Groote Schuur Hospital

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Allergic rhinitis is a symptomatic disorder of the nose\ninduced after allergen exposure by an IgE-mediated\ninflammation of the membranes lining the nose. It is a\nglobal health problem that causes major illness and disability\nworldwide. Over 600 million patients from all\ncountries, all ethnic groups and of all ages suffer from\nallergic rhinitis. It affects social life, sleep, school and\nwork and its economic impact is substantial.\nRisk factors for allergic rhinitis are well identified.\nIndoor and outdoor allergens as well as occupational\nagents cause rhinitis and other allergic diseases.\nThe role of indoor and outdoor pollution is probably\nvery important, but has yet to be fully understood\nboth for the occurrence of the disease and its manifestations.\nIn 1999, during the Allergic Rhinitis and its Impact on\nAsthma (ARIA) WHO workshop, the expert panel\nproposed a new classification for allergic rhinitis which\nwas subdivided into _intermittent_ or _persistent_ disease.\nThis classification is now validated.\nThe diagnosis of allergic rhinitis is often quite easy, but\nin some cases it may cause problems and many patients\nare still under-diagnosed, often because they do not\nperceive the symptoms of rhinitis as a disease impairing\ntheir social life, school and work.\nThe management of allergic rhinitis is well established\nand the ARIA expert panel based its recommendations\non evidence using an extensive review of the literature\navailable up to December 1999. The statements of\nevidence for the development of these guidelines followed\nWHO rules and were based on those of Shekelle et al.\nA large number of papers have been published since 2000\nand are extensively reviewed in the 2008 Update using\nthe same evidence-based system. Recommendations for\nthe management of allergic rhinitis are similar in both the\nARIA workshop report and the 2008 Update. In the\nfuture, the GRADE approach will be used, but is not yet\navailable.\nAnother important aspect of the ARIA guidelines was\nto consider co-morbidities. Both allergic rhinitis and\nasthma are systemic inflammatory conditions and often\nco-exist in the same patients. In the 2008 Update, these\nlinks have been confirmed.\nTheARIAdocument is not intended to be a standard-ofcare\ndocument for individual countries. It is provided as a\nbasis for physicians, health care professionals and\norganizations involved in the treatment of allergic rhinitis\nand asthma in various countries to facilitate the\ndevelopment of relevant local standard-of-care documents\nfor patients.

Asthma is a serious health problem throughout the world. During the past two decades, many scientific advances have improved our understanding of asthma and ability to manage and control it effectively. However, recommendations for asthma care need to be adapted to local conditions, resources and services. Since it was formed in 1993, the Global Initiative for Asthma, a network of individuals, organisations and public health officials, has played a leading role in disseminating information about the care of patients with asthma based on a process of continuous review of published scientific investigations. A comprehensive workshop report entitled "A Global Strategy for Asthma Management and Prevention", first published in 1995, has been widely adopted, translated and reproduced, and forms the basis for many national guidelines. The 2006 report contains important new themes. First, it asserts that "it is reasonable to expect that in most patients with asthma, control of the disease can and should be achieved and maintained," and recommends a change in approach to asthma management, with asthma control, rather than asthma severity, being the focus of treatment decisions. The importance of the patient-care giver partnership and guided self-management, along with setting goals for treatment, are also emphasised.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Abstract The SARS-CoV-2 epidemic in southern Africa has been characterized by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, while the second and third waves were driven by the Beta (B.1.351) and Delta (B.1.617.2) variants, respectively 1–3 . In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron, B.1.1.529) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, which are predicted to influence antibody neutralization and spike function 4 . Here we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.

STUDY QUESTION: What updates of the International Glossary on Infertility and Fertility Care are required, to reflect contemporary scientific knowledge, social needs, and inclusive definitions, while harmonizing international communication across clinical, research, policy, and public domains? SUMMARY ANSWER: This 4th edition presents 348 consensus-based terms and definitions, including numerous revisions from the previous edition and 79 newly introduced definitions reflecting advances in reproductive science, technology, and evolving social contexts. WHAT IS KNOWN ALREADY: Previous glossary editions (2006, 2009, 2017) established internationally recognized definitions related to clinical practice, research, and policy. The 2017 edition comprised 283 terms and, among many others, expanded the concept of infertility to include not only its recognition as a disease, but also as an impairment of function generating disability. The glossary has been extensively used worldwide and has contributed to international standardization of data collection, appropriate comparison of outcome measures, and provided a reference for all stakeholders including policy makers. STUDY DESIGN, SIZE, DURATION: Under guidance of the organizing committee, 21 professionals from across the world, and representing expertise in different sub-specialties, formed five working groups: clinical definitions; outcome measures; embryology laboratory; clinical and laboratory andrology; and epidemiology, public health and gender related definitions. The definitions from the previous glossary were evaluated and new terms identified. All definitions were then reviewed by an international advisory panel of nine experts that evaluated the glossary from scientific, ethical, cultural, and policy perspectives. PARTICIPANTS/MATERIALS, SETTING, METHODS: Between November 2024 and October 2025, periodical virtual meetings were held within and between working groups and the organizing committee. Following circulation of the first consensually agreed draft, a one-day in-person meeting with representatives of all working groups and members of the international advisory panel was held at ESHRE, June 2025. Most terms and definitions were discussed and agreed. In the absence of agreement, further discussions were held between the organizing committee, working group chairs and members of the advisory panel. It had been determined at the outset that final disagreement would be resolved via a two-third majority vote. All terms and definitions were, however, reached by consensus and adopted following a final round of review and approval by all authors. MAIN RESULTS AND THE ROLE OF CHANCE: The glossary now includes 348 terms. Compared to the previous edition, 14 terms were deleted, numerous terms modified and 79 new terms were added. Modifications reflect current scientific knowledge, technological advancements, and inclusivity related to gender and family structures. Chance does not play a role, as all definitions are consensus-based. LIMITATIONS, REASONS FOR CAUTION: Some terms may require future refinement as scientific knowledge evolves and societal contexts change. The glossary reflects consensus rather than empirical testing of all definitions. WIDER IMPLICATIONS OF THE FINDINGS: This glossary provides a global reference for standardized terminology, supporting clinical care, research, international comparisons, policy making, patient communication, and reproductive health literacy. STUDY FUNDING/COMPETING INTEREST(S): Neither ICMART, responsible for conducting this project, nor any of the participants received specific financial support for their activities in this project. Ferring provided ICMART with a fixed amount to cover venue costs and a one-day hotel accommodation for participants attending the in-person meeting held prior to the ESHRE Congress in June 2025. Disclosures were provided by all authors, and none reported any conflict of interest related to this manuscript. TRIAL REGISTRATION NUMBER: N/A.

Abstract The Tokyo Guidelines 2013 (TG13) for acute cholangitis and cholecystitis were globally disseminated and various clinical studies about the management of acute cholecystitis were reported by many researchers and clinicians from all over the world. The 1 st edition of the Tokyo Guidelines 2007 ( TG 07) was revised in 2013. According to that revision, the TG 13 diagnostic criteria of acute cholecystitis provided better specificity and higher diagnostic accuracy. Thorough our literature search about diagnostic criteria for acute cholecystitis, new and strong evidence that had been released from 2013 to 2017 was not found with serious and important issues about using TG 13 diagnostic criteria of acute cholecystitis. On the other hand, the TG 13 severity grading for acute cholecystitis has been validated in numerous studies. As a result of these reviews, the TG 13 severity grading for acute cholecystitis was significantly associated with parameters including 30‐day overall mortality, length of hospital stay, conversion rates to open surgery, and medical costs. In terms of severity assessment, breakthrough and intensive literature for revising severity grading was not reported. Consequently, TG 13 diagnostic criteria and severity grading were judged from numerous validation studies as useful indicators in clinical practice and adopted as TG 18/ TG 13 diagnostic criteria and severity grading of acute cholecystitis without any modification. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47 . Related clinical questions and references are also included.

BACKGROUND: Globally, access to healthcare and diagnostic technologies are known to substantially impact the reported birth prevalence of congenital heart disease (CHD). Previous studies have shown marked heterogeneity between different regions, with a suggestion that CHD prevalence is rising globally, but the degree to which this reflects differences due to environmental or genetic risk factors, as opposed to improved detection, is uncertain. We performed an updated systematic review to address these issues. METHODS: Studies reporting the birth prevalence of CHD between the years 1970-2017 were identified from searches of PubMed, EMBASE, Web of Science and Google Scholar. Data on the prevalence of total CHD and 27 anatomical subtypes of CHD were collected. Data were combined using random-effect models. Subgroup and meta-regression analyses were conducted, focused on geographical regions and levels of national income. RESULTS: Two hundred and sixty studies met the inclusion criteria, encompassing 130 758 851 live births. The birth prevalence of CHD from 1970-2017 progressively increased to a maximum in the period 2010-17 of 9.410/1000 [95% CI (confidence interval) 8.602-10.253]. This represented a significant increase over the fifteen prior years (P = 0.031). The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence, consistent with a major role of improved postnatal detection of less severe lesions. In contrast the prevalence of lesions grouped together as left ventricular outflow tract obstruction (which includes hypoplastic left heart syndrome) decreased from 0.689/1000 (95% CI 0.607-0.776) in 1995-99, to 0.475/1000 (95% CI 0.392-0.565; P = 0.004) in 2010-17, which would be consistent with improved prenatal detection and consequent termination of pregnancy when these very severe lesions are discovered. There was marked heterogeneity among geographical regions, with Africa reporting the lowest prevalence [2.315/1000 (95% CI 0.429-5.696)] and Asia the highest [9.342/1000 (95% CI 8.072-10.704)]. CONCLUSIONS: The reported prevalence of CHD globally continues to increase, with evidence of severe unmet diagnostic need in Africa. The recent prevalence of CHD in Asia for the first time appears higher than in Europe and America, where disease ascertainment is likely to be near-complete, suggesting higher genetic or environmental susceptibility to CHD among Asian people.

BACKGROUND: To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders. METHOD: Data were from the World Health Organization (WHO) World Mental Health (WMH) surveys. Representative household samples were interviewed face to face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n = 63,678) and analyzed at different levels of clinical severity. RESULTS: Among those with a DSM-IV disorder in the past 12 months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. A desire to handle the problem on one's own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers to both initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment drop-out (39.3%), followed by negative experiences with treatment providers (26.9% of respondents with severe disorders). CONCLUSIONS: Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide.

BACKGROUND: Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa. METHODS: viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose. RESULTS: Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups. CONCLUSIONS: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132).

STUDY QUESTION: Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? SUMMARY ANSWER: A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. WHAT IS KNOWN ALREADY: In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, DURATION: Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN RESULTS AND THE ROLE OF CHANCE: A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, REASONS FOR CAUTION: All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary. WIDER IMPLICATIONS OF THE FINDINGS: Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Summary Continued uncontrolled transmission of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in many parts of the world is creating the conditions for significant virus evolution. Here, we describe a new SARS-CoV-2 lineage (501Y.V2) characterised by eight lineage-defining mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y) that may have functional significance. This lineage emerged in South Africa after the first epidemic wave in a severely affected metropolitan area, Nelson Mandela Bay, located on the coast of the Eastern Cape Province. This lineage spread rapidly, becoming within weeks the dominant lineage in the Eastern Cape and Western Cape Provinces. Whilst the full significance of the mutations is yet to be determined, the genomic data, showing the rapid displacement of other lineages, suggest that this lineage may be associated with increased transmissibility.

BACKGROUND: Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low-income and middle-income countries. We estimated global, regional, and national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study. METHODS: We systematically reviewed data on fatal and nonfatal rheumatic heart disease for the period from 1990 through 2015. Two Global Burden of Disease analytic tools, the Cause of Death Ensemble model and DisMod-MR 2.1, were used to produce estimates of mortality and prevalence, including estimates of uncertainty. RESULTS: We estimated that there were 319,400 (95% uncertainty interval, 297,300 to 337,300) deaths due to rheumatic heart disease in 2015. Global age-standardized mortality due to rheumatic heart disease decreased by 47.8% (95% uncertainty interval, 44.7 to 50.9) from 1990 to 2015, but large differences were observed across regions. In 2015, the highest age-standardized mortality due to and prevalence of rheumatic heart disease were observed in Oceania, South Asia, and central sub-Saharan Africa. We estimated that in 2015 there were 33.4 million (95% uncertainty interval, 29.7 million to 43.1 million) cases of rheumatic heart disease and 10.5 million (95% uncertainty interval, 9.6 million to 11.5 million) disability-adjusted life-years due to rheumatic heart disease globally. CONCLUSIONS: We estimated the global disease prevalence of and mortality due to rheumatic heart disease over a 25-year period. The health-related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the poorest regions in the world. (Funded by the Bill and Melinda Gates Foundation and the Medtronic Foundation.).

BACKGROUND: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).

If our overuse and misuse of antibiotics is not halted now, about 10 million people will die annually from drug-resistant bacterial infections within 35 years. The hammer blow will fall hardest on Africa and Asia, accounting for 4.1 and 4.7 million deaths, respec tively, and the world’s economy will lose more than 7% of its gross domestic product (USD210 trillion) by 2050. These numbers should make people sit up, listen and change behaviour.

Updates: This is the fourteenth version (thirteenth update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline. Clinical question: What is the role of drugs in the treatment of patients with covid-19? Context: The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and underway. Emerging SARS-CoV-2 variants and subvariants are changing the role of therapeutics. What is new?: The guideline development group (GDG) defined 1.5% as a new threshold for an important reduction in risk of hospitalisation in patients with non-severe covid-19. Combined with updated baseline risk estimates, this resulted in stratification into patients at low, moderate, and high risk for hospitalisation. New recommendations were added for moderate risk of hospitalisation for nirmatrelvir/ritonavir, and for moderate and low risk of hospitalisation for molnupiravir and remdesivir. New pharmacokinetic evidence was included for nirmatrelvir/ritonavir and molnupiravir, supporting existing recommendations for patients at high risk of hospitalisation. The recommendation for ivermectin in patients with non-severe illness was updated in light of additional trial evidence which reduced the high degree of uncertainty informing previous guidance. A new recommendation was made against the antiviral agent VV116 for patients with non-severe and with severe or critical illness outside of randomised clinical trials based on one RCT comparing the drug with nirmatrelvir/ritonavir. The structure of the guideline publication has also been changed; recommendations are now ordered by severity of covid-19. About this guideline: This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF on the WHO website, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact. Future recommendations: Recommendations on anticoagulation are planned for the next update to this guideline. Updated data regarding systemic corticosteroids, azithromycin, favipiravir and umefenovir for non-severe illness, and convalescent plasma and statin therapy for severe or critical illness, are planned for review in upcoming guideline iterations.

Human cytomegalovirus (CMV) is a leading cause of congenital infections worldwide. In the developed world, following the virtual elimination of circulating rubella, it is the commonest nongenetic cause of childhood hearing loss and an important cause of neurodevelopmental delay. The seroprevalence of CMV in adults and the incidence of congenital CMV infection are highest in developing countries (1 to 5% of births) and are most likely driven by nonprimary maternal infections. However, reliable estimates of prevalence and outcome from developing countries are not available. This is largely due to the dogma that maternal preexisting seroimmunity virtually eliminates the risk for sequelae. However, recent data demonstrating similar rates of sequelae, especially hearing loss, following primary and nonprimary maternal infection have underscored the importance of congenital CMV infection in resource-poor settings. Although a significant proportion of congenital CMV infections are attributable to maternal primary infection in well-resourced settings, the absence of specific interventions for seronegative mothers and uncertainty about fetal prognosis have discouraged routine maternal antibody screening. Despite these challenges, encouraging results from prototype vaccines have been reported, and the first randomized phase III trials of prenatal interventions and prolonged postnatal antiviral therapy are under way. Successful implementation of strategies to prevent or reduce the burden of congenital CMV infection will require heightened global awareness among clinicians and the general population. In this review, we highlight the global epidemiology of congenital CMV and the implications of growing knowledge in areas of prevention, diagnosis, prognosis, and management for both low (50 to 70%)- and high (>70%)-seroprevalence settings.

OBJECTIVE: To revise FIGO staging of carcinoma of the cervix uteri, allowing incorporation of imaging and/or pathological findings, and clinical assessment of tumor size and disease extent. METHODS: Review of literature and consensus view of the FIGO Gynecologic Oncology Committee and related societies and organizations. RESULTS: In stage I, revision of the definition of microinvasion and lesion size as follows. Stage IA: lateral extension measurement is removed; stage IB has three subgroups-stage IB1: invasive carcinomas ≥5 mm and <2 cm in greatest diameter; stage IB2: tumors 2-4 cm; stage IB3: tumors ≥4 cm. Imaging or pathology findings may be used to assess retroperitoneal lymph nodes; if metastatic, the case is assigned stage IIIC; if only pelvic lymph nodes, the case is assigned stage IIIC1; if para-aortic nodes are involved, the case is assigned stage IIIC2. Notations 'r' and 'p' will indicate the method used to derive the stage-i.e., imaging or pathology, respectively-and should be recorded. Routine investigations and other methods (e.g., examination under anesthesia, cystoscopy, proctoscopy, etc.) are not mandatory and are to be recommended based on clinical findings and standard of care. CONCLUSION: The revised cervical cancer staging is applicable to all resource levels. Data collection and publication will inform future revisions.

BACKGROUND: Although the burden of disease in sub-Saharan Africa continues to be dominated by infectious diseases, countries in this region are undergoing a demographic transition leading to increasing prevalence of non-communicable diseases (NCDs). To inform health system responses to these changing patterns of disease, we aimed to assess changes in the burden of NCDs in sub-Saharan Africa from 1990 to 2017. METHODS: We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to analyse the burden of NCDs in sub-Saharan Africa in terms of disability-adjusted life-years (DALYs)-with crude counts as well as all-age and age-standardised rates per 100 000 population-with 95% uncertainty intervals (UIs). We examined changes in burden between 1990 and 2017, and differences across age, sex, and regions. We also compared the observed NCD burden across countries with the expected values based on a country's Socio-demographic Index. FINDINGS: All-age total DALYs due to NCDs increased by 67·0% between 1990 (90·6 million [95% UI 81·0-101·9]) and 2017 (151·3 million [133·4-171·8]), reflecting an increase in the proportion of total DALYs attributable to NCDs (from 18·6% [95% UI 17·1-20·4] to 29·8% [27·6-32·0] of the total burden). Although most of this increase can be explained by population growth and ageing, the age-standardised DALY rate (per 100 000 population) due to NCDs in 2017 (21 757·7 DALYs [95% UI 19 377·1-24 380·7]) was almost equivalent to that of communicable, maternal, neonatal, and nutritional diseases (26 491·6 DALYs [25 165·2-28 129·8]). Cardiovascular diseases were the second leading cause of NCD burden in 2017, resulting in 22·9 million (21·5-24·3) DALYs (15·1% of the total NCD burden), after the group of disorders categorised as other NCDs (28·8 million [25·1-33·0] DALYs, 19·1%). These categories were followed by neoplasms, mental disorders, and digestive diseases. Although crude DALY rates for all NCDs have decreased slightly across sub-Saharan Africa, age-standardised rates are on the rise in some countries (particularly those in southern sub-Saharan Africa) and for some NCDs (such as diabetes and some cancers, including breast and prostate cancer). INTERPRETATION: NCDs in sub-Saharan Africa are posing an increasing challenge for health systems, which have to date largely focused on tackling infectious diseases and maternal, neonatal, and child deaths. To effectively address these changing needs, countries in sub-Saharan Africa require detailed epidemiological data on NCDs. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Centre (Australia).