The Lancet Regional Health - Europe

BACKGROUND: Negative attitudes towards vaccines and an uncertainty or unwillingness to receive vaccinations are major barriers to managing the COVID-19 pandemic in the long-term. We estimate predictors of four domains of negative attitudes towards vaccines and identify groups most at risk of uncertainty and unwillingness to receive a COVID-19 vaccine in a large sample of UK adults. METHODS: Data were cross-sectional and from 32,361 adults in the UCL COVID-19 Social Study. Ordinary least squares regression analyses examined the impact of socio-demographic and COVID-19 related factors on four types of negative vaccine attitudes: mistrust of vaccine benefit, worries about unforeseen effects, concerns about commercial profiteering, and preference for natural immunity. Multinomial regression examined the impact of socio-demographic and COVID-19 related factors, negative vaccine attitudes, and prior vaccine behaviour on uncertainty and unwillingness to be vaccinated for COVID-19. FINDINGS: 16% of respondents displayed high levels of mistrust about vaccines across one or more domains. Distrustful attitudes towards vaccination were higher amongst individuals from ethnic minority backgrounds, with lower levels of education, lower annual income, poor knowledge of COVID-19, and poor compliance with government COVID-19 guidelines. Overall, 14% of respondents reported unwillingness to receive a vaccine for COVID-19, whilst 23% were unsure. The largest predictors of both COVID-19 vaccine uncertainty and refusal were low-income groups (< £16,000, a year), having not received a flu vaccine last year, poor adherence to COVID-19 government guidelines, female gender, and living with children. Amongst vaccine attitudes, intermediate to high levels of mistrust of vaccine benefit and concerns about future unforeseen side effects were the most important determinants of both uncertainty and unwillingness to vaccinate against COVID-19. INTERPRETATION: Negative attitudes towards vaccines are a major public health concern in the UK. General mistrust in vaccines and concerns about future side effects in particular will be barriers to achieving population immunity to COVID-19 through vaccination. Public health messaging should be tailored to address these concerns and specifically to women, ethnic minorities, and people with lower levels of education and incomes. FUNDING: The Nuffield Foundation [WEL/FR-000022583], the MARCH Mental Health Network funded by the Cross-Disciplinary Mental Health Network Plus initiative supported by UK Research and Innovation [ES/S002588/1], and the Wellcome Trust [221400/Z/20/Z and 205407/Z/16/Z].

Abstract Background While the leading symptoms during coronavirus disease 2019 (COVID-19) are acute and the majority of patients fully recover, a significant fraction of patients now increasingly experience long-term health consequences. However, most data available focus on health-related events after severe infection and hospitalization. We present a longitudinal, prospective analysis of health consequences in patients who initially presented with no or minor symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Hence we focus on mild COVID-19 in non-hospitalized patients. Methods We included 958 patients with confirmed SARS-CoV-2 infection in this study. Patients were observed for seven months from April 6 th to December 2 nd 2020 for long-term symptoms and SARS-CoV-2 antibodies. We identified anosmia, ageusia, fatigue or shortness of breath as most common, persisting symptoms at month 4 and 7 and summarized presence of such long-term health consequences as post-COVID syndrome (PCS). Predictors of long-term symptoms were assessed using an uni- and multivariable logistic regression model. Findings We observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8.6% (38/442) of patients presented with shortness of breath, 12.4% (55/442) with anosmia, 11.1% (49/442) with ageusia and 9.7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27.8% (123/442) and 34.8% (123/353) at month 4 and 7 post-infection, respectively. This corresponds to 12.8% patients with long-lasting symptoms relative to the initial total cohort (123/958). A lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhea during acute COVID-19 were associated with higher risk to develop long-term symptoms. Interpretation The on-going presence of either shortness of breath, anosmia, ageusia or fatigue as long-lasting symptoms even in non-hospitalized patients was observed at four and seven months post-infection and summarized as post-COVID syndrome (PCS). The continued assessment of patients with PCS will become a major task to define and mitigate the socioeconomic and medical long-term effects of COVID-19. Funding COVIM:„NaFoUniMedCovid19”(FKZ: 01KX2021) Research in context Evidence before this study Data about long-term health consequences after SARS-CoV-2 infection and COVID-19 is scarce and most available data describe health consequences in hospitalized patients during acute COVID-19. However, these studies do not take into account the vast majority of patients with a milder course of infection (WHO score1-3). Added value of this study Our cohort consists of mostly mild COVID-19 cases that have been prospectively followed for a median time of 6.8 months. At least one trained physician critically reviewed the patients’ reported symptoms at each visit. We assessed SARS-CoV-2 IgG at each visit to correlate reported symptoms with serological data. At 4 months after SARS-CoV-2 infection, shortness of breath occurred in 8.6% (38/442), anosmia in 12.4% (55/442), ageusia in 11.1% (49/442), and fatigue in 9.7% (43/442) of patients. At least one characteristic symptom was present in 27.8% (123/442) and 34.8% (123/353) at months 4 and 7 post-infection, respectively. Symptoms were summarized as post-COVID syndrome (PCS). Relative to our initial total cohort (123/958), this corresponds to 12.8% patients with long-lasting symptoms. Lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhea during acute COVID-19 were associated with higher risk of developing long-term symptoms. Implications of all available evidence We believe that our findings have important implications for the fields of infectious diseases and public health, because we show long-term health consequences may occur even after very mild COVID-19 in the outpatient setting. As up to 81% of all SARS-CoV-2 infected patients present with mild disease, it can be expected that PCS will affect a larger number of individuals than initially assumed, posing major medical, social and economic challenges.

Abstract Background Although the SARS-CoV-2 mRNA vaccines have proven high efficacy, limited data exists on the duration of immune responses and their relation to age and side effects. Methods We studied the antibody and memory T cell responses to Spike protein after the two-dose Comirnaty mRNA vaccine in 122 volunteers up to 3 months and correlated the findings with age and side effects. Findings We found a robust antibody response after the second vaccination dose. However, the antibody levels declined at 6 and 12 weeks postvaccination, indicating a waning of the immune response. Regardless, the average levels remained higher compared to pre-vaccination or in COVID-19 convalescent individuals. The antibodies efficiently blocked ACE2 receptor binding to Spike protein of four variants of concern at one week but this was decreased at three months, in particular with B.1.351 and P1 isolates. 87% of individuals developed Spike-specific memory T cell responses, which were lower in individuals with increased proportions of immunosenescent CD8+ TEMRA cells. We found a decreased vaccination efficacy but fewer adverse events in older individuals, suggesting a detrimental impact of age on outcome. Interpretation The mRNA vaccine induces a strong antibody response to four variants at 1 week postvaccination but decreases thereafter, in particular among older individuals. T cell responses, although detectable in the majority, were lower in individuals with immunosenescence. The deterioration of vaccine response needs to be monitored to define the optimal time for the revaccination. Funding The Estonian Research Council, Icosagen Cell Factory, and SYNLAB Estonia. Research in context Evidence before this study The first studies addressing the immune responses in older individuals after the administration of SARS-CoV-2 mRNA vaccines have been published. We searched PubMed and medRxiv for publications on the immune response of SARS-CoV-2-mRNA vaccines, published in English, using the search terms “SARS-CoV-2”, “COVID-19”, “vaccine response”, “mRNA vaccine”, up to May 20th, 2021. To date, most mRNA vaccine response studies have not been peer-reviewed, and data on the dynamics of antibody response, role of age and side effects on SARS-CoV-2-mRNA vaccines in real vaccination situations is limited. Some studies have found a weaker immune response in older individuals after the first dose and these have been measured at a relatively short period (within one to two weeks) after the first dose but little longer-term evidence exists on the postvaccination antibody persistence. Added value of this study In this study, we assessed the antibody response up to three months after the full vaccination with Pfizer-BioNTech Comirnaty mRNA vaccine in 122 individuals. Our findings show strong Spike RBD antibody responses one week after the second dose with the capacity to block ACE2-Spike protein interaction, however, the antibodies declined significantly at three months after the second dose. The inhibition of ACE2-Spike interaction was weaker with South African (B.1.351) and Brazilian (P.1) than with Wuhan and UK (B.1.1.7) SARS-CoV-2 isolates. At three months 87% of vaccinated individuals developed either CD4+ or CD8+ T cell responses. Those negative for Spike-specific T cell response also tended to have lower Spike-specific antibody levels. In addition, CD4+ T cell response was decreased among vaccinated individuals with elevated levels of senescent CD8+ TEMRA cells. We found a weaker antibody response and faster waning of antibodies in older vaccinated individuals, which correlated with fewer side effects at the time of vaccinations. Implications of all the available evidence Our results show that two doses of Pfizer-BioNTech Comirnaty mRNA vaccine induce a strong antibody and T cell responses to Spike RBD region but the antibody levels are declined at three months after the second dose. Nevertheless, even at three months, the anti-Spike RBD antibody levels stay significantly higher than at prevaccination, after the first dose of vaccine, or in Covid-19 postinfection. Our findings implicate older individuals to have fewer vaccination adverse effects and weaker immune response after the vaccination and point to the need for more individualized vaccination protocols, in particular among older people.

Atrial fibrillation (AF) is highly prevalent with a lifetime risk of about 1 in 3-5 individuals after the age of 45 years. Between 2010 and 2019, the global prevalence of AF has risen markedly from 33.5 million to 59 million individuals living with AF. Early detection of AF and implementation of appropriate treatment could reduce the frequency of complications associated with AF. International AF management guidelines recommend opportunistic and systematic screening for AF, but additional data are needed. Digital approaches and pathways have been proposed for early detection and for the transition to early AF management. Mobile health (mHealth) devices provide an opportunity for digital screening and should be part of novel models of care delivery based on integrated AF care pathways. For a broad implementation of mHealth-based, integrated care for patients with chronic diseases as AF, further high quality evidence is necessary. In this review, we present an overview of the present data on epidemiology, screening techniques, and the contribution of digital health solutions to the integrated management of AF. We also provide a systemic review on current data of digital and integrated AF management.

Background: Mental health is a public health issue for European young people, with great heterogeneity in resource allocation. Representative population-based studies are needed. The Global Burden of Disease (GBD) Study 2019 provides internationally comparable information on trends in the health status of populations and changes in the leading causes of disease burden over time. Methods: Prevalence, incidence, Years Lived with Disability (YLDs) and Years of Life Lost (YLLs) from mental disorders (MDs), substance use disorders (SUDs) and self-harm were estimated for young people aged 10-24 years in 31 European countries. Rates per 100,000 population, percentage changes in 1990-2019, 95% Uncertainty Intervals (UIs), and correlations with Sociodemographic Index (SDI), were estimated. Findings: In 2019, rates per 100,000 population were 16,983 (95% UI 12,823 - 21,630) for MDs, 3,891 (3,020 - 4,905) for SUDs, and 89·1 (63·8 - 123·1) for self-harm. In terms of disability, anxiety contributed to 647·3 (432-912·3) YLDs, while in terms of premature death, self-harm contributed to 319·6 (248·9-412·8) YLLs, per 100,000 population. Over the 30 years studied, YLDs increased in eating disorders (14·9%;9·4-20·1) and drug use disorders (16·9%;8·9-26·3), and decreased in idiopathic developmental intellectual disability (-29·1%;23·8-38·5). YLLs decreased in self-harm (-27·9%;38·3-18·7). Variations were found by sex, age-group and country. The burden of SUDs and self-harm was higher in countries with lower SDI, MDs were associated with SUDs. Interpretation: Mental health conditions represent an important burden among young people living in Europe. National policies should strengthen mental health, with a specific focus on young people. Funding: The Bill and Melinda Gates Foundation.

Background: European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Methods: Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Findings: Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3 ± 10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range [IQR]) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 [60, 117] mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. Interpretation: At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. Trial registration: ClinicalTrials.gov Identifier: NCT04271280. Funding: This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany.

Abstract Evidence before this study It is emerging that long-term symptoms are often present in people who have had acute COVID-19 disease. These symptoms affect a range of organ systems including respiratory, cardiovascular and neurological systems. It is not clear how many patients who required hospitalisation develop these symptoms and the impact they have on quality of life. We searched PubMed on 24 th March 2021 using the terms ‘COVID-19’, ‘long-Covid’, ‘long-term’ and ‘outcomes’. This was supplemented by hand searching relevant references and news reports. We identified several small studies focussing on specific symptoms or diseases, studies of patients in community settings and studies of patients who were hospitalised for acute COVID-19 in Italy, Russia and China. There were no peer-reviewed published data at the time of searching which captured outcomes of patients within the United Kingdom. Added Value of this study We found that over half of patients reported not feeling fully recovered several months after onset of Covid-19 symptoms. The most common symptoms reported were fatigue, followed by breathlessness. Patients reported significant increases in new or worse disability, increases in MRC dyspnoea scale and worse quality of life as measured by EQ5D-5L summary index at the time of follow-up compared to before onset of acute COVID-19 symptoms. Our study found that women, in particular women under the age of 50 were significantly more likely to not feel fully recovered, were more breathless, more fatigued and had higher rates of new or worsened disability, even after taking severity of acute disease into account when compared to men of the same age. Implications of all available evidence Long-term symptoms following hospitalisation for COVID-19 are very common and have significant impacts on quality of life. Women under 50 were most likely to have the worst outcomes. Policy makers need to ensure there is long-term support for people experiencing long-Covid and should plan for lasting long-term population morbidity. Funding for research to understand mechanisms underlying long-Covid and identify potential interventions for testing in randomised trials is urgently required. Structured Abstract Background This study sought to establish the long-term effects of Covid-19 following hospitalisation. Methods 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). Findings 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse at follow-up (median difference 0.1 points on a scale of 0 to 1, IQR: −0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. Interpretation Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females. Role of the funder: The study sponsors and funders had no role in the study design, collection, analysis, interpretation of data, writing of the report, or the decision to submit the article for publication. Investigators were independent from funders and the authors have full access to all of the data, including any statistical analysis and tables.

Background: Digital healthcare systems data could provide insights into the global prevalence of chronic kidney disease (CKD). We designed the CaReMe CKD study to estimate the prevalence, key clinical adverse outcomes and costs of CKD across 11 countries. Methods: Individual-level data of a cohort of 2·4 million contemporaneous CKD patients was obtained from digital healthcare systems in participating countries using a pre-specified common protocol; summarized using random effects meta-analysis. CKD and its stages were defined in accordance with current Kidney Disease: Improving Global Outcomes (KDIGO) criteria. CKD was defined by laboratory values or by a diagnosis code. Findings: The pooled prevalence of possible CKD was 10·0% (95% confidence interval 8.5‒11.4; mean pooled age 75, 53% women, 38% diabetes, 60% using renin-angiotensin-aldosterone system inhibitors). Two out of three CKD patients identified by laboratory criteria did not have a corresponding CKD-specific diagnostic code. Among CKD patients identified by laboratory values, the majority (42%) were in KDIGO stage 3A; and this fraction was fairly consistent across countries. The share with CKD based on urine albumin-creatinine ratio (UACR) alone (KDIGO stages one and two) was 29%, with a substantial heterogeneity between countries. Adverse events were common; 6·5% were hospitalized for CKD or heart failure, and 6·2% died, annually. Costs for renal events and heart failure were consistently higher than costs for atherosclerotic events in CKD patients across all countries. Interpretation: We estimate that CKD is present in one out of ten adults. These individuals experience significant adverse outcomes with associated costs. The prevalence of CKD is underestimated when using diagnostic codes alone. There is considerable public health potential in diagnosing CKD and providing treatments to those currently undiagnosed. Funding: The study was sponsored by AstraZeneca.

Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality. We conducted a prospective study exploring the eight week time course of specific cellular (interferon-γ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273. SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% (p < 0.001) in dialysis and 49% to 26% in transplant patients, respectively. Specific IgG directed against the new binding domain of the spike protein (RDB) were significantly higher in dialysis patients vaccinated by mRNA-1273 (95%) compared to BNT162b2 (85%, p < 0.001). Vaccination appeared safe and highly effective demonstrating an almost complete lack of symptomatic COVID-19 disease after boost vaccination as well as ceased disease incidences during third pandemic wave in dialysis patients. Dialysis patients exhibit a remarkably high seroconversion rate of 95% after boost vaccination, while humoral response is impaired in the majority of transplant recipients. Immunosuppressive drug number and type as well as vaccine type (BNT162b2) are major determinants of seroconversion failure in both dialysis and transplant patients suggesting immune monitoring and adaption of vaccination protocols.

BACKGROUND: In response to the COVID-19 pandemic, governments around the world instituted various public-health measures. Our project aimed to highlight the most significant similarities and differences in key mental-health indicators between four Western and Northern European countries, and identify the population subgroups with the poorest mental-health outcomes during the first months of the pandemic. METHODS: We analysed time-series survey data of 205,084 individuals from seven studies from Denmark, France, the Netherlands, and the UK to assess the impact of the pandemic and associated lockdowns. All analyses focused on the initial lockdown phase (March-July 2020). The main outcomes were loneliness, anxiety, and COVID-19-related worries and precautionary behaviours. FINDINGS: COVID-19-related worries were consistently high in each country but decreased during the gradual reopening phases. While only 7% of the respondents reported high levels of loneliness in the Netherlands, percentages were higher in the rest of the three countries (13-18%). In all four countries, younger individuals and individuals with a history of mental illness expressed the highest levels of loneliness. INTERPRETATION: The pandemic and associated country lockdowns had a major impact on the mental health of populations, and certain subgroups should be closely followed to prevent negative long-term consequences. Younger individuals and individuals with a history of mental illness would benefit from tailored public-health interventions to prevent or counteract the negative effects of the pandemic. Individuals across Western and Northern Europe have thus far responded in psychologically similar ways despite differences in government approaches to the pandemic. FUNDING: See the Funding section.

With the recent approval of maternal RSV vaccines and late-phase trials underway for a GBS vaccine, Europe is entering a new era of maternal immunisation. Yet scientific progress is outpacing pregnancy-specific evidence and preparedness for equitable implementation. Pregnant women are often excluded from early vaccine trials, while national recommendations, surveillance and delivery vary across Europe, even after regulatory authorisation. Without coordinated planning, new maternal vaccines risk reproducing the delays and inequities seen with influenza, pertussis and COVID-19 vaccination. In this Review, we examine scientific advances in the next generation of maternal vaccines, including mRNA, protein conjugate, nanoparticle and combination approaches, and candidates against emerging and other priority pathogens. We discuss barriers to including pregnant women in trials, assess regulatory and pharmacovigilance readiness, and identify health-system and vaccine-confidence risks to equitable rollout. We offer strategic recommendations for Europe's maternal immunisation roadmap, from research investment to policy integration, provider education, and equity-centred planning. Realising this potential will require integrated action across research, regulation, implementation, and communication. This is the final paper in the Series on the future of maternal vaccination in Europe and synthesises its findings into a framework for Europe and beyond.

Academic treatment optimization studies (TOS) play an important role in determining how established and emerging treatments should be combined, sequenced, intensified, de-intensified, or otherwise optimized in routine clinical care. Unlike commercial clinical trials, which primarily support the development and regulatory approval of new medicinal products, academic TOS frequently address questions for which commercial incentives are limited. Such studies therefore contribute directly to the evidence base underlying clinical guidelines and health-care standards. A substantial proportion of academic TOS involves authorized medicinal products used outside the strict wording of their marketing authorization (label), but within evidence-supported clinical practice. Current European clinical-trial regulation does not always adequately reflect the distinction between the label of a medicinal product and the incremental risk and burden introduced by a particular treatment optimization strategy. Increasing administrative and regulatory requirements disproportionately affect investigator-initiated multicentre studies with limited resources. This article presents a policy perspective derived from the experience of investigators, clinical researchers and ethics committee members involved in academic clinical trials. We propose a risk- and burden-adapted regulatory approach for eligible academic TOS. The relevant reference point for assessing proportionality should be normal clinical care rather than the label alone. Evidence-supported TOS involving authorized medicinal products, particularly studies corresponding to OECD categories A and B1, should be considered for a risk-proportionate regulatory pathway when the proposed intervention introduces minimal additional risk and burden compared with normal clinical care. Selected OECD B2 studies could potentially qualify where additional evidence and expert assessment demonstrate similarly low incremental risk. The assessment should be performed on a trial-specific basis. Relevant standards of routine care should be defined by the respective medical societies in the field. Ethics committees, supported by physicians experienced in the relevant disease area, should assess incremental risk and burden. Monitoring, oversight and reporting requirements should likewise be risk-proportionate and prospectively justified in the trial protocol. The objective is not deregulation of academic clinical research but risk-proportionate regulation. A risk-adapted framework for academic TOS could strengthen investigator-initiated evidence generation, particularly for questions with limited commercial incentives, and improve the evidence base for optimizing routine clinical care in Europe.

Background Childhood socioeconomic position (SEP) influences later health, but how inequalities persist into early older age and operate through adult SEP remains unclear. Quantifying these pathways is important for identifying opportunities to reduce health inequalities over the life course. We therefore used an interventional causal mediation framework to quantify the contribution of four distinct dimensions of adult SEP to childhood socioeconomic inequalities in self-reported and objective health outcomes in early older age. Methods We analysed data from the 1958 British Birth Cohort collected at birth, ages 33 and 55, and the most recent sweep, when participants were aged 60–66 years. Sample sizes ranged from 4014 to 8363 depending on the outcome. We examined the extent to which four dimensions of adult SEP — adult occupational class, education, housing tenure, and income — mediated associations between childhood SEP, measured by paternal occupational class at birth, and self-rated health (SRH), C-reactive protein (CRP), cholesterol ratio, glycated haemoglobin (HbA1c), and NT-proBNP. Findings Among men, occupational class mediated 39% of the association with poorer SRH (indirect effect RR 0.90, 95%: CI 0.86–0.95), and education mediated 27% (0.93, 0.90–0.96). Among women, mediation was smaller and most evident via education (10%; 0.95, 0.91–0.98) and housing tenure (6%; 0.97, 0.94–0.99). Mediation was limited for CRP and minimal for cholesterol ratio, HbA1c, and NT-proBNP. Interpretation Improving adult SEP could reduce, but is unlikely to eliminate, early older-age health inequalities associated with childhood SEP, highlighting the importance of interventions across the life course. Funding UK Economic and Social Research Council.

Background Smoking is the primary cause of lung cancer, the leading cause of cancer-related mortality in Norway. To inform disease modeling and tobacco control policies, including lung cancer screening, we estimated sex-specific, birth-cohort smoking behaviors among Norwegians born between 1950 and 2000 using national survey data. Methods We analyzed nationally representative cross-sectional survey data from 1978 to 2024 (n = 78,282) to reconstruct smoking trends and smoking intensity in Norway. We used a previously established Age–Period–Cohort modeling framework to estimate cohort-specific prevalence of daily ever-smoking, probabilities of smoking initiation and cessation, prevalence of daily current-smoking, and average cigarettes smoked per day (CPD). Analyses were conducted separately by sex assigned at birth for cohorts born between 1950 and 2000. Findings Daily ever-smoking prevalence peaked in the 1950 birth cohort, reaching 70% (90% CI 66%–91%) among males and 66% (90% CI 55%–89%) among females, alongside similar peaks in smoking initiation probabilities, 13% (90% CI 12%–24%) for males and 12% (90% CI 10%–23%) for females. Smoking cessation probabilities increased with age within each birth cohort, rising from approximately 0% to 5% over 40 years in earlier cohorts, compared with an increase from about 5% to 15% over 20 years from the 1965 birth cohort onward. Smoking intensity peaked at 15 CPD among males and 12 CPD among females. Although smoking intensity declined in both sexes after the 1975 birth cohort, it remained higher among males, with peak model-estimated CPD decreasing from approximately 13.5 to 10 cigarettes in males and from 11.5 to 7.5 cigarettes in females between the 1980 and 2000 birth cohorts. Interpretation Smoking behavior in Norway has changed across generations, with declining smoking initiation rates, increased smoking cessation, and lower cigarettes per day. Understanding these trends provides essential inputs to inform tobacco control and lung cancer prevention policies in Norway. Funding Norwegian Cancer Society, National Cancer Institute of the National Institutes of Health, U.S. Food and Drug Administration.

Background Lower income is consistently associated with poorer survival after disease diagnosis, even in countries with universal healthcare such as Sweden. While income-related survival differences have been documented for specific conditions, comparative evidence across a range of disease categories with long-term follow-up is lacking. We quantify income-related differences in survival across 100 disease categories focussing on leading non-communicable diseases (NCDs). Methods All individuals aged 16–95 years registered in Sweden between 2001 and 2023 were followed from first diagnosis until death or the end of 2023. By disease category cohort, individuals were matched to five general population controls (no prior diagnosis of that category) on birth year, sex, and income quartile. Flexible parametric models were used to estimate standardised survival curves for diagnosed individuals and their matched controls. Findings For all 100 disease categories, estimated 10-year survival was lower for the lowest income quartile (Q1) than higher quartiles. For 37 conditions, the Q1 vs Q4 10-year survival gap exceeded 10 percentage points; the largest gaps were for other pharynx cancer (10-year survival 34.2% [95% CI 32.5–35.7] in Q1 vs 58.2% [56.3–60.1] in Q4), larynx cancer, mouth cancer, COPD, and endocarditis. Income-related survival disparities accounted for 6.2 million (95% CI 5.9–6.6 million) person-years of survival loss within 10 years of diagnosis across all cohorts compared to a high-income survival counterfactual, with cardiovascular diseases accounting for the largest share for Q1 (1.3 million). Survival loss after diagnosis relative to undiagnosed controls was significantly greater for Q1 compared to Q4 for 73 of 100 conditions. Interpretation Substantial income-related disparities in survival persist in Sweden across all the most prevalent NCDs. Policies addressing income inequality alongside targeted disease-specific interventions are likely required to reduce income disparities in survival. Funding Swedish Research Council for Health, Working Life and Welfare.

Background In patients with acute stroke, early withholding or withdrawal of life-sustaining therapies is associated with an increased risk of death. We used practice variation across nine European countries to assess whether this relation may be causal. Methods We performed a post hoc analysis of the PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial, a randomised clinical trial of metoclopramide, paracetamol, and/or ceftriaxone started within 24 h of symptom onset in older patients with acute ischaemic stroke or intracerebral haemorrhage (ISRCTN82217627). The frequency of early treatment restrictions, defined as those installed within 24 h after randomisation, was calculated per participating country and their relation with the primary outcome ‘death at 90 days' was estimated through: 1) adjustment for confounders with regression analysis with inverse-propensity score reweighting; and 2) comparing patients enrolled in countries with and without early restrictions, adjusted for confounders with regression analysis. Findings Of 1493 patients enrolled in PRECIOUS between 2016 and 2022, 1451/1493 (97%) were included in this analysis, of whom 276/1451 (19%) had an early treatment restriction. The rate of these restrictions ranged from 0% to 48% across the participating countries. Patients with restrictions were more likely to die within 90 days (inverse propensity-weighted odds ratio (OR) 3.39; 95% CI 2.71–4.25). However, there was no difference in the rate of death at 90 days between countries with and those without restrictions (21.3% vs 23.5%, adjusted OR 1.39; 95% CI 0.8–2.39). Interpretation The use of treatment restrictions early after stroke varied widely across Europe. Although restrictions were independently associated with an increased rate of death, the comparison of death rates between countries with and those without such restrictions provides no indication that this relation is causal. Funding European Union's Horizon 2020 research and innovation programme; grant agreement No. 634809.

Background Pediatric obesity is a major global public health challenge, associated with increased risk for numerous sequelae, persistence into adulthood, and growing economic burden. STARKIDS is a stepwise, tailored, e-health-enhanced, family-focused intervention in primary care. It integrates nutritional counseling targeting dietary energy density reduction, physical activity promotion, behavioral strategies, and psychosocial support. Methods We tested whether STARKIDS improves weight development and quality of life (QoL) compared with usual care. A cluster-randomized controlled trial was conducted in pediatric/family practices enrolling children/adolescents with overweight/obesity. Practices were stratified and block-randomized (no blinding) to STARKIDS or one-time counseling (optimized treatment-as-usual, TAU-O). Outcomes were assessed at baseline, 12, and 18 months. Primary outcomes were changes in BMI z-scores and QoL. Trial registration: DRKS00022813. Findings 89 practices were cluster-randomized (44 intervention, 45 TAU-O). Between April 2022 and July 2023, 379 families were assigned to STARKIDS and 232 to TAU-O. 343 and 216 families were included into the intention-to-treat analysis. After 12 months, 114 (33%) participants in the STARKIDS group and 47 (22%) in the TAU-O group achieved a BMI z-score reduction ≥0.2 (risk difference=0.11, 95% CI 0.03, 0.20, p = 0.0256). After 18 months, no group differences in BMI z-score reductions were found ( p = 0.6940). No significant differences in QoL were observed between study arms at either time point among adolescents. Among parents/guardians, a statistically significant between-group difference was observed at 18 months (−2.10, 95% CI −4.13 to −0.06; p = 0.044), though not considered clinically meaningful. No treatment-related serious adverse events were reported. Interpretation STARKIDS improved BMI z-score over 12 months with effects comparable to more intensive programs. The German Federal Joint Committee recommended transferring step 1 into routine care for children/adolescents with obesity. Effects were not sustained at 18 months, indicating a need for adaptations including additional contact hours to reinforce achieved outcomes, followed by a gradual reduction. Funding Innovation Committee of the German Joint Federal Committee (G-BA).

Background Evidence linking transportation noise to depression is limited. We investigated associations between road traffic noise at the most (LdenMax) and least (LdenMin) exposed façades and depression risk in Denmark. Methods We established a nationwide cohort of 2,941,456 adults aged 25–65 years and for sensitivity analyses a nested questionnaire-based cohort, the Danish National Health Survey (DNHS, n=138,987). During follow-up from 2000 to 2017, 413,818 persons developed depression, defined as first hospital contact or ≥2 redeemed antidepressant prescriptions within one year. Road traffic noise (LdenMax and LdenMin) was estimated at all addresses and aggregated as 5-year means. Hazard ratios (HRs) were estimated using Cox models adjusted for individual and area-level socioeconomic factors, air pollution (PM 2.5 , NO 2 ), and green space. DNHS analyses were additionally adjusted for important lifestyle factors. Findings In fully adjusted models, HRs per interquartile range were 1.04 (95% confidence intervals 1.04, 1.05) for LdenMax and 1.07 (1.06, 1.07) for LdenMin. Splines indicated that regardless of LdenMax level, having ≥10 dB difference between LdenMax and LdenMin (reflecting the presence of a quieter side of the dwelling) was associated with lower risk. HRs were similar in DNHS with slight attenuations after lifestyle adjustment. Associations were higher among low socioeconomic groups, defined by low education, low income, and blue-collar work. Interpretation Long-term exposure to road traffic noise was associated with increased depression risk. Having a quiet façade mitigated this association, pointing to the importance of strategies prioritizing silent facades. Funding European Union and the Swiss State Secretariat for Education, Research and Innovation.

Background Spatial variation in heat-related mortality remains poorly understood, particularly at fine geographical scales. We conducted a nationwide small-area study to examine the association between spatial variation in heat-related mortality and environmental, demographic, health, and socio-economic factors. Methods We obtained daily all-cause mortality data for people aged ≥65 years during the summers of 2011–2023 and linked them with municipality-level daily mean temperature estimates from the ERA5-Land reanalysis dataset. We applied a two-stage Bayesian hierarchical model to estimate small-area heat-related mortality and assess the contribution of community characteristics to spatial variability. Findings Heat-related mortality showed marked geographical differences, with the highest rates in southern and southeastern Italy. Across municipalities, the relative risk at the 90th temperature percentile, relative to the minimum mortality temperature, ranged from 1.06 to 1.33. The heat-attributable fraction exceeded 6% in several southern municipalities, while excess mortality surpassed 80 deaths per 10,000 inhabitants in parts of the Po Valley, Tuscany, Apulia, and Sicily. National heat-attributable mortality peaked in 2022, with an estimated 17,828 deaths (95% credible intervals: 17,339, 18,285) among older adults. Municipalities with higher average temperatures, less green space, higher obesity prevalence, and more residents aged ≥ 85 years had higher heat-related mortality. Educational attainment and employment were among the strongest modifiers of spatial variation. Interpretation Our findings highlight substantial small-area differences in heat-related mortality across Italy and identify socio-economic deprivation as a key determinant of vulnerability. Heat is likely to disproportionately affect disadvantaged communities, reinforcing the need for adaptation strategies addressing social inequality. Funding Imperial College Research Fellowship; Italian Ministry of Health; National Institute for Health and Care Research.

Background: European countries implemented a range of policies to enhance uptake of biosimilar medicines, which are interchangeable with the originator but usually offer biological therapies at lower cost. However, challenges to biosimilar uptake persist. The study analysed the effectiveness of policies to improve biosimilar uptake. Methods: Based on 2024 IQVIA MIDAS® data, biosimilar market shares were determined for 27 European countries. Data on supply-side policies (i.e., targeting price and funding) and demand-side policies (i.e., addressing stakeholders) implemented across the countries was obtained from information generated by the Pharmaceutical Pricing and Reimbursement Information (PPRI) network and validated by country experts. Biosimilar market shares were analysed in relation to the policies implemented in each country. Selected case studies illustrated how biosimilar uptake developed before and after the introduction of a policy. A literature review identified evaluations of biosimilar policies implemented individually or as a package. Findings: Biosimilar market shares varied substantially across Europe, ranging from above 50% (e.g., Norway, Italy) to below 10% (Greece, Luxembourg). All countries studied had biosimilar policies in place, but their design varied. Frequent policies were tendering, encouraging prescribers to switch medication from the originator to the biosimilar, and price setting based on the originator's price (biosimilar price link). Gain-sharing models, switching, the biosimilar price link and prescribing quotas were associated with higher biosimilar market shares. Interpretation: The study confirmed the importance of implementing policies and suggested that demand-side measures are particularly effective in increasing biosimilar uptake. Funding: European Commission under the EU4Health Programme.