Frederiksberg Hospital

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.

Principal component analysis is one of the most important and powerful methods in chemometrics as well as in a wealth of other areas.

This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (≤4 weeks; weak recommendation, moderate-quality evidence). Antihistamines, antipsychotics, melatonin and phytotherapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence). Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence). Complementary and alternative treatments (e.g. homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence).

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

This new diagnostic consensus guideline is a joint project of the European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR] that now merges the former ECCO-ESGAR Imaging Guideline and the former ECCO Endoscopy Guideline, also including laboratory parameters. It has been drafted by 30 ECCO and ESGAR members from 17 European countries. All the authors recognize th e work of and are grateful to previous ECCO and ESGAR members who contributed tocreating the earlier consensus guidelines on imaging and endoscopy. The former guidelines have been condensed into this new diagnostic consensus guideline which consists of two papers: the first detailing assessment at initial diagnosis, to monitor treat ment and for the detection of complications; the second dealing with the available scoring systems and general considerations regarding the different diagnostic tools. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, an open call for participants was made, with ECCO participants selected by the Guidelines’ Committee of ECCO [known as GuiCom] on the basis of their publication record and a personal statement and ESGAR participants nominated by ESGAR. The following working parties were established: diagnostics at initial diagnosis, diagnostics for monitoring treatment in patients with known IBD, diagnostics for the detect ion of complications, scores for IBD, and general principles and technical aspects. Provisional guideline statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds. The first voting round introduced a more comprehensive voting procedure, in which each Guidelines participants voted on all statements by explicitly reviewing those statements together with their respective supporting text and references. The second voting round included optional national representative participation of ECCO’s 36 member countries and ESGAR’s 28 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine [www.cebm.net]. The ECCO statements were finalized by the authors at a face-to-face meeting in Barcelona in October 2017 and represent consensus with agreement of at least 80% of the present participants. Consensus statements are intended to be read in context with their qualifying comments and not in isolation. The supporting text was then finalised under the direction of each working group leader [SV, TK, GF, VA, EC], before being integrated by the consensus leaders [CM, JS, AS].

BACKGROUND: Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain. METHODS: We screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies. A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, < or = 35 percent). On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients). The duration of follow-up was 24 to 50 months. RESULTS: During the study period, 304 patients (34.7 percent) in the trandolapril group died, as compared with 369 (42.3 percent) in the placebo group (P = 0.001). The relative risk of death in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91). Trandolapril also reduced the risk of death from cardiovascular causes (relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89; P = 0.001) and sudden death (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98; P = 0.03). Progression to severe heart failure was less frequent in the trandolapril group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). In contrast, the risk of recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13; P = 0.29). CONCLUSIONS: Long-term treatment with trandolapril in patients with reduced left ventricular function soon after myocardial infarction significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction.

BACKGROUND: The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). METHODS: In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. RESULTS: After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). CONCLUSIONS: In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

Clearer understanding is needed of the premises underlying SI and how it relates to food-system priorities.

BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age. METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV. RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group. CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. METHODS: We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. RESULTS: Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONS: Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

OBJECTIVES: The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented. METHODS: Literature databases and other sources of information were searched for studies that could inform on 10 formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations. RESULTS: Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable, an IgG-based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10× ULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10× ULN at least 4 biopsies from the distal duodenum and at least 1 from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely. CONCLUSIONS: CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.

AIMS: Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. METHODS AND RESULTS: DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (> or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups. CONCLUSION: DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.

BACKGROUND: High plasma levels of nonfasting triglycerides are associated with an increased risk of ischemic cardiovascular disease. Whether lifelong low levels of nonfasting triglycerides owing to mutations in the gene encoding apolipoprotein C3 (APOC3) are associated with a reduced risk of ischemic cardiovascular disease in the general population is unknown. METHODS: Using data from 75,725 participants in two general-population studies, we first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease. Second, we tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10,797 participants, and ischemic heart disease developed in 7557 of these 10,797 participants. RESULTS: Participants with nonfasting triglyceride levels of less than 1.00 mmol per liter (90 mg per deciliter) had a significantly lower incidence of cardiovascular disease than those with levels of 4.00 mmol per liter (350 mg per deciliter) or more (hazard ratio for ischemic vascular disease, 0.43; 95% confidence interval [CI], 0.35 to 0.54; hazard ratio for ischemic heart disease, 0.40; 95% CI, 0.31 to 0.52). Heterozygosity for loss-of-function mutations in APOC3, as compared with no APOC3 mutations, was associated with a mean reduction in nonfasting triglyceride levels of 44% (P<0.001). The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers of APOC3 mutations (P=0.009 and P=0.05, respectively), with corresponding risk reductions of 41% (hazard ratio, 0.59; 95% CI, 0.41 to 0.86; P=0.007) and 36% (hazard ratio, 0.64; 95% CI, 0.41 to 0.99; P=0.04). CONCLUSIONS: Loss-of-function mutations in APOC3 were associated with low levels of triglycerides and a reduced risk of ischemic cardiovascular disease. (Funded by the European Union and others.).

Amborella trichopoda is strongly supported as the single living species of the sister lineage to all other extant flowering plants, providing a unique reference for inferring the genome content and structure of the most recent common ancestor (MRCA) of living angiosperms. Sequencing the Amborella genome, we identified an ancient genome duplication predating angiosperm diversification, without evidence of subsequent, lineage-specific genome duplications. Comparisons between Amborella and other angiosperms facilitated reconstruction of the ancestral angiosperm gene content and gene order in the MRCA of core eudicots. We identify new gene families, gene duplications, and floral protein-protein interactions that first appeared in the ancestral angiosperm. Transposable elements in Amborella are ancient and highly divergent, with no recent transposon radiations. Population genomic analysis across Amborella's native range in New Caledonia reveals a recent genetic bottleneck and geographic structure with conservation implications.

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.

Abstract Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

SIGNIFICANCE: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. RECENT ADVANCES: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS: Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker.

BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

BACKGROUND: Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates. OBJECTIVES: To compare the adverse effects of tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS). METHODS: Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework. MAIN RESULTS: We included 163 RCTs with 50,010 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for tuberculosis (TB) reactivation, lymphoma, and congestive heart failure. Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events (odds ratio (OR) 1.19, 95% CI 1.09 to 1.30; number needed to treat to harm (NNTH) = 30, 95% CI 21 to 60) and withdrawals due to adverse events (OR 1.32, 95% CI 1.06 to 1.64; NNTH = 37, 95% CI 19 to 190) and an increased risk of TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706) compared to control.The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment. Certolizumab pegol was associated with significantly higher risk of serious infections compared to control treatment (OR 3.51, 95% CI 1.59 to 7.79; NNTH = 17, 95% CI 7 to 68). Infliximab was associated with significantly higher risk of withdrawals due to adverse events compared to control (OR 2.04, 95% CI 1.43 to 2.91; NNTH = 12, 95% CI 8 to 28). Indirect comparisons revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events compared to most other biologics. Although the overall numbers are relatively small, certolizumab pegol was associated with significantly higher odds of serious infections compared to etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab; abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections. Abatacept, adalimumab, etanercept and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. AUTHORS' CONCLUSIONS: Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results.There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics.

OBJECTIVE: To clarify the grading of recommendations assessment, development and evaluation (GRADE) definition of certainty of evidence and suggest possible approaches to rating certainty of the evidence for systematic reviews, health technology assessments, and guidelines. STUDY DESIGN AND SETTING: This work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance. RESULTS: Certainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less-contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, for example, ranges of what we might consider no effect, trivial, small, moderate, or large effects. CONCLUSION: It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence.