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The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age–sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6–6·6), from 65·3 years (65·0–65·6) in 1990 to 71·5 years (71·0–71·9) in 2013, HALE at birth rose by 5·4 years (4·9–5·8), from 56·9 years (54·5–59·1) to 62·3 years (59·7–64·8), total DALYs fell by 3·6% (0·3–7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6–29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non–communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions. Bill & Melinda Gates Foundation.

This study describes the spatial and temporal distribution between 2005 and 2020 of human and animal leishmaniasis by Leishmania infantum in European countries reporting autochthonous cases, and highlights potential activities to improve disease control. It was based on a review of the scientific literature and data reported by the World Health Organization (WHO), the World Organization for Animal Health (WOAH) and the Ministries of Health, including hospital discharges in some countries. Autochthonous infections were reported in the scientific literature from 22 countries, including 13 and 21 countries reporting human and animal infections, respectively. In contrast, only 17 countries reported autochthonous human leishmaniasis cases to the WHO and 8 countries animal infections to the WOAH. The number of WOAH reported cases were 4,203, comprising 4,183 canine cases and 20 cases in wildlife. Of 8,367 WHO reported human cases, 69% were visceral leishmaniasis cases-of which 94% were autochthonous-and 31% cutaneous leishmaniasis cases-of which 53% were imported and mostly in France. The resulting cumulative incidence per 100,000 population of visceral leishmaniasis between 2005-2020, was highest in Albania (2.15 cases), followed by Montenegro, Malta, Greece, Spain and North Macedonia (0.53-0.42), Italy (0.16), Portugal (0.09) and lower in other endemic countries (0.07-0.002). However, according to hospital discharges, the estimated human leishmaniasis incidence was 0.70 in Italy and visceral leishmaniasis incidences were 0.67 in Spain and 0.41 in Portugal. Overall, there was no evidence of widespread increased incidence of autochthonous human leishmaniasis by L. infantum in European countries. Visceral leishmaniasis incidence followed a decreasing trend in Albania, Italy and Portugal, and peaked in Greece in 2013, 2014 and 2017, and in Spain in 2006-2007 and 2011-2013. Animal and human cutaneous leishmaniasis remain highly underreported. In humans, hospital discharge databases provide the most accurate information on visceral leishmaniasis and may be a valuable indirect source of information to identify hotspots of animal leishmaniasis. Integrated leishmaniasis surveillance and reporting following the One Health approach, needs to be enhanced in order to improve disease control.

Criticisms have emerged that cancer medicines offer modest benefits at increasingly high prices. Reimbursement decisions made by health technology assessment (HTA) agencies have become a complex endeavour for cancer medicines. Most high-income countries (HICs) use HTA criteria to identify high-value medicines for reimbursement under public drug coverage plans. We compared HTA criteria specific for cancer medicines in economically similar HICs, to understand how these criteria contribute to reimbursement decisions. We did an international, cross-sectional analysis in collaboration with author investigators across eight HICs, from the Group of Seven (known as G7; Canada, England, France, Germany, Italy, and Japan) and Oceania (Australia and New Zealand). Publicly available data from HTA agency reports and official documentation were extracted and analysed between Aug 15, 2021, and July 31, 2022. We collected data pertaining to the decision-making criteria used by the national HTA agency; HTA reimbursement status for 34 medicine–indication pairs corresponding to 15 unique US top-selling cancer medicines; and HTA reimbursement status for 18 cancer medicine–indication pairs (13 unique medicines) with minimal clinical benefit (score of 1 on the European Society of Medical Oncology Magnitude of Clinical Benefit Scale). Descriptive statistics were used to compare HTA decision criteria and drug reimbursement recommendations (or for Germany and Japan, final reimbursement status) across the eight countries. Therapeutic impact related to clinical outcomes of the new medicine was a uniform criterion across the eight countries, whereas quality of evidence (under the remit of therapeutic impact assessment) and equity were infrequently cited criteria. Only the German HTA agency mandated that surrogate endpoints be validated in therapeutic impact assessment. All countries except Germany included formal cost-effectiveness analyses within HTA reports. England and Japan were the only countries that specified a cost-effectiveness threshold. Of the 34 medicine–indication pairs corresponding to US top-selling cancer medicines, Germany reimbursed the maximum (34 [100%]), followed by Italy (32 [94%] recommended for reimbursement), Japan (28 [82%] reimbursed), Australia, Canada, England, and France (27 [79%] recommended for reimbursement), and New Zealand (12 [35%] recommended for reimbursement). Of the 18 cancer medicine–indication pairs with marginal clinical benefit, Germany reimbursed 15 (83%) and Japan reimbursed 12 (67%). France recommended nine (50%) for reimbursement, followed by Italy (seven [39%]), Canada (five [28%]), and Australia and England (three [17%] each). New Zealand did not recommend any medicine–indications with marginal clinical benefit for reimbursement. Considering the overall cumulative proportion across the eight countries, 58 (21%) of 272 indications for the US top-selling medicines and 90 (63%) of 144 marginally beneficial medicine–indications were not recommended for reimbursement or reimbursed. Our findings indicate discordance in public reimbursement decisions across economically similar countries, despite overlapping HTA decision criteria. This suggests a need for improved transparency around the nuances of the criteria to ensure improved access to high-value cancer medicines, and deprioritisation of low-value cancer medicines. Health systems have opportunities to improve their HTA decision-making processes by learning from the systems in other countries. None.

The launch of OpenAI’s GPT-3 model in June 2020 began a new era for conversational chatbots. While there are chatbots that do not use artificial intelligence (AI), conversational chatbots integrate AI language models that allow for back-and-forth conversation between an AI system and a human user. GPT-3, since upgraded to GPT-4, harnesses a natural language processing technique called sentence embedding and allows for conversations with users that are more nuanced and realistic than before. The launch of this model came in the first few months of the COVID-19 pandemic, where increases in health care needs globally combined with social distancing measures made virtual medicine more relevant than ever. GPT-3 and other conversational models have been used for a wide variety of medical purposes, from providing basic COVID-19–related guidelines to personalized medical advice and even prescriptions. The line between medical professionals and conversational chatbots is somewhat blurred, notably in hard-to-reach communities where the chatbot replaced face-to-face health care. Considering these blurred lines and the circumstances accelerating the adoption of conversational chatbots globally, we analyze the use of these tools from an ethical perspective. Notably, we map out the many types of risks in the use of conversational chatbots in medicine to the principles of medical ethics. In doing so, we propose a framework for better understanding the effects of these chatbots on both patients and the medical field more broadly, with the hope of informing safe and appropriate future developments.

Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure. For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether–lumefantrine, artesunate–mefloquine, artesunate–amodiaquine, or dihydroartemisinin–piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2–3 and between day 0 and days 5–7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680. Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2–3 were –0·6 g/dL (95% CI –0·7 to –0·5), –0·7 g/dL (–0·8 to –0·5), –0·6 g/dL (–0·7 to –0·4), and –0·5 g/dL (–0·7 to –0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2–3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias. Treatment of patients with G6PD activity of 30% or higher with 0·25–0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25–1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses. Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

Mechanisms underlying variability in transmission of Mycobacterium tuberculosis strains remain undefined. By characterizing high and low transmission strains of M.tuberculosis in mice, we show here that high transmission M.tuberculosis strain induce rapid IL-1R-dependent alveolar macrophage migration from the alveolar space into the interstitium and that this action is key to subsequent temporal events of early dissemination of bacteria to the lymph nodes, Th1 priming, granulomatous response and bacterial control. In contrast, IL-1R-dependent alveolar macrophage migration and early dissemination of bacteria to lymph nodes is significantly impeded in infection with low transmission M.tuberculosis strain; these events promote the development of Th17 immunity, fostering neutrophilic inflammation and increased bacterial replication. Our results suggest that by inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M.tuberculosis strain is poised for greater transmissibility. These findings implicate bacterial heterogeneity as an important modifier of TB disease manifestations and transmission. Halting tuberculosis transmission is crucial to TB elimination. Here the authors implicate IL-1R dependent T cell priming as the underlying mechanism determining variability in transmission of Mycobacterium tuberculosis strains.

Background: In 2014, the World Health Organization (WHO) launched the “post-2015 End TB strategy”, that aims to end the global tuberculosis (TB) epidemic by 2030. However, the COVID-19 pandemic has severely impacted global public health and the strict measures to control the coronavirus spread can affect the management of other diseases, such as TB. Herein, we aimed to assess the impact of the COVID-19 pandemic on the diagnosis of TB in Brazil, during 2020. Methods: We carried out an ecological and population-based study, using spatial analysis techniques. The variables used were the new cases of TB, pulmonary tuberculosis (PTB), and also baciloscopy-positive (BP) cases in Brazil between 2015 and 2020. The percentage of changes (% change) was calculated to verify if there was an increase or decrease of TB cases in 2020, along with time trend analyses given by Joinpoint regression model. Also, interrupted time series analyses were used to assess the trend of TB diagnosis before and after the onset of the COVID-19 in Brazil. Spatial distribution maps were elaborated, considering the % change of each Brazilian state. Findings: Data analyses showed a reduction in the diagnosis of TB (−8.3%) and PTB (−8.1%) in Brazil after the irruption of the COVID-19 pandemic. Likewise, 22 states depicted a reduction in TB diagnosis. An expressive reduction of BP cases (−17.1%) was also observed. Interestingly, interrupted time series analysis showed decline in TB and PTB diagnoses from March 2020. Spatial analyses revealed that all states had a progressive reduction of TB, PTB and PB cases, from March on, with the highest percentages of reduction in December (−100% to −75%). Interpretation: Taken together, our analyses demonstrated a reduction in TB diagnosis after the irruption of the COVID-19 pandemic in Brazil and its regions, signaling a serious impact on the WHO “End TB Strategy” global plan.

Background While integral to decentralising health reforms, Community Health Workers (CHWs) in South Africa experience many challenges. During COVID-19, CHW roles changed rapidly, shifting from communities to clinics. In the contexts of new roles and re-engineered primary healthcare (PHC), the objectives were to: (a) implement a training intervention to support local decision-making capability of CHWs; and (b) assess learning and impacts from the perspectives of CHWs. Methods CHWs from three rural villages ( n  = 9) were trained in rapid Participatory Action Research (PAR) with peers and community stakeholders ( n  = 33). Training equipped CHWs with tools and techniques to convene community groups, raise and/or respond to local health concerns, understand concerns from different perspectives, and facilitate action in communities and public services. CHWs’ perspectives before and after the intervention were gained through semi-structured interviews. Data were collected and analysed using the decision space framework to understand local actors’ power to affect devolved decision-making. Results CHWs demonstrated significant resilience and commitment in the face of COVID-19. They experienced multiple, intersecting challenges including: limited financial, logistical and health systems support, poor role clarity, precarious employment, low and no pay, unstable organisational capacity, fragile accountability mechanisms and belittling treatment in clinics. Together, these restricted decision space and were seen to reflect a low valuing of the cadre in the system. CHWs saw the training as a welcome opportunity to assert themselves as a recognised cadre. Regular, spaces for dialogue and mutual learning supported CHWs to gain tools and skills to rework their agency in more empowered ways. The training improved management capacity, capabilities for dialogue, which expanded role clarity, and strengthened community mobilisation, facilitation and analysis skills. Development of public speaking skills was especially valued. CHWs reported an overall ‘tripe-benefit’ from the training: community-acceptance; peer support; and dialogue with and recognition by the system. The training intervention was recommended for scale-up by the health authority as an implementation support strategy for PHC. Conclusions Lack of recognition of CHWs is coupled with limited opportunities for communication and trust-building. The training supported CHWs to find and amplify their voices in strategic partnerships, and helped build functionality for local decision-making.

•Rotavirus vaccine introduction in Mozambique reduced significantly acute gastroenteritis hospitalizations and rotavirus-associated hospitalizations.•Our data demonstrated similar reduction in rotavirus detection rates such as that observed in urban settings of Mozambique (Maputo, Beira, Quelimane and Nampula cities), demonstrating the importance of the surveillance systems in rural setting like Manhiça.•In our study we reported a decline of rotavirus-associated AGE in the age groups of children not covered by the vaccination program (older than 2 years of age), which supports the beneficial effect of vaccination. Rotavirus vaccine(Rotarix®) was introduced in Mozambique through its Expanded Program of Immunization in September 2015. We assessed the impact of rotavirus vaccination on childhood gastroenteritis-associated hospitalizations post-vaccine introduction in a high HIV prevalence rural setting of southern Mozambique. We reviewed and compared the trend of hospitalizations (prevalence) and incidence rates of acute gastroenteritis (AGE), and rotavirus associated-diarrhea (laboratory confirmed rotavirus) in pre- (January 2008–August 2015) and post-rotavirus vaccine introduction periods (September 2015–December 2020), among children <5 years of age admitted to Manhiça District Hospital. From January 2008 to December 2020, rotavirus vaccination was found to contribute to the decline of the prevalence of AGE from 19% (95% CI: 18.14–20.44) prior to the vaccine introduction to 10% (95% CI: 8.89–11.48) in the post-introduction period, preventing 40% (95 % IE: 38–42) and 84% (95 % IE: 80–87) of the expected AGE and laboratory confirmed rotavirus cases, respectively, among infants. Similarly, the overall incidence of rotavirus was 11.8-fold lower in the post-vaccine introduction period (0.4/1000 child-years-at-risk [CYAR]; 95% CI: 0.3–0.6) compared with the pre-vaccination period (4.7/1000 CYAR; 95% CI: 4.2–5.1) with the highest reduction being observed among infants (16.8-fold lower from the 15.1/1000 CYAR in the pre-vaccine to 0.9/1000 CYAR in the post-vaccine eras). We documented a significant reduction in all-cause diarrhea hospitalizations and rotavirus positivity after vaccine introduction demonstrating the beneficial impact of rotavirus vaccination in a highly vulnerable population.