Journal: Lancet

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<div><h4>Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial.</h4><i>Krystal JH, Kane JM, Correll CU, Walling DP, ... Sanchez R, Renger J</i><br /><b>Background</b><br />Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia.<br /><b>Methods</b><br />We conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18-50 years (part A) or 18-55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5-40 mg (40 mg was administered as 20 mg twice daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873.<br /><b>Findings</b><br />Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6.<br /><b>Interpretation</b><br />These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile.<br /><b>Funding</b><br />Cerevel Therapeutics.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 17 Dec 2023; 400:2210-2220</small></div>
Krystal JH, Kane JM, Correll CU, Walling DP, ... Sanchez R, Renger J
Lancet: 17 Dec 2023; 400:2210-2220 | PMID: 36528376
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<div><h4>Innovation for infection prevention and control-revisiting Pasteur\'s vision.</h4><i>Birgand G, Ahmad R, Bulabula ANH, Singh S, ... Sánchez EC, Holmes A</i><br /><AbstractText>Louis Pasteur has long been heralded as one of the fathers of microbiology and immunology. Less known is Pasteur\'s vision on infection prevention and control (IPC) that drove current infection control, public health, and much of modern medicine and surgery. In this Review, we revisited Pasteur\'s pioneering works to assess progress and challenges in the process and technological innovation of IPC. We focused on Pasteur\'s far-sighted conceptualisation of the hospital as a reservoir of microorganisms and amplifier of transmission, aseptic technique in surgery, public health education, interdisciplinary working, and the protection of health services and patients. Examples from across the globe help inform future thinking for IPC innovation, adoption, scale up and sustained use.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 17 Dec 2023; 400:2250-2260</small></div>
Birgand G, Ahmad R, Bulabula ANH, Singh S, ... Sánchez EC, Holmes A
Lancet: 17 Dec 2023; 400:2250-2260 | PMID: 36528378
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<div><h4>A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.</h4><i>Swen JJ, van der Wouden CH, Manson LE, Abdullah-Koolmees H, ... Guchelaar HJ, Ubiquitous Pharmacogenomics Consortium</i><br /><b>Background</b><br />The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed.<br /><b>Methods</b><br />We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants.<br /><b>Findings</b><br />Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001).<br /><b>Interpretation</b><br />Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe.<br /><b>Funding</b><br />European Union Horizon 2020.<br /><br />Crown Copyright © 2023 Published by Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 04 Feb 2023; 401:347-356</small></div>
Swen JJ, van der Wouden CH, Manson LE, Abdullah-Koolmees H, ... Guchelaar HJ, Ubiquitous Pharmacogenomics Consortium
Lancet: 04 Feb 2023; 401:347-356 | PMID: 36739136
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<div><h4>Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial.</h4><i>Horne AW, Tong S, Moakes CA, Middleton LJ, ... Daniels JP, GEM3 collaborative</i><br /><b>Background</b><br />Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy.<br /><b>Methods</b><br />We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m<sup>2</sup>) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930.<br /><b>Findings</b><br />Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group.<br /><b>Interpretation</b><br />In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions.<br /><b>Funding</b><br />National Institute of Health Research.<br /><br />Copyright © 2023 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.<br /><br /><small>Lancet: 01 Feb 2023; epub ahead of print</small></div>
Horne AW, Tong S, Moakes CA, Middleton LJ, ... Daniels JP, GEM3 collaborative
Lancet: 01 Feb 2023; epub ahead of print | PMID: 36738759
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<div><h4>Cooling cities through urban green infrastructure: a health impact assessment of European cities.</h4><i>Iungman T, Cirach M, Marando F, Pereira Barboza E, ... Thondoo M, Nieuwenhuijsen M</i><br /><b>Background</b><br />High ambient temperatures are associated with many health effects, including premature mortality. The combination of global warming due to climate change and the expansion of the global built environment mean that the intensification of urban heat islands (UHIs) is expected, accompanied by adverse effects on population health. Urban green infrastructure can reduce local temperatures. We aimed to estimate the mortality burden that could be attributed to UHIs and the mortality burden that would be prevented by increasing urban tree coverage in 93 European cities.<br /><b>Methods</b><br />We did a quantitative health impact assessment for summer (June 1-Aug 31), 2015, of the effect of UHIs on all-cause mortality for adults aged 20 years or older in 93 European cities. We also estimated the temperature reductions that would result from increasing tree coverage to 30% for each city and estimated the number of deaths that could be potentially prevented as a result. We did all analyses at a high-resolution grid-cell level (250 × 250 m). We propagated uncertainties in input analyses by using Monte Carlo simulations to obtain point estimates and 95% CIs. We also did sensitivity analyses to test the robustness of our estimates.<br /><b>Findings</b><br />The population-weighted mean city temperature increase due to UHI effects was 1·5°C (SD 0·5; range 0·5-3·0). Overall, 6700 (95% CI 5254-8162) premature deaths could be attributable to the effects of UHIs (corresponding to around 4·33% [95% CI 3·37-5·28] of all summer deaths). We estimated that increasing tree coverage to 30% would cool cities by a mean of 0·4°C (SD 0·2; range 0·0-1·3). We also estimated that 2644 (95% CI 2444-2824) premature deaths could be prevented by increasing city tree coverage to 30%, corresponding to 1·84% (1·69-1·97) of all summer deaths.<br /><b>Interpretation</b><br />Our results showed the deleterious effects of UHIs on mortality and highlighted the health benefits of increasing tree coverage to cool urban environments, which would also result in more sustainable and climate-resilient cities.<br /><b>Funding</b><br />GoGreenRoutes, Spanish Ministry of Science and Innovation, Institute for Global Health, UK Medical Research Council, European Union\'s Horizon 2020 Project Exhaustion.<br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 31 Jan 2023; epub ahead of print</small></div>
Iungman T, Cirach M, Marando F, Pereira Barboza E, ... Thondoo M, Nieuwenhuijsen M
Lancet: 31 Jan 2023; epub ahead of print | PMID: 36736334
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<div><h4>Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study.</h4><i>Verstovsek S, Gerds AT, Vannucchi AM, Al-Ali HK, ... Mesa R, MOMENTUM Study Investigators</i><br /><b>Background</b><br />Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.<br /><b>Methods</b><br />MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting.<br /><b>Findings</b><br />195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).<br /><b>Interpretation</b><br />Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.<br /><b>Funding</b><br />Sierra Oncology.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 28 Jan 2023; 401:269-280</small></div>
Verstovsek S, Gerds AT, Vannucchi AM, Al-Ali HK, ... Mesa R, MOMENTUM Study Investigators
Lancet: 28 Jan 2023; 401:269-280 | PMID: 36709073
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<div><h4>Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored Marburg virus (cAd3-Marburg) vaccine in healthy adults in the USA: a first-in-human, phase 1, open-label, dose-escalation trial.</h4><i>Hamer MJ, Houser KV, Hofstetter AR, Ortega-Villa AM, ... Ledgerwood JE, RV 507 Study Team</i><br /><b>Background</b><br />WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults.<br /><b>Methods</b><br />We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA. Healthy adults aged 18-50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10<sup>10</sup> or 1 × 10<sup>11</sup> particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056.<br /><b>Findings</b><br />Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10<sup>10</sup> pu (n=20) or 1 × 10<sup>11</sup> pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 [68%] of 40 participants), malaise (18 [45%] of 40 participants), headache (17 [43%] of 40 participants), and myalgia (14 [35%] of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 [95% CI 209-846] in the 1 × 10<sup>10</sup> pu group and 545 [276-1078] in the 1 × 10<sup>11</sup> pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13-119] in the 1 ×10<sup>10</sup> pu group and 27 [95-156] in the 1 ×10<sup>11</sup> pu group; both p<0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination.<br /><b>Interpretation</b><br />This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions.<br /><b>Funding</b><br />National Institutes of Health.<br /><br />Copyright © 2020 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 28 Jan 2023; 401:294-302</small></div>
Hamer MJ, Houser KV, Hofstetter AR, Ortega-Villa AM, ... Ledgerwood JE, RV 507 Study Team
Lancet: 28 Jan 2023; 401:294-302 | PMID: 36709074
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<div><h4>Malnutrition in older adults.</h4><i>Dent E, Wright ORL, Woo J, Hoogendijk EO</i><br /><AbstractText>Malnutrition is a highly prevalent condition in older adults, and poses a substantial burden on health, social, and aged-care systems. Older adults are vulnerable to malnutrition due to age-related physiological decline, reduced access to nutritious food, and comorbidity. Clinical guidelines recommend routine screening for malnutrition in all older adults, together with nutritional assessment and individually tailored nutritional support for older adults with a positive screening test. Nutritional support includes offering individualised nutritional advice and counselling; oral nutritional supplements; fortified foods; and enteral or parenteral nutrition as required. However, in clinical practice, the incorporation of nutritional guidelines is inadequate and low-value care is commonplace. This Review discusses the current evidence on identification and treatment of malnutrition in older adults, identifies gaps between evidence and practice in clinical care, and offers practical strategies to translate evidence-based knowledge into improved nutritional care. We also provide an overview of the prevalence, causes, and risk factors of malnutrition in older adults across health-care settings.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 27 Jan 2023; epub ahead of print</small></div>
Dent E, Wright ORL, Woo J, Hoogendijk EO
Lancet: 27 Jan 2023; epub ahead of print | PMID: 36716756
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<div><h4>The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial.</h4><i>Heyland DK, Patel J, Compher C, Rice TW, ... Day AG, EFFORT Protein Trial team</i><br /><b>Background</b><br />On the basis of low-quality evidence, international critical care nutrition guidelines recommend a wide range of protein doses. The effect of delivering high-dose protein during critical illness is unknown. We aimed to test the hypothesis that a higher dose of protein provided to critically ill patients would improve their clinical outcomes.<br /><b>Methods</b><br />This international, investigator-initiated, pragmatic, registry-based, single-blinded, randomised trial was undertaken in 85 intensive care units (ICUs) across 16 countries. We enrolled nutritionally high-risk adults (≥18 years) undergoing mechanical ventilation to compare prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 h of ICU admission and continued for up to 28 days or death or transition to oral feeding. Participants were randomly allocated (1:1) to high-dose protein or usual dose protein, stratified by site. As site personnel were involved in both prescribing and delivering protein dose, it was not possible to blind clinicians, but patients were not made aware of the treatment assignment. The primary efficacy outcome was time-to-discharge-alive from hospital up to 60 days after ICU admission and the secondary outcome was 60-day morality. Patients were analysed in the group to which they were randomly assigned regardless of study compliance, although patients who dropped out of the study before receiving the study intervention were excluded. This study is registered with ClinicalTrials.gov, NCT03160547.<br /><b>Findings</b><br />Between Jan 17, 2018, and Dec 3, 2021, 1329 patients were randomised and 1301 (97·9%) were included in the analysis (645 in the high-dose protein group and 656 in usual dose group). By 60 days after randomisation, the cumulative incidence of alive hospital discharge was 46·1% (95 CI 42·0%-50·1%) in the high-dose compared with 50·2% (46·0%-54·3%) in the usual dose protein group (hazard ratio 0·91, 95% CI 0·77-1·07; p=0·27). The 60-day mortality rate was 34·6% (222 of 642) in the high dose protein group compared with 32·1% (208 of 648) in the usual dose protein group (relative risk 1·08, 95% CI 0·92-1·26). There appeared to be a subgroup effect with higher protein provision being particularly harmful in patients with acute kidney injury and higher organ failure scores at baseline.<br /><b>Interpretation</b><br />Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores.<br /><b>Funding</b><br />None.<br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 25 Jan 2023; epub ahead of print</small></div>
Heyland DK, Patel J, Compher C, Rice TW, ... Day AG, EFFORT Protein Trial team
Lancet: 25 Jan 2023; epub ahead of print | PMID: 36708732
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<div><h4>Sodium bicarbonate for kidney transplant recipients with metabolic acidosis in Switzerland: a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial.</h4><i>Mohebbi N, Ritter A, Wiegand A, Graf N, ... Wagner CA, Wüthrich RP</i><br /><b>Background</b><br />Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients.<br /><b>Methods</b><br />The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m<sup>2</sup> and 89 mL/min per 1·73 m<sup>2</sup>, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5-4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996.<br /><b>Findings</b><br />Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median -0·722 mL/min per 1·73 m<sup>2</sup> (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m<sup>2</sup> (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m<sup>2</sup> (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m<sup>2</sup> (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m<sup>2</sup> per year (95% CI -1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death.<br /><b>Interpretation</b><br />In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis.<br /><b>Funding</b><br />Swiss National Science Foundation.<br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 25 Jan 2023; epub ahead of print</small></div>
Mohebbi N, Ritter A, Wiegand A, Graf N, ... Wagner CA, Wüthrich RP
Lancet: 25 Jan 2023; epub ahead of print | PMID: 36708734
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<div><h4>Efficacy of pyriproxyfen-pyrethroid long-lasting insecticidal nets (LLINs) and chlorfenapyr-pyrethroid LLINs compared with pyrethroid-only LLINs for malaria control in Benin: a cluster-randomised, superiority trial.</h4><i>Accrombessi M, Cook J, Dangbenon E, Yovogan B, ... Protopopoff N, Akogbeto MC</i><br /><b>Background</b><br />New classes of long-lasting insecticidal nets (LLINs) combining mixtures of insecticides with different modes of action could put malaria control back on track after rebounds in transmission across sub-Saharan Africa. We evaluated the relative efficacy of pyriproxyfen-pyrethroid LLINs and chlorfenapyr-pyrethroid LLINs compared with standard LLINs against malaria transmission in an area of high pyrethroid resistance in Benin.<br /><b>Methods</b><br />We conducted a cluster-randomised, superiority trial in Zou Department, Benin. Clusters were villages or groups of villages with a minimum of 100 houses. We used restricted randomisation to randomly assign 60 clusters to one of three LLIN groups (1:1:1): to receive nets containing either pyriproxyfen and alpha-cypermethrin (pyrethroid), chlorfenapyr and alpha-cypermethrin, or alpha-cypermethrin only (reference). Households received one LLIN for every two people. The field team, laboratory staff, analyses team, and community members were masked to the group allocation. The primary outcome was malaria case incidence measured over 2 years after net distribution in a cohort of children aged 6 months-10 years, in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03931473.<br /><b>Findings</b><br />Between May 23 and June 24, 2019, 53 854 households and 216 289 inhabitants were accounted for in the initial census and included in the study. Between March 19 and 22, 2020, 115 323 LLINs were distributed to 54 030 households in an updated census. A cross-sectional survey showed that study LLIN usage was highest at 9 months after distribution (5532 [76·8%] of 7206 participants), but decreased by 24 months (4032 [60·6%] of 6654). Mean malaria incidence over 2 years after LLIN distribution was 1·03 cases per child-year (95% CI 0·96-1·09) in the pyrethroid-only LLIN reference group, 0·84 cases per child-year (0·78-0·90) in the pyriproxyfen-pyrethroid LLIN group (hazard ratio [HR] 0·86, 95% CI 0·65-1·14; p=0·28), and 0·56 cases per child-year (0·51-0·61) in the chlorfenapyr-pyrethroid LLIN group (HR 0·54, 95% CI 0·42-0·70; p<0·0001).<br /><b>Interpretation</b><br />Over 2 years, chlorfenapyr-pyrethroid LLINs provided greater protection from malaria than pyrethroid-only LLINs in an area with pyrethroid-resistant mosquitoes. Pyriproxyfen-pyrethroid LLINs conferred protection similar to pyrethroid-only LLINs. These findings provide crucial second-trial evidence to enable WHO to make policy recommendations on these new LLIN classes. This study confirms the importance of chlorfenapyr as an LLIN treatment to control malaria in areas with pyrethroid-resistant vectors. However, an arsenal of new active ingredients is required for successful long-term resistance management, and additional innovations, including pyriproxyfen, need to be further investigated for effective vector control strategies.<br /><b>Funding</b><br />UNITAID, The Global Fund.<br /><br />Copyright © 2023 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.<br /><br /><small>Lancet: 24 Jan 2023; epub ahead of print</small></div>
Abstract
<div><h4>Performance of cardiovascular disease risk prediction equations in more than 14 000 survivors of cancer in New Zealand primary care: a validation study.</h4><i>Tawfiq E, Selak V, Elwood JM, Pylypchuk R, ... McKeage M, Wells S</i><br /><b>Background</b><br />People with cancer have an increased risk of cardiovascular disease. Risk prediction equations developed in New Zealand accurately predict 5-year cardiovascular disease risk in a general primary care population in the country. We assessed the performance of these equations for survivors of cancer in New Zealand.<br /><b>Methods</b><br />For this validation study, patients aged 30-74 years from the PREDICT open cohort study, which was used to develop the New Zealand cardiovascular disease risk prediction equations, were included in the analysis if they had a primary diagnosis of invasive cancer at least 2 years before the date of the first cardiovascular disease risk assessment. The risk prediction equations are sex-specific and include the following predictors: age, ethnicity, socioeconomic deprivation index, family history of cardiovascular disease, smoking status, history of atrial fibrillation and diabetes, systolic blood pressure, total cholesterol to HDL cholesterol ratio, and preventive pharmacotherapy (blood-pressure-lowering, lipid-lowering, and antithrombotic drugs). Calibration was assessed by comparing the mean predicted 5-year cardiovascular disease risk, estimated using the risk prediction equations, with the observed risk across deciles of risk, for men and women, and according to the three clinical 5-year cardiovascular disease risk groups in New Zealand guidelines (<5%, 5% to <15%, and ≥15%). Discrimination was assessed by Harrell\'s C statistic.<br /><b>Findings</b><br />14 263 patients were included in the study. The mean age was 61 years (SD 9) for men and 60 years (SD 8) for women, with a median follow-up of 5·8 years for men and 5·7 years for women. The observed cardiovascular disease risk was underpredicted by a maximum of 2·5% in male and 3·2% in female decile groups. When patients were grouped according to clinical risk groups, observed cardiovascular disease risk was underpredicted by less than 2% in the lower risk groups and overpredicted by 2·2% for men and 3·3% for women in the highest risk group. Harrell\'s C statistics were 0·67 (SE 0·01) for men and 0·73 (0·01) for women.<br /><b>Interpretation</b><br />The New Zealand cardiovascular disease risk prediction equations reasonably predicted the observed 5-year cardiovascular disease risk in survivors of cancer in the country, in whom risk prediction was considered clinically appropriate. Prediction could be improved by adding cancer-specific variables and considering competing risks. Our findings suggest that the equations are reasonable clinical tools for use in survivors of cancer in New Zealand.<br /><b>Funding</b><br />Auckland Medical Research Foundation, Health Research Council of New Zealand.<br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 23 Jan 2023; epub ahead of print</small></div>
Tawfiq E, Selak V, Elwood JM, Pylypchuk R, ... McKeage M, Wells S
Lancet: 23 Jan 2023; epub ahead of print | PMID: 36702148
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<div><h4>Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.</h4><i>Nakachi K, Ikeda M, Konishi M, Nomura S, ... Furuse J, Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG-HBPOG)</i><br /><b>Background</b><br />S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer.<br /><b>Methods</b><br />This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688).<br /><b>Findings</b><br />Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]).<br /><b>Interpretation</b><br />Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients.<br /><b>Funding</b><br />The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.<br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 21 Jan 2023; 401:195-203</small></div>
Nakachi K, Ikeda M, Konishi M, Nomura S, ... Furuse J, Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG-HBPOG)
Lancet: 21 Jan 2023; 401:195-203 | PMID: 36681415
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<div><h4>A global analysis of One Health Networks and the proliferation of One Health collaborations.</h4><i>Mwatondo A, Rahman-Shepherd A, Hollmann L, Chiossi S, ... Zumla A, Dar O</i><br /><AbstractText>There has been a renewed focus on threats to the human-animal-environment interface as a result of the COVID-19 pandemic, and investments in One Health collaborations are expected to increase. Efforts to monitor the development of One Health Networks (OHNs) are essential to avoid duplication or misalignment of investments. This Series paper shows the global distribution of existing OHNs and assesses their collective characteristics to identify potential deficits in the ways OHNs have formed and to help increase the effectiveness of investments. We searched PubMed, Google, Google Scholar, and relevant conference websites for potential OHNs and identified 184 worldwide for further analysis. We developed four case studies to show important findings from our research and exemplify best practices in One Health operationalisation. Our findings show that, although more OHNs were formed in the past 10 years than in the preceding decade, investment in OHNs has not been equitably distributed; more OHNs are formed and headquartered in Europe than in any other region, and emerging infections and novel pathogens were the priority focus area for most OHNs, with fewer OHNs focusing on other important hazards and pressing threats to health security. We found substantial deficits in the OHNs collaboration model regarding the diversity of stakeholder and sector representation, which we argue impedes effective and equitable OHN formation and contributes to other imbalances in OHN distribution and priorities. These findings are supported by previous evidence that shows the skewed investment in One Health thus far. The increased attention to One Health after the COVID-19 pandemic is an opportunity to focus efforts and resources to areas that need them most. Analyses, such as this Series paper, should be used to establish databases and repositories of OHNs worldwide. Increased attention should then be given to understanding existing resource allocation and distribution patterns, establish more egalitarian networks that encompass the breadth of One Health issues, and serve communities most affected by emerging, re-emerging, or endemic threats at the human-animal-environment interface.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 19 Jan 2023; epub ahead of print</small></div>
Mwatondo A, Rahman-Shepherd A, Hollmann L, Chiossi S, ... Zumla A, Dar O
Lancet: 19 Jan 2023; epub ahead of print | PMID: 36682370
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<div><h4>Advancing One human-animal-environment Health for global health security: what does the evidence say?</h4><i>Zinsstag J, Kaiser-Grolimund A, Heitz-Tokpa K, Sreedharan R, ... Dar O, de la Rocque S</i><br /><AbstractText>In this Series paper, we review the contributions of One Health approaches (ie, at the human-animal-environment interface) to improve global health security across a range of health hazards and we summarise contemporary evidence of incremental benefits of a One Health approach. We assessed how One Health approaches were reported to the Food and Agricultural Organization of the UN, the World Organisation for Animal Health (WOAH, formerly OIE), and WHO, within the monitoring and assessment frameworks, including WHO International Health Regulations (2005) and WOAH Performance of Veterinary Services. We reviewed One Health theoretical foundations, methods, and case studies. Examples from joint health services and infrastructure, surveillance-response systems, surveillance of antimicrobial resistance, food safety and security, environmental hazards, water and sanitation, and zoonoses control clearly show incremental benefits of One Health approaches. One Health approaches appear to be most effective and sustainable in the prevention, preparedness, and early detection and investigation of evolving risks and hazards; the evidence base for their application is strongest in the control of endemic and neglected tropical diseases. For benefits to be maximised and extended, improved One Health operationalisation is needed by strengthening multisectoral coordination mechanisms at national, regional, and global levels.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 19 Jan 2023; epub ahead of print</small></div>
Zinsstag J, Kaiser-Grolimund A, Heitz-Tokpa K, Sreedharan R, ... Dar O, de la Rocque S
Lancet: 19 Jan 2023; epub ahead of print | PMID: 36682371
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<div><h4>Asthma.</h4><i>Porsbjerg C, Melén E, Lehtimäki L, Shaw D</i><br /><AbstractText>Asthma is one of the most common chronic non-communicable diseases worldwide and is characterised by variable airflow obstruction, causing dyspnoea and wheezing. Highly effective therapies are available; asthma morbidity and mortality have vastly improved in the past 15 years, and most patients can attain good asthma control. However, undertreatment is still common, and improving patient and health-care provider understanding of when and how to adjust treatment is crucial. Asthma management consists of a cycle of assessment of asthma control and risk factors and adjustment of medications accordingly. With the introduction of biological therapies, management of severe asthma has entered the precision medicine era-a shift that is driving clinical ambitions towards disease remission. Patients with severe asthma often have co-existing conditions contributing to their symptoms, mandating a multidimensional management approach. In this Seminar, we provide a clinically focused overview of asthma; epidemiology, pathophysiology, diagnosis, and management in children and adults.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 19 Jan 2023; epub ahead of print</small></div>
Porsbjerg C, Melén E, Lehtimäki L, Shaw D
Lancet: 19 Jan 2023; epub ahead of print | PMID: 36682372
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<div><h4>How prepared is the world? Identifying weaknesses in existing assessment frameworks for global health security through a One Health approach.</h4><i>Traore T, Shanks S, Haider N, Ahmed K, ... Socé Fall I, Dar O</i><br /><AbstractText>The COVID-19 pandemic has exposed faults in the way we assess preparedness and response capacities for public health emergencies. Existing frameworks are limited in scope, and do not sufficiently consider complex social, economic, political, regulatory, and ecological factors. One Health, through its focus on the links among humans, animals, and ecosystems, is a valuable approach through which existing assessment frameworks can be analysed and new ways forward proposed. Although in the past few years advances have been made in assessment tools such as the International Health Regulations Joint External Evaluation, a rapid and radical increase in ambition is required. To sufficiently account for the range of complex systems in which health emergencies occur, assessments should consider how problems are defined across stakeholders and the wider sociopolitical environments in which structures and institutions operate. Current frameworks do little to consider anthropogenic factors in disease emergence or address the full array of health security hazards across the social-ecological system. A complex and interdependent set of challenges threaten human, animal, and ecosystem health, and we cannot afford to overlook important contextual factors, or the determinants of these shared threats. Health security assessment frameworks should therefore ensure that the process undertaken to prioritise and build capacity adheres to core One Health principles and that interventions and outcomes are assessed in terms of added value, trade-offs, and cobenefits across human, animal, and environmental health systems.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 19 Jan 2023; epub ahead of print</small></div>
Traore T, Shanks S, Haider N, Ahmed K, ... Socé Fall I, Dar O
Lancet: 19 Jan 2023; epub ahead of print | PMID: 36682374
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<div><h4>Global and regional governance of One Health and implications for global health security.</h4><i>Elnaiem A, Mohamed-Ahmed O, Zumla A, Mecaskey J, ... Kock R, Dar O</i><br /><AbstractText>The apparent failure of global health security to prevent or prepare for the COVID-19 pandemic has highlighted the need for closer cooperation between human, animal (domestic and wildlife), and environmental health sectors. However, the many institutions, processes, regulatory frameworks, and legal instruments with direct and indirect roles in the global governance of One Health have led to a fragmented, global, multilateral health security architecture. We explore four challenges: first, the sectoral, professional, and institutional silos and tensions existing between human, animal, and environmental health; second, the challenge that the international legal system, state sovereignty, and existing legal instruments pose for the governance of One Health; third, the power dynamics and asymmetry in power between countries represented in multilateral institutions and their impact on priority setting; and finally, the current financing mechanisms that predominantly focus on response to crises, and the chronic underinvestment for epidemic and emergency prevention, mitigation, and preparedness activities. We illustrate the global and regional dimensions to these four challenges and how they relate to national needs and priorities through three case studies on compulsory licensing, the governance of water resources in the Lake Chad Basin, and the desert locust infestation in east Africa. Finally, we propose 12 recommendations for the global community to address these challenges. Despite its broad and holistic agenda, One Health continues to be dominated by human and domestic animal health experts. Substantial efforts should be made to address the social-ecological drivers of health emergencies including outbreaks of emerging, re-emerging, and endemic infectious diseases. These drivers include climate change, biodiversity loss, and land-use change, and therefore require effective and enforceable legislation, investment, capacity building, and integration of other sectors and professionals beyond health.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 19 Jan 2023; epub ahead of print</small></div>
Elnaiem A, Mohamed-Ahmed O, Zumla A, Mecaskey J, ... Kock R, Dar O
Lancet: 19 Jan 2023; epub ahead of print | PMID: 36682375
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<div><h4>2 days versus 5 days of postoperative antibiotics for complex appendicitis: a pragmatic, open-label, multicentre, non-inferiority randomised trial.</h4><i>de Wijkerslooth EML, Boerma EG, van Rossem CC, van Rosmalen J, ... van den Boom AL, APPIC Study Group</i><br /><b>Background</b><br />The appropriate duration of postoperative antibiotics for complex appendicitis is unclear. The increasing global threat of antimicrobial resistance warrants restrictive antibiotic use, which could also reduce side-effects, length of hospital stay, and costs.<br /><b>Methods</b><br />In this pragmatic, open-label, non-inferiority trial in 15 hospitals in the Netherlands, patients with complex appendicitis (aged ≥8 years) were randomly assigned (1:1) to receive 2 days or 5 days of intravenous antibiotics after appendicectomy. Randomisation was stratified by centre, and treating physicians and patients were not masked to treatment allocation. The primary endpoint was a composite endpoint of infectious complications and mortality within 90 days. The main outcome was the absolute risk difference (95% CI) in the primary endpoint, adjusted for age and severity of appendicitis, with a non-inferiority margin of 7·5%. Outcome assessment was based on electronic patient records and a telephone consultation 90 days after appendicectomy. Efficacy was analysed in the intention-to-treat and per-protocol populations. Safety outcomes were analysed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register, NL5946.<br /><b>Findings</b><br />Between April 12, 2017, and June 3, 2021, 13 267 patients were screened and 1066 were randomly assigned, 533 to each group. 31 were excluded from intention-to-treat analysis of the 2-day group and 30 from the 5-day group owing to errors in recruitment or consent. Appendicectomy was done laparoscopically in 955 (95%) of 1005 patients. The telephone follow-up was completed in 664 (66%) of 1005 patients. The primary endpoint occurred in 51 (10%) of 502 patients analysed in the 2-day group and 41 (8%) of 503 patients analysed in the 5-day group (adjusted absolute risk difference 2·0%, 95% CI -1·6 to 5·6). Rates of complications and re-interventions were similar between trial groups. Fewer patients had adverse effects of antibiotics in the 2-day group (45 [9%] of 502 patients) than in the 5-day group (112 [22%] of 503 patients; odds ratio [OR] 0·344, 95% CI 0·237 to 0·498). Re-admission to hospital was more frequent in the 2-day group (58 [12%] of 502 patients) than in the 5-day group (29 [6%] of 503 patients; OR 2·135, 1·342 to 3·396). There were no treatment-related deaths.<br /><b>Interpretation</b><br />2 days of postoperative intravenous antibiotics for complex appendicitis is non-inferior to 5 days in terms of infectious complications and mortality within 90 days, based on a non-inferiority margin of 7·5%. These findings apply to laparoscopic appendicectomy conducted in a well resourced health-care setting. Adopting this strategy will reduce adverse effects of antibiotics and length of hospital stay.<br /><b>Funding</b><br />The Netherlands Organization for Health Research and Development.<br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 17 Jan 2023; epub ahead of print</small></div>
de Wijkerslooth EML, Boerma EG, van Rossem CC, van Rosmalen J, ... van den Boom AL, APPIC Study Group
Lancet: 17 Jan 2023; epub ahead of print | PMID: 36669519
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<div><h4>Pregnancy outcomes and vaccine effectiveness during the period of omicron as the variant of concern, INTERCOVID-2022: a multinational, observational study.</h4><i>Villar J, Soto Conti CP, Gunier RB, Ariff S, ... Papageorghiou AT, INTERCOVID-2022 International Consortium</i><br /><b>Background</b><br />In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern.<br /><b>Methods</b><br />INTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile.<br /><b>Findings</b><br />We enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose.<br /><b>Interpretation</b><br />COVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority.<br /><b>Funding</b><br />None.<br /><br />Copyright © 2023 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.<br /><br /><small>Lancet: 17 Jan 2023; epub ahead of print</small></div>
Villar J, Soto Conti CP, Gunier RB, Ariff S, ... Papageorghiou AT, INTERCOVID-2022 International Consortium
Lancet: 17 Jan 2023; epub ahead of print | PMID: 36669520
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<div><h4>Acute aortic dissection.</h4><i>Carrel T, Sundt TM, von Kodolitsch Y, Czerny M</i><br /><AbstractText>Although substantial progress has been made in the prevention, diagnosis, and treatment of acute aortic dissection, it remains a complex cardiovascular event, with a high immediate mortality and substantial morbidity in individuals surviving the acute period. The past decade has allowed a leap forward in understanding the pathophysiology of this disease; the existing classifications have been challenged, and the scientific community moves towards a nomenclature that is likely to unify the current definitions according to morphology and function. The most important pathophysiological pathway, namely the location and extension of the initial intimal tear, which causes a disruption of the media layer of the aortic wall, together with the size of the affected aortic segments, determines whether the patient should undergo emergency surgery, an endovascular intervention, or receive optimal medical treatment. The scientific evidence for the management and follow-up of acute aortic dissection continues to evolve. This Seminar provides a clinically relevant overview of potential prevention, diagnosis, and management of acute aortic dissection, which is the most severe acute aortic syndrome.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 11 Jan 2023; epub ahead of print</small></div>
Carrel T, Sundt TM, von Kodolitsch Y, Czerny M
Lancet: 11 Jan 2023; epub ahead of print | PMID: 36640801
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<div><h4>Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.</h4><i>Butler CC, Hobbs FDR, Gbinigie OA, Rahman NM, ... Little P, PANORAMIC Trial Collaborative Group</i><br /><b>Background</b><br />The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population.<br /><b>Methods</b><br />PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031.<br /><b>Findings</b><br />Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.<br /><b>Interpretation</b><br />Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community.<br /><b>Funding</b><br />UK National Institute for Health and Care Research.<br /><br />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.<br /><br /><small>Lancet: 22 Dec 2022; epub ahead of print</small></div>
Butler CC, Hobbs FDR, Gbinigie OA, Rahman NM, ... Little P, PANORAMIC Trial Collaborative Group
Lancet: 22 Dec 2022; epub ahead of print | PMID: 36566761
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<div><h4>Cataracts.</h4><i>Cicinelli MV, Buchan JC, Nicholson M, Varadaraj V, Khanna RC</i><br /><AbstractText>94 million people are blind or visually impaired globally, and cataract is the most common cause of blindness worldwide. However, most cases of blindness are avoidable. Cataract is associated with decreased quality of life and reduced life expectancy. Most cases of cataract occur after birth and share ageing and oxidative stress as primary causes, although several non-modifiable and modifiable risk factors can accelerate cataract formation. In most patients, phacoemulsification with intraocular lens implantation is the preferred treatment and is highly cost-effective. There has been an increase in the use of comprehensive cataract surgical services, including diagnoses, treatment referrals, and rehabilitation. However, global inequity in surgical service quality is still a limitation. Implementation of preoperative risk assessment, risk reduction strategies, and new surgical technologies have made cataract surgery possible at an earlier stage of cataract severity with the expectation of good refractive outcomes. The main challenge is making the service that is currently available to some patients accessible to all by use of universal health coverage.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 21 Dec 2022; epub ahead of print</small></div>
Cicinelli MV, Buchan JC, Nicholson M, Varadaraj V, Khanna RC
Lancet: 21 Dec 2022; epub ahead of print | PMID: 36565712
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<div><h4>Machine learning-based marker for coronary artery disease: derivation and validation in two longitudinal cohorts.</h4><i>Forrest IS, Petrazzini BO, Duffy Á, Park JK, ... Nadkarni GN, Do R</i><br /><b>Background</b><br />Binary diagnosis of coronary artery disease does not preserve the complexity of disease or quantify its severity or its associated risk with death; hence, a quantitative marker of coronary artery disease is warranted. We evaluated a quantitative marker of coronary artery disease derived from probabilities of a machine learning model.<br /><b>Methods</b><br />In this cohort study, we developed and validated a coronary artery disease-predictive machine learning model using 95 935 electronic health records and assessed its probabilities as in-silico scores for coronary artery disease (ISCAD; range 0 [lowest probability] to 1 [highest probability]) in participants in two longitudinal biobank cohorts. We measured the association of ISCAD with clinical outcomes-namely, coronary artery stenosis, obstructive coronary artery disease, multivessel coronary artery disease, all-cause death, and coronary artery disease sequelae.<br /><b>Findings</b><br />Among 95 935 participants, 35 749 were from the BioMe Biobank (median age 61 years [IQR 18]; 14 599 [41%] were male and 21 150 [59%] were female; 5130 [14%] were with diagnosed coronary artery disease) and 60 186 were from the UK Biobank (median age 62 [15] years; 25 031 [42%] male and 35 155 [58%] female; 8128 [14%] with diagnosed coronary artery disease). The model predicted coronary artery disease with an area under the receiver operating characteristic curve of 0·95 (95% CI 0·94-0·95; sensitivity of 0·94 [0·94-0·95] and specificity of 0·82 [0·81-0·83]) and 0·93 (0·92-0·93; sensitivity of 0·90 [0·89-0·90] and specificity of 0·88 [0·87-0·88]) in the BioMe validation and holdout sets, respectively, and 0·91 (0·91-0·91; sensitivity of 0·84 [0·83-0·84] and specificity of 0·83 [0·82-0·83]) in the UK Biobank external test set. ISCAD captured coronary artery disease risk from known risk factors, pooled cohort equations, and polygenic risk scores. Coronary artery stenosis increased quantitatively with ascending ISCAD quartiles (increase per quartile of 12 percentage points), including risk of obstructive coronary artery disease, multivessel coronary artery disease, and stenosis of major coronary arteries. Hazard ratios (HRs) and prevalence of all-cause death increased stepwise over ISCAD deciles (decile 1: HR 1·0 [95% CI 1·0-1·0], 0·2% prevalence; decile 6: 11 [3·9-31], 3·1% prevalence; and decile 10: 56 [20-158], 11% prevalence). A similar trend was observed for recurrent myocardial infarction. 12 (46%) undiagnosed individuals with high ISCAD (≥0·9) had clinical evidence of coronary artery disease according to the 2014 American College of Cardiology/American Heart Association Task Force guidelines.<br /><b>Interpretation</b><br />Electronic health record-based machine learning was used to generate an in-silico marker for coronary artery disease that can non-invasively quantify atherosclerosis and risk of death on a continuous spectrum, and identify underdiagnosed individuals.<br /><b>Funding</b><br />National Institutes of Health.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 20 Dec 2022; epub ahead of print</small></div>
Forrest IS, Petrazzini BO, Duffy Á, Park JK, ... Nadkarni GN, Do R
Lancet: 20 Dec 2022; epub ahead of print | PMID: 36563696
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<div><h4>Lung cancer screening.</h4><i>Adams SJ, Stone E, Baldwin DR, Vliegenthart R, Lee P, Fintelmann FJ</i><br /><AbstractText>Randomised controlled trials, including the National Lung Screening Trial (NLST) and the NELSON trial, have shown reduced mortality with lung cancer screening with low-dose CT compared with chest radiography or no screening. Although research has provided clarity on key issues of lung cancer screening, uncertainty remains about aspects that might be critical to optimise clinical effectiveness and cost-effectiveness. This Review brings together current evidence on lung cancer screening, including an overview of clinical trials, considerations regarding the identification of individuals who benefit from lung cancer screening, management of screen-detected findings, smoking cessation interventions, cost-effectiveness, the role of artificial intelligence and biomarkers, and current challenges, solutions, and opportunities surrounding the implementation of lung cancer screening programmes from an international perspective. Further research into risk models for patient selection, personalised screening intervals, novel biomarkers, integrated cardiovascular disease and chronic obstructive pulmonary disease assessments, smoking cessation interventions, and artificial intelligence for lung nodule detection and risk stratification are key opportunities to increase the efficiency of lung cancer screening and ensure equity of access.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 20 Dec 2022; epub ahead of print</small></div>
Adams SJ, Stone E, Baldwin DR, Vliegenthart R, Lee P, Fintelmann FJ
Lancet: 20 Dec 2022; epub ahead of print | PMID: 36563698
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<div><h4>Novel and emerging treatments for major depression.</h4><i>Marwaha S, Palmer E, Suppes T, Cons E, Young AH, Upthegrove R</i><br /><AbstractText>Depression is common, costly, debilitating, and associated with increased risk of suicide. It is one of the leading global public health problems. Although existing available pharmacological treatments can be effective, their onset of action can take up to 6 weeks, side-effects are common, and recovery can require treatment with multiple different agents. Although psychosocial interventions might also be recommended, more effective treatments than those currently available are needed for people with moderate or severe depression. In the past 10 years, treatment trials have developed and tested many new targeted interventions. In this Review, we assess novel and emerging biological treatments for major depressive disorder, evaluate their putative brain and body mechanisms, and highlight how close each might be to clinical use.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 16 Dec 2022; epub ahead of print</small></div>
Marwaha S, Palmer E, Suppes T, Cons E, Young AH, Upthegrove R
Lancet: 16 Dec 2022; epub ahead of print | PMID: 36535295
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<div><h4>Effects of race and ethnicity on perinatal outcomes in high-income and upper-middle-income countries: an individual participant data meta-analysis of 2 198 655 pregnancies.</h4><i>Sheikh J, Allotey J, Kew T, Fernández-Félix BM, ... Thangaratinam S, IPPIC Collaborative Network</i><br /><b>Background</b><br />Existing evidence on the effects of race and ethnicity on pregnancy outcomes is restricted to individual studies done within specific countries and health systems. We aimed to assess the impact of race and ethnicity on perinatal outcomes in high-income and upper-middle-income countries, and to ascertain whether the magnitude of disparities, if any, varied across geographical regions.<br /><b>Methods</b><br />For this individual participant data (IPD) meta-analysis we used data from the International Prediction of Pregnancy Complications (IPPIC) Network of studies on pregnancy complications; the full dataset comprised 94 studies, 53 countries, and 4 539 640 pregnancies. We included studies that reported perinatal outcomes (neonatal death, stillbirth, preterm birth, and small-for-gestational-age babies) in at least two racial or ethnic groups (White, Black, south Asian, Hispanic, or other). For our two-step random-effects IPD meta-analysis, we did multiple imputations for confounder variables (maternal age, BMI, parity, and level of maternal education) selected with a directed acyclic graph. The primary outcomes were neonatal mortality and stillbirth. Secondary outcomes were preterm birth and a small-for-gestational-age baby. We estimated the association of race and ethnicity with perinatal outcomes using a multivariate logistic regression model and reported this association with odds ratios (ORs) and 95% CIs. We also did a subgroup analysis of studies by geographical region.<br /><b>Findings</b><br />51 studies from 20 high-income and upper-middle-income countries, comprising 2 198 655 pregnancies, were eligible for inclusion in this IPD meta-analysis. Neonatal death was twice as likely in babies born to Black women than in babies born to White women (OR 2·00, 95% CI 1·44-2·78), as was stillbirth (2·16, 1·46-3·19), and babies born to Black women were at increased risk of preterm birth (1·65, 1·46-1·88) and being small for gestational age (1·39, 1·13-1·72). Babies of women categorised as Hispanic had a three-times increased risk of neonatal death (OR 3·34, 95% CI 2·77-4·02) than did those born to White women, and those born to south Asian women were at increased risk of preterm birth (OR 1·26, 95% CI 1·07-1·48) and being small for gestational age (1·61, 1·32-1·95). The effects of race and ethnicity on preterm birth and small-for-gestational-age babies did not vary across regions.<br /><b>Interpretation</b><br />Globally, among underserved groups, babies born to Black women had consistently poorer perinatal outcomes than White women after adjusting for maternal characteristics, although the risks varied for other groups. The effects of race and ethnicity on adverse perinatal outcomes did not vary by region.<br /><b>Funding</b><br />National Institute for Health and Care Research, Wellbeing of Women.<br /><br />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.<br /><br /><small>Lancet: 10 Dec 2022; 400:2049-2062</small></div>
Sheikh J, Allotey J, Kew T, Fernández-Félix BM, ... Thangaratinam S, IPPIC Collaborative Network
Lancet: 10 Dec 2022; 400:2049-2062 | PMID: 36502843
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<div><h4>Racial disparities in recommendations for surgical resection of primary brain tumours: a registry-based cohort analysis.</h4><i>Butterfield JT, Golzarian S, Johnson R, Fellows E, ... Marcotte EL, Venteicher AS</i><br /><b>Background</b><br />Disparities in treatment and outcomes disproportionately affect minority ethnic and racial populations in many surgical fields. Although substantial research in racial disparities has focused on outcomes, little is known about how surgeon recommendations can be influenced by patient race. The aim of this study was to investigate racial and socioeconomic disparities in the surgical management of primary brain tumors.<br /><b>Methods</b><br />In this registry-based cohort study, we used data from the Surveillance, Epidemiology, and End Results (SEER) database (1975-2016) and the American College of Surgeons National Cancer Database (NCDB) in the USA for independent analysis. Adults (aged ≥20 years) with a new diagnosis of meningioma, glioblastoma, pituitary adenoma, vestibular schwannoma, astrocytoma, and oligodendroglioma, with information on tumour size and surgical recommendation were included in the analysis. The primary outcome of this study was the odds of a surgeon recommending against surgical resection at diagnosis of primary brain neoplasms. This outcome was determined using multivariable logistic regression with clinical, demographic, and socioeconomic factors.<br /><b>Findings</b><br />This study included US national data from the SEER (1975-2016) and NCDB (2004-17) databases of adults with a new diagnosis of meningioma (SEER n=63 674; NCDB n=222 673), glioblastoma (n=35 258; n=104 047), pituitary adenoma (n=27 506; n=87 772), vestibular schwannoma (n=11 525; n=30 745), astrocytoma (n=5402; n=10 631), and oligodendroglioma (n=3977; n=9187). Independent of clinical and demographic factors, including insurance status and rural-urban continuum code, Black patients had significantly higher odds of recommendation against surgical resection of meningioma (adjusted odds ratio 1·13, 95% CI 1·06-1·21, p<0·0001), glioblastoma (1·14, 1·01-1·28, p=0·038), pituitary adenoma (1·13, 1·05-1·22, p<0·0001), and vestibular schwannoma (1·48, 1·19-1·84, p<0·0001) when compared with White patients in the SEER dataset. Additionally, patients of unknown race had significantly higher odds of recommendation against surgical resection for pituitary adenoma (1·80, 1·41-2·30, p<0·0001) and vestibular schwannoma (1·49, 1·10-2·04, p=0·011). Performing a validation analysis using the NCDB dataset confirmed these significant results for Black patients with meningioma (1·18, 1·14-1·22, p<0·0001), glioblastoma (1·19, 1·12-1·28, p<0·0001), pituitary adenoma (1·21, 1·16-1·25, p<0·0001), and vestibular schwannoma (1·19, 1·04-1·35, p=0·0085), and indicated and indicated that the findings are independent of patient comorbidities. When further restricted to the most recent decade in SEER, these inequities held true for Black patients, except those with glioblastoma (meningioma [1·18, 1·08-1·28, p<0·0001], pituitary adenoma [1·20, 1·09-1·31, p<0·0001], and vestibular schwannoma [1·54, 1·16-2·04, p=0·0031]).<br /><b>Interpretation</b><br />Racial disparities in surgery recommendations in the USA exist for patients with primary brain tumours, independent of potential confounders including clinical, demographic, and select socioeconomic factors. Further studies are needed to understand drivers of this bias and enhance equality in surgical care.<br /><b>Funding</b><br />None.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 10 Dec 2022; 400:2063-2073</small></div>
Butterfield JT, Golzarian S, Johnson R, Fellows E, ... Marcotte EL, Venteicher AS
Lancet: 10 Dec 2022; 400:2063-2073 | PMID: 36502844
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<div><h4>The impact of urbanisation on the cardiometabolic health of Indigenous Brazilian peoples: a systematic review and meta-analysis, and data from the Brazilian Health registry.</h4><i>Kramer CK, Leitão CB, Viana LV</i><br /><b>Background</b><br />Indigenous Brazilian peoples have faced an unparalleled increase in the rate of cardiovascular diseases following rapid nutritional transition to more urban diets. We aimed to conduct a systematic review and meta-analysis to evaluate the association between urbanisation (including data from Amazon rainforest deforestation) and cardiometabolic risk factors and outcomes.<br /><b>Methods</b><br />In this systematic review and meta-analysis, we searched Pubmed, Embase, Web of Science, and Scopus for articles published in any language between the year 1950 and March 10, 2022. Studies conducted in Indigenous Brazilian adults that evaluated metabolic health were included. Data for deforestation was obtained by the Amazon Deforestation Monitoring Project. Cardiovascular mortality was obtained from the Brazilian Health registry. Two independent reviewers evaluated studies for risk of bias, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. The main outcomes assessed were the prevalence of obesity and related cardiometabolic risk factors among Indigenous Brazilian peoples and its association with urbanisation. Summary data were extracted from published reports for the meta-analyses. We calculated pooled estimates of the prevalence of each cardiometabolic outcome by using a random-effects model (DerSimonian-Laird method). This study is registered with the International Prospective Register of Systematic Reviews, CRD42021285480.<br /><b>Findings</b><br />46 studies were identified, including a total of 20 574 adults from at least 33 Indigenous Brazilian ethnicities. Meta-analyses of the prevalence of obesity showed that there were higher rates of obesity (midwest region: 23% [95% CI 17-29]; and south region 23% [13-34]) and hypertension (south region: 30% [10-50]) in Indigenous peoples living in urban regions of Brazil, while the lowest rates of obesity (11% [95% CI 8-15]) and hypertension (1% [1-2]) were observed in those in the less urbanised (north) regions of Brazil. The prevalence of obesity was 3·5 times higher in participants living in urbanised Indigenous territories (28%) than in those living in lands with >80% native Amazon rainforest (8%). In meta-analyses that evaluated blood pressure level, there was no incremental change in blood pressure with ageing in Indigenous peoples who lived according to traditional lifestyle, in contrast to those living in urbanised regions. For Indigenous men with traditional lifestyles, systolic blood pressure changed from 109·8 mm Hg to 104·4 mm Hg between the youngest (<30 years) and the oldest (>60 years) age groups, and diastolic blood pressure changed from 69·8 mm Hg to 66·1 mm Hg. For Indigenous women with traditional lifestyles, systolic blood pressure was 100·0 mm Hg for the youngest age group with no changes for older age groups, and diastolic blood pressure was 62 mm Hg for the youngest age group with no changes for older age groups. For Indigenous men with urbanised lifestyles, systolic blood pressure changed from 117·3 mm Hg to 124·9 mm Hg between the youngest and the oldest age groups, and diastolic blood pressure changed from 72·7 mm Hg to 76·4 mm Hg. For Indigenous women with urbanised lifestyles, systolic blood pressure changed from 110·0 mm Hg to 116·0 mm Hg between the youngest and the oldest age groups, and diastolic blood pressure changed from 68·3 mm Hg to 74·0 mm Hg. For the years 1997 and 2019, the cardiovascular mortality rate in individuals living in the southeast region (the most urbanised) was 2·5 times greater than that observed in the north. Conversely, the incremental rise in cardiovascular mortality in the past two decades among Indigenous Brazilians living in the north or northeast (2·7 times increase) stands in stark contrast to the stable rates in those living in already urbanised regions.<br /><b>Interpretation</b><br />The macrosocial changes of Indigenous peoples\' traditional ways of living consequent to urbanisation are associated with an increased prevalence of adverse cardiometabolic outcomes. These data highlight the urgent need for environmental policies to ensure the conservation of the natural ecosystem within Indigenous territories, as well as the development of socio-health policies to improve the cardiovascular health of Indigenous Brazilians peoples living in urban areas.<br /><b>Funding</b><br />None.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 10 Dec 2022; 400:2074-2083</small></div>
Abstract
<div><h4>Population-level contribution of interpersonal discrimination to psychological distress among Australian Aboriginal and Torres Strait Islander adults, and to Indigenous-non-Indigenous inequities: cross-sectional analysis of a community-controlled First Nations cohort study.</h4><i>Thurber KA, Brinckley MM, Jones R, Evans O, ... Calma T, Lovett R</i><br /><b>Background</b><br />International and population-specific evidence identifies elevated psychological distress prevalence among those experiencing interpersonal discrimination. We aim to quantify the potential whole-of-population contribution of interpersonal discrimination to psychological distress prevalence and Indigenous-non-Indigenous gaps in Australia.<br /><b>Methods</b><br />We did a cross-sectional analysis of data from Mayi Kuwayu: the National Study of Aboriginal and Torres Strait Islander Wellbeing. Baseline surveys were completed between June 8, 2018, and Sept 28, 2022. We analysed responses from participants who were aged 18 years or older at survey completion, whose surveys were processed between Oct 1, 2018, and May 1, 2021. Sample weights were developed on the basis of national population benchmarks. We measured everyday discrimination using an eight-item measure modified from the Everyday Discrimination Scale and classified experiences as racial discrimination if participants attributed these experiences to their Indigeneity. Psychological distress was measured using a validated, modified Kessler-5 scale. Applying logistic regression, we calculated unadjusted odds ratios (ORs), to approximate incident rate ratios (IRRs), for high or very high psychological distress in relation to everyday discrimination and everyday racial discrimination across age-gender strata. Population attributable fractions (PAFs), under the hypothetical assumption that ORs represent causal relationships, were calculated using these ORs and population-level exposure prevalence. These PAFs were used to quantify the contribution of everyday racial discrimination to psychological distress gaps between Indigenous and non-Indigenous adults.<br /><b>Findings</b><br />9963 survey responses were eligible for inclusion in our study, of which we analysed 9951 (99·9%); 12 were excluded due to responders identifying as a gender other than man or woman (there were too few responses from this demographic to be included as a category in stratified tables or adjusted analyses). The overall prevalence of psychological distress was 48·3% (95% CI 47·0-49·6) in those experiencing everyday discrimination compared with 25·2% (23·8-26·6) in those experiencing no everyday discrimination (OR 2·77 [95% CI 2·52-3·04]) and psychological distress prevalence was 49·0% (95% CI 47·3-50·6) in those experiencing everyday racial discrimination and 31·8% (30·6-33·1) in those experiencing no everyday racial discrimination (OR 2·06 [95% CI 1·88-2·25]. Overall, 49·3% of the total psychological distress burden among Aboriginal and Torres Strait Islander adults could be attributable to everyday discrimination (39·4-58·8% across strata) and 27·1% to everyday racial discrimination. Everyday racial discrimination could explain 47·4% of the overall gap in psychological distress between Indigenous and non-Indigenous people (40·0-60·3% across strata).<br /><b>Interpretation</b><br />Our findings show that interpersonal discrimination might contribute substantially to psychological distress among Aboriginal and Torres Strait Islander adults, and to inequities compared with non-Indigenous adults. Estimated PAFs include contributions from social and health disadvantage, reflecting contributions from structural racism. Although not providing strictly conclusive evidence of causality, this evidence is sufficient to indicate the psychological harm of interpersonal discrimination. Findings add weight to imperatives to combat discrimination and structural racism at its core. Urgent individual and policy action is required of non-Indigenous people and colonial structures, directed by Aboriginal and Torres Strait Islander peoples.<br /><b>Funding</b><br />National Health and Medical Research Council of Australia, Ian Potter Foundation, Australian Research Council, US National Institutes of Health, and Sierra Foundation.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 10 Dec 2022; 400:2084-2094</small></div>
Abstract
<div><h4>Racism, xenophobia, discrimination, and the determination of health.</h4><i>Devakumar D, Selvarajah S, Abubakar I, Kim SS, ... White AIR, Achiume ET</i><br /><AbstractText>This Series shows how racism, xenophobia, discrimination, and the structures that support them are detrimental to health. In this first Series paper, we describe the conceptual model used throughout the Series and the underlying principles and definitions. We explore concepts of epistemic injustice, biological experimentation, and misconceptions about race using a historical lens. We focus on the core structural factors of separation and hierarchical power that permeate society and result in the negative health consequences we see. We are at a crucial moment in history, as populist leaders pushing the politics of hate have become more powerful in several countries. These leaders exploit racism, xenophobia, and other forms of discrimination to divide and control populations, with immediate and long-term consequences for both individual and population health. The COVID-19 pandemic and transnational racial justice movements have brought renewed attention to persisting structural racial injustice.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 10 Dec 2022; 400:2097-2108</small></div>
Devakumar D, Selvarajah S, Abubakar I, Kim SS, ... White AIR, Achiume ET
Lancet: 10 Dec 2022; 400:2097-2108 | PMID: 36502848
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<div><h4>Racism, xenophobia, and discrimination: mapping pathways to health outcomes.</h4><i>Selvarajah S, Corona Maioli S, Deivanayagam TA, de Morais Sato P, ... Abubakar I, Paradies Y</i><br /><AbstractText>Despite being globally pervasive, racism, xenophobia, and discrimination are not universally recognised determinants of health. We challenge widespread beliefs related to the inevitability of increased mortality and morbidity associated with particular ethnicities and minoritised groups. In refuting that racial categories have a genetic basis and acknowledging that socioeconomic factors offer incomplete explanations in understanding these health disparities, we examine the pathways by which discrimination based on caste, ethnicity, Indigeneity, migratory status, race, religion, and skin colour affect health. Discrimination based on these categories, although having many unique historical and cultural contexts, operates in the same way, with overlapping pathways and health effects. We synthesise how such discrimination affects health systems, spatial determination, and communities, and how these processes manifest at the individual level, across the life course, and intergenerationally. We explore how individuals respond to and internalise these complex mechanisms psychologically, behaviourally, and physiologically. The evidence shows that racism, xenophobia, and discrimination affect a range of health outcomes across all ages around the world, and remain embedded within the universal challenges we face, from COVID-19 to the climate emergency.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 10 Dec 2022; 400:2109-2124</small></div>
Selvarajah S, Corona Maioli S, Deivanayagam TA, de Morais Sato P, ... Abubakar I, Paradies Y
Lancet: 10 Dec 2022; 400:2109-2124 | PMID: 36502849
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<div><h4>Intersectional insights into racism and health: not just a question of identity.</h4><i>Shannon G, Morgan R, Zeinali Z, Brady L, ... Whyle E, Muraya K</i><br /><AbstractText>Intersectionality is a useful tool to address health inequalities, by helping us understand and respond to the individual and group effects of converging systems of power. Intersectionality rejects the notion of inequalities being the result of single, distinct factors, and instead focuses on the relationships between overlapping processes that create inequities. In this Series paper, we use an intersectional approach to highlight the intersections of racism, xenophobia, and discrimination with other systems of oppression, how this affects health, and what can be done about it. We present five case studies from different global locations that outline different dimensions of discrimination based on caste, ethnicity and migration status, Indigeneity, religion, and skin colour. Although experiences are diverse, the case studies show commonalities in how discrimination operates to affect health and wellbeing: how historical factors and coloniality shape contemporary experiences of race and racism; how racism leads to separation and hierarchies across shifting lines of identity and privilege; how racism and discrimination are institutionalised at a systems level and are embedded in laws, regulations, practices, and health systems; how discrimination, minoritisation, and exclusion are racialised processes, influenced by visible factors and tacit knowledge; and how racism is a form of structural violence. These insights allow us to begin to articulate starting points for justice-based action that addresses root causes, engages beyond the health sector, and encourages transnational solidarity.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 10 Dec 2022; 400:2125-2136</small></div>
Shannon G, Morgan R, Zeinali Z, Brady L, ... Whyle E, Muraya K
Lancet: 10 Dec 2022; 400:2125-2136 | PMID: 36502850
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<div><h4>Confronting the consequences of racism, xenophobia, and discrimination on health and health-care systems.</h4><i>Abubakar I, Gram L, Lasoye S, Achiume ET, ... Shannon G, Devakumar D</i><br /><AbstractText>Racism, xenophobia, and discrimination are key determinants of health and equity and must be addressed for improved health outcomes. We conclude that far broader, deeper, transformative action is needed compared with current measures to tackle adverse effects of racism on health. To challenge the structural drivers of racism and xenophobia, anti-racist action and other wider measures that target determinants should implement an intersectional approach to effectively address the causes and consequences of racism within a population. Structurally, legal instruments and human rights law provide a robust framework to challenge the pervasive drivers of disadvantage linked to caste, ethnicity, Indigeneity, migratory status, race, religion, and skin colour. Actions need to consider the historical, economic, and political contexts in which the effects of racism, xenophobia, and discrimination affect health. We propose several specific actions: a commission that explores how we action the approaches laid out in this paper; building a conversation and a series of events with international multilateral agency stakeholders to raise the issue and profile of racism, xenophobia, and discrimination within health; and using our multiple platforms to build coalitions, expand knowledge, highlight inequities, and advocate for change across the world.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 10 Dec 2022; 400:2137-2146</small></div>
Abubakar I, Gram L, Lasoye S, Achiume ET, ... Shannon G, Devakumar D
Lancet: 10 Dec 2022; 400:2137-2146 | PMID: 36502851
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<div><h4>An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study.</h4><i>Guttman-Yassky E, Simpson EL, Reich K, Kabashima K, ... Esfandiari E, Furue M</i><br /><b>Background</b><br />OX40 is crucial for T-cell differentiation and memory induction. The anti-OX40 antibody, rocatinlimab inhibits the OX40 pathway. We evaluated the efficacy and safety of rocatinlimab in adults with moderate-to-severe atopic dermatitis.<br /><b>Methods</b><br />This multicentre, double-blind, placebo-controlled phase 2b study was done at 65 secondary and tertiary sites in the USA, Canada, Japan, and Germany. Eligible patients were adults (aged 18 years or older) with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria or local diagnostic criteria) with moderate-to-severe disease activity, as defined by an Eczema Area and Severity Index (EASI) score of 16 or more, validated Investigator\'s Global Assessment for Atopic Dermatitis score of 3 (moderate) or 4 (severe), and affected body surface area 10% or higher at both screening and baseline, with documented history (within 1 year) of inadequate response to topical medications or if topical treatments were medically inadvisable. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous rocatinlimab every 4 weeks (150 mg or 600 mg) or every 2 weeks (300 mg or 600 mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up. Percentage change from baseline in EASI score was assessed as the primary endpoint at week 16 and during the active extension and follow-up in all randomly assigned patients exposed to study drug with a post-baseline EASI score at week 16 or earlier according to the group they were randomly assigned to. Safety was assessed in all randomly assigned patients exposed to study drug; patients were analysed according to the group they were randomly assigned to. The study is registered with ClinicalTrials.gov, NCT03703102.<br /><b>Findings</b><br />Between Oct 22, 2018, and Oct 21, 2019, 274 patients (114 [42%] women, 160 [58%] men; mean age 38·0 years [SD 14·5]) were randomly assigned to one of the rocatinlimab groups (217 [79%] patients) or to the placebo group (57 [21%] patients). Compared with placebo (-15·0 [95% CI -28·6 to -1·4]), significant least-squares mean percent reductions in EASI score at week 16 were observed in all rocatinlimab groups (rocatinlimab 150 mg every 4 weeks -48·3 [-62·2 to -34·0], p=0·0003; rocatinlimab 600 mg every 4 weeks -49·7 [-64·3 to -35·2], p=0·0002; rocatinlimab 300 mg every 2 weeks -61·1 [-75·2 to -47·0], p<0·0001; and rocatinlimab 600 mg every 2 weeks -57·4 [-71·3 to -43·4], p<0·0001). The most common adverse events during the double-blind period in patients receiving rocatinlimab (adverse events ≥5% of patients in the total rocatinlimab group and more common than the placebo group) were pyrexia (36 [17%] patients), nasopharyngitis (30 [14%] patients), chills (24 [11%] patients), headache (19 [9%] patients), aphthous ulcer (15 [7%] patients), and nausea (13 [6%] patients). There were no deaths.<br /><b>Interpretation</b><br />Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated.<br /><b>Funding</b><br />Kyowa Kirin.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 09 Dec 2022; epub ahead of print</small></div>
Guttman-Yassky E, Simpson EL, Reich K, Kabashima K, ... Esfandiari E, Furue M
Lancet: 09 Dec 2022; epub ahead of print | PMID: 36509097
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<div><h4>Congenital adrenal hyperplasia.</h4><i>Auer MK, Nordenström A, Lajic S, Reisch N</i><br /><AbstractText>Congenital adrenal hyperplasia is a group of autosomal recessive disorders leading to multiple complex hormonal imbalances caused by various enzyme deficiencies in the adrenal steroidogenic pathway. The most common type of congenital adrenal hyperplasia is due to steroid 21-hydroxylase (21-OHase, henceforth 21OH) deficiency. The rare, classic (severe) form caused by 21OH deficiency is characterised by life-threatening adrenal crises and is the most common cause of atypical genitalia in neonates with 46,XX karyotype. After the introduction of life-saving hormone replacement therapy in the 1950s and neonatal screening programmes in many countries, nowadays neonatal survival rates in patients with congenital adrenal hyperplasia are high. However, disease-related mortality is increased and therapeutic management remains challenging, with multiple long-term complications related to treatment and disease affecting growth and development, metabolic and cardiovascular health, and fertility. Non-classic (mild) forms of congenital adrenal hyperplasia caused by 21OH deficiency are more common than the classic ones; they are detected clinically and primarily identified in female patients with hirsutism or impaired fertility. Novel treatment approaches are emerging with the aim of mimicking physiological circadian cortisol rhythm or to reduce adrenal hyperandrogenism independent of the suppressive effect of glucocorticoids.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 08 Dec 2022; epub ahead of print</small></div>
Auer MK, Nordenström A, Lajic S, Reisch N
Lancet: 08 Dec 2022; epub ahead of print | PMID: 36502822
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<div><h4>Evaluation of the safety, immunogenicity, and faecal shedding of novel oral polio vaccine type 2 in healthy newborn infants in Bangladesh: a randomised, controlled, phase 2 clinical trial.</h4><i>Zaman K, Bandyopadhyay AS, Hoque M, Gast C, ... Clemens JD, Tritama E</i><br /><b>Background</b><br />Type 2 circulating vaccine-derived polioviruses (cVDPV2) from Sabin oral poliovirus vaccines (OPVs) are the leading cause of poliomyelitis. A novel type 2 OPV (nOPV2) has been developed to be more genetically stable with similar tolerability and immunogenicity to that of Sabin type 2 vaccines to mitigate the risk of cVDPV2. We aimed to assess these aspects of nOPV2 in poliovirus vaccine-naive newborn infants.<br /><b>Methods</b><br />In this randomised, double-blind, controlled, phase 2 trial we enrolled newborn infants at the Matlab Health Research Centre, Chandpur, Bangladesh. We included infants who were healthy and were a single birth after at least 37 weeks\' gestation. Infants were randomly assigned (2:1) to receive either two doses of nOPV2 or placebo, administered at age 0-3 days and at 4 weeks. Exclusion criteria included receipt of rotavirus or any other poliovirus vaccine, any infection or illness at the time of enrolment (vomiting, diarrhoea, or intolerance to liquids), diagnosis or suspicion of any immunodeficiency disorder in the infant or a close family member, or any contraindication for venipuncture. The primary safety outcome was safety and tolerability after one and two doses of nOPV2, given 4 weeks apart in poliovirus vaccine-naive newborn infants and the primary immunogenicity outcome was the seroconversion rate for neutralising antibodies against type 2 poliovirus, measured 28 days after the first and second vaccinations with nOPV2. Study staff recorded solicited and unsolicited adverse events after each dose during daily home visits for 7 days. Poliovirus neutralising antibody responses were measured in sera drawn at birth and at age 4 weeks and 8 weeks. This study is registered on ClinicalTrials.gov, NCT04693286.<br /><b>Findings</b><br />Between Sept 21, 2020, and Aug 16, 2021, we screened 334 newborn infants, of whom three (<1%) were found to be ineligible and one (<1%) was withdrawn by the parents; the remaining 330 (99%) infants were assigned to receive nOPV2 (n=220 [67%]) or placebo (n=110 [33%]). nOPV2 was well tolerated; 154 (70%) of 220 newborn infants in the nOPV2 group and 78 (71%) of 110 in the placebo group had solicited adverse events, which were all mild or moderate in severity. Severe unsolicited adverse events in 11 (5%) vaccine recipients and five (5%) placebo recipients were considered unrelated to vaccination. 306 (93%) of 330 infants had seroprotective maternal antibodies against type 2 poliovirus at birth, decreasing to 58 (56%) of 104 in the placebo group at 8 weeks. In the nOPV2 group 196 (90%) of 217 infants seroconverted by week 8 after two doses, when 214 (99%) had seroprotective antibodies.<br /><b>Interpretation</b><br />nOPV2 was well tolerated and immunogenic in newborn infants, with two doses, at birth and 4 weeks, resulting in almost 99% of infants having protective neutralising antibodies.<br /><b>Funding</b><br />Bill & Melinda Gates Foundation.<br /><br />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.<br /><br /><small>Lancet: 07 Dec 2022; epub ahead of print</small></div>
Zaman K, Bandyopadhyay AS, Hoque M, Gast C, ... Clemens JD, Tritama E
Lancet: 07 Dec 2022; epub ahead of print | PMID: 36495882
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<div><h4>Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.</h4><i>Hurvitz SA, Hegg R, Chung WP, Im SA, ... Ashfaque S, Cortés J</i><br /><b>Background</b><br />An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.<br /><b>Methods</b><br />This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110.<br /><b>Findings</b><br />Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group.<br /><b>Interpretation</b><br />Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration.<br /><b>Funding</b><br />Daiichi Sankyo and AstraZeneca.<br /><br />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.<br /><br /><small>Lancet: 06 Dec 2022; epub ahead of print</small></div>
Hurvitz SA, Hegg R, Chung WP, Im SA, ... Ashfaque S, Cortés J
Lancet: 06 Dec 2022; epub ahead of print | PMID: 36495879
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<div><h4>Bimekizumab in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α inhibitors: a randomised, double-blind, placebo-controlled, phase 3 trial (BE COMPLETE).</h4><i>Merola JF, Landewé R, McInnes IB, Mease PJ, ... Coarse J, Coates LC</i><br /><b>Background</b><br />Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A. This study compared the efficacy and safety of bimekizumab with placebo over 16 weeks in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α (TNFα) inhibitors.<br /><b>Methods</b><br />BE COMPLETE was a phase 3, multicentre, randomised, double-blind, placebo-controlled trial conducted across 92 sites (including hospitals, clinics, and research centres) in 11 countries (Australia, Canada, Czech Republic, Germany, Hungary, Italy, Japan, Poland, Russia, the UK, and the USA). Eligible patients were aged 18 years or older with adult-onset psoriatic arthritis (meeting the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening) with a history of inadequate response or intolerance to treatment with one or two TNFα inhibitors for either psoriatic arthritis or psoriasis. We stratified patients with active psoriatic arthritis by region and previous TNFα inhibitor use. Patients were randomly assigned (2:1) to receive subcutaneous bimekizumab 160 mg every 4 weeks or placebo by an interactive-voice and web-response system on the basis of a predetermined randomisation schedule. The primary endpoint was the proportion of patients with 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses were done in the randomised population. The safety analysis set comprised patients who received one or more doses of study treatment. This trial was registered at ClinicalTrials.gov, NCT03896581, and is completed.<br /><b>Findings</b><br />Between March 28, 2019, and Feb 14, 2022, 556 patients were screened and 400 patients were randomly assigned to bimekizumab 160 mg every 4 weeks (n=267) or placebo (n=133). The primary and all hierarchical secondary endpoints were met at week 16. 116 (43%) of 267 patients receiving bimekizumab reached ACR50, compared with nine (7%) of 133 patients receiving placebo (adjusted odds ratio [OR] 11·1 [95% CI 5·4-23·0], p<0·0001). 121 (69%) of 176 patients with psoriasis affecting at least 3% body surface area at baseline who received bimekizumab reached 90% or greater improvement in the Psoriasis Area and Severity Index (PASI90), compared with six (7%) of 88 patients who received placebo (adjusted OR 30·2 [12·4-73·9], p<0·0001). Treatment-emergent adverse events up to week 16 were reported in 108 (40%) of 267 patients receiving bimekizumab and 44 (33%) of 132 patients receiving placebo. There were no new safety signals and no deaths.<br /><b>Interpretation</b><br />Bimekizumab treatment led to superior improvements in joint and skin efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis and inadequate response or intolerance to TNFα inhibitors. The safety profile of bimekizumab was consistent with previous phase 3 studies in patients with plaque psoriasis, and studies of IL-17A inhibitors.<br /><b>Funding</b><br />UCB Pharma.<br /><br />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.<br /><br /><small>Lancet: 05 Dec 2022; epub ahead of print</small></div>
Abstract
<div><h4>Bimekizumab in patients with psoriatic arthritis, naive to biologic treatment: a randomised, double-blind, placebo-controlled, phase 3 trial (BE OPTIMAL).</h4><i>McInnes IB, Asahina A, Coates LC, Landewé R, ... Coarse J, Mease PJ</i><br /><b>Background</b><br />Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17A and IL-17F. We assessed the efficacy and safety of bimekizumab in patients with active psoriatic arthritis who were naive to biologic disease-modifying antirheumatic drugs (DMARDs).<br /><b>Methods</b><br />BE OPTIMAL was a 52-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, active reference (adalimumab) trial done at 135 sites (hospitals, clinics, doctors\' offices, and research centres) in 14 countries. Eligible patients were 18 years or older with a documented diagnosis of adult-onset psoriatic arthritis that met the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening. Participants were randomly assigned with an interactive-voice and web-response system on the basis of a predetermined randomisation schedule (3:2:1, stratified by region and bone erosion number at baseline) to bimekizumab 160 mg every 4 weeks, placebo every 2 weeks, or the reference group (adalimumab 40 mg every 2 weeks), all administered subcutaneously. At week 16, patients randomly assigned to placebo switched to bimekizumab 160 mg every 4 weeks. The primary endpoint was the proportion of patients reaching 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses included all patients who were randomly assigned (intention-to-treat population); the safety analysis set comprised patients who received one or more doses of treatment. Data are presented to week 24 (preplanned analysis). This trial is registered at ClinicalTrials.gov, NCT03895203.<br /><b>Findings</b><br />Between April 3, 2019, and Oct 25, 2021, 1163 patients were screened and 852 were randomly assigned to bimekizumab (n=431), placebo (n=281), and reference (adalimumab; n=140) groups. At week 16, significantly more patients receiving bimekizumab (189 [44%] of 431) reached ACR50 response versus placebo (28 [10%] of 281; odds ratio 7·1 [95% CI 4·6-10·9], p<0·0001; adalimumab 64 [46%] of 140). All secondary hierarchical endpoints were met. Treatment-emergent adverse events up to week 16 were reported in 258 [60%] of 431 patients receiving bimekizumab, 139 [49%] of 281 patients receiving placebo, and 83 [59%] of 140 patients receiving adalimumab. No deaths occurred.<br /><b>Interpretation</b><br />Bimekizumab treatment had superior improvements in joint, skin, and radiographic efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis who were naive to biologic DMARDs. The safety profile of bimekizumab, including the occurrence of fungal infections, was consistent with previous phase 3 studies in patients with plaque psoriasis, and with IL-17A inhibitors.<br /><b>Funding</b><br />UCB Pharma.<br /><br />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.<br /><br /><small>Lancet: 05 Dec 2022; epub ahead of print</small></div>
McInnes IB, Asahina A, Coates LC, Landewé R, ... Coarse J, Mease PJ
Lancet: 05 Dec 2022; epub ahead of print | PMID: 36493791
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<div><h4>The path to healthy ageing in China: a Peking University-Lancet Commission.</h4><i>Chen X, Giles J, Yao Y, Yip W, ... Smith J, Zhao Y</i><br /><b>Unlabelled</b><br />Around the world, populations are ageing at a faster pace than in the past and this demographic transition will have impacts on all aspects of societies. In May 2020, the UN General Assembly declared 2021–2030 the Decade of Healthy Ageing, highlighting the importance for policymakers across the world to focus policy on improving the lives of older people, both today and in the future. While rapid population ageing poses challenges, China’s rapid economic growth over the last forty years has created space for policy to assist older persons and families in their efforts to improve health and well-being at older ages. As China is home to 1/5 of the world’s older people, China is often held up as an example for other middle-income countries. This Commission Report aims to help readers to understand the process of healthy ageing in China as a means of drawing lessons from the China experience. In addition, with the purpose of informing the ongoing policy dialogue within China, the Commission Report highlights the policy challenges on the horizon and draws lessons from international experience.<br /><b>The uniqueness of china’s ageing society</b><br />From a global perspective, China shares some of the economic and social challenges faced by other countries with rapidly ageing populations. China stands out, however, as it already has the world’s largest older population, and China’s ageing burdens will increase further as the ‘second baby boomers’ (those born between 1962 and 1975) start to enter retirement in 2022. In addition, China’s rapid demographic transition over the last four decades will lead to a dramatic decline in the number of living children for each older person in China and bring substantial challenges for both family-based care and social care. Compounding demographic changes, personnel planning in geriatric and rehabilitation medicine has not kept pace with the growth of the older age population, and there is a shortage of medical resources targeted at the ageing population. In Section 1, the report stresses the importance of achieving “healthy ageing” in light of socio-economic progress, urbanization and migration, and China’s demographic transition.<br /><b>Health complexity and inequalities among china’s older population</b><br />China completed its epidemiological transition from infectious diseases to non-communicable diseases (NCDs) during the past three decades. As in many other ageing countries, the upward trend in the incidence of NCDs and the presence of multimorbidity pose special challenges for China’s healthcare sector. Even as some older Chinese continue to suffer from such communicable diseases as hepatitis, tuberculosis, and sexually transmitted diseases, chronic conditions, such as cognitive impairments, mental disorders, and frailty, are becoming much more prominent. These chronic conditions are complex to treat and manage and are associated with more functional disability and greater care needs. Along with the emergence of NCDs, substantial gaps in health are apparent by gender, rural versus urban residence, ethnicity, and socio-economic status. Investments in healthy ageing, from promoting education in health literacy to improving access to health care, are promising means of improving the well-being of older adults and reducing the gaps in health across socioeconomic groups in China. Even as China’s population ages, investments in healthy ageing offer a path for older Chinese to play meaningful and productive social roles in society, while limiting burdens on their families. The latest facts on health status and health inequities among China’s older adults are presented in Section 2 of the report.<br /><b>Modifiable factors of healthy ageing: evidence from china.</b><br />Current evidence on the determinants of health and functioning status of China’s older population is summarized in Section 3. In China, as elsewhere, health at older ages results from the cumulative effects of behaviours and events that occur across the life cycle. These include exposures to unhealthy environments and parental decisions influencing in-utero and childhood health, later health behaviours as teenagers and adults (including decisions on educational investments, smoking, drinking, and physical activity), and decisions over food consumption which influence diet and nutritional status. Many of these decisions and behaviors are influenced by health literacy and socio-economic conditions, but they may also be influenced by policy (Section 5). Finally, Section 3 highlights the health benefits of social connections and participating in leisure activities such as square dancing and promoting age-friendly environments in China.<br /><b>Integrating medical and social care for chinese older people.</b><br />Older people require access to high-quality health services that include prevention, promotion, curative, rehabilitative, palliative and end-of-life care. An update on China’s policy initiatives regarding healthcare and social care relevant to the ageing population is provided in Section 4. In addition to achieving universal health insurance coverage, China has invested heavily in public health promotion and the consolidation of the primary healthcare system. Further, as the role of the family in providing care for older people is eroded by dwindling family size and changing living arrangements, especially with the outmigration of adult children, China is taking steps to build up institutional and community care infrastructure as both a substitute for, and complement to, family care. Furthermore, long-term care insurance (LTCI) has been piloted in many cities as a financing mechanism. China’s experience with the LTCI pilots suggests that it will be difficult to sustain LTCI under the current pay-as-you-go framework, and that there will be a considerable public financial risk as the population ages. Although China’s government has placed the integration of health care with long-term care (LTC) at the forefront of its policy agenda, the progress for the integration has been slow.<br /><b>Lessons learned from china and implications for the future.</b><br />An overview of the evidence presented earlier in the report is presented in Section 5, followed by policy recommendations for supporting healthy ageing in China. Policy recommendations outlined here can be generalized to other countries, especially low- and middle-income countries (LMICs). First, health promotion initiatives should focus on changing people’s behavior, especially smoking cessation, weight control, and health literacy education to reduce the incidence of NCDs and care burdens. Second, there is an urgent need to move away from disease-centred care to person-centred care and to increase the supply of health care workers, particularly in geriatric medicine, rehabilitation medicine, and hospice care. Third, innovative measures should be taken to remove obstacles to upgrading community and home environments and thus facilitate mobility and social engagement among older people. There are several other policy areas that should be addressed, given China’s unique institutional environment. These include regional segmentation of health insurance systems and the regulatory environment for healthcare delivery. Specifically, the report suggests that policy in China should focus on: (1) national integration of the health insurance system to eliminate the current segmentation across regions and occupations; (2) capping regionally segmented LTCI initiatives, and striving for a national scheme that is independently funded; (3) switching government subsidies in the aged care sector from subsidising providers to subsidising consumers to facilitate market competition and to help existing care facilities to meet safety regulations; (4) strengthing the capacity to regulate medical service providers, especially in screening for fraud against the national medical insurance schemes and reforming the healthcare delivery sector by lowering barriers to entry and facilitating choice. Older people are an important part of a family and an invaluable asset to society. Healthy ageing will not only enable older people to enjoy their later life to the fullest but has the potential to unleash the intellectual and vocational capacities of society as a whole. Recognizing that China’s older population will continue to grow, it is important to take their needs into account and prepare well in advance by creating an age-friendly environment for the ageing population. As China’s “second baby boomers” start to reach retirement age in 2022, it is imperative to take the window of opportunity afforded by China’s economic growth to make coordinated efforts across sectors to address the concerns of an ageing nation.<br /><br /><br /><br /><small>Lancet: 03 Dec 2022; 400:1967-2006</small></div>
Chen X, Giles J, Yao Y, Yip W, ... Smith J, Zhao Y
Lancet: 03 Dec 2022; 400:1967-2006 | PMID: 36423650
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<div><h4>The evolving landscape of pulmonary arterial hypertension clinical trials.</h4><i>Weatherald J, Boucly A, Peters A, Montani D, ... Humbert M, Evolving Landscape of Pulmonary Arterial Hypertension and Redesigning Pulmonary Arterial Hypertension Clinical Trials Task Force of the 18th Global CardioVascular Clinical Trialists Forum</i><br /><AbstractText>Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 26 Nov 2022; 400:1884-1898</small></div>
Weatherald J, Boucly A, Peters A, Montani D, ... Humbert M, Evolving Landscape of Pulmonary Arterial Hypertension and Redesigning Pulmonary Arterial Hypertension Clinical Trials Task Force of the 18th Global CardioVascular Clinical Trialists Forum
Lancet: 26 Nov 2022; 400:1884-1898 | PMID: 36436527
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<div><h4>Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial.</h4><i>Thompson GR, Soriano A, Cornely OA, Kullberg BJ, ... Pappas PG, ReSTORE trial investigators</i><br /><b>Background</b><br />Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis.<br /><b>Methods</b><br />ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete.<br /><b>Findings</b><br />Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events.<br /><b>Interpretation</b><br />Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development.<br /><b>Funding</b><br />Cidara Therapeutics and Mundipharma.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 25 Nov 2022; epub ahead of print</small></div>
Thompson GR, Soriano A, Cornely OA, Kullberg BJ, ... Pappas PG, ReSTORE trial investigators
Lancet: 25 Nov 2022; epub ahead of print | PMID: 36442484
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<div><h4>Systemic sclerosis.</h4><i>Volkmann ER, Andréasson K, Smith V</i><br /><AbstractText>Systemic sclerosis, also known as scleroderma, is a rare and complex autoimmune connective-tissue disease. Once considered an untreatable and unpredictable condition, research advancements have improved our understanding of its disease pathogenesis and clinical phenotypes and expanded our treatment armamentarium. Early and accurate diagnosis is essential, while ongoing efforts to risk stratify patients have a central role in predicting both organ involvement and disease progression. A holistic approach is required when choosing the optimal therapeutic strategy, balancing the side-effect profile with efficacy and tailoring the treatment according to the goals of care of the patient. This Seminar reviews the multiple clinical dimensions of systemic sclerosis, beginning at a precursor very early stage of disease, with a focus on timely early detection of organ involvement. This Seminar also summarises management considerations according to the pathological hallmarks of systemic sclerosis (eg, inflammation, fibrosis, and vasculopathy) and highlights unmet needs and opportunities for future research and discovery.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 25 Nov 2022; epub ahead of print</small></div>
Volkmann ER, Andréasson K, Smith V
Lancet: 25 Nov 2022; epub ahead of print | PMID: 36442487
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<div><h4>Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: a systematic review and individual patient data meta-analysis.</h4><i>Saito M, McGready R, Tinto H, Rouamba T, ... Ter Kuile FO, Dellicour S</i><br /><b>Background</b><br />Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy.<br /><b>Methods</b><br />For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371.<br /><b>Findings</b><br />We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49-1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47-1·17), stillbirth (aHR=0·71, 0·32-1·57), and major congenital anomalies (aHR=0·60, 0·13-2·87). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36-0·92).<br /><b>Interpretation</b><br />We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted.<br /><b>Funding</b><br />Medicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.<br /><br />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.<br /><br /><small>Lancet: 25 Nov 2022; epub ahead of print</small></div>
Saito M, McGready R, Tinto H, Rouamba T, ... Ter Kuile FO, Dellicour S
Lancet: 25 Nov 2022; epub ahead of print | PMID: 36442488
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<div><h4>Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019.</h4><i>GBD 2019 Antimicrobial Resistance Collaborators</i><br /><b>Background</b><br />Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes.<br /><b>Methods</b><br />We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2·5th and 97·5th percentiles across 1000 posterior draws for each quantity of interest.<br /><b>Findings</b><br />From an estimated 13·7 million (95% UI 10·9-17·1) infection-related deaths in 2019, there were 7·7 million deaths (5·7-10·2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13·6% (10·2-18·1) of all global deaths and 56·2% (52·1-60·1) of all sepsis-related deaths in 2019. Five leading pathogens-Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa-were responsible for 54·9% (52·9-56·9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185-285) per 100 000 population, and lowest in the high-income super-region, with 52·2 deaths (37·4-71·5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths.<br /><b>Interpretation</b><br />The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development.<br /><b>Funding</b><br />Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care, using UK aid funding managed by the Fleming Fund.<br /><br />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.<br /><br /><small>Lancet: 18 Nov 2022; epub ahead of print</small></div>
GBD 2019 Antimicrobial Resistance Collaborators
Lancet: 18 Nov 2022; epub ahead of print | PMID: 36423648
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<div><h4>Monkeypox.</h4><i>Mitjà O, Ogoina D, Titanji BK, Galvan C, ... Marks M, Orkin CM</i><br /><AbstractText>Monkeypox is a zoonotic illness caused by the monkeypox virus, an Orthopoxvirus in the same genus as the variola, vaccinia, and cowpox viruses. Since the detection of the first human case in the Democratic Republic of the Congo in 1970, the disease has caused sporadic infections and outbreaks, mainly restricted to some countries in west and central Africa. In July, 2022, WHO declared monkeypox a Public Health Emergency of International Concern, on account of the unprecedented global spread of the disease outside previously endemic countries in Africa and the need for global solidarity to address this previously neglected disease. The 2022 outbreak has been primarily associated with close intimate contact (including sexual activity) and most cases have been diagnosed among men who have sex with men, who often present with novel epidemiological and clinical characteristics. In the 2022 outbreak, the incubation period ranges from 7 days to 10 days and most patients present with a systemic illness that includes fever and myalgia and a characteristic rash, with papules that evolve to vesicles, pustules, and crusts in the genital, anal, or oral regions and often involve the mucosa. Complications that require medical treatment (eg, antiviral therapy, antibacterials, and pain control) occur in up to 40% of patients and include rectal pain, odynophagia, penile oedema, and skin and anorectal abscesses. Most patients have a self-limited illness; between 1% and 13% require hospital admission (for treatment or isolation), and the case-fatality rate is less than 0·1%. A diagnosis can be made through the presence of Orthopoxvirus DNA in PCRs from lesion swabs or body fluids. Patients with severe manifestations and people at risk of severe disease (eg, immunosuppressed people) could benefit from antiviral treatment (eg, tecovirimat). The current strategy for post-exposure prophylaxis or pre-exposure prophylaxis for people at high risk is vaccination with the non-replicating modified vaccinia Ankara. Antiviral treatment and vaccines are not yet available in endemic countries in Africa.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 17 Nov 2022; epub ahead of print</small></div>
Mitjà O, Ogoina D, Titanji BK, Galvan C, ... Marks M, Orkin CM
Lancet: 17 Nov 2022; epub ahead of print | PMID: 36403582
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<div><h4>Human rights and the COVID-19 pandemic: a retrospective and prospective analysis.</h4><i>Gostin LO, Friedman EA, Hossain S, Mukherjee J, ... Were M, Dhai A</i><br /><AbstractText>When the history of the COVID-19 pandemic is written, the failure of many states to live up to their human rights obligations should be a central narrative. The pandemic began with Wuhan officials in China suppressing information, silencing whistleblowers, and violating the freedom of expression and the right to health. Since then, COVID-19\'s effects have been profoundly unequal, both nationally and globally. These inequalities have emphatically highlighted how far countries are from meeting the supreme human rights command of non-discrimination, from achieving the highest attainable standard of health that is equally the right of all people everywhere, and from taking the human rights obligation of international assistance and cooperation seriously. We propose embedding human rights and equity within a transformed global health architecture as the necessary response to COVID-19\'s rights violations. This means vastly more funding from high-income countries to support low-income and middle-income countries in rights-based recoveries, plus implementing measures to ensure equitable distribution of COVID-19 medical technologies. We also emphasise structured approaches to funding and equitable distribution going forward, which includes embedding human rights into a new pandemic treaty. Above all, new legal instruments and mechanisms, from a right to health treaty to a fund for civil society right to health advocacy, are required so that the narratives of future health emergencies-and people\'s daily lives-are ones of equality and human rights.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 17 Nov 2022; epub ahead of print</small></div>
Gostin LO, Friedman EA, Hossain S, Mukherjee J, ... Were M, Dhai A
Lancet: 17 Nov 2022; epub ahead of print | PMID: 36403583
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<div><h4>Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.</h4><i>Thornhill JP, Palich R, Ghosn J, Walmsley S, ... Orkin CM, Share-Net writing group</i><br /><b>Background</b><br />Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors.<br /><b>Methods</b><br />International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections.<br /><b>Findings</b><br />Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported.<br /><b>Interpretation</b><br />The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high.<br /><b>Funding</b><br />None.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 17 Nov 2022; epub ahead of print</small></div>
Thornhill JP, Palich R, Ghosn J, Walmsley S, ... Orkin CM, Share-Net writing group
Lancet: 17 Nov 2022; epub ahead of print | PMID: 36403584
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<div><h4>Balloon catheters versus vaginal prostaglandins for labour induction (CPI Collaborative): an individual participant data meta-analysis of randomised controlled trials.</h4><i>Jones MN, Palmer KR, Pathirana MM, Cecatti JG, ... Mol BW, Li W</i><br /><b>Background</b><br />Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods.<br /><b>Methods</b><br />We did an individual participant data meta-analysis comparing balloon catheters and vaginal prostaglandins for cervical ripening before labour induction. We systematically identified published and unpublished randomised controlled trials that completed data collection between March 19, 2019, and May 1, 2021, by searching the Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and PubMed. Further trials done before March 19, 2019, were identified through a recent Cochrane review. Data relating to the combined use of the two methods were not included, only data from women with a viable, singleton pregnancy were analysed, and no exclusion was made based on parity or membrane status. We contacted authors of individuals trials and participant-level data were harmonised and recoded according to predefined definitions of variables. Risk of bias was assessed with the ROB2 tool. The primary outcomes were caesarean delivery, indication for caesarean delivery, a composite adverse perinatal outcome, and a composite adverse maternal outcome. We followed the intention-to-treat principle for the main analysis. The primary meta-analysis used two-stage random-effects models and the sensitivity analysis used one-stage mixed models. All models were adjusted for maternal age and parity. This meta-analysis is registered with PROSPERO (CRD42020179924).<br /><b>Findings</b><br />Individual participant data were available from 12 studies with a total of 5460 participants. Balloon catheters, compared with vaginal prostaglandins, did not lead to a significantly different rate of caesarean delivery (12 trials, 5414 women; crude incidence 27·0%; adjusted OR [aOR] 1·09, 95% CI 0·95-1·24; I<sup>2</sup>=0%), caesarean delivery for failure to progress (11 trials, 4601 women; aOR 1·20, 95% CI 0·91-1·58; I<sup>2</sup>=39%), or caesarean delivery for fetal distress (10 trials, 4441 women; aOR 0·86, 95% CI 0·71-1·04; I<sup>2</sup>=0%). The composite adverse perinatal outcome was lower in women who were allocated to balloon catheters than in those allocated to vaginal prostaglandins (ten trials, 4452 neonates, crude incidence 13·6%; aOR 0·80, 95% CI 0·70-0·92; I<sup>2</sup>=0%). There was no significant difference in the composite adverse maternal outcome (ten trials, 4326 women, crude incidence 22·7%; aOR 1·02, 95% CI 0·89-1·18; I<sup>2</sup>=0%).<br /><b>Interpretation</b><br />In induction of labour, balloon catheters and vaginal prostaglandins have comparable caesarean delivery rates and maternal safety profiles, but balloon catheters lead to fewer adverse perinatal events.<br /><b>Funding</b><br />Australian National Health and Medical Research Council and Monash Health Emerging Researcher Fellowship.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 12 Nov 2022; 400:1681-1692</small></div>
Jones MN, Palmer KR, Pathirana MM, Cecatti JG, ... Mol BW, Li W
Lancet: 12 Nov 2022; 400:1681-1692 | PMID: 36366885
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<div><h4>Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: a phase 2, randomised, double-blind, placebo-controlled trial.</h4><i>Vrselja A, Latifi A, Baber RJ, Stuckey BGA, ... Hickey M, Davis SR</i><br /><b>Background</b><br />Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy and safety of Q-122 in women with breast cancer taking oral adjuvant endocrine therapy and experiencing vasomotor symptoms.<br /><b>Methods</b><br />We conducted a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at 18 sites in Australia, New Zealand, and the USA. Eligible participants were women, aged 18-70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week. Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m<sup>2</sup> or >30 kg/m<sup>2</sup>) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin. Q-122 and placebo capsules were identical in appearance and containers identically labelled. During the double-blind treatment and analysis phases, the participants, investigators, clinical research organisation staff, and sponsor were masked to treatment allocation. The primary outcome was the difference in the mean percentage change from baseline in the Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats (msVMS-SS) between Q-122 and placebo after 28 days of treatment. Primary analysis was by modified intention-to-treat and safety was assessed in all participants receiving at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT03518138.<br /><b>Findings</b><br />Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66). Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122 -39% [95% CI -46 to -31] vs placebo -26% [-33 to -18]; p=0·018). Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 [17%] of 65 patients in the Q-122 group vs nine [14%] of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events.<br /><b>Interpretation</b><br />Q-122 is an effective and well tolerated non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Our results support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to menopausal hormone therapy.<br /><b>Funding</b><br />QUE Oncology.<br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>Lancet: 12 Nov 2022; 400:1704-1711</small></div>
Abstract
<div><h4>Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.</h4><i>Goodall RL, Meredith SK, Nunn AJ, Bayissa A, ... Rusen ID, STREAM study collaborators</i><br /><b>Background</b><br />The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen.<br /><b>Methods</b><br />We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631.<br /><b>Findings</b><br />Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss.<br /><b>Interpretation</b><br />Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss.<br /><b>Funding</b><br />USAID and Janssen Research & Development.<br /><br />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.<br /><br /><small>Lancet: 07 Nov 2022; epub ahead of print</small></div>
Goodall RL, Meredith SK, Nunn AJ, Bayissa A, ... Rusen ID, STREAM study collaborators
Lancet: 07 Nov 2022; epub ahead of print | PMID: 36368336
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This program is still in alpha version.