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Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.
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Variación Genética , Estudio de Asociación del Genoma Completo , Células Madre Hematopoyéticas/metabolismo , Enfermedades del Sistema Inmune/genética , Alelos , Diferenciación Celular , Predisposición Genética a la Enfermedad , Células Madre Hematopoyéticas/patología , Humanos , Enfermedades del Sistema Inmune/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Población Blanca/genéticaRESUMEN
Network meta-analysis (NMA), a statistical technique that allows systematic reviewers to simultaneously compare more than two alternatives, makes use of indirect evidence from studies comparing interventions of interest to a common comparator. The capacity for multiple simultaneous comparisons makes NMA appealing for evidence-based decision-makers. This article, aimed at users of SRs with NMAs and at those who are considering conducting SRs with NMAs, provides an introductory level overview of this topic. We describe the main considerations that those conducting systematic reviews with NMA should bear in mind, including decisions regarding grouping interventions into analysis nodes, and testing the assumptions that assure the validity of NMA. We explain and illustrate how both systematic reviewers and users should draw conclusions from NMA that are appropriate and useful for decision-making. Finally, we provide a list of tools that facilitate the conduct and interpretation of NMAs.
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Systematic reviews are a type of evidence synthesis in which authors develop explicit eligibility criteria, collect all the available studies that meet these criteria, and summarize results using reproducible methods that minimize biases and errors. Systematic reviews serve different purposes and use a different methodology than other types of evidence synthesis that include narrative reviews, scoping reviews, and overviews of reviews. Systematic reviews can address questions regarding effects of interventions or exposures, diagnostic properties of tests, and prevalence or prognosis of diseases. All rigorous systematic reviews have common processes that include: 1) determining the question and eligibility criteria, including a priori specification of subgroup hypotheses 2) searching for evidence and selecting studies, 3) abstracting data and assessing risk of bias of the included studies, 4) summarizing the data for each outcome of interest, whenever possible using meta-analyses, and 5) assessing the certainty of the evidence and drawing conclusions. There are several tools that can guide and facilitate the systematic review process, but methodological and content expertise are always necessary.
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Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.
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Hipofosfatasia , Adulto , Niño , Humanos , Adolescente , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Fosfatasa Alcalina/genética , Europa (Continente) , Prevalencia , MutaciónRESUMEN
Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.
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Hipofosfatasia , Lactante , Adulto , Recién Nacido , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/epidemiología , Hipofosfatasia/genética , Fosfatasa Alcalina/genética , Mutación , PrevalenciaRESUMEN
BACKGROUND: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.
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Hipofosfatasia , Adulto , Niño , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Mutación , Estudios Retrospectivos , Fosfatasa Alcalina/genética , Genotipo , FenotipoRESUMEN
INTRODUCTION: To compare neonatal, obstetrical, and maternal outcomes associated with outpatient versus inpatient management of pregnancies with preterm prelabor rupture of membranes (PPROM). MATERIAL AND METHODS: A search of MEDLINE, EMBASE, the Cochrane Database and Central Register from January 1, 1990 to July 31, 2023 identified randomized controlled trials (RCTs) and cohort studies comparing outpatient with inpatient management for pregnant persons diagnosed with PPROM before 37 weeks' gestation. No language restriction was applied. We applied a random effects model for meta-analysis. Trustworthiness was assessed using recently published guidance and Risk of bias using the RoB 2.0 tool for RCTs and ROBINS-I tool for cohort studies. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was used to assess the certainty of evidence (COE). Outcomes of interest included perinatal mortality, neonatal morbidities, latency and gestational age at delivery, and maternal morbidities. RCTs and cohort studies were analyzed separately. This study was registered in the International Prospective Register of Systematic Reviewsr: CRD42022295275. RESULTS: From 2825 records, two RCTs and 10 cohort studies involving 1876 patients were included in the review and meta-analysis. Outpatient management protocols varied but generally included brief initial hospitalization, strict eligibility criteria, and surveillance with laboratory and ultrasound investigations. Outpatient management showed lower rates of neonatal respiratory distress syndrome (cohort: RR 0.63 [0.52-0.77, very low COE]), longer latency to delivery (RCT: MD 7.43 days [1.14-13.72 days, moderate COE], cohort: MD 8.78 days [2.29-15.26 days, low COE]), higher gestational age at birth (cohort: MD 7.70 days [2.02-13.38 days, low COE]), lower rates of Apgar scores <7 at 5 min of life (cohort: RR 0.66 [0.50-0.89, very low COE]), and lower rates of histological chorioamnionitis (cohort: RR 0.74 [0.62-0.89, low COE]) without increased risks of adverse neonatal, obstetrical, or maternal outcomes. CONCLUSIONS: Meta-analysis of data from RCTs and cohort studies with very low-to-moderate certainty of evidence indicates that further high-quality research is needed to evaluate the safety and potential benefits of outpatient management for selected PPROM cases, given the moderate-to-high risk of bias in the included studies.
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BACKGROUND: Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD prescription topical treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT databases to September 5, 2022, for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using 7 groups-group 1 being most potent. This review is registered in the Open Science Framework (https://osf.io/q5m6s). RESULTS: The 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty evidence, pimecrolimus improved 6 of 7 outcomes-among the best for 2; high-dose tacrolimus (0.1%) improved 5-among the best for 2; low-dose tacrolimus (0.03%) improved 5-among the best for 1. With moderate- to high-certainty evidence, group 5 TCS improved 6-among the best for 3; group 4 TCS and delgocitinib improved 4-among the best for 2; ruxolitinib improved 4-among the best for 1; group 1 TCS improved 3-among the best for 2. These interventions did not increase harm. Crisaborole and difamilast were intermediately effective, but with uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus. CONCLUSIONS: For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.
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Asma , Dermatitis Atópica , Fármacos Dermatológicos , Eccema , Humanos , Dermatitis Atópica/tratamiento farmacológico , Tacrolimus/uso terapéutico , Metaanálisis en Red , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Fármacos Dermatológicos/uso terapéutico , Asma/tratamiento farmacológico , Antibacterianos/uso terapéuticoRESUMEN
BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.
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Asma , Dermatitis Atópica , Eccema , Humanos , Dermatitis Atópica/tratamiento farmacológico , Metaanálisis en Red , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.
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Atención a la Salud , HumanosRESUMEN
BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory condition of the upper airways. Optimal management is unclear. OBJECTIVE: We compared the effects of mAbs and aspirin desensitization (ASA-D) for treatment of CRSwNP. METHODS: We searched the Medline, Embase, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, US Food and Drug Administration, and the European Medicines Agency databases from inception to August 4, 2021, for randomized controlled trials comparing the effects of mAbs and ASA-D for CRSwNP. We conducted network meta-analysis of sinusitis symptoms, heath-related quality of life, rescue oral corticosteroids and surgery, endoscopic and radiologic scores, and adverse events. We used the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach to assess certainty of evidence. PROSPERO CRD42020177334. RESULTS: Twenty-nine randomized controlled trials evaluating 8 treatments (n = 3461) were included in the network meta-analysis. Compared to placebo, moderate to high certainty evidence showed that health-related quality of life (SNOT-22) improved with dupilumab (mean difference [MD] -19.91 [95% confidence interval (CI) -22.50, -17.32]), omalizumab (MD -16.09 [95% CI -19.88, -12.30]), mepolizumab (MD -12.89 [95% CI -16.58, -9.19], ASA-D (MD -10.61 [95% CI -14.51, -6.71]), and benralizumab (MD -7.68 [95% CI -12.09, -3.27]). The risk of rescue nasal polyp surgery likely decreased with dupilumab (risk difference [RD] -16.35% [95% CI -18.13, -13.48]), omalizumab (RD -7.40% [95% CI -11.04, -2.43]), mepolizumab (RD -12.33% [95% CI -15.56, -7.22]), and ASA-D (RD -16.00% [95% CI -19.79, 0.21]; all moderate certainty). Comparisons among agents show with moderate to high certainty that dupilumab ranks among the most beneficial for 7 of 7 outcomes, omalizumab for 2 of 7, mepolizumab for 1 of 7, and ASA-D for 1 of 7. CONCLUSIONS: Multiple biologics and ASA-D credibly improve patient-important outcomes, with clinically important differences in effects among agents; dupilumab uniquely ranks among the most beneficial for all outcomes studied.
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Antineoplásicos Inmunológicos , Pólipos Nasales , Sinusitis , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Aspirina/efectos adversos , Enfermedad Crónica , Humanos , Pólipos Nasales/tratamiento farmacológico , Metaanálisis en Red , Omalizumab/uso terapéutico , Calidad de Vida , Sinusitis/tratamiento farmacológicoRESUMEN
BACKGROUND: Von Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long-term prophylaxis. AIM: Systematically summarize the evidence on the clinical outcomes of secondary long-term prophylaxis in patients with VWD and severe recurrent bleedings. METHODS: We searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long-term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non-Randomized Studies of interventions (ROBINS-I) tool to assess the quality of the included studies. We conducted random-effects meta-analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: We included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR], .24; 95% confidence interval [CI], .17-.35; low certainty evidence), and of epistaxis (RR, .38; 95%CI, .21-.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI .12-59.57; low certainty). Evidence from four before-and-after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR .34; 95%CI, .25-.46; very low certainty evidence). CONCLUSION: VWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits.
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Enfermedades de von Willebrand , Enfermedad Crónica , Epistaxis/prevención & control , Hospitalización , Humanos , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/tratamiento farmacológico , Factor de von Willebrand/uso terapéuticoRESUMEN
Network meta-analyses (NMAs) simultaneously estimate the effects of multiple possible treatment options for a given clinical presentation. For allergists to benefit optimally from NMAs, they must understand the process and be able to interpret the results. Through a worked example published in Pediatric Allergy and Immunology, we summarize how to identify credible NMAs and interpret them with a focus on recent innovations in the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation). NMAs build on traditional systematic reviews and meta-analyses that consider only direct paired comparisons by including indirect evidence, thus allowing the simultaneous assessment of the relative effect of all pairs of competing alternatives. Our framework informs clinicians of how to identify credible NMAs and address the certainty of the evidence. Trustworthy NMAs fill a critical gap in providing key inferences using direct and indirect evidence to inform clinical decision making when faced with more than two competing courses of treatment options. This document will help allergists to identify trustworthy NMAs to enhance patient care.
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Alergólogos , Toma de Decisiones Clínicas , Niño , Humanos , Metaanálisis en RedRESUMEN
BACKGROUND: Arthroscopic knee surgery remains a common treatment for symptomatic knee osteoarthritis, including for degenerative meniscal tears, despite guidelines strongly recommending against its use. This Cochrane Review is an update of a non-Cochrane systematic review published in 2017. OBJECTIVES: To assess the benefits and harms of arthroscopic surgery, including debridement, partial menisectomy or both, compared with placebo surgery or non-surgical treatment in people with degenerative knee disease (osteoarthritis, degenerative meniscal tears, or both). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and two trials registers up to 16 April 2021, unrestricted by language. SELECTION CRITERIA: We included randomised controlled trials (RCTs), or trials using quasi-randomised methods of participant allocation, comparing arthroscopic surgery with placebo surgery or non-surgical interventions (e.g. exercise, injections, non-arthroscopic lavage/irrigation, drug therapy, and supplements and complementary therapies) in people with symptomatic degenerative knee disease (osteoarthritis or degenerative meniscal tears or both). Major outcomes were pain, function, participant-reported treatment success, knee-specific quality of life, serious adverse events, total adverse events and knee surgery (replacement or osteotomy). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data, and assessed risk of bias and the certainty of evidence using GRADE. The primary comparison was arthroscopic surgery compared to placebo surgery for outcomes that measured benefits of surgery, but we combined data from all control groups to assess harms and knee surgery (replacement or osteotomy). MAIN RESULTS: Sixteen trials (2105 participants) met our inclusion criteria. The average age of participants ranged from 46 to 65 years, and 56% of participants were women. Four trials (380 participants) compared arthroscopic surgery to placebo surgery. For the remaining trials, arthroscopic surgery was compared to exercise (eight trials, 1371 participants), a single intra-articular glucocorticoid injection (one trial, 120 participants), non-arthroscopic lavage (one trial, 34 participants), non-steroidal anti-inflammatory drugs (one trial, 80 participants) and weekly hyaluronic acid injections for five weeks (one trial, 120 participants). The majority of trials without a placebo control were susceptible to bias: in particular, selection (56%), performance (75%), detection (75%), attrition (44%) and selective reporting (75%) biases. The placebo-controlled trials were less susceptible to bias and none were at risk of performance or detection bias. Here we limit reporting to the main comparison, arthroscopic surgery versus placebo surgery. High-certainty evidence indicates arthroscopic surgery leads to little or no difference in pain or function at three months after surgery, moderate-certainty evidence indicates there is probably little or no improvement in knee-specific quality of life three months after surgery, and low-certainty evidence indicates arthroscopic surgery may lead to little or no difference in participant-reported success at up to five years, compared with placebo surgery. Mean post-operative pain in the placebo group was 40.1 points on a 0 to 100 scale (where lower score indicates less pain) compared to 35.5 points in the arthroscopic surgery group, a difference of 4.6 points better (95% confidence interval (CI) 0.02 better to 9 better; I2 = 0%; 4 trials, 309 participants). Mean post-operative function in the placebo group was 75.9 points on a 0 to 100 rating scale (where higher score indicates better function) compared to 76 points in the arthroscopic surgery group, a difference of 0.1 points better (95% CI 3.2 worse to 3.4 better; I2 = 0%; 3 trials, 302 participants). Mean post-operative knee-specific health-related quality of life in the placebo group was 69.7 points on a 0 to 100 rating scale (where higher score indicates better quality of life) compared with 75.3 points in the arthroscopic surgery group, a difference of 5.6 points better (95% CI 0.36 better to 10.68 better; I2 = 0%; 2 trials, 188 participants). We downgraded this evidence to moderate certainty as the 95% confidence interval does not rule in or rule out a clinically important change. After surgery, 74 out of 100 people reported treatment success with placebo and 82 out of 100 people reported treatment success with arthroscopic surgery at up to five years (risk ratio (RR) 1.11, 95% CI 0.66 to 1.86; I2 = 53%; 3 trials, 189 participants). We downgraded this evidence to low certainty due to serious indirectness (diversity in definition and timing of outcome measurement) and serious imprecision (small number of events). We are less certain if the risk of serious or total adverse events increased with arthroscopic surgery compared to placebo or non-surgical interventions. Serious adverse events were reported in 6 out of 100 people in the control groups and 8 out of 100 people in the arthroscopy groups from eight trials (RR 1.35, 95% CI 0.64 to 2.83; I2 = 47%; 8 trials, 1206 participants). Fifteen out of 100 people reported adverse events with control interventions, and 17 out of 100 people with surgery at up to five years (RR 1.15, 95% CI 0.78 to 1.70; I2 = 48%; 9 trials, 1326 participants). The certainty of the evidence was low, downgraded twice due to serious imprecision (small number of events) and possible reporting bias (incomplete reporting of outcome across studies). Serious adverse events included death, pulmonary embolism, acute myocardial infarction, deep vein thrombosis and deep infection. Subsequent knee surgery (replacement or high tibial osteotomy) was reported in 2 out of 100 people in the control groups and 4 out of 100 people in the arthroscopy surgery groups at up to five years in four trials (RR 2.63, 95% CI 0.94 to 7.34; I2 = 11%; 4 trials, 864 participants). The certainty of the evidence was low, downgraded twice due to the small number of events. AUTHORS' CONCLUSIONS: Arthroscopic surgery provides little or no clinically important benefit in pain or function, probably does not provide clinically important benefits in knee-specific quality of life, and may not improve treatment success compared with a placebo procedure. It may lead to little or no difference, or a slight increase, in serious and total adverse events compared to control, but the evidence is of low certainty. Whether or not arthroscopic surgery results in slightly more subsequent knee surgery (replacement or osteotomy) compared to control remains unresolved.
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Artroscopía , Osteoartritis de la Rodilla , Anciano , Artroscopía/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Osteoartritis de la Rodilla/cirugía , Dimensión del Dolor , Dolor Postoperatorio , Calidad de VidaRESUMEN
Objectives: To estimate the prevalence of missed opportunities for vaccination (MOV) in Latin America and the effect of interventions targeting health systems, health workers, patients, and communities on MOV. Methods: Searches were conducted in MEDLINE, EMBASE, CINAHL, and LILACS electronic databases and relevant organizations were contacted, including the Pan American Health Organization (PAHO), to identify studies meeting eligibility criteria. A pair of reviewers identified 27 randomized and non-randomized studies quantifying the effectiveness of any intervention for reducing MOV and 5 studies assessing the rate of MOV in Latin America. Results are reported narratively when criteria to pool results were not met, and the certainty of this evidence was assessed using the GRADE approach. Results: Evidence suggests the rate of MOV in Latin America ranged from 5% to 37% with a pooled estimate of 17% (95% CI [9, 32]) (low certainty) and that monetary incentives to healthcare teams, training for healthcare teams on how to communicate with patients, and educational interventions for caregivers probably reduce MOV (moderate to very low certainty). Conclusions: There is insufficient evidence supporting the implementation of any intervention as policy based only on the potential reduction of MOV without considering several factors, including costs, feasibility, acceptability, and equity.
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Transcriptional profiling of hematopoietic cell subpopulations has helped to characterize the developmental stages of the hematopoietic system and the molecular bases of malignant and non-malignant blood diseases. Previously, only the genes targeted by expression microarrays could be profiled genome-wide. High-throughput RNA sequencing, however, encompasses a broader repertoire of RNA molecules, without restriction to previously annotated genes. We analyzed the BLUEPRINT consortium RNA-sequencing data for mature hematopoietic cell types. The data comprised 90 total RNA-sequencing samples, each composed of one of 27 cell types, and 32 small RNA-sequencing samples, each composed of one of 11 cell types. We estimated gene and isoform expression levels for each cell type using existing annotations from Ensembl. We then used guided transcriptome assembly to discover unannotated transcripts. We identified hundreds of novel non-coding RNA genes and showed that the majority have cell type-dependent expression. We also characterized the expression of circular RNA and found that these are also cell type-specific. These analyses refine the active transcriptional landscape of mature hematopoietic cells, highlight abundant genes and transcriptional isoforms for each blood cell type, and provide a valuable resource for researchers of hematologic development and diseases. Finally, we made the data accessible via a web-based interface: https://blueprint.haem.cam.ac.uk/bloodatlas/.
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ARN Largo no Codificante , Transcriptoma , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , ARN Circular , ARN Largo no Codificante/genética , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: In 2017, the European Commission's Joint Research Centre (JRC) started developing a methodological framework for a guideline-based quality assurance (QA) scheme to improve cancer quality of care. During the first phase of the work, inconsistency emerged about the use of terminology for the definition, the conceptual underpinnings and the way QA relates to health questions that are answered in guidelines. The objective of this final of three articles is to propose a conceptual framework for an integrated approach to guideline and QA development and clarify terms and definitions for key elements. This work will inform the upcoming European Commission Initiative on Colorectal Cancer (ECICC). METHODS: A multidisciplinary group of 23 experts from key organizations in the fields of guideline development, performance measurement and quality assurance participated in a mixed method approach including face-to-face dialogue and several rounds of virtual meetings. Informed by results of a systematic literature review that indicated absence of an existing framework and practical examples, we first identified the relations of key elements in guideline-based QA and then developed appropriate concepts and terminology to provide guidance. RESULTS: Our framework connects the three key concepts of quality indicators, performance measures and performance indicators integrated with guideline development. Quality indicators are constructs used as a guide to monitor, evaluate, and improve the quality of the structure, process and outcomes of healthcare services; performance measures are tools that quantify or describe measurable elements of practice performance; and performance indicators are quantifiable and measurable units or scores of practice, which should be guided by guideline recommendations. CONCLUSIONS: The inconsistency in the way key terms of QA are used and defined has confused the field. Our conceptual framework defines the role, meaning and interactions of the key elements for improving quality in healthcare. It directly builds on the questions asked in guidelines and answered through recommendations. These findings will be applied in the forthcoming ECICC and for the future updates of ECIBC. These are large-scale integrated projects aimed at improving healthcare quality across Europe through the development of guideline-based QA schemes; this will help in implementing and improving our approach.
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Atención a la Salud , Calidad de la Atención de Salud , Europa (Continente) , Humanos , Garantía de la Calidad de Atención de Salud , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Although quality indicators are frequently derived from guidelines, there is a substantial gap in collaboration between the corresponding parties. To optimise workflow, guideline recommendations and quality assurance should be aligned methodologically and practically. Learning from the European Commission Initiative on Breast Cancer (ECIBC), our objective was to bring the key knowledge and most important considerations from both worlds together to inform European Commission future initiatives. METHODS: We undertook several steps to address the problem. First, we conducted a feasibility study that included a survey, interviews and a review of manuals for an integrated guideline and quality assurance (QA) scheme that would support the European Commission. The feasibility study drew from an assessment of the ECIBC experience that followed commonly applied strategies leading to separation of the guideline and QA development processes. Secondly, we used results of a systematic review to inform our understanding of methodologies for integrating guideline and QA development. We then, in a third step, used the findings to prepare an evidence brief and identify key aspects of a methodological framework for integrating guidelines QA through meetings with key informants. RESULTS: Seven key themes emerged to be taken into account for integrating guidelines and QA schemes: (1) evidence-based integrated guideline and QA frameworks are possible, (2) transparency is key in clearly documenting the source and rationale for quality indicators, (3) intellectual and financial interests should be declared and managed appropriately, (4) selection processes and criteria for quality indicators need further refinement, (5) clear guidance on retirement of quality indicators should be included, (6) risks of an integrated guideline and QA Group can be mitigated, and (7) an extension of the GIN-McMaster Guideline Development Checklist should incorporate QA considerations. DISCUSSION: We concluded that the work of guideline and QA developers can be integrated under a common methodological framework and we provided key findings and recommendations. These two worlds, that are fundamental to improving health, can both benefit from integration.
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Lista de Verificación , Medicina Basada en la Evidencia , Humanos , Garantía de la Calidad de Atención de SaludRESUMEN
BACKGROUND: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19). PURPOSE: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19. DATA SOURCES: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020. STUDY SELECTION: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included. DATA EXTRACTION: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews). DATA SYNTHESIS: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs. LIMITATION: Direct studies in COVID-19 are limited and poorly reported. CONCLUSION: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers. PRIMARY FUNDING SOURCE: World Health Organization. (PROSPERO: CRD42020178187).
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Infecciones por Coronavirus , Neumonía Viral , Respiración Artificial , Animales , Humanos , Aerosoles , Betacoronavirus , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/transmisión , COVID-19 , Pandemias , Neumonía Viral/mortalidad , Neumonía Viral/transmisión , Ensayos Clínicos Controlados Aleatorios como Asunto , Respiración Artificial/efectos adversos , Respiración Artificial/métodos , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/transmisión , Organización Mundial de la SaludRESUMEN
IMPORTANCE: Clinicians may rely on recommendations from clinical practice guidelines for management of patients. OBSERVATIONS: A clinical practice guideline is a published statement that includes recommendations that are intended to optimize patient care. In the guideline development process, a panel of experts formulates recommendation questions that guide the retrieval of evidence that is used to inform the recommendations. Typically, methods of guideline development, a summary of the supporting evidence, and a justification of the panel's decisions accompany the recommendations. To use such guidelines optimally, clinicians must understand the implications of the recommendations, assess the trustworthiness of the development process, and evaluate the extent to which the recommendations are applicable to patients in their practice settings. Helpful recommendations are clear and actionable, and explicitly specify whether they are strong or weak, are appropriate for all patients, or depend on individual patients' circumstances and values. Rigorous guidelines and recommendations are informed by appropriately conducted, up-to-date systematic reviews that consider outcomes important to patients. Because judgments are involved in the interpretation of the evidence and the process of moving from evidence to recommendations, useful guidelines consider all relevant factors that have a bearing in a clinical decision and are not influenced by conflicts of interest. CONCLUSIONS AND RELEVANCE: In considering a guideline's recommendations, clinicians must decide whether there are important differences between the factors the guideline panel has considered in making recommendations and their own practice setting.