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The backbone of all colorectal cancer classifications including the consensus molecular subtypes (CMS) highlights microsatellite instability (MSI) as a key molecular pathway. Although mucinous histology (generally defined as >50% extracellular mucin-to-tumor area) is a “typical” feature of MSI, it is not limited to this subgroup. Here, we investigate the association of CMS classification and mucin-to-tumor area quantified using a deep learning algorithm, and the expression of specific mucins in predicting CMS groups and clinical outcome. A weakly supervised segmentation method was developed to quantify extracellular mucin-to-tumor area in H&E images. Performance was compared to two pathologists’ scores, then applied to two cohorts: (1) TCGA (n = 871 slides/412 patients) used for mucin-CMS group correlation and (2) Bern (n = 775 slides/517 patients) for histopathological correlations and next-generation Tissue Microarray construction. TCGA and CPTAC (n = 85 patients) were used to further validate mucin detection and CMS classification by gene and protein expression analysis for MUC2, MUC4, MUC5AC and MUC5B. An excellent inter-observer agreement between pathologists’ scores and the algorithm was obtained (ICC = 0.92). In TCGA, mucinous tumors were predominantly CMS1 (25.7%), CMS3 (24.6%) and CMS4 (16.2%). Average mucin in CMS2 was 1.8%, indicating negligible amounts. RNA and protein expression of MUC2, MUC4, MUC5AC and MUC5B were low-to-absent in CMS2. MUC5AC protein expression correlated with aggressive tumor features (e.g., distant metastases (p = 0.0334), BRAF mutation (p

Purpose To report the incidence of post-operative endophthalmitis (PE) after immediate sequential bilateral cataract surgery (ISBCS) in Sweden. Design Retrospective cohort registry study. Participants Patient data from 1 457 172 cataract extractions including 1 364 934 unilateral surgeries and 92 238 ISBCS. Methods Endophthalmitis cases reported to the Swedish National Cataract Register (NCR) during a 16-year period (2002 – 2017) were analyzed in comparison to all control cases with regard to patient characteristics, surgical technique and capsule complication. Main Outcome Measure Incidence and determinants for PE in ISBCS compared to unilateral surgeries. Results A total of 422 cases of PE were identified in 1 457 172 cataract extractions, yielding an overall incidence of 0.029% [95% confidence interval (CI); 0.0262 - 0.0317]. For unilateral procedures, the rate was 0.0299% [95% CI; 0.0270 – 0.0328] or 408 cases in 1 364 934 operations, while that for ISBCS was 0.0152% [95% CI; 0.0072 – 0.0231] or 14 incidents in 92 238 operations, p = 0.01. In a logistic regression model including all cataract procedures, non-use of intracameral antibiotics, capsule complication, age 85 years or more, male gender and ocular comorbidity were found to be independent risk factors for PE. All these parameters were less frequent in ISBCS. Notwithstanding, in the same multivariate analysis ISBCS in itself was associated with a significantly lower risk for PE. At follow-up, 5 of the 14 PE cases in the ISBCS cohort had a visual acuity of 20/200 or worse. One 93-year-old ISBCS patient developed bilateral infection. Conclusions After ISBCS in Sweden, PE occurred once in 6 600 surgeries. The risk of sustaining a final visual acuity of 20/200 or less, was 1 incident in 18 000 operated eyes. When counselling potential ISBCS patients about the risk of PE, it seems reasonable to state that the reported risk in the literature is lower than that with unilateral surgery, but not negligible and precautions remain necessary.

Background: In Europe, the number of elderly end-stage kidney disease patients is increasing. Few of those patients receive peritoneal dialysis (PD), as many cannot perform PD autonomously. Assisted PD programmes are available in most European countries, but the percentage of patients receiving assisted PD varies considerably. Hence, we assessed which factors are associated with the availability of an assisted PD programme at a centre level and whether the availability of this programme is associated with proportion of home dialysis patients. Methods: An online survey was sent to healthcare professionals of European nephrology units. After selecting one respondent per centre, the associations were explored by χ 2 tests and (ordinal) logistic regression. Results: In total, 609 respondents completed the survey. Subsequently, 288 respondents from individual centres were identified; 58% worked in a centre with an assisted PD programme. Factors associated with availability of an assisted PD programme were Western European and Scandinavian countries (OR: 5.73; 95% CI: 3.07–10.68), non-academic centres (OR: 2.01; 95% CI: 1.09–3.72) and centres with a dedicated team for education (OR: 2.87; 95% CI: 1.35–6.11). Most Eastern & Central European respondents reported that the proportion of incident and prevalent home dialysis patients was 30% for both incident and prevalent home dialysis patients. Availability of an assisted PD programme was associated with a higher incidence (cumulative OR: 1.91; 95% CI: 1.21–3.01) and prevalence (cumulative OR: 2.81; 95% CI: 1.76–4.47) of patients on home dialysis. Conclusions: Assisted PD was more commonly offered among non-academic centres with a dedicated team for education across Europe, especially among Western European and Scandinavian countries where higher incidence and prevalence of home dialysis patients was reported.

The aim of this study was to evaluate chronic pain 1 year after surgery, and risk factors for chronic pain after groin hernia repair in women.Groin hernia surgery in women is less frequently studied than in men. Chronic pain is common after groin hernia surgery and remains an important area with room for improvement. Previous studies are small or inconclusive. Guidelines recommend timely repair of all female groin hernias.From the Swedish Hernia Register 4021 female and 37,542 male patients operated between September 1, 2012 and August 30, 2017 responded to a patient-reported outcome questionnaire (response rate 70.0%) 1 year after primary groin hernia surgery. Multivariable analysis was performed to compare chronic postoperative pain in women with men as a control group, and to evaluate risk factors for chronic pain in women.Among women operated for groin hernia, 18% suffered chronic postoperative pain. The risk for chronic pain was significantly higher for women [odds ratio 1.3 (95% confidence interval 1.16-1.46). Three risk factors for chronic pain in women were found: high body mass index, high American Society of Anesthesiologists classification, and femoral hernia. No differences in chronic pain in women were seen when comparing surgical methods or emergency versus elective surgery.Almost one-fifth of women suffered of chronic pain affecting daily activity after groin hernia repair. Chronic pain was more common for women than men. In view of the high-rate chronic postoperative pain, further research on management strategies in female groin hernia is warranted.

Olfactory dysfunction is a prevalent non-motor symptom of Parkinson’s disease (PD). This dysfunction is a result of neurodegeneration within the olfactory bulb (OB), the first processing area of the central olfactory system, and commonly precedes the characteristic motor symptoms in PD by several years. Functional measurements of the OB could therefore potentially be used as an early biomarker for PD. Here, we used a non-invasive method, so-called electrobulbogram (EBG), to measure OB function in PD and age-matched healthy controls to assess whether EBG measures can dissociate PDs from controls. We estimated the spectrogram of the EBG signal during exposure to odor in PD (n = 20) and age-matched controls (n = 18) as well as identified differentiating patterns of odor-related synchronization in the gamma, beta, and theta frequency bands. Moreover, we assessed if these PD-EBG components could dissociate PD from control as well as their relationship with PD characteristics. We identified six EBG components during the initial and later stages of odor processing which dissociated PD from controls with 90% sensitivity and 100% specificity with links to PD characteristics. These PD-EBG components were related to medication, disease duration, and severity, as well as clinical odor identification performance. These findings support using EBG as a tool to experimentally assess PD interventions, potentially aid diagnosis, and the potential development of EBG into an early biomarker for PD.

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. Registration: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.

Purpose: To report practice patterns of corneal transplantation in Europe.Setting: Corneal clinics in 10 European member states (MS), the United Kingdom, and Switzerland.Design: Multinational registry study.Methods: Corneal transplant procedures registered in the European Cornea and Cell Transplantation Registry were identified. Preoperative donor and recipient characteristics, indication and reason for transplantation, and surgical techniques were analyzed.Results: A total of 12 913 corneal transplants were identified from 10 European Union MS, the United Kingdom, and Switzerland. Most countries were self-sufficient with regard to donor tissue. Fuchs endothelial corneal dystrophy was the most common indication (41%, n = 5325), followed by regraft (16%, n = 2108), pseudophakic bullous keratopathy (12%, n = 1594), and keratoconus (12%, n = 1506). Descemet stripping automated endothelial keratoplasty (DSAEK, 46%, n = 5918) was the most commonly performed technique, followed by penetrating keratoplasty (30%, n = 3886) and Descemet membrane endothelial keratoplasty (9%, n = 1838). Vision improvement was the main reason for corneal transplantation (90%, n = 11 591). Surgical technique and reason for transplantation differed between indications.Conclusions: This report provides the most comprehensive overview of corneal transplantation practice patterns in Europe to date. Fuchs endothelial dystrophy is the most common indication, vision improvement the leading reason, and DSAEK the predominant technique for corneal transplantation. Copyright (C) 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS

Regular physical activity is widely recommended in the primary and secondary prevention of stroke. Physical activity may enhance cognitive performance after stroke, but cognitive impairments could also hinder a person to take part in physical activity. However, a majority of previous studies have not found any association between post-stroke cognitive impairments and a person’s subsequent level of activity. In this explorative, longitudinal study, we describe the intraindividual change in physical activity from before to 6 months after stroke, in relation to early screening of post-stroke cognitive impairments. Participants were recruited at 2 to 15 days after stroke, and screened for cognitive impairments using the Montreal Cognitive Assessment tool. Information on pre-stroke physical activity was retrospectively collected at hospital admittance by physiotherapists. Post-stroke physical activity was evaluated after 6 months. Of 49 participants included, 44 were followed up. The level of physical activity changed in more than half of all participants after stroke. Participants who were physically active 6 months after stroke presented with significantly less cognitive impairments. These results highlight that many stroke survivors experience a change in their physical activity level following stroke, and that unimpaired cognition may be important for a stroke survivors’ ability to be physically active.

Purpose To investigate case mix in relation to capsule complication, possible associations between case mix and operation volume, and change in case mix over time. Design Register-based study. Participants Swedish patients who underwent cataract surgery between 2007 and 2016. Methods Demographics and data on ocular comorbidity, intraoperative difficulties, and capsule complications were registered from 2007 to 2016 and analyzed retrospectively in relation to coded data on individual surgeons’ operation volume. Single factor analysis and logistic regression were performed, and a composite risk score was created. Main Outcome Measures Risk of capsule complication, given as adjusted and composite odds ratio in relation to cataract surgery volume. Results Preoperative and intraoperative variables significantly associated with capsule complications were best-corrected visual acuity (BCVA) ≤0.1 (decimal, adjusted odds ratio [aOR], 1.82; P 88 years, patients with BCVA ≤0.1, and patients with intraoperative difficulties decreased. Conclusions Case mix, as calculated from a composite risk score based on preoperative and intraoperative parameters registered in the National Cataract Register (NCR), may contribute to the decrease in capsule complications from 2007 to 2016 and the lower complication rate observed in cases managed by high-volume cataract surgeons.

Background: Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population.Methods: AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921.Findings: Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [Interpretation: Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke.Funding: National Health and Medical Research Council of Australia.

Background Hospitalisation of patients with advanced dementia is generally regarded as less preferable compared to care at home or in a nursing home. For patients with other diagnoses, young age has been associated with better end-of-life care. However, studies comparing the quality of palliative care for persons with advanced dementia in hospitals and nursing homes are scarce. The aim of this study was to investigate whether quality of end-of-life care for patients with dementia depends on age, gender and place of death. Methods The Swedish Register of Palliative Care (SRPC) was used to identify patients who died from dementia in hospitals or nursing homes during a three-year period. The likelihood of death occurring at a hospital, based on age and gender differences, was calculated. Associations between 13 end-of-life care quality indicators collected from the SRPC and age, gender and place of care were examined in a logistic regression model. Results Death at a hospital was associated with poorer quality of end-of-life care for 10 of the 13 measured outcomes when compared to death at a nursing home, and with better quality according to two of the outcomes. Death at a hospital was more common for men compared to women and for younger patients compared to older. Receiving fluids intravenously or via enteral tube in the last 24 h of life was strongly associated with death at a hospital. Women were more likely to have their oral health assessed and less likely to have pressure ulcers at death. Eight of 12 end-of-life care outcomes showed better results for the age group 65 to 84 years compared to those 85 years or older. Conclusions Death in hospitals was associated with poorer quality of end-of-life care compared to death in nursing homes. Our data support the importance of advance care planning and individual assessments in nursing homes to avoid referral to hospitals during end of life. Despite established recommendations to avoid hospitalisation if possible, there were strong associations between younger age, male gender and hospitalisation in the end of life. Further studies are needed to investigate the role of socioeconomic factors in end-of-life care for this patient group.

BACKGROUND This study is the first to evaluate the short-term efficacy and long-term safety of AZD0585, a mixture of omega-3 free fatty acids, in Japanese patients with dyslipidemia.Methods and Results:In this randomized double-blind placebo-controlled Phase III study, 383 patients were randomized to 2 g AZD0585, 4 g AZD0585, or placebo once daily for 52 weeks. Eligible patients had low-density lipoprotein cholesterol (LDL-C) levels controlled regardless of statin use, and triglyceride levels between 150 and 499 mg/dL. The least-squares (LS) mean percentage changes in triglyceride concentrations from baseline to the 12-week endpoint (mean of measurements at Weeks 10 and 12) in the 2 and 4 g AZD0585 and placebo groups were -15.57%, -21.75%, and 11.15% respectively (P

Purpose The primary aim of the study was to develop and investigate a patient interactive digital support (an app) for patients on adjuvant endocrine breast cancer treatment. Patient’s interactive digital applications are a fast-growing area for research and development. In general, patients want more information and support with regard to their diagnosis, treatment and self-care. At the same time, the health care system has limited resources for follow-up. Our primary endpoints were usability of the app and if it added any value to the patients. Methods We designed and constructed a prototype, in dialogue with patients, containing four main modules for registration of drug compliance, performed physical exercise, self-care activities, and questions on health and quality of life. The app was then tested by patients and improved further before we completed a pilot study in which 15 patients used the app for 3 months. Results Patients perceived the app easy to use with a very high median system usability score of 88.8, range 30–100. The 15 women registered in total 4251 times, range 118 to 372. The majority of registrations concerned compliance (adherence to treatment) and physical exercise. Conclusion The app was perceived easy to use and of support in every-day life of breast cancer survivors. How to best integrate electronically collected patient reported outcome measures in clinical routine needs to be further studied, and future research will show if it will be cost-effective in terms of better health outcome and less resource use.

The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe).

BackgroundTo address the reactivity and affinity against histidyl-transfer RNA synthetase (HisRS) autoantigen of anti-Jo1 autoantibodies from serum and bronchoalveolar lavage fluid (BALF) in patients with idiopathic inflammatory myopathies/anti-synthetase syndrome (IIM/ASSD). To investigate the associations between the reactivity profile and clinical data over time.MethodsSamples and clinical data were obtained from (i) 25 anti-Jo1+patients (19 sera with 16 longitudinal samples and 6 BALF/matching sera at diagnosis), (ii) 29 anti-Jo1−patients (25 sera and 4 BALF/matching sera at diagnosis), and (iii) 27 age/gender-matched healthy controls (24 sera and 3 BALF/matching sera). Reactivity towards HisRS full-length (HisRS-FL), three HisRS domains (WHEP, antigen binding domain (ABD), and catalytic domain (CD)), and the HisRS splice variant (SV) was tested. Anti-Jo1 IgG reactivity was evaluated by ELISA and western blot using IgG purified from serum by affinity chromatography. In paired serum-BALF, anti-Jo1 IgG and IgA reactivity was analyzed by ELISA. Autoantibody affinity was measured by surface plasmon resonance using IgG purified from sera. Correlations between autoantibody reactivity and clinical data were evaluated at diagnosis and longitudinally.ResultsAnti-Jo1 IgG from serum and BALF bound HisRS-FL, WHEP, and SV with high reactivity at the time of diagnosis and recognized both conformation-dependent and conformation-independent HisRS epitopes. Anti-HisRS-FL IgG displayed high affinity early in the disease. At the time of IIM/ASSD diagnosis, the highest autoantibody levels against HisRS-FL were found in patients ever developing interstitial lung disease (ILD) and arthritis, but with less skin involvement. Moreover, the reactivity of anti-WHEP IgG in BALF correlated with poor pulmonary function.Levels of autoantibodies against HisRS-FL, HisRS domains, and HisRS splice variant generally decreased over time. With some exceptions, longitudinal anti-HisRS-FL antibody levels changed in line with ILD activity.ConclusionHigh levels and high-affinity anti-Jo1 autoantibodies towards HisRS-FL were found early in disease in sera and BALF. In combination with the correlation of anti-HisRS-FL antibody levels with ILD and ILD activity in longitudinal samples as well as of anti-WHEP IgG in BALF with poor pulmonary function, this supports the previously raised hypothesis that the lung might have a role in the immune reaction in anti-Jo1-positive patients.

PURPOSE: To analyze the incidence and risk factors of posterior capsule rupture (PCR) in cataract surgery. SETTING: European clinics affiliated with the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO). DESIGN: Retrospective cross-sectional register-based study. METHODS: Data was obtained from the EUREQUO. The database contains data on demographics, comorbidities, and intraoperative complications, including PCR for the study period from January 1, 2008, to December 31, 2018. Univariable and multivariable logistic regression analyses were performed to estimate the (adjusted) odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Data was available of 2,853,376 patients and 31,749 (1.1%) cataract surgeries were complicated by a PCR. The PCR rate ranged from 0.60 to 1.65 percent throughout the years, with a decreasing trend (p

Objective The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA-DRB1 alleles and immunological and clinical data. Methods An unsupervised cluster analysis was performed based on detection of 13 SLE-associated autoantibodies (double-stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjogren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjogren's syndrome antigen B [SSB]/La, cardiolipin [CL]-Immunoglobulin G [IgG], CL-Immunoglobulin M [IgM], and β2 glycoprotein I [β2 GPI]-IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA-DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446). Results Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti-SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA-DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52-4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18-2.47). Subgroup 2 (28.7%) was dominated by anti-nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA-DRB1*15 (OR = 1.62, 95% CI = 1.41-1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14-2.26). Subgroup 3 (23.8%) was characterized by anti-s2 GPI-IgG/anti-CL-IgG/IgM autoantibodies and a higher frequency of HLA-DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2-2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA-DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups. Conclusion Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA-DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.

Objective: Carotid stenosis is a major risk factor for stroke and surgical treatment is key in preventing recurrent ischaemic events. Previous randomised trials have demonstrated the net benefit of surgery for significant symptomatic carotid stenosis but, with present day medical treatment, there is limited evidence on the risk of late ipsilateral ischaemic stroke (IS) and its main risk factors. Method: Ipsilateral IS after the peri-operative period (

IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here compare these antibodies in systemic rheumatic conditions and study their properties. Anti-PC and anti-MDA was measured using ELISA in patients with SLE (374), RA (354), Mixed connective tissue disease (MCTD, 77), Systemic sclerosis (SSc, 331), Sjögren’s syndrome (SjS, 324), primary antiphospholipid syndrome (PAPs, 65), undifferentiated connective tissue disease (UCTD, 118) and 515 matched healthy controls (HC). Cardiovascular score (CV) was broadly defined based on clinical disease symptoms. Anti-PC and anti-MDA peptide/protein characterization were compared using a proteomics de novo sequencing approach. anti-MDA and anti-PC were extracted from total IgM. The proportion of Treg cells was determined by flow cytometry. The maximal difference between cases and controls was shown for MCTD: significantly lower IgM Anti-PC but not anti-MDA among patients (median 49.3RU/ml vs 70.4 in healthy controls, p(t-test) = 0.0037). IgM low levels were more prevalent in MCTD, SLE, SjS, SSc and UCTD. IgM anti-PC variable region profiles were different from and more homologous than anti-MDA. Anti-PC but not anti-MDA were significantly negatively correlated with CV in the whole patient group. In contrast to IgM anti-PC, anti-MDA did not promote polarization of Tregs. Taken together, Anti-PC is decreased in MCTD and also in SLE, SjS and SSc but not in other studied diseases. Anti-PC may thus differentiate between these. In contrast, anti-MDA did not show these differences between diseases studied. Anti-PC level is negatively correlated with CV in the patient group cohort. In contrast to anti-PC, anti-MDA did not promote Treg polarization. These findings could have both diagnostic and therapeutic implications, one possibility being active or passive immunization with PC in some rheumatic conditions.

Background:Cognitive behavioural therapy (CBT) is an effective treatment for panic disorder with agoraphobia (PDA). However, implementation of some of the procedures involved, particularly in vivo exposure, can be time consuming and taxing for routine health care services. CBT with exposure taking place in virtual reality (VR-CBT) is a more time-efficient option and has shown promising results in the treatment of PDA. However, VR-CBT requires expensive equipment and appropriate virtual environments, which historically has been costly and cumbersome to produce. Thus, access to VR-CBT has been sparse in regular care environments.Aims:The aim of this study was to investigate whether VR-CBT using filmed virtual environments produced with a low-cost 360-degree film camera can be a feasible and acceptable treatment for PDA when implemented in a primary care context.Method:This was an open feasibility trial with a within-group design, with assessments conducted at pre-test, post-test, and 6-month follow-up. Participants (n = 12) received a 10–12 week treatment programme of VR-CBT and PDA-related symptoms were assessed by the primary outcome measure The Mobility Inventory for Agoraphobia (MIA) and the Panic-Disorder Severity Scale-Self Rated (PDSS-SR).Results:The results showed that treatment satisfaction was high and participants were significantly improved on PDA-related measures at post-treatment and at 6-month follow-up with large effect sizes (Cohen’s d range = 1.46–2.82). All 12 participants completed the treatment.Conclusions:These findings suggest that VR-CBT with 360-degree video virtual environments delivered to primary care patients with PDA is feasible, acceptable, and potentially efficacious.

BackgroundAutistic traits are influenced by both genetic and environmental factors, and are known to vary geographically in prevalence. But to what extent does their aetiology also vary from place to place?MethodsWe applied a novel spatial approach to data on autistic traits from two large twin studies, the Child and Adolescent Twin Study in Sweden (CATSS; N=16,677, including 8,307 twin pairs) and the Twins Early Development Study in the UK (TEDS; N=11,594, including 5,796 twin pairs), to explore how the influence of nature and nurture on autistic traits varies from place to place.ResultsWe present maps of gene- and environment-by geography interactions in Sweden and the United Kingdom (UK), showing geographical variation in both genetic and environmental influences across the two countries. In Sweden genetic influences appear higher in the far south and in a band running across the centre of the country. Environmental influences appear greatest in the south and north, with reduced environmental influence across the central band. In the UK genetic influences appear greater in the south, particularly in more central southern areas and the southeast, the Midlands and the north of England. Environmental influences appear greatest in the south and east of the UK, with less influence in the north and the west.ConclusionsWe hope this systematic approach to identifying aetiological interactions will inspire research to examine a wider range of previously unknown environmental influences on the aetiology of autistic traits. By doing so, we will gain greater understanding of how these environments draw out or mask genetic predisposition and interact with other environmental influences in the development of autistic traits.

Background Polygenic scores (PGS) for attention‐deficit/hyperactivity disorder (ADHD) negatively predicts educational attainment (EA), but it remains unclear how ADHD symptoms, PGS for EA, and shared familiar factors influence the associations between PGS for ADHD and school performance. Method We combined survey data on ADHD symptoms, PGS, and register‐based, objective measures of compulsory school performance at age 16 for 6049 twins in the Child and Adolescent Twin Study in Sweden. Linear and instrumental variable (IV) regression models were used to estimate the association between PGS for ADHD and grade point average (GPA), overall and by natural science, humanities, and practically oriented (e.g., sports, arts, music) subject categories. The models were adjusted for parent‐rated ADHD symptoms, PGS for EA, and shared familial factors (dizygotic twin comparisons) to examine how these factors influenced the associations between PGS for ADHD and school performance. Results PGS for ADHD were negatively associated with school performance; β = −0.12, 95% confidence interval = (−0.15, −0.09) for overall GPA with minor differences by subject category. Adjustment for ADHD symptoms attenuated these associations to a small degree compared to PGS for EA, and shared familial factors respectively. Stronger associations were observed using IV regressions compared to linear regression. However, in the IV regression analyses, most associations between PGS for ADHD and GPA in the practically oriented subject category were not significant. Conclusion Associations between PGS for ADHD and school performance are to a small degree influenced by ADHD symptoms, compared to PGS for EA and shared familial factors. These results highlight important considerations for research using PGS for ADHD to control for genetic factors, and for future clinical applications aiming to determine genetic liability towards ADHD.

Background and Purpose: The EFFECTS (Efficacy of Fluoxetine—a Randomised Controlled Trial in Stroke) recently reported that 20 mg fluoxetine once daily for 6 months after acute stroke did not improve functional outcome but reduced depression and increased fractures and hyponatremia at 6 months. The purpose of this predefined secondary analysis was to identify if any effects of fluoxetine were maintained or delayed over 12 months. Methods: EFFECTS was an investigator-led, randomized, placebo-controlled, double-blind, parallel group trial in Sweden that enrolled adult patients with stroke. Patients were randomized to 20 mg oral fluoxetine or matching placebo for 6 months and followed for another 6 months. The primary outcome was functional outcome (modified Rankin Scale), at 6 months. Predefined secondary outcomes for these analyses included the modified Rankin Scale, health status, quality of life, fatigue, mood, and depression at 12 months. Results: One thousand five hundred patients were recruited from 35 centers in Sweden between 2014 and 2019; 750 were allocated fluoxetine and 750 placebo. At 12 months, modified Rankin Scale data were available in 715 (95%) patients allocated fluoxetine and 712 (95%) placebo. The distribution of modified Rankin Scale categories was similar in the 2 groups (adjusted common odds ratio, 0.92 [95% CI, 0.76–1.10]). Patients allocated fluoxetine scored worse on memory with a median value of 89 (interquartile range, 75–100) versus 93 (interquartile range, 82–100); P =0.0021 and communication 93 (interquartile range, 82–100) versus 96 (interquartile range, 86–100); P =0.024 domains of the Stroke Impact Scale compared with placebo. There were no other differences in secondary outcomes. Conclusions: Fluoxetine after acute stroke had no effect on functional outcome at 12 months. Patients allocated fluoxetine scored worse on memory and communication on the Stroke Impact Scale compared with placebo, but this is likely to be due to chance. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02683213.

Although highly heritable, environment also contributes to the etiology of autism spectrum disorder (ASD), with several specific environmental factors previously suggested. A registry-linked population-based twin cohort of 15,701 pairs (586 individuals with an ASD diagnosis), was established within the Child and Adolescent Twin Study in Sweden. Participants were evaluated for autistic symptoms at age 9 using the Autism-Tics, ADHD and other Comorbidities parental interview. A series of binary cut-offs indicated whether participants scored over various ASD symptom percentiles. Three early medical factors previously associated with ASD, beyond familial confounding (low birth weight, congenital malformations and perinatal hypoxia), were summed up creating an individual cumulative exposure load. A series of unconditional logistic regressions between all individuals and conditional regressions within twin pairs were performed for each outcome and exposure level. Between all individuals increasing cumulative early exposure loads were associated with increasing risk of ASD diagnosis (OR 3.33 (95%CI 1.79–6.20) for three exposures) and autistic symptoms (ranging from OR 2.12 (1.57–2.86) for three exposures at the 55th symptom percentile cut-off to OR 3.39 (2.2–5.24) at the 95th). Within twin pairs, the association between three exposures and an ASD diagnosis remained similar, but not statistically significant (OR 2.39 (0.62–9.24)). Having a higher load of early cumulative exposure was consistently associated with autistic symptoms after adjusting for familial confounding and sex (OR 3.45 (1.66–7.15) to OR 7.36 (1.99–27.18)). This study gives support to the cumulative stress hypothesis of ASD, and the dimensional model regarding environmental exposures, after adjustment for familial confounding.

BackgroundAccumulating evidence suggests that many psychiatric disorders etiologically represent the extreme end of dimensionally distributed features rather than distinct entities. The extent to which this applies to eating disorders (EDs) is unknown.MethodsWe investigated if there is similar etiology in (a) the continuous distribution of the Eating Disorder Inventory-2 (EDI-2), (b) the extremes of EDI-2 score, and (c) registered ED diagnoses, in 1481 female twin pairs at age 18 years (born 1992–1999). EDI-2 scores were self-reported at age 18. ED diagnoses were identified through the Swedish National Patient Register, parent-reported treatment and/or self-reported purging behavior of a frequency and duration consistent with DSM-IV criteria. We differentiated between anorexia nervosa (AN) and other EDs.ResultsThe heritability of the EDI-2 score was 0.65 (95% CI 0.61–0.68). The group heritabilities in DeFries–Fulker extremes analyses were consistent over different percentile-based extreme groups [0.59 (95% CI 0.37–0.81) to 0.65 (95% CI 0.55–0.75)]. Similarly, the heritabilities in liability threshold models were consistent over different levels of severity. In joint categorical-continuous models, the twin-based genetic correlation was 0.52 (95% CI 0.39–0.65) between EDI-2 score and diagnoses of other EDs, and 0.26 (95% CI 0.08–0.42) between EDI-2 score and diagnoses of AN. The non-shared environmental correlations were 0.52 (95% CI 0.32–0.70) and 0.60 (95% CI 0.38–0.79), respectively.ConclusionsOur findings suggest that some EDs can partly be conceptualized as the extreme manifestation of continuously distributed ED features. AN, however, might be more distinctly genetically demarcated from ED features in the general population than other EDs.

Background Anxiety disorders in adolescence have been associated with several psychiatric outcomes. We sought to describe the prospective relationship between various levels of adolescent anxiety and psychiatric diagnoses (anxiety-, bipolar/psychotic-, depressive-, and alcohol and drug misuse disorders) and suicidal ideation in early adulthood while adjusting for childhood attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental coordination disorder (DCD). Furthermore, we aimed to estimate the proportion attributable to the various anxiety levels for the outcomes. Methods We used a nation-wide population-based Swedish twin study comprising 14,106 fifteen-year-old twins born in Sweden between 1994 and 2002 and a replication sample consisting of 9211 Dutch twins, born between 1985 and 1999. Adolescent anxiety was measured with parental and self-report. Psychiatric diagnoses and suicidal ideation were retrieved from the Swedish National Patient Register and via self-report. Results Adolescent anxiety, of various levels, predicted, in the Swedish National Patient Register, anxiety disorders: hazard ratio (HR) = 4.92 (CI 3.33–7.28); depressive disorders: HR = 4.79 (3.23–7.08), and any psychiatric outcome: HR = 3.40 (2.58–4.48), when adjusting for ADHD, ASD, and DCD. The results were replicated in the Dutch data. The proportion of psychiatric outcome attributable to adolescent anxiety over time (age 15–21) was 29% for any psychiatric outcome, 43–40% for anxiety disorders, and 39–38% for depressive disorders. Conclusion Anxiety in adolescence constitutes an important risk factor in the development of psychiatric outcomes, revealing unique predictions for the different levels of anxiety, and beyond the risk conferred by childhood ADHD, ASD, and DCD. Developmental trajectories leading into psychiatric outcomes should further empirically investigated.

It has been suggested that alterations in inflammation molecules maintain chronic pain although little is known about how these factors influence homeostatic and inflammatory events in common chronic pain conditions. Nonpharmacological interventions might be associated with alterations in inflammation markers in blood. This study of patients with chronic pain investigates whether an interdisciplinary multimodal rehabilitation program (IMMRP) was associated with significant alterations in the plasma pattern of 68 cytokines/chemokines 1 year after rehabilitation and whether such changes were associated with clinical changes. Blood samples and self-reports of pain, psychological distress, and physical activity of 25 complex chronic pain patients were collected pre-IMMRP and at 12-month follow-up. Analyses of inflammatory proteins (cytokines/chemokines/growth factors) were performed directly in plasma using the multiplex immunoassay technology Meso Scale Discovery. This explorative pilot study found that 12 substances, mainly pro-inflammatory, decreased after IMMRP. In two other relatively small IMMRP studies, four of these proinflammatory markers were also associated with decreases. The pattern of cytokines/chemokines pre-IMMRP was associated with changes in psychological distress but not with pain or physical activity. The present study cannot impute cause and effect. These results together with the results of the two previous IMMRP studies suggest that there is a need for larger and more strictly controlled studies of IMMRP with respect to inflammatory markers in blood. Such studies need to consider responders/non-responders, additional therapies, involved pain mechanisms and diagnoses. This and the two other studies open up for developing biologically measurable outcomes from plasma. Such biomarkers will be an important tool for further development of IMMRP and possibly other treatments for patients w ith chronic pain.

Recent studies have demonstrated a role of neutrophils in both venous and arterial thrombosis. A key prothrombotic feature of neutrophils is their ability to release web-like structures composed of DNA filaments coated with histones and granule proteins referred to as neutrophil extracellular traps (NETs). NETs were discovered over a decade ago as part of our first line of host defense against invading microorganisms. Although NETs have a protective role against pathogens, recent data suggest that an uncontrolled and excessive NET formation within the vasculature may contribute to pathological thrombotic disorders. In vitro studies suggest that NETs promote vessel occlusion by providing a scaffold for platelets, red blood cells, extracellular vesicles, and procoagulant molecules, such as von Willebrand factor and tissue factor. In addition, NET components enhance coagulation by both activating the intrinsic pathway and degrading an inhibitor of the extrinsic pathway (tissue factor pathway inhibitor). NET formation has, therefore, been proposed to contribute to thrombus formation and propagation in arterial, venous, and cancer-associated thrombosis. This review will describe animal and human studies suggesting a role of NETs in the pathogenesis of various thrombotic disorders. Targeting NETs may be a novel approach to reduce thrombosis without affecting hemostasis.

There are no previous data on the influence of drospirenone (DRSP) in combination with estradiol (E2) on the breast in postmenopausal women. The objective of this study was to evaluate the effect of DRSP or norethisterone acetate (NETA) in continuous combination with E2 on two surrogate markers for breast cancer - mammographic breast density and proliferation of breast epithelial cells - in healthy postmenopausal women.120 healthy, naturally postmenopausal women were randomized to either 2 mg of DRSP or 0.5 mg of NETA in continuous combination with 1 mg of oral E2. The women underwent mammography and fine-needle aspiration biopsy of the breast at baseline and after six months of treatment.Digitized mammographic breast density and breast cell proliferation.There was a significant increase in mammographic breast density after treatment in both groups (median increase 5.5% for E2/DRSP and 2.3% for E2/NETA, respectively, p 0.001), but with no significant difference between groups. The proliferation of breast epithelial cells also increased in both groups (p 0.001, respectively), with a significantly larger increase in the E2/DRSP group than in the E2/NETA group (2.5% versus 0.7%, respectively, p 0.05). Systolic blood pressure had decreased significantly after 6 months of treatment in the E2/DRSP group (p 0.05) but not in the E2/NETA group.Breast density increased to a similar degree with E2/DRSP and E2/NETA. Proliferation of breast epithelial cells also increased significantly in both groups but was slightly more pronounced in the E2/DRSP group.

Objectives: To estimate the incidence of men seeking specialized care and receiving treatment for hydro or spermatocele complaints. Also, to determine the risk of complications of treatment.Materia...

People with severe mental illness (SMI) experience an increased risk of physical ill health and premature death, which appears to be partly related to unhealthy lifestyle habits. The aim of this study was to describe the distribution of health-related lifestyle habits and perceived health among people with severe mental illness. A further aim was to explore if there were any gender differences or differences based on degree of sense of coherence. The study adopted a cross-sectional design based on data from 65 people with SMI. The results show that degree of Sense of Coherence (SOC) does have relevance for perceived health and for dimensions of Quality of Life (QOL). Furthermore, among the participants with strong SOC, there were less daily smokers and they seemed to have less sedentary leisure time than those with low SOC. Men reported more anxiety/depression than women and women ate fruit more often than men, otherwise there were no gender differences. In comparison with the general population, people with SMI show a higher Body Mass Index are more sedentary, more often daily smokers, have lower SOC and perceive a lower QOL. This emphasizes the importance of health-promotion support that focuses on lifestyle changes, and support for strengthening SOC and QOL for people with SMI.

BACKGROUND The prevalence of diagnosed Autism Spectrum Disorder (ASD) has increased substantially across the world. Much - or even most - prevalence increase seems to reflect changes in diagnostic practice and ascertainment. A key part of ASD assessment is to document that the relevant symptoms are associated with clinical impairment. The aim of the present study is to capitalize on a nationwide longitudinal study spanning 15 consecutive birth year cohorts in order to investigate whether there has been a secular change in how parents perceive the impairment and suffering conferred by autism symptomatology in their children. METHODS Data came from the Child and Adolescent Twin Study in Sweden (27,240 individuals), where parents had reported on their child's ASD symptoms and impairment. Impairment due to ASD symptoms was regressed on an ASD symptom score across time. This was done for five 3-year birth cohorts (1995-1997, 1998-2000, 2001-2003, 2004-2006, and 2007-2009). RESULTS Reported impairment increased with consecutively later birth cohorts. This was evident across all levels of autism symptomatology. At clinically relevant levels of symptomatology, parents of those born 2007-2009 reported a 23% higher degree of impairment as compared with parents of those born in 1995-1997. The relative difference, however, was even greater at levels that previously would have been considered below the diagnostic threshold. DISCUSSION The results presented here contribute to the notion of a growing diffuseness in the conceptualization of the ASD diagnosis by adding the element of secular changes in the parental perception of the consequences of ASD symptom expression.

Purpose: To analyze real-world graft survival and visual acuity outcomes of corneal transplantation in Europe.Setting: Corneal clinics in 10 European Union member states, the United Kingdom, and Switzerland.Design: Multinational registry study.Methods: All corneal transplant procedures registered in the European Cornea and Cell Transplantation Registry (ECCTR) were identified. Graft survival of primary corneal transplants were analyzed using Kaplan-Meier survival curves with log-rank test and Cox regression. Corrected distance visual acuities (CDVAs) are reported at baseline and 2 years postoperatively using the Lundstro & uml;m distribution matrix.& nbsp;Results: A total of 12913 corneal transplants were identified. Overall, 32-year graft survival of corneal transplants was high (89%) but differed between indications, ranging from 98% in keratoconus and 80% for trauma. Overall, CDVA improved postoperatively, but the risk for losing vision ranged from 7% (baseline vision = 1.0 Snellen).Conclusions: This report provides a comprehensive overview of graft survival and visual outcomes of corneal transplantation in Europe. In addition, it provides real-world estimates of outcomes for a variety of indications and surgical techniques to support benchmarking and demonstrates the relationship between baseline and postoperative vision.

Background Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design. Methods We conducted a cohort study in twins (7–12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden. Results Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively). Conclusions Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.

Objective: The pathways from internalizing psychopathology to substance misuse remain largely unclear. We estimated associations between childhood internalizing problems and subsequent substance misuse in 2 family-based samples. We also investigated sex differences and the role of externalizing comorbidity. Method: We studied associations of childhood internalizing psychopathology with register-based substance misuse after age 13 years. Sample 1 included all individuals born in Sweden from 1984 to 2000 (N = 1,768,516). Depressive and anxiety disorders were included as register-based International Classification of Diseases Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses before age 13. Sample 2 was a subsample within the population sample, the Child and Adolescent Twin Study in Sweden (CATSS) twin cohort (n = 12,408; born 1992-1998), with mood and anxiety problems assessed at age 9/12 by parents. In both samples, substance misuse was defined as an ICD-9/10 alcohol/drug use disorder or an alcohol/drug-related criminal conviction until December 2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Results: In the population sample, both depressive (hazard ratio [HR] = 2.75, 95% CI = 2.36-3.20) and anxiety disorders (HR = 1.52, 95% CI = 1.35-1.73) were associated with substance misuse. Childhood mood problems (HR = 2.28, 95% CI = 1.69-3.08) were associated with substance misuse in the CATSS sample. The associations were partially explained by familial factors, and comorbid externalizing disorders explained the associations in men but not in women. Conclusion: Childhood mood problems were associated with substance misuse, but familial factors shared by siblings partially explained the associations. The relationship of anxiety with substance misuse was complex and depended on measurement and the type of anxiety disorder. Internalizing problems may be especially important for substance misuse risk in women.

The use of quinolones has recently been questioned due to reports on side effects including an increased risk of aortic aneurysm. The aim of the study was to examine the risk of aortic aneurysm (AA) after short-term ciprofloxacin as prophylaxis for prostate biopsy. We used the Prostate Cancer data Base Sweden and investigated 192,024 prostate biopsy exposures vs. 554,974 non-exposures for risk of AA. Prostate biopsy was used as a proxy for quinolone use as short-term ciprofloxacin is the recommended and documented prophylaxis in Sweden for this procedure. The outcome was the hazard ratio (HR) of AA in men who underwent a biopsy vs. those that did not. The absolute risk of AA was small, 39/10,000 person years for all AÁs and for ruptured AÁs 3.5/10,000 person years. In multivariate analyses, there were small, non-significant increases in risk of all AA’s (adjusted HR = 1.13, 95% CI: 0.91 to 1.39) and ruptured AÁs (adjusted HR = 1.05, 95% CI: 0.52 to 2.15) in men who underwent biopsy. A significantly increased risk of AA was observed in men diagnosed with high-risk prostate cancer on biopsy (HR = 1.50, 95% CI: 1.15–2.21). The use of prostate biopsy as a proxy for exposure to ciprofloxacin was a limitation of the study. Short-term ciprofloxacin was not associated with an increased risk of aortic aneurysm and the increased risk in men with high-risk prostate cancer was likely due detection bias caused by imaging more commonly performed in these men.

BackgroundThere is evidence that autism spectrum disorders (ASDs) co-occur with bipolar disorder (BD) relatively frequently. Individuals with BD often report symptoms of mania and hypomania during adolescence, prior to the age of onset for BD. It is unknown whether these symptoms are associated with ASDs. We examined whether diagnoses of ASDs and autistic traits were associated with hypomania in a large, population-based Swedish twin sample.MethodsParental structured interviews assessed autistic traits, and were used to assign screening diagnoses of ASDs, when twins were aged 9 or 12 (N = 13 533 pairs). Parents then completed questionnaires assessing hypomania when the twins were aged 15 and 18 (N = 3852 pairs at age 15, and 3013 pairs at age 18). After investigating the phenotypic associations between these measures, we used the classical twin design to test whether genetic and environmental influences on autistic traits influence variation in adolescent hypomania.ResultsAutistic traits and ASD diagnoses in childhood were associated with elevated scores on the measures of adolescent hypomania. Twin analyses indicated that 6–9% of the variance in hypomania was explained by genetic influences that were shared with autistic traits in childhood. When repeating these analyses for specific autistic trait domains, we found a stronger association between social interaction difficulties and hypomania than for other autistic trait domains.ConclusionsThese results indicate a genetic link between autistic traits and hypomania in adolescence. This adds to the growing evidence base of genetic factors associated with ASDs showing links with psychiatric outcomes across childhood and into adulthood.

The primary aim of this study was to explore the overlaps between dyslexia and a range of neurodevelopmental disorders and problems (NDPs), specifically symptoms of attention-deficit/hyperactivity disorder, autism spectrum disorder, atypical sensory perception and developmental coordination disorder. Capitalizing on a population-based sample of twins, secondary aims included estimating the heritability of dyslexia and reporting on the measurement characteristics of the scale used to assess dyslexia. A telephone interview regarding symptoms of dyslexia and other NDPs was conducted with parents of 1,688 nine-year-old twins. The prevalence and the heritability of dyslexia were estimated at 8 and 52%, respectively. The boy: girl ratio was 1.5:1. Results revealed that there was more than an eight-fold increase in (diagnostic proxy) NDPs prevalence in the dyslexia group as compared to typical readers. Quantitatively measured symptoms of inattention, oral language problems and atypical sensory perception significantly predicted dyslexia status in a multivariate analysis. By contrast, ASD-related inflexibility was inversely associated with dyslexia in the multivariate model. In sum, dyslexia often overlaps with other NDPs. The current study provides new knowledge supporting the position to move beyond isolated diagnostic categories into behavioural profiles of co-occurring problems when trying to understand the pattern of strengths and needs in individuals with dyslexia.

Background - Stroke has transitioned from an untreatable, unpreventable disease to a highly treatable and preventable disease over recent decades, and the number of stroke survivors is expected to increase. The number is also foreseen to grow larger as a result of an aging population. With an escalating number of stroke survivors, research on how to improve life after stroke is needed. Aims - The primary aim was to determine which area of research related to life after stroke that stroke patients and their informal carers prioritized as being relevant and valuable. Methods - A cross-sectional study of all patients who had completed the 12 months of follow-up in the EFFECTS trial. In the questionnaire the stroke patients and their informal carers were asked to prioritize areas of research they considered important and valuable with respect to their life after stroke. Results - Of the 731 patients who were still alive after the 12 months-follow-up, 589 responded. The most prioritized areas of research were Balance and walking difficulties (290 (49%) responders) and Post-stroke fatigue (173 (29%) responders). Women answered the undefined alternative “other” more often than men (43 women (11%) versus 11 men (6%), p = .04). Younger patients prioritized Post-stroke fatigue to a higher extent (88 (45%) versus (22%), p < .001), and elderly prioritized Balance and walking difficulties (214 (54%) versus 76 (40%), p = .002) and Speech difficulties (38 (10%) versus 9 (5%), p = .045). Conclusions - Life after stroke is perceived differentely with aging. Future research should address strategies to face challenges such as imbalance and walking difficulties and post-stroke-fatigue.

Purpose: To analyse if patients with diabetic retinopathy (DR) subjected to cataract surgery differ in outcome compared to patients without DR with regard to best-corrected visual acuity (BCVA), deviation from target refraction, intraoperative difficulties and risk of complications. Methods: A register-based study from the Swedish National Cataract Register (NCR) during the years 2015–2017 including 358 040 cataract procedures. Patients with other ocular pathology than cataract and DR were omitted from outcome analyses. Results: Diabetic retinopathy was reported in 13 724 of all eyes (3.8%). Preoperative BCVA was significantly worse in DR patients than in patients without DR, 0.54 ± 0.33 compared to 0.40 ± 0.27 (logMAR, mean ± SD, p < 0.001). The same was evident for postoperative BCVA, 0.15 ± 0.25 for DR patients versus 0.06 ± 0.13 (p < 0.001). The improvement in BCVA was slightly better in DR than in non-DR, −0.40 ± 0.32 (logMAR; mean ± SD) versus −0.35 ± 0.27, p < 0.001. The absolute mean biometry prediction error was 0.42 ± 0.50 diopters (D) in DR and 0.43 ± 0.71 D in non-DR patients, p = 0.768. One or more intraoperative difficulties, including mechanical pupil dilation, capsular stain, hooks at capsulorhexis margin or capsular tension ring, had an adjusted odds ratio (OR) of 1.75 (95% confidence interval [CI] 1.61–1.90, p < 0.001) in DR versus non-DR cases and the rate of posterior capsular tears (PCR) had an adjusted OR of 1.76 (95% CI 1.40–2.20, p < 0.001). Conclusion: Eyes with DR have inferior pre- and postoperative BCVA compared to non-DR eyes. There is little difference in improvement of BCVA and no difference in absolute mean biometry prediction error. Importantly, intraoperative difficulties and PCRs are almost twice as common in DR patients, strongly indicating that these patients should be managed by experienced surgeons.

Purpose: To characterize pre- and perioperative factors associated with treatment for wet age-related macular degeneration (wet AMD) after cataract surgery. Methods: This register-based cohort study with data from the Swedish National Cataract Register (NCR) and the Swedish Macula Register (SMR) from 2010 to 2017 compared eyes with and without preoperative AMD that had undergone cataract surgery and was subsequently treated for wet AMD to eyes not treated within the study period. All first-eye surgeries registered in the NCR from 2010 to 2017 and matching eyes found in the SMR that had undergone treatment for wet AMD ≥ 1 year after the cataract procedure were included. Data for cataract surgery date, age and gender, use of a blue-blocking IOL, preoperative visual acuity, ocular comorbidities, posterior capsule rupture and date of AMD treatment initiation were extracted. Results: The only independent factor associated with postoperative treatment of wet AMD in both groups was female gender (67.3% vs. 58.8%, p < 0.001 and 66.4% vs. 60.6%, p = 0.001, respectively). Older age was an independent factor in eyes without preoperative AMD (78.4 ± 6.5 vs. 73.4 ± 9.6 years, p < 0.001). A blue-blocking IOL appeared to decrease the likelihood of subsequent wet AMD treatment slightly but not statistically significant in eyes with preoperative AMD (52.7% vs. 56.8%, p = 0.110). Conclusions: Some factors (female gender, high age) are associated with undergoing subsequent treatment for wet AMD to a higher extent. If the use of a blue-blocking IOL offers any protection from undergoing AMD treatment after cataract surgery, such an effect must be very small. (Less)

Background Coronavirus disease 2019 (COVID-19), is a disease with diverse presentation. Several studies have shown different occurrence of symptoms for women and men, but no studies have been found examining sex differences in clinical presentation for nursing home residents dying from COVID-19. The objective of this study was to describe sex and age differences and the impact of a dementia diagnosis on symptom occurrence during the last week in life for persons dying from COVID-19 in nursing homes. Methods This is a population-based retrospective study based on data from the Swedish Register of Palliative Care. A total of 1994 residents aged 65 or older who died from COVID-19 in nursing homes were identified. The impact of sex, age and a dementia diagnosis on six different symptoms was analysed using chi2-test and multivariate logistic regression. Results Residents dying from COVID-19 were more often men (p p p Conclusions We found sex differences in symptom presentation for fatal COVID-19 in nursing home settings which remained after adjusting for age. Residents with a dementia diagnosis had fewer symptoms reported before death compared to those without dementia. Clinical presentation of fatal COVID-19 differs between women and men in nursing homes. Residents with fatal COVID-19 present with more unspecific and less prominent symptoms when also suffering from dementia.

Objective:To evaluate whetherdaily mobile-phone delivered messages with training instructions during three months increase physical activity and overall mobility in patients soon after stroke or transient ischemic attack.Design:Randomised controlled trial with intention-to-treat analyses.Setting:University hospital. Data collection from November 2016 until December2018.Subjects:Seventy-nine patients (mean (SD) age 63.9 (10.4) years, 29 were women) were allocated to either intervention ( n = 40) or control group ( n = 39). Participants had to be independent (modified Ranking Scale ⩽2) and able to perform the six-minute walking test at discharge from the hospital.Interventions:The intervention group received standard care and daily mobile phone instructional text messages to perform regular outdoor walking and functional leg exercises. The control group received standard care; that is, primary care follow-up.Main measures:Walking performance by six-minute walking test (m), lower body strength by five times chair-stand test (s), the short physical performance battery (0–12 points) and 10-metres walk test (m/s) were assessed at baseline and after three months.Results:The estimated median difference in the six-minute walking test was in favour of the intervention group by 30 metres (95% CI, 55 to 1; effect size 0.64; P = 0.037) and in the chair-stand test by 0.88 seconds (95% CI, 0.02 to 1.72; effect size 0.64; P = 0.034). There were no differences between groups on the short physical performance battery or in 10-metres walking time.Conclusions:Three months of daily mobile phone text messages with guided training instructions improved composite mobility measures; that is, walking performanceand lower body strength.Clinical Trial Registry:The study is registered with ClinicalTrials.gov , number NCT02902367.

Objective: Abdominal aortic graft and endograft infection (AGI) is primarily treated by resection of the infected graft and restoration of distal perfusion through extra-anatomic bypass (EAB) or in situ reconstruction/repair (ISR). The aim of this study was to compare these surgical strategies in a nationwide multicentre retrospective cohort study. Methods: The Swedish Vascular Registry (Swedvasc) was used to identify surgically treated abdominal AGIs in Sweden between January 1995 andMay 2017. The primary aimwas to compare short and long termsurvival, as well as complications for EAB and ISR. Results: Some 126 radically surgically treated AGI patients were identified - 102 graft infections and 24 endograft infections - treated by EAB: 71 and ISR: 55 (23 neo-aorto-iliac systems, NAISs). No differences in early 30 day (EAB 81.7% vs. ISR 76.4%, p = .46), or long term five year survival (48.2% vs. 49.9%, p = .87) were identified. There was no survival difference comparing NAIS to other ISR strategies. The frequency of recurrent graft infection during follow up was similar: EAB 20.3% vs. ISR 17.0% (p = .56). Survival and re-infection rates of the new conduit did not differ between NAIS and other ISR strategies. Age >= 75 years (odds ratio [OR] 4.0, confidence interval [CI] 1.1 - 14.8), coronary artery disease (OR 4.2, CI 1.2 - 15.1) and post-operative circulatory complications (OR 5.2, CI 1.2 - 22.5) were associated with early death. Prolonged antimicrobial therapy (> 3 months) was associated with reduced long term mortality (HR 0.3, CI 0.1 - 0.9). Conclusion: In this nationwide multicentre study comparing outcomes of radically treated AGI, no differences in survival or re-infection rate could be identified comparing EAB and ISR.

Background Three large trials of fluoxetine for stroke recovery (FOCUS (fluoxetine or control under supervision), AFFINITY (the Assessment oF FluoxetINe In sTroke recovery) and EFFECTS (Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke)) have been collaboratively designed with the same basic protocol to facilitate an individual patient data analysis (IPDM). The statistical analysis plan for the three individual trials has already been reported in Trials, including a brief description of the IPDM. In this protocol, we describe in detail how we will perform the IPDM. Methods/design Data from EFFECTS and AFFINITY will be transferred securely to the FOCUS statistician, who will perform a one-stage IPDM and a two-stage IPDM. For the one-stage IPDM, data will be combined into a single data set and the same analyses performed as described for the individual trials. For the two-stage IPDM, the results for the three individual trials will be combined using fixed effects meta-analyses. The primary and secondary outcome domains for the IPDM are the same as for individual trials. We will also perform analyses according to several subgroups including country of recruitment, ethnicity and trial. We will also explore the effects of fluoxetine on our primary and secondary outcomes in subgroups defined by combinations of characteristics. We also describe additional research questions that will be addressed using the combined data set, and published subsequently, including predictors of important post-stroke problems such as seizures, low mood and bone fractures. Discussion An IPDM of our three large trials of fluoxetine for stroke recovery will allow us to provide the most precise estimates of any risks and benefits of fluoxetine vs placebo, to detect reliably a smaller overall effect size than those detectable by the individual trials, to better determine the effects of fluoxetine vs placebo in subgroups of patients and outcomes and to broaden the generalisability of the results. Also, we may identify differences in treatment effects between studies. Trial registration FOCUS: ISRCTN ISRCTN83290762. Registered on 23 May 2012. EudraCT 2011-005616-29. Registered on 3 February 2012. AFFINITY: Australian New Zealand Clinical Trials Registry ACTRN12611000774921. Registered on 22 July 2011. EFFECTS: ISRCTN ISRCTN13020412. Registered on 19 December 2014. ClinicalTrials.gov NCT02683213. Registered on 2 February 2016. EudraCT 2011-006130-16. Registered on 8 August 2014.

Importance It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk. Objective To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk. Design, Setting, and Participants A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa. Interventions Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins. Main Outcomes and Measures The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Results When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09];P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil–treated patients (14.7%). Conclusions and Relevance Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients. Trial Registration ClinicalTrials.gov Identifier:NCT02104817

Predicting survival accurately in patients with advanced cancer is important in guiding interventions and planning future care. Objective tools are therefore needed. Blood biomarkers are appealing due to their rapid measurement and objective nature. Thrombosis is a common complication in cancer. Recent data indicate that tumor-induced neutrophil extracellular traps (NETs) are pro-thrombotic. We therefore performed a comprehensive investigation of circulating markers of neutrophil activation, NET formation, coagulation and fibrinolysis in 106 patients with terminal cancer. We found that neutrophil activation and NET markers were prognostic in terminal cancer patients. Interestingly, markers of coagulation and fibrinolysis did not have a prognostic value in this patient group, and there were weak or no correlations between these markers and markers of neutrophil activation and NETs. This suggest that NETs are linked to a poor prognosis through pathways independent of coagulation. Additional studies are needed to determine the utility of circulating neutrophil activation and NET markers, alone or in concert with established clinical parameters, as objective and reliable prognostic tools in advanced cancer.

Previous studies have shown an association between IQ and adaptive global functioning, i.e. how well a person is functioning in different domains of life. However, it is unclear to what extent such an association applies in children with neurodevelopmental disorders (NDDs). The study group consisted of 550 population-screened children assessed with the K-SADS, WISC-IV, and the C-GAS. Approximately half of the sample had been diagnosed with one or several NDDs (ADHD, autism, language disorder and tic disorder). A factorial ANOVA with IQ level and the presence of NDD was conducted, with C-GAS score as the dependent variable. Results revealed a significant interaction effect between IQ-group and NDD-status. In the non-NDD group (49% girls), higher IQ scores were clearly linked with better global adaptive functioning. Among children with NDDs (35% girls), however, higher IQ scores were not clearly associated with better functioning. Thus, the association between IQ and adaptive functioning were found to differ depending on the presence of NDD. These results have implications for the interpretation of IQ test results in neurodevelopmental assessments and point towards the importance of providing support based on an assessment of needs and functioning rather than scores from IQ tests.