Elevated blood pressure, antihypertensive medications and bone health in the population: revisiting old hypotheses and exploring future research directions.

Blood pressure and bone metabolism appear to share commonalities in their physiologic regulation. Specific antihypertensive drug classes may also influence bone mineral density. However, current evidence from existing observational studies and randomised trials is insufficient to establish causal associations for blood pressure and use of blood pressure-lowering drugs with bone health outcomes, particularly with the risks of osteoporosis and fractures. The availability and access to relevant large-scale biomedical data sources as well as developments in study designs and analytical approaches provide opportunities to examine the nature of the association between blood pressure and bone health more reliably and in greater detail than has ever been possible. It is unlikely that a single source of data or study design can provide a definitive answer. However, with appropriate considerations of the strengths and limitations of the different data sources and analytical techniques, we should be able to advance our understanding of the role of raised blood pressure and its drug treatment on the risks of low bone mineral density and fractures. As elevated blood pressure is highly prevalent and blood pressure-lowering drugs are widely prescribed, even small effects of these exposures on bone health outcomes could be important at a population level.

The causal role of smoking on the risk of headache. A Mendelian randomization analysis in the HUNT study.

BACKGROUND AND PURPOSE: Headache has been associated with various lifestyle and psychosocial factors, one of which is smoking. The aim of the present study was to investigate whether the association between smoking intensity and headache is likely to be causal. METHOD: A total of 58 316 participants from the Nord-Trøndelag Health (HUNT) study with information on headache status were genotyped for the rs1051730 C>T single-nucleotide polymorphism (SNP). The SNP was used as an instrument for smoking intensity in a Mendelian randomization analysis. The association between rs1051730 T alleles and headache was estimated by odds ratios with 95% confidence intervals. Additionally, the association between the SNP and migraine or non-migrainous headache versus no headache was investigated. All analyses were adjusted for age and sex. RESULTS: There was no strong evidence that the rs1051730 T allele was associated with headache in ever smokers (odds ratio 0.99, 95% confidence interval 0.95-1.02). Similarly, there was no association between the rs1051730 T allele and migraine or non-migrainous headache versus no headache. CONCLUSION: The findings from this study do not support that there is a strong causal relationship between smoking intensity and any type of headache. Larger Mendelian randomization studies are required to examine whether higher smoking quantity can lead to a moderate increase in the risk of headache subtypes.

Fear of hypoglycaemia and its relation to hypoglycaemia awareness and symptom intensity in Type 1 diabetes.

AIMS: To investigate fear of hypoglycaemia (FoH) in relation to hypoglycaemia awareness, history of severe hypoglycaemia (SH) and hypoglycaemia symptoms in adults with Type 1 diabetes. METHODS: Questionnaire-based cross-sectional survey. We assessed FoH with the Hypoglycaemia Fear Survey-II Worry subscale, hypoglycaemia awareness status with the Gold score, and used the Edinburgh Hypoglycaemia Scale to grade the presence and intensity of hypoglycaemia symptoms. All these measures have previously been validated for research application. We used multivariable linear regression to examine associations between FoH and hypoglycaemia awareness status, history of SH and hypoglycaemia symptom score. RESULTS: Of 636 invitees, 445 (70%) responded, with 435 responses eligible for analyses. Seventy-four persons had IAH (17%). Among those, 47 (64%) reported ≥ 1 SH during the preceding year, in contrast to this being reported by 113 (31%) of persons with normal awareness. The mean (SD) FoH worry score was 1.33 (0.78). This score was 0.64 (95% CI, 0.45-0.83) higher among people with impaired vs. normal hypoglycaemia awareness and 0.53 (95% CI, 0.33-0.73) higher among people with ≥ 3 episodes of SH the preceding year vs. people with no such episode. A higher number and intensity of hypoglycaemia symptoms was associated with higher FoH, as demonstrated by an increase in mean FoH worry score of 0.30 (95% CI, 0.23-0.36) per point increase in mean Edinburgh hypoglycaemia score. CONCLUSIONS: Impaired awareness of hypoglycaemia, history of SH and higher Edinburgh hypoglycaemia scores were all associated with increased FoH in adults with Type 1 diabetes.

The association between the clinical diversity of psoriasis and depressive symptoms: the HUNT Study, Norway.

BACKGROUND: While a number of observational hospital-based studies have reported an association between psoriasis and depression, less is known about the clinical diversity of psoriasis and depressive symptoms. OBJECTIVE: To investigate the associations of inverse psoriasis, psoriasis severity and psoriasis duration with depressive symptoms in a general population. METHODS: We linked data from the population-based third Nord-Trøndelag Health Study (HUNT3) to the Norwegian Prescription Database (NorPD) and Statistics Norway. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). Associations between psoriasis and depressive symptoms (HADS ≥ 8) were estimated using logistic regression. RESULTS: Among 37 833 participants in HUNT3, we found a weak association between any psoriasis and the prevalence of depressive symptoms [fully adjusted odds ratio (OR) 1.12, 95% confidence interval (CI) 0.97-1.28]. The association with depressive symptoms was stronger when psoriasis was characterized by inverse anatomical distribution (OR 1.32, 95% CI 1.02-1.70), requirement of systemic psoriasis medication (OR 1.47, 95% CI 1.00-2.17) or long disease duration (OR 1.33, 95% CI 1.09-1.64). Conversely, when there was no inverse psoriasis distribution, no requirement of systemic medication, or shorter disease duration, psoriasis was not meaningfully associated with depressive symptoms. CONCLUSION: Overall, depressive symptoms do not seem to be a major concern among subjects with psoriasis in a general Norwegian population. However, among subjects with inverse anatomical distribution, requirement of systemic psoriasis medication or long disease duration, depressive symptoms may be particularly important to address when evaluating the burden of psoriasis.

The causal role of smoking on the risk of hip or knee replacement due to primary osteoarthritis: a Mendelian randomisation analysis of the HUNT study.

OBJECTIVE: Smoking has been associated with a reduced risk of hip and knee osteoarthritis (OA) and subsequent joint replacement. The aim of the present study was to assess whether the observed association is likely to be causal. METHOD: 55,745 participants of a population-based cohort were genotyped for the rs1051730 C > T single-nucleotide polymorphism (SNP), a proxy for smoking quantity among smokers. A Mendelian randomization analysis was performed using rs1051730 as an instrument to evaluate the causal role of smoking on the risk of hip or knee replacement (combined as total joint replacement (TJR)). Association between rs1051730 T alleles and TJR was estimated by hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were adjusted for age and sex. RESULTS: Smoking quantity (no. of cigarettes) was inversely associated with TJR (HR 0.97, 95% CI 0.97-0.98). In the Mendelian randomization analysis, rs1051730 T alleles were associated with reduced risk of TJR among current smokers (HR 0.84, 95% CI 0.76-0.98, per T allele), however we found no evidence of association among former (HR 0.97, 95% CI 0.88-1.07) and never smokers (HR 0.97, 95% CI 0.89-1.06). Neither adjusting for body mass index (BMI), cardiovascular disease (CVD) nor accounting for the competing risk of mortality substantially changed the results. CONCLUSION: This study suggests that smoking may be causally associated with the reduced risk of TJR. Our findings add support to the inverse association found in previous observational studies. More research is needed to further elucidate the underlying mechanisms of this causal association.

Psoriasis, fracture risk and bone mineral density: the HUNT Study, Norway.

BACKGROUND: An association between psoriasis and osteoporosis has been reported. OBJECTIVES: To investigate, in a large prospective population-based Norwegian study, whether psoriasis is associated with increased risk of forearm or hip fracture; to investigate the cross-sectional association between psoriasis and bone mineral density (BMD) T-score in a subpopulation. METHODS: Hospital-derived fracture data from Nord-Trøndelag County (1995-2013) were linked to psoriasis information, BMD measurements and lifestyle factors from the third survey of the Nord-Trøndelag Health Study 2006-08 (HUNT3); socioeconomic data from the National Education Database; and use of medication from the Norwegian Prescription Database. RESULTS: Among 48 194 participants in HUNT3, we found no increased risk of forearm or hip fracture in 2804 patients with self-reported psoriasis [overall age- and sex-adjusted hazard ratio 1·03, 95% confidence interval (CI) 0·82-1·31]. No clear association was found between psoriasis and mean BMD T-score; overall age- and sex-adjusted differences in total hip, femoral neck and lumbar spine BMD T-scores were 0·02 (95% CI -0·11 to 0·14), 0·05 (95% CI -0·06 to 0·17) and 0·07 (95% CI -0·09 to 0·24), respectively. No clear association was found between psoriasis and prevalent osteoporosis in either total hip, femoral neck or lumbar spine; overall age- and sex-adjusted odds ratio was 0·77 (95% CI 0·54-1·10). Associations did not change substantially after adjustment for education, smoking, systemic steroid use and body mass index. CONCLUSIONS: We found no association between psoriasis and risk of fracture. The study did not indicate reduced BMD T-score or higher prevalence of osteoporosis among patients with psoriasis.

Prior statin use and 90-day mortality in Gram-negative and Gram-positive bloodstream infection: a prospective observational study.

In several studies on patients with bloodstream infection (BSI), prior use of statins has been associated with improved survival. Gram-positive and Gram-negative bacteria alert the innate immune system in different ways. We, therefore, studied whether the relation between prior statin use and 90-day total mortality differed between Gram-positive and Gram-negative BSI. We conducted a prospective observational cohort study of 1,408 adults with BSI admitted to Levanger Hospital between January 1, 2002, and December 31, 2011. Data on the use of statins and other medications at admission, comorbidities, functional status, treatment, and outcome were obtained from the patients' hospital records. The relation of statin use with 90-day mortality differed between Gram-negative and Gram-positive BSI (p-value for interaction 0.01). Among patients with Gram-negative BSI, statin users had significantly lower 90-day total mortality [odds ratio (OR) 0.42, 95 % confidence interval (CI) 0.23-0.75, p = 0.003]. The association remained essentially unchanged after adjusting for the effect of sex, age, functional status before the infection, and underlying diseases that were considered confounders (adjusted OR 0.38, 95 % CI 0.20-0.72, p = 0.003). A similar analysis of patients with Gram-positive BSI showed no association of statin use with mortality (adjusted OR 1.22, 95 % CI 0.69-2.17, p = 0.49). The present study suggests that prior statin use is associated with a lower 90-day total mortality in Gram-negative BSI, but not in Gram-positive BSI.

Hypoglycaemia symptoms and impaired awareness of hypoglycaemia in adults with Type 1 diabetes: the association with diabetes duration.

AIMS: To examine the association between diabetes duration and hypoglycaemia symptom profiles and the presence of impaired awareness of hypoglycaemia. METHODS: A cross-sectional study was performed, using validated methods for recording hypoglycaemia symptoms and assessing hypoglycaemia awareness. The associations between symptom intensity, hypoglycaemia awareness and diabetes duration were examined, and the prevalence of impaired awareness was ascertained for Type 1 diabetes of differing durations. RESULTS: Questionnaires were mailed to 636 adults with Type 1 diabetes, of whom 445 (70%) returned them. A total of 440 completed questionnaires were suitable for analysis. Longer diabetes duration was associated with lower intensity of autonomic symptoms (P for trend <0.001), but no association was observed with neuroglycopenic symptoms. The overall prevalence of impaired awareness of hypoglycaemia in this cohort was 17% (95% CI 14-21%) and increased with diabetes duration, from 3% for duration 2-9 years to 28% for duration ≥30 years (P for trend <0.001). Low autonomic symptom scores were not associated with a higher prevalence of impaired awareness. CONCLUSIONS: Longer diabetes duration was associated with lower intensity of autonomic symptoms and a higher prevalence of impaired awareness of hypoglycaemia, suggesting that subjective symptoms of hypoglycaemia change over time. These observations underline the need for regular patient education about hypoglycaemia symptomatology and clinical screening for impaired awareness of hypoglycaemia.

Concentrations of human chorionic gonadotrophin in very early pregnancy and subsequent pre-eclampsia: a cohort study.

STUDY QUESTION: Are low serum concentrations of human chorionic gonadotrophin (hCG) in very early pregnancy associated with pre-eclampsia risk? SUMMARY ANSWER: Low hCG concentrations in very early pregnancy are associated with increased risk of severe pre-eclampsia. WHAT IS KNOWN ALREADY: Low maternal serum concentrations of hCG early in pregnancy may indicate impaired proliferation or invasion of trophoblast cells, and thus low hCG concentrations may serve as a marker for impaired placental development. Impaired placental development is assumed to be a cause of pre-eclampsia, but there is little prospective evidence to support this hypothesis. STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study of pregnancies after IVF at Oslo University Hospital 1996-2010 with linkage to the Medical Birth Registry of Norway to obtain information on pre-eclampsia development. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 2405 consecutive singleton pregnancies and examined the association of maternal serum hCG concentrations (measured using Elecsys, Roche) on Day 12 after embryo transfer with the risk of any pre-eclampsia and of mild and severe pre-eclampsia. MAIN RESULTS AND THE ROLE OF CHANCE: HCG concentrations were inversely associated with pre-eclampsia risk in a dose-dependent manner (Ptrend 0.02). Compared with women with hCG ≥150 IU/l, women with hCG <50 IU/l were at 2-fold higher overall risk of pre-eclampsia [absolute risk 6.4 versus 2.8%; odds ratio (OR) 2.3, 95% confidence interval (CI) 1.2-4.7]. The inverse association was restricted to severe pre-eclampsia (Ptrend 0.01), thus, women with hCG <50 IU/l were at 4-fold higher risk of severe pre-eclampsia than women with hCG ≥150 IU/l (absolute risk 3.6 versus 0.9%; OR 4.2, 95% CI 1.4-12.2). For mild pre-eclampsia, there was no corresponding association (Ptrend 0.36). LIMITATIONS, REASONS FOR CAUTION: Results for IVF pregnancies may not be generalizable to spontaneously conceived pregnancies. WIDER IMPLICATIONS OF THE FINDINGS: Plausible causes of low maternal hCG concentrations very early in pregnancy include impaired placental development and delayed implantation. Thus, these results provide prospective evidence to support the hypothesis that impaired placental development may be associated with subsequent development of severe pre-eclampsia. STUDY FUNDING/COMPETING INTEREST: The study was financially supported by the Research Council of Norway. None of the authors has any conflict of interest to declare.

Increased levels of free thyroxine and risk of venous thrombosis in a large population-based prospective study.

BACKGROUND: Recent studies have shown that high levels of free thyroxine (FT4), even without leading to hyperthyroidism, are associated with a procoagulant state. OBJECTIVES: The aim of our study was to determine whether high levels of thyroid hormones are associated with an increased risk of venous thrombosis. PATIENTS/METHODS: From a prospective nested case-cohort design within the second Nord-Trøndelag Health Study (HUNT2) cohort (1995-1997; 66,140 subjects), all patients with venous thrombosis during follow-up (n=515) and 1476 randomly selected age-stratified and sex-stratified controls were included. Relative and absolute risks for venous thrombosis were calculated for different cut-off levels of thyroid hormones on the basis of percentiles in the controls and different times between blood sampling and thombosis. RESULTS: In subjects with an FT4 level above the 98th percentile (17.3 pmol L(-1)), the odds ratio (OR) was 2.5 (95% confidence interval [CI] 1.3-5.0) as compared with subjects with levels below this percentile. For venous thrombosis within 1 year from blood sampling, this relative risk was more pronounced, with an OR of 4.8 (95% CI 1.7-14.0). Within 0.5 years, the association was even stronger, with an OR of 9.9 (95% CI 2.9-34.0, adjusted for age, sex, and body mass index). For thyroid-stimulating hormone, the relationship was inverse and less pronounced. The absolute risk within 6 months in the population for FT4 levels above the 98th percentile was 6.1 per 1000 person-years (95% CI 1.7-15.7). CONCLUSIONS: Levels of FT4 at the upper end of the normal range are a strong risk factor for venous thrombosis. The risk increased with higher levels of thyroxine and shorter time between blood sampling and thrombosis. Further studies on the effect of clinical hyperthyroidism are warranted.

Quantitative EEG in type 1 diabetic adults with childhood exposure to severe hypoglycaemia: a 16 year follow-up study.

AIMS/HYPOTHESIS: In diabetic children and adolescents, a history of severe hypoglycaemia (SH) has been associated with increased slow EEG activity and reduced cognition, possibly due to harmful effects of SH on the developing brain. In a group of type 1 diabetic patients with early exposure to SH, who had EEG abnormalities and reduced cognition in childhood, we have recently demonstrated that the reduced cognition may persist into adulthood. We have now assessed whether the reduced cognition was accompanied by lasting EEG abnormalities. METHODS: In 1992-1993, we studied EEG and cognition in 28 diabetic children and 28 matched controls. 16 years later, we re-investigated the same participants, with 96% participation rate. Diabetic participants were classified as with (n = 9) or without (n = 18) early SH, defined as episodes with convulsions or loss of consciousness by 10 years of age. For each EEG band (delta, theta, alpha and beta) and cerebral region (frontocentral, temporal, and parietooccipital), we calculated relative amplitudes and amplitude asymmetry. We also calculated occipital alpha mean frequency, alpha peak frequency at maximum amplitude, alpha peak width, and theta regional mean frequencies. We examined whether these EEG measures, relative to age- and sex-matched controls, differed between diabetic participants with and without early SH. RESULTS: We found no association of early SH with any of the EEG measures. CONCLUSIONS/INTERPRETATION: Childhood SH was not associated with EEG abnormalities in young type 1 diabetic adults. Our findings suggest that the reduced adulthood cognition associated with childhood exposure to SH is not accompanied by lasting EEG abnormalities.

[Three primary stents in extensive esophageal cancer]. / Tre primaere stenter ved langstrakt cancer oesophagi.

BACKGROUND: Most patients with oesophageal cancer have unresectable disease at initial assessment. Dysphagia is the most common symptom. Laser ablation and self-expandable metal stents are among the possible treatments for dysphagia caused by oesophageal cancer. There are two types of self-expandable metal stents: covered and uncovered. Tumour can easily grow through uncovered stents. Such tumour ingrowth can be treated with laser ablation or Argon plasma coagulation. MATERIAL AND METHODS: We present a 54-year-old man with metastatic oesophageal cancer. RESULTS: Because of dysphagia, self-expandable stents were inserted into his oesophagus. At the time of stent insertion, the primary tumour was 23 cm in craniocaudal direction. We inserted three stents, each 10 cm long. The patient restored normal swallowing and had no pain, dyspepsia or unpleasant sensation from his stents. Uncovered stents were used. Tumour ingrowth was treated with Argon plasma coagulation. INTERPRETATION: In this patient, with a long tumour, the use of three primary stents reduced dysphagia.

[Increased cardiovascular risk in patients with type 2 diabetes treated with sulfonylurea?]. / Gir sulfonylurea økt kardiovaskulaer risiko hos type 2-diabetikere?

BACKGROUND: The use of sulphonylureas for type 2 diabetes has been debated since 1970, when the University Group Diabetes Program (UGDP) reported increased cardiovascular mortality with tolbutamide treatment. MATERIAL AND METHODS: We try to present a balanced review of the current knowledge of the possible cardiovascular side effects of sulphonylureas. RESULTS: Recent studies on the molecular actions of sulphonylureas show that sulphonylureas, in addition to closing K+ ATP channels in insulin producing cells, also do so in the myocard and in vascular smooth muscle. This action could theoretically have adverse effects during ischaemia. Experimental studies show effects on cardiac parameters and also differences in such effects between sulphonylureas, but leave the net effect of sulphonylureas during ischaemia uncertain. The United Kingdom Prospective Diabetes Study (UKPDS), published in September 1998, found no increase in cardiovascular mortality with the use of sulphonylureas. One possible explanation for the difference in relation to the UGDP is the exclusion of cardiovascular patients in the UKPDS. INTERPRETATION: Our interpretation is that sulphonylureas are without clinically important cardiovascular side effects in type 2 diabetic patients without cardiovascular disease. Clinical studies focusing on the effects of sulphonylurea in cardiovascular patients are, however, lacking. More studies are also needed on the effect of newly developed and possibly more selective sulphonylureas as well as related compounds.