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Globally, dietary factors are responsible for about one in five deaths. In many low- and middle-income countries different forms of malnutrition (including obesity and undernutrition) can co-exist within the same population. This double burden of malnutrition is placing a disproportional strain on health systems, slowing progress towards universal health coverage (UHC). Poor nutrition also impedes the growth of local economies, ultimately affecting the global economy. In this article, we argue that comprehensive primary health care should be used as a platform to address the double burden of malnutrition. We use a conceptual framework based on human rights and the Astana Declaration on primary health care to examine existing recommendations and propose guidance on how policy-makers and providers of community-oriented primary health care can strengthen the role of nutrition within the UHC agenda. Specifically, we propose four thematic areas for action: (i) bridging narratives and strengthening links between the primary health care and the nutrition agenda with nutrition as a human rights issue; (ii) encouraging primary health-care providers to support local multisectoral action on nutrition; (iii) empowering communities and patients to address unhealthy diets; and (iv) ensuring the delivery of high-quality promotive, preventive, curative and rehabilitative nutrition interventions. For each theme we summarize the available strategies, policies and interventions that can be used by primary health-care providers and policy-makers to strengthen nutrition in primary health care and thus the UHC agenda.Environ un décès sur cinq dans le monde est dû à des facteurs alimentaires. Dans de nombreux pays à faible et moyen revenu, différentes formes de malnutrition (y compris l'obésité et la dénutrition) peuvent coexister au sein d'une même population. Ce double fardeau de malnutrition exerce une pression démesurée sur les systèmes de santé, ralentissant la progression vers une couverture maladie universelle (CMU). Une mauvaise alimentation entrave également la croissance des économies locales, ce qui en fin de compte affecte l'économie mondiale. Dans cet article, nous estimons qu'il est impératif d'utiliser une approche globale des soins de santé primaires comme plateforme pour s'attaquer au double fardeau de la malnutrition. Nous avons employé un cadre conceptuel fondé sur les droits humains et la Déclaration d'Astana sur les soins de santé primaires. D'une part pour examiner les recommandations existantes, et d'autre part pour fournir un éclairage sur la manière dont les législateurs et les prestataires de soins de santé primaires, implantés au niveau communautaire, peuvent renforcer le rôle de la nutrition dans le programme de CMU. Nous proposons plus exactement quatre champs d'action : (i) aligner les discours et consolider les liens entre les soins de santé primaires et le programme de nutrition, en intégrant ce dernier dans la thématique des droits humains; (ii) encourager les prestataires de soins de santé primaires à soutenir les initiatives locales multisectorielles portant sur la nutrition; (iii) donner aux patients et aux collectivités le pouvoir de lutter contre l'alimentation déséquilibrée; et enfin, (iv) assurer la mise en œuvre d'interventions de qualité pour la promotion, la prévention, le traitement et la réhabilitation en matière de nutrition. Pour chaque champ d'action, nous résumons les stratégies, politiques et interventions à la disposition des législateurs et prestataires de soins de santé primaires pour renforcer le rôle de la nutrition dans les soins de santé primaires et, par conséquent, le programme de CMU.Los factores alimentarios son responsables de aproximadamente una de cada cinco muertes en todo el mundo. Diferentes tipos de malnutrición (incluidas la obesidad y la desnutrición) pueden coexistir en la misma población de muchos países de ingresos bajos y medios. Esta doble carga de la malnutrición está ejerciendo una presión desproporcionada sobre los sistemas sanitarios, lo que ralentiza los progresos hacia la cobertura sanitaria universal (CSU). Además, la mala nutrición dificulta el crecimiento de las economías locales, lo que en última instancia afecta a la economía global. En este artículo, se argumenta que la atención primaria de salud integral se debería utilizar como plataforma para abordar la doble carga de la malnutrición. Se utiliza un marco conceptual basado en los derechos humanos y en la Declaración de Astaná sobre la atención primaria de salud para analizar las recomendaciones existentes y proponer directrices sobre cómo los responsables de formular las políticas y los proveedores de atención primaria de salud orientada a la comunidad pueden fortalecer la función de la nutrición dentro del programa de la CSU. En concreto, se proponen cuatro áreas temáticas de acción: (i) narrativas de vinculación y fortalecimiento de los vínculos entre la atención primaria de salud y el programa de nutrición en donde la nutrición sea una cuestión de derechos humanos; (ii) alentar a los proveedores de atención primaria de salud a que apoyen la medida multisectorial local sobre la nutrición; (iii) potenciar a las comunidades y a los pacientes para tratar las dietas poco saludables; y (iv) garantizar la realización de intervenciones de nutrición de alta calidad de tipo promocional, preventivo, curativo y de rehabilitación. Para cada tema se resumen las estrategias, políticas e intervenciones disponibles que los proveedores de atención primaria de salud y los responsables de formular las políticas pueden utilizar para fortalecer la nutrición en la atención primaria de salud y, por consiguiente, el programa de la CSU.على المستوى العالمي، تعتبر العوامل الغذائية مسؤولة تقريباً عن حالة واحدة من كل خمس وفيات. يمكن أن تتعايش أشكال مختلفة من سوء التغذية في العديد من الدول منخفضة الدخل ومتوسطة الدخل (بما يشمل السمنة وفقر التغذية) ضمن نفس السكان. يضع هذا العبء المزدوج لسوء التغذية ضغطاً غير متناسب على النظم الصحية، مما يبطئ من التقدم نحو التغطية الصحية الشاملة (UHC). كما تعوّق التغذية السيئة نمو النظم الاقتصادية المحلية، مما يؤثر في النهاية على النظام الاقتصاد العالمي. نحن نقرر في هذه المقالة أنه يجب الاستعانة بالرعاية الصحية الأولية الشاملة كمنصة للتعامل مع العبء المزدوج لسوء التغذية. نحن نستخدم إطارًا مفاهيمي يعتمد على حقوق الإنسان وإعلان الأستانة بشأن الرعاية الصحية الأولية لفحص التوصيات القائمة، واقتراح إرشادات حول كيف يمكن لواضعي السياسة ومقدمي الرعاية الصحية المجتمعية الأولية، تعزيز دور التغذية في جدول أعمال التغطية الصحية الشاملة. نحن نقترح على وجه التحديد أربعة مجالات مواضيعية للعمل: (1) ترابط الإجراءات وتعزيز الروابط بين الرعاية الصحية الأولية، وجدول أعمال التغذية مع التغذية، كقضية من قضايا حقوق الإنسان؛ و(2) تشجيع مقدمي الرعاية الصحية الأولية على دعم إجراءات الدعم المحلي متعدد القطاعات بشأن التغذية؛ و(3) تمكين المجتمعات والمرضى للتعامل مع الأنظمة الغذائية غير الصحية؛ و(4) ضمان تقديم تدخلات تغذوية تأهيلية وعلاجية وقائية ومشجعة عالية الجودة. بالنسبة لكل موضوع، نحن نقوم بتلخيص الاستراتيجيات والسياسات والتدخلات المتاحة، والتي يمكن استخدامها بواسطة مقدمي الرعاية الصحية الأولية، وواضعي السياسات لتعزيز التغذية في الرعاية الصحية الأولية، وبالتالي جدول أعمال التغطية الصحية الشاملة.在全球范围内，大约五分之一的死亡与饮食因素相关。在许多中低收入水平的国家内，同一人群中可能同时存在不同形式的营养不良（包括肥胖症和缺乏营养）。营养不良的双重负担给卫生系统造成了太大的压力，减缓了全民健康覆盖 (UHC) 的进程。营养不良也阻碍了当地经济的增长，最终影响了全球经济。在本文中，我们认为应将全面的初级卫生保健用作解决营养不良双重负担的平台。我们采用基于人权的概念框架以及关于初级卫生保健的《阿斯塔纳宣言》来审查现有的建议，并且针对政策制定者和面向社区的初级卫生保健提供者可以如何在全民健康覆盖 (UHC) 议程中强调营养的作用提供指导。具体而言，我们提出了四个主题行动领域：(i) 以营养作为人权问题，衔接叙述并加强初级卫生保健和营养议程之间的联系；(ii) 鼓励初级卫生保健提供者支持当地有关营养的多部门行动；(iii) 使社区和患者有能力解决不健康的饮食问题；以及 (iv) 确保提供高质量的促进性、预防性、治疗性和康复性营养干预措施。我们针对每个主题总结了可供初级卫生保健提供者和决策者在初级卫生保健以及全民健康覆盖 (UHC) 议程中采用的加强营养策略、政策和干预措施。.Каждая пятая смерть в мире связана с факторами питания. Во многих странах с низким и средним уровнем дохода в рамках одной и той же популяции могут встречаться различные формы нарушения питания, включая ожирение и недоедание. Такое двойное бремя неполноценного питания налагает несоразмерную нагрузку на системы здравоохранения, замедляя прогресс в обеспечении всеобщего охвата услугами здравоохранения (ВОУЗ). Неудовлетворительное питание также подрывает рост местной экономики и в конечном счете оказывает влияние на глобальную экономику. В этой статье авторы приводят доводы в пользу того, что комплексную первичную медико-санитарная помощь следует использовать в качестве платформы для решения проблемы двойного бремени неполноценного питания. Авторы используют концептуальную схему, основанную на правах человека и Астанинской декларации по вопросам первичной медико-санитарной помощи, для изучения существующих рекомендаций и составления руководящих указаний, призванных помочь ответственным за принятие решений и поставщикам социально ориентированной первичной медико-санитарной помощи в усилении роли питания для обеспечения ВОУЗ. В частности, предлагаются четыре направления деятельности: (i) избавление от укоренившихся стереотипов и укрепление связей между первичной медико-санитарной помощью и вопросами питания, в которых питание рассматривается как часть прав человека; (ii) поощрение поставщиков первичной медико-санитарной помощи к оказанию поддержки местным многосекторальным мероприятиям в области питания; (iii) расширение прав и возможностей общин и пациентов для решения вопросов, связанных с неполноценным питанием; (iv) проведение высококачественных рекламных, профилактических, лечебных и реабилитационных мероприятий в сфере питания. Для каждой темы авторы приводят сводку доступных стратегий, политик и вмешательств, которые могут использоваться поставщиками первичной медико-санитарной помощи и лицами, ответственными за принятие решений, для улучшения питания в системе первичной медико-санитарной помощи и достижения поставленных целей в области ВОУЗ.

We consider disease mapping of early- and late-stage cancer, in order to identify and monitor inequalities in early detection. Our method is demonstrated by mapping cancer incidence at high geographical resolution using data on 10,302 cutaneous malignant melanoma (CMM) cases within the 3.7 million population of South-West Sweden. The cases were geocoded into small-areas, each with a population size between 600 and 2600 and accessible socio-demographic data. Using the disease mapping application Rapid Inquiry Facility (RIF) 4.0, we produced regional maps to visualise spatial variations in stage I, II and III–IV CMM incidences, complemented by local maps to explore the variations within two urban areas. Pronounced spatial disparities in stage I CMM incidence were revealed by the regional and local maps. Stage I CMM incidence was markedly higher in wealthier small-areas, in particular within each urban area. A twofold higher stage I incidence was observed, on average, in the wealthiest small-areas (upper quintile) than in the poorest small-areas (lower quintile). We identified in the regional map of stage III–IV CMM two clusters of higher or lower than expected late-stage incidences which were quite distinct from those identified for stage I. In conclusion, our analysis of CMM incidences supported the use of this method of cancer stage incidence mapping for revealing geographical and socio-demographic disparities in cancer detection. Electronic supplementary material The online version of this article (10.1007/s10654-020-00637-0) contains supplementary material, which is available to authorized users.

The Global Initiative for Asthma (GINA) recommends 2 alternative treatments for patients receiving treatment at steps 3 to 5: single inhaler combination inhaled corticosteroid-formoterol as both maintenance and reliever (SMART) or inhaled corticosteroid-long-acting β2-agonist as maintenance plus short-acting β2-agonist as reliever.To assess whether switching to SMART is associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever among patients with poorly controlled asthma.For this systematic review and meta-analysis, the literature, internal study databases at AstraZeneca and the Medical Research Institute of New Zealand, and references from a previous systematic review and meta-analysis on SMART were searched to identify randomized clinical trials published from January 1990 to February 2018, that compared budesonide-formoterol by SMART with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever.Trials of at least 24 weeks' duration were included if they reported baseline data on GINA treatment step, asthma control status, and efficacy measures of severe exacerbations. Included patients were adults and adolescents with asthma and baseline Asthma Control Questionnaire 5-item version scores of 1.5 or higher.Patient-level data were identified by independent extraction, and analyses were performed using a fixed-effect model. Data analysis was performed from August 2018 to November 2021.The primary outcome was time to first severe asthma exacerbation associated with each treatment, analyzed by Cox proportional hazards regression.Overall, 4863 patients were included (3034 [62.4%] female; mean [SD] age, 39.8 [16.3] years). Switching patients with uncontrolled asthma at GINA step 3 (n = 1950) to SMART at either step 3 or 4 was associated with a prolonged time to first severe asthma exacerbation, with a 29% reduced risk compared with stepping up to step 4 inhaled corticosteroid-long-acting β2-agonist maintenance plus short-acting β2-agonist reliever (hazard ratio, 0.71; 95% CI, 0.52-0.97). For patients with uncontrolled asthma at step 3 and step 4 (n = 2913), switching to SMART was associated with a prolonged time to first severe asthma exacerbation and a 30% reduced risk compared with remaining at the same treatment step (hazard ratio, 0.70; 95% CI, 0.58-0.85).In this systematic review and meta-analysis, for patients with poorly controlled asthma, SMART was associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever. These findings suggest that if an adult or adolescent receiving treatment at GINA step 3 or 4 has poorly controlled asthma, it is preferable to switch to the SMART regimen rather than to step up or continue the GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever therapy.

Uganda continues extensive mobilization and administration of the Covid 19 vaccine to its people albeit some vaccine hesitancy with in the population. Amongst the health workers however, approximately 70% had received their first dose while 40% had received their second dose of the Covid-19 vaccine by September 2021 respectively. These figures represent a recognizable acceptance rate among health workers. Exploring motivators to vaccine uptake among health workers is vital for the government’s general population vaccine rollout plan.We conducted 12 focus group discussions and 20 in-depth interviews with health workers (vaccinated and unvaccinated) to understand motivators to vaccine acceptance in their own perspective in central and eastern Uganda. Reported motivators to vaccine acceptance included; risk susceptibility/protection, fear of death and/or cost of treatment and experiences of Covid related grief. Other were trust in the vaccine, call to government policy and vaccine success stories elsewhere, real or perceived benefits of vaccination and peer influence.We recommend intensified dissemination of health worker tailor made tools/guides for information, education and communication about the Covid 19 vaccine. The tools need to emphasize the elicited themes/motivators. We also recommend use of peers who have taken up the vaccine and survived Covid-19 or got a mild form of the disease to elicit positive peer influence about the vaccine amongst health workers. The information dissemination and peer narratives could be done through the health worker’s social media platforms, union or association websites, personal statements, editorials or other media.

Covid 19 Vaccine hesitancy among health workers remains a major hindrance to the governments vaccine roll out plan among health workers and other target populations in Uganda.We conducted 12 focus group discussions and 20 in-depth interviews with health workers (vaccinated and unvaccinated) to understand barriers to vaccine acceptance in their own perspective and context in central and eastern Uganda. Reported barriers to vaccine acceptance included: gross lack of trust, fear of side effects, risk denial and insufficient information about the vaccine amidst negative publicity about the vaccine from the internet and social media platforms. Others were health system inhibition factors and religious beliefs against the vaccine.We recommend a health work context specific information, education and dissemination strategy to create awareness, information and more knowledge about the vaccine to health workers.We also recommend a sustained government media campaign to give more information about the vaccine and also dispel the negative publicity and misinformation about the vaccine.Dialogue with health workers at all levels of care, positive peer influence, use of religious and opinion leaders as well as government ensuring accessibly to various Covid 19 vaccines and putting vaccine posts outside hospital settings to limit exposure to Covid patients could also increase uptake of the vaccine among health workers.

Background: Multiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. Methods: We conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. Results: 146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. Conclusion: Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection. Trial Registration: ClinicalTrials.gov number, NCT04416399 Funding: Oxford NIHR Biomedical Research Centre and AstraZeneca Declaration of Interests: Dr. Ramakrishnan reports grants and non-financial support from Oxford Respiratory NIHR BRC, during the conduct of the study; non-financial support from AstraZeneca, personal fees from Australian Government Research Training Program, outside the submitted work; . Dr. Nicolau has nothing to disclose. Mrs Langford has nothing to disclose. Mr. Mahdi has nothing to disclose. Mrs Helen Jeffers reports personal fees from AstraZeneca, outside the submitted work; . Miss Mwasuku has nothing to disclose. Mrs Krassowska has nothing to disclose. Dr Fox has nothing to disclose. Dr Binnian has nothing to disclose. Dr Glover has nothing to disclose. Dr Bright has nothing to disclose. Dr. Butler reports grants from National Institute for Health Research (NIHR), Roche Molecular Diagnostics, Janssen Pharmaceuticals, and various public funding bodies for research related to diagnostics and infections. He has revcied personal fees from Pfizer INC, Roche Diagnostics, and Janssen Pharmaceuticals, outside the submitted work. Dr. Cane has nothing to disclose. Mr. Halner has nothing to disclose. Dr. Matthews has nothing to disclose. Dr. Donnelly reports grants from AstraZeneca, from Boehringer-Ingelheim, outside the submitted work; . Dr. Simpson has nothing to disclose. Dr Baker has nothing to disclose. Dr. Fadai has nothing to disclose. Dr. Peterson reports personal fees from AstraZeneca, outside the submitted work; . Mr. Bengtsson reports personal fees from AstraZeneca, outside the submitted work; Dr. Barnes reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Teva, personal fees from Covis, during the conduct of the study; Dr. Russell reports grants from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi UK, personal fees from Glaxo-SmithKline, during the conduct of the study; . Dr. Bafadhel reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi, GSK, other from Albus Health, ProAxsis, outside the submitted work; . Ethics Approval Statement: The trial was sponsored by the University of Oxford, and was approved by the Fulham London Research Ethics Committee (20/HRA/2531) and the National Health Research Authority.The ethical approval number is 20/HRA/2531.

Background Sociodemographic and spatial disparities in incidence and mortality burden of colorectal cancer (CRC) are important to consider in the implementation of population screening, in order to achieve expected benefit and not increase health inequities. Analytic methods should be adapted to provide rational support for targeted interventions. Methods CRC incidence rates by tumor stage (I-IV) and location (colon vs. rectum) were analyzed for the time period 2008–2016 within a screening-relevant age interval of 55–74 years for the population of South and West Sweden, where screening is planned for. The study population was stratified by sex, country of birth, educational level (for Swedish-born citizens) and residential area. We also estimated disparities in excess mortality from CRC across groups of patients accordant to relevant population groups. Results The analyses were based on 8961 patients with a first CRC diagnosis. There were marked socioeconomic gradients in the stage II-IV CRC incidence rates among Swedish-born men and women. Compared to men with high educational level, the incidence rate ratios (IRRs) of stage II, III, and IV CRC in men with low educational level were 1.38 (95% confidence interval 1.18, 1.62), 1.09 (0.95, 1.26), and 1.18 (1.02, 1.37), respectively. In women, the corresponding figures were 1.26 (1.06, 1.51), 1.19 (1.01, 1.39), and 1.45 (1.20, 1.80). The groups of patients with low educational level showed relatively high excess mortality burdens from CRC. Conclusions Our analytic approach provided rational support for targeted intervention when implementing CRC screening, aiming at optimizing participation in groups with low educational level.

For exercise testing of COPD patients, a standard endurance test (ET) with constant workload is recommended. The test suffers from large inter-individual variability and need for large sample sizes in order to evaluate treatment effects.A new protocol for ET in COPD was designed. In contrast to the standard ET, the new ET involved an increasing workload in order to reduce the standard deviation of endurance time. Two new ETs were compared with the standard ET. In Study A, the new ET started at 75% of the patient's maximum workload (WIn Study A, that included 15 patients, the standard deviation and range for endurance time and work capacity were narrower for the new versus the standard ET. However, the higher mean workload at end and the low mean work capacity relative to the standard ET indicated that the stepwise increase was too aggressive. In Study B, that included 18 patients, with a modified protocol, the averages for endurance time, workload at end and work capacity were similar for new and standard ET, while the standard deviations and ranges for endurance time and work capacity were kept more narrow in the new ET. The variances for endurance time were not equal between the standard ET and the two new ETs (p0.05 for both according to Levene's test).The new ET reduced the number of patients with extreme endurance times (short and long) compared to the standard test. The new test showed a significant lower variance for endurance time, which potentially can lead to fewer patients needed in comparative studies. The overall best results were observed with a low linear increase during endurance.

Rationale aims and objectives: Appropriate treatment of pediatric fever in rural areas remains a challenge and maybe partly due to inadequate supervision of licensed drug sellers. This study assessed the effectiveness of peer-supervision among drug sellers on the appropriate treatment of pneumonia symptoms, uncomplicated malaria, and non-bloody diarrhea among children less than 5 years of age in the intervention (Luuka) and comparison (Buyende) districts, in East-Central Uganda. Methods: Data on pneumonia symptoms, uncomplicated malaria, and non-bloody diarrhea among children less than 5 years of age was abstracted from drug shop sick child registers over a 12-month period; 6 months before and 6 months after the introduction of peer-supervision. Interrupted time series were applied to determine the effectiveness of the peer-supervision intervention on the appropriate treatment of pneumonia, uncomplicated malaria, and non-bloody diarrhea among children less than 5 years of age attending drug shops in East Central Uganda. Results: The proportion of children treated appropriately for pneumonia symptoms was 10.84% (P

BACKGROUND: Embedded implementation research (IR) can play a critical role in health systems strengthening by tackling systems and implementation bottlenecks of a program. To achieve this aim, with the financial support of GAVI, the Vaccine Alliance, in 2016, the Government of Pakistan, UNICEF and the Alliance for Health Policy and Systems Research (AHPSR) launched an Embedded IR for Immunisation Initiative (the Initiative) to explore health systems and implementation bottlenecks, and potential strategies to tackle such bottlenecks in the Expanded Programme on Immunisation (EPI) in Pakistan. In total, 10 research teams were involved in the Initiative, which was the first of its kind in the country. In this paper, we provided a brief overview of the Initiative's approach as well as the key learnings including challenges and successes of the research teams which could inform future embedded IR Initiatives. METHODS: Data were collected from members of the IR teams through an online survey. In addition, in-depth interviews were conducted via phone and in-person from IR team members to explore further the challenges they faced while conducting IR in Pakistan and recommendations for future IR initiatives. The qualitative information obtained from these sources was collated and categorized into themes reflecting some of the challenges, successes, and lessons learned, as well as teams' recommendations for future initiatives. RESULTS: The embedded IR Initiative in Pakistan followed several steps starting with a desk review to compile information on key implementation challenges of EPI and ended with a dissemination workshop where all the research teams shared their IR results with policymakers and implementers. Key factors that facilitated the successful and timely completion of the studies included appreciation by and leadership of implementers in generation and use of local knowledge, identification of research priorities jointly by EPI managers and researchers and provision of continuous and high-quality support from in-country research partners. Participants in the Initiative indicated that challenges included a lack of clarity on the role and responsibilities of each partner involved and need for further support to facilitate use and dissemination of research findings. CONCLUSIONS: The Initiative established that an immunisation programme in a lower middle-income country can use small and time-bound embedded IR, based on partnerships between programme managers and local researchers, to generate information and evidence that can inform decision-making. Future embedded IR initiatives should strive to ensure effective coordination and active participation of all key stakeholders, a clear research utilisation plan from the outset, and efforts to strengthen research teams' capacity to foster utilisation of research findings.

Summary Background Multiple early reports of patients admitted to hospital with COVID-19 showed that patients with chronic respiratory disease were significantly under-represented in these cohorts. We hypothesised that the widespread use of inhaled glucocorticoids among these patients was responsible for this finding, and tested if inhaled glucocorticoids would be an effective treatment for early COVID-19. Methods We performed an open-label, parallel-group, phase 2, randomised controlled trial (Steroids in COVID-19; STOIC) of inhaled budesonide, compared with usual care, in adults within 7 days of the onset of mild COVID-19 symptoms. The trial was done in the community in Oxfordshire, UK. Participants were randomly assigned to inhaled budsonide or usual care stratified for age (≤40 years or >40 years), sex (male or female), and number of comorbidities (≤1 and ≥2). Randomisation was done using random sequence generation in block randomisation in a 1:1 ratio. Budesonide dry powder was delivered using a turbohaler at a dose of 400 μg per actuation. Participants were asked to take two inhalations twice a day until symptom resolution. The primary endpoint was COVID-19-related urgent care visit, including emergency department assessment or hospitalisation, analysed for both the per-protocol and intention-to-treat (ITT) populations. The secondary outcomes were self-reported clinical recovery (symptom resolution), viral symptoms measured using the Common Cold Questionnare (CCQ) and the InFLUenza Patient Reported Outcome Questionnaire (FLUPro), body temperature, blood oxygen saturations, and SARS-CoV-2 viral load. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. This trial is registered with ClinicalTrials.gov, NCT04416399. Findings From July 16 to Dec 9, 2020, 167 participants were recruited and assessed for eligibility. 21 did not meet eligibility criteria and were excluded. 146 participants were randomly assigned—73 to usual care and 73 to budesonide. For the per-protocol population (n=139), the primary outcome occurred in ten (14%) of 70 participants in the usual care group and one (1%) of 69 participants in the budesonide group (difference in proportions 0·131, 95% CI 0·043 to 0·218; p=0·004). For the ITT population, the primary outcome occurred in 11 (15%) participants in the usual care group and two (3%) participants in the budesonide group (difference in proportions 0·123, 95% CI 0·033 to 0·213; p=0·009). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was eight. Clinical recovery was 1 day shorter in the budesonide group compared with the usual care group (median 7 days [95% CI 6 to 9] in the budesonide group vs 8 days [7 to 11] in the usual care group; log-rank test p=0·007). The mean proportion of days with a fever in the first 14 days was lower in the budesonide group (2%, SD 6) than the usual care group (8%, SD 18; Wilcoxon test p=0·051) and the proportion of participants with at least 1 day of fever was lower in the budesonide group when compared with the usual care group. As-needed antipyretic medication was required for fewer proportion of days in the budesonide group compared with the usual care group (27% [IQR 0–50] vs 50% [15–71]; p=0·025) Fewer participants randomly assigned to budesonide had persistent symptoms at days 14 and 28 compared with participants receiving usual care (difference in proportions 0·204, 95% CI 0·075 to 0·334; p=0·003). The mean total score change in the CCQ and FLUPro over 14 days was significantly better in the budesonide group compared with the usual care group (CCQ mean difference −0·12, 95% CI −0·21 to −0·02 [p=0·016]; FLUPro mean difference −0·10, 95% CI −0·21 to −0·00 [p=0·044]). Blood oxygen saturations and SARS-CoV-2 load, measured by cycle threshold, were not different between the groups. Budesonide was safe, with only five (7%) participants reporting self-limiting adverse events. Interpretation Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19. Funding National Institute for Health Research Biomedical Research Centre and AstraZeneca.

BackgroundMultiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness.MethodsWe conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment.Results146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care.ConclusionEarly administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.(Funded by Oxford NIHR Biomedical Research Centre and AstraZeneca;ClinicalTrials.govnumber,NCT04416399)Research in contextEvidence before this studyThe majority of interventions studied for the COVID-19 pandemic are focused on hospitalised patients. Widely available and broadly relevant interventions for mild COVID-19 are urgently needed.Added value of this studyIn this open label randomised controlled trial, inhaled budesonide, when given to adults with early COVID-19 illness, reduces the likelihood of requiring urgent care, emergency department consultation or hospitalisation. There was also a quicker resolution of fever, a known poor prognostic marker in COVID-19 and a faster self-reported and questionnaire reported symptom resolution. There were fewer participants with persistent COVID-19 symptoms at 14 and 28 days after budesonide therapy compared to usual care.Implications of all the available evidenceThe STOIC trial potentially provides the first easily accessible effective intervention in early COVID-19. By assessing health care resource utilisation, the study provides an exciting option to help with the worldwide pressure on health care systems due to the COVID-19 pandemic. Data from this study also suggests a potentially effective treatment to prevent the long term morbidity from persistent COVID-19 symptoms.

A recent review of cancer care clinical registry initiatives in Scandinavian countries, published in this Journal [1], highlighted that further developments and coordination are needed to make full...

Goran Tomson and colleagues argue that our ability to control pandemics requires global action to counter inequalities from demographic, environmental, technological, and other megatrends

A locally developed, low-cost package of interventions implemented in a regional network of hospitals resulted in significant reductions in mortality for mothers and newborns as well as the institutionalization of the quality improvement initiative. This work demonstrates that it is possible to achieve the World Health Organization/United Nations Children's Fund Quality of Care targets in hospitals., Key Findings The interventions implemented led to improvements in maternal and newborn outcomes and the institutionalization and scale-up of the quality improvement process at both hospitals and high-volume health centers.Critical factors for success included codesigning and implementing a package of services that fit the context. This package was locally led, integrated but simple, and built on and sustained by mainly local resources to develop local champions.Challenges included lack of participation from doctors due to high doctor-patient ratio, scarcity of human and other resources, inadequate infrastructure, unstable electricity, and multiplicity of other initiatives. Key Implications Successful quality improvement projects must be integrated but feasible, based on the context and building onto the available resources, and implemented over a fairly long time. Creating a network of regional hospitals via a quality improvement collaborative rapidly leads to improved referral care and increased access to high-quality services for mothers and newborns. Once these efforts are operationalized and functional in hospitals, high-volume primary health centers can be brought aboard, which leads to scale-up.Having a network of hospitals working to improve quality can be a platform for learning, research, and knowledge generation and for building advanced neonatal care units in places where they hitherto never existed. However, such efforts must be complemented by recruiting more specialized health workers, such as neonatal nurses, pediatricians, and neonatologists, into regional and district hospitals so that nurses and midwives are well supported., Introduction: Despite the rapid increase in facility deliveries in Uganda, the number of adverse birth outcomes (e.g., neonatal and maternal deaths) has remained high. We aimed to codesign and co-implement a locally designed package of interventions to improve the quality of care in hospitals in the Busoga region. Design and Implementation: This project was designed and implemented in 3 phases in the 6 main hospitals in east-central Uganda from 2013 to 2016. First, the inception phase engaged health system managers to codesign the intervention. Second, the implementation phase involved training health providers, strengthening the data information system, and providing catalytic equipment and medicines to establish newborn care units (NCUs) within the existing infrastructure. Third, the hospital collaborative phase focused on clinical mentorship, maternal and perinatal death reviews (MPDRs), and collaborative learning sessions. Achievements: In all 6 participating hospitals, we achieved institutionalization of NCUs in maternity units by establishing kangaroo mother care areas, resuscitation corners, and routine MPDRs. These improvements were associated with reduced maternal and neonatal deaths. Facilitators of success included a simple, low-cost, and integrated package designed with local health managers; the emergence of local neonatal care champions; implementation and support over a reasonably long period; decentralization of newborn care services; and use of mainly existing local resources (e.g., physical space, human resources, and commodities). Barriers to success related to limited hospital resources, unstable electricity, and limited participation from doctors. More advanced NCUs have been established in 3 of the 6 hospitals, and 7 high-volume comprehensive health centers have been established with functional NCUs. Conclusion: The involvement of local health workers and leaders was the foundation for designing, sustaining, and scaling up feasible interventions by harnessing available resources. These findings are relevant for the quality of care improvement efforts in Uganda and other resource-restrained settings.

Background: Allergen avoidance is important in allergic asthma management. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA) has been shown to provide a significant reduction in the exposure to allergens in the breathing zone, leading to a long-term reduction in airway inflammation and improvement in Quality of life (QoL). Allergic asthma patients symptomatic on Global Initiative for Asthma (GINA) step 4/5 were found to benefit the most as measured by Asthma Quality of Life Questionnaire (AQLQ). However, the effect of TLA on severe asthma exacerbations is uncertain and therefore a meta-analysis was performed.Methods: Patients with severe allergic asthma (GINA 4/5) were extracted from two 1-year randomised, double-blind, placebo-controlled trials conducted with TLA. A meta-analysis of the effect on severe exacerbations was performed by negative binomial regression in a sequential manner, defined by baseline markers of asthma control (symptoms and QoL scores).Results: The pooled dataset included 364patients. Patients with more symptoms at baseline (ACT3; N=179), had a significant mean 41% reduction in severe exacerbations (RR=0.59 (0.38-0.90); p=0.015) in favour of TLA. Higher ACQ7 cut-points of 3.5-4.5 resulted in significant reductions of 48-59%.More uncontrolled patients based on AQLQ total and symptom domains ≤3.0 at baseline also showed a significant reduction in severe exacerbations for TLA vs. placebo ((47% (p=0.037) and 53% (p=0.011), respectively). The meta-analysis also confirmed a significant difference in AQLQ-responders ((Minimal Clinically Important Difference)≥0.5; 74% vs. 43%, p=0.04).Conclusion: This meta-analysis of individual patient data shows a beneficial effect on severe exacerbations and quality of life for TLA over placebo in more symptomatic patients with severe allergic asthma. These outcomes support the national management recommendations for patients with symptomatic severe allergic asthma. The actual effect of TLA on severe exacerbations should be confirmed in a prospective study with larger numbers of patients.

BackgroundPeer supervision improves health care delivery by health workers. However, in rural Uganda, self-supervision is what is prescribed for licensed private drug sellers by statutory guidelines. Evidence shows that self-supervision encourages inappropriate treatment of children less than 5 years of age by private drug sellers. This study constructed a model for an appropriate peer supervisor to augment the self-supervision currently practiced by drug sellers at district level in rural Uganda.MethodsIn this qualitative study, six Key informant interviews were held with inspectors while ten focus group discussions were conducted with 130 drug sellers. Data analysis was informed by the Kathy Charmaz constructive approach to grounded theory. Atlas ti.7 software package was used for data management.ResultsA model with four dimensions defining an appropriate peer supervisor was developed. The dimensions included; incentives, clearly defined roles, mediation and role model peer supervisor. While all dimensions were regarded as being important, all participants interviewed agreed that incentives for peer supervisors were the most crucial. Overall, an appropriate peer supervisor was described as being exemplary to other drug sellers, operated within a defined framework, well facilitated to do their role and a good go-between drug sellers and government inspectors.ConclusionFour central contributions advance literature by the model developed by our study. First, the model fills a supervision gap for rural private drug sellers. Second, it highlights the need for terms of reference for peer supervisors. Third, it describes who an appropriate peer supervisor should be. Lastly, it elucidates the kind of resources needed for peer supervision.

Vaz and colleagues1 used regression analysis to conclude that mandatory vaccination led to increased vaccination coverage and reduced measles incidence in Europe. They compared 21 countries classified without mandatory vaccination and 7 countries classified with: Bulgaria, Czech Republic, Hungary, Latvia, Poland, Slovenia, and Slovakia. The authors found positive association between vaccination coverage and size of monetary fines imposed for not taking children for vaccination. We have several reservations on the methodology and analysis. While the 7 countries have indeed reported high coverage rates for several decades, we do not believe that mandatory vaccination is the primary reason. Instead, strong immunization programs is the major … E-mail: rnandy{at}unicef.org

The initial impression that pediatric SARS-CoV-2 infection is uncommon and generally mild has been replaced by a more nuanced understanding of infectious manifestations in children and adolescents across low-, middle-, and high-income countries and by demographic structure, with recognition of a widening disease spectrum. Critical knowledge gaps, especially in low- and middle-income countries remain, that have significant public policy and programme implications. Insufficient data dis-aggregated by age, geography and race/ethnicity are hindering efforts to fully assess prevalence of infection and disease in children and adolescents and their role in transmission. Potential biologic differences in susceptibility to infection and transmissibility between children and adults need to be assessed. Determination of mother-to-child SARS-CoV-2 transmission during pregnancy or peripartum requires appropriate samples obtained with proper timing, lacking in most studies. Finally, predictors of disease progression, morbidity and mortality in children need to be determined particularly as the pandemic moves to low- and middle-income countries, where poor nutritional and health conditions and other vulnerabilities are more frequent among children than in higher-income settings. Countries, UN agencies, public health communities, donors and academia need to coordinate the efforts and work collectively to close the data and knowledge gaps in all countries (high, middle and low income) for better evidence to guide policy and programme decision-making for children and COVID-19 (coronavirus) disease.

Background Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients. Methods In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations. Findings At 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size. Interpretation COPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants.

BackgroundPeer supervision improves health care delivery by health workers. However, in rural Uganda, self-supervision is what is prescribed for licensed private drug sellers by statutory guidelines. Evidence shows that self-supervision encourages inappropriate treatment of children less than five years of age by private drug sellers. This study constructed a model for an appropriate peer supervisor to augment the self-supervision currently practiced by drug sellers at district level in rural Uganda.MethodsIn this qualitative study, six Key informant interviews were held with inspectors while ten focus group discussions were conducted with one hundred and thirty drug sellers. Data analysis was informed by the Kathy Charmaz constructive approach to grounded theory. Atlas ti.7 software package was used for data management.Results A model with four dimensions defining an appropriate peer supervisor was developed. The dimensions included; incentives, clearly defined roles, mediation and role model peer supervisor. While all dimensions were regarded as being important, all participants interviewed agreed that incentives for peer supervisors were the most crucial. Overall, an appropriate peer supervisor was described as being exemplary to other drug sellers, operated within a defined framework, well facilitated to do their role and a good go-between drug sellers and government inspectors. Conclusion Four central contributions advance literature by the model developed by our study. First, the model fills a supervision gap for rural private drug sellers. Second, it highlights the need for terms of reference for peer supervisors. Third, it describes who an appropriate peer supervisor should be. Lastly, it elucidates the kind of resources needed for peer supervision.

Background: Appropriate treatment of paediatric fever in rural areas remains a challenge and may be partly due to inadequate supervision of licensed drug sellers. This study assessed the effectiveness of peer-supervision among drug sellers on appropriate treatment of pneumonia symptoms, uncomplicated malaria and non-bloody diarrhoea among children less than five years of age in the intervention (Luuka) and comparison (Buyende) districts, in East-Central Uganda.Methods: Data on pneumonia symptoms, uncomplicated malaria and non-bloody diarrhoea among children less than five years of age was abstracted from drug shop sick child registers over a 12-month period; six months before and six months after introduction of peer-supervision. Interrupted time series was applied to determine the effectiveness of the peer-supervision intervention on appropriate treatment of pneumonia, uncomplicated malaria and non-bloody diarrhoea among children less than five years of age attending drug shops in East Central Uganda.Results: The proportion of children treated appropriately for pneumonia symptoms was 10.84% (P Conclusions: Peer-supervision increased the proportion of children less than five years of age that received appropriate treatment for pneumonia symptoms but not for uncomplicated malaria and non-bloody diarrhoea. Implementation of community level interventions to improve paediatric fever management should consider including peer-supervision among drug sellers.

Background Clinically Important Deterioration (CID) is a novel composite measure to assess treatment effect in chronic obstructive pulmonary disease (COPD). We examined the performance and utility of CID in assessing the effect of inhaled corticosteroids (ICS) in COPD. Methods This post-hoc analysis of four budesonide/formoterol (BUD/FORM) studies comprised 3576 symptomatic moderate-to-very-severe COPD patients with a history of exacerbation. Analysis of time to first CID event (exacerbation, deterioration in forced expiratory volume in 1 second [FEV1] or worsening St George’s Respiratory Questionnaire [SGRQ] score) was completed using Cox proportional hazards models. Results The proportion of patients with ≥1 CID in the four studies ranged between 63 and 77% and 69–84% with BUD/FORM and FORM, respectively, with an average 25% reduced risk of CID with BUD/FORM. All components contributed to the CID event rate. Experiencing a CID during the first 3 months was associated with poorer outcomes (lung function, quality of life, symptoms and reliever use) and increased risk of later CID events. The effect of BUD/FORM versus FORM in reducing CID risk was positively associated with the blood eosinophil count. Conclusions Our findings suggest that BUD/FORM offers protective effects for CID events compared with FORM alone, with the magnitude of the effect dependent on patients’ eosinophil levels. CID may be an important tool for evaluation of treatment effect in a complex, multifaceted, and progressive disease like COPD, and a valuable tool to allow for shorter and smaller future outcome predictive trials in early drug development.

Hospitals in low- and middle-income countries urgently need to improve their oxygen systems for COVID-19 and other health emergencies. We share practical tips to improve pulse oximetry and oxygen use, support biomedical engineers to optimize existing oxygen supplies, and expand existing oxygen systems with robust equipment and smart design., Key Messages The COVID-19 pandemic has highlighted and exacerbated deficiencies in hospital oxygen systems globally but is also an opportunity to “build back better.”Our collated field experience from African and Asia-Pacific contexts reveal practical strategies whereby hospitals can rapidly improve their oxygen systems. We share guidance documents (all open access) for local use and adaptation. Key Implications Using our practical guides, hospital staff can help:Improve pulse oximetry and oxygen useOptimize existing oxygen suppliesExpand existing oxygen systems with robust equipment and smart designPolicy makers and program managers can use our recommendations to ensure that investments in oxygen systems are deployed and implemented more effectively and efficiently., Oxygen therapy is an essential medicine and core component of effective hospital systems. However, many hospitals in low- and middle-income countries lack reliable oxygen access—a deficiency highlighted and exacerbated by the coronavirus disease (COVID-19) pandemic. Oxygen access can be challenged by equipment that is low quality and poorly maintained, lack of clinical and technical training and protocols, and deficiencies in local infrastructure and policy environment. We share learnings from 2 decades of oxygen systems work with hospitals in Africa and the Asia-Pacific regions, highlighting practical actions that hospitals can take to immediately expand oxygen access. These include strategies to: (1) improve pulse oximetry and oxygen use, (2) support biomedical engineers to optimize existing oxygen supplies, and (3) expand on existing oxygen systems with robust equipment and smart design. We make all our resources freely available for use and local adaptation.

Background Retail drug shops play a significant role in managing pediatric fevers in rural areas in Uganda. Targeted interventions to improve drug seller practices require understanding of the retail drug shop market and motivations that influence practices. This study aimed at describing the operational environment in relation to the Uganda National Drug Authority guidelines for setup of drug shops; characteristics, and dispensing practices of private retail drug shops in managing febrile conditions among under-five children in rural western Uganda. Methods Cross sectional survey of 74 registered drug shops, observation checklist, and 428 exit interviews using a semi-structured questionnaire with care-seekers of children under five years of age, who sought care at drug shops during the survey period. The survey was conducted in Mbarara and Bushenyi districts, South Western Uganda, in May 2013. Results Up to 90 and 79% of surveyed drug shops in Mbarara and Bushenyi, largely operate in premises that meet National Drug Authority requirements for operational suitability and ensuring medicines safety and quality. Drug shop attendants had some health or medical related training with 60% in Mbarara and 59% in Bushenyi being nurses or midwives. The rest were clinical officers, pharmacists. The most commonly stocked medicines at drug shops were Paracetamol, Quinine, Cough syrup, ORS/Zinc, Amoxicillin syrup, Septrin® syrup, Artemisinin-based combination therapies, and multivitamins, among others. Decisions on what medicines to stock were influenced by among others: recommended medicines from Ministry of Health, consumer demand, most profitable medicines, and seasonal disease patterns. Dispensing decisions were influenced by: prescriptions presented by client, patients’ finances, and patient preferences, among others. Most drug shops surveyed had clinical guidelines, iCCM guidelines, malaria and diarrhea treatment algorithms and charts as recommended by the Ministry of Health. Some drug shops offered additional services such as immunization and sold non-medical goods, as a mechanism for diversification. Conclusion Most drug shops premises adhered to the recommended guidelines. Market factors, including client demand and preferences, pricing and profitability, and seasonality largely influenced dispensing and stocking practices. Improving retail drug shop practices and quality of services, requires designing and implementing both supply-side and demand side strategies. Electronic supplementary material The online version of this article (10.1186/s12913-018-3343-z) contains supplementary material, which is available to authorized users.

Cadres, content and costs for community-based care for mothers and newborns from seven countries : implications for universal health coverage

Summary Background Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx). CompEx needs to strongly mirror results seen with the severe exacerbation-validated outcome, to allow the design of clinical trials of shorter duration and that include fewer patients than trials assessing severe exacerbations. Methods Data from 12 asthma trials of 6 months or 12 months duration and, with standardised collection of exacerbations and diary card variables, were used to construct and test CompEx. The study populations had a mean age of 35–53 years, 59–69% were female, and had a mean FEV 1 percentage of predicted normal of 63–84%. With data from five trials, we established a series of diary events based on peak expiratory flow (P), reliever use (R), symptoms (S), awakenings (A), and threshold values for change from baseline and slopes to assess trends. For the development phase, we evaluated different variable combinations and deterioration criteria to select the most robust algorithm to define a diary event for the composite outcome. We defined a composite outcome, CompEx, as first occurrence of a diary event or a severe exacerbation. We assessed the performance of CompEx in seven trials by comparing the event frequency, treatment effect (hazard ratio; HR), and the sample size needed for future trials for the CompEx versus episodes of severe exacerbations. Findings CompEx (based on PRS) was the algorithm that best fulfilled our two-set criteria. When censored at 3 months, CompEx resulted in 2·8 times more events than severe exacerbations, and while preserving the treatment effect observed on severe exacerbations (CompEx over severe exacerbation average HR 1·01). The increased number of events, together with the sustained treatment effect, resulted in a large net gain in power, with a 67% mean reduction in the number of patients required in a drug trial for severe exacerbations. In six of seven comparisons tested, CompEx reduced the sample size needed by at least 50%. Validation of independent test populations confirmed the ability of CompEx to increase event frequencies, preserve treatment effect, and reduce the number of patients needed. Interpretation CompEx is a composite outcome for evaluation of new asthma therapies. CompEx allows design of shorter trials that require fewer patients than studies of severe exacerbations, while preserving the ability to show a treatment effect compared with severe exacerbations. Funding AstraZeneca.

Leadership, action, learning and accountability to deliver quality care for women, newborns and children.

To describe the functional limitations and associated impairments of children with cerebral palsy (CP) in rural Uganda, and care-seeking behaviour and access to assistive devices and education.Ninety-seven children with CP (42 females, 55 males; age range 2-17y) were identified in a three-stage population-based screening with subsequent medical examinations and functional assessments. Information on school and access to care was collected using questionnaires. The data were compared with Swedish and Australian cohorts of children with CP. We used the χYounger children were more severely impaired than older children. Two-fifths of the children had severe impairments in communication, about half had intellectual disability, and one third had seizures. Of 37 non-walking children, three had wheelchairs and none had walkers. No children had assistive devices for hearing, seeing, or communication. Care-seeking was low relating to lack of knowledge, insufficient finances, and 'lost hope'. One-third of the children attended school. Ugandan children exhibited lower developmental trajectories of mobility and self-care than a Swedish cohort.The needs for children with CP in rural Uganda are not met, illustrated by low care-seeking, low access to assistive devices, and low school attendance. A lack of rehabilitation and stimulation probably contribute to the poor development of mobility and self-care skills. There is a need to develop and enhance locally available and affordable interventions for children with CP in Uganda.Development of mobility and self-care skills is lower in Ugandan than Swedish children with cerebral palsy (CP). Older children in Uganda with CP are less impaired than younger children. Untreated seizures and impairments of communication and intellect are common. Access to health services, assistive devices, and education is low. Caregivers lack knowledge and finances to seek care and often lose hope of their child improving.DEFICIENCIAS, LIMITACIONES FUNCIONALES Y ACCESO A SERVICIOS DE SALUD Y EDUCACIÓN EN UGANDA PARA NIÑOS CON PARÁLISIS CEREBRAL: UN ESTUDIO BASADO EN LA POBLACIÓN: OBJETIVO: Describir las limitaciones funcionales y las deficiencias asociadas en niños con parálisis cerebral (PC) en las zonas rurales de Uganda, y el comportamiento de búsqueda y acceso a la atención y a dispositivos de tecnología asistiva y educación.Se realizó una pesquisa poblacional en tres etapas con exámenes médicos y evaluaciones funcionales. Se identificaron 97 niños y niñas con PC (42 mujeres, 55 varones; rango de edad de 2 a 17 años). La información sobre el acceso a la escuela y a la atención se obtuvo mediante cuestionarios. Los datos obtenidos se compararon con cohortes suecas y australianas de niños con PC. Utilizamos la prueba de Chi2 y modelos de regresión lineal para analizar las diferencias entre los grupos.Los niños más pequeños tenían deficiencias más graves que los niños mayores. Dos quintos de los niños tenían impedimentos severos en la comunicación, aproximadamente la mitad tenía discapacidad intelectual y un tercio tenía convulsiones. De los 37 niños que no caminaban, tres tenían sillas de ruedas, ninguno tenía andadores y ninguno tenía dispositivos de asistencia para escuchar, ver o comunicarse. El comportamiento de búsqueda de atención fue bajo y se relacionó con la falta de conocimiento, con ingresos económicos insuficientes y con la "pérdida de esperanza". Un tercio de los niños asistían a la escuela. Los niños ugandeses exhibieron trayectorias de movilidad y autocuidado con menor desarrollo que una cohorte sueca.Las necesidades de los niños con PC en las zonas rurales de Uganda no son satisfechas. Esto lo demuestra la baja búsqueda de atención, el acceso limitado a dispositivos de asistencia y el bajo nivel de asistencia a la escuela. La falta de rehabilitación y estimulación probablemente contribuyan al pobre desarrollo de la movilidad y de las habilidades de autocuidado. Existe la necesidad de desarrollar y mejorar las intervenciones locales disponibles y asequibles para niños con PC en Uganda.DEFICIÊNCIAS, LIMITAÇÕES FUNCIONAIS, E ACESSO A SERVIÇOS E EDUCAÇÃO DE CRIANÇAS COM PARALISIA CEREBRAL EM UGANDA: UM ESTUDO POPULACIONAL: OBJETIVO: Descrever as limitações funcionais e deficiências associadas de crianças com paralisia cerebral (PC) em Uganda rural, e o comportamento de busca por cuidados e acesso a dispositivos assitivos e educação. MÉTODO: Noventa e sete crianças com PC (42 do sexo feminino, 55 do sexo masculino; variação de idade 2-17a) foram identificadas em um levantamento populacional em três estágios com exames médicos e avaliações funcionais subsequentes. Informações sobre escolas e acesso a cuidados foram coletadas usando questionários. Os dados foram comparados a coortes suecas e australianas de crianças com PC. Usamos o teste

Background In a decentralised health system, district health managers are tasked with planning for health service delivery, which should be evidence based. However, planning in low-income countries such as Uganda has been described as ad hoc. A systematic approach to the planning process using district-specific evidence was introduced to district health managers in Uganda. However, little is known about how the use of district-specific evidence informs the planning process. In this study, we investigate how the use of this evidence affects decision-making in the planning process and how stakeholders in the planning process perceived the use of evidence. Methods A convergent parallel mixed-methods study design was used, where quantitative data was collected from district health annual work plans for the financial years 2012/2013, 2013/2014, 2014/2015 and 2015/2016 as well as from bottleneck analysis reports for 2012, 2013, 2014 and 2015. Qualitative data was collected through semi-structured interviews with key informants from the two study districts. Results District managers reported that they were able to produce more robust district annual work plans when they used the systematic approach of using district-specific evidence. Approximately half of the prioritised activities in the annual work plans were evidence based. Procurement and logistics, training, and support supervision activities were the most prioritised activities. Between 4% and 5.5% of the total planned expenditure was for child survival, of which 47% to 94% was from donor and other partner contributions. Conclusion District-specific evidence and a structured process for its use to prioritise activities and make decisions in the planning process at the district level helped systematise the planning process. However, the reported limited decision and fiscal space, inadequate funding and high dependency on donor funding did not always allow for the use of district-specific evidence in the planning process.

Executive summaryDespite dramatic improvements in survival, nutrition, and education over recent decades, today’s children face an uncertain future. Climate change, ecological degradation, migrating populations, conflict, pervasive inequalities, and predatory commercial practices threaten the health and future of children in every country. In 2015, the world’s countries agreed on the Sustainable Development Goals (SDGs), yet nearly 5 years later, few countries have recorded much progress towards achieving them. This Commission presents the case for placing children, aged 0–18 years, at the centre of the SDGs: at the heart of the concept of sustainability and our shared human endeavour. Governments must harness coalitions across sectors to overcome ecological and commercial pressures to ensure children receive their rights and entitlements now and a liveable planet in the years to come.

In the summer of 1970, Drs Raj and Mabelle Arole finished their graduate public health studies in the USA and arrived in rural Maharashtra, India, searching for a community where they could make a difference. They had a primary health care (PHC) blueprint for community health improvement in rural India that had everything anyone could ask for. They envisioned a small hospital surrounded by subcentres, teams of nurses and paramedical workers, sanitation work, integration of prevention and cure and community participation. A community meeting with villagers in a potential site seemed like a textbook beginning. They described their first such meeting in Osmanabad district.1 The village leader had ordered 40 village heads to the meeting. None of them spoke; they nodded assent to all of the leader’s suggestions. Dr Arole suggested that they should hear from the villagers. The host found the suggestion perplexing, saying ‘I just have to give the order and the people will follow’. If they had merely been interested in building a medical clinic to provide primary medical care, then an alliance with a powerful local politician would have been supremely attractive. That power would have helped to secure facilities and patronage that propel success in organising medical care. However, the Aroles dreamed of much more than just delivering primary care, and they clung to their vision. They moved to a neighbouring district and persisted in building the community partnerships that became the foundation of their half century of success in Jamkhed.2 The slow path to create those partnerships started with building trust by listening and being willing to adapt their original blueprint. As it turned out, the highest priority of the people of Jamkhed was just to secure better access to medical care, and so the doctors focused on clinical services first, even …

Background Delivery in a facility with a skilled health provider is considered the most important intervention to reduce maternal and early newborn deaths. Providing care close to people’s homes is an important strategy to facilitate equitable access, but many women are known to bypass the closest delivery facility for a higher level one. The aim of this study was to investigate to what extent mothers in rural Uganda bypassed their nearest facility for childbirth care and the determinants for their choice. Methods The study used data collected as part of the Expanded Quality Management Using Information power (EQUIP) study in the Mayuge District of Eastern Uganda between 2011 and 2014. In this study, bypassing was defined as delivering in a health facility that was not the nearest childbirth facility to the mother’s home. Multilevel logistic regression was used to model the relationship between bypassing the nearest health facility for childbirth and the different independent factors. Results Of all women delivering in a health facility, 45% (499/1115) did not deliver in the nearest facility regardless of the level of care. Further, after excluding women who delivered in health centre II (which is not formally equipped to provide childbirth care) and excluding those who were referred or had a caesarean section (because their reasons for bypassing may be different), 29% (204/717) of women bypassed their nearest facility to give birth in another facility, 50% going to the only hospital of the district. The odds of bypassing increased if a mother belonged to highest wealth quintile compared to the lowest quintile (AOR 2.24, 95% CI: 1.12–4.46) and decreased with increase of readiness of score of the nearest facility for childbirth (AOR = 0.84, 95% CI: 0.69–0.99). Conclusions The extent of bypassing the nearest childbirth facility in this rural Ugandan setting was 29%, and was associated primarily with the readiness of the nearest facility to provide care as well as the wealth of the household. These results suggest inequalities in bypassing for better quality care that have important implications for improving Uganda’s maternal and newborn health outcomes.

The burden of type 2 diabetes is increasing rapidly, not least in Sub-Saharan Africa, and disadvantaged populations are disproportionally affected. Self-management is a key strategy for people at risk of or with type 2 diabetes, but implementation is a challenge. The objective of this study is to assess the determinants of self-management from an implementation perspective in three settings: two rural districts in Uganda, an urban township in South Africa, and socio-economically disadvantaged suburbs in Sweden. Data collection followed an exploratory multiple-case study design, integrating data from interviews, focus group discussions, and observations. Data collection and analysis were guided by a contextualized version of a transdisciplinary framework for self-management. Findings indicate that people at risk of or with type 2 diabetes are aware of major self-management strategies, but fail to integrate these into their daily lives. Depending on the setting, opportunities to facilitate implementation of self-management include: improving patient-provider interaction, improving health service delivery, and encouraging community initiatives supporting self-management. Modification of the physical environment (e.g. accessibility to healthy food) and the socio-cultural environment (i.e. norms, values, attitudes, and social support) may have an important influence on people's lifestyle. Regarding the study methodology, we learned that this innovative approach can lead to a comprehensive analysis of self-management determinants across different settings. An important barrier was the difficult contextualization of concepts like perceived autonomy and self-efficacy. Intervention studies are needed to confirm whether the pathways suggested by this study are valid and to test the proposed opportunities for change.

IntroductionUganda’s district-level administrative units buttress the public healthcare system. In many districts, however, local capacity is incommensurate with that required to plan and implement quality health interventions. This study investigates how a district management strategy informed by local data and community dialogue influences health services.MethodsA 3-year randomised controlled trial (RCT) comprised of 16 Ugandan districts tested a management approach, Community and District-management Empowerment for Scale-up (CODES). Eight districts were randomly selected for each of the intervention and comparison areas. The approach relies on a customised set of data-driven diagnostic tools to identify and resolve health system bottlenecks. Using a difference-in-differences approach, the authors performed an intention-to-treat analysis of protective, preventive and curative practices for malaria, pneumonia and diarrhoea among children aged 5 and younger.ResultsIntervention districts reported significant net increases in the treatment of malaria (+23%), pneumonia (+19%) and diarrhoea (+13%) and improved stool disposal (+10%). Coverage rates for immunisation and vitamin A consumption saw similar improvements. By engaging communities and district managers in a common quest to solve local bottlenecks, CODES fostered demand for health services. However, limited fiscal space-constrained district managers’ ability to implement solutions identified through CODES.ConclusionData-driven district management interventions can positively impact child health outcomes, with clinically significant improvements in the treatment of malaria, pneumonia and diarrhoea as well as stool disposal. The findings recommend the model’s suitability for health systems strengthening in Uganda and other decentralised contexts.Trial registration numberISRCTN15705788.

Specialized immune responses have evolved to eliminate pathogens in the gastrointestinal tract. In particular, intestinal epithelial cells (IECs) are uniquely responsive to interferon lambda (IFN-λ) and depend on IFN-λ for antiviral defense to a greater extent than other types of IFN. IFN-λ signaling protects IECs by inducing expression of antiviral IFN-stimulated genes (ISGs), but it is unclear if the intestinal microbiome interacts with the IFN-λ pathway. We find that commensal microbes stimulate a steady-state ISG signal in the gastrointestinal tract that is depleted with broad-spectrum antibiotics, as assessed by whole-tissue RNA sequencing. Steady-state ISG expression is also significantly reduced in mice lacking IFN-λ receptor (IFNLR) specifically in IECs. These data suggest that enteric bacteria stimulate expression of IFN-λ and, subsequently, epithelial ISGs at homeostasis. Strikingly, imaging data reveals that these steady-state ISGs are present in distinct pockets throughout the small intestinal epithelium and are concentrated in IECs at the tips of individual villi. Furthermore, we find that IFNLR protects IECs during initiation of murine rotavirus infection at early time-points post-infection, suggesting that steady-state ISGs are protective against viral infection. Lastly, we find that steady-state ISGs are expressed in a subpopulation of human IECs when we re-analyze publicly available single-cell RNA sequencing datasets. These novel observations indicate that commensal microbes stimulate ISGs in localized regions of the intestinal epithelium at homeostasis and may preemptively activate antiviral defenses in vulnerable IECs to improve host fitness against enteric viruses.

Background: Two new protocols have been developed for bicycle exercise testing in chronic obstructive pulmonary disease (COPD) with an individualized cardiopulmonary exercise test (ICPET) and subsequent customized endurance test (CET), which generate less interindividual spread in endurance time compared with the standard endurance test. Main objectives of this study were to improve the prediction algorithm for WMAX for the ICPET and validate the CET by examining treatment effects on exercise performance of indacaterol/glycopyrronium (IND/GLY) compared with placebo. Methods: COPD patients, with forced expiratory volume in 1 s ( FEV1) 40–80% predicted, were recruited. Pooled baseline data from two previous studies ( n = 38) were used for the development of an improved WMAX prediction algorithm. Additional COPD patients ( n = 14) were recruited and performed the ICPET, using the new prediction formula at visit 1. Prior to the CET at visits 2 and 3, they were randomized to a single dose of IND/GLY (110/50 µg) or placebo. Results: The improved multiple regression algorithm for WMAX includes diffusing capacity for carbon monoxide ( DLCO), FEV1, sex, age and height and correlated to measured WMAX ( R2 = 0.89 and slope = 0.89). Treatment with IND/GLY showed improvement in endurance time versus placebo, mean 113 s [95% confidence interval (CI): 6–220], p = 0.037, with more prominent effect in patients with FEV1 Conclusion: The two new protocols for ICPET (including the new improved algorithm) and CET were retested with consistent results. In addition, the CET showed a significant and clinically relevant prolongation of endurance time for IND/GLY versus placebo in a small number of patients.

Screening strategies need to consider differences in late-stage disease detection linked to socio-demographic and geographic factors. We specifically addressed disparity in melanoma stage at diagnosis linked to residential municipality, gender and marital status within the middle- and old-age population of southern and western Sweden. Population-based registers were used to identify the melanoma cases diagnosed in 2004-2013 (n=7,417). Disease mapping for each population group based on gender and marital status showed marked spatial disparities in melanoma incidences and the overall patterns differed by stage at diagnosis. The incidence of early-stage melanoma was markedly higher in the western region, whereas the incidence of late-stage melanoma was markedly higher in the southern region except for married women. Excess mortality among cases was observed to be higher in the southern than in the western region, with significant regional differences for the married male cases and the unmarried female cases.

Linnea Jarenbäck,1 Göran Eriksson,1 Stefan Peterson,2 Jaro Ankerst,1 Leif Bjermer,1 Ellen Tufvesson1 1Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, 2Regional Cancer Center South, Skåne University Hospital, Lund, Sweden Background: COPD is defined as partly irreversible airflow obstruction. The response pattern of bronchodilators has not been followed in advanced lung function parameters. Purpose: The aim of this study was to investigate bronchodilator response pattern in advanced lung function parameters in a continuous fashion along forced expiratory volume in 1second (FEV1) percent predicted (%p) in COPD patients and controls. Patients and methods: Eighty-one smokers/ex-smokers (41 controls and 40 COPD) performed spirometry, body plethysmography, impulse oscillometry and single-breath helium dilution carbon monoxide diffusion at baseline, after salbutamol inhalation and then after an additional inhalation of ipratropium. Results: Most pulmonary function parameters showed a linear increase in response to decreased FEV1%p. The subjects were divided into groups of FEV1%p 65, and the findings from continuous analysis were verified. The exceptions to this linear response were inspiratory capacity (IC), forced vital capacity (FVC), FEV1/FVC and expiratory resistance (Rex), which showed a segmented response relationship to FEV1%p. IC and FVC, with break points (BP) of 57 and 58 FEV1%p respectively, showed no response above, but an incresed slope below the BP. In addition, in patients with FEV1%p 65, response of FEV1%p did not correlate to response of volume parameters. Conclusion: Response of several advanced lung function parameters differs depending on patients’ baseline FEV1%p, and specifically response of volume parameters is most pronounced in COPD patients with FEV1%p

Background Preventive measures are needed to counteract the increasing burden of cutaneous malignant melanoma (CMM). As a basis for rational melanoma prevention, we investigated geographic differences and impact from socioeconomic factors related to incidence, clinical stage at diagnosis and outcome. Material and methods All patients with primary invasive CMM diagnosed in 2004-2013 in the southern and the western Swedish health care regions with a population of 2.9 million adults were eligible for the study. Population-based data were obtained from the national Cancer Register and the national Melanoma Quality Register. Geographic and socioeconomic differences in incidence per stage at diagnosis were mapped and correlated to excess mortality. Results Disease mapping based on 9743 cases in 99 municipalities and 20 metropolitan districts showed marked, regional disparities in stage-specific incidence of CMM. The incidence of stage I-II tumors was higher in the western health care region, whereas the incidence of stage III-IV CMMs was higher in the southern region. The divergent incidence patterns per stage at diagnosis were consistent across population strata based on educational level. The geographic disparities in CMM stage influenced relative survival with an excess five-year mortality ratio in the southern region versus the western region of 1.49 (95% confidence interval 1.22-1.82). The excess mortality ratio for patients with low versus high educational level was 1.81 (1.37-2.40). Conclusion Residential region and educational level influenced CMM stage and, thereby, excess mortality. These observations suggest that geographic as well as socioeconomic data should be considered in prevention of CMM.

Peter M Calverley,1 Dirkje S Postma,2 Antonio R Anzueto,3,4 Barry J Make,5 Göran Eriksson,6 Stefan Peterson,7 Christine R Jenkins8 1Pulmonary and Rehabilitation Research Group, University Hospital Aintree, Liverpool, UK; 2Department of Pulmonary Medicine and Tuberculosis, Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 3Division of Pulmonary Diseases and Critical Care Medicine, University of Texas Health Sciences Center, School of Medicine, University of Texas, 4South Texas Veterans Health Care System, San Antonio, TX, 5Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, CO, USA; 6Department of Respiratory Medicine and Allergology, University Hospital, 7StatMind AB, Lund, Sweden; 8George Institute for Global Health, Concord Clincal School, The University of Sydney, Sydney, NSW, Australia Background: Early treatment response markers, for example, improvement in forced expiratory volume in 1 second (FEV1) and St George’s Respiratory Questionnaire (SGRQ) total score, may help clinicians to better manage patients with chronic obstructive pulmonary disease (COPD). We investigated the prevalence of clinically important improvements in FEV1 and SGRQ scores after 2-month budesonide/formoterol or formoterol treatment and whether such improvements predict subsequent improvements and exacerbation rates.Methods: This post hoc analysis is based on data from three double-blind, randomized studies in patients with moderate-to-very-severe COPD receiving twice-daily budesonide/formoterol or formoterol alone for 6 or 12 months. Prebronchodilator FEV1 and SGRQ total score were measured before treatment and at 2 and 12 months; COPD exacerbation rates were measured during months 2–12. Responders were defined by ≥100 mL improvement in prebronchodilator FEV1 and ≥4-point decrease in SGRQ total score.Results: Overall, 2,331 and 1,799 patients were included in the 0–2- and 0–12-month responder analyses, respectively, and 2,360 patients in the 2–12-month exacerbation rate analysis. At 2 months, 35.1% of patients were FEV1 responders and 44.3% were SGRQ responders. The probability of response was significantly greater with budesonide/formoterol than with formoterol or placebo for both parameters. Two-month responders had a greater chance of 12-month response than 2-month nonresponders for both FEV1 (odds ratio, 5.57; 95% confidence interval, 4.14–7.50) and SGRQ (odds ratio, 3.87; 95% confidence interval, 2.83–5.31). Two-month response in FEV1 (P

Distinct cellular responses have evolved that are specialized for eliminating pathogens in mucosal surfaces, such as the gastrointestinal tract. In particular, intestinal epithelial cells (IECs) are uniquely responsive to interferon lambda (IFN-λ) and depend on this cytokine for antiviral defense to a greater extent than other types of interferon. IFN-λ signaling protects IECs by inducing expression of antiviral IFN-stimulated genes (ISGs), but it is unclear how this signaling pathway interacts with the intestinal microbiome. We find that depletion of the intestinal microbiome with broad spectrum antibiotics significantly reduces steady-state ISGs in the gastrointestinal tract when assessed by whole-tissue RNA sequencing. Steady-state ISG expression is also significantly reduced in mice with conditional knockout of IFN-λ receptor (IFNLR) in IECs. These data suggest that enteric bacteria stimulate expression of IFN-λ and, subsequently, epithelial ISGs at homeostasis. Strikingly, imaging data reveals distinct pockets of IFNLR-dependent ISGs throughout the small intestinal epithelium. These highly localized ISGs are also dependent on the presence of bacteria and IFNLR expression by IECs. Notably, in addition to localized ISG expression along the length of the gastrointestinal tract, ISG expression is concentrated in the most mature IECs at the tips of individual villi. These novel observations indicate that ISGs are robustly expressed in localized regions of the intestinal epithelium at homeostasis. This robust ISG expression depends on the bacterial microbiome and may preemptively activate antiviral defenses in vulnerable IECs to improve host fitness against enteric viruses.

Background: Allergen avoidance is important in allergic asthma management. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA; Airsonett®) has been shown to provide significant reduction of exposure to allergens in the breathing zone, leading to long-term reduction in airway inflammation and improvement in quality of life. Allergic asthma patients uncontrolled on GINA step 4 were found to benefit the most. A frequently asked question from clinicians and funders is related to time to onset (TTO) of improvements for patients using TLA. Methods: Asthma Quality of Life Questionnaire (AQLQ) scores were collected in a previous study. TTO of improvements in Quality of Life was analysed for difference (TLA-placebo) in Area-under-Curve using backwards deletion from 12, 9, 6, 3 down to 1 month for the AQLQ total score, the four individual domains and specifically the sleep question. Results: Patients with uncontrolled asthma on GINA step 4 (n = 87)) reported a statistically significant and clinically relevant (≥0.5 point) improvement in total AQLQ score (0.57; p = 0.009) after 3 months treatment for TLA over placebo. The shortest TTO was within 1 month for the environmental domain (0.68; p = 0.016) and the sleep question (0.771; p = 0.037). TTO for the emotional and symptom domains was 3 months (0.66; p = 0.020 and 0.64; p = 0.014 respectively) and for the activity domain 6 months (0.47; p = 0.036). Conclusion: Nocturnal avoidance of allergens using TLA provided a statistically significant and clinically relevant improvement in total AQLQ score within 3 months in patients in the GINA 4 + ACT