Rate of avoidable deaths in a Norwegian hospital trust as judged by retrospective chart review.

BACKGROUND: The proportion of avoidable hospital deaths is challenging to estimate, but has great implications for quality improvement and health policy. Many studies and monitoring tools are based on selected high-risk populations, which may overestimate the proportion. Mandatory reporting systems, however, under-report. We hypothesise that a review of an unselected sample of hospital deaths will provide an estimate of avoidability in-between the estimates from these methods. METHODS: A retrospective case record review of an unselected population of 1000 consecutive non-psychiatric hospital deaths in a Norwegian hospital trust was conducted. Reviewers evaluated to what degree each death could have been avoided, and identified problems in care. RESULTS: We found 42 (4.2%) of deaths to be at least probably avoidable (more than 50% chance of avoidability). Life expectancy was shortened by at least 1 year among 34 of the 42 patients with an avoidable death. Patients whose death was found to be avoidable were less functionally dependent compared with patients in the non-avoidable death group. The surgical department had the greatest proportion of such deaths. Very few of the avoidable deaths were reported to the hospital's report system. CONCLUSIONS: Avoidable hospital deaths occur less frequently than estimated by the national monitoring tool, but much more frequently than reported through mandatory reporting systems. Regular reviews of an unselected sample of hospital deaths are likely to provide a better estimate of the proportion of avoidable deaths than the current methods

Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

Funder: Folkehelseinstituttet/Norwegian Institute of Public HealthFunder: Norwegian Ministry of Health and Care ServicesFunder: Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and ResearchFunder: Norwegian Ministry of Education and ResearchStudy questionWhat is the association between BMI and subfertility?Summary answerWe observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization (MR) analysis.What is known alreadyHigh BMI in both women and men is associated with subfertility in observational studies and this relationship is further substantiated by a few small randomized controlled trials of weight reduction and success of assisted reproduction. Women with low BMI also have lower conception rates with assisted reproduction technologies.Study design, size, durationCohort study (the Norwegian Mother, Father and Child Cohort Study), 28 341 women and 26 252 men, recruited from all over Norway between 1999 and 2008.Participants/materials, setting, methodsWomen (average age 30, average BMI 23.1 kg/m2) and men (average age 33, average BMI 25.5 kg/m2) had available genotype data and provided self-reported information on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months).Main results and the role of chanceOur findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear MR validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 18% greater odds of subfertility (95% CI 5% to 31%) in obese women (≥30.0 kg/m2) and 15% lower odds of subfertility (-24% to -2%) in women with BMI Limitations, reasons for cautionThe main limitations of our study were that we did not know whether the subfertility was driven by the women, men or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values Wider implications of the findingsOur results support a causal effect of obesity on subfertility in women and men. Our findings also expand the current evidence by indicating that individuals with BMI values Study funding/competing interest(s)The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). It was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. D.A.L. is a UK National Institute for Health Research Senior Investigator (NF-SI-0611-10196) and is supported by the US National Institutes of Health (R01 DK10324) and a European Research Council Advanced Grant (DevelopObese; 669545). The funders had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. D.A.L. receives (or has received in the last 10 years) research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. The rest of the authors declare that no competing interests exist.Trial registration numberN/A

Insomnia symptoms and risk of bloodstream infections : prospective data from the prospective population-based Nord-Trøndelag Health Study (HUNT), Norway

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Iron status and the risk of sepsis and severe COVID-19: a two-sample Mendelian randomization study

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Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

Objective To investigate the association between smoking and infertility. Design Prospective study. Setting Nationwide cohort. Patients 28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study. Intervention Self-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization. Main outcome measure Infertility (time-to-pregnancy ≥12 months). Results Having ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11–1.28; ORadjusted 1.12; 95% CI, 1.03–1.21), also after adjusting for the partner’s tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88–0.99; ORadjusted 0.89; 95% CI, 0.84–0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75–0.91; ORadjusted, 0.83; 95% CI, 0.75–0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization. Conclusions We did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.publishedVersio

Body mass index and risk of dying from a bloodstream infection: A Mendelian randomization study.

BACKGROUND: In observational studies of the general population, higher body mass index (BMI) has been associated with increased incidence of and mortality from bloodstream infection (BSI) and sepsis. On the other hand, higher BMI has been observed to be apparently protective among patients with infection and sepsis. We aimed to evaluate the causal association of BMI with risk of and mortality from BSI. METHODS AND FINDINGS: We used a population-based cohort in Norway followed from 1995 to 2017 (the Trøndelag Health Study [HUNT]), and carried out linear and nonlinear Mendelian randomization analyses. Among 55,908 participants, the mean age at enrollment was 48.3 years, 26,324 (47.1%) were men, and mean BMI was 26.3 kg/m2. During a median 21 years of follow-up, 2,547 (4.6%) participants experienced a BSI, and 451 (0.8%) died from BSI. Compared with a genetically predicted BMI of 25 kg/m2, a genetically predicted BMI of 30 kg/m2 was associated with a hazard ratio for BSI incidence of 1.78 (95% CI: 1.40 to 2.27; p < 0.001) and for BSI mortality of 2.56 (95% CI: 1.31 to 4.99; p = 0.006) in the general population, and a hazard ratio for BSI mortality of 2.34 (95% CI: 1.11 to 4.94; p = 0.025) in an inverse-probability-weighted analysis of patients with BSI. Limitations of this study include a risk of pleiotropic effects that may affect causal inference, and that only participants of European ancestry were considered. CONCLUSIONS: Supportive of a causal relationship, genetically predicted BMI was positively associated with BSI incidence and mortality in this cohort. Our findings contradict the "obesity paradox," where previous traditional epidemiological studies have found increased BMI to be apparently protective in terms of mortality for patients with BSI or sepsis

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Causes and Consequences of Small Size at Birth: Maternal Glucose Tolerance and Vitamin B12 Levels in Pregnancy, and Later Brain Volumes and Cognitive Function in the Offspring

Small size at birth may be caused by restricted fetal growth or preterm birth. Each year, preterm birth and low birth weight (LBW) cause roughly half of the 2.9 million neonatal deaths globally. Additionally, small birth size has been associated with long-term outcomes such as all-cause mortality and reduced cognitive function. But when is a newborn too small? Some newborns may be physiologically small (e.g. small parents), while others are born small due to a pathological process. The latter is often referred to as fetal growth restriction (FGR). The aim of this thesis was to explore some potential causes and consequences of small birth size. We studied two potential causes of small birth size: maternal glucose tolerance and vitamin B12 (B12) levels in pregnancy. We also studied the association between fetal growth pattern and offspring cognitive function and regional brain volumes. The first paper in this thesis was based on a large, long-term follow-up study in Scandinavia. The population was enriched with women at an increased risk of giving birth to a child with LBW. Ultrasound measurements were used to estimate fetal growth in the second and third trimesters, and an oral glucose tolerance test was performed in the third trimester. The difference between the two-hour and fasting blood glucose values was labeled delta (Δ) glucose. A total of 855 women were included in the study. We found that the most glucose tolerant women, identified by a low Δ glucose, were associated with an increased risk of carrying fetuses with suboptimal growth. These women also gave birth to thinner newborns, but of similar weight, compared with the other women. Offspring of the women followed in the Scandinavian study were followed after birth. Cognitive function was assessed at five and nine years of age, and regional brain volumes were estimated at age 15 years. The second paper included 83 children born small-for-gestationalage (SGA; birth weight <10th percentile) at term and 105 non-SGA children. Based on serial ultrasound measurements, 13 children in the SGA-group were classified as FGR (SGA-FGR) and 36 were classified as non-FGR (SGA non-FGR). We found that children born SGA due to FGR (SGA-FGR) – but not those born constitutionally small (SGA non-FGR) – had impaired performance intelligence quotient scores and smaller thalamic and cerebellar white matter volumes compared with controls. The last paper in this thesis is a systematic review where we evaluated the association between maternal vitamin B12 blood levels in pregnancy and newborn birth weight and length of gestation. Eligible studies provided individual patient data (IPD), and when IPD could not be provided, relevant estimates from individual studies were included in the analyses. Twentytwo eligible studies were identified, of which 18 were included in the meta-analysis (11,216 pregnancies; 94% of all eligible pregnancies). B12-deficiency in pregnancy was associated with an increased risk of preterm birth and LBW, but not SGA. The increased risk of preterm birth among B12-deficient women was similar in high-income countries and low- and middleincome countries. This thesis suggests that pregnant women who have a high glucose tolerance may have an increased risk for carrying fetuses with suboptimal growth. Vitamin B12, however, seems to be associated with the length of gestation, but not fetal growth. The risk of reduced cognitive function and smaller regional brain volumes in childhood and adolescence seems to be higher among children born small due to restricted fetal growth than in other children born small