Journal: Lancet

Sorted by: date / impact
Abstract

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

Li Y, Wang X, Blau DM, Caballero MT, ... Nair H, RESCEU investigators
Background
Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development.
Methods
In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400).
Findings
In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs).
Interpretation
RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented.
Funding
EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 19 May 2022; epub ahead of print
Li Y, Wang X, Blau DM, Caballero MT, ... Nair H, RESCEU investigators
Lancet: 19 May 2022; epub ahead of print | PMID: 35598608
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Abstract

Global health diplomacy-reconstructing power and governance.

Kickbusch I, Liu A
Over the past two decades, global health diplomacy, foreign policy for health, and global health policy have changed substantially. Diplomacy is a constitutive part of the system of global health governance. COVID-19 hit the world when multilateral cooperation was subject to major challenges, and global health has since become integral to geopolitics. The importance of global health diplomacy, especially at WHO, in keeping countries jointly committed to improving health for everyone, has once again been shown. Through a systematic review, this Series paper explores how international relations concepts and theories have been applied to better understand the role of power in shaping positions, negotiations, and outcomes in global health diplomacy. We apply an international relations perspective to reflect on the effect that those concepts and theories have had on global health diplomacy over the past two decades. This Series paper argues that a more central role of international relations concepts and theories in analysing global health diplomacy would help develop a more nuanced understanding of global health policy making. However, the world has changed to an extent that was not envisioned in academic discourse. This shift calls for new international relations concepts and theories to inform global health diplomacy.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 17 May 2022; epub ahead of print
Kickbusch I, Liu A
Lancet: 17 May 2022; epub ahead of print | PMID: 35594877
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Abstract

The politics of universal health coverage.

Ho CJ, Khalid H, Skead K, Wong J
The UN has declared universal health coverage an urgent global goal. Efforts to achieve this goal have been supported by rigorous research on the scientific, technical, and administrative aspects of health systems design. Yet a substantial portion of the world\'s population does not have access to essential health services. There is growing recognition that achieving universal health coverage is a political challenge. However, fundamental concepts from the political science discipline are often overlooked in the health literature. This Series paper draws on political science research to highlight the ways in which politics can facilitate, or stymie, policy reform. Specifically, we present a framework of analysis that explores how interests, ideas, and institutions shape universal health coverage. We then examine key considerations relating to the implementation of relevant policies. This Series paper shows that a political understanding of universal health coverage is needed to achieve health for all.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 17 May 2022; epub ahead of print
Ho CJ, Khalid H, Skead K, Wong J
Lancet: 17 May 2022; epub ahead of print | PMID: 35594878
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Abstract

The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial.

Pollack A, Karrison TG, Balogh AG, Gomella LG, ... Feng F, Sandler HM
Background
In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT.
Methods
The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing.
Findings
Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6-9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0-74·9) in group 1, 81·3% (78·0-84·6) in group 2, and 87·4% (84·7-90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group.
Interpretation
The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer.
Funding
National Cancer Institute.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 14 May 2022; 399:1886-1901
Pollack A, Karrison TG, Balogh AG, Gomella LG, ... Feng F, Sandler HM
Lancet: 14 May 2022; 399:1886-1901 | PMID: 35569466
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Abstract

Framing and the formation of global health priorities.

Shiffman J, Shawar YR
Health issues vary in the amount of attention and resources they receive from global health organisations and national governments. How issues are framed could shape differences in levels of priority. We reviewed scholarship on global health policy making to examine the role of framing in shaping global health priorities. The review provides evidence of the influence of three framing processes-securitisation, moralisation, and technification. Securitisation refers to an issue\'s framing as an existential threat, moralisation as an ethical imperative, and technification as a wise investment that science can solve. These framing processes concern more than how issues are portrayed publicly. They are socio-political processes, characterised by contestation among actors in civil society, government, international organisations, foundations, and research institutions. These actors deploy various forms of power to advance particular frames as a means of securing attention and resources for the issues that concern them. The ascription of an issue as a security concern, an ethical imperative, or a wise investment is historically contingent: it is not inevitable that any given issue will be framed in one or more of these ways. A health issue\'s inherent characteristics-such as the lethality of a pathogen that causes it-also shape these ascriptions, but do not fully determine them. Although commonly facing resistance, global health elites often determine which frames prevail, raising questions about the legitimacy of priority-setting processes. We draw on the review to offer ideas on how to make these processes fairer than they are at present, including a call for democratic representation even as necessary space is preserved for elite expertise.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 13 May 2022; epub ahead of print
Shiffman J, Shawar YR
Lancet: 13 May 2022; epub ahead of print | PMID: 35594874
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Abstract

Chronic obstructive pulmonary disease.

Christenson SA, Smith BM, Bafadhel M, Putcha N
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and health-care use worldwide. COPD is caused by exposure to inhaled noxious particles, notably tobacco smoke and pollutants. However, the broad range of factors that increase the risk of development and progression of COPD throughout the life course are increasingly being recognised. Innovations in omics and imaging techniques have provided greater insight into disease pathobiology, which might result in advances in COPD prevention, diagnosis, and treatment. Although few novel treatments have been approved for COPD in the past 5 years, advances have been made in targeting existing therapies to specific subpopulations using new biomarker-based strategies. Additionally, COVID-19 has undeniably affected individuals with COPD, who are not only at higher risk for severe disease manifestations than healthy individuals but also negatively affected by interruptions in health-care delivery and social isolation. This Seminar reviews COPD with an emphasis on recent advances in epidemiology, pathophysiology, imaging, diagnosis, and treatment.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 06 May 2022; epub ahead of print
Christenson SA, Smith BM, Bafadhel M, Putcha N
Lancet: 06 May 2022; epub ahead of print | PMID: 35533707
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Abstract

Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial.

Delgado-Lista J, Alcala-Diaz JF, Torres-Peña JD, Quintana-Navarro GM, ... Lopez-Miranda J, CORDIOPREV Investigators
Background
Mediterranean and low-fat diets are effective in the primary prevention of cardiovascular disease. We did a long-term randomised trial to compare the effects of these two diets in secondary prevention of cardiovascular disease.
Methods
The CORDIOPREV study was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive a Mediterranean diet or a low-fat diet intervention, with a follow-up of 7 years. Clinical investigators (physicians, investigators, and clinical endpoint committee members) were masked to treatment assignment; participants were not. A team of dietitians did the dietary interventions. The primary outcome (assessed by intention to treat) was a composite of major cardiovascular events, including myocardial infarction, revascularisation, ischaemic stroke, peripheral artery disease, and cardiovascular death. This study is registered with ClinicalTrials.gov, NCT00924937.
Findings
From Oct 1, 2009, to Feb 28, 2012, a total of 1002 patients were enrolled, 500 (49·9%) in the low-fat diet group and 502 (50·1%) in the Mediterranean diet group. The mean age was 59·5 years (SD 8·7) and 827 (82·5%) of 1002 patients were men. The primary endpoint occurred in 198 participants: 87 in the Mediterranean diet group and 111 in the low-fat group (crude rate per 1000 person-years: 28·1 [95% CI 27·9-28·3] in the Mediterranean diet group vs 37·7 [37·5-37·9] in the low-fat group, log-rank p=0·039). Multivariable-adjusted hazard ratios (HRs) of the different models ranged from 0·719 (95% CI 0·541-0·957) to 0·753 (0·568-0·998) in favour of the Mediterranean diet. These effects were more evident in men, with primary endpoints occurring in 67 (16·2%) of 414 men in the Mediterranean diet group versus 94 (22·8%) of 413 men in the low-fat diet group (multiadjusted HR 0·669 [95% CI 0·489-0·915], log-rank p=0·013), than in 175 women for whom no difference was found between groups.
Interpretation
In secondary prevention, the Mediterranean diet was superior to the low-fat diet in preventing major cardiovascular events. Our results are relevant to clinical practice, supporting the use of the Mediterranean diet in secondary prevention.
Funding
Fundacion Patrimonio Comunal Olivarero; Fundacion Centro para la Excelencia en Investigacion sobre Aceite de Oliva y Salud; local, regional, and national Spanish Governments; European Union.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 04 May 2022; epub ahead of print
Delgado-Lista J, Alcala-Diaz JF, Torres-Peña JD, Quintana-Navarro GM, ... Lopez-Miranda J, CORDIOPREV Investigators
Lancet: 04 May 2022; epub ahead of print | PMID: 35525255
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Abstract

Suicide and self-harm.

Knipe D, Padmanathan P, Newton-Howes G, Chan LF, Kapur N
Suicide and self-harm are major health and societal issues worldwide, but the greatest burden of both behaviours occurs in low-income and middle-income countries. Although rates of suicide are higher in male than in female individuals, self-harm is more common in female individuals. Rather than having a single cause, suicide and self-harm are the result of a complex interplay of several factors that occur throughout the life course, and vary by gender, age, ethnicity, and geography. Several clinical and public health interventions show promise, although our understanding of their effectiveness has largely originated from high-income countries. Attempting to predict suicide is unlikely to be helpful. Intervention and prevention must include both a clinical and community focus, and every health professional has a crucial part to play.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 02 May 2022; epub ahead of print
Knipe D, Padmanathan P, Newton-Howes G, Chan LF, Kapur N
Lancet: 02 May 2022; epub ahead of print | PMID: 35512727
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Abstract

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.

WHO Solidarity Trial Consortium
Background
The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date.
Methods
Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.
Findings
Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82-1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89-1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76-0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46-1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76-0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77-1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75-0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings.
Interpretation
Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).
Funding
WHO.

© 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article\'s original URL.

Lancet: 02 May 2022; epub ahead of print
WHO Solidarity Trial Consortium
Lancet: 02 May 2022; epub ahead of print | PMID: 35512728
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Abstract

Health and development from preconception to 20 years of age and human capital.

Black RE, Liu L, Hartwig FP, Villavicencio F, ... Lawn JE, Victora CG
Optimal health and development from preconception to adulthood are crucial for human flourishing and the formation of human capital. The Nurturing Care Framework, as adapted to age 20 years, conceptualises the major influences during periods of development from preconception, through pregnancy, childhood, and adolescence that affect human capital. In addition to mortality in children younger than 5 years, stillbirths and deaths in 5-19-year-olds are important to consider. The global rate of mortality in individuals younger than 20 years has declined substantially since 2000, yet in 2019 an estimated 8·6 million deaths occurred between 28 weeks of gestation and 20 years of age, with more than half of deaths, including stillbirths, occurring before 28 days of age. The 1000 days from conception to 2 years of age are especially influential for human capital. The prevalence of low birthweight is high in sub-Saharan Africa and even higher in south Asia. Growth faltering, especially from birth to 2 years, occurs in most world regions, whereas overweight increases in many regions from the preprimary school period through adolescence. Analyses of cohort data show that growth trajectories in early years of life are strong determinants of nutritional outcomes in adulthood. The accrual of knowledge and skills is affected by health, nutrition, and home resources in early childhood and by educational opportunities in older children and adolescents. Linear growth in the first 2 years of life better predicts intelligence quotients in adults than increases in height in older children and adolescents. Learning-adjusted years of schooling range from about 4 years in sub-Saharan Africa to about 11 years in high-income countries. Human capital depends on children and adolescents surviving, thriving, and learning until adulthood.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 30 Apr 2022; 399:1730-1740
Black RE, Liu L, Hartwig FP, Villavicencio F, ... Lawn JE, Victora CG
Lancet: 30 Apr 2022; 399:1730-1740 | PMID: 35489357
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Abstract

Effects of early-life poverty on health and human capital in children and adolescents: analyses of national surveys and birth cohort studies in LMICs.

Victora CG, Hartwig FP, Vidaletti LP, Martorell R, ... Bhutta ZA, Black RE
The survival and nutrition of children and, to a lesser extent, adolescents have improved substantially in the past two decades. Improvements have been linked to the delivery of effective biomedical, behavioural, and environmental interventions; however, large disparities exist between and within countries. Using data from 95 national surveys in low-income and middle-income countries (LMICs), we analyse how strongly the health, nutrition, and cognitive development of children and adolescents are related to early-life poverty. Additionally, using data from six large, long-running birth cohorts in LMICs, we show how early-life poverty can have a lasting effect on health and human capital throughout the life course. We emphasise the importance of implementing multisectoral anti-poverty policies and programmes to complement specific health and nutrition interventions delivered at an individual level, particularly at a time when COVID-19 continues to disrupt economic, health, and educational gains achieved in the recent past.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 30 Apr 2022; 399:1741-1752
Victora CG, Hartwig FP, Vidaletti LP, Martorell R, ... Bhutta ZA, Black RE
Lancet: 30 Apr 2022; 399:1741-1752 | PMID: 35489358
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Abstract

A village doctor-led multifaceted intervention for blood pressure control in rural China: an open, cluster randomised trial.

Sun Y, Mu J, Wang DW, Ouyang N, ... He J, CRHCP Study Group
Background
The prevalence of uncontrolled hypertension is high and increasing in low-income and middle-income countries. We tested the effectiveness of a multifaceted intervention for blood pressure control in rural China led by village doctors (community health workers on the front line of primary health care).
Methods
In this open, cluster randomised trial (China Rural Hypertension Control Project), 326 villages that had a regular village doctor and participated in the China New Rural Cooperative Medical Scheme were randomly assigned (1:1) to either village doctor-led multifaceted intervention or enhanced usual care (control), with stratification by provinces, counties, and townships. We recruited individuals aged 40 years or older with an untreated blood pressure of 140/90 mm Hg or higher (≥130/80 mm Hg among those with a history of cardiovascular disease, diabetes, or chronic kidney disease) or a treated blood pressure of 130/80 mm Hg or higher. In the intervention group, trained village doctors initiated and titrated antihypertensive medications according to a standard protocol with supervision from primary care physicians. Village doctors also conducted health coaching on home blood pressure monitoring, lifestyle changes, and medication adherence. The primary outcome (reported here) was the proportion of patients with a blood pressure of less than 130/80 mm Hg at 18 months. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03527719, and is ongoing.
Findings
Between May 8 and November 28, 2018, we enrolled 33 995 individuals from 163 intervention and 163 control villages. At 18 months, 8865 (57·0%) of 15 414 patients in the intervention group and 2895 (19·9%) of 14 500 patients in the control group had a blood pressure of less than 130/80 mm Hg, with a group difference of 37·0% (95% CI 34·9 to 39·1%; p<0·0001). Mean systolic blood pressure decreased by -26·3 mm Hg (95% CI -27·1 to -25·4) from baseline to 18 months in the intervention group and by -11·8 mm Hg (-12·6 to -11·0) in the control group, with a group difference of -14·5 mm Hg (95% CI -15·7 to -13·3 mm Hg; p<0·0001). Mean diastolic blood pressure decreased by -14·6 mm Hg (-15·1 to -14·2) from baseline to 18 months in the intervention group and by -7·5 mm Hg (-7·9 to -7·2) in the control group, with a group difference of -7·1 mm Hg (-7·7 to -6·5 mm Hg; p<0·0001). No treatment-related serious adverse events were reported in either group.
Interpretation
Compared with enhanced usual care, village doctor-led intervention resulted in statistically significant improvements in blood pressure control among rural residents in China. This feasible, effective, and sustainable implementation strategy could be scaled up in rural China and other low-income and middle-income countries for hypertension control.
Funding
Ministry of Science and Technology of China.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 29 Apr 2022; epub ahead of print
Sun Y, Mu J, Wang DW, Ouyang N, ... He J, CRHCP Study Group
Lancet: 29 Apr 2022; epub ahead of print | PMID: 35500594
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Abstract

Algorithm-based care versus usual care for the early recognition and management of complications after pancreatic resection in the Netherlands: an open-label, nationwide, stepped-wedge cluster-randomised trial.

Smits FJ, Henry AC, Besselink MG, Busch OR, ... van Santvoort HC, Dutch Pancreatic Cancer Group
Background
Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection.
Methods
We did an open-label, nationwide, stepped-wedge cluster-randomised trial that included all patients having pancreatic resection during a 22-month period in the Netherlands. In this trial design, all 17 centres that did pancreatic surgery were randomly allocated for the timing of the crossover from usual care (the control group) to treatment given in accordance with a multimodal, multidisciplinary algorithm for the early recognition and minimally invasive management of postoperative complications (the intervention group). Randomisation was done by an independent statistician using a computer-generated scheme, stratified to ensure that low-medium-volume centres alternated with high-volume centres. Patients and investigators were not masked to treatment. A smartphone app was designed that incorporated the algorithm and included the daily evaluation of clinical and biochemical markers. The algorithm determined when to do abdominal CT, radiological drainage, start antibiotic treatment, and remove abdominal drains. After crossover, clinicians were trained in how to use the algorithm during a 4-week wash-in period; analyses comparing outcomes between the control group and the intervention group included all patients other than those having pancreatic resection during this wash-in period. The primary outcome was a composite of bleeding that required invasive intervention, organ failure, and 90-day mortality, and was assessed by a masked adjudication committee. This trial was registered in the Netherlands Trial Register, NL6671.
Findings
From Jan 8, 2018, to Nov 9, 2019, all 1805 patients who had pancreatic resection in the Netherlands were eligible for and included in this study. 57 patients who underwent resection during the wash-in phase were excluded from the primary analysis. 1748 patients (885 receiving usual care and 863 receiving algorithm-centred care) were included. The primary outcome occurred in fewer patients in the algorithm-centred care group than in the usual care group (73 [8%] of 863 patients vs 124 [14%] of 885 patients; adjusted risk ratio [RR] 0·48, 95% CI 0·38-0·61; p<0·0001). Among patients treated according to the algorithm, compared with patients who received usual care there was a decrease in bleeding that required intervention (47 [5%] patients vs 51 [6%] patients; RR 0·65, 0·42-0·99; p=0·046), organ failure (39 [5%] patients vs 92 [10%] patients; 0·35, 0·20-0·60; p=0·0001), and 90-day mortality (23 [3%] patients vs 44 [5%] patients; 0·42, 0·19-0·92; p=0·029).
Interpretation
The algorithm for the early recognition and minimally invasive management of complications after pancreatic resection considerably improved clinical outcomes compared with usual care. This difference included an approximate 50% reduction in mortality at 90 days.
Funding
The Dutch Cancer Society and UMC Utrecht.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 28 Apr 2022; epub ahead of print
Smits FJ, Henry AC, Besselink MG, Busch OR, ... van Santvoort HC, Dutch Pancreatic Cancer Group
Lancet: 28 Apr 2022; epub ahead of print | PMID: 35490691
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Impact:
Abstract

Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial.

Trutnovsky G, Reich O, Joura EA, Holter M, ... Regauer S, Tamussino K
Background
The optimal management of vulvar high-grade squamous intraepithelial lesions (vHSILs) is challenging. Surgery is the standard treatment, but recurrences are observed in half of patients. Medical treatment with imiquimod is an effective alternative, but the two modalities have not been compared in a randomised trial. The aim of this study was to compare the clinical effectiveness, histological response, human papillomavirus (HPV) clearance, acceptance, and psychosexual morbidity of primary imiquimod treatment versus surgical treatment in women with vHSIL.
Methods
This study was a multicentre, randomised, phase 3, non-inferiority clinical trial done by the Austrian Gynaecological Oncology group at six hospitals in Austria. We recruited female patients aged 18-90 years with histologically confirmed vHSIL with visible unifocal or multifocal lesions. Main exclusion criteria were clinical suspicion of invasion, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, and any active treatment for vHSIL within the previous 3 months. Women with known immunodeficiency, who were pregnant, or who were lactating were excluded. Patients were randomly assigned (1:1) by block randomisation to imiquimod or surgery, and stratified by unifocal or multifocal disease. Treatment with imiquimod was self-administered in a slowly escalating dosage scheme up to three times per week for a period of 4-6 months. Surgery consisted of excision or ablation. Patients were assessed with vulvoscopy, vulvar biopsy, HPV tests, and patient-reported outcomes at baseline and after 6 months and 12 months. The primary endpoint was complete clinical response (CCR) at 6 months after local imiquimod treatment or one surgical intervention. Primary analysis was per protocol with a non-inferiority margin of 20%. This trial is registered at ClinicalTrials.gov, NCT01861535.
Findings
110 patients with vHSIL (78% with unifocal vHSIL and 22% with multifocal vHSIL) were randomly assigned between June 7, 2013, and Jan 8, 2020. Clinical response to treatment could be assessed in 107 patients (54 in the imiquimod group and 53 in the surgery group), and 98 patients (46 in the imiquimod group and 52 in the surgery group) completed the study per protocol. 37 (80%) of 46 patients using imiquimod had CCR, compared with 41 (79%) of 52 patients after one surgical intervention, showing non-inferiority of the new treatment (difference in proportion -0·016, 95% CI -0·15 to -0·18; p=0·0056). Invasive disease was found in five patients at primary or secondary surgery, but not in patients with per-protocol imiquimod treatment. There was no significant difference in HPV clearance, adverse events, and treatment satisfaction between study groups.
Interpretation
Imiquimod is a safe, effective, and well accepted alternative to surgery for women with vHSIL and can be considered as first-line treatment.
Funding
Austrian Science Fund and Austrian Gynaecological Oncology group.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 25 Apr 2022; epub ahead of print
Trutnovsky G, Reich O, Joura EA, Holter M, ... Regauer S, Tamussino K
Lancet: 25 Apr 2022; epub ahead of print | PMID: 35483400
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Impact:
Abstract

What can work and how? An overview of evidence-based interventions and delivery strategies to support health and human development from before conception to 20 years.

Vaivada T, Lassi ZS, Irfan O, Salam RA, ... Black RE, Bhutta ZA
Progress has been made globally in improving the coverage of key maternal, newborn, and early childhood interventions in low-income and middle-income countries, which has contributed to a decrease in child mortality and morbidity. However, inequities remain, and many children and adolescents are still not covered by life-saving and nurturing care interventions, despite their relatively low costs and high cost-effectiveness. This Series paper builds on a large body of work from the past two decades on evidence-based interventions and packages of care for survival, strategies for delivery, and platforms to reach the most vulnerable. We review the current evidence base on the effectiveness of a variety of essential and emerging interventions that can be delivered from before conception until age 20 years to help children and adolescents not only survive into adulthood, but also to grow and develop optimally, support their wellbeing, and help them reach their full developmental potential. Although scaling up evidence-based interventions in children younger than 5 years might have the greatest effect on reducing child mortality rates, we highlight interventions and evidence gaps for school-age children (5-9 years) and the transition from childhood to adolescence (10-19 years), including interventions to support mental health and positive development, and address unintentional injuries, neglected tropical diseases, and non-communicable diseases.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 25 Apr 2022; epub ahead of print
Vaivada T, Lassi ZS, Irfan O, Salam RA, ... Black RE, Bhutta ZA
Lancet: 25 Apr 2022; epub ahead of print | PMID: 35489360
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Impact:
Abstract

Improving health and social systems for all children in LMICs: structural innovations to deliver high-quality services.

Kruk ME, Lewis TP, Arsenault C, Bhutta ZA, ... Waiswa P, Yousafzai AK
Despite health gains over the past 30 years, children and adolescents are not reaching their health potential in many low-income and middle-income countries (LMICs). In addition to health systems, social systems, such as schools, communities, families, and digital platforms, can be used to promote health. We did a targeted literature review of how well health and social systems are meeting the needs of children in LMICs using the framework of The Lancet Global Health Commission on high-quality health systems and we reviewed evidence for structural reforms in health and social sectors. We found that quality of services for children is substandard across both health and social systems. Health systems have deficits in care competence (eg, diagnosis and management), system competence (eg, timeliness, continuity, and referral), user experience (eg, respect and usability), service provision for common and serious conditions (eg, cancer, trauma, and mental health), and service offerings for adolescents. Education and social services for child health are limited by low funding and poor coordination with other sectors. Structural reforms are more likely to improve service quality substantially and at scale than are micro-level efforts. Promising approaches include governing for quality (eg, leadership, expert management, and learning systems), redesigning service delivery to maximise outcomes, and empowering families to better care for children and to demand quality care from health and social systems. Additional research is needed on health needs across the life course, health system performance for children and families, and large-scale evaluation of promising health and social programmes.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 25 Apr 2022; epub ahead of print
Kruk ME, Lewis TP, Arsenault C, Bhutta ZA, ... Waiswa P, Yousafzai AK
Lancet: 25 Apr 2022; epub ahead of print | PMID: 35489361
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Impact:
Abstract

Subacromial balloon spacer for irreparable rotator cuff tears of the shoulder (START:REACTS): a group-sequential, double-blind, multicentre randomised controlled trial.

Metcalfe A, Parsons H, Parsons N, Brown J, ... Drew S, START:REACTS team
Background
New surgical procedures can expose patients to harm and should be carefully evaluated before widespread use. The InSpace balloon (Stryker, USA) is an innovative surgical device used to treat people with rotator cuff tears that cannot be repaired. We aimed to determine the effectiveness of the InSpace balloon for people with irreparable rotator cuff tears.
Methods
We conducted a double-blind, group-sequential, adaptive randomised controlled trial in 24 hospitals in the UK, comparing arthroscopic debridement of the subacromial space with biceps tenotomy (debridement only group) with the same procedure but including insertion of the InSpace balloon (debridement with device group). Participants had an irreparable rotator cuff tear, which had not resolved with conservative treatment, and they had symptoms warranting surgery. Eligibility was confirmed intraoperatively before randomly assigning (1:1) participants to a treatment group using a remote computer system. Participants and assessors were masked to group assignment. Masking was achieved by using identical incisions for both procedures, blinding the operation note, and a consistent rehabilitation programme was offered regardless of group allocation. The primary outcome was the Oxford Shoulder Score at 12 months. Pre-trial simulations using data from early and late timepoints informed stopping boundaries for two interim analyses. The primary analysis was on a modified intention-to-treat basis, adjusted for the planned interim analysis. The trial was registered with ISRCTN, ISRCTN17825590.
Findings
Between June 1, 2018, and July 30, 2020, we assessed 385 people for eligibility, of which 317 were eligible. 249 (79%) people consented for inclusion in the study. 117 participants were randomly allocated to a treatment group, 61 participants to the debridement only group and 56 to the debridement with device group. A predefined stopping boundary was met at the first interim analysis and recruitment stopped with 117 participants randomised. 43% of participants were female, 57% were male. We obtained primary outcome data for 114 (97%) participants. The mean Oxford Shoulder Score at 12 months was 34·3 (SD 11·1) in the debridement only group and 30·3 (10·9) in the debridement with device group (mean difference adjusted for adaptive design -4·2 [95% CI -8·2 to -0·26];p=0·037) favouring control. There was no difference in adverse events between the two groups.
Interpretation
In an efficient, adaptive trial design, our results favoured the debridement only group. We do not recommend the InSpace balloon for the treatment of irreparable rotator cuff tears.
Funding
Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health and Care Research partnership.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 21 Apr 2022; epub ahead of print
Metcalfe A, Parsons H, Parsons N, Brown J, ... Drew S, START:REACTS team
Lancet: 21 Apr 2022; epub ahead of print | PMID: 35461618
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Impact:
Abstract

Management of common clinical problems experienced by survivors of cancer.

Emery J, Butow P, Lai-Kwon J, Nekhlyudov L, Rynderman M, Jefford M
Improvements in early detection and treatment have led to a growing prevalence of survivors of cancer worldwide. Models of care fail to address adequately the breadth of physical, psychosocial, and supportive care needs of those who survive cancer. In this Series paper, we summarise the evidence around the management of common clinical problems experienced by survivors of adult cancers and how to cover these issues in a consultation. Reviewing the patient\'s history of cancer and treatments highlights potential long-term or late effects to consider, and recommended surveillance for recurrence. Physical consequences of specific treatments to identify include cardiac dysfunction, metabolic syndrome, lymphoedema, peripheral neuropathy, and osteoporosis. Immunotherapies can cause specific immune-related effects most commonly in the gastrointestinal tract, endocrine system, skin, and liver. Pain should be screened for and requires assessment of potential causes and non-pharmacological and pharmacological approaches to management. Common psychosocial issues, for which there are effective psychological therapies, include fear of recurrence, fatigue, altered sleep and cognition, and effects on sex and intimacy, finances, and employment. Review of lifestyle factors including smoking, obesity, and alcohol is necessary to reduce the risk of recurrence and second cancers. Exercise can improve quality of life and might improve cancer survival; it can also contribute to the management of fatigue, pain, metabolic syndrome, osteoporosis, and cognitive impairment. Using a supportive care screening tool, such as the Distress Thermometer, can identify specific areas of concern and help prioritise areas to cover in a consultation.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 16 Apr 2022; 399:1537-1550
Emery J, Butow P, Lai-Kwon J, Nekhlyudov L, Rynderman M, Jefford M
Lancet: 16 Apr 2022; 399:1537-1550 | PMID: 35430021
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Impact:
Abstract

Improved models of care for cancer survivors.

Jefford M, Howell D, Li Q, Lisy K, ... Rynderman M, Emery J
The number of survivors of cancer is increasing substantially. Current models of care are unsustainable and fail to address the many unmet needs of survivors of cancer. Numerous trials have investigated alternate models of care, including models led by primary-care providers, care shared between oncology specialists and primary-care providers, and care led by oncology nurses. These alternate models appear to be at least as effective as specialist-led care and are applicable to many survivors of cancer. Choosing the most appropriate care model for each patient depends on patient-level factors (such as risk of longer-term effects, late effects, individual desire, and capacity to self-manage), local services, and health-care policy. Wider implementation of alternative models requires appropriate support for non-oncologist care providers and endorsement of these models by cancer teams with their patients. The COVID-19 pandemic has driven some changes in practice that are more patient-centred and should continue. Improved models should shift from a predominant focus on detection of cancer recurrence and seek to improve the quality of life, functional outcomes, experience, and survival of survivors of cancer, reduce the risk of recurrence and new cancers, improve the management of comorbidities, and reduce costs to patients and payers. This Series paper focuses primarily on high-income countries, where most data have been derived. However, future research should consider the applicability of these models in a wider range of health-care settings and for a wider range of cancers.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 16 Apr 2022; 399:1551-1560
Jefford M, Howell D, Li Q, Lisy K, ... Rynderman M, Emery J
Lancet: 16 Apr 2022; 399:1551-1560 | PMID: 35430022
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Impact:
Abstract

Long-term care for people treated for cancer during childhood and adolescence.

Tonorezos ES, Cohn RJ, Glaser AW, Lewin J, ... Wakefield CE, Oeffinger KC
Worldwide advances in treatment and supportive care for children and adolescents with cancer have resulted in a increasing population of survivors growing into adulthood. Yet, this population is at very high risk of late occurring health problems, including significant morbidity and early mortality. Unique barriers to high-quality care for this group include knowledge gaps among both providers and survivors as well as fragmented health-care delivery during the transition from paediatric to adult care settings. Survivors of childhood and adolescent cancer are at risk for a range of late-occuring side-effects from treatment, including cardiac, endocrine, pulmonary, fertility, renal, psychological, cognitive, and socio-developmental impairments. Care coordination and transition to adult care are substantial challenges, but can be empowering for survivors and improve outcomes, and could be facilitated by clear, effective communication and support for self-management. Resources for adult clinical care teams and primary care providers include late-effects surveillance guidelines and web-based support services.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 16 Apr 2022; 399:1561-1572
Tonorezos ES, Cohn RJ, Glaser AW, Lewin J, ... Wakefield CE, Oeffinger KC
Lancet: 16 Apr 2022; 399:1561-1572 | PMID: 35430023
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Impact:
Abstract

Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial.

Nguyen TT, Chiu CH, Lin CY, Chiu NC, ... Tai IC, Huang LM
Background
Children are susceptible to severe or fatal enterovirus 71 (EV71) infections. We aimed to evaluate the efficacy, safety, and immunogenicity of EV71vac, an aluminium phosphate-adjuvanted inactivated EV71 vaccine in children aged 2-71 months.
Methods
We did a randomised, double-blinded, placebo-controlled, phase 3 trial at five hospitals in Taiwan and two in Vietnam. Children aged 2-71 months were stratified by country and age, and randomly assigned (1:1) to receive two doses of EV71vac or placebo via intramuscular injection 56 days apart. Children aged 2-23 months received a third booster dose on day 366. The primary endpoint was the clinical efficacy of the total vaccinated cohort against EV71-associated diseases during the follow-up period, from 14 days after the second dose to when 15 cases of EV71 infections were confirmed in the per-protocol population. Our safety analysis included all participants who received at least one dose of EV71vac. This trial is registered with ClinicalTrials.gov, NCT03865238, and is complete.
Findings
Between April 23 and Dec 25, 2019, of 3663 children assessed, 3061 were randomly assigned, of whom 3049 were vaccinated: 1521 children in the EV71vac group and 1528 in the placebo group. By May 20, 2021, our primary efficacy analysis included 2959 children, with 1476 children in the EV71vac group and 1483 children in the placebo group. The vaccine efficacy of EV71vac was 96·8% (95% CI 85·5-100) against EV71 associated diseases (p<0·0001). The percentage of participants who reported solicited adverse events were similar in both groups: 865 (56·9%) in the EV71vac group and 852 (55·8%) in the placebo group. Almost all reported solicited adverse events were mild and self-limited.
Interpretation
EV71vac is safe, well-tolerated, and highly effective in preventing EV71 associated diseases in children aged 2-71 months.
Funding
Medigen Vaccine Biologics and A+ Industrial Innovative R&D Program of the Ministry of Economic Affairs, Taiwan.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 12 Apr 2022; epub ahead of print
Nguyen TT, Chiu CH, Lin CY, Chiu NC, ... Tai IC, Huang LM
Lancet: 12 Apr 2022; epub ahead of print | PMID: 35427481
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Impact:
Abstract

Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study.

Piccini JP, Caso V, Connolly SJ, Fox KAA, ... Patel MR, PACIFIC-AF Investigators
Background
Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation.
Methods
In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35.
Findings
Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban.
Interpretation
The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation.
Funding
Bayer.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 09 Apr 2022; 399:1383-1390
Piccini JP, Caso V, Connolly SJ, Fox KAA, ... Patel MR, PACIFIC-AF Investigators
Lancet: 09 Apr 2022; 399:1383-1390 | PMID: 35385695
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Impact:
Abstract

Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.

Mahfoud F, Kandzari DE, Kario K, Townsend RR, ... Fahy M, Böhm M
Background
Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group.
Methods
This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial.
Findings
Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was -18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and -8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference -10·0 mm Hg, 95% CI -16·6 to -3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were -5·9 mm Hg (95% CI -10·1 to -1·8; p=0·0055) for mean ambulatory diastolic blood pressure, -11·0 mm Hg (-19·8 to -2·1; p=0·016) for morning systolic blood pressure, and -11·8 mm Hg (-19·0 to -4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation.
Interpretation
Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension.
Funding
Medtronic.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 09 Apr 2022; 399:1401-1410
Mahfoud F, Kandzari DE, Kario K, Townsend RR, ... Fahy M, Böhm M
Lancet: 09 Apr 2022; 399:1401-1410 | PMID: 35390320
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Impact:
Abstract

Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial.

Ezekowitz JA, Colin-Ramirez E, Ross H, Escobedo J, ... Zieroth S, SODIUM-HF Investigators
Background
Dietary restriction of sodium has been suggested to prevent fluid overload and adverse outcomes for patients with heart failure. We designed the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) to test whether or not a reduction in dietary sodium reduces the incidence of future clinical events.
Methods
SODIUM-HF is an international, open-label, randomised, controlled trial that enrolled patients at 26 sites in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand). Eligible patients were aged 18 years or older, with chronic heart failure (New York Heart Association [NYHA] functional class 2-3), and receiving optimally tolerated guideline-directed medical treatment. Patients were randomly assigned (1:1), using a standard number generator and varying block sizes of two, four, or six, stratified by site, to either usual care according to local guidelines or a low sodium diet of less than 100 mmol (ie, <1500 mg/day). The primary outcome was the composite of cardiovascular-related admission to hospital, cardiovascular-related emergency department visit, or all-cause death within 12 months in the intention-to-treat (ITT) population (ie, all randomly assigned patients). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT02012179, and is closed to accrual.
Findings
Between March 24, 2014, and Dec 9, 2020, 806 patients were randomly assigned to a low sodium diet (n=397) or usual care (n=409). Median age was 67 years (IQR 58-74) and 268 (33%) were women and 538 (66%) were men. Between baseline and 12 months, the median sodium intake decreased from 2286 mg/day (IQR 1653-3005) to 1658 mg/day (1301-2189) in the low sodium group and from 2119 mg/day (1673-2804) to 2073 mg/day (1541-2900) in the usual care group. By 12 months, events comprising the primary outcome had occurred in 60 (15%) of 397 patients in the low sodium diet group and 70 (17%) of 409 in the usual care group (hazard ratio [HR] 0·89 [95% CI 0·63-1·26]; p=0·53). All-cause death occurred in 22 (6%) patients in the low sodium diet group and 17 (4%) in the usual care group (HR 1·38 [0·73-2·60]; p=0·32), cardiovascular-related hospitalisation occurred in 40 (10%) patients in the low sodium diet group and 51 (12%) patients in the usual care group (HR 0·82 [0·54-1·24]; p=0·36), and cardiovascular-related emergency department visits occurred in 17 (4%) patients in the low sodium diet group and 15 (4%) patients in the usual care group (HR 1·21 [0·60-2·41]; p=0·60). No safety events related to the study treatment were reported in either group.
Interpretation
In ambulatory patients with heart failure, a dietary intervention to reduce sodium intake did not reduce clinical events.
Funding
Canadian Institutes of Health Research and the University Hospital Foundation, Edmonton, Alberta, Canada, and Health Research Council of New Zealand.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 09 Apr 2022; 399:1391-1400
Ezekowitz JA, Colin-Ramirez E, Ross H, Escobedo J, ... Zieroth S, SODIUM-HF Investigators
Lancet: 09 Apr 2022; 399:1391-1400 | PMID: 35381194
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Impact:
Abstract

Endometrial cancer.

Crosbie EJ, Kitson SJ, McAlpine JN, Mukhopadhyay A, Powell ME, Singh N
Endometrial cancer is the most common gynaecological cancer in high income countries and its incidence is rising globally. Although an ageing population and fewer benign hysterectomies have contributed to this trend, the growing prevalence of obesity is the major underlying cause. Obesity poses challenges for diagnosis and treatment and more research is needed to offer primary prevention to high-risk women and to optimise endometrial cancer survivorship. Early presentation with postmenopausal bleeding ensures most endometrial cancers are cured by hysterectomy but those with advanced disease have a poor prognosis. Minimally invasive surgical staging and sentinel-lymph-node biopsy provides a low morbidity alternative to historical surgical management without compromising oncological outcomes. Adjuvant radiotherapy reduces loco-regional recurrence in intermediate-risk and high-risk cases. Advances in our understanding of the molecular biology of endometrial cancer have paved the way for targeted chemotherapeutic strategies, and clinical trials will establish their benefit in adjuvant, advanced, and recurrent disease settings in the coming years.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 09 Apr 2022; 399:1412-1428
Crosbie EJ, Kitson SJ, McAlpine JN, Mukhopadhyay A, Powell ME, Singh N
Lancet: 09 Apr 2022; 399:1412-1428 | PMID: 35397864
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Abstract

Cholera.

Kanungo S, Azman AS, Ramamurthy T, Deen J, Dutta S
Cholera was first described in the areas around the Bay of Bengal and spread globally, resulting in seven pandemics during the past two centuries. It is caused by toxigenic Vibrio cholerae O1 or O139 bacteria. Cholera is characterised by mild to potentially fatal acute watery diarrhoeal disease. Prompt rehydration therapy is the cornerstone of management. We present an overview of cholera and its pathogenesis, natural history, bacteriology, and epidemiology, while highlighting advances over the past 10 years in molecular epidemiology, immunology, and vaccine development and deployment. Since 2014, the Global Task Force on Cholera Control, a WHO coordinated network of partners, has been working with several countries to develop national cholera control strategies. The global roadmap for cholera control focuses on stopping transmission in cholera hotspots through vaccination and improved water, sanitation, and hygiene, with the aim to reduce cholera deaths by 90% and eliminate local transmission in at least 20 countries by 2030.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 09 Apr 2022; 399:1429-1440
Kanungo S, Azman AS, Ramamurthy T, Deen J, Dutta S
Lancet: 09 Apr 2022; 399:1429-1440 | PMID: 35397865
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Impact:
Abstract

Estimating global, regional, and national daily and cumulative infections with SARS-CoV-2 through Nov 14, 2021: a statistical analysis.

COVID-19 Cumulative Infection Collaborators
Background
Timely, accurate, and comprehensive estimates of SARS-CoV-2 daily infection rates, cumulative infections, the proportion of the population that has been infected at least once, and the effective reproductive number (Reffective) are essential for understanding the determinants of past infection, current transmission patterns, and a population\'s susceptibility to future infection with the same variant. Although several studies have estimated cumulative SARS-CoV-2 infections in select locations at specific points in time, all of these analyses have relied on biased data inputs that were not adequately corrected for. In this study, we aimed to provide a novel approach to estimating past SARS-CoV-2 daily infections, cumulative infections, and the proportion of the population infected, for 190 countries and territories from the start of the pandemic to Nov 14, 2021. This approach combines data from reported cases, reported deaths, excess deaths attributable to COVID-19, hospitalisations, and seroprevalence surveys to produce more robust estimates that minimise constituent biases.
Methods
We produced a comprehensive set of global and location-specific estimates of daily and cumulative SARS-CoV-2 infections through Nov 14, 2021, using data largely from Johns Hopkins University (Baltimore, MD, USA) and national databases for reported cases, hospital admissions, and reported deaths, as well as seroprevalence surveys identified through previous reviews, SeroTracker, and governmental organisations. We corrected these data for known biases such as lags in reporting, accounted for under-reporting of deaths by use of a statistical model of the proportion of excess mortality attributable to SARS-CoV-2, and adjusted seroprevalence surveys for waning antibody sensitivity, vaccinations, and reinfection from SARS-CoV-2 escape variants. We then created an empirical database of infection-detection ratios (IDRs), infection-hospitalisation ratios (IHRs), and infection-fatality ratios (IFRs). To estimate a complete time series for each location, we developed statistical models to predict the IDR, IHR, and IFR by location and day, testing a set of predictors justified through published systematic reviews. Next, we combined three series of estimates of daily infections (cases divided by IDR, hospitalisations divided by IHR, and deaths divided by IFR), into a more robust estimate of daily infections. We then used daily infections to estimate cumulative infections and the cumulative proportion of the population with one or more infections, and we then calculated posterior estimates of cumulative IDR, IHR, and IFR using cumulative infections and the corrected data on reported cases, hospitalisations, and deaths. Finally, we converted daily infections into a historical time series of Reffective by location and day based on assumptions of duration from infection to infectiousness and time an individual spent being infectious. For each of these quantities, we estimated a distribution based on an ensemble framework that captured uncertainty in data sources, model design, and parameter assumptions.
Findings
Global daily SARS-CoV-2 infections fluctuated between 3 million and 17 million new infections per day between April, 2020, and October, 2021, peaking in mid-April, 2021, primarily as a result of surges in India. Between the start of the pandemic and Nov 14, 2021, there were an estimated 3·80 billion (95% uncertainty interval 3·44-4·08) total SARS-CoV-2 infections and reinfections combined, and an estimated 3·39 billion (3·08-3·63) individuals, or 43·9% (39·9-46·9) of the global population, had been infected one or more times. 1·34 billion (1·20-1·49) of these infections occurred in south Asia, the highest among the seven super-regions, although the sub-Saharan Africa super-region had the highest infection rate (79·3 per 100 population [69·0-86·4]). The high-income super-region had the fewest infections (239 million [226-252]), and southeast Asia, east Asia, and Oceania had the lowest infection rate (13·0 per 100 population [8·4-17·7]). The cumulative proportion of the population ever infected varied greatly between countries and territories, with rates higher than 70% in 40 countries and lower than 20% in 39 countries. There was no discernible relationship between Reffective and total immunity, and even at total immunity levels of 80%, we observed no indication of an abrupt drop in Reffective, indicating that there is not a clear herd immunity threshold observed in the data.
Interpretation
COVID-19 has already had a staggering impact on the world up to the beginning of the omicron (B.1.1.529) wave, with over 40% of the global population infected at least once by Nov 14, 2021. The vast differences in cumulative proportion of the population infected across locations could help policy makers identify the transmission-prevention strategies that have been most effective, as well as the populations at greatest risk for future infection. This information might also be useful for targeted transmission-prevention interventions, including vaccine prioritisation. Our statistical approach to estimating SARS-CoV-2 infection allows estimates to be updated and disseminated rapidly on the basis of newly available data, which has and will be crucially important for timely COVID-19 research, science, and policy responses.
Funding
Bill & Melinda Gates Foundation, J Stanton, T Gillespie, and J and E Nordstrom.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 08 Apr 2022; epub ahead of print
COVID-19 Cumulative Infection Collaborators
Lancet: 08 Apr 2022; epub ahead of print | PMID: 35405084
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Abstract

Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design.

Fizazi K, Foulon S, Carles J, Roubaud G, ... Bossi A, PEACE-1 investigators
Background
Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care.
Methods
We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436.
Findings
Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8-4·6) for radiographic progression-free survival and 4·4 years (3·5-5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41-0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69-0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34-0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59-0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone.
Interpretation
Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients.
Funding
Janssen-Cilag, Ipsen, Sanofi, and the French Government.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 08 Apr 2022; epub ahead of print
Fizazi K, Foulon S, Carles J, Roubaud G, ... Bossi A, PEACE-1 investigators
Lancet: 08 Apr 2022; epub ahead of print | PMID: 35405085
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Abstract

Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study.

Menni C, Valdes AM, Polidori L, Antonelli M, ... Ourselin S, Spector TD
Background
The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population.
Methods
In this prospective longitudinal observational study, we collected data from participants who were self-reporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16-99 years, based in the UK, with a body-mass index between 15 and 55 kg/m2, had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence.
Findings
Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16-0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43-1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57-0·98, p=0·03).
Interpretation
The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work-health policies and public health advice.
Funding
Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, and Medical Research Council.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 07 Apr 2022; epub ahead of print
Menni C, Valdes AM, Polidori L, Antonelli M, ... Ourselin S, Spector TD
Lancet: 07 Apr 2022; epub ahead of print | PMID: 35397851
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Abstract

Health system performance in Iran: a systematic analysis for the Global Burden of Disease Study 2019.

GBD 2019 Iran Collaborators
Background
Better evaluation of existing health programmes, appropriate policy making against emerging health threats, and reducing inequalities in Iran rely on a comprehensive national and subnational breakdown of the burden of diseases, injuries, and risk factors.
Methods
In this systematic analysis, we present the national and subnational estimates of the burden of disease in Iran using the Global Burden of Disease Study 2019. We report trends in demographics, all-cause and cause-specific mortality, as well as years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) caused by major diseases and risk factors. A multi-intervention segmented-regression model was used to explore the overall impact of health sector changes and sanctions. For this analysis, we used a variety of sources and reports, including vital registration, census, and survey data to provide estimates of mortality and morbidity at the national and subnational level in Iran.
Findings
Iran, which had 84·3 million inhabitants in 2019, had a life expectancy of 79·6 years (95% uncertainty interval 79·2-79·9) in female individuals and 76·1 (75·6-76·5) in male individuals, an increase compared with 1990. The number of DALYs remained stable and reached 19·8 million (17·3-22·6) in 2019, of which 78·1% were caused by non-communicable diseases (NCDs) compared with 43·0% in 1990. During the study period, age-standardised DALY rates and YLL rates decreased considerably; however, YLDs remained nearly constant. The share of age-standardised YLDs contributing to the DALY rate steadily increased to 44·5% by 2019. With regard to the DALY rates of different provinces, inequalities were decreasing. From 1990 to 2019, although the number of DALYs attributed to all risk factors decreased by 16·8%, deaths attributable to all risk factors substantially grew by 43·8%. The regression results revealed a significant negative association between sanctions and health status.
Interpretation
The Iranian health-care system is encountering NCDs as its new challenge, which necessitates a coordinated multisectoral approach. Although the Iranian health-care system has been successful to some extent in controlling mortality, it has overlooked the burden of morbidity and need for rehabilitation. We did not capture alleviation of the burden of diseases in Iran following the 2004 and 2014 health sector reforms; however, the sanctions were associated with deaths of Iranians caused by NCDs.
Funding
Bill & Melinda Gates Foundation.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 06 Apr 2022; epub ahead of print
GBD 2019 Iran Collaborators
Lancet: 06 Apr 2022; epub ahead of print | PMID: 35397236
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Abstract

Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study.

Nyberg T, Ferguson NM, Nash SG, Webster HH, ... Presanis AM, Thelwall S
Background
The omicron variant (B.1.1.529) of SARS-CoV-2 has demonstrated partial vaccine escape and high transmissibility, with early studies indicating lower severity of infection than that of the delta variant (B.1.617.2). We aimed to better characterise omicron severity relative to delta by assessing the relative risk of hospital attendance, hospital admission, or death in a large national cohort.
Methods
Individual-level data on laboratory-confirmed COVID-19 cases resident in England between Nov 29, 2021, and Jan 9, 2022, were linked to routine datasets on vaccination status, hospital attendance and admission, and mortality. The relative risk of hospital attendance or admission within 14 days, or death within 28 days after confirmed infection, was estimated using proportional hazards regression. Analyses were stratified by test date, 10-year age band, ethnicity, residential region, and vaccination status, and were further adjusted for sex, index of multiple deprivation decile, evidence of a previous infection, and year of age within each age band. A secondary analysis estimated variant-specific and vaccine-specific vaccine effectiveness and the intrinsic relative severity of omicron infection compared with delta (ie, the relative risk in unvaccinated cases).
Findings
The adjusted hazard ratio (HR) of hospital attendance (not necessarily resulting in admission) with omicron compared with delta was 0·56 (95% CI 0·54-0·58); for hospital admission and death, HR estimates were 0·41 (0·39-0·43) and 0·31 (0·26-0·37), respectively. Omicron versus delta HR estimates varied with age for all endpoints examined. The adjusted HR for hospital admission was 1·10 (0·85-1·42) in those younger than 10 years, decreasing to 0·25 (0·21-0·30) in 60-69-year-olds, and then increasing to 0·47 (0·40-0·56) in those aged at least 80 years. For both variants, past infection gave some protection against death both in vaccinated (HR 0·47 [0·32-0·68]) and unvaccinated (0·18 [0·06-0·57]) cases. In vaccinated cases, past infection offered no additional protection against hospital admission beyond that provided by vaccination (HR 0·96 [0·88-1·04]); however, for unvaccinated cases, past infection gave moderate protection (HR 0·55 [0·48-0·63]). Omicron versus delta HR estimates were lower for hospital admission (0·30 [0·28-0·32]) in unvaccinated cases than the corresponding HR estimated for all cases in the primary analysis. Booster vaccination with an mRNA vaccine was highly protective against hospitalisation and death in omicron cases (HR for hospital admission 8-11 weeks post-booster vs unvaccinated: 0·22 [0·20-0·24]), with the protection afforded after a booster not being affected by the vaccine used for doses 1 and 2.
Interpretation
The risk of severe outcomes following SARS-CoV-2 infection is substantially lower for omicron than for delta, with higher reductions for more severe endpoints and significant variation with age. Underlying the observed risks is a larger reduction in intrinsic severity (in unvaccinated individuals) counterbalanced by a reduction in vaccine effectiveness. Documented previous SARS-CoV-2 infection offered some protection against hospitalisation and high protection against death in unvaccinated individuals, but only offered additional protection in vaccinated individuals for the death endpoint. Booster vaccination with mRNA vaccines maintains over 70% protection against hospitalisation and death in breakthrough confirmed omicron infections.
Funding
Medical Research Council, UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research, Community Jameel, and Engineering and Physical Sciences Research Council.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 02 Apr 2022; 399:1303-1312
Nyberg T, Ferguson NM, Nash SG, Webster HH, ... Presanis AM, Thelwall S
Lancet: 02 Apr 2022; 399:1303-1312 | PMID: 35305296
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Abstract

Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India.

Khobragade A, Bhate S, Ramaiah V, Deshpande S, ... Koradia P, ZyCoV-D phase 3 Study Investigator Group
Background
ZyCoV-D, a DNA-based vaccine, showed promising safety and immunogenicity in a phase 1/2 trial. We now report the interim efficacy results of phase 3 clinical trial with ZyCoV-D vaccine in India.
Methods
We conducted an interim analysis of a multicentre, double-blind, randomised, placebo-controlled phase 3 trial at 49 centres in India. Healthy participants aged at least 12 years were enrolled and randomly assigned (1:1) to receive either ZyCov-D vaccine (Cadila Healthcare; 2 mg per dose) or placebo. An interactive web response system was used for randomisation (blocks of four) of participants as well as to enrol those aged 60 years and older with or without comorbid conditions, and those aged 12-17 years. It was also used to identify 600 participants for immunogenicity (blocks of six). Participants, investigators, and outcome assessors were masked to treatment assignment. Three doses of vaccine or placebo were administered intradermally via a needle-free injection system 28 days apart. The primary outcome was the number of participants with first occurrence of symptomatic RT-PCR-positive COVID-19 28 days after the third dose, until the targeted number of cases (interim analysis n=79, full analysis n=158) have been achieved. The analysis was done in the per-protocol population, which consisted of all participants with negative baseline SARS-CoV-2 status who received three doses of vaccine or placebo. Assessment of safety and tolerability was based on the safety population, which consisted of all enrolled participants who were known to have received at least one dose of study vaccine or placebo. This trial is registered with Clinical Trial Registry India, CTRI/2021/01/030416, and is ongoing.
Findings
Between Jan 16, and June 23, 2021 (data cutoff), 33 194 individuals were screened, of whom 5241 did not meet screening criteria and 27 703 were enrolled and randomly assigned to receive ZyCoV-D (n=13 851) or placebo (n=13 852). Per-protocol, 81 cases were eligible and included in efficacy analysis (20 of 12 350 in the ZyCoV-D group and 61 of 12 320 in placebo group). The ZyCoV-D vaccine efficacy was found to be 66·6% (95% CI 47·6-80·7). The occurrence of solicited adverse events was similar between the treatment groups (623 [4·49%] in the ZyCoV-D group vs 620 [4·47%] in the placebo group). There were two deaths (one in each group) reported at the data cutoff, neither of which was considered related to the study treatments.
Interpretation
In this interim analysis, ZyCoV-D vaccine was found to be efficacious, safe, and immunogenic in a phase 3 trial.
Funding
National Biopharma Mission, Department of Biotechnology, Government of India and Cadila Healthcare, Ahmedabad, Gujarat India.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 02 Apr 2022; 399:1313-1321
Khobragade A, Bhate S, Ramaiah V, Deshpande S, ... Koradia P, ZyCoV-D phase 3 Study Investigator Group
Lancet: 02 Apr 2022; 399:1313-1321 | PMID: 35367003
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Abstract

Rubella.

Winter AK, Moss WJ
Rubella is an acute illness caused by rubella virus and characterised by fever and rash. Although rubella is a clinically mild illness, primary rubella virus infection in early pregnancy can result in congenital rubella syndrome, which has serious medical and public health consequences. WHO estimates that approximately 100 000 congenital rubella syndrome cases occur per year. Rubella virus is transmitted through respiratory droplets and direct contact. 25-50% of people infected with rubella virus are asymptomatic. Clinical disease often results in mild, self-limited illness characterised by fever, a generalised erythematous maculopapular rash, and lymphadenopathy. Complications include arthralgia, arthritis, thrombocytopenic purpura, and encephalitis. Common presenting signs and symptoms of congenital rubella syndrome include cataracts, sensorineural hearing impairment, congenital heart disease, jaundice, purpura, hepatosplenomegaly, and microcephaly. Rubella and congenital rubella syndrome can be prevented by rubella-containing vaccines, which are commonly administered in combination with measles vaccine. Although global rubella vaccine coverage reached only 70% in 2020 global rubella eradiation remains an ambitious but achievable goal.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 02 Apr 2022; 399:1336-1346
Winter AK, Moss WJ
Lancet: 02 Apr 2022; 399:1336-1346 | PMID: 35367004
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Abstract

Acute coronary syndromes.

Bergmark BA, Mathenge N, Merlini PA, Lawrence-Wright MB, Giugliano RP
Although substantial progress has been made in the diagnosis and treatment of acute coronary syndromes, cardiovascular disease remains the leading cause of death globally, with nearly half of these deaths due to ischaemic heart disease. The broadening availability of high-sensitivity troponin assays has allowed for rapid rule-out algorithms in patients with suspected non-ST-segment elevated myocardial infarction (NSTEMI). Dual antiplatelet therapy is recommended for 12 months following an acute coronary syndrome in most patients, and additional secondary prevention measures including intensive lipid-lowering therapy (LDL-C <1·4 mmol/L), neurohormonal agents, and lifestyle modification, are crucial. The scientific evidence for diagnosis and management of acute coronary syndromes continues to evolve rapidly, including adapting to the COVID-19 pandemic, which has impacted all aspects of care. This Seminar provides a clinically relevant overview of the pathobiology, diagnosis, and management of acute coronary syndromes, and describes key scientific advances.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 02 Apr 2022; 399:1347-1358
Bergmark BA, Mathenge N, Merlini PA, Lawrence-Wright MB, Giugliano RP
Lancet: 02 Apr 2022; 399:1347-1358 | PMID: 35367005
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Abstract

Aggressive intraoperative warming versus routine thermal management during non-cardiac surgery (PROTECT): a multicentre, parallel group, superiority trial.

Sessler DI, Pei L, Li K, Cui S, ... Lam CKM, PROTECT Investigators
Background
Moderate intraoperative hypothermia promotes myocardial injury, surgical site infections, and blood loss. Whether aggressive warming to a truly normothermic temperature near 37°C improves outcomes remains unknown. We aimed to test the hypothesis that aggressive intraoperative warming reduces major perioperative complications.
Methods
In this multicentre, parallel group, superiority trial, patients at 12 sites in China and at the Cleveland Clinic in the USA were randomly assigned (1:1) to receive either aggressive warming to a target core temperature of 37°C (aggressively warmed group) or routine thermal management to a target of 35·5°C (routine thermal management group) during non-cardiac surgery. Randomisation was stratified by site, with computer-generated, randomly sized blocks. Eligible patients (aged ≥45 years) had at least one cardiovascular risk factor, were scheduled for inpatient non-cardiac surgery expected to last 2-6 h with general anaesthesia, and were expected to have at least half of the anterior skin surface available for warming. Patients requiring dialysis and those with a body-mass index exceeding 30 kg/m2 were excluded. The primary outcome was a composite of myocardial injury (troponin elevation, apparently of ischaemic origin), non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery, as assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03111875.
Findings
Between March 27, 2017, and March 16, 2021, 5056 participants were enrolled, of whom 5013 were included in the intention-to-treat population (2507 in the aggressively warmed group and 2506 in the routine thermal management group). Patients assigned to aggressive warming had a mean final intraoperative core temperature of 37·1°C (SD 0·3) whereas the routine thermal management group averaged 35·6°C (SD 0·3). At least one of the primary outcome components (myocardial injury after non-cardiac surgery, cardiac arrest, or mortality) occurred in 246 (9·9%) of 2497 patients in the aggressively warmed group and in 239 (9·6%) of 2490 patients in the routine thermal management group. The common effect relative risk of aggressive versus routine thermal management was an estimated 1·04 (95% CI 0·87-1·24, p=0·69). There were 39 adverse events in patients assigned to aggressive warming (17 of which were serious) and 54 in those assigned to routine thermal management (30 of which were serious). One serious adverse event, in an aggressively warmed patient, was deemed to be possibly related to thermal management.
Interpretation
The incidence of a 30-day composite of major cardiovascular outcomes did not differ significantly in patients randomised to 35·5°C and to 37°C. At least over a 1·5°C range from very mild hypothermia to full normothermia, there was no evidence that any substantive outcome varied. Keeping core temperature at least 35·5°C in surgical patients appears sufficient.
Funding
3M and the Health and Medical Research Fund, Food and Health Bureau, Hong Kong.
Translation
For the Chinese translation of the abstract see Supplementary Materials section.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 01 Apr 2022; epub ahead of print
Sessler DI, Pei L, Li K, Cui S, ... Lam CKM, PROTECT Investigators
Lancet: 01 Apr 2022; epub ahead of print | PMID: 35390321
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Abstract

Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial.

Delany-Moretlwe S, Hughes JP, Bock P, Ouma SG, ... Hosseinipour MC, HPTN 084 study group
Background
Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women.
Methods
HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564.
Findings
From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -2% [-1·3% to -2·7%]). In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported.
Interpretation
Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women.
Funding
National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 01 Apr 2022; epub ahead of print
Delany-Moretlwe S, Hughes JP, Bock P, Ouma SG, ... Hosseinipour MC, HPTN 084 study group
Lancet: 01 Apr 2022; epub ahead of print | PMID: 35378077
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Impact:
Abstract

Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.

Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, ... Eggermont AMM, KEYNOTE-716 Investigators
Background
Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival.
Methods
In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12-17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual.
Findings
Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52-69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2-18·7] in the pembrolizumab group and 14·3 months [10·1-18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46-0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7-25·3] in the pembrolizumab group and 20·9 months [16·6-25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45-0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3-4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred.
Interpretation
Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile.
Funding
Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 31 Mar 2022; epub ahead of print
Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, ... Eggermont AMM, KEYNOTE-716 Investigators
Lancet: 31 Mar 2022; epub ahead of print | PMID: 35367007
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Impact:
Abstract

Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

McDonald CM, Marbán E, Hendrix S, Hogan N, ... Marbán L, HOPE-2 Study Group
Background
Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy.
Methods
In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780.
Findings
Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7-59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred.
Interpretation
CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy.
Funding
Capricor Therapeutics.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 11 Mar 2022; 399:1049-1058
McDonald CM, Marbán E, Hendrix S, Hogan N, ... Marbán L, HOPE-2 Study Group
Lancet: 11 Mar 2022; 399:1049-1058 | PMID: 35279258
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Abstract

Transmission of SARS-CoV-2 delta variant (AY.127) from pet hamsters to humans, leading to onward human-to-human transmission: a case study.

Yen HL, Sit THC, Brackman CJ, Chuk SSY, ... Poon LLM, HKU-SPH study team
Background
Transmission of SARS-CoV-2 from humans to other mammals, including pet animals, has been reported. However, with the exception of farmed mink, there is no previous evidence that these infected animals can infect humans, resulting in sustained human-to-human transmission. Following a confirmed SARS-CoV-2 infection of a pet shop worker, animals in the shop and the warehouse supplying it were tested for evidence of SARS-CoV-2 infection.
Methods
In this case study, viral swabs and blood samples were collected from animals in a pet shop and its corresponding warehouse in Hong Kong. Nasal swab or saliva samples from human COVID-19 patients epidemiologically linked to the pet shop and from subsequent local cases confirmed to be infected by SARS-CoV-2 delta variant were collected. Oral swabs were tested by quantitative RT-PCR (RT-qPCR) for SARS-CoV-2 and blood samples were serologically tested by a surrogate virus neutralisation test and plaque reduction neutralisation test. The SARS-CoV-2 RT-qPCR positive samples were sequenced by next generation viral full genome sequencing using the ISeq sequencing platform (Illumina), and the viral genomes were phylogenetically analysed.
Findings
Eight (50%) of 16 individually tested Syrian hamsters in the pet shop and seven (58%) of 12 Syrian hamsters in the corresponding warehouse were positive for SARS-CoV-2 infection in RT-qPCR or serological tests. None of the dwarf hamsters (n=75), rabbits (n=246), guinea pigs (n=66), chinchillas (n=116), and mice (n=2) were confirmed positive for SARS-CoV-2 in RT-qPCR tests. SARS-CoV-2 viral genomes deduced from human and hamster cases in this incident all belong to the delta variant of concern (AY.127) that had not been circulating locally before this outbreak. The viral genomes obtained from hamsters were phylogenetically related with some sequence heterogeneity. Phylogenetic dating suggests infection in these hamsters occurred around Oct 14, 2021 (95% CI Sept 15 to Nov 9, 2021). Multiple zoonotic transmission events to humans were detected, leading to onward human-to-human transmission.
Interpretation
Pet hamsters can be naturally infected with SARS-CoV-2. The virus can circulate among hamsters and lead to human infections. Both genetic and epidemiological results strongly suggest that there was more than one hamster-to-human transmission event in this study. This incident also led to onward human transmission. Importation of SARS-CoV-2-infected hamsters was a likely source of this outbreak.
Funding
US National Institutes of Health, Research Grants Council of Hong Kong, Food and Health Bureau, and InnoHK.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 11 Mar 2022; 399:1070-1078
Yen HL, Sit THC, Brackman CJ, Chuk SSY, ... Poon LLM, HKU-SPH study team
Lancet: 11 Mar 2022; 399:1070-1078 | PMID: 35279259
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Abstract

Drug therapy for osteoporosis in older adults.

Reid IR, Billington EO
The goal of osteoporosis management is to prevent fractures. Several pharmacological agents are available to lower fracture risk, either by reducing bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used anti-resorptives, reducing bone turnover markers to low premenopausal concentrations and reducing fracture rates (vertebral by 50-70%, non-vertebral by 20-30%, and hip by ~40%). Bisphosphonates bind avidly to bone mineral and have an offset of effect measured in months to years. Long term, continuous use of oral bisphosphonates is usually interspersed with drug holidays of 1-2 years, to minimise the risk of atypical femoral fractures. Denosumab is a monoclonal antibody against RANKL that potently inhibits osteoclast development and activity. Denosumab is administered by subcutaneous injection every 6 months. Anti-fracture effects of denosumab are similar to those of the bisphosphonates, but there is a pronounced loss of anti-resorptive effect from 7 months after the last injection, which can result in clusters of rebound vertebral fractures. Two classes of anabolic drugs are now available to stimulate bone formation. Teriparatide and abaloparatide both target the parathyroid hormone-1 receptor, and are given by daily subcutaneous injection for up to 2 years. Romosozumab is an anti-sclerostin monoclonal antibody that stimulates bone formation and inhibits resorption. Romosozumab is given as monthly subcutaneous injections for 1 year. Head-to-head studies suggest that anabolic agents have greater anti-fracture efficacy and produce larger increases in bone density than anti-resorptive drugs. The effects of anabolic agents are transient, so transition to anti-resorptive drugs is required. The optimal strategy for cycling anabolics, anti-resorptives, and off-treatment periods remains to be determined.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 11 Mar 2022; 399:1080-1092
Reid IR, Billington EO
Lancet: 11 Mar 2022; 399:1080-1092 | PMID: 35279261
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Impact:
Abstract

Progress in health among regions of Ethiopia, 1990-2019: a subnational country analysis for the Global Burden of Disease Study 2019.

GBD 2019 Ethiopia Subnational-Level Disease Burden Initiative Collaborators
Background
Previous Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) studies have reported national health estimates for Ethiopia. Substantial regional variations in socioeconomic status, population, demography, and access to health care within Ethiopia require comparable estimates at the subnational level. The GBD 2019 Ethiopia subnational analysis aimed to measure the progress and disparities in health across nine regions and two chartered cities.
Methods
We gathered 1057 distinct data sources for Ethiopia and all regions and cities that included census, demographic surveillance, household surveys, disease registry, health service use, disease notifications, and other data for this analysis. Using all available data sources, we estimated the Socio-demographic Index (SDI), total fertility rate (TFR), life expectancy, years of life lost, years lived with disability, disability-adjusted life-years, and risk-factor-attributable health loss with 95% uncertainty intervals (UIs) for Ethiopia\'s nine regions and two chartered cities from 1990 to 2019. Spatiotemporal Gaussian process regression, cause of death ensemble model, Bayesian meta-regression tool, DisMod-MR 2.1, and other models were used to generate fertility, mortality, cause of death, and disability rates. The risk factor attribution estimations followed the general framework established for comparative risk assessment.
Findings
The SDI steadily improved in all regions and cities from 1990 to 2019, yet the disparity between the highest and lowest SDI increased by 54% during that period. The TFR declined from 6·91 (95% UI 6·59-7·20) in 1990 to 4·43 (4·01-4·92) in 2019, but the magnitude of decline also varied substantially among regions and cities. In 2019, TFR ranged from 6·41 (5·96-6·86) in Somali to 1·50 (1·26-1·80) in Addis Ababa. Life expectancy improved in Ethiopia by 21·93 years (21·79-22·07), from 46·91 years (45·71-48·11) in 1990 to 68·84 years (67·51-70·18) in 2019. Addis Ababa had the highest life expectancy at 70·86 years (68·91-72·65) in 2019; Afar and Benishangul-Gumuz had the lowest at 63·74 years (61·53-66·01) for Afar and 64.28 (61.99-66.63) for Benishangul-Gumuz. The overall increases in life expectancy were driven by declines in under-5 mortality and mortality from common infectious diseases, nutritional deficiency, and war and conflict. In 2019, the age-standardised all-cause death rate was the highest in Afar at 1353·38 per 100 000 population (1195·69-1526·19). The leading causes of premature mortality for all sexes in Ethiopia in 2019 were neonatal disorders, diarrhoeal diseases, lower respiratory infections, tuberculosis, stroke, HIV/AIDS, ischaemic heart disease, cirrhosis, congenital defects, and diabetes. With high SDIs and life expectancy for all sexes, Addis Ababa, Dire Dawa, and Harari had low rates of premature mortality from the five leading causes, whereas regions with low SDIs and life expectancy for all sexes (Afar and Somali) had high rates of premature mortality from the leading causes. In 2019, child and maternal malnutrition; unsafe water, sanitation, and handwashing; air pollution; high systolic blood pressure; alcohol use; and high fasting plasma glucose were the leading risk factors for health loss across regions and cities.
Interpretation
There were substantial improvements in health over the past three decades across regions and chartered cities in Ethiopia. However, the progress, measured in SDI, life expectancy, TFR, premature mortality, disability, and risk factors, was not uniform. Federal and regional health policy makers should match strategies, resources, and interventions to disease burden and risk factors across regions and cities to achieve national and regional plans, Sustainable Development Goals, and universal health coverage targets.
Funding
Bill & Melinda Gates Foundation.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 10 Mar 2022; epub ahead of print
GBD 2019 Ethiopia Subnational-Level Disease Burden Initiative Collaborators
Lancet: 10 Mar 2022; epub ahead of print | PMID: 35294898
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Impact:
Abstract

Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020-21.

COVID-19 Excess Mortality Collaborators
Background
Mortality statistics are fundamental to public health decision making. Mortality varies by time and location, and its measurement is affected by well known biases that have been exacerbated during the COVID-19 pandemic. This paper aims to estimate excess mortality from the COVID-19 pandemic in 191 countries and territories, and 252 subnational units for selected countries, from Jan 1, 2020, to Dec 31, 2021.
Methods
All-cause mortality reports were collected for 74 countries and territories and 266 subnational locations (including 31 locations in low-income and middle-income countries) that had reported either weekly or monthly deaths from all causes during the pandemic in 2020 and 2021, and for up to 11 year previously. In addition, we obtained excess mortality data for 12 states in India. Excess mortality over time was calculated as observed mortality, after excluding data from periods affected by late registration and anomalies such as heat waves, minus expected mortality. Six models were used to estimate expected mortality; final estimates of expected mortality were based on an ensemble of these models. Ensemble weights were based on root mean squared errors derived from an out-of-sample predictive validity test. As mortality records are incomplete worldwide, we built a statistical model that predicted the excess mortality rate for locations and periods where all-cause mortality data were not available. We used least absolute shrinkage and selection operator (LASSO) regression as a variable selection mechanism and selected 15 covariates, including both covariates pertaining to the COVID-19 pandemic, such as seroprevalence, and to background population health metrics, such as the Healthcare Access and Quality Index, with direction of effects on excess mortality concordant with a meta-analysis by the US Centers for Disease Control and Prevention. With the selected best model, we ran a prediction process using 100 draws for each covariate and 100 draws of estimated coefficients and residuals, estimated from the regressions run at the draw level using draw-level input data on both excess mortality and covariates. Mean values and 95% uncertainty intervals were then generated at national, regional, and global levels. Out-of-sample predictive validity testing was done on the basis of our final model specification.
Findings
Although reported COVID-19 deaths between Jan 1, 2020, and Dec 31, 2021, totalled 5·94 million worldwide, we estimate that 18·2 million (95% uncertainty interval 17·1-19·6) people died worldwide because of the COVID-19 pandemic (as measured by excess mortality) over that period. The global all-age rate of excess mortality due to the COVID-19 pandemic was 120·3 deaths (113·1-129·3) per 100 000 of the population, and excess mortality rate exceeded 300 deaths per 100 000 of the population in 21 countries. The number of excess deaths due to COVID-19 was largest in the regions of south Asia, north Africa and the Middle East, and eastern Europe. At the country level, the highest numbers of cumulative excess deaths due to COVID-19 were estimated in India (4·07 million [3·71-4·36]), the USA (1·13 million [1·08-1·18]), Russia (1·07 million [1·06-1·08]), Mexico (798 000 [741 000-867 000]), Brazil (792 000 [730 000-847 000]), Indonesia (736 000 [594 000-955 000]), and Pakistan (664 000 [498 000-847 000]). Among these countries, the excess mortality rate was highest in Russia (374·6 deaths [369·7-378·4] per 100 000) and Mexico (325·1 [301·6-353·3] per 100 000), and was similar in Brazil (186·9 [172·2-199·8] per 100 000) and the USA (179·3 [170·7-187·5] per 100 000).
Interpretation
The full impact of the pandemic has been much greater than what is indicated by reported deaths due to COVID-19 alone. Strengthening death registration systems around the world, long understood to be crucial to global public health strategy, is necessary for improved monitoring of this pandemic and future pandemics. In addition, further research is warranted to help distinguish the proportion of excess mortality that was directly caused by SARS-CoV-2 infection and the changes in causes of death as an indirect consequence of the pandemic.
Funding
Bill & Melinda Gates Foundation, J Stanton, T Gillespie, and J and E Nordstrom.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 09 Mar 2022; epub ahead of print
COVID-19 Excess Mortality Collaborators
Lancet: 09 Mar 2022; epub ahead of print | PMID: 35279232
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Impact:
Abstract

Efficacy and safety of gefapixant, a P2X receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials.

McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, ... Smith JA, COUGH-1 and COUGH-2 Investigators
Background
Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough.
Methods
COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2).
Findings
From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9-0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1-1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2).
Interpretation
Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough.
Funding
Merck Sharp & Dohme.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.

Lancet: 04 Mar 2022; 399:909-923
McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, ... Smith JA, COUGH-1 and COUGH-2 Investigators
Lancet: 04 Mar 2022; 399:909-923 | PMID: 35248186
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Impact:
Abstract

Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial.

Craig T, Magerl M, Levy DS, Reshef A, ... Pragst I, Doyle MK
Background
Hereditary angioedema is associated with dysregulation of the kallikrein-kinin system. Factor XII (FXII) is a key initiator of the kallikrein-kinin system, which produces bradykinin, a central mediator of angioedema. Garadacimab (CSL Behring) is a first-in-class, fully human, immunoglobulin G4 monoclonal antibody targeting activated FXII, intended to prevent attacks in patients with C1-esterase inhibitor-deficient hereditary angioedema (HAE-C1-INH). We aimed to investigate garadacimab as a treatment every 4 weeks for patients with HAE-C1-INH.
Methods
In this double-blind, placebo-controlled, phase 2 study, patients with HAE-C1-INH were recruited from 12 research centres in Canada, Germany, Israel, and the USA. Eligible patients were aged 18-65 years and must have had at least four attacks of any severity over a consecutive 2-month period during the 3 months before screening or initiation of previous hereditary angioedema prophylaxis. After a run-in period of 4-8 weeks, patients were randomly assigned (1:1:1:1), using an interactive response technology via block randomisation (block sizes of 1-4), to either placebo or 75 mg, 200 mg, or 600 mg garadacimab. Patients were given an initial intravenous loading dose, and then, on day 6 and every 4 weeks for 12 weeks, they were given a subcutaneous dose of their allocated treatment. The primary endpoint was the number of monthly attacks in the intention-to-treat population (defined as all patients who underwent screening, provided consent, and were assigned to treatment) during the 12-week subcutaneous administration period assessed in the 200 mg and 600 mg garadacimab groups versus placebo. Safety was assessed in all patients who received at least one dose or partial dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03712228.
Findings
Between Oct 29, 2018, and Aug 28, 2019, 54 patients were screened, of whom 32 were randomly assigned to either placebo (n=8) or 75 mg (n=9), 200 mg (n=8), or 600 mg (n=7) garadacimab. The median age was 39·5 years (28·0-52·5) and 18 (56%) of 32 patients were female and 14 (34%) were male. The median number of monthly attacks during the 12-week subcutaneous treatment period was 4·6 (IQR 3·1-5·0) with placebo, 0·0 (0·0-0·4) with 75 mg garadacimab, 0·0 (0·0-0·0) with 200 mg garadacimab, and 0·3 (0·0-0·7) with 600 mg garadacimab. Compared with placebo, the rate of attacks was significantly reduced with garadacimab at 200 mg (reduced by 100% [95% CI 98-101]; p=0·0002) and 600 mg (reduced by 93% [54-110]; p=0·0003). No serious adverse events, deaths, or adverse events of special interest (anaphylaxis, thromboembolic events, and bleeding events) were observed.
Interpretation
Garadacimab 200 mg and 600 mg every 4 weeks significantly reduced the number of monthly attacks versus placebo and was well tolerated during the study. Garadacimab is an efficacious, subcutaneous prophylaxis in patients with HAE-C1-INH and warrants phase 3 evaluation.
Funding
CSL Behring.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 04 Mar 2022; 399:945-955
Craig T, Magerl M, Levy DS, Reshef A, ... Pragst I, Doyle MK
Lancet: 04 Mar 2022; 399:945-955 | PMID: 35219377
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Abstract

Quantifying the effects of the COVID-19 pandemic on gender equality on health, social, and economic indicators: a comprehensive review of data from March, 2020, to September, 2021.

Flor LS, Friedman J, Spencer CN, Cagney J, ... Gakidou E, Gender Equality Metrics team and the COVID-19 Forecasting team at the Institute for Health Metrics and Evaluation
Background
Gender is emerging as a significant factor in the social, economic, and health effects of COVID-19. However, most existing studies have focused on its direct impact on health. Here, we aimed to explore the indirect effects of COVID-19 on gender disparities globally.
Methods
We reviewed publicly available datasets with information on indicators related to vaccine hesitancy and uptake, health care services, economic and work-related concerns, education, and safety at home and in the community. We used mixed effects regression, Gaussian process regression, and bootstrapping to synthesise all data sources. We accounted for uncertainty in the underlying data and modelling process. We then used mixed effects logistic regression to explore gender gaps globally and by region.
Findings
Between March, 2020, and September, 2021, women were more likely to report employment loss (26·0% [95% uncertainty interval 23·8-28·8, by September, 2021) than men (20·4% [18·2-22·9], by September, 2021), as well as forgoing work to care for others (ratio of women to men: 1·8 by March, 2020, and 2·4 by September, 2021). Women and girls were 1·21 times (1·20-1·21) more likely than men and boys to report dropping out of school for reasons other than school closures. Women were also 1·23 (1·22-1·23) times more likely than men to report that gender-based violence had increased during the pandemic. By September 2021, women and men did not differ significantly in vaccine hesitancy or uptake.
Interpretation
The most significant gender gaps identified in our study show intensified levels of pre-existing widespread inequalities between women and men during the COVID-19 pandemic. Political and social leaders should prioritise policies that enable and encourage women to participate in the labour force and continue their education, thereby equipping and enabling them with greater ability to overcome the barriers they face.
Funding
The Bill & Melinda Gates Foundation.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 01 Mar 2022; epub ahead of print
Flor LS, Friedman J, Spencer CN, Cagney J, ... Gakidou E, Gender Equality Metrics team and the COVID-19 Forecasting team at the Institute for Health Metrics and Evaluation
Lancet: 01 Mar 2022; epub ahead of print | PMID: 35247311
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Abstract

Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial.

van der Steen W, van de Graaf RA, Chalos V, Lingsma HF, ... Roozenbeek B, MR CLEAN-MED investigators
Background
Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke.
Methods
We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621.
Findings
Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13-3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14-3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69-1·21]) and unfractionated heparin (0·81 [0·61-1·08]) led to a non-significant shift towards worse modified Rankin Scale scores.
Interpretation
Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome.
Funding
The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 27 Feb 2022; epub ahead of print
van der Steen W, van de Graaf RA, Chalos V, Lingsma HF, ... Roozenbeek B, MR CLEAN-MED investigators
Lancet: 27 Feb 2022; epub ahead of print | PMID: 35240044
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Abstract

Comparative efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the maintenance treatment of adults with schizophrenia: a systematic review and network meta-analysis.

Schneider-Thoma J, Chalkou K, Dörries C, Bighelli I, ... Salanti G, Leucht S
Background
Schizophrenia is a common, severe, and usually chronic disorder. Maintenance treatment with antipsychotic drugs can prevent relapse but also causes side-effects. We aimed to compare the efficacy and tolerability of antipsychotics as maintenance treatment for non-treatment resistant patients with schizophrenia.
Methods
In this systematic review and network meta-analysis, we searched, without language restrictions, the Cochrane Schizophrenia Group\'s specialised register between database inception and April 27, 2020, PubMed from April 1, 2020, to Jan 15, 2021, and the lists of included studies from related systematic reviews. We included randomised controlled trials (RCTs; ≥12 weeks of follow-up) that recruited adult participants with schizophrenia or schizoaffective disorder with stable symptoms who were treated with antipsychotics (monotherapy; oral or long-acting injectable) or placebo. We excluded RCTs of participants with specific comorbidities or treatment resistance. In duplicate, two authors independently selected eligible RCTs and extracted aggregate data. The primary outcome was the number of participants who relapsed and was analysed by random-effects, Bayesian network meta-analyses. The study was registered on PROSPERO, CRD42016049022.
Findings
We identified 4157 references through our search, from which 501 references on 127 RCTs of 32 antipsychotics (comprising 18 152 participants) were included. 100 studies including 16 812 participants and 30 antipsychotics contributed to our network meta-analysis of the primary outcome. All antipsychotics had risk ratios (RRs) less than 1·00 when compared with placebo for relapse prevention and almost all had 95% credible intervals (CrIs) excluding no effect. RRs ranged from 0·20 (95% CrI 0·05-0·41) for paliperidone oral to 0·65 (0·16-1·14) for cariprazine oral (moderate-to-low confidence in estimates). Generally, we interpret that there was no clear evidence for the superiority of specific antipsychotics in terms of relapse prevention because most comparisons between antipsychotics included a probability of no difference.
Interpretation
As we found no clear differences between antipsychotics for relapse prevention, we conclude that the choice of antipsychotic for maintenance treatment should be guided mainly by their tolerability.
Funding
The German Ministry of Education and Research and Oxford Health Biomedical Research Centre.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Lancet: 25 Feb 2022; 399:824-836
Schneider-Thoma J, Chalkou K, Dörries C, Bighelli I, ... Salanti G, Leucht S
Lancet: 25 Feb 2022; 399:824-836 | PMID: 35219395
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Abstract

Variation in the COVID-19 infection-fatality ratio by age, time, and geography during the pre-vaccine era: a systematic analysis.

COVID-19 Forecasting Team
Background
The infection-fatality ratio (IFR) is a metric that quantifies the likelihood of an individual dying once infected with a pathogen. Understanding the determinants of IFR variation for COVID-19, the disease caused by the SARS-CoV-2 virus, has direct implications for mitigation efforts with respect to clinical practice, non-pharmaceutical interventions, and the prioritisation of risk groups for targeted vaccine delivery. The IFR is also a crucial parameter in COVID-19 dynamic transmission models, providing a way to convert a population\'s mortality rate into an estimate of infections.
Methods
We estimated age-specific and all-age IFR by matching seroprevalence surveys to total COVID-19 mortality rates in a population. The term total COVID-19 mortality refers to an estimate of the total number of deaths directly attributable to COVID-19. After applying exclusion criteria to 5131 seroprevalence surveys, the IFR analyses were informed by 2073 all-age surveys and 718 age-specific surveys (3012 age-specific observations). When seroprevalence was reported by age group, we split total COVID-19 mortality into corresponding age groups using a Bayesian hierarchical model to characterise the non-linear age pattern of reported deaths for a given location. To remove the impact of vaccines on the estimated IFR age pattern, we excluded age-specific observations of seroprevalence and deaths that occurred after vaccines were introduced in a location. We estimated age-specific IFR with a non-linear meta-regression and used the resulting age pattern to standardise all-age IFR observations to the global age distribution. All IFR observations were adjusted for baseline and waning antibody-test sensitivity. We then modelled age-standardised IFR as a function of time, geography, and an ensemble of 100 of the top-performing covariate sets. The covariates included seven clinical predictors (eg, age-standardised obesity prevalence) and two measures of health system performance. Final estimates for 190 countries and territories, as well as subnational locations in 11 countries and territories, were obtained by predicting age-standardised IFR conditional on covariates and reversing the age standardisation.
Findings
We report IFR estimates for April 15, 2020, to January 1, 2021, the period before the introduction of vaccines and widespread evolution of variants. We found substantial heterogeneity in the IFR by age, location, and time. Age-specific IFR estimates form a J shape, with the lowest IFR occurring at age 7 years (0·0023%, 95% uncertainty interval [UI] 0·0015-0·0039) and increasing exponentially through ages 30 years (0·0573%, 0·0418-0·0870), 60 years (1·0035%, 0·7002-1·5727), and 90 years (20·3292%, 14·6888-28·9754). The countries with the highest IFR on July 15, 2020, were Portugal (2·085%, 0·946-4·395), Monaco (1·778%, 1·265-2·915), Japan (1·750%, 1·302-2·690), Spain (1·710%, 0·991-2·718), and Greece (1·637%, 1·155-2·678). All-age IFR varied by a factor of more than 30 among 190 countries and territories. After age standardisation, the countries with the highest IFR on July 15, 2020, were Peru (0·911%, 0·636-1·538), Portugal (0·850%, 0·386-1·793), Oman (0·762%, 0·381-1·399), Spain (0·751%, 0·435-1·193), and Mexico (0·717%, 0·426-1·404). Subnational locations with high IFRs also included hotspots in the UK and southern and eastern states of the USA. Sub-Saharan African countries and Asian countries generally had the lowest all-age and age-standardised IFRs. Population age structure accounted for 74% of logit-scale variation in IFRs estimated for 39 in-sample countries on July 15, 2020. A post-hoc analysis showed that high rates of transmission in the care home population might account for higher IFRs in some locations. Among all countries and territories, we found that the median IFR decreased from 0·466% (interquartile range 0·223-0·840) to 0·314% (0·143-0·551) between April 15, 2020, and Jan 1, 2021.
Interpretation
Estimating the IFR for global populations helps to identify relative vulnerabilities to COVID-19. Information about how IFR varies by age, time, and location informs clinical practice and non-pharmaceutical interventions like physical distancing measures, and underpins vaccine risk stratification. IFR and mortality risk form a J shape with respect to age, which previous research, such as that by Glynn and Moss in 2020, has identified to be a common pattern among infectious diseases. Understanding the experience of a population with COVID-19 mortality requires consideration for local factors; IFRs varied by a factor of more than 30 among 190 countries and territories in this analysis. In particular, the presence of elevated age-standardised IFRs in countries with well resourced health-care systems indicates that factors beyond health-care capacity are important. Potential extenuating circumstances include outbreaks among care home residents, variable burdens of severe cases, and the population prevalence of comorbid conditions that increase the severity of COVID-19 disease. During the pre-vaccine period, the estimated 33% decrease in median IFR over 8 months suggests that treatment for COVID-19 has improved over time. Estimating IFR for the pre-vaccine era provides an important baseline for describing the progression of COVID-19 mortality patterns.
Funding
Bill & Melinda Gates Foundation, J Stanton, T Gillespie, and J and E Nordstrom.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 23 Feb 2022; epub ahead of print
COVID-19 Forecasting Team
Lancet: 23 Feb 2022; epub ahead of print | PMID: 35219376
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Impact:

This program is still in alpha version.