Broader Population Research Articles

Clinical characterization of the mutational landscape of 24,639 real-world samples from patients with myeloid malignancies

Myeloid neoplasms represent a broad spectrum of hematological disorders for which somatic mutation status in key driver genes is important for diagnosis, prognosis and treatment. Here we summarize the findings of a targeted, next generation sequencing laboratory developed test in 24,639 clinical myeloid samples. Data were analyzed comprehensively and as part of individual cohorts specific to acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). Overall, 48,015 variants were detected, and variants were found in all 50 genes in the panel. The mean number of mutations per patient was 1.95. Mutation number increased with age (Spearman's rank correlation coefficient, ρ = 0.29, P < 0.0001) and was higher in patients with AML than MDS or MPN (Student's t-test, P < 0.0001). TET2 was the most common mutation detected (19.1% of samples; 4,695/24,639) including 7.7% (1,908/24,639) with multi-hit TET2 mutations. Mutation frequency was correlated between patients with cytopenias and MDS (Spearman's, ρ = 0.97, P < 2.2×10–16) with the MDS diagnostic gene SF3B1 being the only notable outlier. This large retrospective study shows the utility of NGS testing to inform clinical decisions during routine clinical care and highlights the mutational landscape of a broad population of myeloid patients.

Cas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing

Chronic wounds impose a significant healthcare burden to a broad patient population. Cell-based therapies, while having shown benefits for the treatment of chronic wounds, have not yet achieved widespread adoption into clinical practice. We developed a CRISPR/Cas9 approach to precisely edit murine dendritic cells to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing of tolerogenic dendritic cells, we identified N-myc downregulated gene 2 (Ndrg2), which marks a specific population of dendritic cell progenitors, as a promising target for CRISPR knockout. Ndrg2-knockout alters the transcriptomic profile of dendritic cells and preserves an immature cell state with a strong pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a therapeutic hydrogel for in vivo cell delivery and developed an effective translational approach for dendritic cell-based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in dendritic cells for treating various types of chronic wounds.

The Impact of SGLT2 Inhibitors on Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

To evaluate the role of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF). A literature search of PubMed, the Cochrane Library, and Google Scholar databases (January 2015 to June 20, 2023) was performed with keywords: sodium-glucose co-transporter 2 inhibitors OR SGLT2 inhibitors OR bexagliflozin OR canagliflozin OR dapagliflozin OR empagliflozin OR ertugliflozin OR sotagliflozin AND heart failure OR heart failure with preserved ejection fraction, and terms related to CV outcomes including cardiovascular death, hospitalization, hospitalization for heart failure, mortality, death, and major adverse cardiovascular event (MACE). The reference list from retrieved articles as well as relevant review articles was considered. Pivotal randomized controlled trials and meta-analyses with a primary or secondary end point of CV death or heart failure hospitalization were included. Studies conducted solely in a diabetic patient population were excluded. Dapagliflozin and empagliflozin, in a broad population of heart failure patients including, HFrEF, HFmrEF, HFpEF, and without diabetes, have shown consistent improvement in the combined outcome of CV death and hospitalization for heart failure (HR 0.80, 95% CI 0.73-0.87) and in the reduction of heart failure hospitalizations (HR 0.74, 95% CI 0.67-0.83). In patients with HFpEF, cardiovascular mortality was not demonstrated (HR 0.88, 95% CI 0.77-1.00). Rates of adverse events were low. Patients with HFpEF and NYHA class II-III with frequent symptoms or hospitalizations for heart failure derive the most benefit from SGLT2 inhibitors with an overall goal of a reduction in heart failure hospitalizations. The treatment of HFpEF has made progress, but there is still work to be done. Now, SGLT2 inhibitor therapy can be used to further help with symptom control and reduce overall hospitalizations for heart failure.

Effectiveness of an Emergency Department-Based Machine Learning Clinical Decision Support Tool to Prevent Outpatient Falls Among Older Adults: Protocol for a Quasi-Experimental Study.

Emergency department (ED) providers are important collaborators in preventing falls for older adults because they are often the first health care providers to see a patient after a fall and because at-home falls are often preceded by previous ED visits. Previous work has shown that ED referrals to falls interventions can reduce the risk of an at-home fall by 38%. Screening patients at risk for a fall can be time-consuming and difficult to implement in the ED setting. Machine learning (ML) and clinical decision support (CDS) offer the potential of automating the screening process. However, it remains unclear whether automation of screening and referrals can reduce the risk of future falls among older patients. The goal of this paper is to describe a research protocol for evaluating the effectiveness of an automated screening and referral intervention. These findings will inform ongoing discussions about the use of ML and artificial intelligence to augment medical decision-making. To assess the effectiveness of our program for patients receiving the falls risk intervention, our primary analysis will be to obtain referral completion rates at 3 different EDs. We will use a quasi-experimental design known as a sharp regression discontinuity with regard to intent-to-treat, since the intervention is administered to patients whose risk score falls above a threshold. A conditional logistic regression model will be built to describe 6-month fall risk at each site as a function of the intervention, patient demographics, and risk score. The odds ratio of a return visit for a fall and the 95% CI will be estimated by comparing those identified as high risk by the ML-based CDS (ML-CDS) and those who were not but had a similar risk profile. The ML-CDS tool under study has been implemented at 2 of the 3 EDs in our study. As of April 2023, a total of 1326 patient encounters have been flagged for providers, and 339 unique patients have been referred to the mobility and falls clinic. To date, 15% (45/339) of patients have scheduled an appointment with the clinic. This study seeks to quantify the impact of an ML-CDS intervention on patient behavior and outcomes. Our end-to-end data set allows for a more meaningful analysis of patient outcomes than other studies focused on interim outcomes, and our multisite implementation plan will demonstrate applicability to a broad population and the possibility to adapt the intervention to other EDs and achieve similar results. Our statistical methodology, regression discontinuity design, allows for causal inference from observational data and a staggered implementation strategy allows for the identification of secular trends that could affect causal associations and allow mitigation as necessary. ClinicalTrials.gov NCT05810064; https://www.clinicaltrials.gov/study/NCT05810064. DERR1-10.2196/48128.

Incidence and prevalence of heart failure in England: a descriptive analysis of linked primary and secondary care data – the PULSE study

BackgroundHeart failure (HF) is associated with high morbidity and mortality, yet data on HF subtype (HF with reduced ejection fraction [HFrEF] and preserved ejection fraction [HFpEF]) in broad populations are lacking. Additionally, it is unknown whether current HF incidence and prevalence rates are consistent with historical data. Here, we estimate the incidence and prevalence of HF in England and describe the characteristics of patients with HF, both overall and by subtype.MethodsThis was a non-interventional cohort study based on data from the UK Clinical Practice Research Datalink (CPRD), linked to Hospital Episode Statistics data and Office for National Statistics mortality data. Patients aged ≥ 18 years who were registered in the CPRD Aurum database between 1st January 2015 and 31st December 2019 formed the base cohort, from which patients with a recorded chronic HF diagnosis (historical or incident) from 2015–2019 contributed to the incidence and prevalence calculations.ResultsThe eligible denominator over the study period comprised 11,414,490 patients, from which 383,896 patients with HF were included as prevalent or incident HF cases. From 2015 to 2019, the incidence rate of newly diagnosed HF increased from 4.1/1,000 person-years to 4.9/1,000 person-years, and HF prevalence increased from 2.1% to 2.4%. Phenotype data were available for 100,224 (26.1%) patients, of which 68,780 patients had HFrEF and 31,444 had HFpEF (HFrEF/HFpEF ratio: 70.1%/29.9%). Comorbidity levels were high and broadly similar across HF subgroups.ConclusionsPrimary care recording of HF subtype is suboptimal, with more than 7/10 patients with HF lacking subtype data. In patients with a recorded subtype (n = 100,224), a HFrEF/HFpEF ratio of 70%/30% was observed. Comorbidity levels were high regardless of subtype. Between 2015 and 2019, we observed modest but consistent increases in the incidence and prevalence of chronic HF in adults, in line with historical data.

Targeted vaccine development against Bilophila wadsworthia to curb colon diseases: A multiepitope approach based on reverse vaccinology and computational analysis

The presence of excessive hydrogen sulfide (H2S)-producing bacteria, particularly Bilophila wadsworthia in appendices, is linked to a weaker colonic mucus barrier, inflammatory bowel disease, and colorectal cancer. Thus, targeting this bacterium could reduce sulfide levels and address associated health concerns. Here, we utilized reverse vaccinology and immunoinformatics to design a chimeric vaccine against B. wadsworthia, focusing on membrane-bound and extracellular proteins. Subtractive proteome analysis identified 18 potential vaccine candidates (PVCs), from which six B-cell, eight CD8+ T cell, and six CD4+ T cell epitopes were predicted. Chosen epitopes were assessed for immunological properties and cross-reactivity with human and mouse proteomes. Subsequently, these epitopes were fused with appropriate linkers, PADRE epitope, TAT peptide, and Cholera Toxin B subunit adjuvant to form a robust multi-epitope vaccine (MEV). The MEV's tertiary structure was modelled and validated for reliable analysis. Molecular docking and dynamics simulations demonstrated stable binding of MEV with Toll-like receptor 4. The MEV showed favorable physicochemical characteristics, high expression potential in Escherichia coli, broad population coverage (∼98 %), and cross-protection against different B. wadsworthia strains. Immune simulation suggested induction of strong B and T cell responses, including primary, secondary, and tertiary immune responses. Further experimental studies are necessary to validate these findings.

Public engagement with genomics

As detailed in its flagship report, Genome UK, the UK government recognises the vital role that broad public engagement across whole populations plays in the field of genomics. However, there is limited evidence about how to do this at scale, particularly for public audiences who are not especially interested in the science, are unsure of the relevance to their lives or who feel disengaged from it. We use a narrative review to explore: (i) UK attitudes towards genetics and genomics and what may influence reluctance to engage with these topics; (ii) innovative public engagement approaches that have been used to bring diverse public audiences into conversations about the technology. Whilst we have found some novel engagement methods that have used participatory arts, film, social media and deliberative methods, there is no clear agreement on best practice. We did not find a consistently used, evidence-based strategy for delivering public engagement about genomics across diverse and broad populations, nor a specific method that is known to encourage engagement from groups that have historically felt (in terms of perception) and been (in reality) excluded from genomic research. We argue there is a need for well-defined, tailor-made engagement strategies that clearly articulate the audience, the purpose and the proposed impact of the engagement intervention. This needs to be coupled with robust evaluation frameworks to build the evidence-base for population-level engagement strategies.

Diagnostic management of acute pulmonary embolism: a prediction model based on a patient data meta-analysis.

Risk stratification is used for decisions regarding need for imaging in patients with clinically suspected acute pulmonary embolism (PE). The aim was to develop a clinical prediction model that provides an individualized, accurate probability estimate for the presence of acute PE in patients with suspected disease based on readily available clinical items and D-dimer concentrations. An individual patient data meta-analysis was performed based on sixteen cross-sectional or prospective studies with data from 28 305 adult patients with clinically suspected PE from various clinical settings, including primary care, emergency care, hospitalized and nursing home patients. A multilevel logistic regression model was built and validated including ten a priori defined objective candidate predictors to predict objectively confirmed PE at baseline or venous thromboembolism (VTE) during follow-up of 30 to 90 days. Multiple imputation was used for missing data. Backward elimination was performed with a P-value <0.10. Discrimination (c-statistic with 95% confidence intervals [CI] and prediction intervals [PI]) and calibration (outcome:expected [O:E] ratio and calibration plot) were evaluated based on internal-external cross-validation. The accuracy of the model was subsequently compared with algorithms based on the Wells score and D-dimer testing. The final model included age (in years), sex, previous VTE, recent surgery or immobilization, haemoptysis, cancer, clinical signs of deep vein thrombosis, inpatient status, D-dimer (in µg/L), and an interaction term between age and D-dimer. The pooled c-statistic was 0.87 (95% CI, 0.85-0.89; 95% PI, 0.77-0.93) and overall calibration was very good (pooled O:E ratio, 0.99; 95% CI, 0.87-1.14; 95% PI, 0.55-1.79). The model slightly overestimated VTE probability in the lower range of estimated probabilities. Discrimination of the current model in the validation data sets was better than that of the Wells score combined with a D-dimer threshold based on age (c-statistic 0.73; 95% CI, 0.70-0.75) or structured clinical pretest probability (c-statistic 0.79; 95% CI, 0.76-0.81). The present model provides an absolute, individualized probability of PE presence in a broad population of patients with suspected PE, with very good discrimination and calibration. Its clinical utility needs to be evaluated in a prospective management or impact study. PROSPERO ID 89366.

The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20mg/0.4ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses≥30mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20mg/0.4ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20mg dose was developed and is available for use in clinical practice.

Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer

The efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease. To evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted). This multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months. Patients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/μL [to convert to ×109/μL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy. The primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population. A total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events. This randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting. ClinicalTrials.gov Identifier: NCT03709316.

Effects of sodium-glucose co-transporter-2 inhibitors by background cardiovascular medications: A systematic review and meta-analysis.

To explore whether the beneficial cardiovascular (CV) effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease. We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs). We included 12 trials comprising 83 804 patients. SGLT-2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), b-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b-blocker plus MRA, or an ARNI plus b-blocker plus MRA (HRs ranged from 0.61 to 0.83; P > .1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all-cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate. The benefit of SGLT-2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified.

Dashboards as Mechanisms for Community Empowerment: Developing a Prototype for Child and Adolescent Well-being in California.

In recent years, stakeholders in public health have emphasized measuring young peoples' well-being as a more holistic and upstream approach to understanding their health and development. However, summarizing the available indicators of well-being in ways that strengthen ongoing policy and community efforts remains a challenge. Our objective was to develop a measurement framework of young peoples' well-being that would be engaging and actionable to a broad and diverse set of stakeholders in California. We began with a scan of the relevant literature documenting previous efforts to measure young peoples' well-being, both within the United States and internationally. Subsequently, we individually interviewed a set of key informants and then convened a multidisciplinary panel of experts to solicit feedback on our approach. Throughout this iterative and collaborative process, we developed and refined a measurement framework based on the information provided across these various sources. Findings suggest data dashboards are a promising approach for presenting a parsimonious yet holistic picture of young peoples' well-being. Dashboards can highlight well-being's multidimensionality by categorizing indicators over different domains. Our framework organizes indicators over 5 types: child-centric, subjective well-being, contextual determinants, developmental, and equity-focused. The design and flexibility of dashboards can also highlight important gaps in data collection that are of interest to end users such as indicators not yet collected among the broader population. Furthermore, dashboards can include interactive features, such as selecting key data elements, that can help communities articulate priority areas for policy action, thereby generating momentum and enthusiasm for future iterations and improvements. Data dashboards are well suited for engaging a variety of stakeholders on complex multidimensional concepts such as young peoples' well-being. However, to fulfill their promise, they should be codesigned and codeveloped through an iterative process with the stakeholders and community members they intend to serve.

Effects of baseline age and disease duration on the efficacy and safety of siponimod in patients with active SPMS: Post hoc analyses from the EXPAND study.

Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS. This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥1 relapse in the 2 years before the study and/or ≥1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: <45 year ≥45 years; and secondary cut-off: <50 years or ≥50 years) and by DD at baseline (<16 years or ≥16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation. Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), <50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with <16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged <45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥45 years (HR: 0.67; 95% CI: 0.45-0.99), <50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with <16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND. In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.

Cost-effectiveness analysis of noninvasive tests to identify advanced fibrosis in non-alcoholic fatty liver disease.

Advanced fibrosis is associated with end-stage liver disease (ESLD) and mortality in NAFLD. As treatments specifically targeted at NAFLD are lacking, patient management focuses on surveillance for early detection of complications related to end-stage liver disease. Although current and emerging diagnostic tools for the detection of advanced fibrosis are crucial for surveillance, their added value is unclear. The aim of this study was to evaluate the costs and health outcomes of noninvasive tests in patient management strategies for diagnosing advanced fibrosis in NAFLD patients. A decision analytical model was developed to evaluate 13 patient management strategies, including a no-testing strategy and 12 diagnostic algorithms with noninvasive tests (fibrosis 4- score, enhanced liver fibrosis, vibration controlled transient elastography), and liver biopsy. Model inputs were synthesized from the literature and Swedish registries. Lifetime health care costs, life years, quality-adjusted life years, clinical outcomes, and incremental cost-effectiveness ratios were calculated for a cohort of 55-year-old patients diagnosed with NAFLD. The cost per quality-adjusted life year was above €50 000 for all diagnostic algorithms compared to no-testing. The cost per quality-adjusted life year of the most promising diagnostic algorithm (fibrosis 4- score, enhanced liver fibrosis, vibration controlled transient elastography, and liver biopsy) was ∼ €181 000 compared with no testing. Sensitivity analysis indicated that if treatment slowed down disease progression, the value of testing increased. The result questions the overall value of comprehensive diagnostic testing in a broad NAFLD population in current routine clinical care. The role of noninvasive tests may change if evidence-based treatments to slow down disease progression emerge.

Sirolimus-Coated Balloon in an All-Comer Population of Coronary Artery Disease Patients: The EASTBOURNE Prospective Registry

BackgroundDrug-coated balloons (DCB) represent 1 of the most promising innovations in interventional cardiology and may represent a valid alternative to drug-eluting stents. Currently, some sirolimus-coated balloons (SCB) are being investigated for several coronary artery disease applications. ObjectivesThis study sought to understand the role of a novel SCB for the treatment of coronary artery disease. MethodsEASTBOURNE (All-Comers Sirolimus-Coated Balloon European Registry) is a prospective, multicenter, investigator-driven clinical study that enrolled real-world patients treated with SCB. Primary endpoint was target lesion revascularization (TLR) at 12 months. Secondary endpoints were procedural success, myocardial infarction (MI), all-cause death, and major adverse clinical events (a composite of death, MI, and TLR). All adverse events were censored and adjudicated by an independent clinical events committee. ResultsA total population of 2,123 patients (2,440 lesions) was enrolled at 38 study centers in Europe and Asia. The average age was 66.6 ± 11.3 years, and diabetic patients were 41.5%. De novo lesions (small vessels) were 56%, in-stent restenosis (ISR) 44%, and bailout stenting occurred in 7.7% of the patients. After 12 months, TLR occurred in 5.9% of the lesions, major adverse clinical events in 9.9%, and spontaneous MI in 2.4% of the patients. The rates of cardiac/all-cause death were 1.5% and 2.5%, respectively. The primary outcome occurred more frequently in the ISR cohort (10.5% vs 2.0%; risk ratio: 1.90; 95% CI: 1.13-3.19). After multivariate Cox regression model, the main determinant for occurrence of the primary endpoint was ISR (OR: 5.5; 95% CI: 3.382-8.881). ConclusionsEASTBOURNE, the largest DCB study in the coronary field, shows the safety and efficacy of a novel SCB in a broad population of coronary artery disease including small vessels and ISR patients at mid-term follow-up. (The All-Comers Sirolimus-Coated Balloon European Registry [EASTBOURNE]; NCT03085823)

Imagine All the People: A Guided Internet-Based Imagery Training to Increase Assertiveness among University Students-Study Protocol for a Randomized Controlled Trial.

The importance of communication skills for well-being and self-realization is widely accepted. Despite that, research on assertiveness and assertiveness training has declined significantly in recent decades. Consequently, traditional training does not consider the most recent novel technologies used to spread psychological interventions. This study proposes the development of ComunicaBene: a guided Internet-based imagery intervention to promote assertiveness. Moreover, it describes the study protocol for a randomized control trial to investigate the intervention's efficacy and acceptability. Participants will be randomly assigned to an experimental (ComunicaBene) or waitlist control condition. ComunicaBene consists of different online training modules corresponding to three phases: psychoeducation, imaginative exposure, and in vivo-exposure. Each module provides participants with theoretical and practical content about needs, emotions, communication style, and assertiveness. Moreover, during the program, every student is supervised by a Tutor. Participants in the control condition will be included in a waiting list. Primary and secondary outcomes will include changes in assertiveness, well-being, emotional awareness, worry, and rumination. Outcomes will be assessed at pre- and post-intervention, and via a 6-month follow-up. We expect that the results will support the efficacy of ComunicaBene as an innovative, scalable, affordable, and acceptable intervention to spread assertive training through the Internet and among a broad population.

GATEKEEPER's Strategy for the Multinational Large-Scale Piloting of an eHealth Platform: Tutorial on How to Identify Relevant Settings and Use Cases.

The World Health Organization's strategy toward healthy aging fosters person-centered integrated care sustained by eHealth systems. However, there is a need for standardized frameworks or platforms accommodating and interconnecting multiple of these systems while ensuring secure, relevant, fair, trust-based data sharing and use. The H2020 project GATEKEEPER aims to implement and test an open-source, European, standard-based, interoperable, and secure framework serving broad populations of aging citizens with heterogeneous health needs. We aim to describe the rationale for the selection of an optimal group of settings for the multinational large-scale piloting of the GATEKEEPER platform. The selection of implementation sites and reference use cases (RUCs) was based on the adoption of a double stratification pyramid reflecting the overall health of target populations and the intensity of proposed interventions; the identification of a principles guiding implementation site selection; and the elaboration of guidelines for RUC selection, ensuring clinical relevance and scientific excellence while covering the whole spectrum of citizen complexities and intervention intensities. Seven European countries were selected, covering Europe's geographical and socioeconomic heterogeneity: Cyprus, Germany, Greece, Italy, Poland, Spain, and the United Kingdom. These were complemented by the following 3 Asian pilots: Hong Kong, Singapore, and Taiwan. Implementation sites consisted of local ecosystems, including health care organizations and partners from industry, civil society, academia, and government, prioritizing the highly rated European Innovation Partnership on Active and Healthy Aging reference sites. RUCs covered the whole spectrum of chronic diseases, citizen complexities, and intervention intensities while privileging clinical relevance and scientific rigor. These included lifestyle-related early detection and interventions, using artificial intelligence-based digital coaches to promote healthy lifestyle and delay the onset or worsening of chronic diseases in healthy citizens; chronic obstructive pulmonary disease and heart failure decompensations management, proposing integrated care management based on advanced wearable monitoring and machine learning (ML) to predict decompensations; management of glycemic status in diabetes mellitus, based on beat to beat monitoring and short-term ML-based prediction of glycemic dynamics; treatment decision support systems for Parkinson disease, continuously monitoring motor and nonmotor complications to trigger enhanced treatment strategies; primary and secondary stroke prevention, using a coaching app and educational simulations with virtual and augmented reality; management of multimorbid older patients or patients with cancer, exploring novel chronic care models based on digital coaching, and advanced monitoring and ML; high blood pressure management, with ML-based predictions based on different intensities of monitoring through self-managed apps; and COVID-19 management, with integrated management tools limiting physical contact among actors. This paper provides a methodology for selecting adequate settings for the large-scale piloting of eHealth frameworks and exemplifies with the decisions taken in GATEKEEPER the current views of the WHO and European Commission while moving forward toward a European Data Space.

How to achieve the net-zero target? Lessons learned from past transformations

Transformations–defined as deep, radical, non-linear, multi-dimensional, systemic processes of change–are required to avert serious threats to humanity and the environment. In this study, we have analysed past transformations in Switzerland in four environmental domains, with the aim to draw conclusions for current challenges, such as the net-zero transformation. Firstly, we have conceptualised and defined transformations. Secondly, we have applied and further developed two theoretical frameworks to (i) identify actual transformations in the four domains, and (ii) analyse crucial characteristics of these profound changes. Furthermore, we have examined relevant enabling and hindering factors for transformations. Our study is based on literature review and expert interviews, as well as triangulation workshops to align the collected information. We conclude that providing general blueprints for transformations is not possible due to the complexity and context-specific nature of these processes. However, for the net-zero transformation to be successful, we found that unprecedent efforts are needed with respect to pace, sectors involved, levels of initiative, mindset change in the broader population, and involvement of technology and research. Specifically, we recommend fast action to (i) implement a steering committee combined with citizens’ assemblies and cross-sectoral discussion platforms, (ii) encourage different actors to take initiatives at multiple levels, and (iii) enable a broad mindset change across different societal groups.

Epidemiological Aspect of Pathologies That Led to Hospitalization at the Military Medico-Surgical Center of Bamako

Military health plays a crucial role in ensuring the well-being of soldiers, their families, and the broader population. It encompasses various aspects of healthcare and is an integral part of national health systems. This study aimed to provide a descriptive cross-sectional analysis, spanning one year, by examining hospitalization records, reference sheets, and discharge bulletins. Methods: To gather the necessary data, a comprehensive collection sheet was created, encompassing sociodemographic variables, diagnosis, treatment, and patient outcomes. The data were entered and analyzed using Microsoft Word 2016 and IBM SPSS Statistics software. Results: Among the study participants, males accounted for the majority at 60%, with the age group of 61 and over being the most represented. Internal medicine and neurology were the dominant specialties, respectively comprising 35.8% and 27% of cases. Encouragingly, a significant 83.1% of patients showed improvement and were discharged, while a 6% fatality rate was observed. Furthermore, noteworthy advancements were made in the technical infrastructure, including the establishment of a dialysis unit and an operating theatre.

Characteristics of Medical Evacuation by Train in Ukraine, 2022

The 2022 war in Ukraine severely affected access to health care for patients in the conflict-affected regions and limited options for medical evacuation. Air transport, a common method of medical evacuation in war zones, was unsafe due to the conflict of 2 modernized military forces that were in possession of aircraft and surface-to-air weapons; therefore, Médecins Sans Frontières, in collaboration with the Ukrainian railway company and Ukrainian health agencies, addressed this by initiating medical evacuation via medically customized trains. To describe the implementation of medical evacuation trains aimed at improving the access to health care for war-affected patients. This case series describes the remodeling of 2 trains used for medical evacuation in a conflict zone during the war in Ukraine. The study was conducted from March 30 to November 30, 2022. One train had minimal adjustments and could be rapidly deployed to address the most pressing humanitarian needs, while the other underwent major structural modifications to provide intensive care capacity. The report details the medical capabilities of the trains, the organization of referrals, and operational challenges encountered. Additionally, it includes a case series on the characteristics of patients transported in the initial 8 months, based on routinely collected programmatic descriptive data of all patients transported by the medical trains. In 8 months, 2481 patients (male-female ratio, 1.07; male, 1136 [46%]; female 1058 [43%]; missing data, 287 [12%]; median age, 63 years [range, 0-98 years]) were evacuated from 11 cities near the Ukrainian conflict frontline to safer areas. Initially, the trains predominantly evacuated trauma patients, but over the course of the war, the patient characteristics changed with more medical and nonacute conditions, and fewer trauma patients. The main reason for entry into the intensive care unit train carriage was for close monitoring and observation, and the main interventions performed were primarily for respiratory failure. The findings of this study suggest that medical evacuation in a war zone by converted trains is possible and can improve access to health care for war-affected patients. The presence of intensive care capacity on board allows for transport of more severely ill or injured individuals. However, the target population should not be limited to trauma patients, as health care institutions affected host a much broader population whose needs and urgency for evacuation may change over time.