvedilol treatment, and determining the specificity of hs-cTnI monitoring for cardiotoxicity. The study summarised clinically relevant thresholds for grading anthracycline cardiotoxicity based on treatment, but no formal statistical testing was performed due to inadequate power and the risk of testing multiple hypotheses simultaneously. Methods The study was conducted in accordance with the Declaration of Helsinki and received approval from the South East Scotland Research Ethics Committee (17/ES/0071). It followed a prospective, randomised, open-label, blinded end-point design. All patients received standard of care and underwent cardiac magnetic resonance imaging before and 6 months after completing anthracycline chemotherapy. Patients with high sensitivity plasma cTnI concentrations in the upper tertile during chemotherapy were randomly assigned in a 1 : 1 ratio to receive either standard of care alone or standard of care along with combined candesartan and carvedilol therapy. Patients aged ≥18 years who were starting anthracycline treatment for adjuvant or neo-adjuvant therapy of breast cancer or non-Hodgkin lymphoma were eligible to participate. To focus on the dose-dependent nature of anthracycline cardiotoxicity and considering the lower incidence observed in recent studies, only patients scheduled to receive a cumulative dose of at least 300 mg/m2 of epirubicin or 150 mg/m2 of doxorubicin over three, four or six cycles of treatment were approached. In comparison, the Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) study included 60% of patients receiving low-dose anthracycline (cumulative epirubicin dose ≤ 240 mg/m2), and around 20% of them also received trastuzumab. Cardiac CARE excluded patients with HER2-positive disease scheduled for trastuzumab treatment. Although studying the outcomes of patients receiving anthracycline followed by trastuzumab is clinically relevant, it would require a larger study to account for the effects of two agents with interacting but distinct mechanisms of myocardial injury and potentially reversible changes in left ventricular ejection fraction occurring over an additional 15 months of trastuzumab administration. Plasma hs-cTnI concentrations were measured before and during chemotherapy to identify patients at high risk. The thresholds for randomisation were based on findings from a pilot study that identified patients with high sensitivity plasma cTnI concentrations in the upper tertile on completion of anthracycline chemotherapy. Patients were randomised using a web-based service to ensure allocation concealment and avoid bias. Randomisation was performed between the standard of care alone and the standard of care plus combined candesartan and carvedilol (cardioprotection) therapy groups. Patients assigned to the treatment intervention started with 8 mg of candesartan once daily, with dosage increases of at least 3 days to reach 16 mg and 32 mg once daily. Simultaneously, carvedilol was initiated at 6.25 mg twice daily and increased to 12.5 mg and 25 mg twice daily. The medications were dispensed on the day of randomisation and continued until patients completed the study or withdrew from participation. Adherence to medication was recorded through dose titration clinics and in patient diaries. Patients with plasma hs-cTnI concentrations below the randomisation threshold remained on standard of care alone. Health utility, measured with the EuroQol-5 Dimensions, five-level version (EQ-5D-5L) questionnaire, was assessed at chemotherapy cycle 1 by a research nurse and approximately every 9 weeks until the completion of the study (a total of five times). Sample size and statistical analysis The Cardiac CARE trial aimed to enrol at least 168 patients from various regional cancer centres in the UK. It was estimated that approximately one-third of the enrolled patients (n = 56) would develop high-sensitivity plasma cTnI concentrations that met the criteria for high risk based on the Cardiac CARE pilot study. We assumed that this threshold would select all patients at risk of experiencing a ≥ 5%-point reduction in left ventricular ejection fraction, which may be associated with long-term clinical outcomes. The randomisation was set at a 1 : 1 ratio between the treatment arm and standard care. Treatment allocation employed dynamic randomisation, with minimisation of group imbalances in prognostic factors, including age (≥ 65 or < 65 years), baseline LVEF (≥ 60% or < 60%) and planned cumulative epirubicin equivalent dose (300 or > 300 mg/m2). To detect a difference of 5 percentage points between groups (standard deviation 5) with 90% power at a significance level of = 0.05, we needed to randomise 23 patients per group. Accounting for an estimated 17% missing data, the sample size requirement increased to 28 patients per group, resulting in a total randomised trial size of 56 patients. Since one-third of enrolled patients were expected to be randomised, the total enrolment needed to be at least 168 patients. To assess the specificity of the plasma hs-cTnI assay for left ventricular systolic dysfunction in non-randomised patients, we aimed to demonstrate that there was no change in left ventricular ejection fraction percentage (with equivalence limits of ± 2%). To achieve this, we needed complete paired magnetic resonance imaging scans from 68 non-randomised patients for a paired t-test with two-sided p-value of 0.05, 90% power, and a standard deviation of differences of 5%. Results Between 4 October 2017 and 30 June 2021, 175 patients were enrolled. Fifty-seven (32.6%) of patients were randomised. Twenty-nine were allocated to cardioprotection, with two patients in this group not completing the final follow-up magnetic resonance imaging (MRI) scan. Twenty-eight were allocated to standard care, with one patient not completing the final follow-up MRI scan. Within the remaining 118 non-randomised group, 21 patients did not complete the final follow-up magnetic resonance imaging scan. Twenty patients (68.9%) were adherent to cardioprotection treatment at 6 months. Two patients (6.9%) randomised to cardioprotection did not receive medication owing to illness at the time of randomisation. Adverse events were more common in cardioprotection than in the standard care groups (71.4% and 10.3%, respectively). Seven (24.1%) participants stopped both cardioprotection drugs within 2 months owing to symptoms. The mean (standard deviation) patient age in the non-randomised, cardioprotection and standard care groups was 52.1 (11.0) years, 54 (14.1) years and 53.5 (13.3) years, respectively. Mean mass (standard deviation) was higher in the standard care group (82.5 kg; 6.7 kg) than in the cardioprotection (70.7 kg; 16.5 kg) and non-randomised groups (76.6 kg; 6.5 kg); 71.2% of patients had received a diagnosis of breast cancer. Non-Hodgkin lymphoma patients were more frequently randomised than breast cancer patients, making up 43.9% of the randomised and 21.2% of the non-randomised groups. Cardiovascular risk markers and concomitant cardiovascular medication prescription were uncommon across all three groups. Hypertension and coronary disease were more common in the standard care group (14.3% and 7.1%, respectively) than in the non-randomised (8.5% and 3%) and cardioprotection groups (6.9% and 0%). The mean anthracycline dose was higher in the cardioprotection (469 mg/m2) and standard care groups (479 mg/m2) than in the non-randomised group (424 mg/m2). Radiotherapy was more commonly prescribed in the non-randomised group (71.2%) than in the cardioprotection (57.1%) and standard care groups (53.6%). Patients randomised to cardioprotection or standard care had a mean (standard deviation) LVEF 6 months after completion of anthracycline chemotherapy of 65.7% (6.6%) and 64.9% (5.9%), respectively. After adjustment, the estimated mean difference in 6-month LVEF between the cardioprotection and standard care groups was –0.4% points [95% confidence interval (CI) –3.6 to 2.8 points; p = 0.82]. We examined the per-protocol primary efficacy outcome between the randomised groups in a post hoc sensitivity analysis. When only 19 cardioprotection patients who were adherent to treatment were included, there was no change in the primary outcome. The estimated mean difference in the change in 6-month LVEF between the cardioprotection and standard care groups was –0.7 percentage points (95% CI –4.3 to 2.9 percentage points; p = 0.70). In non-randomised patients, the baseline and 6-month LVEF (standard deviation) were 69.3% (5.7%) and 66.4% (6.3%), respectively. The estimated mean difference was 2.9 percentage points (95% CI 1.45 to 4.28 percentage points; p = 0.92). The main secondary objective of demonstrating zero-percentage-point change with equivalence of ± 2% was not met. Secondary analysis identified a difference between cardioprotection and standard care groups in adjusted left ventricular end-diastolic volume indexed for body surface area of 6.0 ml/m2 (95% CI 0.6 to 11.4 ml/m2; p = 0.03). There was no difference between the groups in global longitudinal and circumferential strain, left ventricular mass or left atrial area. hs-cTnI concentrations were higher in the randomised groups. The adjusted change in hs-cTnI concentration from baseline to 2 months in the cardioprotection and standard care groups was 27.3 ng/l (7.4 ng/l) and 28.8 ng/l (8.8 ng/l) [estimated mean (standard error)]. The estimated mean difference was –1.6 ng/l (95% CI –17.6 to 14.4 ng/l; p = 0.85). No cardiovascular deaths or new atrial fibrillation were recorded during the trial. One patient in the standard care treatment group developed congestive cardiac failure. This patient received heart failure treatment including candesartan and their ejection fraction was seen to have recovered on the 6-month cardiac MRI scan. No patients met the criteria for asymptomatic cancer therapy-related cardiac dysfunction (CTRCD) of a 10-percentage-point LVEF fall and fall to an absolute LVEF below 50%. Similarly, the CTRCD criterion of > 15% fall in global longitudinal strain was uncommon across the groups. Chronic myocardial injury 2 months after completion of chemotherapy was not uncommon and was similar in the non-randomised (32.1%) and cardioprotection (35.7%) groups. The proportion with chronic myocardial injury was higher (60%) in the standard care treatment group. Any recording of high hs-cTnI concentration was confined to randomised groups. Conclusions We found no evidence of cardioprotection effect with combined candesartan and carvedilol. This combination was associated with side effects, and discontinuation of therapy was not uncommon. Our findings do not support the European Society Guidelines that give a class II recommendation to use of either an angiotensin blocker or B-blockers for high-risk anthracycline-treated patients. Furthermore, the small decline in LVEF at 6 months in all groups together with the low levels of other cardiotoxicity measures cast doubt over whether any form of broadly administered cardioprotection therapy is required for these patients. The recently published European Society of Cardio-Oncology Guidelines provide a class I recommendation for the use of cTn monitoring in anthracycline patients at high risk of cardiotoxicity. The Cardiac CARE trial findings raise doubt about whether this monitoring strategy is helpful when patients with both low- and high-risk hs-cTnI concentration profiles developed small reductions in left ventricular ejection fraction. Although the pathological link between cTn as a biomarker of anthracycline myocardial injury is clear, we found no evidence that elevated concentrations strongly predict cardiotoxicity, inform disease management or improve care when added to current treatment pathways. Further analysis of the data will establish the correlation between hs-cTnI concentrations and change in LVEF and global longitudinal strain. We will also examine whether there is a threshold hs-cTnI concentration below which patients do not develop a decline in LVEF. An LVEF decline of 4.3% at 6 months after chemotherapy may not have immediate clinical implications for an individual patient. Applied across a population, this magnitude of LVEF decline is likely to confer a generalised increased risk of future cardiac dysfunction and heart failure. Future research should be directed at understanding the factors determining the evolution of cardiac dysfunction with monitoring and longer-term follow-up studies. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Introduction The large reservoir of tuberculosis (TB) infections is one of the main reasons for the persistent incidence of TB. Accurate diagnostic tests are crucial to correctly identify and treat people with TB infection, which is vital to eliminate TB globally. The rdESAT-6 and rCFP-10 (Cy-Tb) injection (‘Cy-Tb’), a TB-specific antigen skin test and STANDARD F TB-Feron FIA (‘Standard F TB’) measuring interferon-gamma by fluorescence immunoassay assay are two novel tools for the diagnosis of TB infection which offer advantages compared with current tests in low-resource settings and reduced costs to both health systems and TB-affected people. The proposed study aims to evaluate the diagnostic accuracy of these two new tests for TB infection diagnosis.Methods and analysis This cross-sectional study aims to assess the diagnostic accuracy for TB infection of the Cy-Tb skin test and Standard F TB assay (investigational tests) compared with the QuantiFERON-TB Gold Plus (QFT-Plus) assay as the immunological reference standard. Three different cohorts of study participants will be recruited at the Vietnam National Lung Hospital: adults with bacteriologically confirmed pulmonary TB (n=100), household contacts of people with TB (n=200) and people without TB infection (n=50). All consenting participants will undergo simultaneous testing with Cy-Tb, Standard F TB and QFT-Plus. The primary endpoint is the diagnostic accuracy of the Cy-Tb skin test and Standard F TB assay, expressed as sensitivity and specificity against the reference standard.Ethics and dissemination Ethical approval was granted by the Vietnam National Lung Hospital Institutional Review Board (65/23/CN-HDDD-BVPTU) and the Swedish Ethical Review Authority (Dnr 2023-04271-01). Study results will be disseminated to the scientific community and policymakers through scientific publications.Trial registration number NCT06221735.

Objectives In the face of unprecedented demand, the Welsh Ambulance Services University NHS Trust developed ‘Blue Light Hub’: a new app to educate primary school-aged children about emergency services. Our overarching aim was to examine the effectiveness of the app.Design Primary school-aged children from three schools in South Wales, UK, played with the app for 2 hours over 2 weeks in class time. Children completed quizzes to assess their knowledge and awareness of, and confidence in engaging with, emergency services before and after using the app.Participants Our evaluation focused on N=393 children who completed both the pre-test and post-test quizzes. On average, children were 8–9 years old (median school year, Year 4); 47.8% were male and 50.9% were female.Results After using the app, there was a significant increase in the proportion of children who knew of appropriate actions to take in non-emergency scenarios, χ2(1) = 26.01, and could provide a question a call handler would ask them if they called 999, χ2(1) = 13.79. There was also an increase in the proportion of children who could identify an National Health Service (NHS) service that could help them if they were unwell, χ2(1) = 33.31, name different roles in the NHS, χ2(1) = 12.80 and knew how dialling 111 could help them χ2(1) = 90.05 (all p values

Abstract Glioblastoma is a highly heterogeneous disease, with variations observed at both phenotypical and molecular levels. Personalized therapies would be facilitated by non-invasive in vivo approaches for characterizing this heterogeneity. In this study, we developed unsupervised joint machine learning between radiomic and genomic data, thereby identifying distinct glioblastoma subtypes. A retrospective cohort of 571 IDH-wildtype glioblastoma patients were included in the study, and pre-operative multi-parametric MRI scans and targeted next-generation sequencing (NGS) data were collected. L21-norm minimization was used to select a subset of 12 radiomic features from the MRI scans, and 13 key driver genes from the five main signal pathways most affected in glioblastoma were selected from the genomic data. Subtypes were identified using a joint learning approach called Anchor-based Partial Multi-modal Clustering on both radiomic and genomic modalities. Kaplan–Meier analysis identified three distinct glioblastoma subtypes: high-risk, medium-risk, and low-risk, based on overall survival outcome (p

Abstract Background In 2009, Yvonne Steinert et al., at McGill University, published a study exploring barriers to faculty development (FD) participation among urban faculty. Over a decade later, we set out to replicate and expand on that study to learn what has changed in continued professional development (CPD) and what the current barriers are to participation in CPD for specialists and family physicians in rural and urban locations. Methods Informed by a collaborative inquiry research framework, we invited faculty across rural and urban Saskatchewan to focus groups and interview sessions. The results were analyzed for themes. Results Thirty-four faculty members from both rural and urban areas participated in this study. Of these, 50% were female, 74% practiced in urban areas, and 56% had over 20 years of experience. Frequently cited reasons for nonparticipation included time constraints, organizational and logistical challenges, poor resonance with material and presenters, and lack of recognition for teaching provided. Racism contributed to feelings of disconnectedness among physician faculty members. Conclusion Even after more than a decade, our research uncovered consistent reasons for nonparticipation in locally organized CPD events. New findings highlighted feelings of disconnectedness, notably stemming from racism and workplace discrimination. However, with recent societal developments brought about by the COVID-19 pandemic, can we ride these major waves of change to a new future of engagement? The pandemic led to a shift to virtual and hybrid professional development programs, presenting both benefits and challenges. Additionally, the peri-COVID anti-racism movement may positively address previously unidentified reasons for nonattendance. Harnessing these major changes could lead to a new future of engagement for continued professional development.

Abstract The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m2 and hepatic steatosis with threshold SHAD ≥ − 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients—lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p

BackgroundScreening, brief intervention, and referral to treatment for adolescents (SBIRT-A) is widely recommended to promote detection and early intervention for alcohol and other drug (AOD) use in pediatric primary care. Existing SBIRT-A procedures rely almost exclusively on adolescents alone, despite the recognition of caregivers as critical protective factors in adolescent development and AOD use. Moreover, controlled SBIRT-A studies conducted in primary care have yielded inconsistent findings about implementation feasibility and effects on AOD outcomes and overall developmental functioning. There is urgent need to investigate the value of systematically incorporating caregivers in SBIRT-A procedures. ObjectiveThis randomized effectiveness trial will advance research and scope on SBIRT-A in primary care by conducting a head-to-head test of 2 conceptually grounded, evidence-informed approaches: a standard adolescent-only approach (SBIRT-A-Standard) versus a more expansive family-based approach (SBIRT-A-Family). The SBIRT-A-Family approach enhances the procedures of the SBIRT-A-Standard approach by screening for AOD risk with both adolescents and caregivers; leveraging multidomain, multireporter AOD risk and protection data to inform case identification and risk categorization; and directly involving caregivers in brief intervention and referral to treatment activities. MethodsThe study will include 2300 adolescents (aged 12-17 y) and their caregivers attending 1 of 3 hospital-affiliated pediatric settings serving diverse patient populations in major urban areas. Study recruitment, screening, randomization, and all SBIRT-A activities will occur during a single pediatric visit. SBIRT-A procedures will be delivered digitally on handheld tablets using patient-facing and provider-facing programming. Primary outcomes (AOD use, co-occurring behavior problems, and parent-adolescent communication about AOD use) and secondary outcomes (adolescent quality of life, adolescent risk factors, and therapy attendance) will be assessed at screening and initial assessment and 3-, 6-, 9-, and 12-month follow-ups. The study is well powered to conduct all planned main and moderator (age, sex, race, ethnicity, and youth AOD risk status) analyses. ResultsThis study will be conducted over a 5-year period. Provider training was initiated in year 1 (December 2023). Participant recruitment and follow-up data collection began in year 2 (March 2024). We expect the results from this study to be published in early 2027. ConclusionsSBIRT-A is widely endorsed but currently underused in pediatric primary care settings, and questions remain about optimal approaches and overall effectiveness. In particular, referral to treatment procedures in primary care remains virtually untested among youth. In addition, whereas research strongly supports involving families in interventions for adolescent AOD, SBIRT-A effectiveness trial testing approaches that actively engage family members in primary care are absent. This trial is designed to help fill these research gaps to inform the critical health decision of whether and how to include caregivers in SBIRT-A activities conducted in pediatric primary care. Trial RegistrationClinicalTrials.gov NCT05964010; https://www.clinicaltrials.gov/study/NCT05964010 International Registered Report Identifier (IRRID)PRR1-10.2196/54486

BackgroundChronic pain is common among individuals with opioid use disorder (OUD) who are maintained on medications for OUD (MOUD; eg, buprenorphine or methadone). Chronic pain is associated with worse retention and higher levels of substance use. Treatment of individuals with chronic pain receiving MOUD can be challenging due to their increased clinical complexity. Given the acute and growing nature of the opioid crisis, MOUD is increasingly offered in a wide range of settings, where high-quality, clinician-delivered, empirically validated behavioral treatment for chronic pain may not be available. Therefore, digital treatments that support patient self-management of chronic pain and OUD have the potential for wider implementation to fill this gap. ObjectiveThis study aims to evaluate the efficacy of Integrating the Management of Pain and Addiction via Collaborative Treatment (IMPACT), an interactive digital treatment program with asynchronous coach feedback, compared to treatment as usual (TAU) in individuals with chronic pain and OUD receiving MOUD. MethodsAdult participants (n=160) receiving MOUD and reporting bothersome or high-impact chronic pain will be recruited from outpatient opioid treatment programs in Connecticut (United States) and randomized 1:1 to either IMPACT+TAU or TAU only. Participants randomized to IMPACT+TAU will complete an interactive digital treatment that includes 9 modules promoting training in pain and addiction coping skills and a progressive walking program. The program is augmented with a weekly personalized voice message from a trained coach based on daily participant-reported pain intensity and interference, craving to use opioids, sleep quality, daily steps, pain self-efficacy, MOUD adherence, and engagement with IMPACT collected through digital surveys. Outcomes will be assessed at 3, 6, and 9 months post randomization. The primary outcome is MOUD retention at 3 months post randomization (ie, post treatment). Secondary outcomes include pain interference, physical functioning, MOUD adherence, substance use, craving, pain intensity, sleep disturbance, pain catastrophizing, and pain self-efficacy. Semistructured qualitative interviews with study participants (n=34) randomized to IMPACT (completers and noncompleters) will be conducted to evaluate the usability and quality of the program and its outcomes. ResultsThe study has received institutional review board approval and began recruitment at 1 site in July 2022. Recruitment at a second site started in January 2023, with a third and final site anticipated to begin recruitment in January 2024. Data collection is expected to continue through June 2025. ConclusionsEstablishing efficacy for a digital treatment for addiction and chronic pain that can be integrated into MOUD clinics will provide options for individuals with OUD, which reduce barriers to behavioral treatment. Participant feedback on the intervention will inform updates or modifications to improve engagement and efficacy. Trial RegistrationClinicalTrials.gov NCT05204576; https://clinicaltrials.gov/ct2/show/NCT05204576 International Registered Report Identifier (IRRID)DERR1-10.2196/54342

Far-ultraviolet C light, with a wavelength of 200–230 nm, has demonstrated broad-spectrum germicidal efficacy. However, due to increased interest in its use as an alternative antimicrobial, further knowledge about its fundamental bactericidal efficacy is required. This study had two objectives. Firstly, it investigated experimentally the Far-UVC dose–response of common bacteria suspended at various cell densities in transparent buffer, ensuring no influence from photosensitive suspending media. Increasing doses of Far-UVC were delivered to Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus in PBS at 101, 102, 103, 105 and 107 CFU·mL−1, with surviving colony-forming units enumerated (n ≥ 3). Secondly, through a systematised literature review, this work sought to explore the impact of genus/species, Gram type, cell form, cell density and irradiance on dose–response. The screening of 483 publications was performed with 25 included in the study. Data for 30 species were collated, analysed and compared with the experimental results. Overall, Gram-positive species showed greater resilience to Far-UVC than Gram-negative; some inter-species and inter-genera differences in resilience were identified; endospores were more resilient than vegetative cells; the results suggested that inactivation efficiency may decrease as cell density increases; and no significant correlation was identified between irradiance and bactericidal dose effect. In conclusion, this study has shown Far-UVC light to be an effective decontamination tool against a vast range of bacterial vegetative cells and endospores.

Trypanosoma cruzi (T. cruzi) is the causative agent of Chagas' disease, a parasitic infection responsible for significant morbidity and mortality in Latin America. The current treatments have many serious drawbacks and new drugs are urgently required. In the UK, T. cruzi is classified by the Advisory Committee on Dangerous Pathogens (ACDP) as a Hazard Group 3 organism and strict safety practices must be adhered to when handling this pathogen in the laboratory. Validated inactivation techniques are required for safe T. cruzi waste disposal and removal from Containment Level 3 (CL3) facilities for storage, transportation and experimental analysis. Here we assess three T. cruzi. inactivation methods. These include three freeze-thaw cycles, chemical inactivation with Virkon disinfectant, and air drying on Whatman FTA cards (A, B, C, Elute) and on a Mitra microsampling device. After each treatment parasite growth was monitored for 4-6 weeks by microscopic examination. Three freeze-thaw cycles were sufficient to inactivate all T. cruzi CLBrener Luc life cycle stages and Silvio x10/7 A1 large epimastigote cell pellets up to two grams wet weight. Virkon treatment for one hour inactivated T. cruzi Silvio x10/7 subclone A1 and CLBrener Luc both in whole blood and cell culture medium when incubated at a final concentration of 2.5% Virkon, or at ≥1% Virkon when in tenfold excess of sample volume. Air drying also inactivated T. cruzi CLBrener Luc spiked blood when dried on FTA A, B or Elute cards for ≥30 minutes and on a Mitra Microsampler for two hours. However, T. cruzi CLBrener Luc were not inactivated on FTA C cards when dried for up to two hours. These experimentally confirmed conditions provide three validated T. cruzi inactivation methods which can be applied to other related ACDP Hazard Group 2-3 kinetoplastid parasites.

Background. Over the last 25 years, clinical practice guidelines have emerged as a means to standardize and improve care. As pharmaceutical innovations develop, guidelines are updated to incorporate new interventions. However, the extent to which pharmacotherapies are represented as treatment options in guideline recommendations has not been well elucidated. This study aimed to quantify the role pharmacotherapy has played in clinical practice guidelines across a range of chronic diseases over the past 20 years. Methods. Clinical practice guidelines published from 2000 to 2021 were identified for five chronic diseases: ischemic heart disease (IHD), non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD), Alzheimer’s disease (AD), and type 2 diabetes (T2D). Guidelines were reviewed and data on treatment recommendations were collected, including the type of intervention, line of therapy, and, for pharmacotherapies, year of regulatory approval and year of inclusion in guidelines. Results. In total, 92 clinical practice guidelines were reviewed. Among the 184 discrete recommended interventions across the five disease areas, 146 (79.3%) were pharmacotherapies, 21 (11.4%) were behavioral modifications, 6 (3.3%) were surgical interventions, and 11 (6%) were other interventions. Across guidelines, when a line of therapy was specified, behavioral modifications and pharmacotherapies were most frequently recommended as first-line interventions, whereas surgical interventions were more often recommended for subsequent lines of treatment. The time from regulatory approval of novel pharmacotherapies to inclusion in guideline recommendations varied considerably by disease area and geography. Conclusions. Across the reviewed disease areas, behavioral interventions and pharmacotherapies are shown to be critical components of clinical practice. Over the last 20 years, novel pharmaceutical innovations have been incorporated into clinical practice guideline recommendations; however, with varying speeds of adoption. Given the increasing pace of pharmacologic innovation, timely updates of clinical practice guidelines are critical to evolving the standard of care and practicing evidence-based medicine.

Abstract Background Accurate differentiation of pseudoprogression (PsP) from tumor progression (TP) in glioblastomas (GBMs) is essential for appropriate clinical management and prognostication of these patients. In the present study, we sought to validate the findings of our previously developed multiparametric MRI model in a new cohort of GBM patients treated with standard therapy in identifying PsP cases. Methods Fifty-six GBM patients demonstrating enhancing lesions within 6 months after completion of concurrent chemo-radiotherapy (CCRT) underwent anatomical imaging, diffusion and perfusion MRI on a 3 T magnet. Subsequently, patients were classified as TP + mixed tumor (n = 37) and PsP (n = 19). When tumor specimens were available from repeat surgery, histopathologic findings were used to identify TP + mixed tumor (> 25% malignant features; n = 34) or PsP (

A common infection, human cytomegalovirus (HCMV) has been associated with a variety of human diseases, including cardiovascular disease and possibly certain cancers. HCMV has also been associated with cognitive, psychiatric, and neurological conditions. Children with congenital or early-life HCMV are at risk for microcephaly, cerebral palsy, and sensorineural hearing loss, although in many cases sensorineural loss may resolve. In addition, HCMV can be associated with neurodevelopmental impairment, which may improve with time. In young, middle-aged, and older adults, HCMV has been adversely associated with cognitive function in some but not in all studies. Research has linked HCMV to Alzheimer’s and vascular dementia, but again not all findings consistently support these associations. In addition, HCMV has been associated with depressive disorder, bipolar disorder, anxiety, and autism-spectrum disorder, although the available findings are likewise inconsistent. Given associations between HCMV and a variety of neurocognitive and neuropsychiatric disorders, additional research investigating reasons for the considerable inconsistencies in the currently available findings is needed. Additional meta-analyses and more longitudinal studies are needed as well. Research into the effects of antiviral medication on cognitive and neurological outcomes and continued efforts in vaccine development have potential to lower the neurocognitive, neuropsychiatric, and neurological burden of HCMV infection.

Introduction Approximately 40% of children aged 6–59 months worldwide are anaemic. Iron-containing multiple micronutrient powders (MNPs) and iron supplements (syrup/drops) are used to combat anaemia in children in different parts of the world. However, evidence for functional benefits of iron supplementation in children is scarce, and potential risks remain poorly defined, particularly concerning diarrhoea and malaria. This trial aims to determine if: (1) the efficacy of iron supplements or MNPs (containing iron) given with malaria chemoprevention is superior to malaria chemoprevention alone, or (2) if the efficacy of malaria chemoprevention alone is superior to placebo on child cognitive development.Methods and analysis IRMA is a four-arm, parallel-group, double-blinded, placebo-controlled, triple-dummy, randomised trial in Southern Malawi. The study recruits 2168 infants aged 6 months, with an intervention period of 6 months and a post-intervention period of a further 6 months. Children are randomised into four arms: (1) No intervention (placebo); (2) malaria chemoprevention only; (3) MNPs and malaria chemoprevention; and (4) iron syrup and malaria chemoprevention. The primary outcome, cognitive development (Cognitive Composite Score (CogCS)), is measured at the end of the 6 months intervention. Secondary outcomes include CogCS at a further 6 months post-intervention, motor, language and behavioural development, physical growth and prevalence of anaemia and iron deficiency. Safety outcomes include incidence of malaria and other infections, and prevalence of malaria parasitaemia during and post-intervention period.Ethics and dissemination The trial is approved by the National Health Sciences Research Committee (#19/01/2213) (Malawi) and the Human Research Ethics Committee (WEHI: 19/012) (Australia). Written informed consent in the local language is obtained from each participant before conducting any study-related procedure. Results will be shared with the local community and internationally with academic and policy stakeholders.Trial registration number ACTRN12620000386932.

Objectives To explore the impact of Long Covid (LC) on the school experiences of children and young people (CYP).Design Qualitative study using narrative interviews.Participants 22 CYP (aged 10–18 years, 15 female) with LC and 15 parents/caregivers (13 female) of CYP (aged 5–18 years) with LC.Setting Interviews were conducted between October 2021 and July 2022 via online video call or telephone. Recruitment routes included social media, LC support groups, clinicians, community groups and snowballing.Results Three key findings were identified. Finding 1: Going to school is a valued part of CYP’s lives and participants viewed educational attainment as important for their future trajectories. Returning to school full time was highlighted as a key part of regaining ‘normal life’. Finding 2: Attending school (in-person or online) with LC is extremely difficult; even a gradual return required CYP to balance the impact of being at and engaging with school, with the need to manage symptoms to prevent relapse. Often this meant prioritising school and rest over other aspects of their lives. Finding 3: School responses to CYP with LC were reported to be mixed and hampered by difficulties communicating with healthcare professionals during the pandemic and a lack of awareness of LC among healthcare and education professionals. Participants viewed supportive school responses as staff believing, understanding and taking them seriously, alongside schools offering tailored and flexible adaptations which allowed engagement with school while limiting any deterioration of symptoms.Conclusions This study describes how LC affects the school experiences of CYP and generates recommendations for supportive school responses alongside supportive healthcare professionals. Further research could explore the approaches that facilitate a successful return to school for CYP with LC and investigate education professionals’ perspectives on support they require to positively engage with returning pupils.

Introduction Treatment-resistant hypertension (RH), defined as uncontrolled blood pressure (≥140/90 mm Hg) despite treatment with ≥3 medications of different classes (including diuretics) at optimal doses, is associated with poor prognosis and an elevated risk of end-organ damage. In areas where HIV is endemic, such as sub-Saharan Africa, the risk of hypertension is high in people living with HIV. It remains unknown if HIV infection further increases the risk of RH. This study seeks to determine the association between HIV and RH as well as investigate other factors associated with RH in hypertensive Malawian adults.Methods and analysis A case–control study will be conducted among adult hypertensive patients attending a clinic at a referral hospital in Malawi. The cases will be hypertensive patients with a confirmed diagnosis of RH. For each case, two controls (hypertensive patients without RH), frequency matched for age group and sex, will be selected from among hospital clients attending the same hypertension clinic as the case. In both groups, HIV status will be ascertained. Additionally, information on other potential risk factors of RH, such as chronic kidney disease, obesity, hypercholesteraemia, diabetes, smoking, alcohol use, antiretroviral therapy regimen and duration, will be collected in both cases and controls. For each of the potential risk factors, ORs will be calculated to quantify the strength of their association with RH. In a multivariate analysis, conditional logistic regression will be used to assess the independent association between HIV and RH as well as the influence of the other potential drivers of RH.Ethics and dissemination This protocol has been approved by the College of Medicine Research Ethics Committee (COMREC) in Malawi (P.05/22/3637). Findings from this study will be disseminated through a peer-reviewed publication in an open-access international journal. Furthermore, anonymised data will be available on request from the authors.

Antimicrobial peptides (AMPs) offer a promising solution to the antibiotic resistance crisis. However, an unresolved serious concern is that the evolution of resistance to therapeutic AMPs may generate cross-resistance to host AMPs, compromising a cornerstone of the innate immune response. We systematically tested this hypothesis using globally disseminated mobile colistin resistance (MCR) that has been selected by the use of colistin in agriculture and medicine. Here, we show that MCR provides a selective advantage to Escherichia coli in the presence of key AMPs from humans and agricultural animals by increasing AMP resistance. Moreover, MCR promotes bacterial growth in human serum and increases virulence in a Galleria mellonella infection model. Our study shows how the anthropogenic use of AMPs can drive the accidental evolution of resistance to the innate immune system of humans and animals. These findings have major implications for the design and use of therapeutic AMPs and suggest that MCR may be difficult to eradicate, even if colistin use is withdrawn.

This article presents a critical analysis of the use of biometrics in clinical practice and their inadequacies for Indigenous populations in Canada and globally. Misclassifications of health status based on biometrics have health implications across the lifespan, from gestation to older adulthood, which are also examined. The social determinants of health and of Indigenous health compound the impact of inaccurate biometrics on First Nations, Inuit and Métis populations. Moving forward, biometric use should be done in partnership with Indigenous peoples and with consideration of the surrounding context. Future research should consider bridging existing gaps in knowledge on this topic in culturally safe ways, to improve the quality and depth of information available and inform more equitable health care for Indigenous populations.

When multiple stimuli appear together in the receptive field of a visual cortical neuron, the response is typically close to the average of that neuron's response to each individual stimulus. The departure from a linear sum of each individual response is referred to as normalization. In mammals, normalization has been best characterized in the visual cortex of macaques and cats. Here we study visually evoked normalization in the visual cortex of awake mice using imaging of calcium indicators in large populations of layer 2/3 (L2/3) V1 excitatory neurons and electrophysiological recordings across layers in V1. Regardless of recording method, mouse visual cortical neurons exhibit normalization to varying degrees. The distributions of normalization strength are similar to those described in cats and macaques, albeit slightly weaker on average.

BackgroundLong-term noninvasive positive airway pressure (PAP) treatment is effective treatment for sleep-related breathing disorders and chronic hypercarbic respiratory failure secondary to chronic obstructive pulmonary disease (COPD). PAP treatment may be delivered as continuous positive airway pressure or noninvasive ventilation. Success in initiating PAP treatment and barriers to its use in adult patients with COPD are largely unknown. This systematic review aims to identify the acceptance of and adherence to PAP treatment prescribed for long-term use in adult patients with COPD and to summarize variables associated with these measures.MethodsSeven online electronic databases will be searched by an experienced medical librarian to identify records containing the concepts "obstructive airways disease" and "noninvasive positive airway pressure" and "acceptance" or "adherence". Randomized and non-randomized studies of interventions will be included. Citation lists from relevant articles will be reviewed, and experts will be contacted regarding unpublished studies. Abstracts from key conferences between 2018-2023 and Google Scholar search results will be reviewed for inclusion. Titles, abstracts and full texts will be reviewed independently for inclusion by two reviewers. Data extraction will be completed by one author using a pre-established form and primary outcomes confirmed by a second author. Methodological quality will be evaluated. If sufficient data are available for meta-analysis, a pooled summary statistic for the primary outcome will be calculated using a random-effects generic inverse-variance meta-analysis, weighted proportion or weighted medians-based approach. Subgroup analysis will explore clinically meaningful sources of heterogeneity. Variables that are associated with acceptance and adherence will be described.DiscussionLong-term PAP treatment is a complex intervention prescribed to patients with COPD for several indications. Synthesis of the evidence on success with PAP treatment and variables associated with acceptance or adherence will inform program and policy development for supporting patients with COPD who are prescribed this therapy.Trial registrationSystematic review registration: This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on July 13, 2021 (registration number CRD42021259262), with revisions submitted on April 17, 2023.

ObjectivesThe SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this.MethodsIn this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1st November 2020 and 30th January 2021 were sequenced. We matched sequence data to clinical outcomes as the Alpha variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death.ResultsOur cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus pre-Alpha variants).ConclusionsThe Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages.

BackgroundInformation needs are one of the most prevalent unmet supportive care needs of those living with cancer, including patients and their informal caregivers. Understanding how existing questionnaires for evaluating information needs have been developed is important for guiding appropriate use and informing future research. A literature review examining how information needs assessment questionnaires for use in the cancer context have been developed, with a specific focus on how questionnaire items have been identified, does not exist. ObjectiveThis scoping review will examine how questionnaires for assessing the information needs of those living with cancer have been developed with special focus on how patients, informal caregivers, and health care professionals have been involved in the selection and identification of questionnaire items. MethodsThis review will include published studies describing the development and validation of information needs assessment questionnaires for use in the oncology context. MEDLINE (Ovid), Embase (Ovid), CINAHL, Scopus, Web of Science, the Cochrane Database of Systematic Reviews, and PsycInfo will be searched. Articles published at any point up to the date of the search will be eligible for inclusion. One person will screen titles and abstracts, and 2 people will screen and extract data from full-text articles. ResultsResults are expected to be available in early 2023. Summary tables and a narrative summary will be used to describe results. ConclusionsThis scoping review will assist in identifying appropriate information needs assessment tools to incorporate into clinical and research contexts in oncology. It will also identify if additional information needs assessment tools are needed. International Registered Report Identifier (IRRID)PRR1-10.2196/35639

Bacterial pathogens show high levels of chromosomal genetic diversity, but the influence of this diversity on the evolution of antibiotic resistance by plasmid acquisition remains unclear. Here, we address this problem in the context of colistin, a ‘last line of defence’ antibiotic. Using experimental evolution, we show that a plasmid carrying the MCR-1 colistin resistance gene dramatically increases the ability of Escherichia coli to evolve high-level colistin resistance by acquiring mutations in lpxC, an essential chromosomal gene involved in lipopolysaccharide biosynthesis. Crucially, lpxC mutations increase colistin resistance in the presence of the MCR-1 gene, but decrease the resistance of wild-type cells, revealing positive sign epistasis for antibiotic resistance between the chromosomal mutations and a mobile resistance gene. Analysis of public genomic datasets shows that lpxC polymorphisms are common in pathogenic E. coli, including those carrying MCR-1, highlighting the clinical relevance of this interaction. Importantly, lpxC diversity is high in pathogenic E. coli from regions with no history of MCR-1 acquisition, suggesting that pre-existing lpxC polymorphisms potentiated the evolution of high-level colistin resistance by MCR-1 acquisition. More broadly, these findings highlight the importance of standing genetic variation and plasmid/chromosomal interactions in the evolutionary dynamics of antibiotic resistance.

Background: Understanding how stress dynamically associates with alcohol use could provide a finer-grain resolution of drinking behavior, facilitating development of more effective and personalized interventions. The primary aim of this systematic review was to examine research using Intensive Longitudinal Designs (ILDs) to determine if greater naturalistic reports of subjective stress (e.g., those assessed moment-to-moment, day-to-day) in alcohol-drinkers associated with a) greater frequency of subsequent drinking, b) greater quantity of subsequent drinking, and c) whether between-/within-person variables moderate or mediate any relationships between stress and alcohol use. Methods: Using PRISMA guidelines, we searched EMBASE, PubMed, PsycINFO, and Web of Science databases in December 2020, ultimately identifying 18 eligible articles, representing 14 distinct studies, from a potential pool of 2,065 studies. Results: Results suggested subjective stress equivocally predicted subsequent alcohol use; in contrast, alcohol use consistently demonstrated an inverse relationship with subsequent subjective stress. These findings remained across ILD sampling strategy and most study characteristics, except for sample type (treatment-seeking vs. community/collegiate). Conclusions: Results appear to emphasize the stress-dampening effects of alcohol on subsequent stress levels and reactivity. Classic tension-reduction models may instead be most applicable to heavier-drinking samples and appear nuanced in lighter-drinking populations, and may depend on specific moderators/mediators (e.g., race/ethnicity, sex, relative coping-strategy use). Notably, a preponderance of studies utilized once-daily, concurrent assessments of subjective stress and alcohol use. Future studies may find greater consistency by implementing ILDs that integrate multiple within-day signal-based assessments, theoretically-relevant event-contingent prompts (e.g., stressor-occurrence, consumption initiation/cessation), and ecological context (e.g., weekday, alcohol availability).

How circuits self-assemble starting from neuronal stem cells is a fundamental question in developmental neurobiology. Here, we addressed how neurons from different stem cell lineages wire with each other to form a specific circuit motif. In Drosophila larvae, we combined developmental genetics (twin-spot mosaic analysis with a repressible cell marker, multi-color flip out, permanent labeling) with circuit analysis (calcium imaging, connectomics, network science). For many lineages, neuronal progeny are organized into subunits called temporal cohorts. Temporal cohorts are subsets of neurons born within a tight time window that have shared circuit-level function. We find sharp transitions in patterns of input connectivity at temporal cohort boundaries. In addition, we identify a feed-forward circuit that encodes the onset of vibration stimuli. This feed-forward circuit is assembled by preferential connectivity between temporal cohorts from different lineages. Connectivity does not follow the often-cited early-to-early, late-to-late model. Instead, the circuit is formed by sequential addition of temporal cohorts from different lineages, with circuit output neurons born before circuit input neurons. Further, we generate new tools for the fly community. Our data raise the possibility that sequential addition of neurons (with outputs oldest and inputs youngest) could be one fundamental strategy for assembling feed-forward circuits.

Nowadays, as technology takes on a more important role in our everyday lives, telehealth is emerging. Evidence proves that it can ease and improve access to quality care.(1) This commentary offers a synopsis of the narrative on the use of B.E.L.T. mnemonic to be used by a nurse champion to structure the implementation of telehealth services. This opinion and later research indicate that further testing is needed to adapt and validate the tool. The COVID-19 worldwide pandemic could not be a better opportunity to further test the tool through the implementation of telehealth in different settings across the world.

Quasi-stiffness characterizes the dynamics of a joint in specific sections of stance-phase and is used in the design of wearable devices to assist walking. We sought to investigate the effect of simulated reduced gravity and walking speed on quasi-stiffness of the hip, knee, and ankle in overground walking. 12 participants walked at 0.4, 0.8, 1.2, and 1.6 m/s in 1, 0.76, 0.54, and 0.31 gravity. We defined 11 delimiting points in stance phase (4 each for the ankle and hip, 3 for the knee) and calculated the quasi-stiffness for 4 phases for both the hip and ankle, and 2 phases for the knee. The R2 value quantified the suitability of the quasi-stiffness models. We found gravity level had a significant effect on 6 phases of quasi-stiffness, while speed significantly affected the quasi-stiffness in 5 phases. We concluded that the intrinsic muscle-tendon unit stiffness was the biggest determinant of quasi-stiffness. Speed had a significant effect on the R2 of all phases of quasi-stiffness. Slow walking (0.4 m/s) was the least accurately modelled walking speed. Our findings showed adaptions in gait strategy when relative power and strength of the joints were increased in low gravity, which has implications for prosthesis and exoskeleton design.

Recent research suggests that dysbiosis of the oral microbial community is associated with head and neck cancer (HNC). It remains unclear whether this dysbiosis causes chemo-radiotherapy (CRT)-related complications. However, to address this question, it is essential to determine the most representative oral site for microbiome sampling. In this study, our purpose was to determine the optimal site for oral sample collection and whether the presence of HNC is associated with altered oral microbiome from this site. In 21 newly diagnosed HNC patients and 27 healthy controls, microbiome samples were collected from saliva, swabs from buccal mucosa, tongue, hard palate, faucial pillars and all mucosal sites combined. Microbial DNA was extracted and underwent 16S rRNA amplicon gene sequencing. In healthy controls, analysis of observed taxonomic units detected differences in alpha- and beta-diversity between sampling sites. Saliva was found to have the highest intra-community microbial diversity and lowest within-subject (temporal) and between-subject variance. Feature intersection showed that most species were shared between all sites, with saliva demonstrating the most unique species as well as highest overlap with other sites. In HNC patients, saliva was found to have the highest diversity but differences between sites were not statistically significant. Across all sites, HNC patients had lower alpha diversity than healthy controls. Beta-diversity analysis showed HNC patients’ microbiome to be compositionally distinct from healthy controls. This pattern was confirmed when the salivary microbiome was considered alone. HNC patients exhibited reduced diversity of the oral microbiome. Salivary samples demonstrate temporal stability, have the richest diversity and are sufficient to detect perturbation due to presence of HNC. Hence, they can be used as representative oral samples for microbiome studies in HNC patients.

BackgroundThe COVID-19 pandemic is a public health emergency that poses challenges to the mental health of approximately 1.4 million university students in Canada. Preliminary evidence has shown that the COVID-19 pandemic had a detrimental impact on undergraduate student mental health and well-being; however, existing data are predominantly limited to cross-sectional survey-based studies. Owing to the evolving nature of the pandemic, longer-term prospective surveillance efforts are needed to better anticipate risk and protective factors during a pandemic. ObjectiveThe overarching aim of this study is to use a mobile (primarily smartphone-based) surveillance system to identify risk and protective factors for undergraduate students’ mental health. Factors will be identified from weekly self-report data (eg, affect and living accommodation) and device sensor data (eg, physical activity and device usage) to prospectively predict self-reported mental health and service utilization. MethodsUndergraduate students at Western University (London, Ontario, Canada), will be recruited via email to complete an internet-based baseline questionnaire with the option to participate in the study on a weekly basis, using the Student Pandemic Experience (SPE) mobile app for Android/iOS. The app collects sensor samples (eg, GPS coordinates and steps) and self-reported weekly mental health and wellness surveys. Student participants can opt in to link their mobile data with campus-based administrative data capturing health service utilization. Risk and protective factors that predict mental health outcomes are expected to be estimated from (1) cross-sectional associations among students’ characteristics (eg, demographics) and key psychosocial factors (eg, affect, stress, and social connection), and behaviors (eg, physical activity and device usage) and (2) longitudinal associations between psychosocial and behavioral factors and campus-based health service utilization. ResultsData collection began November 9, 2020, and will be ongoing through to at least October 31, 2021. Retention from the baseline survey (N=427) to app sign-up was 74% (315/427), with 175-215 (55%-68%) app participants actively responding to weekly surveys. From November 9, 2020, to August 8, 2021, a total of 4851 responses to the app surveys and 25,985 sensor samples (consisting of up to 68 individual data items each; eg, GPS coordinates and steps) were collected from the 315 participants who signed up for the app. ConclusionsThe results of this real-world longitudinal cohort study of undergraduate students’ mental health based on questionnaires and mobile sensor metrics is expected to show psychosocial and behavioral patterns associated with both positive and negative mental health–related states during pandemic conditions at a relatively large, public, and residential Canadian university campus. The results can be used to support decision-makers and students during the ongoing COVID-19 pandemic and similar future events. For comparable settings, new interventions (digital or otherwise) might be designed using these findings as an evidence base. International Registered Report Identifier (IRRID)DERR1-10.2196/30504

Acid-sensing ion channels (ASICs) are trimeric cation-selective channels activated by decreases in extracellular pH. The intracellular N and C terminal tails of ASIC1 influence channel gating, trafficking, and signaling in ischemic cell death. Despite several X-ray and cryo-EM structures of the extracellular and transmembrane segments of ASIC1, these important intracellular tails remain unresolved. Here, we describe the coarse topography of the chicken ASIC1 intracellular domains determined by fluorescence resonance energy transfer (FRET), measured using either fluorescent lifetime imaging or patch clamp fluorometry. We find the C terminal tail projects into the cytosol by approximately 35 Å and that the N and C tails from the same subunits are closer than adjacent subunits. Using pH-insensitive fluorescent proteins, we fail to detect any relative movement between the N and C tails upon extracellular acidification but do observe axial motions of the membrane proximal segments toward the plasma membrane. Taken together, our study furnishes a coarse topographic map of the ASIC intracellular domains while providing directionality and context to intracellular conformational changes induced by extracellular acidification.

Adoption of targeted mass spectrometry (MS) approaches such as multiple reaction monitoring (MRM) to study biological and biomedical questions is well underway in the proteomics community. Successful application depends on the ability to generate reliable assays that uniquely and confidently identify target peptides in a sample. Unfortunately, there is a wide range of criteria being applied to say that an assay has been successfully developed. There is no consensus on what criteria are acceptable and little understanding of the impact of variable criteria on the quality of the results generated. Publications describing targeted MS assays for peptides frequently do not contain sufficient information for readers to establish confidence that the tests work as intended or to be able to apply the tests described in their own labs. Guidance must be developed so that targeted MS assays with established performance can be made widely distributed and applied by many labs worldwide. To begin to address the problems and their solutions, a workshop was held at the National Institutes of Health with representatives from the multiple communities developing and employing targeted MS assays. Participants discussed the analytical goals of their experiments and the experimental evidence needed to establish that the assays they develop work as intended and are achieving the required levels of performance. Using this "fit-for-purpose" approach, the group defined three tiers of assays distinguished by their performance and extent of analytical characterization. Computational and statistical tools useful for the analysis of targeted MS results were described. Participants also detailed the information that authors need to provide in their manuscripts to enable reviewers and readers to clearly understand what procedures were performed and to evaluate the reliability of the peptide or protein quantification measurements reported. This paper presents a summary of the meeting and recommendations.

Despite significant advances in ensuring the safety of the blood supply, there is continued risk of transfusion transmitted infections (TTIs) from newly emerging or re-emerging infections. Globally, several pathogen reduction technologies (PRTs) for blood safety have been in development as an alternative to traditional treatment methods. Despite broad spectrum antimicrobial efficacy, some of the approved ultraviolet (UV) light-based PRTs, understandably due to UV light-associated toxicities, fall short in preserving the full functional spectrum of the treated blood components. As a safer alternative to the UV-based microbicidal technologies, investigations into the use of violet-blue light in the region of 405 nm have been on the rise as these wavelengths do not impair the treated product at doses that demonstrate microbicidal activity. Recently, we have demonstrated that a 405 nm violet-blue light dose of 270 J/cm2 was sufficient for reducing bacteria and the parasite in plasma and platelets suspended in plasma while preserving the quality of the treated blood product stored for transfusion. Drawn from the previous experience, here we evaluated the virucidal potential of 405 nm violet-blue light dose of 270 J/cm2 on an important blood-borne enveloped virus, the human immunodeficiency virus 1 (HIV-1), in human plasma. Both test plasma (HIV-1 spiked and treated with various doses of 405 nm light) and control plasma (HIV-1 spiked, but not treated with the light) samples were cultured with HIV-1 permissive H9 cell line for up to 21 days to estimate the viral titers. Quantitative HIV-1 p24 antigen (HIV-1 p24) levels reflective of HIV-1 titers were measured for each light dose to assess virus infectivity. Our results demonstrate that a 405 nm light dose of 270 J/cm2 is also capable of 4–5 log HIV-1 reduction in plasma under the conditions tested. Overall, this study provides the first proof-of-concept that 405 nm violet-blue light successfully inactivates HIV-1 present in human plasma, thereby demonstrating its potential towards being an effective PRT for this blood component safety.

Mobile integrons are widespread genetic platforms that allow bacteria to modulate the expression of antibiotic resistance cassettes by shuffling their position from a common promoter. Antibiotic stress induces the expression of an integrase that excises and integrates cassettes, and this unique recombination and expression system is thought to allow bacteria to ‘evolve on demand’ in response to antibiotic pressure. To test this hypothesis, we inserted a custom three-cassette integron into Pseudomonas aeruginosa and used experimental evolution to measure the impact of integrase activity on adaptation to gentamicin. Crucially, integrase activity accelerated evolution by increasing the expression of a gentamicin resistance cassette through duplications and by eliminating redundant cassettes. Importantly, we found no evidence of deleterious off-target effects of integrase activity. In summary, integrons accelerate resistance evolution by rapidly generating combinatorial variation in cassette composition while maintaining genomic integrity.

Forum Theatre (FT) was created by Brazilian theatre director Augusto Boal (1985) as an approach for promoting dialogue between the audience and those performing on stage for his “Theater for the Oppressed.” FT offers an accessible, interactive approach to exploring challenging topics and situations.  In FT, a short scene is performed.  It is then replayed again and again with audience members invited to intervene and offer different options for addressing various aspects of the problematic situation.  Originally directed to helping people address and transform oppressive conditions that characterized their lives, FT has evolved and found expression in many different communities and contexts, including health professional education.  Inspired by David Diamond’s (2008) “Theatre for Living” model (which approaches living communities as a complex, living entities), we introduced FT in the “Introduction to Medicine & Dentistry” (DMED 511) course offered as part of the Undergraduate Medical Education program in the Faculty of Medicine & Dentistry (FoMD).  In this article, we describe how we have successfully engaged first year medical and dental students in discussion and critical reflection of professionalism issues relevant to their experiences of small group learning using FT.

Enhancing humanities in medical education is a pressing concern in China. Similar to other countries, medical education in China evolved over the past century to emphasize bioscience and technology in treating illness and disease. Increasing recognition of the limitations of biomedical technology led to emergence of the medical humanities in the West in the latter half of the 20th century, an interdisciplinary area that has continued to expand and grow. In China and elsewhere, activity in this area developed somewhat later. Ongoing patient-doctor disputes and decline in public trust in the medical profession in China has led many to advocate for enhanced emphasis on humanism and medical humanities. In 2017, the Chinese government introduced new healthcare reforms which included an education and training plan that promotes medical humanities teaching. Global developments have led to a wide variety of models and approaches that may be considered in cultivating medical humanities and humanism in China. With the support of China Medical University in Shenyang, Liaoning Province, PRC, Professor Wei visited the Faculty of Medicine & Dentistry at the University of Alberta through the 2019/20 academic year. This article provides an overview of a wide array of medical humanities teaching and learning opportunities associated with the undergraduate medical education program at the University of Alberta. Professor Wei reflects on possibilities for medical humanities in medical education in China given all she learned and experienced as a visiting professor at the University of Alberta, which may be of interest to others who are also developing new approaches to introducing medical humanities as part of their health professions education program. Additional reflections regarding possibilities for global medical humanities are also offered.

Introduction Obesity can lead to a late-onset nonallergic (LONA) form of asthma for reasons that are not understood. We sought to determine whether this form of asthma is characterised by any unique physiological features. Methods Spirometry, body plethysmography, multiple breath nitrogen washout (MBNW) and methacholine challenge were performed in four subject groups: Lean Control (n=11), Lean Asthma (n=11), Obese Control (n=11) and LONA Obese Asthma (n=10). The MBNW data were fitted with a novel computational model that estimates functional residual capacity (FRC), dead space volume (VD), the coefficient of variation of regional specific ventilation (CV,V′E) and a measure of structural asymmetry at the level of the acinus (sacin). Results Body mass index and waist circumference values were similar in both obese groups, and significantly greater than in lean asthmatic individuals and controls. Forced vital capacity was significantly lower in the LONA Asthma group compared with the other groups (p

Background: Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point mutation in ALDH2*2 (E504K) that leads to accumulation of toxic reactive aldehydes. Methods: Sequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants. Findings: In a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants. Interpretation: Since ~80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new ‘precision medicine’ for carriers of these inactive ALDH2.

Background: Since 2015, the World Health Organization (WHO) has recommended a commercially available lateral-flow urine LAM test (Alere-LAM) to assist in the diagnosis of tuberculosis (TB) in severely ill people living with HIV (PLHIV). The test can rapidly detect TB in severely ill PLHIV and can identify PLHIV most at-risk of death, leading to mortality reductions. However, its uptake in countries with high burdens of TB and HIV has been slow. To assess the current use landscape and identify barriers to the adoption of Alere-LAM, we conducted a questionnaire-based study in 31 high TB and HIV/AIDS burden countries. Methods: Between November 2018 and December 2019, we collected responses to a semi-structured questionnaire that had been emailed to staff and affiliates of National TB Programs or HIV/AIDS Programs, Ministries of Health, and TB or HIV institutes of 31 high TB/HIV burden countries. Questions concerned country policies, adoption, and current use of Alere-LAM testing, as well as testing algorithms and barriers preventing Alere-LAM uptake. Results: We received questionnaire responses from 24 out of 31 (77%) high TB/HIV burden countries. Of these 24 countries, 11 (46%) had adopted Alere-LAM policies, with only five (21%) countries currently using Alere-LAM testing. Testing algorithms were generally aligned with WHO recommendations. Fifteen countries (63%) said they were planning to implement Alere-LAM testing in the near future. The most commonly cited constraint to adoption and implementation was budget limitations. Additional barriers to Alere-LAM implementation included lack of country-specific data and piloting, administrative hurdles such as regulatory agency approval, lack of coordination between National TB and HIV programs, and small perceived patient population. Conclusion: Responses to our questionnaire demonstrate the persistent gap between country-level policy and real-world use of Alere-LAM, as well as specific barriers that must be addressed to scale-up testing in PLHIV.

Acid-sensing ion channels (ASICs) are neuronal sodium-selective channels activated by reductions in extracellular pH. Structures of the three presumptive functional states, high-pH resting, low-pH desensitized, and toxin-stabilized open, have all been solved for chicken ASIC1. These structures, along with prior functional data, suggest that the isomerization or flipping of the β11–12 linker in the extracellular, ligand-binding domain is an integral component of the desensitization process. To test this, we combined fast perfusion electrophysiology, molecular dynamics simulations and state-dependent non-canonical amino acid cross-linking. We find that both desensitization and recovery can be accelerated by orders of magnitude by mutating resides in this linker or the surrounding region. Furthermore, desensitization can be suppressed by trapping the linker in the resting state, indicating that isomerization of the β11–12 linker is not merely a consequence of, but a necessity for the desensitization process in ASICs.

SCUBA divers are predisposed to otitis externa caused by Pseudomonas aeruginosa, which is becoming increasingly multi-drug resistant (MDR). The present work assessed the antibiotic resistance profiles of P. aeruginosa obtained from SCUBA divers and their environment in Sodwana Bay, South Africa. Bacterial isolates from a total of 137 random water and ear swab samples were identified using biochemical and molecular methods. P. aeruginosa strains were further evaluated for antibiotic susceptibility using the Kirby–Bauer assay. Double disk synergy test (DDST) to confirm metallo-β-lactamase (MBL) production and PCR amplification of specific antibiotic resistance genes was performed. All (100%) 22 P. aeruginosa isolates recovered were resistant to 6 of the β-lactams tested including imipenem but exhibited susceptibility to trimethoprim–sulfamethoxazole. MBL production was observed in 77% of isolates while the most prevalent extended-spectrum β-lactamase (ESBL) genes present included blaAmpC (86.9%) followed by blaTEM (82.6%). Sulfonamide resistance was largely encoded by sul1 (63.6%) and sul2 (77.3%) genes with a high abundance of class 1 integrons (77.3%) of which 18.2% carried both Intl1 and Intl2. P. aeruginosa found in Sodwana Bay exhibits multi-drug resistance (MDRce) to several pharmaceutically important drugs with the potential to transfer antibiotic resistance to other bacteria if the judicious use of antibiotics for their treatment is not practiced.