Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study.

OBJECTIVE: To investigate risks of multiple adverse outcomes associated with use of antipsychotics in people with dementia. DESIGN: Population based matched cohort study. SETTING: Linked primary care, hospital and mortality data from Clinical Practice Research Datalink (CPRD), England. POPULATION: Adults (≥50 years) with a diagnosis of dementia between 1 January 1998 and 31 May 2018 (n=173 910, 63.0% women). Each new antipsychotic user (n=35 339, 62.5% women) was matched with up to 15 non-users using incidence density sampling. MAIN OUTCOME MEASURES: The main outcomes were stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, fracture, pneumonia, and acute kidney injury, stratified by periods of antipsychotic use, with absolute risks calculated using cumulative incidence in antipsychotic users versus matched comparators. An unrelated (negative control) outcome of appendicitis and cholecystitis combined was also investigated to detect potential unmeasured confounding. RESULTS: Compared with non-use, any antipsychotic use was associated with increased risks of all outcomes, except ventricular arrhythmia. Current use (90 days after a prescription) was associated with elevated risks of pneumonia (hazard ratio 2.19, 95% confidence interval (CI) 2.10 to 2.28), acute kidney injury (1.72, 1.61 to 1.84), venous thromboembolism (1.62, 1.46 to 1.80), stroke (1.61, 1.52 to 1.71), fracture (1.43, 1.35 to 1.52), myocardial infarction (1.28, 1.15 to 1.42), and heart failure (1.27, 1.18 to 1.37). No increased risks were observed for the negative control outcome (appendicitis and cholecystitis). In the 90 days after drug initiation, the cumulative incidence of pneumonia among antipsychotic users was 4.48% (4.26% to 4.71%) versus 1.49% (1.45% to 1.53%) in the matched cohort of non-users (difference 2.99%, 95% CI 2.77% to 3.22%). CONCLUSIONS: Antipsychotic use compared with non-use in adults with dementia was associated with increased risks of stroke, venous thromboembolism, myocardial infarction, heart failure, fracture, pneumonia, and acute kidney injury, but not ventricular arrhythmia. The range of adverse outcomes was wider than previously highlighted in regulatory alerts, with the highest risks soon after initiation of treatment.

The Effect of COVID-19 on Oncology Care for Adolescents and Young Adults in Latin America.

Children with cancer in low- and middle-income countries were disproportionately impacted by the COVID-19 pandemic, but little is known about how adolescents and young adults (AYAs) with cancer were affected. Sixty-seven physicians and nonphysician providers were interviewed about their experiences caring for AYAs with cancer in Latin America. Quotes related to the COVID-19 pandemic were identified and grouped into themes. Barriers from the COVID-19 pandemic included limited space, restrictions on travel, reduced funding, limited staff, limited services, and changes to treatment. However, improvements to care that arose from the COVID-19 pandemic included better access to distance learning and telemedicine.

Impact of the early COVID-19 pandemic on adult mental health-related dispensed medications, hospitalizations and specialist outpatient visits in Norway and Sweden: Interrupted time series analysis.

AIMS: Norway and Sweden had different early pandemic responses that may have impacted mental health management. The aim was to assess the impact of the early COVID-19 pandemic on mental health-related care. METHODS: We used national registries in Norway and Sweden (1 January 2018-31 December 2020) to define 2 cohorts: (i) general adult population; and (ii) mental health adult population. Interrupted times series regression analyses evaluated step and slope changes compared to prepandemic levels for monthly rates of medications (antidepressants, antipsychotics, anxiolytics, hypnotics/sedatives, lithium, opioid analgesics, psychostimulants), hospitalizations (for anxiety, bipolar, depressive/mood, eating and schizophrenia/delusional disorders) and specialist outpatient visits. RESULTS: In Norway, immediate reductions occurred in the general population for medications (-12% antidepressants to -7% hypnotics/sedatives) except for antipsychotics; and hospitalizations (-33% anxiety disorders to -17% bipolar disorders). Increasing slope change occurred for all medications except psychostimulants (+1.1%/month hypnotics/sedatives to +1.7%/month antidepressants); and hospitalization for anxiety disorders (+5.5%/month), depressive/mood disorders (+1.7%/month) and schizophrenia/delusional disorders (+2%/month). In Sweden, immediate reductions occurred for antidepressants (-7%) and opioids (-10%) and depressive/mood disorder hospitalizations (-11%) only with increasing slope change in psychostimulant prescribing of (0.9%/month). In contrast to Norway, increasing slope changes occurred in specialist outpatient visits for depressive/mood disorders, eating disorders and schizophrenia/delusional disorders (+1.5, +1.9 and +2.3%/month, respectively). Similar changes occurred in the pre-existing mental health cohorts. CONCLUSION: Differences in early COVID-19 policy response may have contributed to differences in adult mental healthcare provision in Norway and Sweden.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis.

Background: Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to account for direct treatment disutility (i.e. the hassle of taking treatments). We explored these issues using two case studies: primary prevention of cardiovascular disease using statins and osteoporotic fracture using bisphosphonates. Objectives: Externally validate three risk prediction tools [QRISK®3, QRISK®-Lifetime, QFracture-2012 (ClinRisk Ltd, Leeds, UK)]; derive and internally validate new risk prediction tools for cardiovascular disease [competing mortality risk model with Charlson Comorbidity Index (CRISK-CCI)] and fracture (CFracture), accounting for competing-cause death; quantify direct treatment disutility for statins and bisphosphonates; and examine the effect of competing risks and direct treatment disutility on the cost-effectiveness of preventative treatments. Design, participants, main outcome measures, data sources: Discrimination and calibration of risk prediction models (Clinical Practice Research Datalink participants: aged 25-84 years for cardiovascular disease and aged 30-99 years for fractures); direct treatment disutility was elicited in online stated-preference surveys (people with/people without experience of statins/bisphosphonates); costs and quality-adjusted life-years were determined from decision-analytic modelling (updated models used in National Institute for Health and Care Excellence decision-making). Results: CRISK-CCI has excellent discrimination, similar to that of QRISK3 (Harrell's c = 0.864 vs. 0.865, respectively, for women; and 0.819 vs. 0.834, respectively, for men). CRISK-CCI has systematically better calibration, although both models overpredict in high-risk subgroups. People recommended for treatment (10-year risk of ≥ 10%) are younger when using QRISK-Lifetime than when using QRISK3, and have fewer observed events in a 10-year follow-up (4.0% vs. 11.9%, respectively, for women; and 4.3% vs. 10.8%, respectively, for men). QFracture-2012 underpredicts fractures, owing to under-ascertainment of events in its derivation. However, there is major overprediction among people aged 85-99 years and/or with multiple long-term conditions. CFracture is better calibrated, although it also overpredicts among older people. In a time trade-off exercise (n = 879), statins exhibited direct treatment disutility of 0.034; for bisphosphonates, it was greater, at 0.067. Inconvenience also influenced preferences in best-worst scaling (n = 631). Updated cost-effectiveness analysis generates more quality-adjusted life-years among people with below-average cardiovascular risk and fewer among people with above-average risk. If people experience disutility when taking statins, the cardiovascular risk threshold at which benefits outweigh harms rises with age (≥ 8% 10-year risk at 40 years of age; ≥ 38% 10-year risk at 80 years of age). Assuming that everyone experiences population-average direct treatment disutility with oral bisphosphonates, treatment is net harmful at all levels of risk. Limitations: Treating data as missing at random is a strong assumption in risk prediction model derivation. Disentangling the effect of statins from secular trends in cardiovascular disease in the previous two decades is challenging. Validating lifetime risk prediction is impossible without using very historical data. Respondents to our stated-preference survey may not be representative of the population. There is no consensus on which direct treatment disutilities should be used for cost-effectiveness analyses. Not all the inputs to the cost-effectiveness models could be updated. Conclusions: Ignoring competing mortality in risk prediction overestimates the risk of cardiovascular events and fracture, especially among older people and those with multimorbidity. Adjustment for competing risk does not meaningfully alter cost-effectiveness of these preventative interventions, but direct treatment disutility is measurable and has the potential to alter the balance of benefits and harms. We argue that this is best addressed in individual-level shared decision-making. Study registration: This study is registered as PROSPERO CRD42021249959. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/12/22) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

Before offering a medicine to prevent disease, prescribers must expect it to do more good than harm. This balance depends on how likely it is that the person will develop the disease we want to prevent. But people might first die for other reasons. We call this a 'competing risk'. In most cases, the mathematical tools we use to estimate the chance of developing a disease do not account for competing risks. Another problem is that, when weighing up the benefits and harms of medicines, we ignore the hassle they cause patients, even when they do not cause side effects. We used two examples: statins to prevent heart disease and bisphosphonates to prevent fractures. First, we assessed if existing tools get predictions wrong by not accounting for competing risks. We found that they exaggerate the chance of heart attacks and strokes. However, the exaggeration is greatest among people who would clearly benefit from preventative treatment. So it may not change treatment decisions much. The fracture prediction tool we studied was very inaccurate, exaggerating risk among older people, but underestimating risk among younger people. We made a new fracture risk prediction tool. It gave better predictions, but it was still inaccurate for people aged > 85 years and those with several health problems. Next, we asked people questions designed to put a number on the hassle that statins and bisphosphonates cause. Most people thought that taking either is inconvenient, but the hassle factor for bisphosphonates is bigger. Finally, we updated the mathematical models that the National Institute for Health and Care Excellence used when recommending statins and bisphosphonates. We worked out if competing risks and the hassle of taking medicines make a difference to results. Statins remain a good idea for almost everyone, unless they really hate the idea of taking them. But bisphosphonates would do more harm than good for anyone who agrees with the hassle factor we found.

Student survey after ten years of continuous blended teaching of echocardiography.

OBJECTIVE: To analyse the impact of 10 years of blended echocardiography teaching. METHODS AND RESULTS: A questionnaire was emailed to all medical doctors who graduated from the blended learning diploma in echocardiography developed by the University of Chile and taught by a team from Chile and Spain. One hundred and forty of the 210 students who graduated from the program between 2011 and 2020 completed the questionnaire: 53.57% were anaesthesiologists, and 26.42% were intensivists. More than 85% of respondents indicated that the online teaching met their expectations, and 70.2% indicated that the hands-on practice fulfilled the stated objectives. In a retrospective analysis using self-reported data, graduates reported that their use of transthoracic and transoesophageal echocardiography has increased from 24.29% to 40.71% and from 13.57% to 27.86%, repectively, after the programme compared to before the programme. They used echocardiography mainly in the perioperative period (56.7%) and during intensive care (32.3%), while only 11% of respondents used it in emergency care units. Nearly all (92.4%) respondents reported that the skills learned was very useful in their professional practice. CONCLUSIONS: Ten years after its launch, the blended learning diploma in echocardiography was well rated by graduate specialists, and is associated with a significant increase in the use of echocardiography in the perioperative period and during intensive care. The main challenges are to establish a longer period of practice and achieve greater implantation in emergency medicine.

METTL3 alters capping enzyme expression and its activity on ribosomal proteins.

The 5' cap, catalyzed by RNA guanylyltransferase and 5'-phosphatase (RNGTT), is a vital mRNA modification for the functionality of mRNAs. mRNA capping occurs in the nucleus for the maturation of the functional mRNA and in the cytoplasm for fine-tuning gene expression. Given the fundamental importance of RNGTT in mRNA maturation and expression there is a need to further investigate the regulation of RNGTT. N6-methyladenosine (m6A) is one of the most abundant RNA modifications involved in the regulation of protein translation, mRNA stability, splicing, and export. We sought to investigate whether m6A could regulate the expression and activity of RNGTT. A motif for the m6A writer methyltransferase 3 (METTL3) in the 3'UTR of RNGTT mRNA was identified. Knockdown of METTL3 resulted in destabilizing RNGTT mRNA, and reduced protein expression. Sequencing of capped mRNAs identified an underrepresentation of ribosomal protein mRNA overlapping with 5' terminal oligopyrimidine (TOP) mRNAs and genes are dysregulated when cytoplasmic capping is inhibited. Pathway analysis identified disruptions in the mTOR and p70S6K pathways. A reduction in RPS6 mRNA capping, protein expression, and phosphorylation was detected with METTL3 knockdown.

A plasma miRNA-based classifier for small cell lung cancer diagnosis.

Introduction: Small cell lung cancer (SCLC) is characterized by poor prognosis and challenging diagnosis. Screening in high-risk smokers results in a reduction in lung cancer mortality, however, screening efforts are primarily focused on non-small cell lung cancer (NSCLC). SCLC diagnosis and surveillance remain significant challenges. The aberrant expression of circulating microRNAs (miRNAs/miRs) is reported in many tumors and can provide insights into the pathogenesis of tumor development and progression. Here, we conducted a comprehensive assessment of circulating miRNAs in SCLC with a goal of developing a miRNA-based classifier to assist in SCLC diagnoses. Methods: We profiled deregulated circulating cell-free miRNAs in the plasma of SCLC patients. We tested selected miRNAs on a training cohort and created a classifier by integrating miRNA expression and patients' clinical data. Finally, we applied the classifier on a validation dataset. Results: We determined that miR-375-3p can discriminate between SCLC and NSCLC patients, and between SCLC and Squamous Cell Carcinoma patients. Moreover, we found that a model comprising miR-375-3p, miR-320b, and miR-144-3p can be integrated with race and age to distinguish metastatic SCLC from a control group. Discussion: This study proposes a miRNA-based biomarker classifier for SCLC that considers clinical demographics with specific cut offs to inform SCLC diagnosis.

Multinational patterns of second line antihyperglycaemic drug initiation across cardiovascular risk groups: federated pharmacoepidemiological evaluation in LEGEND-T2DM.

Objective: To assess the uptake of second line antihyperglycaemic drugs among patients with type 2 diabetes mellitus who are receiving metformin. Design: Federated pharmacoepidemiological evaluation in LEGEND-T2DM. Setting: 10 US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network in eight countries from 2011 to the end of 2021. Participants: 4.8 million patients (≥18 years) across US and non-US based databases with type 2 diabetes mellitus who had received metformin monotherapy and had initiated second line treatments. Exposure: The exposure used to evaluate each database was calendar year trends, with the years in the study that were specific to each cohort. Main outcomes measures: The outcome was the incidence of second line antihyperglycaemic drug use (ie, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, and sulfonylureas) among individuals who were already receiving treatment with metformin. The relative drug class level uptake across cardiovascular risk groups was also evaluated. Results: 4.6 million patients were identified in US databases, 61 382 from Spain, 32 442 from Germany, 25 173 from the UK, 13 270 from France, 5580 from Scotland, 4614 from Hong Kong, and 2322 from Australia. During 2011-21, the combined proportional initiation of the cardioprotective antihyperglycaemic drugs (glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) increased across all data sources, with the combined initiation of these drugs as second line drugs in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased more significantly among populations with no cardiovascular disease compared with patients with established cardiovascular disease. No data source provided evidence of a greater increase in the uptake of these two drug classes in populations with cardiovascular disease compared with no cardiovascular disease. Conclusions: Despite the increase in overall uptake of cardioprotective antihyperglycaemic drugs as second line treatments for type 2 diabetes mellitus, their uptake was lower in patients with cardiovascular disease than in people with no cardiovascular disease over the past decade. A strategy is needed to ensure that medication use is concordant with guideline recommendations to improve outcomes of patients with type 2 diabetes mellitus.

Quantifying the impact of taking medicines for primary prevention: a time-trade off study to elicit direct treatment disutility in the UK.

BACKGROUND: Direct treatment disutility (DTD) represents an individual's disutility associated with the inconvenience of taking medicine over a long period of time. OBJECTIVES: The main aim of this study was to elicit DTD values for taking a statin or a bisphosphonate for primary prevention. A secondary aim was to understand factors which influence DTD values. METHODS: Design: We used a cross-sectional study consisting of time-trade off exercises embedded within online surveys. Respondents were asked to compare a one-off pill ('Medicine A') assumed to have no inconvenience and a daily pill ('Medicine B') over 10 years (statins) or 5 years (bisphosphonates).Setting: Individuals from National Health Service (NHS) primary care and the general population were surveyed using an online panel company.Participants: Two types of participants were recruited. First, a purposive sample of patients with experience of taking a statin (n=260) or bisphosphonate (n=100) were recruited from an NHS sampling frame. Patients needed to be aged over 30, have experience of taking the medicine of interest and have no diagnosis of dementia or of using dementia drugs. Second, a demographically balanced sample of members of the public were recruited for statins (n=376) and bisphosphonates (n=359).Primary and secondary outcome measures: Primary outcome was mean DTD. Regression analysis explored factors which could influence DTD values. RESULTS: A total of 879 respondents were included for analysis (514 for statins and 365 for bisphosphonates). The majority of respondents reported a disutility associated with medicine use. Mean DTD for statins was 0.034 and for bisphosphonates 0.067, respectively. Respondent characteristics including age and sex did not influence DTD. Experience of bisphosphonate-use reduced reported disutilities. CONCLUSIONS: Statins and bisphosphonates have a quantifiable DTD. The size of estimated disutilities suggest they are likely to be important for cost-effectiveness, particularly in individuals at low-risk when treated for primary prevention.

Impact of data source choice on multimorbidity measurement: a comparison study of 2.3 million individuals in the Welsh National Health Service.

BACKGROUND: Measurement of multimorbidity in research is variable, including the choice of the data source used to ascertain conditions. We compared the estimated prevalence of multimorbidity and associations with mortality using different data sources. METHODS: A cross-sectional study of SAIL Databank data including 2,340,027 individuals of all ages living in Wales on 01 January 2019. Comparison of prevalence of multimorbidity and constituent 47 conditions using data from primary care (PC), hospital inpatient (HI), and linked PC-HI data sources and examination of associations between condition count and 12-month mortality. RESULTS: Using linked PC-HI compared with only HI data, multimorbidity was more prevalent (32.2% versus 16.5%), and the population of people identified as having multimorbidity was younger (mean age 62.5 versus 66.8 years) and included more women (54.2% versus 52.6%). Individuals with multimorbidity in both PC and HI data had stronger associations with mortality than those with multimorbidity only in HI data (adjusted odds ratio 8.34 [95% CI 8.02-8.68] versus 6.95 (95%CI 6.79-7.12] in people with ≥ 4 conditions). The prevalence of conditions identified using only PC versus only HI data was significantly higher for 37/47 and significantly lower for 10/47: the highest PC/HI ratio was for depression (14.2 [95% CI 14.1-14.4]) and the lowest for aneurysm (0.51 [95% CI 0.5-0.5]). Agreement in ascertainment of conditions between the two data sources varied considerably, being slight for five (kappa < 0.20), fair for 12 (kappa 0.21-0.40), moderate for 16 (kappa 0.41-0.60), and substantial for 12 (kappa 0.61-0.80) conditions, and by body system was lowest for mental and behavioural disorders. The percentage agreement, individuals with a condition identified in both PC and HI data, was lowest in anxiety (4.6%) and highest in coronary artery disease (62.9%). CONCLUSIONS: The use of single data sources may underestimate prevalence when measuring multimorbidity and many important conditions (especially mental and behavioural disorders). Caution should be used when interpreting findings of research examining individual and multiple long-term conditions using single data sources. Where available, researchers using electronic health data should link primary care and hospital inpatient data to generate more robust evidence to support evidence-based healthcare planning decisions for people with multimorbidity.

Antipsychotic drug prescribing and mortality in people with dementia before and during the COVID-19 pandemic: a retrospective cohort study in Wales, UK.

BACKGROUND: Concerns have been raised that antipsychotic drug prescribing, which has been associated with increased mortality in people with dementia, might have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of SARS-CoV-2. We used multisource, routinely collected health-care data from Wales, UK to investigate prescribing and mortality variations in people with dementia before and during the COVID-19 pandemic. METHODS: In this retrospective cohort study, we used individual-level, anonymised, population-scale linked health data to identify adults aged 60 years and older with a diagnosis of dementia in Wales, UK. We used the CVD-COVID-UK initiative to access Welsh routinely collected electronic health record data from the Secure Anonymised Information Linkage (SAIL) Databank. Patients who were alive and registered with a SAIL general practice on Jan 1, 2016, and who received a dementia diagnosis before the age of 60 years and before or during the study period were included. We explored antipsychotic drug prescribing rate changes over 67 months, between Jan 1, 2016, and Aug 1, 2021, overall and stratified by age and dementia subtype. We used time-series analyses to examine all-cause and myocardial infarction and stroke mortality over the study period and identified the leading causes of death in people with dementia between Jan 1, 2020, and Aug 1, 2021. FINDINGS: Of 3 106 690 participants in SAIL between Jan 1, 2016 and Aug 1, 2021, 57 396 people (35 148 [61·2%] women and 22 248 [38·8%] men) met inclusion criteria for this study and contributed 101 428 person-years of follow-up. Of the 57 396 people with dementia, 11 929 (20·8%) were prescribed an antipsychotic drug at any point during follow-up. Accounting for seasonality, antipsychotic drug prescribing increased during the second half of 2019 and throughout 2020. However, the absolute difference in prescribing rates was small, ranging from 1253 prescriptions per 10 000 person-months in March, 2019, to 1305 per 10 000 person-months in September, 2020. All-cause mortality and stroke mortality increased throughout 2020, while myocardial infarction mortality declined. From Jan 1, 2020, to Aug 1, 2021, 1286 (17·1%) of 7508 participants who died had COVID-19 recorded as the underlying cause of death. INTERPRETATION: During the COVID-19 pandemic, antipsychotic drug prescribing in people with dementia in the UK increased slightly; however, it is unlikely that this was solely related to the pandemic and this increase was unlikely to be a major factor in the substantial increase in mortality during 2020. The long-term increase in antipsychotic drug prescribing in younger people and in those with Alzheimer's disease warrants further investigation using resources with access to more granular clinical data. Although deprescribing antipsychotic medications remains an essential aspect of dementia care, the results of this study suggest that changes in prescribing and deprescribing practices as a result of the COVID-19 pandemic are not required. FUNDING: British Heart Foundation (via the British Heart Foundation Data Science Centre led by Health Data Research UK), and the Scottish Neurological Research Fund.

Intranasal steroid use and COVID-19 mortality among patients with asthma and COPD: A retrospective cohort study.

BACKGROUND: Systemic corticosteroids have been widely used for treating patients with severe acute respiratory distress syndrome. Inhaled corticosteroids may have a protective effect for treating acute coronavirus disease 2019 (COVID-19); however, little is known about the potential effect of intranasal corticosteroids (INCS) on COVID-19 outcomes and severity. OBJECTIVE: To assess the impact of prior long-term INCS exposure on COVID-19 mortality among patients with chronic respiratory disease and in the general population. METHODS: A retrospective cohort study was conducted. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between INCS exposure and all-cause and COVID-19 mortality, adjusted by age, sex, deprivation, exacerbations in the last year, and comorbidities. RESULTS: Exposure to INCS did not have a significant association with COVID-19 mortality among the general population or cohorts with chronic obstructive pulmonary disease or asthma, with HRs of 0.8 (95% CI, 0.6-1.0, P = .06), 0.6 (95% CI, 0.3-1.1, P = .1), and 0.9 (95% CI, 0.2-3.9, P = .9), respectively. Exposure to INCS was, however, significantly associated with reduction in all-cause mortality in all groups, which was 40% lower (HR, 0.6 [95% CI, 0.5-0.6, P < .001]) among the general population, 30% lower (HR, 0.7; 95% CI, 0.6-0.8, P < .001) among patients with chronic obstructive pulmonary disease, and 50% lower (HR, 0.5; 95% CI, 0.3-0.7, P = .003) among patients with asthma. CONCLUSION: The role of INCS in COVID-19 is still unclear, but exposure to INCS does not adversely affect COVID-19 mortality. Further studies are needed to explore the association between their use and inflammatory activation, viral load, angiotensin-converting enzyme 2 gene expression, and outcomes, exploring different types and doses of INCS.

Diffuse intrinsic pontine gliomas: First registry effort in Mexico.

INTRODUCTION: Brainstem tumors comprise 10.9% of all brain tumors, and pediatric diffuse intrinsic pontine gliomas (DIPG) have a fatal prognosis. Some countries have developed national and international register databases to characterize their populations to aid clinical and public policy decisions. This study provides information regarding the clinical characteristics of a retrospective cohort of children with DIPG in México from 2001 to 2021, and assesses the proposed prognostic factors previously described for survival outcome. METHODS: Health institutions from Mexico were invited to contribute to a retrospective electronic registry of patients with DIPG based on the International DIPG Registry. Fisher's exact test was used to compare long- and short-term survivors. Overall survival was estimated using the Kaplan-Meier method. Differences between survival curves were evaluated using the log-rank test and Cox proportional hazard regression analysis. RESULTS: Total 110 patients were included. The median age of the patients at diagnosis was 7 years. Sixty patients (54.5%) presented with symptoms in less than 6 months; the most frequent symptom was ataxia (56.4%). Ninety patients received treatment (81.8%), the overall survival at 4 years was 11.4%, and 16 patients (14.5%) were admitted for palliative end-of-life care. We found no significant survival differences for any of the prognostic factors. CONCLUSION: This study highlights the need to develop strategies to standardize healthcare processes and enhance the quality of care to improve clinical diagnosis in Mexico. We also observed a barrier to the acceptance of palliative end-of-life care in the family and medical teams.

Sodium Rich Vanadium Oxy-Fluorophosphate - Na3.2 Ni0.2 V1.8 (PO4 )2 F2 O - as Advanced Cathode for Sodium Ion Batteries.

Conventional sodium-based layered oxide cathodes are extremely air sensitive and possess poor electrochemical performance along with safety concerns when operating at high voltage. The polyanion phosphate, Na3 V2 (PO4 )3 stands out as an excellent candidate due to its high nominal voltage, ambient air stability, and long cycle life. The caveat is that Na3 V2 (PO4 )3 can only exhibit reversible capacities in the range of 100 mAh g-1 , 20% below its theoretical capacity. Here, the synthesis and characterizations are reported for the first time of the sodium-rich vanadium oxyfluorophosphate, Na3.2 Ni0.2 V1.8 (PO4 )2 F2 O, a tailored derivative compound of Na3 V2 (PO4 )3 , with extensive electrochemical and structural analyses. Na3.2 Ni0.2 V1.8 (PO4 )2 F2 O delivers an initial reversible capacity of 117 mAh g-1 between 2.5 and 4.5 V under the 1C rate at room temperature, with 85% capacity retention after 900 cycles. The cycling stability is further improved when the material is cycled at 50 °C within 2.8-4.3 V for 100 cycles. When paired with a presodiated hard carbon, Na3.2 Ni0.2 V1.8 (PO4 )2 F2 O cycled with a capacity retention of 85% after 500 cycles. Cosubstitution of the transition metal and fluorine in Na3.2 Ni0.2 V1.8 (PO4 )2 F2 O as well as the sodium-rich structure are the major factors behind the improvement of specific capacity and cycling stability, which paves the way for this cathode in sodium-ion batteries.

Crosstalk between miRNAs and DNA Methylation in Cancer.

miRNAs are some of the most well-characterized regulators of gene expression. Integral to several physiological processes, their aberrant expression often drives the pathogenesis of both benign and malignant diseases. Similarly, DNA methylation represents an epigenetic modification influencing transcription and playing a critical role in silencing numerous genes. The silencing of tumor suppressor genes through DNA methylation has been reported in many types of cancer and is associated with tumor development and progression. A growing body of literature has described the crosstalk between DNA methylation and miRNAs as an additional layer in the regulation of gene expression. Methylation in miRNA promoter regions inhibits its transcription, while miRNAs can target transcripts and subsequently regulate the proteins responsible for DNA methylation. Such relationships between miRNA and DNA methylation serve an important regulatory role in several tumor types and highlight a novel avenue for potential therapeutic targets. In this review, we discuss the crosstalk between DNA methylation and miRNA expression in the pathogenesis of cancer and describe how miRNAs influence DNA methylation and, conversely, how methylation impacts the expression of miRNAs. Finally, we address how these epigenetic modifications may be leveraged as biomarkers in cancer.

The impact of varying the number and selection of conditions on estimated multimorbidity prevalence: A cross-sectional study using a large, primary care population dataset.

BACKGROUND: Multimorbidity prevalence rates vary considerably depending on the conditions considered in the morbidity count, but there is no standardised approach to the number or selection of conditions to include. METHODS AND FINDINGS: We conducted a cross-sectional study using English primary care data for 1,168,260 participants who were all people alive and permanently registered with 149 included general practices. Outcome measures of the study were prevalence estimates of multimorbidity (defined as ≥2 conditions) when varying the number and selection of conditions considered for 80 conditions. Included conditions featured in ≥1 of the 9 published lists of conditions examined in the study and/or phenotyping algorithms in the Health Data Research UK (HDR-UK) Phenotype Library. First, multimorbidity prevalence was calculated when considering the individually most common 2 conditions, 3 conditions, etc., up to 80 conditions. Second, prevalence was calculated using 9 condition-lists from published studies. Analyses were stratified by dependent variables age, socioeconomic position, and sex. Prevalence when only the 2 commonest conditions were considered was 4.6% (95% CI [4.6, 4.6] p < 0.001), rising to 29.5% (95% CI [29.5, 29.6] p < 0.001) considering the 10 commonest, 35.2% (95% CI [35.1, 35.3] p < 0.001) considering the 20 commonest, and 40.5% (95% CI [40.4, 40.6] p < 0.001) when considering all 80 conditions. The threshold number of conditions at which multimorbidity prevalence was >99% of that measured when considering all 80 conditions was 52 for the whole population but was lower in older people (29 in >80 years) and higher in younger people (71 in 0- to 9-year-olds). Nine published condition-lists were examined; these were either recommended for measuring multimorbidity, used in previous highly cited studies of multimorbidity prevalence, or widely applied measures of "comorbidity." Multimorbidity prevalence using these lists varied from 11.1% to 36.4%. A limitation of the study is that conditions were not always replicated using the same ascertainment rules as previous studies to improve comparability across condition-lists, but this highlights further variability in prevalence estimates across studies. CONCLUSIONS: In this study, we observed that varying the number and selection of conditions results in very large differences in multimorbidity prevalence, and different numbers of conditions are needed to reach ceiling rates of multimorbidity prevalence in certain groups of people. These findings imply that there is a need for a standardised approach to defining multimorbidity, and to facilitate this, researchers can use existing condition-lists associated with highest multimorbidity prevalence.

An atomically smooth container: Can the native oxide promote supercooling of liquid gallium?

Metals tend to supercool-that is, they freeze at temperatures below their melting points. In general, supercooling is less favorable when liquids are in contact with nucleation sites such as rough surfaces. Interestingly, bulk gallium (Ga) can significantly supercool, even when it is in contact with heterogeneous surfaces that could provide nucleation sites. We hypothesized that the native oxide on Ga provides an atomically smooth interface that prevents Ga from directly contacting surfaces, and thereby promotes supercooling. Although many metals form surface oxides, Ga is a convenient metal for studying supercooling because its melting point of 29.8°C is near room temperature. Using differential scanning calorimetry (DSC), we show that freezing of Ga with the oxide occurs at a lower temperature (-15.6 ± 3.5°C) than without the oxide (6.9 ± 2.0°C when the oxide is removed by HCl). We also demonstrate that the oxide enhances supercooling via macroscopic observations of freezing. These findings explain why Ga supercools and have implications for emerging applications of Ga that rely on it staying in the liquid state.

Contextualising adverse events of special interest to characterise the baseline incidence rates in 24 million patients with COVID-19 across 26 databases: a multinational retrospective cohort study.

Background: Adverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population. Methods: A multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases. Findings: Substantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism. Interpretation: Our findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term. Funding: None.