4,170 research outputs found
Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy
No full textPublisher Copyright: © 2023, The Author(s).Introduction: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. Methods: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. Results: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10–10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10–7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10–7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10–15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10–15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. Conclusion: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment. Trial Registration Number: ClinicalTrials.gov: NCT03759379.Peer reviewe
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial
No full textBackground: Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations. Methods: 20 536 UK adults (aged 40–80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These “intention-to-treat” comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1·0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. Findings: All-cause mortality was significantly reduced (1328 [12·9%] deaths among 10 269 allocated simvastatin versus 1507 [14·7%] among 10 267 allocated placebo; p=0·0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5·7%] vs 707 [6·9%]; p=0·0005), a marginally significant reduction in other vascular deaths (194 [1·9%] vs 230 [2·2%]; p=0·07), and a non-significant reduction in non-vascular deaths (547 [5·3%] vs 570 [5·6%]; p=0·4). There were highly significant reductions of about one-quarter in the first event rate for nonfatal myocardial infarction or coronary death (898 [8·7%] vs 1212 [11·8%]; p<0·0001), for non-fatal or fatal stroke (444 [4·3%] vs 585 [5·7%]; p<0·0001), and for coronary or noncoronary revascularisation (939 [9·1%] vs 1205 [11·7%]; p<0·0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19–28) reduction in the event rate (2033 [19·8%] vs 2585 [25·2%] affected individuals; p<0·0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and—most notably—even those who presented with LDL cholesterol below 3·0 mmol/L (116 mg/dL), or total cholesterol below 5·0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0·01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause. Interpretation: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70–100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone
Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
No full textBackground Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surger
Publisher Correction: Global estimates on the number of people blind or visually impaired by cataract: a meta-analysis from 2000 to 2020
No full textFully disaggregated data is not available publicly due to data sharing agreements with some principal investigators yet requests for summary data can be made to the corresponding author.” Furthermore, the information in the “Funding” section was incomplete. The following information was added: “This study was funded by Brien Holden Vision Institute, Fondation Thea, Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation (LCIF), Sightsavers International, and University of Heidelberg.” The “Competing interests” section has been corrected from “The authors declare no competing interests” to the following detailed information: GBD 2019 Blindness and Vision Impairment Collaborators Declarations N S Bayileyegn reports participation on a Data Safety Monitoring Board or Advisory Board with Jimma University, and leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with Jimma University as a discipline committee member; outside the submitted work. S Bhaskar reports grants or contracts from the Japan Society for the Promotion of Science (JSPS), JSPS International Fellowship, Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Australian Academy of Science, Grant-in-Aid for Scientific Research (KAKENHI); leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with Rotary District 9675 as the District Chair of Diversity, Equity, and Inclusion; the Global Health & Migration Hub Community and the Global Health Hub Germany (Berlin, Germany) as the Chair and Manager; PLOS One, BMC Neurology, Frontiers In Neurology, Frontiers in Stroke, Frontiers in Public Health and BMC Medical Research Methodology as an Editorial Board Member; and with the College of Reviewers, Canadian Institutes of Health Research (CIHR), and the Government of Canada as a Member; outside the submitted work. X Dai reports support for the present manuscript from the Institute for Health Metrics and Evaluation and the University of Washington. M Cenderadewi reports grants or contracts from James Cook University (International Research Training Program Scholarship for doctoral study), and support for attending meetings and travel from James Cook University; all outside the submitted work. M Foschi reports consulting fees from Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sanofi, Merck, and Novartis; support for attending meetings and travel from Novartis and Roche; leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with MSBase as a scientific leadership board member, and Cochrane Review Group for Multiple Sclerosis and other rate diseases of the CNS as a member; all outside the submitted work. F Ghassemi reports support for the present manuscript from medical writing. B N G Goulart reports stock or stock options with Bristo Myers-Squibb and Pfizer; outside the submitted work. V B Gupta reports grants or contracts from the National Health and Medical Research Council (NHMRC); outside the submitted work. S Hallaj reports support for the present manuscript from the National Institute of Health, Bridge to AI common fund (grant number: OT2 OD032644). I M Ilic reports support for the present manuscript from the Ministry of Education, Science and Technological development, Republic of Serbia (project No 175042, 2011-2023). S Islam reports support for the present manuscript from the National Health and Medical Research Council (NHMRC) Investigator Grant and the Heart Foundation Vanguard Grant. J H Kempen reports support for the present manuscript from Sight for Souls and Mass Eye and Ear Global Surgery Program; and leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with Sight for Souls as the President. K Krishan reports other non-financial support from the UGC Centre of Advanced Study, CAS II, awarded to the Department of Anthropology, Panjab University (Chandigarh, India); outside the submitted work. O P Kurmi reports grants or contracts from the British Council India paid to Coventry University; outside the submitted work. V C Lansingh reports consulting fees from HelpMeSee, and financial support for attending meetings and travel from HelpMeSee; outside the submitted work. J L Leasher leadership or fiduciary roles in board, society, committee or advocacy groups, unpaid with the National Eye Institute as a member and the National Eye Health Education Program as a planning committee member; outside the submitted work. M Lee reports support for the present manuscript from the Ministry of Education of the Republic of Korea, and the National Research Foundation of Korea (NRF-2021R1I1A4A01057428) and Bio-convergence Technology Education Program through the Korea Institute for Advancement Technology (KIAT) funded by the Ministry of Trade, Industry and Energy (No. P0017805). C McAlinden reports grants or contracts from the Welsh Government on the following study: Feasibility of an alternative pathway for hospital referrals from Diabetic Eye Screening Wales (DESW) for people suspected with sight-threatening diabetic eye disease (diabetic maculopathy). No funds will be received from the author’s institution or personally related to this study. Any work conducted as part of this study is as an unpaid collaborator; consulting fees from Acufocus (Irvine, California, USA), Atia Vision (Campbell, California, USA), Bausch and Lomb (Bridgewater, New Jersey, USA), BVI / PhysIOL (Liège, Belgium), Coopervision (Pleasanton, California, USA), Cutting Edge (Labége, France), Fudan University (Fudan, China), Hoya (Frankfurt, Germany), Knowledge Gate Group (Copenhagen, Denmark), Johnson & Johnson Surgical Vision (Santa Ana, California, USA), Keio University (Tokyo, Japan), Ludwig-Maximilians-University (München, Germany), Medevise Consulting SAS (Strasbourg, France), Novartis (Basel, Switzerland), Ophtec BV (Groningen, The Netherlands), Sun Yat-sen University (Guangzhou, China), SightGlass vision (Menlo Park, California, USA), Science in Vision (Bend, Oregan, USA), SpyGlass (Aliso Viejo, California, USA), Targomed GmbH (Bruchsal, Germany), University of São Paulo (São Paulo, Brazil), and Vold Vision (Arkansas, USA); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Scope (Crawley, UK), Bausch and Lomb (Bridgewater, New Jersey, USA), and Thea pharmaceuticals (Clemont-Ferrand, France); support for attending meetings and/or travel from Royal College of Ophthalmologists (London, UK), Scope (Crawley, UK), Portuguese Society of Ophthalmology (Portugal), British Society of Refractive surgery (BSRS), Thea pharmaceuticals (Clemont-Ferrand, France), Bausch and Lomb (Bridgewater, New Jersey, USA); leadership or fiduciary roles in board, society, committee or advocacy groups, paid or unpaid with the British Society of Refractive Surgery (BSRS) as an unpaid council member, and the Royal College of Ophthalmologists (London, UK) as an unpaid PROM advisor; other financial interests from the Quality of Vision (QoV) Questionnaire tool, the Orthokeratology and Contact Lens Quality of Life Questionnaire (OCL-QoL), and paid peer reviews for Research Square; outside of the submitted work. Finally, the section “Author Contributions” has been added and an Appendix with more detailed information for individual author contributions has been included in the form of electronic supplementary material. The original article has been corrected
Morning vs. evening administration of antiviral therapy in COVID-19 patients. A preliminary retrospective study in Ferrara, Italy
No full textOBJECTIVE: At the end of 2019, the Novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), spread rapidly from China to the whole world. Circadian rhythms can play crucial role in the complex interplay between viruses and organisms, and temporized schedules (chronotherapy) have been positively tested in several medical diseases. We aimed to compare the possible effects of a morning vs. evening antiviral administration in COVID patients.
PATIENTS AND METHODS: We retrospectively evaluated all patients admitted to COVID internal medicine units with confirmed SARSCoV-2 infection, and treated with darunavir-ritonavir (single daily dose, for seven days). Age, sex, length of stay (LOS), pharmacological treatment, and timing of antiviral administration (morning or evening), were recorded. Outcome
indicators were death or LOS, and laboratory parameters, e.g., variations in C-reactive protein (CRP) levels, ratio of arterial oxygen partial pressure (PaO2, mmHg) to fractional inspired oxygen (FiO2) (PaO2/FiO2), and leucocyte count.
RESULTS: The total sample consisted of 151 patients, 33 (21.8%) of whom were selected for antiviral treatment. The mean age was 61.8±18.3 years, 17 (51.5%) were male, and the mean LOS was 13.4±8.6 days. Nine patients (27.3%) had their antiviral administration in the morning, and 24 (72.7%) had antiviral administration in the evening. No fatalities occurred. Despite the extremely limited sample size, morning group subjects showed a significant difference in CRP variation, compared to that in evening
The association between tobacco and the risk of asthma, rhinoconjunctivitis and eczema in children and adolescents : analyses from Phase Three of the ISAAC programme
No full textWe are grateful to the children and parents who participated
in ISAAC Phase Three and the coordination and assistance by the school staff is
sincerely appreciated. The authors also acknowledge and thank the many funding
bodies throughout the world that supported the individual ISAAC centres and
collaborators and their meetings.Background: Exposure to parental smoking is associated
with wheeze in early childhood, but in 2006 the US
Surgeon General stated that the evidence is insufficient
to infer a causal relationship between exposure and
asthma in childhood and adolescents.
Aims:To examine the association between maternal and
paternal smoking and symptoms of asthma, eczema and
rhinoconjunctivitis.
Methods: Parents or guardians of children aged
6-7 years completed written questionnaires about
symptoms of asthma, rhinoconjunctivitis and eczema,
and several risk factors, including maternal smoking in
the child’s first year of life, current maternal smoking
(and amount) and paternal smoking. Adolescents aged
13-14 years self completed the questionnaires on these
symptoms and whether their parents currently smoked.
Results: In the 6-7-year age group there were 220 407
children from 75 centres in 32 countries. In the 13-14-
year age group there were 350 654 adolescents from
118 centres in 53 countries. Maternal and paternal
smoking was associated with an increased risk of
symptoms of asthma, eczema and rhinoconjunctivitis in
both age groups, although the magnitude of the OR is
higher for symptoms of asthma than the other outcomes.
Maternal smoking is associated with higher ORs than
paternal smoking. For asthma symptoms there is a clear
dose relationship (1e9 cigarettes/day, OR 1.27; 10-19
cigarettes/day, OR 1.35; and 20+ cigarettes/day, OR
1.56). When maternal smoking in the child’s first year of
life and current maternal smoking are considered, the
main effect is due to maternal smoking in the child’s first
year of life. There was no interaction between maternal
and paternal smoking.
Conclusions: This study has confirmed the importance
of maternal smoking, and the separate and additional
effect of paternal smoking. The presence of
a dose-response effect relationship with asthma
symptoms suggests that the relationship is causal,
however for eczema and rhinoconjunctivitis causality is
less certain.peer-reviewe
The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial
No full textBackground: At the time of feasibility work and final design of the trial there was no randomised control trial evidence for the long-term risks and benefits of hormone replacement therapy. Observational studies had suggested that long term use of estrogen was likely to be associated, amongst other things, with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer. Concomitant use of progestogens had been shown to protect against endometrial cancer, but there were few data showing how progestogen might affect estrogen actions on other conditions. Disease specific risks from observational studies suggested that, overall, long-term HRT was likely to be beneficial. Several studies showed that mortality from all causes was lower in HRT users than in non-users. Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women. The WISDOM trial was designed to compare combined estrogen and progestogen versus placebo, and estrogen alone versus combined estrogen and progestogen. During the development of WISDOM the Women's Health Initiative trial was designed, funded and started in the US. Design: Randomised, placebo, controlled, trial. Methods: The trial was set in general practices in the UK (384), Australia (94), and New Zealand (24). In these practices 284175 women aged 50–69 years were registered with 226282 potentially eligible. We sought to randomise 22300 postmenopausal women aged 50 – 69 and treat for ten years. The interventions were: conjugated equine estrogens, 0.625 mg orally daily; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily; matched placebo. Primary outcome measures were: major cardiovascular disease, osteoporotic fractures, breast cancer and dementia. Secondary outcomes were: other cancers, all cause death, venous thromboembolism and cerebro-vascular disease. Results: The trial was prematurely closed during recruitment following publication of early results from the Women's Health Initiative. At the time of closure, 56583 had been screened, 8980 entered run-in, and 5694 (26% of target of 22,300) randomised. Those women randomised had received a mean of one year of therapy, mean age was 62.8 years and total follow-up time was 6491 person years. Discussion: The WISDOM experience leads to some simple messages. The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery. When a trial is very costly and beyond the resources of one country, funders and investigators should make every effort to develop international collaboration with joint funding
Correction to. Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients. the DecubICUs study
No full textThe original version of this article unfortunately contained a mistake. The members of the ESICM Trials Group Collaborators were not shown in the article but only in the ESM. The full list of collaborators is shown below. The original article has been corrected
Utilization of mechanical power and associations with clinical outcomes in brain injured patients : a secondary analysis of the extubation strategies in neuro-intensive care unit patients and associations with outcome (ENIO) trial
No full textFunding Information: The authors received no direct funding for this work. SW is supported by institutional research grants and the National Institutes of Health. MS receives support from NIMH K01MH115789. ST is supported by the Eliot Phillipson Clinician Scientist Training Program and Clinician Investigator Program at the University of Toronto. RDS is supported on NIA R33AG071744. Publisher Copyright: © 2023, The Author(s).Peer reviewe
Early life exposure to farm animals and symptoms of asthma, rhinoconjunctivitis and eczema : an ISAAC Phase Three study
No full textWe are grateful to the children and parents who willingly
cooperated and participated in ISAAC Phase
Three and the coordination and assistance by the
school staff is sincerely appreciated. The authors also
acknowledge and thank the many funding bodies
throughout the world that supported the individual
ISAAC centres and collaborators and their meetings.
The funders of the study had no role in study design;
in the collection, analysis, and interpretation of data;
in the writing of the report; or in the decision to
submit the paper for publication.Background: Associations between early life exposure to farm animals and respiratory symptoms and allergy in children have been reported in developed countries, but little is known about such associations in developing countries.
Objective: To study the association between early life exposure to farm animals and symptoms of asthma, rhinoconjunctivitis and eczema in a worldwide study.
Methods: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) was carried out in 6- to 7-year-old children in urban populations across the world. Questions about early life exposure to farm animals (at least once/week) were included in an additional questionnaire. The association between such exposures and symptoms of asthma, rhinoconjunctivitis and eczema was investigated with logistic regression. Adjustments were made for gender, region of the world, language, gross national income and 10 other subject-specific covariates.
Results: A positive association was found between early exposure to farm animals and the prevalence of symptoms of asthma, rhinoconjunctivitis and eczema, especially in non-affluent countries. In these countries, odds ratios (ORs) for 'current wheeze', 'farm animal exposure in the first year of life' and 'farm animal exposure in pregnancy' were 1.27 [95% confidence interval (CI) 1.12-1.44] and 1.38 (95% CI 1.21-1.58), respectively. The corresponding ORs for affluent countries were 0.96 (95% CI 0.86-1.08) and 0.95 (95% CI 0.84-1.08), respectively.
Conclusion: Exposure to farm animals during pregnancy and in the first year of life was associated with increased symptoms of asthma, rhinoconjunctivitis and eczema in 6- to 7-year-old children living in non-affluent but not in affluent countries.peer-reviewe
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