Copenhagen University Hospital

BACKGROUND: In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. METHODS: In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. RESULTS: Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).

BACKGROUND: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. METHODS: We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. RESULTS: The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. CONCLUSIONS: In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)

Rhinosinusitis is a significant and increasing health problem which results in a large financial burden on society. This evidence based position paper describes what is known about rhinosinusitis and nasal polyps, offers evidence based recommendations on diagnosis and treatment, and considers how we can make progress with research in this area. Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, the correct terminology is now rhinosinusitis. Rhinosinusitis (including nasal polyps) is defined as inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), +/- facial pain/pressure, +/- reduction or loss of smell; and either endoscopic signs of polyps and/or mucopurulent discharge primarily from middle meatus and/or; oedema/mucosal obstruction primarily in middle meatus, and/or CT changes showing mucosal changes within the ostiomeatal complex and/or sinuses. The paper gives different definitions for epidemiology, first line and second line treatment and for research. Furthermore the paper describes the anatomy and (patho)physiology, epidemiology and predisposing factors, inflammatory mechanisms, evidence based diagnosis, medical and surgical treatment in acute and chronic rhinosinusitis and nasal polyposis in adults and children. Evidence based schemes for diagnosis and treatment are given for the first and second line clinicians. Moreover attention is given to complications and socio-economic cost of chronic rhinosinusitis and nasal polyps. Last but not least the relation to the lower airways is discussed.

BACKGROUND: The 5-item World Health Organization Well-Being Index (WHO-5) is among the most widely used questionnaires assessing subjective psychological well-being. Since its first publication in 1998, the WHO-5 has been translated into more than 30 languages and has been used in research studies all over the world. We now provide a systematic review of the literature on the WHO-5. METHODS: We conducted a systematic search for literature on the WHO-5 in PubMed and PsycINFO in accordance with the PRISMA guidelines. In our review of the identified articles, we focused particularly on the following aspects: (1) the clinimetric validity of the WHO-5; (2) the responsiveness/sensitivity of the WHO-5 in controlled clinical trials; (3) the potential of the WHO-5 as a screening tool for depression, and (4) the applicability of the WHO-5 across study fields. RESULTS: A total of 213 articles met the predefined criteria for inclusion in the review. The review demonstrated that the WHO-5 has high clinimetric validity, can be used as an outcome measure balancing the wanted and unwanted effects of treatments, is a sensitive and specific screening tool for depression and its applicability across study fields is very high. CONCLUSIONS: The WHO-5 is a short questionnaire consisting of 5 simple and non-invasive questions, which tap into the subjective well-being of the respondents. The scale has adequate validity both as a screening tool for depression and as an outcome measure in clinical trials and has been applied successfully across a wide range of study fields.

The WHO Nomenclature Committee for Factors of the HLA System has met several times since the publication of the last major report in 2010.1 It met most recently in September 2023, to discuss additions to the serological defined HLA antigens. This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports.1-19 Links to these reports and details of HLA Nomenclature can be found on the website: hla.alleles.org The HLA-OLI pseudogene has been reported and officially named HLA-R. A full list of all recognised HLA genes is given in Table 1.20 Although at present it is only a recommendation that full-length sequences of the coding region of novel alleles be submitted, it was widely felt that in the future this should become a requirement for submission. Such requirement would remove many of the currently encountered ambiguities in the assignment of names to alleles for which partial sequences have been submitted and should not be burdensome as sequencing techniques have improved substantially since the submission conditions were first devised. In cases where novel mutations or polymorphisms are detected in non-coding regions of the gene, it will be a requirement that full-length sequences be submitted of both the novel allele and its most closely related allele. It should be noted with some caution that cells from which only partial sequences have been obtained may later be shown to have different or novel alleles when further sequencing is performed. This is of particular importance in cases where partial sequences of what appears to be the same allele have been obtained from several different cells. In such cases, all cells studied have been listed in this report. The list of those genes in the HLA region considered by the WHO Nomenclature Committee for Factors of the HLA System is given in Table 1. Current practice is that official designations will be promptly assigned to newly described alleles in periods between Nomenclature Committee meetings, provided that the submitted data and its accompanying description meet the criteria outlined above. A list of the newly reported alleles is published every three months in nomenclature updates in the journals HLA, Human Immunology and the International Journal of Immunogenetics. The listing of references to new sequences does not imply priority of publication. The use of numbers or names for alleles, genes or specificities which pre-empt assignment of official designations by the Nomenclature Committee is strongly discouraged. A total of 43,758 HLA alleles have been named as of December 2025. A complete listing of the numbers of alleles assigned for each HLA genes is given in Table 2. In September 2023, the WHO Nomenclature Committee for Factors of the HLA System met at the Stanford Blood Center located at Stanford University following the 18th International HLA and Immunogenetics Workshop held in Noordwijkerhout, the Netherlands in May 2022. The committee met to evaluate a proposal for the definition of additional and novel antigens defined in silico21. The in silico definition of HLA antigens was achieved by the systematic examination and cataloguing the amino acid (AA) replacements at specific residues determining epitopes (DEP) in all common HLA alleles at the classical HLA class I and class II loci [Common and Well Documented (CWD2.0) for alleles of HLA-DRB3, -DRB4, -DRB5, -DQA1 and -DPA1 and Common, Intermediate and Well Documented (CIWD3.0) for alleles of HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1].21-23 The committee voted to accept the proposed serologic nomenclature update provided that a validation study was conducted. The manuscript aiming to confirm these computationally predicted antigens defined by DEP residues for the 11 HLA loci was designed to assess and compare the antibody reactivity of patients' sera in solid phase assays with Single Antigen Bead (SAB) preparations from various HLA proteins24. The differences in correlation confirmed the distinctions between proposed associated antigens and identified a few additional antigens.21, 25 A full listing of all the serological specificities for HLA-A, -B, -C, -DR, -DQ, and -DP and cellular defined specificities for HLA-Dw and HLA-DPw are given in Table 3. The concept of an HLA Associated Antigen was introduced in 1991, with the understanding that serological types would be more closely associated with the allele sequence defining them. Thirteen associated antigens were named at this time: A203, A210, A2403, B703, B3901, B3902, B4005, B5102, B5103, B7801, DR103, DR1403, and DR1404.12 In 1996 the B2708 associated antigen was named and it was decided to shorten the B7801 antigen name to B78.15 Following the definition of novel associated antigens documented below, it has been necessary to update the names of four of these: A203, A210, B703, and DR103, have been updated to A0203, A0210, B0703, and DR0103. A full listing of all the Associated Antigens for HLA-A, -B, -C, −and -DR are given in Table 4. This report includes nomenclature for the serological specificities encoded by both the HLA-DQA1 and HLA-DQB1 genes. As such it is now possible to define a nomenclature for the paired combination of both subunits of HLA-DQ molecules. Table 5 lists those proteins encoded in cis by common DQ haplotype blocks. The specificities resulting from trans-encoded heterodimers should be presented in the same format. The newly assigned HLA antigens and associated antigens will be implemented in April 2026 and will be made available through the IPD-IMGT/HLA Database (www.ebi.ac.uk/ipd/imgt/hla) with the April 2026 release of the database.26-28 The IPD-IMGT/HLA Database continues to act as the official repository for HLA sequences named by the WHO Nomenclature Committee for Factors of the HLA System.26-28 The database contains sequences for all HLA alleles officially recognised by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools, and detailed descriptions of the source cells. The online IPD-IMGT/HLA Database submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. New releases of the database are made every three months, in January, April, July and October, with the latest version (release 3.63.0 January 2026) containing 43,758 HLA alleles. The database may be accessed via the worldwide web at www.ebi.ac.uk/ipd/imgt/hla. The IPD-IMGT/HLA Database is currently supported by the following organisations: NMDP, TxMiller Foundation, CareDx, DKMS, Gift of Life, Werfen, Scisco Genetics, the European Federation for Immunogenetics (EFI), GenDx, Pirche, ThermoFisher, the American Society for Histocompatibility and Immunogenetics (ASHI), LabCorp, Histogenetics, the Asia-Pacific Histocompatibility and Immunogenetics Association (APHIA), BAG Diagnostics, Protrans, Inno-train, and Anthony Nolan. The Committee would like to thank Dominic Barker, Michael Cooper, Sebastian Hopper and Surayia Akter for their work with the IPD-IMGT/HLA Database. Also thanked is Andy Yates and the staff at the European Bioinformatics Institute for their continued support of the IPD-IMGT/HLA Database. We would also like to thank the many organisations that provide financial support for the IPD-IMGT/HLA Database and Benjamin Hester of the ‘NMDP Foundation’ for his work in soliciting and coordinating the funding of this project. We are grateful to Stanford Blood Center for covering the cost for providing open access for this article. SGE Marsh, University College London, London, UK (Chairman) WF Bodmer, Oncology Department, Oxford University, Oxford, UK MN Carrington, Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA & Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA HA Erlich, Benioff UCSF Children's Hospital Oakland Research Institute, Oakland, USA M Fernández-Viña, Stanford Blood Center, Palo Alto, USA & Department of Pathology, Stanford University School of Medicine, Stanford, USA S Heidt, Erasmus Medical Center, Rotterdam, & Leiden University Medical Center, Leiden, The Netherlands R Holdsworth, University of Melbourne, Melbourne, Australia WR Mayr, University of Vienna, Vienna, Austria M Maiers, Center for International Blood and Marrow Transplant Research, (CIBMTR), NMDP, Minneapolis, USA P Parham, Stanford University School of Medicine, Stanford, USA EW Petersdorf, Fred Hutchinson Cancer Center, Seattle, USA J Robinson, Anthony Nolan Research Institute, & University College London, London, UK J Trowsdale, Cambridge University, Cambridge, UK RE Bontrop, Biomedical Primate Research Centre, Rijswijk, The Netherlands K Osoegawa, Stanford Blood Center, Palo Alto, USA New sequences should be communicated to the WHO Nomenclature Committee for Factors of the HLA System via the sequence submission tool of the IPD-IMGT/HLA Database to receive official names, www.ebi.ac.uk/ipd/imgt/hla. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Importance: Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation. Objective: To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies. Design, Setting, and Participants: The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021. Findings: The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed. Conclusions and Relevance: STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results.

AIMS: To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. CONCLUSION: Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.

Previous studies have shown that statin therapy reduces high-sensitivity C-reactive protein levels as well as cholesterol, but no prospective trials have directly addressed the issue of whether elevated levels of high-sensitivity C-reactive protein are beneficial for apparently healthy persons with levels of LDL cholesterol below current thresholds for treatment. This randomized, double-blind, placebo-controlled, multicenter trial study was part of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) Study. The present study evaluated the effects of rosuvastatin, 20 mg daily, or placebo in 17,802 apparently healthy men and women with LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher. Following randomization, study subjects were followed for the occurrence of the combined primary end point: myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The trial was terminated after a median follow-up of 1.9 years (maximum, 5.0). As compared with the placebo at the 12-month visit, rosuvastatin reduced LDL cholesterol levels by 50%, high-sensitivity C-reactive protein levels by 37%, and triglyceride levels by 17% (P < .001 for all three comparisons). For rosuvastatin and placebo, the rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up, respectively; the hazard ratio (HR) for rosuvastatin was 0.56, with a 95% confidence interval [CI] of 0.46–0.69 (P < .00001). The rates of the individual components of the primary trial end point for rosuvastatin and placebo, respectively, were as follows: (1) 0.17 and 0.37 for fatal or nonfatal myocardial infarction (HR, 0.46; 95% CI, 0.30– 0.70; P < .0002); (2) 0.18 and 0.34 for fatal or nonfatal stroke (HR, 0.52; 95% CI, 0.34–0.79; P < .002); (3) 0.41 and 0.77 for arterial revascularization or unstable angina (HR, 0.53; 95% CI, 0.40–0.70; P < .00001); and (4) 0.45 and 0.85 for the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (HR, 0.53; 95% CI, 0.40–0.69; P < .00001). The rates of death from any cause in the rosuvastatin and placebo groups, respectively, were 1.00 and 1.25 per 100 person-years of follow-up; the HR for the rosuvastatin group was 0.80, with a 95% CI of 0.67– 0.97 (P < .02). These effects were consistent in women and all subgroups evaluated including black and Hispanic populations. The rosuvastatin group had a higher incidence of physician-reported diabetes but did not show a significant increase in myopathy or cancer. The findings show that rosuvastatin significantly reduces the incidence of major cardiovascular events in a population of apparently healthy men and women without hyperlipidemia but with elevated levels of high-sensitivity C-reactive protein.

BACKGROUND: Intensified multifactorial intervention - with tight glucose regulation and the use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents - has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes. METHODS: In the Steno-2 Study, we randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy; the mean treatment period was 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until December 31, 2006. The primary end point at 13.3 years of follow-up was the time to death from any cause. RESULTS: Twenty-four patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (hazard ratio, 0.54; 95% confidence interval [CI], 0.32 to 0.89; P=0.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (P=0.04). Fewer patients in the intensive-therapy group required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; P=0.02). Few major side effects were reported. CONCLUSIONS: In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes. (ClinicalTrials.gov number, NCT00320008.)

Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.

Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

INTRODUCTION Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection (1). Sepsis and septic shock are major healthcare problems, impacting millions of people around the world each year and killing between one in three and one in six of those it affects (2–4). Early identification and appropriate management in the initial hours after the development of sepsis improve outcomes. The recommendations in this document are intended to provide guidance for the clinician caring for adult patients with sepsis or septic shock in the hospital setting. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when presented with a unique patient’s clinical variables. These guidelines are intended to reflect best practice (Table 1). TABLE 1. - Table of Current Recommendations and Changes From Previous 2016 Recommendations Recommendations 2021 Recommendation Strength and Quality of Evidence Changes From 2016 Recommendations 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong , moderate-quality evidence (for screening) Changed from Best practice statement “We recommend that hospitals and hospital systems have a performance improvement program for sepsis including sepsis screening for acutely ill, high-risk patients.” Strong , very low-quality evidence (for standard operating procedures) 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a single-screening tool for sepsis or septic shock. Strong , moderate-quality evidence NEW 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak , low quality of evidence INITIAL RESUSCITATION 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice statement 5. For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hr of resuscitation. Weak, low quality of evidence DOWNGRADE from Strong , low quality of evidence “We recommend that in the initial resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given within the first 3 hr” 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation, over physical examination, or static parameters alone. Weak , very low quality of evidence 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak , low quality of evidence 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak , low quality of evidence NEW MEAN ARTERIAL PRESSURE 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong , moderate-quality evidence ADMISSION TO INTENSIVE CARE 10. For adults with sepsis or septic shock who require we suggest the patients to the within Weak , low quality of evidence For adults with suspected sepsis or septic shock we recommend and for and an of is or Best practice statement For adults with septic shock or a for sepsis, we recommend within hr of Strong , low quality of evidence from “We recommend that of should be as as after and within one for septic shock and sepsis Strong , very low quality of evidence , quality of evidence For adults with sepsis shock, we recommend of the of of Best practice statement For adults with sepsis shock, we suggest a of and for infection the of within 3 hr from the time when sepsis first Weak , very low quality of evidence NEW from “We recommend that of IV should be as as after and within hr for septic shock and sepsis , quality of evidence For adults with a low of infection and shock, we suggest to the Weak , very low quality of evidence NEW from “We recommend that of IV should be as as after and within hr for septic shock and sepsis , quality of evidence For adults with suspected sepsis or septic shock, we suggest against using clinical to when to as compared to clinical alone. Weak , very low quality of evidence For adults with sepsis or septic shock at of we recommend using with over using Best practice statement NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock at low of we suggest against using with as compared with using Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock and for we suggest using with for treatment over one Weak , very low quality of evidence For adults with sepsis or septic shock and low for we suggest against using for as compared to one Weak , very low quality of evidence For adults with sepsis or septic shock, we suggest against using the and the are Weak , very low quality of evidence For adults with sepsis or septic shock at of we suggest using over Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence For adults with sepsis or septic shock at low of we suggest against of Weak , low quality of evidence NEW from “We recommend with one or for patients with sepsis or septic shock to and or Strong , quality of evidence We on the of For adults with sepsis or septic shock, we suggest using of for an initial over Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend of on and Best practice statement For adults with sepsis or septic shock, we recommend or a of infection that and as as and Best practice statement For adults with sepsis or septic shock, we recommend of that are a of sepsis or septic shock after other Best practice statement For adults with sepsis or septic shock, we suggest for of over using of for Weak , very low quality of evidence For adults with an initial of sepsis or septic shock and we suggest using over of Weak , very low quality of evidence For adults with an initial of sepsis or septic shock and of is we suggest using clinical to when to over clinical alone. Weak , low quality of evidence For adults with sepsis or septic shock, we recommend using as fluid for resuscitation. Strong , moderate-quality evidence For adults with sepsis or septic shock, we suggest using of for resuscitation. Weak , low quality of evidence from , low quality of “We suggest using or for fluid resuscitation of patients with sepsis or septic For adults with sepsis or septic shock, we suggest using in patients who of Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend against using for resuscitation. Strong , evidence For adults with sepsis and septic shock, we suggest against using for resuscitation. Weak , moderate-quality evidence from , low quality of evidence “We suggest using over when patients with sepsis or septic For adults with septic shock, we recommend using as the over other Strong evidence evidence quality of evidence quality of evidence low-quality evidence For adults with septic shock on with mean arterial pressure we suggest of the of Weak , quality evidence For adults with septic shock and mean arterial pressure and we suggest Weak , low quality of evidence For adults with septic shock, we suggest against using Weak , low quality of evidence For adults with septic shock and dysfunction with hypoperfusion and arterial blood we suggest to or using alone. Weak , low quality of evidence For adults with septic shock and dysfunction with hypoperfusion and arterial blood we suggest against using Weak , low quality of evidence NEW For adults with septic shock, we suggest of arterial blood pressure over as as and are Weak , very low quality of evidence For adults with septic shock, we suggest to mean arterial pressure a is Weak , very low quality of evidence NEW is evidence to a on the of fluid in the first hr of resuscitation in patients with sepsis and septic shock who have of hypoperfusion and after the initial resuscitation. NEW “We suggest using or for fluid resuscitation of patients with sepsis or septic Weak , low quality of evidence “We suggest using over when patients with sepsis or septic Weak , low quality of evidence is evidence to a on the of in adults with sepsis-induced For adults with sepsis-induced we suggest the of over Weak , low quality of evidence NEW is evidence to a on the of in to for adults with sepsis-induced For adults with sepsis-induced we recommend using a low over a Strong , evidence For adults with sepsis-induced we recommend using an for of 30 over higher Strong , moderate-quality evidence For adults with to sepsis-induced we suggest using higher over Weak , moderate-quality evidence For adults with sepsis-induced we suggest using low as compared with Weak , low quality of evidence For adults with sepsis-induced we suggest using Weak , moderate-quality evidence using we recommend against using Strong , moderate-quality evidence For adults with sepsis-induced we recommend using for hr Strong , moderate-quality evidence For adults with sepsis induced we suggest using over Weak , moderate-quality evidence For adults with sepsis-induced we suggest using when in with the in to Weak , low quality of evidence NEW For adults with septic shock and an for we suggest using IV Weak , moderate-quality evidence from Weak , low quality of evidence “We suggest against using IV to septic shock patients fluid resuscitation and are to for this is not we suggest IV at a of For adults with sepsis or septic shock we suggest against using Weak , low quality of evidence NEW from “We the of blood is evidence to a on the of other blood For adults with sepsis or septic shock we recommend using a Strong , moderate-quality evidence For adults with sepsis or septic shock we suggest against using IV Weak , low quality of evidence For adults with sepsis or septic shock, and who have for we suggest using Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend using a to Strong , moderate-quality evidence For adults with sepsis or septic shock, we recommend using low over for Strong , moderate-quality evidence For adults with sepsis or septic shock, we suggest against using in to over alone. Weak , low quality of evidence adults with sepsis or septic shock and we suggest using or Weak , low quality of evidence adults with sepsis or septic shock and with for we suggest against using Weak , moderate-quality evidence For adults with sepsis or septic shock, we recommend at a of Strong , moderate-quality evidence For adults with sepsis or septic shock we suggest against using IV Weak , low quality of evidence NEW For adults with septic shock and we suggest against using to improve or to Weak , low quality of evidence For adults with septic shock and and or we suggest using Weak , low quality of evidence For adult patients with sepsis or septic shock who be we suggest of Weak , very low quality of evidence CARE For adults with sepsis or septic shock, we recommend of and with patients and over Best practice statement For adults with sepsis or septic shock, we suggest of over hr or Weak , low quality of evidence For adults with sepsis or septic shock, is evidence to a on to of For adults with sepsis or septic shock, we recommend that the of on clinician be the treatment when to and and Best practice statement For adults with sepsis or septic shock, we suggest against for patients over on clinician Weak , low quality of evidence For adult of sepsis or septic shock and we suggest to over Weak , very low quality of evidence For adults with sepsis or septic shock, we suggest using a of at of over Weak , very low quality of evidence For adults with sepsis or septic shock, is evidence to a on the of tool over For adults with sepsis or septic shock and we recommend screening for and and and to these Best practice statement For adults with sepsis or septic shock and we suggest and sepsis and to hospital and in the setting. Weak , very low quality of evidence For adults with sepsis or septic shock and we recommend the clinical provide the to in in and hospital to are and Best practice statement For adults with sepsis and septic shock and we suggest using a compared with to the Weak , very low quality of evidence For adults with sepsis and septic shock, we recommend at and hospital Best practice statement For adult of sepsis and septic shock and we recommend including the sepsis and and after sepsis in the and hospital Best practice statement For adults with sepsis or septic shock who we recommend hospital with to and and Best practice statement For adults with sepsis or septic shock and is evidence to a on compared with For adults with sepsis or septic shock, is evidence to a for or against For adult of sepsis or septic shock, we recommend and for and after hospital Best practice statement For adult of sepsis or septic shock, we suggest to a program Weak , very low quality of evidence For adult of sepsis or septic shock for or an of we suggest to a Weak , very low quality of evidence are to in the be at for Sepsis and - Recommendation 1. For hospitals and health systems, we recommend using a performance improvement program for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment. Strong quality of evidence for Strong very low-quality evidence for standard operating Sepsis performance improvement of sepsis of sepsis and for a of on the of performance improvement that these with to sepsis with a in in patients with sepsis and septic shock The of performance improvement not to be as as the of a program that sepsis screening and Sepsis screening are to identification of sepsis and of or of the health is in of these with having the of with in of clinical and are for sepsis as response of or Early or Early improve performance of screening and in a of patients from for hospital sepsis the the operating and higher for the for screening as MEWS and target patients in as or of three not a of screening is in and of sepsis screening are an of sepsis for operating procedures are a of that a response to clinical Sepsis standard operating as Early have to a standard with of the sepsis and the between of sepsis and of sepsis to hospitals in the in a and after of sepsis with a from other this time in hospitals with higher with the sepsis a of in higher with standard operating procedures compared with it in one - Recommendation 2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a screening tool for sepsis or septic shock. Strong moderate-quality The qSOFA three to and in patients with or suspected a a and a blood pressure mm of these are the is qSOFA to the recommendations of the on the of Sepsis qSOFA as a of in patients with or suspected to as a screening tool that time have the of the qSOFA as a screening tool for sepsis The have as to have that qSOFA is having of for identification of infection induced organ dysfunction qSOFA are screening for sepsis and the clinician to the of the that of patients a qSOFA or these patients for of have when against the Early and the Early the of a qSOFA should the clinician to the of sepsis in given the of the the a against as a screening - Recommendation 3. For adults suspected of having sepsis, we suggest measuring blood lactate. Weak low-quality The of lactate with in patients with suspected infection and sepsis is is as of the sepsis for those patients with sepsis and an elevated lactate is of the of septic shock that lactate be to for the of sepsis adult patients with suspected not have the of lactate in this The lactate an elevated from of the from with from and from the three are and an between the of lactate at and the are the of an elevated or lactate or the of a of sepsis in patients with suspected lactate is to or the on not be in we a the of serum lactate as an to the of sepsis in patients with suspected not - Recommendations 4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately. Best practice 5. For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hours of resuscitation. Weak low-quality 6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation over physical or static parameters alone. Weak very low-quality parameters response to a or a fluid using pressure or 7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate. Weak low-quality resuscitation, serum lactate should be the clinical and other of elevated lactate. 8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak low-quality fluid resuscitation is for the of sepsis-induced hypoperfusion in sepsis and septic shock. Previous guidelines recommend appropriate resuscitation of sepsis or septic shock and having a low for it in those patients sepsis is not is the evidence from this is a best practice and are that a is The 2016 a for using a of 30 mL/kg of IV in initial fluid resuscitation. of initial resuscitation on evidence are for initial resuscitation in sepsis or septic shock. of adults to an with sepsis or septic shock that to 30 mL/kg of crystalloid fluid within 3 hours of sepsis with of of and of in of including and the and the of fluid in the of 30 that this fluid in clinical practice patients require fluid initial resuscitation. to be with the of fluid and with fluid of and of the of septic patients is the for a initial and of the response to treatment. and fluid the initial resuscitation should be by of and organ perfusion. pressure and blood pressure are of fluid measures have at fluid compared with static measures with fluid against pressure or and of in response to in a and dynamic to guide fluid with to of to and of to in one other in between septic patients with a compared with standard from and a of evidence in to guide of fluid resuscitation as as the appropriate in patients with sepsis and in that resuscitation with of IV by and arterial with fluid in the first hours and higher hospital standard fluid the initial 30 mL/kg is by measures of fluid of mL/kg compared to to 3 mL/kg the of fluid and on of of or not be a in pressure that the is fluid a for lactate is an of and is not a of of septic shock in lactate as evidence of to (1). Previous of these guidelines have using lactate as a target of resuscitation in the of sepsis and septic shock, on to and of in serum lactate in with or in The that serum lactate are not in patients with septic shock, these that decrease lactate lactate should be the clinical and other of elevated lactate. with sepsis lactate not be in is not measures of organ be to the and of of the and capillary refill time have and to be of The a resuscitation a resuscitation at or lactate by hours in the first hours of septic shock the organ dysfunction as by in the and in the lactate this not the of a on using resuscitation and is and this should be by and to or fluid are of the or to the should management - Recommendation 9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong moderate-quality MAP is a of mean in is the major of and MAP in blood and the of perfusion. as the and have the to blood a to be mm are with organ with MAP Previous guidelines a MAP of 65 mm Hg for initial resuscitation. The on a in septic shock patients who given to target a MAP of mm a target of mm Hg in a a in with higher MAP patients with higher MAP with with a higher of of this that the MAP in the of on this that higher MAP not improve in septic shock to and MAP target compared a mm with a that and MAP by the in patients 65 and with septic shock The in this a mean MAP of mm compared with mm Hg in the to in the by of and in in the and the of with higher MAP and the of patients with MAP of mm the a MAP of 65 mm Hg in the initial resuscitation of patients with septic shock who require to - Recommendation 10. For adults with sepsis or septic shock who require we suggest the patients to the within Weak low-quality The of patients on of in an appropriate the septic patients are in the and hospital of patients from are with sepsis and and and hospital of on the time for to the from and an of an in of for each of to of patients in the a higher hospital for the higher to time hr and compared with the to time for of an to time hr with hospital in patients with higher of with sepsis not patients to when hours hospital the a hospital higher and higher of and of patients in hospitals in the that to to higher and on of patients to an in outcomes. is evidence of and are best in an are of patients with sepsis to an not be in in and be this and appropriate treatment should not be of of - Recommendation For adults with suspected sepsis or septic shock we recommend and for and an of is or Best practice of these we the of a for to it is to in a a best practice we that appropriate should be in patients with suspected sepsis and septic shock it in in the of not in this as as The and of sepsis are and other is to sepsis, the cannot have a of sepsis in a with organ a or of patients with sepsis to have Best practice is to the to other are or a patient’s clinical after hospital or the of a of this be in when it is to or major is a that to on the that the is each as in and of the that by or in each in of or that the for a in the or a We not or evidence this are to a an that not from is or this is not of the should the of patients and patients that is not to - Recommendations For adults with septic shock or a for sepsis, we recommend within one of Strong low quality of evidence very low quality of evidence For adults with sepsis shock, we recommend of the of of Best practice and clinical examination, for and of and treatment for that this should be within 3 hours of that a be as to the of an of the patient’s and the of sepsis is to be For adults with sepsis shock, we suggest a of and for infection the of within 3 hours from the time when sepsis first Weak very low quality of For adults with a low of infection and shock, we suggest to the Weak very low quality of Early of appropriate is one of the to in patients with sepsis to patients with sepsis or septic shock should be as an The to provide as as be against the with to patients infection These a of as or and sepsis is as sepsis in and that first to be sepsis to be the of infection and of for each with suspected sepsis should the and of The with in patients with septic shock, have a between time to and in patients with septic shock in patients septic shock a of patients at each of time from to of with of for patients for patients not on a of patients at each of time from to of with of for patients with sepsis at least one of or or organ and for patients with septic to a for sepsis and a for septic shock in a of patients in each in time from to of with of and of in patients with in patients not an between and should be that the and at of to the of with or other patients with sepsis shock, the between time to and within the first hours from is have one to a in between and the other in a in time to suggest that after hours from hospital sepsis We suggest in patients with sepsis shock as as sepsis to be the and 3 hours after sepsis first suspected for sepsis at that given the of with septic shock and the of and the a to and within one in patients with septic shock. for patients with sepsis, we recommend be 1). For patients with sepsis shock, we recommend a of and of be to within 3 should be or should be to the Recommendations on of from suggest that of in patients with sepsis and septic shock is and and of a of in The and time for by and the of and of on is to recommendations to the of in patients with sepsis and septic shock in are in with the recommendations to - Recommendation For adults with suspected sepsis or septic shock, we suggest against using clinical to when to as compared to clinical alone. Weak very low quality of is in in response to in with clinical the of and of a of 30 a of and of for sepsis in patients We evidence from three that compared for of the three in to of to or of to and not in of the and on the with of the and the quality of evidence very guidelines for the management of recommend of for patients with of and in including the a against using to guide in to clinical - Recommendations For adults with sepsis or septic shock at of we recommend using with over using Best practice For adults with sepsis or septic shock at low of we suggest against using with as compared with using Weak low quality of The on to an against in an treatment for sepsis and septic shock the that the patient’s infection is caused by the of with treatment for in a with and the of with treatment in a for of patients and be to The of by from in to in and by for of infection or IV of or of hospital and of on the of including in on patients with the of in patients with of hours are with in not in patients with or sepsis, including against with higher patients The with are by an between of and in patients with or to for in a with be in a be from including the of to for are and on and clinical for are - Recommendations For adults with sepsis or septic shock and for we suggest using with for treatment over one Weak very low quality of For adults with sepsis or septic shock and low for we suggest against using for compared with one Weak very low quality of For adults with sepsis or septic shock, we suggest against using the and the are Weak very low quality of the of in of the world and between in and the initial of is to the at least one that is against the the and are the of on the of for and the of the and are is for patients with in a with of in or other between in adult patients with sepsis or septic shock when from the in the of of and in a low with the from the Recommendations the of one for treatment over one are given clinical including of and the of the of sepsis is to the appropriate For this we from recommendations in patients with sepsis or septic shock recommend the of on of to guide this infection or with within the of within the to a within the and within the the and are is not for patients with with and quality of evidence very and the of with the of for treatment. have an in in patients at for we suggest using for treatment to the of in patients with a low for we suggest using a for as are of using and the a of including infection and development of of is in patients at for with septic shock. - Recommendations For adults with sepsis or septic shock at of we suggest using over Weak low quality of For adults with sepsis or septic shock at low of we suggest against of Weak low quality of Sepsis and septic shock to are in and are with that of appropriate

Signal peptides (SPs) are short amino acid sequences that control protein secretion and translocation in all living organisms. SPs can be predicted from sequence data, but existing algorithms are unable to detect all known types of SPs. We introduce SignalP 6.0, a machine learning model that detects all five SP types and is applicable to metagenomic data.

BACKGROUND: Missing data may seriously compromise inferences from randomised clinical trials, especially if missing data are not handled appropriately. The potential bias due to missing data depends on the mechanism causing the data to be missing, and the analytical methods applied to amend the missingness. Therefore, the analysis of trial data with missing values requires careful planning and attention. METHODS: The authors had several meetings and discussions considering optimal ways of handling missing data to minimise the bias potential. We also searched PubMed (key words: missing data; randomi*; statistical analysis) and reference lists of known studies for papers (theoretical papers; empirical studies; simulation studies; etc.) on how to deal with missing data when analysing randomised clinical trials. RESULTS: Handling missing data is an important, yet difficult and complex task when analysing results of randomised clinical trials. We consider how to optimise the handling of missing data during the planning stage of a randomised clinical trial and recommend analytical approaches which may prevent bias caused by unavoidable missing data. We consider the strengths and limitations of using of best-worst and worst-best sensitivity analyses, multiple imputation, and full information maximum likelihood. We also present practical flowcharts on how to deal with missing data and an overview of the steps that always need to be considered during the analysis stage of a trial. CONCLUSIONS: We present a practical guide and flowcharts describing when and how multiple imputation should be used to handle missing data in randomised clinical.

BACKGROUND: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter. METHODS: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause. RESULTS: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions. CONCLUSIONS: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter. (Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).

These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments.

BACKGROUND: Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. METHODS: In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. RESULTS: In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. CONCLUSIONS: In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).

AIMS: The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). METHODS AND RESULTS: Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. CONCLUSION: Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.

BACKGROUND: Irradiation after mastectomy can reduce locoregional recurrences in women with breast cancer, but whether it prolongs survival remains controversial. We conducted a randomized trial of radiotherapy after mastectomy in high-risk premenopausal women, all of whom also received adjuvant systemic chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF). METHODS: A total of 1708 women who had undergone mastectomy for pathological stage II or III breast cancer were randomly assigned to receive eight cycles of CMF plus irradiation of the chest wall and regional lymph nodes (852 women) or nine cycles of CMF alone (856 women). The median length of follow-up was 114 months. The end points were locoregional recurrence, distant metastases, disease-free survival, and overall survival. RESULTS: The frequency of locoregional recurrence alone or with distant metastases was 9 percent among the women who received radiotherapy plus CMF and 32 percent among those who received CMF alone (P<0.001). The probability of survival free of disease after 10 years was 48 percent among the women assigned to radiotherapy plus CMF and 34 percent among those treated only with CMF (P<0.001). Overall survival at 10 years was 54 percent among those given radiotherapy and CMF and 45 percent among those who received CMF alone (P<0.001). Multivariate analysis demonstrated that irradiation after mastectomy significantly improved disease-free survival and overall survival, irrespective of tumor size, the number of positive nodes, or the histopathological grade. CONCLUSIONS: The addition of postoperative irradiation to mastectomy and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal women with breast cancer.

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.