The George Institute for Global Health

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.

Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).

BACKGROUND: In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. METHODS: We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. RESULTS: After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). CONCLUSIONS: A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 10 10 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs 71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p interaction =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

BACKGROUND: In the face of rapidly changing data, a range of case fatality ratio estimates for coronavirus disease 2019 (COVID-19) have been produced that differ substantially in magnitude. We aimed to provide robust estimates, accounting for censoring and ascertainment biases. METHODS: We collected individual-case data for patients who died from COVID-19 in Hubei, mainland China (reported by national and provincial health commissions to Feb 8, 2020), and for cases outside of mainland China (from government or ministry of health websites and media reports for 37 countries, as well as Hong Kong and Macau, until Feb 25, 2020). These individual-case data were used to estimate the time between onset of symptoms and outcome (death or discharge from hospital). We next obtained age-stratified estimates of the case fatality ratio by relating the aggregate distribution of cases to the observed cumulative deaths in China, assuming a constant attack rate by age and adjusting for demography and age-based and location-based under-ascertainment. We also estimated the case fatality ratio from individual line-list data on 1334 cases identified outside of mainland China. Using data on the prevalence of PCR-confirmed cases in international residents repatriated from China, we obtained age-stratified estimates of the infection fatality ratio. Furthermore, data on age-stratified severity in a subset of 3665 cases from China were used to estimate the proportion of infected individuals who are likely to require hospitalisation. FINDINGS: Using data on 24 deaths that occurred in mainland China and 165 recoveries outside of China, we estimated the mean duration from onset of symptoms to death to be 17·8 days (95% credible interval [CrI] 16·9-19·2) and to hospital discharge to be 24·7 days (22·9-28·1). In all laboratory confirmed and clinically diagnosed cases from mainland China (n=70 117), we estimated a crude case fatality ratio (adjusted for censoring) of 3·67% (95% CrI 3·56-3·80). However, after further adjusting for demography and under-ascertainment, we obtained a best estimate of the case fatality ratio in China of 1·38% (1·23-1·53), with substantially higher ratios in older age groups (0·32% [0·27-0·38] in those aged <60 years vs 6·4% [5·7-7·2] in those aged ≥60 years), up to 13·4% (11·2-15·9) in those aged 80 years or older. Estimates of case fatality ratio from international cases stratified by age were consistent with those from China (parametric estimate 1·4% [0·4-3·5] in those aged <60 years [n=360] and 4·5% [1·8-11·1] in those aged ≥60 years [n=151]). Our estimated overall infection fatality ratio for China was 0·66% (0·39-1·33), with an increasing profile with age. Similarly, estimates of the proportion of infected individuals likely to be hospitalised increased with age up to a maximum of 18·4% (11·0-37·6) in those aged 80 years or older. INTERPRETATION: These early estimates give an indication of the fatality ratio across the spectrum of COVID-19 disease and show a strong age gradient in risk of death. FUNDING: UK Medical Research Council.

Importance: Elevated systolic blood (SBP) pressure is a leading global health risk. Quantifying the levels of SBP is important to guide prevention policies and interventions. Objective: To estimate the association between SBP of at least 110 to 115 mm Hg and SBP of 140 mm Hg or higher and the burden of different causes of death and disability by age and sex for 195 countries and territories, 1990-2015. Design: A comparative risk assessment of health loss related to SBP. Estimated distribution of SBP was based on 844 studies from 154 countries (published 1980-2015) of 8.69 million participants. Spatiotemporal Gaussian process regression was used to generate estimates of mean SBP and adjusted variance for each age, sex, country, and year. Diseases with sufficient evidence for a causal relationship with high SBP (eg, ischemic heart disease, ischemic stroke, and hemorrhagic stroke) were included in the primary analysis. Main Outcomes and Measures: Mean SBP level, cause-specific deaths, and health burden related to SBP (≥110-115 mm Hg and also ≥140 mm Hg) by age, sex, country, and year. Results: Between 1990-2015, the rate of SBP of at least 110 to 115 mm Hg increased from 73 119 (95% uncertainty interval [UI], 67 949-78 241) to 81 373 (95% UI, 76 814-85 770) per 100 000, and SBP of 140 mm Hg or higher increased from 17 307 (95% UI, 17 117-17 492) to 20 526 (95% UI, 20 283-20 746) per 100 000. The estimated annual death rate per 100 000 associated with SBP of at least 110 to 115 mm Hg increased from 135.6 (95% UI, 122.4-148.1) to 145.2 (95% UI 130.3-159.9) and the rate for SBP of 140 mm Hg or higher increased from 97.9 (95% UI, 87.5-108.1) to 106.3 (95% UI, 94.6-118.1). For loss of DALYs associated with systolic blood pressure of 140 mm Hg or higher, the loss increased from 95.9 million (95% uncertainty interval [UI], 87.0-104.9 million) to 143.0 million (95% UI, 130.2-157.0 million) [corrected], and for SBP of 140 mm Hg or higher, the loss increased from 5.2 million (95% UI, 4.6-5.7 million) to 7.8 million (95% UI, 7.0-8.7 million). The largest numbers of SBP-related deaths were caused by ischemic heart disease (4.9 million [95% UI, 4.0-5.7 million]; 54.5%), hemorrhagic stroke (2.0 million [95% UI, 1.6-2.3 million]; 58.3%), and ischemic stroke (1.5 million [95% UI, 1.2-1.8 million]; 50.0%). In 2015, China, India, Russia, Indonesia, and the United States accounted for more than half of the global DALYs related to SBP of at least 110 to 115 mm Hg. Conclusions and Relevance: In international surveys, although there is uncertainty in some estimates, the rate of elevated SBP (≥110-115 and ≥140 mm Hg) increased substantially between 1990 and 2015, and DALYs and deaths associated with elevated SBP also increased. Projections based on this sample suggest that in 2015, an estimated 3.5 billion adults had SBP of at least 110 to 115 mm Hg and 874 million adults had SBP of 140 mm Hg or higher.

Jena Univ Hosp, Jena, Germany

BACKGROUND: Large-scale and contemporary population-based studies of heart failure incidence are needed to inform resource planning and research prioritisation but current evidence is scarce. We aimed to assess temporal trends in incidence and prevalence of heart failure in a large general population cohort from the UK, between 2002 and 2014. METHODS: For this population-based study, we used linked primary and secondary electronic health records of 4 million individuals from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex. Eligible patients were aged 16 years and older, had contributed data between Jan 1, 2002, and Dec 31, 2014, had an acceptable record according to CPRD quality control, were approved for CPRD and Hospital Episodes Statistics linkage, and were registered with their general practice for at least 12 months. For patients with incident heart failure, we extracted the most recent measurement of baseline characteristics (within 2 years of diagnosis) from electronic health records, as well as information about comorbidities, socioeconomic status, ethnicity, and region. We calculated standardised rates by applying direct age and sex standardisation to the 2013 European Standard Population, and we inferred crude rates by applying year-specific, age-specific, and sex-specific incidence to UK census mid-year population estimates. We assumed no heart failure for patients aged 15 years or younger and report total incidence and prevalence for all ages (>0 years). FINDINGS: From 2002 to 2014, heart failure incidence (standardised by age and sex) decreased, similarly for men and women, by 7% (from 358 to 332 per 100 000 person-years; adjusted incidence ratio 0·93, 95% CI 0·91-0·94). However, the estimated absolute number of individuals with newly diagnosed heart failure in the UK increased by 12% (from 170 727 in 2002 to 190 798 in 2014), largely due to an increase in population size and age. The estimated absolute number of prevalent heart failure cases in the UK increased even more, by 23% (from 750 127 to 920 616). Over the study period, patient age and multi-morbidity at first presentation of heart failure increased (mean age 76·5 years [SD 12·0] to 77·0 years [12·9], adjusted difference 0·79 years, 95% CI 0·37-1·20; mean number of comorbidities 3·4 [SD 1·9] vs 5·4 [2·5]; adjusted difference 2·0, 95% CI 1·9-2·1). Socioeconomically deprived individuals were more likely to develop heart failure than were affluent individuals (incidence rate ratio 1·61, 95% CI 1·58-1·64), and did so earlier in life than those from the most affluent group (adjusted difference -3·51 years, 95% CI -3·77 to -3·25). From 2002 to 2014, the socioeconomic gradient in age at first presentation with heart failure widened. Socioeconomically deprived individuals also had more comorbidities, despite their younger age. INTERPRETATION: Despite a moderate decline in standardised incidence of heart failure, the burden of heart failure in the UK is increasing, and is now similar to the four most common causes of cancer combined. The observed socioeconomic disparities in disease incidence and age at onset within the same nation point to a potentially preventable nature of heart failure that still needs to be tackled. FUNDING: British Heart Foundation and National Institute for Health Research.

The aim of this study was to present and compare the content of (inter)national clinical guidelines for the management of low back pain. To rationalise the management of low back pain, evidence-based clinical guidelines have been issued in many countries. Given that the available scientific evidence is the same, irrespective of the country, one would expect these guidelines to include more or less similar recommendations regarding diagnosis and treatment. We updated a previous review that included clinical guidelines published up to and including the year 2000. Guidelines were included that met the following criteria: the target group consisted mainly of primary health care professionals, and the guideline was published in English, German, Finnish, Spanish, Norwegian, or Dutch. Only one guideline per country was included: the one most recently published. This updated review includes national clinical guidelines from 13 countries and 2 international clinical guidelines from Europe published from 2000 until 2008. The content of the guidelines appeared to be quite similar regarding the diagnostic classification (diagnostic triage) and the use of diagnostic and therapeutic interventions. Consistent features for acute low back pain were the early and gradual activation of patients, the discouragement of prescribed bed rest and the recognition of psychosocial factors as risk factors for chronicity. For chronic low back pain, consistent features included supervised exercises, cognitive behavioural therapy and multidisciplinary treatment. However, there are some discrepancies for recommendations regarding spinal manipulation and drug treatment for acute and chronic low back pain. The comparison of international clinical guidelines for the management of low back pain showed that diagnostic and therapeutic recommendations are generally similar. There are also some differences which may be due to a lack of strong evidence regarding these topics or due to differences in local health care systems. The implementation of these clinical guidelines remains a challenge for clinical practice and research.

OBJECTIVES: To determine the effects of exercise on falls prevention in older people and establish whether particular trial characteristics or components of exercise programs are associated with larger reductions in falls. DESIGN: Systematic review with meta-analysis. Randomized controlled trials that compared fall rates in older people who undertook exercise programs with fall rates in those who did not exercise were included. SETTING: Older people. PARTICIPANTS: General community and residential care. MEASUREMENTS: Fall rates. RESULTS: The pooled estimate of the effect of exercise was that it reduced the rate of falling by 17% (44 trials with 9,603 participants, rate ratio (RR)=0.83, 95% confidence interval (CI)=0.75-0.91, P<.001, I(2)=62%). The greatest relative effects of exercise on fall rates (RR=0.58, 95% CI=0.48-0.69, 68% of between-study variability explained) were seen in programs that included a combination of a higher total dose of exercise (>50 hours over the trial period) and challenging balance exercises (exercises conducted while standing in which people aimed to stand with their feet closer together or on one leg, minimize use of their hands to assist, and practice controlled movements of the center of mass) and did not include a walking program. CONCLUSION: Exercise can prevent falls in older people. Greater relative effects are seen in programs that include exercises that challenge balance, use a higher dose of exercise, and do not include a walking program. Service providers can use these findings to design and implement exercise programs for falls prevention.

BACKGROUND: Peripheral artery disease is a major cardiovascular disease that affected 202 million people worldwide in 2010. In the past decade, new epidemiological data on peripheral artery disease have emerged, enabling us to provide updated estimates of the prevalence and risk factors for peripheral artery disease globally and regionally and, for the first time, nationally. METHODS: For this systematic review and analysis, we did a comprehensive literature search for studies reporting on the prevalence of peripheral artery disease in the general population that were published between Jan 1, 2011, and April 30, 2019, in PubMed, MEDLINE, Embase, the Global Health database, CINAHL, the Global Health Library, the Allied and Complementary Medicine Database, and ProQuest Dissertations and Theses Global. We also included the Global Peripheral Artery Disease Study of 2013 and the China Peripheral Artery Disease Study as sources. Peripheral artery disease had to be defined as an ankle-brachial index lower than or equal to 0·90. With a purpose-built data collection form, data on study characteristics, sample characteristics, prevalence, and risk factors were abstracted from all the included studies identified from the sources. Age-specific and sex-specific prevalence of peripheral artery disease was estimated in both high-income countries (HICs) and low-income and middle-income countries (LMICs). We also did random-effects meta-analyses to pool the odds ratios of 30 risk factors for peripheral artery disease in HICs and LMICs. UN population data were used to generate the number of people affected by the disease in 2015. Finally, we derived the regional and national numbers of people with peripheral artery disease on the basis of a risk factor-based model. FINDINGS: We included 118 articles for systematic review and analysis. The prevalence of peripheral artery disease increased consistently with age. At younger ages, prevalence was slightly higher in LMICs than HICs (4·32%, 95% CI 3·01-6·29, vs 3·54%, 1·17-10·24, at 40-44 years), but the increase with age was greater in HICs than LMICs, leading to a higher prevalence in HICs than LMICs at older ages (21·24%, 15·22-28·90, vs 12·04%, 8·67-16·60, at 80-84 years). In HICs, prevalence was slightly higher in women than in men up to age 75 years (eg, 7·81%, 3·97-14·77, vs 6·60%, 3·74-11·38, at 55-59 years), whereas in LMICs little difference was found between women and men (eg, 6·40%, 5·06-8·05, vs 6·37%, 4·74-8·49, at 55-59 years). Overall, the global prevalence of peripheral artery disease in people aged 25 years and older was 5·56%, 3·79-8·55, and the prevalence estimate was higher in HICs than that in LMICs (7·37%, 4·35-13·66, vs 5·09%, 3·64-7·24). Smoking, diabetes, hypertension, and hypercholesterolaemia were major risk factors for peripheral artery disease. Globally, a total of 236·62 million people aged 25 years and older were living with peripheral artery disease in 2015, among whom 72·91% were in LMICs. The Western Pacific Region had the most peripheral artery disease cases (74·08 million), whereas the Eastern Mediterranean Region had the least (14·67 million). More than two thirds of the global peripheral artery disease cases were concentrated in 15 individual countries in 2015. INTERPRETATION: Peripheral artery disease continues to become an increasingly serious public health problem, especially in LMICs. With the demographic trend towards ageing and projected rise in important risk factors, a larger burden of peripheral artery disease is to be expected in the foreseeable future. FUNDING: None.

Background Chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity, disability, and mortality worldwide. We aimed to estimate global, regional, and national COPD prevalence and risk factors to guide policy and population interventions. Methods For this systematic review and modelling study, we searched MEDLINE, Embase, Global Health, and CINAHL, for population-based studies on COPD prevalence published between Jan 1, 1990, and Dec 31, 2019. We included data reported using the two main case definitions: the Global Initiative for Chronic Obstructive Lung Disease fixed ratio (GOLD; FEV 1 /FVC<0·7) and the lower limit of normal (LLN; FEV 1 /FVC Findings We identified 162 articles reporting population-based studies conducted across 260 sites in 65 countries. In 2019, the global prevalence of COPD among people aged 30–79 years was 10·3% (95% CI 8·2–12·8) using the GOLD case definition, which translates to 391·9 million people (95% CI 312·6–487·9), and 7·6% (5·8–10·1) using the LLN definition, which translates to 292·0 million people (219·8–385·6). Using the GOLD definition, we estimated that 391·9 million (95% CI 312·6–487·9) people aged 30–79 years had COPD worldwide in 2019, with most (315·5 million [246·7–399·6]; 80·5%) living in LMICs. The overall prevalence of GOLD-COPD among people aged 30–79 years was the highest in the Western Pacific region (11·7% [95% CI 9·3–14·6]) and lowest in the region of the Americas (6·8% [95% CI 5·6–8·2]). Globally, male sex (OR 2·1 [95% CI 1·8–2·3]), smoking (current smoker 3·2 [2·5–4·0]; ever smoker 2·3 [2·0–2·5]), body-mass index of less than 18·5 kg/m 2 (2·2 [1·7–2·7]), biomass exposure (1·4 [1·2–1·7]), and occupational exposure to dust or smoke (1·4 [1·3–1·6]) were all substantial risk factors for COPD. Interpretation With more than three-quarters of global COPD cases in LMICs, tackling this chronic condition is a major and increasing challenge for health systems in these settings. In the absence of targeted population-wide efforts and health system reforms in these settings, many of which are under-resourced, achieving a substantial reduction in the burden of COPD globally might remain a difficult task. Funding National Institute for Health Research and Health Data Research UK.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

The October 2020 Global TB report reviews TB control strategies and United Nations (UN) targets set in the political declaration at the September 2018 UN General Assembly high-level meeting on TB held in New York. Progress in TB care and prevention has been very slow. In 2019, TB remained the most common cause of death from a single infectious pathogen. Globally, an estimated 10.0 million people developed TB disease in 2019, and there were an estimated 1.2 million TB deaths among HIV-negative people and an additional 208, 000 deaths among people living with HIV. Adults accounted for 88% and children for 12% of people with TB. The WHO regions of South-East Asia (44%), Africa (25%), and the Western Pacific (18%) had the most people with TB. Eight countries accounted for two thirds of the global total: India (26%), Indonesia (8.5%), China (8.4%), the Philippines (6.0%), Pakistan (5.7%), Nigeria (4.4%), Bangladesh (3.6%) and South Africa (3.6%). Only 30% of the 3.5 million five-year target for children treated for TB was met. Major advances have been development of new all oral regimens for MDRTB and new regimens for preventive therapy. In 2020, the COVID-19 pandemic dislodged TB from the top infectious disease cause of mortality globally. Notably, global TB control efforts were not on track even before the advent of the COVID-19 pandemic. Many challenges remain to improve sub-optimal TB treatment and prevention services. Tuberculosis screening and diagnostic test services need to be ramped up. The major drivers of TB remain undernutrition, poverty, diabetes, tobacco smoking, and household air pollution and these need be addressed to achieve the WHO 2035 TB care and prevention targets. National programs need to include interventions for post-tuberculosis holistic wellbeing. From first detection of COVID-19 global coordination and political will with huge financial investments have led to the development of effective vaccines against SARS-CoV2 infection. The world now needs to similarly focus on development of new vaccines for TB utilizing new technological methods.

November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

These guidelines have been written to provide a straightforward approach to managing hypertension in the community. We have intended that this brief curriculum and set of recommendations be useful not only for primary care physicians and medical students, but for all professionals who work as hands-on practitioners. We are aware that there is great variability in access to medical care among communities. Even in so-called wealthy countries there are sizable communities in which economic, logistic, and geographic issues put constraints on medical care. And, at the same time, we are been reminded that even in countries with highly limited resources, medical leaders have assigned the highest priority to supporting their colleagues in confronting the growing toll of devastating strokes, cardiovascular events, and kidney failure caused by hypertension. Our goal has been to give sufficient information to enable health care practitioners, wherever they are located, to provide professional care for people with hypertension. All the same, we recognize that it will often not be possible to carry out all of our suggestions for clinical evaluation, tests, and therapies. Indeed, there are situations where the most simple and empirical care for hypertension—simply distributing whatever antihypertensive drugs might be available to people with high blood pressure—is better than doing nothing at all. We hope that we have allowed sufficient flexibility in this statement to enable responsible clinicians to devise workable plans for providing the best possible care for patients with hypertension in their communities. Note: This preferably should be a fasting sample so that a fasting blood glucose level and more accurate lipid profiles can be obtained. Several lifestyle interventions have been shown to reduce blood pressure. Apart from contributing to the treatment of hypertension, these strategies are beneficial in managing most of the other cardiovascular risk factors. In patients with hypertension that is no more severe than stage 1 and is not associated with evidence of abnormal cardiovascular findings or other cardiovascular risks, 6 to 12 months of lifestyle changes can be attempted in the hope that they may be sufficiently effective to make it unnecessary to use medicines. However, it may be prudent to start treatment with drugs sooner if it is clear that the blood pressure is not responding to the lifestyle methods or if other risk factors appear. Also, in practice settings where patients have logistical difficulties in making regular clinic visits, it might be most practical to start drug therapy early. In general, lifestyle changes should be regarded as a complement to drug therapy rather than an alternative. Starting treatment: (see the algorithm in the Figure). Treatment with drugs should be started in patients with blood pressures >140/90 mm Hg in whom lifestyle treatments have not been effective. (Note: As discussed earlier in Section 12 on Nonpharmacologic Treatment, drug treatment can be delayed for some months in patients with stage 1 hypertension who do not have evidence of abnormal cardiovascular findings or other risk factors. In settings where healthcare resources are highly limited, clinicians can consider extending the nondrug observation period in uncomplicated stage 1 hypertensive patients provided there is no evidence for an increase in blood pressure or the appearance of cardiovascular or renal findings). In patients with stage 2 hypertension (blood pressure ≥160/100 mm Hg), drug treatment should be started immediately after diagnosis, usually with a 2-drug combination, without waiting to see the effects of lifestyle changes. Drug treatment can also be started immediately in all hypertensive patients in whom, for logistical or other practical reasons, the practitioner believes it is necessary to achieve more rapid control of blood pressure. The presence of other cardiovascular risk factors should also accelerate the start of hypertension treatment. Note: There is an assumption, unless otherwise stated, that all drugs in a class are similar to each other. We only mention individual agents if they have an important property that is not shared by the others in its class. Table 2 provides a list of commonly used antihypertensive drugs and their doses. Note: Thiazides plus β-blockers are also an effective combination for reducing blood pressure, but since both classes can increase blood glucose concentrations this combination should be used with caution in patients at risk for developing diabetes. The authors of this statement acknowledge that there are insufficient published data from clinical trials in hypertension to create recommendations that are completely evidence-based, and so inevitably some of our recommendations reflect expert opinion and experience. We also should point out that because of the major differences in resources among points of care it is not possible to create a uniform set of guidelines. For this reason we have written a broad statement on the management of hypertension and have not presumed to anticipate the conditions or shortfalls that might exist in particular communities. We expect that experts who are familiar with local circumstances will feel free to use their own judgment in modifying our recommendations and to create practical instructions to help guide front-line practitioners in providing the best care possible. The authors of this statement would welcome comments and suggestions from colleagues. We recognize that in this initial version of the guidelines there will probably be omissions, redundancies, and inaccuracies. Please feel free to get in touch with us either by letters to the Journal or by personal communication. This statement was written under the sponsorship of the American Society of Hypertension and the International Society of Hypertension. In addition, the Asia Pacific Society of Hypertension has endorsed these guidelines. The statement was prepared without any external funding. The work and time of the authors was provided by them entirely on a volunteer basis. MAW: Research funding: Medtronics. Consulting: Boehringer-Ingelheim, Novartis, Daichi Sankyo, Takeda, Forest. Speaker: Daiichi Sankyo, Takeda, Forest. ELS: Research Funding: Canadian Institutes of Health Research, Canada Research Chairs program of CIHR/Government of Canada, Servier France. Consultant: Servier, Novartis. Speaker: Forest Canada, Pfizer Japan. WBW: Research Funding: National Institutes of Health. Consulting: Safety Committees (DSMB, CEC, Steering Committees); Ardea Biosciences, Inc.; AstraZeneca; Dendreon, Forest Research Institute, Inc.; Roche; St. Jude's Medical, Takeda Global Research, Teva Neuroscience. SM, LHL, JGK, BJM, DLC, JCC, RRJC, ST, AJR, AES, RMT: No conflicts of interest. JMF: Research Funding: Novartis, Medtronic. Consultant: Novartis, Medtronic, Back Beat Hypertension. BLC: Research Funding: NIH and VA. VSR: Consultant: Medtronic, Daiichi-Sankyo, Forest. DK: Research Funding: Medtronic. RT: Research Funding: NIH. Consultant: Medtronic, Janssen, Merck, GSK. JC: Research Funding and Speaker: Servier in relation to ADVANCE trial and Post-trial study. GLB: Research Funding: Takeda. Consultant: Takeda, AbbVie, Daiichi-Sankyo, Novartis, CVRx, Medtronic, Relypsa, Janssen, BMS. JW: Consultant and Speaker: Boehringer-Ingelheim, MSD, Novartis, Omron, Pfizer, Servier, and Takeda. JDB: Research and Consultant: CVRx. DS: Research: Medtronic, CVRx. Consultant: Takeda, UCB, Novartis, Medtronic, CVRx. Speaker: Takeda. SBH: Speaker: Novartis, Servier.

BACKGROUND: COVID-19 has the potential to cause substantial disruptions to health services, due to cases overburdening the health system or response measures limiting usual programmatic activities. We aimed to quantify the extent to which disruptions to services for HIV, tuberculosis, and malaria in low-income and middle-income countries with high burdens of these diseases could lead to additional loss of life over the next 5 years. METHODS: Assuming a basic reproduction number of 3·0, we constructed four scenarios for possible responses to the COVID-19 pandemic: no action, mitigation for 6 months, suppression for 2 months, or suppression for 1 year. We used established transmission models of HIV, tuberculosis, and malaria to estimate the additional impact on health that could be caused in selected settings, either due to COVID-19 interventions limiting activities, or due to the high demand on the health system due to the COVID-19 pandemic. FINDINGS: In high-burden settings, deaths due to HIV, tuberculosis, and malaria over 5 years could increase by up to 10%, 20%, and 36%, respectively, compared with if there was no COVID-19 pandemic. The greatest impact on HIV was estimated to be from interruption to antiretroviral therapy, which could occur during a period of high health system demand. For tuberculosis, the greatest impact would be from reductions in timely diagnosis and treatment of new cases, which could result from any prolonged period of COVID-19 suppression interventions. The greatest impact on malaria burden could be as a result of interruption of planned net campaigns. These disruptions could lead to a loss of life-years over 5 years that is of the same order of magnitude as the direct impact from COVID-19 in places with a high burden of malaria and large HIV and tuberculosis epidemics. INTERPRETATION: Maintaining the most critical prevention activities and health-care services for HIV, tuberculosis, and malaria could substantially reduce the overall impact of the COVID-19 pandemic. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust, UK Department for International Development, and Medical Research Council.

IMPORTANCE: Lowering blood pressure (BP) is widely used to reduce vascular risk in individuals with diabetes. OBJECTIVE: To determine the associations between BP-lowering treatment and vascular disease in type 2 diabetes. DATA SOURCES AND STUDY SELECTION: We searched MEDLINE for large-scale randomized controlled trials of BP-lowering treatment including patients with diabetes, published between January 1966 and October 2014. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted study characteristics and vascular outcome data. Estimates were stratified by baseline BP and achieved BP, and pooled using fixed-effects meta-analysis. MAIN OUTCOMES AND MEASURES: All-cause mortality, cardiovascular events, coronary heart disease events, stroke, heart failure, retinopathy, new or worsening albuminuria, and renal failure. RESULTS: Forty trials judged to be of low risk of bias (100,354 participants) were included. Each 10-mm Hg lower systolic BP was associated with a significantly lower risk of mortality (relative risk [RR], 0.87; 95% CI, 0.78-0.96); absolute risk reduction (ARR) in events per 1000 patient-years (3.16; 95% CI, 0.90-5.22), cardiovascular events (RR, 0.89 [95% CI, 0.83-0.95]; ARR, 3.90 [95% CI, 1.57-6.06]), coronary heart disease (RR, 0.88 [95% CI, 0.80-0.98]; ARR, 1.81 [95% CI, 0.35-3.11]), stroke (RR, 0.73 [95% CI, 0.64-0.83]; ARR, 4.06 [95% CI, 2.53-5.40]), albuminuria (RR, 0.83 [95% CI, 0.79-0.87]; ARR, 9.33 [95% CI, 7.13-11.37]), and retinopathy (RR, 0.87 [95% CI, 0.76-0.99]; ARR, 2.23 [95% CI, 0.15-4.04]). When trials were stratified by mean baseline systolic BP at greater than or less than 140 mm Hg, RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline systolic BP (P interaction <0.1). The associations between BP-lowering treatments and outcomes were not significantly different, irrespective of drug class, except for stroke and heart failure. Estimates were similar when all trials, regardless of risk of bias, were included. CONCLUSIONS AND RELEVANCE: Among patients with type 2 diabetes, BP lowering was associated with improved mortality and other clinical outcomes with lower RRs observed among those with baseline BP of 140 mm Hg and greater. These findings support the use of medications for BP lowering in these patients.

BACKGROUND: Estimation of the epidemiological burden of carotid atherosclerosis can serve as a basis for prevention and management of cardiovascular disease. We aimed to provide the first estimation on the prevalence, number of cases, and risk factors for carotid atherosclerosis in the general population globally and regionally. METHODS: In this systematic review, meta-analysis, and modelling study, we searched PubMed, MEDLINE, Embase, Global Health, and China National Knowledge Infrastructure for articles published from database inception until May 7, 2019, with no language restrictions, for population-based studies that quantified prevalence of carotid atherosclerosis by means of increased carotid intima-media thickness, carotid plaque, and carotid stenosis. Studies were eligible if they included bilaterally scanned carotid arteries using ultrasonography and defined increased carotid intima-media thickness as a thickness of 1·0 mm or more, carotid plaque as a focal carotid intima-media thickness of 1·5 mm or more encroaching into the lumen or at least 0·5 mm or 50% compared with the surrounding carotid intima-media thickness values, and carotid stenosis as 50% or more stenosis. Studies were excluded if the sample was not representative of the general population. We also included studies identified in our previous systematic review and meta-analysis of the prevalence of carotid atherosclerosis in China. We estimated age-specific and sex-specific prevalences of increased carotid intima-media thickness, carotid plaque, and carotid stenosis. We used UN population data to generate the number of people affected in 2000, 2015, and 2020. We did random-effects meta-analyses to assess the effects of risk factors for increased carotid intima-media thickness and carotid plaque. We derived regional numbers of people living with increased carotid intima-media thickness and carotid plaque in 2015 using a risk factors-based model by WHO region. All analyses were done in populations aged 30-79 years due to availability of data. This systematic review and meta-analysis is registered online on PROSPERO, CRD42019134709. FINDINGS: We identified 8632 articles through our database search, of which 515 were eligible for full-text review, including 37 articles from our previous study, and 59 articles were eligible for inclusion in our systematic review and meta-analysis. Overall, in people aged 30-79 years in 2020, the global prevalence of increased carotid intima-media thickness is estimated to be 27·6% (95% CI 16·9-41·3), equivalent to 1066·70 million affected people and a percentage change of 57·46% from 2000; of carotid plaque is estimated to be 21·1% (13·2-31·5), equivalent to 815·76 million affected people and a percentage change of 58·97% from 2000; and carotid stenosis is estimated to be 1·5% (1·1-2·1), equivalent to 57·79 million affected people and a percentage change of 59·13% from 2000. The prevalence of increased carotid intima-media thickness, carotid plaque, and carotid stenosis increased consistently with age and was higher in men than in women. Current smoking, diabetes, and hypertension were common risk factors for increased carotid intima-media thickness and carotid plaque. In 2015, the Western Pacific region had the largest share of global cases of increased carotid intima-media thickness (317·62 million [33·36%] of 952·13 million affected people) and carotid plaque (240·77 million [33·20%] of 725·25 million), whereas the African region had the smallest share of cases of increased carotid intima-media thickness (59·08 million [6·21%]) and the Eastern Mediterranean region had the smallest share of carotid plaque cases (44·59 million [6·15%]). INTERPRETATION: A substantial global burden of carotid atherosclerosis exists. Effective strategies are needed for primary prevention and management of carotid atherosclerosis. High-quality epidemiological investigations on carotid atherosclerosis are needed to better address the global burden of carotid atherosclerosis at finer levels. FUNDING: None.

This systematic review update includes 54 randomised controlled trials and confirms that exercise as a single intervention can prevent falls (pooled rate ratio 0.84, 95% CI 0.77-0.91). Meta-regression revealed programs that included balance training, contained a higher dose of exercise and did not include walking training to have the greatest effect on reducing falls. We therefore recommend that exercise for falls prevention should provide a moderate or high challenge to balance and be undertaken for at least 2 hours per week on an ongoing basis. Additionally, we recommend that: falls prevention exercise should target both the general community and those at high risk for falls; exercise may be undertaken in a group or home-based setting; strength and walking training may be included in addition to balance training but high risk individuals should not be prescribed brisk walking programs; and other health-related risk factors should also be addressed.