Working Status in Patients With Untreated Unruptured Intracranial Aneurysms: A Descriptive Longitudinal Study.

BACKGROUND AND OBJECTIVES: Many patients with unruptured intracranial aneurysms (UIAs) remain untreated if the risk of treatment exceeds the estimated risk of aneurysm rupture, potentially leading to diagnosis-related stress and anxiety. Working status may serve as a marker for the total level of function including mental health and psychological burden of the condition. The aim of the study was to assess the working status before and after a diagnosis of an untreated UIA. METHODS: This was a retrospective nationwide registry-based descriptive longitudinal study. It included all working-age patients diagnosed with an UIA in Norway between 2008 and 2018 and 1:1 age-matched and sex-matched controls without a diagnosis of an intracranial aneurysm that were randomly selected from the Norwegian population. The history of sickness absence in the period of 1 year before and after diagnosis was retrieved from The Norwegian Labour and Welfare Administration records and compared between the groups. RESULTS: In total, 2141 patients and 2141 controls were included in the study. Proportion of working patients decreased from 62.1% (95% CI 60.0%-64.1%) 1 year before the diagnosis to 51.3% (95% CI 49.1%-53.4%) 1 year after the diagnosis (P < .001). In comparison, the proportion of working controls decreased from 77.9% (95% CI 76.1%-79.6%) 1 year before day 0 to 73.4% (95% CI 71.5%-75.2%) 1 year after day 0 (P = .001). The odds of working were 86.7% lower among the patients than among the controls (odds ratio 0.133, 95% CI 0.091-0.194; P < .001) when controlled for the baseline working status. The older the individuals, the less likely they were to work (odds ratio 0.908, 95% CI 0.889-0.926; P < .001). CONCLUSION: The work participation of patients diagnosed with UIA is low prediagnosis compared with the general population and decreases significantly postdiagnosis.

Dispensed prescription medications and short-term risk of pulmonary embolism in Norway and Sweden.

Scandinavian electronic health-care registers provide a unique setting to investigate potential unidentified side effects of drugs. We analysed the association between prescription drugs dispensed in Norway and Sweden and the short-term risk of developing pulmonary embolism. A total of 12,104 pulmonary embolism cases were identified from patient- and cause-of-death registries in Norway (2004-2014) and 36,088 in Sweden (2005-2014). A case-crossover design was used to compare individual drugs dispensed 1-30 days before the date of pulmonary embolism diagnosis with dispensation in a 61-90 day time-window, while controlling for the receipt of other drugs. A BOLASSO approach was used to select drugs that were associated with short-term risk of pulmonary embolism. Thirty-eight drugs were associated with pulmonary embolism in the combined analysis of the Norwegian and Swedish data. Drugs associated with increased risk of pulmonary embolism included certain proton-pump inhibitors, antibiotics, antithrombotics, vasodilators, furosemide, anti-varicose medications, corticosteroids, immunostimulants (pegfilgrastim), opioids, analgesics, anxiolytics, antidepressants, antiprotozoals, and drugs for cough and colds. Mineral supplements, hydrochlorothiazide and potassium-sparing agents, beta-blockers, angiotensin 2 receptor blockers, statins, and methotrexate were associated with lower risk. Most associations persisted, and several additional drugs were associated, with pulmonary embolism when using a longer time window of 90 days instead of 30 days. These results provide exploratory, pharmacopeia-wide evidence of medications that may increase or decrease the risk of pulmonary embolism. Some of these findings were expected based on the drugs' indications, while others are novel and require further study as potentially modifiable precipitants of pulmonary embolism.

The influence of diagnostic subgroups, patient- and hospital characteristics for the validity of cardiovascular diagnoses-Data from a Norwegian hospital trust.

BACKGROUND: Cardiovascular discharge diagnoses may serve as endpoints in epidemiological studies if they have a high validity. Aim was to study if diagnoses-specific characteristics like type, sub-categories, and position of cardiovascular diagnoses affected diagnostic accuracy. METHODS: Patients (n = 7,164) with a discharge diagnosis of acute myocardial infarction, heart failure or cerebrovascular disease were included. Data were presented as positive predictive values (PPV) and sensitivity. RESULTS: PPV was high (≥88%) for acute myocardial infarction (n = 2,189) (except for outpatients). For heart failure (n = 4,026) PPV was 67% overall, but higher (>99%) when etiology or echocardiography was included. For hemorrhagic (n = 257) and ischemic (n = 1,034) strokes PPVs were 87% and 80%, respectively, with sensitivity of 79% and 75%. Transient ischemic attacks (n = 926) had PPV 56%, but sensitivity 86%. Primary diagnoses showed higher validity than subsequent diagnoses and inpatient diagnoses were more valid than outpatient diagnoses (except for transient ischemic attack). The diagnoses of acute myocardial infarction and heart failure where most valid when placed at cardiology units, while ischemic stroke when discharged from an internal medicine unit. CONCLUSIONS: The diagnoses of acute myocardial infarction and stroke had excellent validity when placed during hospital stays. Similarly, heart failure diagnoses had excellent validity when echocardiography was performed before placing the diagnosis, while overall the diagnoses of heart failure and transient ischemic attack were less valid. In conclusion, the results indicate that cardiovascular diagnoses based on objective findings such as acute myocardial infarction and stroke have excellent validity and may be used as endpoints in clinical epidemiological studies with less rigid validation.

Insight into the relationship between resting heart rate and atrial fibrillation: a Mendelian randomization study.

AIMS: A low resting heart rate (RHR) implies a more efficient heart function and a lower risk of cardiovascular disease. However, observational studies have reported a U-shaped association between RHR and atrial fibrillation (AF). In contrast, Mendelian randomization (MR) studies have found an inverse causal association between RHR and AF. Hence, the causal nature of the relationship is not clear. The aim is to investigate the causal association and its shape between RHR on AF using linear and non-linear MR (NLMR). METHODS AND RESULTS: Linear and non-linear MR were performed on individual-level data in the Trøndelag Health Study (HUNT) and UK Biobank (UKB). HUNT consists of 69 155 individuals with 7,062 AF cases, while UKB provides data on 431 852 individuals with 20 452 AF cases. The linear MR found an inverse relationship between RHR and AF with an OR = 0.95 [95% confidence interval (CI): 0.93-0.98] and OR = 0.96 (95% CI: 0.95-0.97) per unit decrease in RHR in HUNT and UKB, respectively. The NLMR was supportive of an inverse linear relationship in both HUNT and UKB for RHR values <90 beats per minute (bpm). Several sensitivity analyses were also consistent. CONCLUSION: In contrast with the current observational knowledge of RHR and AF, an inverse causal association between RHR and AF was demonstrated in both linear and non-linear MR for RHR values up to 90 bpm. Further exploring the underlying mechanisms of the genetic instrument for RHR may shed light on whether pleiotropy is biasing this association.

Return to Work after Surgical Clipping versus Endovascular Treatment of Unruptured Intracranial Aneurysms: A Nationwide Registry-Based Study.

PURPOSE: To assess return to work following the treatment of unruptured intracranial aneurysms (UIAs). MATERIALS AND METHODS: This retrospective, nationwide registry-based study included all adult patients of working age treated for a UIA in Norway between 2008 and 2018 who had a record of sickness leave on the day of treatment. Data from The Norwegian Patient Registry and The Norwegian Labour and Welfare Administration were linked on an individual level. Daily sickness and recipiency of disability benefits, as an indirect measure of working status, from 1 year before treatment to 1 year after treatment were analyzed. Return to work after endovascular treatment and surgical clipping was compared. RESULTS: In total, 412 patients were included. Of patients who worked 1 year before treatment, 83% returned to work 1 year after treatment. The number of days from treatment to the first day back at work in a continuous 3-month working period was lower in patients who underwent endovascular treatment than in those treated with surgical clipping (median, 69 days; 95% confidence interval [CI], 51-87; vs 201 days, 95% CI, 163-239; P < .001). Return to work was more likely in patients who underwent endovascular treatment at 3 months after treatment (hazard ratio, 3.53; 95% CI, 2.54-4.93; P < .001). There was no difference in return to work at 6 and 12 months after treatment. CONCLUSIONS: The treatment of UIAs affects patients' postoperative working status. Patients treated endovascularly return to work earlier than those who undergo open surgery.

APOBEC3A/B deletion polymorphism and endometrial cancer risk.

BACKGROUND: A common 30 kb deletion affecting the APOBEC3A and APOBEC3B genes has been linked to increased APOBEC activity and APOBEC-related mutational signatures in human cancers. The role of this deletion as a cancer risk factor remains controversial. MATERIALS AND METHODS: We genotyped the APOBEC3A/B deletion in a sample of 1,470 Norwegian endometrial cancer cases and compared to 1,918 healthy controls. For assessment across Caucasian populations, we mined genotypes of the SNP rs12628403, which is in strong linkage disequilibrium with the deletion, in a GWAS dataset of 4,274 cases and 18,125 healthy controls, through the ECAC consortium. RESULTS: We found the APOBEC3A/B deletion variant to be significantly associated with reduced risk of endometrial cancer among Norwegian women (OR = 0.75; 95% CI = 0.62-0.91; p = 0.003; dominant model). Similar results were found in the subgroup of endometrioid endometrial cancer (OR = 0.64; 95% CI = 0.51-0.79; p = 3.6 × 10-5 ; dominant model). The observed risk reduction was particularly strong among individuals in the range of 50-60 years of age (OR = 0.51; 95% CI = 0.33-0.78; p = 0.002; dominant model). In the different populations included in the ECAC dataset, the ORs varied from 0.85 to 1.05. Although five out of six populations revealed ORs <1.0, the overall estimate was nonsignificant and, as such, did not formally validate the findings in the Norwegian cohort. CONCLUSION: The APOBEC3A/B deletion polymorphism is associated with a decreased risk of endometrial cancer in the Norwegian population.

Return to work after surgical clipping versus endovascular treatment for ruptured intracranial aneurysms - A nationwide registry-based study.

OBJECTIVES: The aim of this study was to assess return to work following aneurysmal subarachnoid haemorrhage (SAH) and compare working status after open surgical clipping and endovascular treatment. METHODS: This nationwide registry-based study included all adult patients in working age treated for a ruptured intracranial aneurysm in Norway between 2008 and 2018 who had a record of sickness leave on the day of treatment. Data from The Norwegian Patient Registry and The Norwegian Labour and Welfare Administration were linked on an individual level. Daily sickness and disability benefits recipiency one year preoperatively to one year postoperatively was analysed. Return to work after endovascular treatment and surgical clipping was compared. RESULTS: 183 patients were included in the study. Among patients who worked at one year preoperatively, 57% had returned to work one year after treatment. Mean number of days from treatment to the first day back at work in a continuous 3-month working period was 298 (95% CI: 276-321) vs. 319 (95% CI: 299-339) for patients who underwent endovascular treatment compared to patients treated with clipping (p = 0.365). Older patients were less likely to return to work after treatment (hazard ratio 0.977 per year of age, 95% CI 0.956-1.000, p = 0.046). There was no significant association between return to work and patient sex or location of the aneurysm. CONCLUSIONS: Aneurysmal SAH profoundly affects patient working status. This study found no significant difference in time to return to work after treatment between patients treated with endovascular techniques compared to patients undergoing open surgery.

Cervical cancer mortality in Norway according to screening attendance and age.

INTRODUCTION: The association between cervical cancer screening and reduction of cervical cancer has been dealt with in much research. However, little has been published on the association between screening and cervical cancer mortality. We assessed cervical cancer deaths according to screening history, histopathology, and age among women in, under, and above screening age. MATERIAL AND METHODS: In this nationwide, registry-based case-control study from Norway, we included 817 cervical cancer deaths in women diagnosed with cervical cancer in the period 1998-2009. We matched each case with 10 population-based controls free from cervical cancer, obtained by density-based sampling. Odds ratios (ORs) with 95% confidence intervals (CIs) for the association between screening attendance and cervical cancer mortality were estimated using conditional logistic regression models. RESULTS: Of all fatal cervical cancers, 35% were diagnosed among women over screening age and altogether, 83% were either in age groups not covered by the screening program or in non-attenders of screening age. The estimated risk reduction associated with a cytology test in the preceding 3.5 years was 80% in screening age 25-69 years (OR 0.20; 95% CI 0.16-0.24) with the largest reduction in squamous cell carcinomas (84%) but also a substantial estimated risk reduction of 65% for adenocarcinomas. The associated risk reduction was strongest in women aged 45-69 years, with ORs in the range 0.09-0.18, compared with ORs 0.42-1.35 in women aged 25-39 years. CONCLUSIONS: To reduce the mortality of cervical cancer, screening programs should focus on increasing adherence to the program, as half of all the fatal cases were in the non-attender group. Further assessments regarding the potential preventive impact of extending screening to women over the current screening age should be considered.

Ten-Year Cardiovascular Disease Risk Trajectories by Obstetric History: A Longitudinal Study in the Norwegian HUNT Study.

Background Women with a history of obstetric complications are at increased risk of cardiovascular disease, but whether they should be specifically targeted for cardiovascular disease (CVD) risk screening is unknown. Methods and Results We used linked data from the Norwegian HUNT (Trøndelag Health) Study and the Medical Birth Registry of Norway to create a population-based, prospective cohort of parous women. Using an established CVD risk prediction model (A Norwegian risk model for cardiovascular disease), we predicted 10-year risk of CVD (nonfatal myocardial infarction, fatal coronary heart disease, and nonfatal or fatal stroke) based on established risk factors (age, systolic blood pressure, total and high-density lipoprotein cholesterol, smoking, antihypertensive use, and family history of myocardial infarction). Predicted 10-year CVD risk scores in women aged between 40 and 60 years were consistently higher in those with a history of obstetric complications. For example, when aged 40 years, women with a history of preeclampsia had a 0.06 percentage point higher mean risk score than women with all normotensive deliveries, and when aged 60 years this difference was 0.86. However, the differences in the proportion of women crossing established clinical thresholds for counseling and treatment in women with and without a complication were modest. Conclusions Findings do not support targeting parous women with a history of pregnancy complications for CVD screening. However, pregnancy complications identify women who would benefit from primordial and primary prevention efforts such as encouraging and supporting behavioral changes to reduce CVD risk in later life.

A Clinical Description of Chronic Pain in a General Population Using ICD-10 and ICD-11 (The HUNT Pain Examination Study).

The purpose was to present a total description, distribution, and ranking of chronic pain conditions in the general population. This was based on structured clinical examinations of a random sample from a population-based survey (HUNT3) with a calculated oversampling of participants with chronic pain. Supplemented with access to hospital reports, the examination was performed by experienced physicians and psychologists using a consistent definition of chronic pain as well as ICD-10- and the new ICD-11-classification. The main findings were that a higher proportion of the 551 participants had chronic pain assessed by clinical examination (399) than by self-report in a survey the same day (337). Among those with examination-verified chronic pain estimated from HUNT3 to represent 27.9% of the general population, 63% had chronic primary pain, 81% musculoskeletal pain, and 77% more than one chronic pain condition. When separating chronic primary from chronic secondary pain according to ICD-11, the weighted prevalence was 17.7% for chronic pain conditions of unknown and 10.2% of known cause. When all the participants' conditions were accounted for, the most prevalent was nonspecific low back (10.8%) and neck pain (7.6%). Participants with chronic primary pain did not have significantly more psychopathology than those with chronic secondary pain: 14.5% versus 12.5%. PERSPECTIVE: Since this study confirms the high prevalence in self-report surveys and indicates that two thirds of chronic pain conditions cannot be explained by underlying diseases, this huge health and societal problem should be solved primarily on a public health level directed toward prevention and rehabilitation.

Laryngeal and Pharyngeal Squamous Cell Carcinoma After Antireflux Surgery in the 5 Nordic Countries.

OBJECTIVE: The aim of this study was to clarify whether antireflux surgery prevents laryngeal and pharyngeal squamous cell carcinoma. SUMMARY BACKGROUND DATA: Gastroesophageal reflux disease (GERD) seems to increase the risk of laryngeal and pharyngeal squamous cell carcinoma. METHODS: All-Nordic (Denmark, Finland, Iceland, Norway, and Sweden) population-based cohort study of adults with documented GERD in 1980 to 2014. First, cancer risk after antireflux surgery was compared to the expected risk in the corresponding background population by calculating standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). Second, cancer risk among antireflux surgery patients was compared to nonoperated GERD patients using multivariable Cox regression, providing hazard ratios (HR) with 95% CIs, adjusted for sex, age, calendar period, and diagnoses related to tobacco smoking, obesity, and alcohol overconsumption. RESULTS: Among 814,230 GERD patients, 47,016 (5.8%) underwent antireflux surgery. The overall SIRs and HRs of the combined outcome laryngeal or pharyngeal squamous cell carcinoma (n=39) were decreased after antireflux surgery [SIR=0.62 (95% CI 0.44-0.85) and HR=0.55 (95% CI 0.38-0.80)]. The point estimates were further decreased >10 years after antireflux surgery [SIR=0.48 (95% CI 0.26-0.80) and HR=0.47 (95% CI 0.26-0.85)]. The risk estimates of laryngeal squamous cell carcinoma were particularly decreased >10 years after antireflux surgery [SIR=0.28 (95% CI 0.08-0.72) and HR=0.23 (95% CI 0.08-0.69)], whereas no such decrease over time after surgery was found for pharyngeal squamous cell carcinoma. Analyses of patients with severe GERD (reflux esophagitis or Barrett esophagus) showed similar results. CONCLUSION: Antireflux surgery may decrease the risk of laryngeal squamous cell carcinoma and possibly also of pharyngeal squamous cell carcinoma.

Trace elements in whole blood in the general population in Trøndelag County, Norway: The HUNT3 Survey.

BACKGROUND: Biomonitoring of a cohort within a large health survey can provide reliable information on trace element status. The main aims of this study were 1) to determine the concentrations of 28 trace elements in whole blood samples from the general population of the Nord-Trøndelag region, Norway, and 2) to investigate how trace element concentrations vary with geographical area, lifestyle, and socio-demographic factors. METHODS: Whole blood samples were collected in the third survey of the Trøndelag Health Survey (HUNT3), a large population-based study in Norway. In total, 1011 whole blood samples from individuals aged 20-91 years were analyzed using high resolution inductively coupled plasma-mass spectrometry (HR-ICP-MS). We compared trace element concentrations (As, B, Be, Br, Ca, Cd, Cr, Cs, Cu, Ga, Au, In, Fe, Pb, Hg, Tl, Mg, Mn, Mo, Ni, Rb, Sc, Se, Ag, Sr, Sn, W and Zn) between three geographical areas (coastal, fjord/town, inland/mountain) using multivariable linear regression and assessed differences in trace element concentrations with socio-demographic and lifestyle factors using general linear models. RESULTS: Trace element concentrations were generally comparable to levels reported in other recent studies and suggest low exposure to toxic trace elements in the region. We found geographical differences in concentrations of 19 trace elements. As, Br, Hg, and Se concentrations were higher on the coast compared to the fjord/town and inland/mountain areas, suggesting that the marine environment is an important source of exposure for these trace elements. In addition, socio-demographic and lifestyle characteristics, particularly age and sex, were associated with differences in trace element concentrations. CONCLUSIONS: We report concentrations of 28 trace elements in the general population of a rural region with low exposure to pollution. Whole blood concentrations of trace elements varied with geographical area, the participants' lifestyle, and socio-demographic characteristics, highlighting the importance of considering these factors when evaluating trace element status in a population.

Obesity Does Not Protect From Subarachnoid Hemorrhage: Pooled Analyses of 3 Large Prospective Nordic Cohorts.

BACKGROUND: Several population-based cohort studies have related higher body mass index (BMI) to a decreased risk of subarachnoid hemorrhage (SAH). The main objective of our study was to investigate whether the previously reported inverse association can be explained by modifying effects of the most important risk factors of SAH-smoking and hypertension. METHODS: We conducted a collaborative study of three prospective population-based Nordic cohorts by combining comprehensive baseline data from 211 972 adult participants collected between 1972 and 2012, with follow-up until the end of 2018. Primarily, we compared the risk of SAH between three BMI categories: (1) low (BMI<22.5), (2) moderate (BMI: 22.5-29.9), and (3) high (BMI≥30) BMI and evaluated the modifying effects of smoking and hypertension on the associations. RESULTS: We identified 831 SAH events (mean age 62 years, 55% women) during the total follow-up of 4.7 million person-years. Compared with the moderate BMI category, persons with low BMI had an elevated risk for SAH (adjusted hazard ratio [HR], 1.30 [1.09-1.55]), whereas no significant risk difference was found in high BMI category (HR, 0.91 [0.73-1.13]). However, we only found the increased risk of low BMI in smokers (HR, 1.49 [1.19-1.88]) and in hypertensive men (HR, 1.72 [1.18-2.50]), but not in nonsmokers (HR, 1.02 [0.76-1.37]) or in men with normal blood pressure values (HR, 0.98 [0.63-1.54]; interaction HRs, 1.68 [1.18-2.41], P=0.004 between low BMI and smoking and 1.76 [0.98-3.13], P=0.06 between low BMI and hypertension in men). CONCLUSIONS: Smoking and hypertension appear to explain, at least partly, the previously reported inverse association between BMI and the risk of SAH. Therefore, the independent role of BMI in the risk of SAH is likely modest.

Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer.

A germline 29.5-kb deletion variant removes the 3' end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in hospital-based samples of 1398 Norwegian epithelial ovarian cancer patients without detected BRCA1/2 germline mutations and compared to 1,918 healthy female controls, to assess the potential cancer risk associated with the deletion. We observed an association between APOBEC3A/B status and reduced risk for ovarian cancer (OR = 0.75; CI = 0.61-0.91; p = 0.003) applying the dominant model. Similar results were found in other models. The association was observed both in non-serous and serous cases (dominant model: OR = 0.69; CI = 0.50-0.95; p = 0.018 and OR = 0.77; CI = 0.62-0.96; p = 0.019, respectively) as well as within high-grade serous cases (dominant model: OR = 0.79; CI = 0.59-1.05). For validation purposes, we mined an available large multinational GWAS-based data set of > 18,000 cases and > 26,000 controls for SNP rs12628403, known to be in linkage disequilibrium with the APOBEC3A/B deletion. We found a non-significant trend for SNP rs12628403 being linked to reduced risk of ovarian cancer in general and similar trends for all subtypes. For clear cell cancers, the risk reduction reached significance (OR = 0.85; CI = 0.69-1.00).

Assessing short-term risk of ischemic stroke in relation to all prescribed medications.

We examined the short-term risk of stroke associated with drugs prescribed in Norway or Sweden in a comprehensive, hypothesis-free manner using comprehensive nation-wide data. We identified 27,680 and 92,561 cases with a first ischemic stroke via the patient- and the cause-of-death registers in Norway (2004-2014) and Sweden (2005-2014), respectively, and linked these data to prescription databases. A case-crossover design was used that compares the drugs dispensed within 1 to 14 days before the date of ischemic stroke occurrence with those dispensed 29 to 42 days before the index event. A Bolasso approach, a version of the Lasso regression algorithm, was used to select drugs that acutely either increase or decrease the apparent risk of ischemic stroke. Application of the Bolasso regression algorithm selected 19 drugs which were associated with increased risk for ischemic stroke and 11 drugs with decreased risk in both countries. Morphine in combination with antispasmodics was associated with a particularly high risk of stroke (odds ratio 7.09, 95% confidence intervals 4.81-10.47). Several potentially intriguing associations, both within and across pharmacological classes, merit further investigation in focused, follow-up studies.

The role of cardiovascular risk factors in maternal cardiovascular disease according to offspring birth characteristics in the HUNT study.

A history of preterm or small (SGA) or large (LGA) for gestational age offspring is associated with smoking and unfavorable levels of BMI, blood pressure, glucose and lipids. Whether and to what extent the excess cardiovascular risk observed in women with these pregnancy complications is explained by conventional cardiovascular risk factors (CVRFs) is not known. We examined the association between a history of SGA, LGA or preterm birth and cardiovascular disease among 23,284 parous women and quantified the contribution of individual CVRFs to the excess cardiovascular risk using an inverse odds weighting approach. The hazard ratios (HR) between SGA and LGA offspring and CVD were 1.30 (95% confidence interval (CI) 1.15, 1.48) and 0.89 (95% CI 0.76, 1.03), respectively. Smoking explained 49% and blood pressure may have explained ≈12% of the excess cardiovascular risk in women with SGA offspring. Women with preterm birth had a 24% increased risk of CVD (HR 1.24, 95% CI 1.06, 1.45), but we found no evidence for CVRFs explaining any of this excess cardiovascular risk. While smoking explains a substantial proportion of excess cardiovascular risk in women with SGA offspring and blood pressure may explain a small proportion in these women, we found no evidence that conventional CVRFs explain any of the excess cardiovascular risk in women with preterm birth.

Polymorphisms in the TP53-MDM2-MDM4-axis in patients with rheumatoid arthritis.

BACKGROUND: In addition to being a tumour suppressor, TP53 is a suppressor of inflammation, and dysfunction of this gene has been related to autoimmune diseases. Patients with autoimmunity, such as rheumatoid arthritis (RA) have an increased risk of certain cancers, like lymphomas, indicating that some underlying mechanisms may modulate risk of both cancers and autoimmunity. METHODS: We genotyped 5 common genetic variants in TP53 and its main regulators MDM2 and MDM4 in a sample of 942 RA patients and 3,747 healthy controls, and mined previously published GWAS-data, to assess the potential impact of these variants on risk of RA. RESULTS: For the TP53 Arg72Pro polymorphism (rs1042522), MDM4 SNP34091 (rs4245739) and MDM2 SNP285C (rs117039649), we found no association to risk of RA. For MDM2 SNP309 (rs2279744), the minor G-allele was associated with a reduced risk of RA (OR: 0.87; CI: 0.79-0.97). This association was also seen in genotype models (OR: 0.86; CI: 0.74-0.99 and OR: 0.79; CI 0.63-0.99; dominant and recessive model, respectively), but was not validated in a large GWAS data set. For MDM2 del1518 (rs3730485), the minor del-allele was associated with an increased risk of RA in the dominant model (OR: 1.18; CI: 1.02-1.38). Stratifying RA cases and controls into phylogenetic subgroups according to the combined genotypes of all three MDM2 polymorphism, we found individuals with the del158-285-309 genotype del/ins-G/G-T/T to have an increased risk of RA as compared to those with the ins/ins-G/G-G/G genotype (OR: 1.56; CI: 1.18-2.06) indicating opposite effects of the del1518 del-allele and the SNP309 G-allele. CONCLUSION: We find a potential association between the MDM2 del1518 variant and RA, and indications that combinatorial genotypes and haplotypes in the MDM2 locus may be related to RA.

Impact of MDM2 promoter SNP55 (rs2870820) on risk of endometrial and ovarian cancer.

BACKGROUND: While large GWAS analyses have not found convincing associations between MDM2 promoter SNP55 and gynaecological cancers, SNP55 is in linkage disequilibrium with two other functional SNPs in the same promoter, likely to obscure associations between single SNPs and cancer risk. Here, we assessed the impact of SNP55 on risk of endometrial and ovarian cancer, including sub-analyses stratified for other functional SNPs in the region. MATERIAL AND METHODS: Using a custom LightSNiP assay, we genotyped SNP55 in two large hospital-based cohorts of patients with ovarian (n = 1,332) and endometrial (n = 1,363) cancer and compared genotypes to healthy female controls (n = 1,858). RESULTS: Among individuals harbouring the SNP309TT genotype, the minor SNP55T-allele was associated with a reduced risk of endometrial (dominant model: OR = 0.63; CI = 0.45-0.88; p = 0.01). Regardless of the genotype in neighbouring SNPs, the SNP55T-allele was also associated with a reduced risk of endometrial cancer before 50 years of age (dominant model: OR = 0.56; CI = 0.34-0.90; p = 0.02). No association between SNP55 status and ovarian cancer risk was observed. CONCLUSIONS: MDM2 SNP55T-allele may correlate with reduced risk for endometrial cancer in a SNP309T-, but not SNP309G, context.

Fatigue in young adults with juvenile idiopathic arthritis 18 years after disease onset: data from the prospective Nordic JIA cohort.

BACKGROUND: To study fatigue in young adults with juvenile idiopathic arthritis (JIA) 18 years after disease onset, and to compare with controls. METHODS: Consecutive children with onset of JIA between 1997 and 2000, from geographically defined areas of Norway, Sweden, Denmark and Finland were followed for 18 years in a close to population-based prospective cohort study. Clinical features, demographic and patient-reported data were collected. Inclusion criteria in the present study were a baseline visit 6 months after disease onset, followed by an 18-year follow-up with available self-reported fatigue score (Fatigue Severity Scale (FSS), 1-7). Severe fatigue was defined as FSS ≥4. For comparison, Norwegian age and sex matched controls were used. RESULTS: Among 377 young adults with JIA, 26% reported severe fatigue, compared to 12% among controls. We found higher burden of fatigue among participants with sleep problems, pain, poor health, reduced participation in school/work, physical disability, active disease, or use of disease-modifying anti-rheumatic drugs (DMARDs)/biologics/systemic steroids. In contrast, participants without these challenges, had fatigue scores similar to controls. Active disease assessed at all three time points (baseline, 8-year and 18-year follow-up) was associated with higher mean fatigue score and higher percentage of severe fatigue compared to disease courses characterized by periods of inactive disease. Predictors of fatigue at the 18-year follow-up were female sex and diagnostic delay of ≥6 months at baseline, and also pain, self-reported poor health, active disease, and previous/ongoing use of DMARDs/biologics at 8 years. CONCLUSIONS: Fatigue is a prominent symptom in young adults with JIA, with higher fatigue burden among participants with poor sleep, pain, self-reported health problems, active disease, or use of DMARDs/biologics. Participants without these challenges have results similar to controls. Patient- and physician-reported variables at baseline and during disease course predicted fatigue at 18-year follow-up.

Normotensive preterm delivery and maternal cardiovascular risk factor trajectories across the life course: The HUNT Study, Norway.

INTRODUCTION: Preterm delivery (<37 weeks) predicts later cardiovascular disease risk in mothers, even among normotensive deliveries. However, development of subclinical cardiovascular risk before and after preterm delivery is not well understood. We sought to investigate differences in life course cardiovascular risk factor trajectories based on preterm delivery history. MATERIAL AND METHODS: The HUNT Study (1984-2008) linked with the Medical Birth Registry of Norway (1967-2012) yielded clinical measurements and pregnancy outcomes for 19 806 parous women with normotensive first deliveries. Women had up to three measurements of body mass index, waist-to-hip ratio, blood pressure, lipids, non-fasting glucose, and C-reactive protein during follow up between 21 years before to 41 years after first delivery. Using mixed effects models, we compared risk factor trajectories for women with preterm vs term/postterm first deliveries. RESULTS: Trajectories overlapped for women with preterm compared with term/postterm first deliveries for all cardiovascular risk factors examined. For instance, the mean difference in systolic blood pressure in women with preterm first deliveries compared with those with term deliveries was 0.2 mm Hg (95% CI -1.8 to 2.3) at age 20 and 1.5 mm Hg (95% CI -0.5 to 3.6) at age 60. CONCLUSIONS: A history of preterm delivery was not associated with different life course trajectories of common cardiovascular risk factors in our study population. This suggests that the robust association between preterm delivery and cardiovascular end points in Norway or similar contexts is not explained by one or more commonly measured cardiovascular risk factors. Overall, we did not find evidence for a single cardiovascular disease prevention strategy that would reduce risk among the majority of women who had preterm delivery.