Exposure to risperidone versus other antipsychotics and risk of osteoporosis-related fractures: a population-based study.

OBJECTIVE: Antipsychotics may increase serum prolactin, which has particularly been observed with risperidone. Further, hyperprolactinemia has been linked to osteoporosis-related fractures. Therefore, we investigated fracture risk in a nationwide cohort exposed to antipsychotics. METHODS: Swedish registers were used to identify adults with two consecutive dispensations of risperidone (n = 38 211), other atypical antipsychotics not including paliperidone (n = 60 691), or typical antipsychotics (n = 17 445) within three months between 2006 and 2013. An osteoporosis-related fracture was defined as a non-open hip/femur fracture in primary analyses. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Risperidone users were on average older (mean age of 68, 44, and 63 years for risperidone, other atypical antipsychotics, and typical antipsychotics respectively). Compared with other atypical antipsychotics, there was no association between risperidone and osteoporosis-related fractures in the overall (HR = 1.04, CI: 0.91-1.19) or age-stratified analyses. A significantly increased risk of typical antipsychotics (HR = 1.24, CI: 1.07-1.45) compared with other atypical antipsychotics remained for ages >45 years. CONCLUSION: Risperidone does not appear to be associated with an increased risk of osteoporosis-related fracture compared with other atypical antipsychotic agents as a group. For typical antipsychotics, a moderately elevated risk of hip fractures was noted compared with other atypical antipsychotics, possibly because of residual confounding.

Improving identification of idiopathic intracranial hypertension patients in Swedish patient register.

OBJECTIVE: Idiopathic intracranial hypertension (IIH) is often misdiagnosed. This can cause problems if conducting register-based studies. The study purpose was to produce algorithms that better identify patients with correct diagnosis of IIH in the Swedish National Patient Register (NPR). METHODS: Patients with ICD-10 code G93.2 for IIH registered in the NPR (2006-2013, Stockholm County) were included and diagnosis validated by medical record reviews. Patients were randomized into two groups: one used to produce the algorithm (n = 105) and one for validation (n = 102). We tested variables possible to extract from registries and used forward stepwise logistic regression which provided a predicted probability of correct diagnosis for each patient. RESULTS: We included 207 patients of which 135 had confirmed IIH. This gave a positive predictive value of 65.2% (CI: 58.4-71.4). The algorithm produced with variables extracted from registries, that is, age, number of times with diagnosis code G93.2 recorded (>2 times), and acetazolamide treatment, predicted the diagnosis correctly 88.2% (CI: 80.3-93.3) of the time. Excluding treatment data from the algorithm did not change the prediction notably, 86.3% (CI: 78.1-91.7). CONCLUSION: We produced two algorithms that with improved accuracy predict whether an IIH diagnosis in the NPR is correct. This can be a useful tool when performing register-based studies.

Population-based incidence and clinical characteristics of idiopathic intracranial hypertension.

OBJECTIVE: To validate the diagnosis of idiopathic intracranial hypertension (IIH) from the Swedish National Patient Register (NPR) and investigate the incidence of IIH, as well as co-morbidities and medication use in a large Swedish population-based sample. METHODS: We searched the NPR to find all patients ≥18 years old with the ICD-10 diagnosis code (G93.2) for IIH in Stockholm County from Jan 1, 2006, to Dec 31, 2013. All medical records were reviewed to validate the diagnosis and to collect additional information. RESULTS: We included 207 patients with an IIH diagnosis, of which 135 (65%) were correctly diagnosed when validated by charts review. Eighty-three patients had disease onset during the study period. This gave a yearly incidence of 0.65/100 000. Female-to-male ratio was 6.1:1. Females, mean age 31.0 (CI 28.8-33.1), were younger at time of diagnosis compared to males, mean age 42.9 (CI 36.4-49.5), P<.001. The most common co-morbidities were obesity (92%), hormonal conditions (21%) and recent infections preceding the diagnosis (21%). Prior treatment with tetracycline derivatives were seen in 9%. CONCLUSION: The incidence of IIH in Stockholm is in the lower range of previously reported rates, possibly due to a lower prevalence of obesity. A substantial proportion of patients (35%) did not fulfill diagnostic criteria. Disease onset occurs at younger age in females. Co-morbidities were mainly associated with diseases affecting hormonal balance or causing inflammatory activation. These findings raise new hypothetical theories regarding mechanisms involved in IIH pathogenesis.

Multiple sclerosis and risk of attempted and completed suicide - a cohort study.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated. The relation between education level and suicidality has not been investigated in MS patients. Our objective was to estimate attempted suicide and completed suicide risks amongst MS patients. METHODS: A total of 29 617 Swedish MS patients were identified through the Swedish Patient Register and matched with 296 164 people without MS from the general population. Cox regression analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education and calendar period. RESULTS: The adjusted HR for attempted suicide amongst MS patients is 2.18 (95% CI 1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (95% CI 1.53-2.30). In both groups women are at higher risk of attempting suicide, whilst men are at higher risk of completing suicide. Education level is inversely associated with completed suicide amongst the non-MS cohort (0.68, 0.51-0.91), but not amongst MS patients (1.10, 0.60-2.04). CONCLUSION: Multiple sclerosis patients are at higher risk of both attempted and completed suicide. No evidence was found of an inverse association between educational level and risk of completed suicide amongst MS patients.

Increased susceptibility to infections before the diagnosis of immune thrombocytopenia.

BACKGROUND: Infections after diagnosis of primary chronic immune thrombocytopenia (cITP) have mostly been connected to the immunomodulation treatment. Infections may trigger autoimmune diseases and may be a complication of an already impaired immune system. OBJECTIVES: To investigate the association of cITP with infection before diagnosis. We also estimated the incidence of cITP based on the new definition by the International ITP Working Group. METHODS: We identified 1087 adults with primary cITP between 2006 and 2012 using the Swedish Patient Register. Data on infections not already associated with secondary ITP were also retrieved from the register. The standardized incidence ratios (SIRs), using the rates from the general population, and 95% confidence intervals (CIs) were estimated as a measure of relative risk. We used data from the Prescribed Drug Register to estimate SIR for anti-infective treatment. RESULTS: The incidence of cITP was 2.30 per 100 000 person-years (95% CI, 2.15-2.45). cITP was associated with an increased risk of serious infections requiring inpatient or outpatient care within 5 years before cITP diagnosis (SIR = 8.74; 95% CI, 7.47-10.18). Higher magnitude SIRs were observed for candidiasis, viral infection at an unspecified site and acute upper respiratory infections. For anti-infective drugs the SIR was 1.37 (1.25-1.50) and the highest SIRs were observed for amoxicillin, macrolides, nitrofurantoin and antivirals. CONCLUSION: Patients with cITP have increased risks of infection and anti-infective treatments before their cITP diagnosis, with a more marked risk for candidiasis and viral infections. The findings indicate that infection is not only related to the immunomodulation treatment but also to the disease itself.

All-cause mortality following a cancer diagnosis amongst multiple sclerosis patients: a Swedish population-based cohort study.

BACKGROUND AND PURPOSE: A reduced cancer risk amongst patients with multiple sclerosis (MS) has been reported. Theoretically, this could represent a genuine reduction in risk or, alternatively, 'diagnostic neglect', where cancer is undiagnosed when symptoms are misattributed to MS. OBJECTIVE: Assess all-cause mortality risk following a cancer diagnosis in patients with MS compared with a cohort without MS. PATIENTS: A cohort of MS patients (n = 19,364) and a cohort of the general population (n = 192,519) were extracted from national Swedish registers from 1969 to 2005. All-cause mortality after cancer in MS was compared with the general population. Poisson regression analysis was conducted in the MS and non-MS cohorts separately. The models were adjusted for follow-up duration, year at entry, sex, region and socioeconomic index. The two cohorts were combined and differences in mortality risk were assessed using interaction testing. RESULTS: The adjusted relative risk (and 95% confidence interval) for all-cause mortality following a cancer diagnosis in MS patients (compared with MS patients without cancer) is 3.06 (2.86-3.27; n = 1768) and amongst those without MS 5.73 (5.62-5.85; n = 24,965). This lower magnitude mortality risk in the MS patients was confirmed by multiplicative interaction testing (P < 0.001). CONCLUSIONS: A consistent pattern of lower magnitude of all-cause mortality risk following cancer in MS patients for a range of organ-specific cancer types was found. It suggests that cancer diagnoses tend not to be delayed in MS and diagnostic neglect is unlikely to account for the reduced cancer risk associated with MS. The lower magnitude cancer risk in MS may be due to disease-associated characteristics or exposures.

Characteristics in childhood and adolescence associated with future multiple sclerosis risk in men: cohort study.

BACKGROUND AND PURPOSE: Associations with multiple sclerosis (MS) of living conditions in childhood and characteristics in adolescence including physical fitness, cognitive function and psychological stress resilience were investigated. METHODS: A cohort of male Swedish residents born 1952-1956 who were included in the Swedish Military Conscription Register was used to create a nested case-control study comprising 628 MS cases and 6187 controls matched on birth year, county of residence and vital status at time of diagnosis. Conscription examination records were linked with other national register data. Conditional logistic regression was used to evaluate associations with MS subsequent to the conscription examination. RESULTS AND CONCLUSIONS: Men with MS were less likely to be from more crowded households in childhood (>two persons per room) with an adjusted odds ratio of 0.67 (95% confidence interval 0.51-0.86, P = 0.023). They had lower physical working capacity in adolescence with adjusted odds ratio of 0.94 (95% confidence interval 0.89-0.99, P = 0.026). Cognitive function and stress resilience scores displayed no significant differences between cases and controls. Parental occupation in childhood and body mass index in adolescence were not associated with future MS risk. The inverse association of MS risk with higher levels of household crowding may reflect environmental factors such as the pattern of exposure to microorganisms. Lower physical fitness in men at MS risk may indicate a protective effect of exercise or could be due to prodromal disease activity, although there was no association with cognitive function. Poor psychological stress resilience (and thus risk of chronic stress arousal) was not associated with MS.

Multiple sclerosis clinical course and cardiovascular disease risk - Swedish cohort study.

BACKGROUND AND PURPOSE: Cardiovascular disease (CVD) risk amongst multiple sclerosis (MS) patients appears raised, but few studies have examined CVD risk amongst an unselected MS patient group. MS course may be relevant for CVD risk. Our aim was to assess CVD risk and variation by course in MS patients. METHODS: The Multiple Sclerosis Register identified 7667 patients who received an MS diagnosis between 1964 and 2005. They were matched by age, period, region and sex with 76 045 members of the general population without MS using Swedish registers. Poisson regression compared the two cohorts to estimate the relative risk for CVD, overall, as well as grouped and individual CVD diagnoses. RESULTS: MS patients had an increased adjusted relative risk (with 95% confidence intervals; number of MS cohort events) for CVD of 1.31 (1.22-1.41; n = 847), with some variation by course: relapsing-remitting 1.38 (1.17-1.62; n = 168); secondary progressive 1.30 (1.18-1.53; n = 405) and primary progressive 1.15 (0.93-1.41; n = 108). The association for the relapsing-remitting course was not significant after excluding the first year of follow-up. Overall incidence rates per 1000 person-years for CVD are 11.8 (11.06-12.66) for the MS cohort and 8.8 (8.60-9.05) for the non-MS cohort. The most pronounced association was for deep vein thrombosis: relapsing-remitting 2.16 (1.21-3.87; n = 14), secondary progressive 3.41 (2.45-4.75; n = 52) and primary progressive 3.57 (1.95-6.56; n = 15). MS was associated with ischaemic stroke but largely during the first year of follow-up. MS was associated with a decreased relative risk for angina pectoris and atrial fibrillation. CONCLUSIONS: There is a significantly increased relative risk for CVD in MS, particularly for venous thromboembolic disorders in progressive MS, suggesting immobility as a possible factor. An increased frequency of ischaemic stroke in MS is most probably due to surveillance bias resulting from diagnostic investigations for MS. There is no increased relative risk for ischaemic heart disease in MS and atrial fibrillation appears to be less common than amongst the general population.

Hospital admission due to infections in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients are at increased infection risk. Here the influences of susceptibility, severity and surveillance bias on infection-related hospital admission are assessed. METHODS: Swedish registers identified 20,276 patients with MS, matched with 203,951 people from the general population without MS. Risk of first hospital admission for infection and mortality over 36 years was estimated by Poisson regression. RESULTS: Multiple sclerosis was associated with an increased hospital admission risk for all infections, with an adjusted relative risk (and 95% confidence interval) of 4.26 (4.13-4.40). A proportion of this raised risk was probably due to surveillance and referral bias, although a raised risk remained when MS was compared with other immune-mediated diseases. The 1-month mortality rate following hospital admission for infection was higher in MS patients than in the comparison cohort, with a relative risk of 4.69 (4.21-5.22). There was no clear temporal trend in the results, and risks were higher in males and varied by MS phenotype. CONCLUSIONS: Higher hospital admission rates among MS patients for infection are likely to be due to a combination of surveillance bias, cautious medical management and greater susceptibility to severe infections. MS-related functional limitations may increase infection risk and this should be considered in MS management.

Shared genetic factors may not explain the raised risk of comorbid inflammatory diseases in multiple sclerosis.

BACKGROUND: Comorbid inflammatory conditions in multiple sclerosis (MS) patients suggest shared risks with MS. OBJECTIVE: To estimate if the risk of immune-mediated disease in MS patients and their parents is increased. METHODS: Swedish register data were analysed using Cox regression to estimate immune-mediated disease risk among 11284 fathers and 12006 mothers of MS patients, compared with 123158 fathers and 129409 mothers of index subjects without MS. Similar analyses were conducted among 20276 index subjects with MS and 203951 without. RESULTS: Parents of patients with MS did not have a significantly altered immune-mediated disease risk. Patients with MS had a consistently raised risk for several immune-mediated diseases: ulcerative colitis, Crohn's disease, type 1 diabetes, psoriasis, polyarthritis nodosa and pemphigoid. The risk was more pronounced for diseases diagnosed subsequent to MS onset. CONCLUSION: The increased occurrence of other immune-mediated diseases in MS patients may not be due to shared genetic factors and surveillance bias is likely to be the main or possibly the entire explanation. If not entirely explained by surveillance bias, a modestly raised occurrence of comorbid diseases may be due to shared environmental risks or factors related to MS disease characteristics.

Appendicectomy and multiple sclerosis risk.

BACKGROUND: Appendicectomy for acute appendicitis, but not for other causes, is inversely associated with immune-mediated diseases such as ulcerative colitis, suggesting appendicitis is a marker of immune characteristics influencing immune-mediated disease risk. This study investigated the association of appendectomy and its underlying diagnosis with multiple sclerosis (MS). METHODS: Swedish general population registers and the Swedish MS register provided information on 20,542 cases with MS diagnosed between 1964-2006 and 204,157 controls matched for age, sex, period and region. Appendicectomy prior to MS diagnosis was identified in 673 cases and 6518 controls. Conditional logistic regression, with adjustment for socio-economic index, assessed the association of diagnosis underlying appendicitis with MS risk. RESULTS: A perforated appendix, the best indicator of acute appendicitis in this material, was inversely associated with MS, although not statistically significantly, with an odds ratio (and 95% confidence interval of 0.86 (0.70-1.04). The odds ratios are 1.04 (0.94-1.16) for appendicitis without perforation and 1.14 (0.98-1.33) for appendectomy without appendicitis. CONCLUSION: Although inconclusive in terms of assessing the hypothesis, these results may help to explain why earlier studies of appendicitis and MS risk have been inconsistent, as there may be variation in association by diagnosis underlying appendicectomy.

Family stress and BMI in young children.

AIM: The aim of this study was to investigate if family stress and parental attachment style are associated with body mass index (BMI) in young children, and identify possible explanations. METHODS: A cross-sectional survey with a two-stage design was used. Parents of 873 children participated. They completed a demographic questionnaire, the Swedish Parenthood Stress Questionnaire (SPSQ), the Relationship Questionnaire (RQ) and reported their children's television-viewing habits (as a marker of physical activity). Children's height, weight and BMI were obtained from a general population-based register, BASTA. Associations with over- and underweight in children were assessed using multiple logistic regression analysis. RESULTS: Family stress indicated by SPSQ-score was associated with suboptimal BMI. Maternal, but not paternal, SPSQ-stress score was statistically significantly associated with overweight and underweight, with adjusted odds ratios (and 95% confidence interval) of 4.61 (3.11-6.84; p < 0.001) and 3.08 (1.64-5.81; p < 0.001) respectively. Associations between childhood BMI and parental attachment style were identified, but were not independent of maternal SPSQ-score. CONCLUSION: Our findings support a role for family stress in development of both overweight and underweight among young children. This is likely to be attributed to behavioural mechanisms but a more direct metabolic influence of stress could also be involved.

Risk of suicide among operated and non-operated patients hospitalised for peptic ulcers.

BACKGROUND: Some small studies have reported high risk of suicide after surgical treatment for peptic ulcer. The aim of the present study was to explore the risk of suicide in hospitalised gastric ulcer and duodenal ulcer patients separately among operated and non-operated cohorts. METHODS: Retrospective cohorts of 163,579 non-operated patients with gastric ulcer or duodenal ulcer and 28,112 patients with surgical treatment for ulcer, recorded in the Swedish Inpatient Register since 1965, were followed from the first hospitalisation, or operation for the surgery cohort, until death, any cancer, emigration, or 31 December 2003. Standardised mortality ratios (SMRs) were calculated, and Poisson regression produced adjusted relative risk estimates among operated and non-operated patients. RESULTS: Non-operated patients hospitalised for peptic ulcer showed a 70% excess risk of suicide (SMR 1.7, 95% CI 1.6 to 1.9) and those who underwent operation had a 60% increased risk (SMR 1.6, 95% CI 1.4 to 1.8). The risk of suicide was very high during the first year after hospitalisation (SMR 4.0, 95% CI 3.4 to 4.7) and more marked among women, patients under 70 and patients hospitalised without complications of ulcer. Both gastric ulcer and duodenal ulcer patients had high risk of suicide completion. CONCLUSION: Hospitalised patients with gastric ulcer or duodenal ulcer have an increased risk of suicide regardless of surgical treatment. These patients, especially women, are at very high risk during the first year after first hospitalisation/operation. The evaluation and management of suicidal thoughts in patients in medical settings should be further considered.

Cancer risk among patients with multiple sclerosis and their parents.

BACKGROUND: We investigated cancer risk among patients with multiple sclerosis (MS) and whether variation by age at MS diagnosis helps to elucidate mechanisms underlying the previously reported reduced cancer risk. We also studied cancer risk among parents to ascertain if MS susceptibility genes may confer protection against cancer in relatives. METHODS: Cox proportional hazards regression, adjusted for age, sex, area, and socioeconomic index, estimated cancer risk among 20,276 patients with MS and 203,951 individuals without MS, using Swedish general population register data. Similar analyses were conducted among 11,284 fathers and 12,006 mothers of patients with MS, compared with 123,158 fathers and 129,409 mothers of controls. RESULTS: With an average of 35 years of follow-up, there was a decreased overall cancer risk among patients with MS (hazard ratio = 0.91, 0.87-0.95). Increased risks were observed for brain tumors (1.44, 1.21-1.72) and urinary organ cancer (1.27, 1.05-1.53). Parents of patients with MS did not have a notably increased or decreased overall cancer risk. CONCLUSIONS: The reduction in cancer risk in patients with multiple sclerosis (MS) may result from behavioral change, treatment, or we speculate that some immunologic characteristics of MS disease activity improve antitumor surveillance. The lack of association among parents indicates that a simple inherited characteristic is unlikely to explain the reduced cancer risk among patients with MS. MS is associated with increased risk for some cancers, such as of urinary organs and brain tumors (although surveillance bias may be responsible).

Maternal smoking during pregnancy and multiple sclerosis amongst offspring.

INTRODUCTION: An association between parental smoking and multiple sclerosis (MS) in offspring has been reported. This study examined whether maternal smoking during pregnancy is associated with MS in offspring. METHODS: Swedish general population registers provided prospectively recorded information on maternal smoking during pregnancy. The study identified 143 cases with MS diagnosed by 2006 and 1730 matched controls. Subjects were born since 1982 and individually matched by year of birth, age, sex and region of residence. Conditional logistic regression assessed the association of maternal smoking with MS in offspring with adjustment for socioeconomic index. RESULTS: Maternal smoking during pregnancy was not associated with MS in offspring, with an odds ratio (and 95% confidence interval) of 0.96 (0.65-1.44). When stratified by paediatric or later MS onset there was no association with maternal smoking in either stratum. CONCLUSION: It is unlikely that smoking during pregnancy represents a risk for early-onset MS amongst offspring.

Parity and risk of stomach cancer by sub-site: a national Swedish study.

We investigated stomach cancer risk by anatomic sub-site in relation to parity, as a marker for higher exposure to sex hormones, in a case-control study, nested within a cohort of 2,406,439 Swedish women born in 1925 or later and followed from 1970 or age 30 until emigration, death, any cancer diagnosis, or through 2004, whichever occurred first. We identified 286 cardia and 2498 non-cardia stomach cancer cases with five matched controls for each case. Cross-linkage with the Multi-Generation Register provided information about reproductive history. Using conditional logistic regression models for estimating odds ratios (ORs) and corresponding 95% confidence intervals (CIs), adjusted for education level and occupation, we found no association between any aspect of parity and non-cardia stomach cancer (OR=1.01, 95% CI 0.89-1.15, comparing parous with nulliparous women). However, a 30% risk reduction for postmenopausal cardia cancer (OR=0.7, 95% CI 0.4-1.0) was noted among parous relative to nulliparous women and the risk for premenopausal cardia cancer fell with increasing number of children (P for trend=0.04). Our results indicate that exposure to female sex hormones does not protect against non-cardia stomach cancer and does not explain male predominance. The observed moderate inverse relationship between parity and cardia cancer may be mediated by non-hormonal factors and warrants further study.

Proximity effects in the palladium-catalyzed substitution of aryl fluorides.

[reaction: see text] The aryl fluoride bond has long been considered inert toward Pd-catalyzed insertion reactions. This paper reports for the first time that aryl fluorides bearing an o-carboxylate group can undergo Pd-catalyzed couplings. On the basis of this computational study and subsequent experimental verifications of its predictions, we herein report that such reactions are facilitated by stabilization of the transition state by proximal oxyanions.

Origins of opposite absolute stereoselectivities in proline-catalyzed direct Mannich and aldol reactions.

[structure: see text] The first computational studies to elucidate the stereoselectivity of the proline-catalyzed direct Mannich reaction have been performed using density functional theory (B3LYP/6-31G*). The transition states for the proline-catalyzed direct Mannich reaction of the proline enamine of acetone with the N-phenyl imine of acetaldehyde are reported here. The computed transition states provide a general model that explains the origin of the opposite stereoselectivities of proline-catalyzed Mannich and aldol reactions.

Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolecular aldol reactions.

Quantum mechanical calculations were employed to predict the ratio of four stereoisomeric products expected from two complex reactions involving the aldol reactions of cyclohexanone with benzaldehyde or with isobutyraldehyde catalyzed by (S)-proline. Experimental tests of these predictions provide an assessment of the state-of-the-art in quantum mechanical prediction of products of complex organic reactions in solution.