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Sara Marie Nilsen, 1,* Johan Håkon Bjørngaard, 2, 3,* Fredrik Carlsen, 4 Kjartan Sarheim Anthun, 2, 5 Lars Gunnar Johnsen, 6, 7 Lars Johan Vatten, 2 Andreas Asheim 1, 8 1Center for Health Care Improvement, Trondheim University Hospital, Trondheim, Norway; 2Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway; 3Faculty of Nursing and Health Sciences, Nord University, Levanger, Norway; 4Department of Economics, Norwegian University of Science and Technology, Trondheim, Norway; 5Department of Health Research, SINTEF Digital, Trondheim, Norway; 6Department of Orthopaedic Surgery, Trondheim University Hospital, Trondheim, Norway; 7Department of Neuromedicine, Norwegian University of Science and Technology, Trondheim, Norway; 8Department of Mathematical Sciences, Norwegian University of Science and Technology, Trondheim, Norway*These authors contributed equally to this workCorrespondence: Johan Håkon BjørngaardNTNU, Institutt for samfunnsmedisin og sykepleie, Postboks 8905, Trondheim 7491, NorwayTel +47 92242734Fax +47 73597577Email johan.h.bjorngaard@ntnu.noPurpose: A reduction in the length of hospital stay may threaten patient safety. This study aimed to estimate the effect of organizational pressure to discharge on 60-day mortality among hip fracture patients.Patients and Methods: In this cohort study, hip fracture patients were analyzed as if they were enrolled in a sequence of trials for discharge. A hospital’s discharge tendency was defined as the proportion of patients with other acute conditions who were discharged on a given day. Because the hospital’s tendency to discharge would affect hip fracture patients in an essentially random manner, this exposure could be regarded as analogous to being randomized to treatment in a clinical trial. The study population consisted of 59,971 Norwegian patients with hip fractures, hospitalized between 2008 and 2016, aged 70 years and older. To calculate the hospital discharge tendency for a given day, we used data from all 5,013,773 other acute hospitalizations in the study period.Results: The probability of discharge among hip fracture patients increased by 5.5 percentage points (95% confidence interval (CI)=5.3– 5.7) per 10 percentage points increase in hospital discharges of patients with other acute conditions. The increased risk of death that could be attributed to a discharge from organizational causes was estimated to 3.7 percentage points (95% CI=1.4– 6.0). The results remained stable under different time adjustments, follow-up periods, and age cut-offs.Conclusion: This study showed that discharges from organizational causes may increase the risk of death among hip fracture patients.Keywords: length of stay, causality, bed occupancy, quality of healthcare, mortality, orthopedic procedures

Julie Horn,1,2 Lars J Vatten1 1Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; 2Department of Gynecology and Obstetrics, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway Abstract: The complexity of breast cancer etiology has puzzled scientists for more than 300 years. In this brief review, we emphasize the importance of reproductive and hormonal factors in relation to the risk of breast cancer. By following the historical course of how various risk factors have been determined, this study attempts to illustrate the origin of hypotheses, their subsequent rejection, and development of new hypotheses. Starting with the contributions of Italian physicians in the 18th century and covering the activity of British epidemiologists before World War II, this review ends up with the international collaboration that became increasingly important in the second half of the 20th century. Keywords: age at first birth, epidemiology, estrogen, lactation, parity, pregnancy

Objective: To study whether pregnancy week at delivery is an independent risk factor for shoulder dystocia.Design: Population study.Setting: Medical Birth Registry of Norway.Population: All vaginal deliveries of singleton offspring in cephalic presentation in Norway during 1967 through 2009 (n = 2,014,956).Methods: The incidence of shoulder dystocia was calculated according to pregnancy week at delivery. The associations of pregnancy week at delivery with shoulder dystocia were estimated as crude and adjusted odds ratios using logistic regression analyses. We repeated the analyses in pregnancies with and without maternal diabetes.Main Outcome Measures: Shoulder dystocia at delivery.Results: The overall incidence of shoulder dystocia was 0.73% (n = 14,820), and the incidence increased by increasing pregnancy week at delivery. Birthweight was strongly associated with shoulder dystocia. After adjustment for birthweight, induction of labour, use of epidural analgesia at delivery, prolonged labour, forceps-assisted and vacuum-assisted delivery, parity, period of delivery and maternal age in multivariable analyses, the adjusted odds ratios for shoulder dystocia were 1.77 (1.42-2.20) for deliveries at 32-35 weeks of gestation, and 0.84 (0.79-0.88) at 42-43 weeks of gestation, using weeks 40-41 as the reference. In pregnancies affected by diabetes (n = 11,188), the incidence of shoulder dystocia was 3.95%, and after adjustment for birthweight the adjusted odds ratio for shoulder dystocia was 2.92 (95% CI 1.54-5.52) for deliveries at weeks 32-35 of gestation, and 0.91 (95% CI 0.50-1.66) at 42-43 weeks of gestation.Conclusion: The risk of shoulder dystocia was associated with increased birthweight, diabetes, induction of labour, use of epidural analgesia at delivery, prolonged labour, forceps-assisted and vacuum-assisted delivery, parity and period of delivery but not with post-term delivery. [ABSTRACT FROM AUTHOR]

Objective To study whether pregnancy week at delivery is an independent risk factor for shoulder dystocia. Design Population study. Setting Medical Birth Registry of Norway. Population All vaginal deliveries of singleton offspring in cephalic presentation in Norway during 1967 through 2009 ( n = 2 014 956). Methods The incidence of shoulder dystocia was calculated according to pregnancy week at delivery. The associations of pregnancy week at delivery with shoulder dystocia were estimated as crude and adjusted odds ratios using logistic regression analyses. We repeated the analyses in pregnancies with and without maternal diabetes. Main outcome measures Shoulder dystocia at delivery. Results The overall incidence of shoulder dystocia was 0.73% ( n = 14 820), and the incidence increased by increasing pregnancy week at delivery. Birthweight was strongly associated with shoulder dystocia. After adjustment for birthweight, induction of labour, use of epidural analgesia at delivery, prolonged labour, forceps-assisted and vacuum-assisted delivery, parity, period of delivery and maternal age in multivariable analyses, the adjusted odds ratios for shoulder dystocia were 1.77 (1.42-2.20) for deliveries at 32-35 weeks of gestation, and 0.84 (0.79-0.88) at 42-43 weeks of gestation, using weeks 40-41 as the reference. In pregnancies affected by diabetes ( n = 11 188), the incidence of shoulder dystocia was 3.95%, and after adjustment for birthweight the adjusted odds ratio for shoulder dystocia was 2.92 (95% CI 1.54-5.52) for deliveries at weeks 32-35 of gestation, and 0.91 (95% CI 0.50-1.66) at 42-43 weeks of gestation. Conclusion The risk of shoulder dystocia was associated with increased birthweight, diabetes, induction of labour, use of epidural analgesia at delivery, prolonged labour, forceps-assisted and vacuum-assisted delivery, parity and period of delivery but not with post-term delivery. [ABSTRACT FROM AUTHOR]

Background- Few prospective studies have investigated insomnia in relation to risk for coronary heart disease. We assessed insomnia symptoms and risk of acute myocardial infarction (AMI) in a large, population-based study. Methods and Results- A total of 52 610 men and women were followed up for a first AMI, and 2368 incident AMIs occurred during 11.4 years of follow-up, either identified at hospitals or by the National Cause of Death Registry. In our analyses, we adjusted for age, sex, marital status, education, shift work, blood pressure, lipids, diabetes mellitus, body mass index, physical activity, smoking, and alcohol consumption. Difficulties initiating and maintaining sleep and having a feeling of nonrestorative sleep were associated with a moderate increase in AMI risk. The multiadjusted hazard ratios for AMI were 1.45 (95% confidence interval 1.18-1.80) for people with difficulties initiating sleep almost every night, 1.30 (1.01-1.68) for those with difficulties maintaining sleep almost every night, and 1.27 (1.03-1.57) for those with a feeling of nonrestorative sleep more than once a week compared with people who never experienced these sleep difficulties. When we combined the symptoms, a dose-dependent association was seen between the number of insomnia symptoms and AMI risk (P for trend 0.003). Alternative multivariable models and different sensitivity analyses suggest that the results were robust, especially concerning difficulties initiating sleep. Conclusions- Insomnia is associated with a moderately increased risk for AMI. [ABSTRACT FROM AUTHOR]

BACKGROUND: The combined effect of resting heart rate (RHR) and physical activity (PA) on ischaemic heart disease (IHD) has never been assessed. The objective of this study was to assess the association of RHR with IHD mortality, and to evaluate the potentially modifying effect of PA on this association. METHODS: In a prospective cohort study of 24 999 men and 25 089 women free from cardiovascular disease at baseline, Cox proportional hazard models were used to estimate adjusted hazard ratios of death from IHD related to RHR measured at baseline. The combined effect of RHR and self-reported PA on the risk of death from IHD was also assessed. RESULTS: During a mean of 18.2 (SD 4) years of follow-up, 2566 men and 1814 women died from cardiovascular causes. For each increment of 10 heart beats per minute, risk of death from IHD was 18% higher in women <70 years of age (p<0.001); no such association was observed among women > or =70 years. Among men, there was a corresponding 10% higher risk in the younger (p = 0.004), and 11% higher risk in the older age group (p = 0.01). Among women, the risk associated with high RHR was substantially attenuated in those who reported a high level of PA, whereas in men, there was no clear indication that PA could modify the positive effect of RHR. CONCLUSION: RHR is positively associated with the risk of death from IHD, and among women, the results suggest that by engaging in PA, the risk associated with a high RHR may be substantially reduced. [ABSTRACT FROM AUTHOR]

Low birth weight of offspring has been associated with increased risk of maternal cardiovascular mortality, and cardiovascular risk factors measured within pregnancy have been related to offspring birth weight. It is not clear whether cardiovascular risk factors assessed prior to pregnancy are associated with the offspring's birth weight. The authors combined baseline data from 3,461 women in the HUNT Study (1995-1997) and data on deliveries from the Medical Birth Registry of Norway up to 2005. They used linear regression to prospectively study associations between diastolic and systolic blood pressures, concentrations of triglycerides, serum total cholesterol, and high density lipoprotein cholesterol measured before conception and birth weight for gestational age of the offspring. Blood pressure measured before pregnancy was inversely associated with birth weight for gestational age, whereas unfavorable levels of serum total cholesterol, high density lipoprotein cholesterol, triglycerides, and glucose were positively associated with birth weight for gestational age. Thus, women with relatively high blood pressure tend to deliver small babies, whereas women with unfavorable lipid levels tend to give birth to large babies, suggesting reduced glucose tolerance. These findings suggest that low as well as high birth weight of the offspring may indicate increased cardiovascular risk for the mother. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to assess changes in placenta growth factor and soluble fms-like tyrosine kinase-1 as predictors of preeclampsia. Study Design: Nested case-control study of 154 preeclampsia cases delivered preterm and 190 delivered at term, and 392 controls. Results: Comparing the lowest and highest quartile of placenta growth factor increase from first to second trimester, the odds for preterm preeclampsia was 13.8 (95% CI, 4.4-43.2) higher for women with the lowest increase. Compared with controls, women with preterm preeclampsia had lower soluble fms-like tyrosine kinase-1 in the first, but higher in second trimester. Comparing highest and lowest quartile of increase, the odds for preterm preeclampsia was 9.2 (95% CI 3.4-25.0) higher for women with highest increase. Low placenta growth factor and high soluble fms-like tyrosine kinase-1 increase combined yielded extremely high relative risk of preterm preeclampsia (odds ratio, 35.3, 95% CI, 7.6-164.2), compared with the combination of high (placenta growth factor) and low (soluble fms-like tyrosine kinase-1) increase. Conclusion: Low placenta growth factor and high soluble fms-like tyrosine kinase-1 increase from first to second trimester are strong predictors of preeclampsia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Research suggests that singleton births following assisted fertilisation are associated with adverse outcomes; however, these results might be confounded by factors that affect both fertility and pregnancy outcome. We therefore compared pregnancy outcomes in women who had singleton pregnancies conceived both spontaneously and after assisted fertilisation. METHODS: In a population-based cohort study, we assessed differences in birthweight, gestational age, and odds ratios (OR) of small for gestational age babies, premature births, and perinatal deaths in singletons (gestation >/=22 weeks or birthweight >/=500 g) born to 2546 Norwegian women (>20 years) who had conceived at least one child spontaneously and another after assisted fertilisation among 1 200 922 births after spontaneous conception and 8229 after assisted fertilisation. FINDINGS: In the whole study population, assisted-fertilisation conceptions were associated with lower mean birthweight (difference 25 g, 95% CI 14 to 35), shorter duration of gestation (2.0 days, 1.6 to 2.3) and increased risks of small for gestational age (OR 1.26, 1.10 to 1.44), and perinatal death (1.31, 1.05 to 1.65) than were spontaneous conceptions. In the sibling-relationship comparisons, the spontaneous versus the assisted-fertilisation conceptions showed a difference of only 9 g (-18 to 36) in birthweight and 0.6 days (-0.5 to 1.7) in gestational age. For assisted fertilisation versus spontaneous conception in the sibling-relationship comparisons, the OR for small for gestational age was 0.99 (0.62 to 1.57) and that for perinatal mortality was 0.36 (0.20 to 0.67). INTERPRETATION: Birthweight, gestational age, and risks of small for gestational age babies, and preterm delivery did not differ among infants of women who had conceived both spontaneously and after assisted fertilisation. The adverse outcomes of assisted fertilisation that we noted compared with those in the general population could therefore be attributable to the factors leading to infertility, rather than to factors related to the reproductive technology. [ABSTRACT FROM AUTHOR]

Purpose: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer., Methods: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity., Results: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( P nonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; P het = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity., Conclusion: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Background: Some breast carcinomas detected at screening, especially ductal carcinoma in situ, may have limited potential for progression to symptomatic disease. To determine non-progression is a challenge, but if all screening-detected breast tumors eventually reach a clinical stage, the cumulative incidence at a reasonably high age would be similar for women with or without screening, conditional on the women being alive., Methods: Using high-quality population data with 24 years of follow-up from the gradually introduced BreastScreen Norway program, we studied whether all breast carcinomas detected at mammography screening 50-69 years of age would progress to clinical symptoms within 85 years of age. First, we estimated the incidence rates of breast carcinomas by age in scenarios with or without screening, based on an extended age-period-cohort incidence model. Next, we estimated the frequency of non-progressive tumors among screening-detected cases, by calculating the difference in the cumulative rate of breast carcinomas between the screening and non-screening scenarios at 85 years of age., Results: Among women who attended BreastScreen Norway from the age of 50 to 69 years, we estimated that 1.1% of the participants were diagnosed with a breast carcinoma without the potential to progress to symptomatic disease by 85 years of age. This proportion of potentially non-progressive tumors corresponded to 15.7% [95% CI 3.3, 27.1] of breast carcinomas detected at screening., Conclusions: Our findings suggest that nearly one in six breast carcinomas detected at screening may be non-progressive., (© 2023. The Author(s).)

Background: Women who experience complications in first pregnancy are at increased risk of cardiovascular disease (CVD) later in life. Little corresponding knowledge is available for complications in later pregnancies. Therefore, we assessed complications (preeclampsia, preterm birth, and offspring small for gestational age) in first and last pregnancies and the risk of long-term maternal CVD death, taking women´s complete reproduction into account., Data and Methods: We linked data from the Medical Birth Registry of Norway to the national Cause of Death Registry. We followed women whose first birth took place during 1967-2013, from the date of their last birth until death, or December 31st 2020, whichever occurred first. We analysed risk of CVD death until 69 years of age according to any complications in last pregnancy. Using Cox regression analysis, we adjusted for maternal age at first birth and level of education., Results: Women with any complications in their last or first pregnancy were at higher risk of CVD death than mothers with two-lifetime births and no pregnancy complications (reference). For example, the adjusted hazard ratio (aHR) for women with four births and any complications only in the last pregnancy was 2.85 (95% CI, 1.93-4.20). If a complication occurred in the first pregnancy only, the aHR was 1.74 (1.24-2.45). Corresponding hazard ratios for women with two births were 1.82 (CI, 1.59-2.08) and 1.41 (1.26-1.58), respectively., Conclusions: The risk for CVD death was higher among mothers with complications only in their last pregnancy compared to women with no complications, and also higher compared to mothers with a complication only in their first pregnancy., (© 2023. The Author(s).)

Background. Several studies have evaluated the effect of mammography screening on breast cancer mortality based on overall breast cancer mortality trends, with varied conclusions. The statistical power of such trend analyses is, however, not carefully studied. Methods. We estimated how the effect of screening on overall breast cancer mortality is likely to unfold. Because a screening effect is based on earlier treatment, screening can affect only new incident cases after screening introduction. To evaluate the likelihood of detecting screening effects on overall breast cancer mortality time trends, we calculated the statistical power of joinpoint regression analysis on breast cancer mortality trends around screening introduction using simulations. Results. We found that a very gradual increase in population-level screening effect is expected due to prescreening incident cases. Assuming 25% effectiveness of a biennial screening program in reducing breast cancer mortality among women 50 to 69 y of age, the expected reduction in overall breast cancer mortality was 3% after 2 y and reached a long-term effect of 18% after 20 y. In common settings, the statistical power to detect any screening effects using joinpoint regression analysis is very low (<50%), even in an artificial setting of constant risk of baseline breast cancer mortality over time. Conclusions. Population effects of screening on breast cancer mortality emerge very gradually and are expected to be considerably lower than the effects reported in trials excluding women diagnosed before screening. Studies of overall breast cancer mortality time trends have too low statistical power to reliably detect screening effects in most populations. Implications. Researchers and policy makers evaluating mammography screening should avoid using breast cancer mortality trend analysis that does not separate pre- and postscreening incident cases., Highlights: Population-level mammography screening effects on breast cancer mortality emerge gradually following screening introduction, resulting in very low statistical power of trend analysis.Researchers and policy makers evaluating mammography screening should avoid relying on population-wide breast cancer mortality trends.Expected mammography screening effects at population level are lower than those from screening trials, as many cases of breast cancer fall outside the screening age range., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The study used data from the Cancer Registry of Norway. The interpretation and reporting of these data are the sole responsibility of the authors, and no endorsement by the Cancer Registry of Norway is intended nor should be inferred., (© The Author(s) 2022.)

Objective: To study mortality and readmissions for older patients admitted during more and less busy hospital circumstances., Design: Cohort study where we identified patients that were admitted to the same hospital, during the same month and day of the week. We estimated effects of inflow of acute patients and the number of concurrent acute inpatients. Mortality and readmissions were analysed using stratified Cox-regression., Setting: All people 80 years and older acutely admitted to Norwegian hospitals between 2008 and 2016., Main Outcome Measures: Mortality and readmissions within 60 days from admission., Results: Among 294 653 patients with 685 197 admissions, mean age was 86 years (standard deviation 5). Overall, 13% died within 60 days. An interquartile range difference in inflow of acute patients was associated with a hazard ratio (HR) of 0.99, 95% confidence interval (95% CI) 0.98 to 1.00). There was little evidence of differences in readmissions, but a 7% higher risk (HR 1.07, 95% CI 1.06 to 1.09) of being discharged outside ordinary daytime working hours., Conclusions: Older patients admitted during busier circumstances had similar mortality and readmissions to those admitted during less busy periods. Yet, they showed a higher risk of discharge outside daytime working hours. Despite limited effects of busyness on a hospital level, there could still be harmful effects of local situations., (Copyright © 2022. Published by Elsevier B.V.)

Aims: To study the consequences of crowded wards among patients with cardiovascular disease., Methods and Results: This is a cohort study among 201 801 patients with 258 807 admissions who were acutely admitted for myocardial infarction (N = 107 895), stroke (N = 87 336), or heart failure (N = 63 576) to any Norwegian hospital between 2008 and 2016. The ward admitting most patients with the given clinical condition was considered a patient's home ward. We compared patients with the same condition admitted when home ward occupancy was different, at the same hospital and during comparable time periods. Occupancy was standardized such that a one-unit difference corresponded to the interquartile range in occupancy in the given month. One interquartile increase in home ward occupancy was associated with 7% higher odds of admission to an alternate ward [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.09 to 1.11], and length of stay was shorter (-0.10 days, 95% CI -0.18 to -0.09). Patients with heart failure had 15% higher odds of admission to alternate wards (OR 1.15, 95% CI 1.08 to 1.23) and increased mortality [hazard ratio (HR) 1.08, 95% CI 1.03 to 1.15]. We found no apparent effect on mortality for patients with myocardial infarction (HR 0.99, 95% CI 0.94 to 1.05) or stroke (HR 1.00, 95% CI 0.96 to 1.05)., Conclusions: Patients with heart failure had higher risk of admission to alternate wards when home ward occupancy was high. These patients may be negatively affected by full wards., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Although physical activity is an established protective factor for cardiovascular diseases such as ischemic heart disease and stroke, less is known with regard to the association between specific domains of physical activity and heart failure, as well as the association between cardiorespiratory fitness and heart failure. We conducted a systematic review and meta-analysis of prospective observational studies to clarify the relations of total physical activity, domains of physical activity and cardiorespiratory fitness to risk of heart failure. PubMed and Embase databases were searched up to January 14th, 2020. Summary relative risks (RRs) were calculated using random effects models. Twenty-nine prospective studies (36 publications) were included in the review. The summary RRs for high versus low levels were 0.77 (95% CI 0.70-0.85, I 2  = 49%, n = 7) for total physical activity, 0.74 (95% CI 0.68-0.81, I 2  = 88.1%, n = 16) for leisure-time activity, 0.66 (95% CI 0.59-0.74, I 2  = 0%, n = 2) for vigorous activity, 0.81 (95% CI 0.69-0.94, I 2  = 86%, n = 3) for walking and bicycling combined, 0.90 (95% CI 0.86-0.95, I 2  = 0%, n = 3) for occupational activity, and 0.31 (95% CI 0.19-0.49, I 2  = 96%, n = 6) for cardiorespiratory fitness. In dose-response analyses, the summary RRs were 0.89 (95% CI 0.83-0.95, I 2  = 67%, n = 4) per 20 MET-hours per day of total activity and 0.71 (95% CI 0.65-0.78, I 2  = 85%, n = 11) per 20 MET-hours per week of leisure-time activity. Nonlinear associations were observed in both analyses with a flattening of the dose-response curve at 15-20 MET-hours/week for leisure-time activity. These findings suggest that high levels of total physical activity, leisure-time activity, vigorous activity, occupational activity, walking and bicycling combined and cardiorespiratory fitness are associated with reduced risk of developing heart failure.

Background: Because birth size appears to be positively associated with breast cancer risk, we have studied whether this risk may differ according to molecular breast cancer subtypes., Methods: A cohort of 22,931 women born 1920-1966 were followed up for breast cancer occurrence from 1961 to 2012, and 870 were diagnosed during follow-up. Archival diagnostic material from 537 patients was available to determine molecular breast cancer subtype, specified as Luminal A, Luminal B (human epidermal growth factor receptor 2 (HER2)-), Luminal B (HER2+), HER2 type, and Triple negative (TN) breast cancer. Information on the women's birth weight, birth length and head circumference at birth was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for each molecular subtype, applying Cox regression, and stratified by maternal height., Results: Birth length (per 2 cm increments) was positively associated with Luminal A (HR = 1.2, 95% CI, 1.0-1.3), Luminal B (HER2+) (HR = 1.3, 95% CI, 1.0-1.7), and TN breast cancer (HR = 1.4, 95% CI, 1.0-1.9). No clear association was found for birth weight and head circumference. The positive associations of birth length were restricted to women whose mothers were relatively tall (above population median)., Conclusion: We found a positive association of birth length with risk of Luminal A, Luminal B (HER2+) and TN breast cancer that appears to be restricted to women whose mothers were relatively tall. This may support the hypothesis that breast cancer risk is influenced by determinants of longitudinal growth and that this finding deserves further scrutiny.

Aims: Few studies have investigated potential consequences of strained surgical resources. The aim of this cohort study was to assess whether a high proportion of concurrent acute surgical admissions, tying up hospital surgical capacity, may lead to delayed surgery and affect mortality for hip fracture patients., Methods: This study investigated time to surgery and 60-day post-admission death of patients 70 years and older admitted for acute hip fracture surgery in Norway between 2008 and 2016. The proportion of hospital capacity being occupied by newly admitted surgical patients was used as the exposure. Hip fracture patients admitted during periods of high proportion of recent admissions were compared with hip fracture patients admitted at the same hospital during the same month, on similar weekdays, and times of the day with fewer admissions., Results: Among 60,072 patients, mean age was 84.6 years (SD 6.8), 78% were females, and median time to surgery was 20 hours (IQR 11 to 29). Overall, 14% (8,464) were dead 60 days after admission. A high (75 th percentile) proportion of recent surgical admission compared to a low (25 th percentile) proportion resulted in 20% longer time to surgery (95% confidence interval (CI) 16 to 25) and 20% higher 60-day mortality (hazard ratio 1.2, 95% CI 1.1 to 1.4)., Conclusion: A high volume of recently admitted acute surgical patients, indicating probable competition for surgical resources, was associated with delayed surgery and increased 60-day mortality. Cite this article: Bone Joint J 2021;103-B(2):264-270.

Women with small or large for gestational age offspring are at increased risk of cardiovascular disease later in life. How their cardiovascular risk factors develop across the life course is incompletely known. We linked data from the population-based HUNT Study (1984-2008) and the Medical Birth Registry of Norway (1967-2012) for 22,487 women. Mixed effect models were used to compare cardiovascular risk factor trajectories for women according to first offspring birthweight for gestational age. Women with small for gestational age (SGA) offspring had 1-2 mmHg higher systolic and diastolic blood pressure across the life course, but lower measures of adiposity, compared to women with offspring who were appropriate for gestational age (AGA). In contrast, women with large for gestational age (LGA) offspring had higher measures of adiposity, ~0.1 mmol/l higher non-HDL cholesterol and triglycerides and 0.2 mmol/l higher non-fasting glucose, compared with mothers of AGA offspring. These differences were broadly stable from prior to first pregnancy until 60 years of age. Our findings point to different cardiovascular risk profiles in mothers of SGA versus LGA offspring, where giving birth to SGA offspring might primarily reflect adverse maternal vascular health whereas LGA offspring might reflect the mother's metabolic health.

Importance: Women with a history of hypertensive disorders of pregnancy (HDP) have higher risk of cardiovascular disease (CVD). It is not known how much of the excess CVD risk in women with a history of HDP is associated with conventional cardiovascular risk factors., Objective: To quantify the excess risk of CVD in women with a history of HDP and estimate the proportion associated with conventional cardiovascular risk factors., Design, Setting, and Participants: Prospective cohort study with a median follow-up of 18 years. Population-based cohort of women participating in the Nord-Trøndelag Health Study in Norway. We linked data for 31 364 women from the Nord-Trøndelag Health Study (1984-2008) to validated hospital records (1987-2015), the Cause of Death Registry (1984-2015), and the Medical Birth Registry of Norway (1967-2012). A total of 7399 women were excluded based on selected pregnancy characteristics, incomplete data, or because of emigrating or experiencing the end point before start of follow-up, leaving 23 885 women for study. Data were analyzed between January 1, 2018, and June 6, 2018., Exposures: Experiencing 1 or more pregnancies complicated by HDP before age 40 years vs only experiencing normotensive pregnancies., Main Outcomes and Measures: We used Cox proportional hazards models to estimate the hazard ratios (HRs) for the association between HDP and CVD. The proportion of excess risk associated with conventional cardiovascular risk factors was estimated using an inverse odds ratio weighting approach., Results: Our study population consisted of 23 885 parous women from Nord-Trøndelag County, Norway. A total of 21 766 women had only normotensive pregnancies, while 2199 women experienced ever having an HDP. From age 40 to 70 years, women with history of HDP had an increased risk of CVD compared with women with only normotensive pregnancies (HR, 1.57; 95% CI, 1.32-1.87) but not at older age (β = 0.98; 95% CI, 0.96-1.00; P for interaction by age = .01). Blood pressure and body mass index were associated with up to 77% of the excess risk of CVD in women with history of HDP, while glucose and lipid levels were associated with smaller proportions., Conclusion and Relevance: In this study, the risk of excess CVD in women with history of HDP was associated with conventional cardiovascular risk factors, indicating that these risk factors are important targets for cardiovascular prevention in these women.

Wholesale, unbiased assessment of Scandinavian electronic health-care databases offer a unique opportunity to reveal potentially important undiscovered drug side effects. We examined the short-term risk of acute myocardial infarction (AMI) associated with drugs prescribed in Norway or Sweden. We identified 24,584 and 97,068 AMI patients via the patient- and the cause-of-death registers and linked to prescription databases in Norway (2004-2014) and Sweden (2005-2014), respectively. A case-crossover design was used to compare the drugs dispensed 1-7 days before the date of AMI diagnosis with 15-21 days' time -window for all the drug individually while controlling the receipt of other drugs. A BOLASSO approach was used to select drugs that acutely either increase or decrease the apparent risk of AMI. We found 48 drugs to be associated with AMI in both countries. Some antithrombotics, antibiotics, opioid analgesics, adrenergics, proton-pump inhibitors, nitroglycerin, diazepam, metoclopramide, acetylcysteine were associated with higher risk for AMI; whereas angiotensin-II-antagonists, calcium-channel blockers, angiotensin-converting-enzyme inhibitors, serotonin-specific reuptake inhibitors, allopurinol, mometasone, metformin, simvastatin, levothyroxine were inversely associated. The results were generally robust in different sensitivity analyses. This study confirms previous findings for certain drugs. Based on the known effects or indications, some other associations could be anticipated. However, inverse associations of hydroxocobalamin, levothyroxine and mometasone were unexpected and needs further investigation. This pharmacopeia-wide association study demonstrates the feasibility of a systematic, unbiased approach to pharmacological triggers of AMI and other diseases with acute, identifiable onsets.

Background: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups., Methods: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models., Results: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function., Conclusions: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

It is not known whether increased breast cancer risk caused by menopausal hormone therapy (HT) depends on body mass patterns through life. In a prospective study of 483,241 Norwegian women aged 50-69 years at baseline, 7656 women developed breast cancer during follow-up (2006-2013). We combined baseline information on recalled body mass in childhood/adolescence and current (baseline) body mass index (BMI) to construct mutually exclusive life-course body mass patterns. We assessed associations of current HT use with breast cancer risk according to baseline BMI and life-course patterns of body mass, and estimated relative excess risk due to interaction (RERI). Within all levels of baseline BMI, HT use was associated with increased risk. Considering life-course body mass patterns as a single exposure, we used women who "remained at normal weight" through life as the reference, and found that being "overweight as young" was associated with lower risk (hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.76-0.94), whereas women who "gained weight" had higher risk (HR 1.20, 95% CI 1.12-1.28). Compared to never users of HT who were "overweight as young", HT users who either "remained at normal weight" or "gained weight" in adulthood were at higher risk than expected when adding the separate risks (RERI 0.52, 95% CI 0.09-0.95, and RERI 0.37, 95% CI - 0.07-0.80), suggesting effect modification. Thus, we found that women who remain at normal weight or gain weight in adulthood may be more susceptible to the risk increasing effect of HT compared to women who were overweight as young.

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation., Methods and Findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose., Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TE declared employment, research support, and stock in AstraZeneca and research support from Bayer and Pfizer. PCH is a population health fellow of Cancer Research UK. GDS is a member of the Editorial Board of PLOS Medicine.

Greater body mass index (BMI) has been associated with increased risk of psoriasis in case-control and cross-sectional studies, however, the evidence from prospective studies has been limited. We conducted a systematic review and dose-response meta-analysis of different adiposity measures and the risk of psoriasis to provide a more robust summary of the evidence based on data from prospective studies. PubMed and Embase databases were searched for relevant studies up to August 8th 2017. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random effects model. The summary relative risk (RR) for a 5 unit increment in BMI was 1.19 (95% CI 1.10-1.28, I 2  = 83%, n = 7). The association appeared to be stronger at higher compared to lower levels of BMI, p nonlinearity  < 0.0001, and the lowest risk was observed at a BMI around 20. The summary RR was 1.24 (95% CI 1.17-1.31, I 2  = 0%, p heterogeneity  = 0.72, n = 3) per 10 cm increase in waist circumference, 1.37 (95% CI 1.23-1.53, I 2  = 0%, p heterogeneity  = 0.93, n = 3) per 0.1 unit increase in waist-to-hip ratio, and 1.11 (95% CI 1.07-1.16, I 2  = 47%, p heterogeneity  = 0.15, n = 3) per 5 kg of weight gain. Adiposity as measured by BMI, waist circumference, waist-to-hip ratio, and weight gain is associated with increased risk of psoriasis.

Background: High dietary intake or blood concentrations (as biomarkers of dietary intake) of vitamin C, carotenoids, and vitamin E have been associated with reduced risk of cardiovascular disease, cancer, and mortality, but these associations have not been systematically assessed., Objective: We conducted a systematic review and meta-analysis of prospective studies of dietary intake and blood concentrations of vitamin C, carotenoids, and vitamin E in relation to these outcomes., Design: We searched PubMed and Embase up to 14 February 2018. Summary RRs and 95% CIs were calculated with the use of random-effects models., Results: Sixty-nine prospective studies (99 publications) were included. The summary RR per 100-mg/d increment of dietary vitamin C intake was 0.88 (95% CI: 0.79, 0.98, I2 = 65%, n = 11) for coronary heart disease, 0.92 (95% CI: 0.87, 0.98, I2 = 68%, n = 12) for stroke, 0.89 (95% CI: 0.85, 0.94, I2 = 27%, n = 10) for cardiovascular disease, 0.93 (95% CI: 0.87, 0.99, I2 = 46%, n = 8) for total cancer, and 0.89 (95% CI: 0.85, 0.94, I2 = 80%, n = 14) for all-cause mortality. Corresponding RRs per 50-μmol/L increase in blood concentrations of vitamin C were 0.74 (95% CI: 0.65, 0.83, I2 = 0%, n = 4), 0.70 (95% CI: 0.61, 0.81, I2 = 0%, n = 4), 0.76 (95% CI: 0.65, 0.87, I2 = 56%, n = 6), 0.74 (95% CI: 0.66, 0.82, I2 = 0%, n = 5), and 0.72 (95% CI: 0.66, 0.79, I2 = 0%, n = 8). Dietary intake and/or blood concentrations of carotenoids (total, β-carotene, α-carotene, β-cryptoxanthin, lycopene) and α-tocopherol, but not dietary vitamin E, were similarly inversely associated with coronary heart disease, stroke, cardiovascular disease, cancer, and/or all-cause mortality., Conclusions: Higher dietary intake and/or blood concentrations of vitamin C, carotenoids, and α-tocopherol (as markers of fruit and vegetable intake) were associated with reduced risk of cardiovascular disease, total cancer, and all-cause mortality. These results support recommendations to increase fruit and vegetable intake, but not antioxidant supplement use, for chronic disease prevention.

Faciogenital dysplasia 5 ( FGD5) amplification drives tumor cell proliferation, and is present in 9.5% of breast cancers. We describe FGD5 expression, assess associations between FGD5 amplification and FGD5 expression, and assess FGD5 expression in relation to proliferation and prognosis. FGD5 immunohistochemistry was done on primary tumors ( n=829) and lymph node metastases ( n=231) from a cohort of Norwegian patients. We explored associations between FGD5 amplification, FGD5 expression, and proliferation, and analyzed the prognostic value of FGD5 expression by estimating cumulative risks of death and hazard ratios (HRs). We identified nuclear and cytoplasmic expression in 64% and 73% of primary tumors, respectively, and found an association between gene amplification and nuclear expression ( p=0.02). The proportion of cases with FGD5 expression was higher in lymph node metastases, compared with primary tumors ( p=0.004 for nuclear and p=0.001 for cytoplasmic staining). Neither proliferation nor prognosis was associated with FGD5 expression (age-adjusted HR 1.12 [95% confidence interval = 0.89-1.41] for nuclear expression; and 0.88 [95% CI = 0.70-1.12] for cytoplasmic expression). FGD5 is expressed in a high proportion of breast cancers and lymph node metastases. There was a correlation between FGD5 amplification and nuclear expression, but no association between FGD5 expression and proliferation or prognosis.