Evidence of gene-gene interaction in hidradenitis suppurativa: a nationwide registry study of Danish twins.

BACKGROUND: Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease that, apart from rare causative loss-of-function mutations, has a widely unknown genetic aetiology. OBJECTIVES: To estimate the relative importance of genetic and environmental factors underlying susceptibility to HS. METHODS: Via the Danish Twin Registry and the Danish National Patient Registry we pulled together information on zygosity with that of HS status. Cases of HS were identified by the International Classification of Diseases (ICD)-8 (705·91) and ICD-10 (L73·2). Heritability was assessed by the classic biometric model and the possibility of gene-gene interaction via the multilocus modelling approach. RESULTS: Among 100 044 registered twins, we found 170 twins (from 163 pairs) diagnosed with HS. The seven concordant pairs were all monozygotic. Monozygotic twins had a case-wise concordance rate of 28% [95% confidence interval (CI) 7-49], corresponding to a familial risk of 73 (95% CI 13-133) times that of the background population. The biometrical modelling suggested a heritability of 0·80 (95% CI 0·67-0·93), and the multilocus index estimate was 230 (95% CI 60-400). This is highly indicative of gene-gene interactions, with the possibility of up to six interacting loci. CONCLUSIONS: This twin study was substantially larger and employed a more valid phenotype than previous studies. Genetics account for the majority of HS susceptibility, and HS is most likely caused by gene-gene interactions rather than monogenetic mutations or solely additive genetic factors. New approaches aimed at assessing potential interactions at a single-nucleotide polymorphism (SNP)-SNP level should be implemented in future HS genome-wide association studies.

Impaired fecundity as a marker of health and survival: a Danish twin cohort study.

STUDY QUESTION: Is fecundity, measured as self-reported time to first pregnancy (TTP), a marker for subsequent health and survival? SUMMARY ANSWER: Long TTP was a marker for increased mortality among women and higher hospitalization rates for both women and men. WHAT IS KNOWN ALREADY: Poor semen quality has been linked to increased mortality and morbidity from a wide range of diseases. Associations among fecundity, health and survival among women are still uncertain and studies on actual measures of fecundity and health outcomes are rare. STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study of 7825 women and 6279 men, aged 18 and above with measures on first TTP, who participated in one of the Danish nation-wide twin surveys in 1994 (twins born 1953-1976) and 1998 (twins born 1931-1952). They were followed-up for mortality and hospital admissions from the interview until 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twins were identified in the Danish Twin Registry and linked to Danish registers. TTP was restricted to the first pregnancy as a categorical outcome with cut-off points at 2, 10 and 18 months. We analysed the association between TTP and survival using a Cox proportional hazards model estimating hazards ratios (HRs) with 95% confidence intervals (CIs). Fine-Gray survival models were used to estimate sub-hazard ratios for specific causes of death allowing for competing risks. Using negative binomial regression, we estimated incidence rate ratios (IRRs) with 95% CIs for all-cause and cause-specific hospitalizations. All analyses were stratified by sex and adjusted for age at interview, birth cohorts, age at first attempt to become pregnant, smoking, years in school and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: In the total study population, 49.9% of women and 52.7% of men reported a TTP of less than 2 months, 30.8% of women and 29.6% of men reported a TTP of 2-9 months, 6.6% of women and 5.7% of men reported a TTP of 10-17 months, and 13.3% of women and 12.0% of men reported a TTP of 18 months or more. Among 1305 deaths, we found a higher mortality for women (HR = 1.46; 95% CI 1.15, 1.87) with a TTP of ≥18 months relative to those with a TTP of <2 months, while the highest mortality was indicated for men with a TTP of 10-17 months (HR = 1.31; 95% CI 0.98, 1.74). Among 53 799 hospitalizations, we found an increased hospitalization rate among women (HR = 1.21; 95% CI 1.0-1.41) and men (HR = 1.16; 95% CI 1.00-1.35) with a TTP of ≥18 months, and for men with a TTP of 2-9 months (HR = 1.14; 95% CI 1.01-1.30). A dose-response relationship was found for women regarding both mortality (P = 0.022) and hospitalizations (P = 0.018). Impaired fecundity was associated with a wide range of diseases and some causes of death, indicating a multi-factorial causal influence on fecundity, especially among women. LIMITATIONS, REASONS FOR CAUTION: A major limitation was that fecundity depends on both partners, which was not considered in this study. Moreover, we could not obtain information on a number of potential confounders. WIDER IMPLICATIONS OF THE FINDINGS: Fecundity seems positively correlated with overall health and may be a universal marker of future health and survival. These results add knowledge to the limited findings showing that reduced fecundity in women and poor semen quality in men may reflect worse health and a shorter life, particularly among women. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by NIH grant HD096468 (M.L.E., T.K.J. and R.L.J.). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Intrauterine testosterone exposure and depression risk in opposite-sex and same-sex twins, a Danish register study.

BACKGROUND: Males have a lower prevalence of depression than females and testosterone may be a contributing factor. A comparison of opposite-sex and same-sex twins can be used indirectly to establish the role of prenatal testosterone exposure and the risk of depression. We therefore aimed to explore differences in depression risk using opposite-sex and same-sex twins. METHODS: We included 126 087 opposite-sex and same-sex twins from the Danish Twin Registry followed in nationwide Danish registers. We compared sex-specific incidences of depression diagnosis and prescriptions of antidepressants between opposite-sex and same-sex twins using Cox proportional hazard regression. RESULTS: During follow-up, 2664 (2.1%) twins were diagnosed with depression and 19 514 (15.5%) twins had purchased at least one prescription of antidepressants. First, in male twins, we found that the opposite-sex male twins had the same risk of depression compared to the same-sex male twins {hazard ratio (HR) = 1.01 [95% confidence interval (CI) 0.88-1.17)]}. Revealing the risk of use of antidepressants, the opposite-sex male twins had a slightly higher risk of 4% (HR = 1.04 (95% CI 1.00-1.11)) compared with the same-sex male twins. Second, in the female opposite-sex twins, we revealed a slightly higher, however, not statistically significant risk of depression (HR = 1.08 (95% CI 0.97-1.29)) or purchase of antidepressants (HR = 1.01 (95% CI 0.96-1.05)) when compared to the same-sex female twins. CONCLUSIONS: We found limited support for the hypothesis that prenatal exposure to testosterone was associated with the risk of depression later in life.

Early ovarian ageing: is a low number of oocytes harvested in young women associated with an earlier and increased risk of age-related diseases?

STUDY QUESTION: Do young women with early ovarian ageing (EOA), defined as unexplained, and repeatedly few oocytes harvested in ART have an increased risk of age-related events? SUMMARY ANSWER: At follow-up, women with idiopathic EOA had an increased risk of age-related events compared to women with normal ovarian ageing (NOA). WHAT IS KNOWN ALREADY: Early and premature menopause is associated with an increased risk of cardiovascular diseases (CVDs), osteoporosis and death. In young women, repeated harvest of few oocytes in well-stimulated ART cycles is a likely predictor of advanced menopausal age and may thus serve as an early marker of accelerated general ageing. STUDY DESIGN, SIZE, DURATION: A register-based national, historical cohort study. Young women (≤37 years) having their first ART treatment in a public or private fertility clinic during the period 1995-2014 were divided into two groups depending on ovarian reserve status: EOA (n = 1222) and NOA (n = 16 385). Several national registers were applied to assess morbidity and mortality. PARTICIPANTS/MATERIALS, SETTING, METHODS: EOA was defined as ≤5 oocytes harvested in a minimum of two FSH-stimulated cycles and NOA as ≥8 oocytes in at least one cycle. Cases with known causes influencing the ovarian reserve (endometriosis, ovarian surgery, polycystic ovary syndrome, chemotherapy etc.) were excluded. To investigate for early signs of ageing, primary outcome was an overall risk of ageing-related events, defined as a diagnosis of either CVD, osteoporosis, type 2 diabetes, cancer, cataract, Alzheimer's or Parkinson's disease, by death of any-cause as well as a Charlson comorbidity index score of ≥1 or by registration of early retirement benefit. Cox regression models were used to assess the risk of these events. Exposure status was defined 1 year after the first ART cycle to assure reliable classification, and time-to-event was measured from that time point. MAIN RESULTS AND THE ROLE OF CHANCE: Median follow-up time from baseline to first event was 4.9 years (10/90 percentile 0.7/11.8) and 6.4 years (1.1/13.3) in the EOA and NOA group, respectively. Women with EOA had an increased risk of ageing-related events when compared to women with a normal oocyte yield (adjusted hazard ratio 1.24, 95% CI 1.08 to 1.43). Stratifying on categories, the EOA group had a significantly increased risk for CVD (1.44, 1.19 to 1.75) and osteoporosis (2.45, 1.59 to 3.90). Charlson comorbidity index (1.15, 0.93 to 1.41) and early retirement benefit (1.21, 0.80 to 1.83) was also increased, although not reaching statistical significance. LIMITATIONS, REASONS FOR CAUTION: Cycles never reaching oocyte aspiration were left out of account in the inclusion process and we may therefore have missed women with the most severe forms of EOA. We had no information on the total doses of gonadotrophin administered in each cycle. WIDER IMPLICATIONS OF THE FINDINGS: These findings indicate that oocyte yield may serve as marker of later accelerated ageing when, unexpectedly, repeatedly few oocytes are harvested in young women. Counselling on life-style factors as a prophylactic effort against cardiovascular and other age-related diseases may be essential for this group of women. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The Hidradenitis Suppurativa Quality of Life (HiSQOL) score: development and validation of a measure for clinical trials.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory condition that can have a large negative impact on health-related quality of life (HRQOL). A reliable and validated measure of HS-specific HRQOL in clinical studies is needed. OBJECTIVES: To develop and validate the Hidradenitis Suppurativa Quality Of Life (HiSQOL©) scale, for clinical trial measurement of HS-specific HRQOL. METHODS: In stage 1, qualitative concept elicitation interviews were conducted with patients with HS in Denmark (n = 21) and the U.S.A. (n = 21). In stage 2, cognitive debriefing interviews were performed with U.S. (n = 30) and Danish patients with HS (n = 30). In stage 3 an observational study of 222 patients with HS in the U.S.A. was conducted for item reduction, measure validation and assessment of psychometric properties. In stage 4, an observational study of 215 patients with HS in Denmark was conducted to confirm the psychometric structure derived in stage 3. In both studies the Dermatology Life Quality Index, Hospital Anxiety and Depression Scale and numerical rating scale for pain were also included. RESULTS: In concept elicitation, 99 items were generated, which were reduced to 41 after removing duplicates. In cognitive debriefing, two items were added and one item removed. A 42-item instrument was psychometrically assessed. Based on psychometric analyses and patient input, the instrument was reduced to 17 items that had strong psychometric properties in both the U.S. and Danish samples. CONCLUSIONS: The HiSQOL is a reliable and valid instrument to measure HS-specific HRQOL in clinical trials.

Traumatic brain injury and risk of dementia at different levels of cognitive ability and education.

BACKGROUND AND PURPOSE: The effect of cognitive resources on the risk of dementia following traumatic brain injury (TBI) has hardly been investigated. The aim of this study was to examine the influence of cognitive ability and education in young adulthood on the association between TBI and dementia in men. METHOD: A cohort of 658 447 Danish men, born between 1939 and 1959, who had been cognitively assessed at conscription were followed in the Danish National Patient Registry and the National Prescription Registry from 1977 through 2016 for incident TBI and dementia. The association between TBI and dementia was analysed using Cox proportional regression. RESULTS: During follow-up, 29 781(4.5%) men experienced TBI and 10 971(1.7%) developed dementia. TBI was associated with a higher risk of subsequent dementia after adjustment for cognitive ability, education and psychiatric comorbidity. The risk estimate was higher for early-onset dementia (hazard ratio 5.49, 95% confidence interval 4.97-6.06) than for dementia diagnosed after age 60 years (hazard ratio 2.85, 95% confidence interval 2.63-3.10). The association was slightly stronger in men with the highest cognitive scores or education than amongst those at lower levels. CONCLUSION: Young adult cognitive ability did not explain a relatively strong association between TBI and dementia, and no evidence was found that cognitive ability or education was protective.

Validation and assessment of minimally clinically important difference of the unadjusted Health Assessment Questionnaire in a Danish cohort: uncovering ordinal bias.

Objectives: The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a widely used patient-reported outcome for functional disability in rheumatoid arthritis (RA). Minimal clinically important differences (MCIDs) in the HAQ-DI were previously calculated based on device-corrected ordinal HAQ-DI scores, leading to limited generalizability and validity for today's patients. Our objectives were to examine the internal construct validity of the unadjusted HAQ-DI and to determine an MCID in a cohort of Danish RA patients based on the transformed linear logit scale of the HAQ-DI.Method: The study included 362 RA patients registered in the DANBIO registry. The Rasch model was fitted to HAQ-DI data at baseline and after 3 months' follow-up. MCID was calculated as the median changes in the original HAQ-DI score and logit HAQ-DI score in those patients who had experienced minimal improvement (15-30 mm on a 0-100 mm Patient Global scale).Results: HAQ-DI data showed acceptable fit to the Rasch model at both time-points, and consistent item ranking across time indicated instrument invariance. Sixty-one patients (16.8%, ~1/6) had an improvement above the MCID on the logit scale but improvement below the MCID on the original scale, while the opposite was not the case for any patients.Conclusions: The Danish unadjusted version of the HAQ-DI showed acceptable internal construct validity. Application of the logit MCID classified an additional one in six patients as having achieved an MCID compared to the MCID calculated on the ordinal scale, which may have potential implications for the powering of future studies.

Familial risk and heritability of depression by age at first diagnosis in Danish twins.

OBJECTIVE: Familial and genetic factors seem to contribute to the development of depression but whether this varies with age at diagnosis remains unclear. We examined the influence of familial factors on the risk of depression by age at first diagnosis. METHODS: We included 23 498 monozygotic and 39 540 same-sex dizygotic twins from the population-based Danish Twin Registry, followed from 1977 through 2011 in nationwide registers. We used time-to-event analyses accounting for censoring and competing risk of death to estimate cumulative incidence, casewise concordance, relative recurrence risk, and heritability of first depression by age using monozygotic and same-sex dizygotic twin pairs. RESULTS: During follow-up, a total of 1545 twins were diagnosed with depression. For twins at age 35 or younger at first depression, heritability was estimated to be 24.8% (95% confidence interval [CI], 4.6-43.1%), whereas at age 90 it was 14.7% (95% CI, 3.1-26.3%). The relative recurrence risk was higher at younger ages: At age 35, the risk was 27.7-fold (95% CI, 20.0-35.5) and 6.9-fold (95% CI, 3.9-9.8) higher than the population risk for monozygotic and same-sex dizygotic twins, respectively, while the corresponding numbers were 3.0 (95% CI, 2.3-3.6) and 1.8 (95% CI, 1.3-2.2) at age 90. Heritability seemed similar for male and female twins. CONCLUSION: Familial risk of depression, caused either by genes or shared environment, seemed to slightly decrease with age at diagnosis and an elevated concordance risk for monozygotic over same-sex dizygotic pairs suggested a genetic contribution to the development of depression.

Carotenoid pigmentation in salmon: variation in expression at BCO2-l locus controls a key fitness trait affecting red coloration.

Carotenoids are primarily responsible for the characteristic red flesh coloration of salmon. Flesh coloration is an economically and evolutionarily significant trait that varies inter- and intra-specifically, yet the underlying genetic mechanism is unknown. Chinook salmon (Oncorhynchus tshawytscha) represents an ideal system to study carotenoid variation as, unlike other salmonids, they exhibit extreme differences in carotenoid utilization due to genetic polymorphisms. Here, we crossed populations of Chinook salmon with fixed differences in flesh coloration (red versus white) for a genome-wide association study to identify loci associated with pigmentation. Here, the beta-carotene oxygenase 2-like (BCO2-l) gene was significantly associated with flesh colour, with the most significant single nucleotide polymorphism explaining 66% of the variation in colour. BCO2 gene disruption is linked to carotenoid accumulation in other taxa, therefore we hypothesize that an ancestral mutation partially disrupting BCO2-l activity (i.e. hypomorphic mutation) allowed the deposition and accumulation of carotenoids within Salmonidae. Indeed, we found elevated transcript levels of BCO2-l in white Chinook salmon relative to red. The long-standing mystery of why salmon are red, while no other fishes are, is thus probably explained by a hypomorphic mutation in the proto-salmonid at the time of divergence of red-fleshed salmonid genera (approx. 30 Ma).

Incidence of medically treated depression in Denmark among individuals 15-44 years old: a comprehensive overview based on population registers.

OBJECTIVE: Examine the overall incidence of medically treated depression in Denmark among individuals 15-44 years old, and estimate the 5-year cumulative incidence of psychiatric hospital care among individuals treated first in non-hospital-based care. METHODS: We followed all individuals born in Denmark between 1969 and 1998 from age 15 or 2006 (whichever came first) until first depression treatment; death; emigration; or December 31, 2013. Incidence rates were estimated using Poisson regression. Cumulative incidence of hospital care following treatment in non-hospital care was estimated using Kaplan-Meier curves. RESULTS: In this sample of 2 014 760 individuals, incidence rates of depression in non-hospital and hospital-based care in 2012-2013 were 6.6 (95% Confidence Interval: 6.5-6.7) per 1000 person-years and 1.5 (95% CI: 1.5-1.6) per 1000 person-years, respectively. Overall, 85-90% of first medical treatment for depression took place outside of psychiatric hospitals, but a quarter (26.3%) of individuals treated for depression received hospital care initially or within 5 years. Incidence of hospital care was higher in women and younger individuals. CONCLUSIONS: Most medical treatment for depression in Denmark takes place in non-hospital settings. Women and younger individuals are more likely to receive hospital care both initially and within 5 years after first antidepressant treatment.

The association between depressive mood and ischemic heart disease: a twin study.

OBJECTIVE: Individuals with mood disorders have increased risk of cardiovascular disease. The aims of this study were to evaluate if the risk of cardiovascular disease in individuals with mood disorder could be explained by shared genetic and early environmental factors. METHODS: We included 6714 Danish middle and old aged twins from two large population-based studies. Cox proportional hazards regression was used to perform individual-level and intra-pair analyses of the association between self-reported depression symptomatology scores and register-based diagnoses of ischemic heart disease. RESULTS: Higher depression symptomatology scores (both total, affective, and somatic) were associated with higher incidence of ischemic heart disease after multivariable adjustment in individual-level analyses. In intra-pair analyses, this association was similar but with slightly larger confidence intervals. There was no interaction with gender and no major differences between mono- or dizygotic twins. Within twin pairs, the twin scoring highest on depressive symptoms developed ischemic heart disease more often or earlier than the lower scoring twin. A sensitivity analysis including a 2-year time lag of depression symptomatology to limit the risk of reverse causality showed similar results. CONCLUSION: Genetic factors and early life environment do not seem to explain the association between depressive mood and ischemic heart disease.

Systematic review of the QoR-15 score, a patient- reported outcome measure measuring quality of recovery after surgery and anaesthesia.

BACKGROUND: The QoR-15 is a patient-reported outcome questionnaire that measures the quality of recovery after surgery and anaesthesia. We aimed to perform a systematic review and meta-analysis of the measurement properties of the QoR-15. METHODS: Studies reporting measurement properties or interpretability of the QoR-15 after surgery were eligible for inclusion. All languages were included in the PubMed and Embase search. The COSMIN guidelines for systematic reviews of patient-reported outcome measurements were followed. Criteria for good measurement properties outlined in the consensus-based guidelines for selecting outcome measurement instruments for clinical trials were applied. A metaanalysis and synthesis of data across studies was performed. RESULTS: Nine hundred and thirty-three titles were identified, and six articles were included in the study. The study population comprised 1548 patients undergoing a variety of surgical elective procedures. The QoR-15 was validated in English, Danish, Chinese, and Portuguese. High-quality evidence for good content validity, good internal consistency (Cronbach's α of 0.836), and essential unidimensionality of the QoR-15 as a measurement of postoperative quality of recovery was found. There was at least moderate-quality evidence of good reliability of the QoR-15 (intraclass correlation of 0.989) and good error of measurement (standard error of measurement of 1.85). The upper 95% confidence limit of the smallest detectable change was 3.63, and the minimal clinical important difference was 8.0. CONCLUSIONS: The QoR-15 fulfils requirements for outcome measurement instruments in clinical trials and is the first measurement instrument of postoperative quality of recovery to undergo a systematic review according to the COSMIN checklist.

Needs and preferences among patients with high-grade glioma and their caregivers - A longitudinal mixed methods study.

Previous reports on the patient perspective of daily life during a 1-year high-grade glioma (HGG) trajectory from the time of diagnosis are sparse. The aim of this longitudinal mixed methods study is to identify the specific needs and preferences for rehabilitation and supportive care and how it links with physical activity, psychological measures and health quality longitudinally over the first year after diagnosis among patients with HGG and their caregivers by integrating qualitative and quantitative findings. Using a longitudinal mixed methods design, patients with malignant glioma (n = 30) and their caregivers (n = 33) were interviewed and completed questionnaires (patients only) about physical activity level, anxiety/depression and quality of life five times during the 1-year period. Their needs and preferences included interventions designed to re-define hope after diagnosis, health promoting physical activities initiated early, psychological symptom management strategies, and life planning. Caregivers are committed to their caregiving role, but their engagement is nonetheless challenged over time by enormous caregiver burdens. The identified specific needs and preferences favour supportive care, education, information and rehabilitation. Guidelines attentive to these needs and implemented in clinical practice have the potential to improve patients' health-related quality of life and support caregivers by involving them more actively in care and management.

Genetic overlap between type 2 diabetes and depression in Swedish and Danish twin registries.

A bidirectional association between type 2 diabetes (T2DM) and depression has been consistently reported. Depression is associated with worse biomedical outcomes and increased mortality. The mechanisms underlying the association of T2DM with depression remain unclear. One possible question we can address is the extent to which the co-occurrence of diabetes and depression is due to correlated genetic and/or environmental risk factors. In this study, we performed structural equation model fitting to population-level data from the Swedish (n=68 606) and Danish (n=95 403) twin registries. The primary outcomes were clinical diagnosis of T2DM and depression using national hospital discharge registries. The phenotypic correlation between T2DM and depression is modest in both samples. In the Swedish sample, unique environmental effects explain a greater proportion of the covariance in males, whereas the association is primarily attributed to genetic effects in females. In the Danish sample, genetic effects account for the majority of the covariance in both males and females. Qualitative genetic sex differences are observed in both samples. We believe this is the first study to demonstrate significant genetic overlap between T2DM and depression.

Visualization of haemophilic arthropathy in F8-/- rats by ultrasonography and micro-computed tomography.

INTRODUCTION: A major complication of haemophilia is haemophilic arthropathy (HA), a debilitating disorder with an incompletely defined pathobiology. High-resolution imaging may provide new knowledge about onset and progression of HA, and thereby support identification of new treatment opportunities. Recently, a F8-/- rat model of HA was developed. The size of the rat allows for convenient and high resolution imaging of the joints, which could enable in vivo studies of HA development. AIM: To determine whether HA in the F8-/- rat can be visualized using ultrasonography (US) and micro-computed tomography (µCT). METHODS: Sixty F8-/- and 20 wild-type rats were subjected to a single or two induced knee bleeds. F8-/- rats were treated with either recombinant human FVIII (rhFVIII) or vehicle before the induction of knee bleeds. Haemophilic arthropathy was visualized using in vivo US and ex vivo µCT, and the observations correlated with histological evaluation. RESULTS: US and µCT detected pathologies in the knee related to HA. There was a strong correlation between disease severity determined by µCT and histopathology. rhFVIII treatment reduced the pathology identified with both imaging techniques. CONCLUSION: US and µCT are suitable imaging techniques for detection of blood-induced joint disease in F8-/- rats and may be used for longitudinal studies of disease progression.

Development of LRRK2 Inhibitors for the Treatment of Parkinson's Disease.

Linkage and genome-wide association studies have identified a genetic risk locus for late-onset Parkinson's disease in chromosome 12, originally identified as PARK6. The causative gene was identified to code for a large multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). The combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment. Although LRRK2 has so far not been crystallised, the use of homology modelling and crystallographic surrogates has allowed the optimisation of chemical structures such that compounds of high selectivity with good brain penetration and appropriate pharmacokinetic properties are now available for understanding the biology of LRRK2 in vitro and in vivo. This chapter reviews LRRK2 biology, the structural biology of LRRK2 and gives an overview of inhibitors of LRRK2.

Spanish version of the Actinic Keratosis Quality of Life questionnaire.

BACKGROUND: Patient-reported outcome measures are very important outcomes. For specific diseases, health-related quality of life-instruments (HRQoL) are increasingly used to provide data on patients' overall perceptions of the course of a given disease. Actinic keratoses (AKs) are common keratotic lesions that occur on chronically sunlight-exposed skin. Only few studies regarding HRQoL in AKs have been made. OBJECTIVE: In order to be able to compare HRQoL among different countries and cultures, we aimed to translate and validate the Actinic Keratosis Quality of Life (AKQoL) questionnaire into Spanish and quantify the impairment caused by AKs in Spanish patients. METHODS: The AKQoL was translated. Then, 15 patients with AKs were interviewed to ensure cultural adaption before it was tested in one hundred patients with AK lesions at the Melanoma Unit of Hospital Clinic in Barcelona. RESULTS: Validation showed high interitem correlations, as well as a high correlation of each item and the total score. Internal consistency (Cronbach's coefficient alpha) was also high at 0.91 and an alpha value of 0.90 at retest. The test-retest correlation was 0.96, and the intraclass coefficient was 0.98. CONCLUSION: The presented data support the AKQoL Spanish version as a valid and reliable HRQoL questionnaire for the description of AK-related QoL and may provide a method for comparison of AK specific QoL between different cultures and countries.

Glenohumeral and scapulothoracic strength impairments exists in patients with subacromial impingement, but these are not reflected in the shoulder pain and disability index.

BACKGROUND: Pain and loss of function are cardinal symptoms associated with Subacromial impingement syndrome (SIS), while the presence and magnitude of deficits in strength and range of motion (ROM) are largely undescribed in non-athletic patients with SIS. Moreover, the relevance of impairments in strength and ROM to patient-reported shoulder function is not well described, even though testing of strength is recommended in clinical guidelines. The purpose of this study was, first, to investigate impairments in glenohumeral and scapulothoracic strength and in abduction and internal rotation ROM in patients with SIS. Secondly, to investigate the influence of these impairments on patient-reported shoulder function. METHODS: Cross-sectional study based on a consecutive cohort of 157 patients referred to specialist examination and diagnosed with shoulder impingement (SIS) using predefined validated diagnostic criteria. Prior to specialist examination, questionnaires regarding shoulder function (Shoulder Pain And Disability Index, SPADI) demographics and kinesiophobia (TSK-11) were collected, and shoulder strength and ROM was measured by trained testers, with the patient reporting pain levels during testing and for the last week. Impairments in strength (abduction, external-rotation, (protraction and horizontal-extension) and ROM (abduction and internal rotation) were investigated in patients with unilateral shoulder pain, using one-sample t-tests. SPADI total score (SPADI) and SPADI function score (SPADI-F), were chosen as dependent variables in multiple regressions to investigate the influence of impairments on patient-reported shoulder function. Independent variables of interest were; strength in abduction and external rotation, abduction ROM, pain-during-tests, pain-last-week and kinesiophobia. RESULTS: Significant impairments were found for all impairment tests, but most pronounced for glenohumeral strength and abduction ROM (29-33% deficits), and less for scapulothoracic strength and internal rotation ROM (8-18% deficits). Pain variables influenced SPADI and SPADI-F score to a high degree (R2 = 23.4-31.6%, p < 0.001), while strength and ROM did not. CONCLUSION: Substantial strength and ROM impairments were found in patients with SIS. Only pain significantly influenced patient-reported function, while impairments did not. As SPADI score does not reflect the substantial strength and ROM impairments in external rotation and abduction observed in patients with SIS, supplemental assessment of these impairments seems important.

Faith Moves Mountains-Mountains Move Faith: Two Opposite Epidemiological Forces in Research on Religion and Health.

Research suggests opposite epidemiological forces in religion and health: (1). Faith seems to move mountains in the sense that religion is associated with positive health outcomes. (2). Mountains of bad health seem to move faith. We reflected on these forces in a population of 3000 young Danish twins in which all religiosity measures were associated with severe disease. We believe the reason for this novel finding is that the sample presents as a particularly secular population-based study and that the second epidemiological force has gained the upper hand in this sample. We suggest that all cross-sectional research on religion and health should be interpreted in light of such opposite epidemiological forces potentially diluting each other.

Disclosing genetic risk for coronary heart disease: effects on perceived personal control and genetic counseling satisfaction.

We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45-65 years) were randomized to receive estimated 10-year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 ± 2.7 vs 24.1 ± 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 ± 5.3 vs 15.9 ± 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation.