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Background and purpose — Knowing how to interpret values obtained with patient reported outcome measures (PROMs) is essential. We estimated the substantial clinical benefit (SCB) and patient acceptable symptom state (PASS) for Forgotten Joint Score 12 (FJS) and explored differences depending on methods used for the estimates. Patients and methods — The study was based on 195 knee arthroplasties (KA) performed at a university hospital. We used 1 item from the Knee injury and Osteoarthritis Outcome Score domain quality of life and satisfaction with surgery, obtained 1-year postoperatively, to assess SCB and PASS thresholds of the FJS with anchor-based methods. We used different combinations of anchor questions for SCB and PASS (satisfied, satisfied with no or mild knee difficulties, and satisfied with no knee difficulties). A novel predictive approach and receiver-operating characteristics curve were applied for the estimates. Results — 70 and 113 KAs were available for the SCB and PASS estimates, respectively. Depending on method, SCB of the FJS (range 0–100) was 28 (95% CI 21–35) and 22 (12–45) respectively. PASS was 31 (2–39) and 20 (10–29) for satisfied patients, 40 (31–47) and 38 (32–43) for satisfied patients with no/mild difficulties, and 76 (39–80) and 64 (55–74) for satisfied patients with no difficulties. The areas under the curve ranged from 0.82 to 0.88. Interpretation — Both the SCB and PASS thresholds varied depending on methodology. This may indicate a problem using meaningful values from other studies defining outcomes after KA. This study supports the premise of the FJS as a PROM with good discriminatory ability in patients undergoing KA.

Introduction Autoimmune pancreatitis (AIP) is a special form of pancreatitis that responds well to glucocorticoid (GC) treatment. Relapses of AIP are common. The anti-CD20 antibody rituximab (RTX) has shown promising results in GC refractory cases, but long-term data are scarce. The study aims to determine the clinical and imaging response to RTX and summarize the existing data on RTX therapy in patients with AIP type 1 in the literature. Patients and methods Retrospective analysis of electronic medical records was conducted. Additionally, we conducted a systematic review of the literature concerning RTX use in AIP type 1. Results Twelve (11.7%) of 103 patients with AIP type 1 were treated with RTX during the study period: eight (66.7%) achieved complete and four (33.3%) partial remission. RTX was discontinued in one patient who developed fever and reactivation of latent tuberculosis. None of the remaining 11 patients relapsed during a median follow-up of 17 months. No significant differences were detected in baseline clinical characteristics or history of relapse between the patients who obtained complete and partial remission. Altogether, eight studies with 110 AIP type-1 patients treated with RTX were analyzed. Adverse effects ranged from 11-43% and the relapse-free period during follow-up (range 2-173 months) ranged from 38-94%. Conclusions Our results confirm that RTX is efficacious in the treatment of AIP type 1 by inducing remission and preventing relapse. In addition, there are few adverse effects of the treatment.

Background: Infection with human herpesvirus 6A (HHV-6A) has been suggested to increase multiple sclerosis (MS) risk. However, potential interactions between HHV-6A and environmental/lifestyle risk factors for MS have not previously been studied. Methods: We used two Swedish population-based case-control studies comprising 5993 cases and 5995 controls. Using logistic regression models, subjects with different HHV-6A antibody levels, environmental exposures, and lifestyle habits were compared regarding MS risk, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). Potential interactions between high HHV-6A antibody levels and common environmental exposures and lifestyle factors were evaluated on the additive scale. Results: High HHV-6A antibody levels were associated with increased risk of developing MS (OR = 1.5, 95% CI = 1.4–1.6). Regarding MS risk, significant interactions were observed between high HHV-6A antibody levels and both smoking (attributable proportion (AP) = 0.2, 95% CI = 0.1–0.3), low ultraviolet radiation (UVR) exposure (AP = 0.3, 95% CI = 0.1–0.4), and low vitamin D levels (AP = 0.3, 95% CI = 0.0–0.6). Conclusion: High HHV-6A antibody levels are associated with increased MS risk and act synergistically with common environmental/lifestyle risk factors for MS. Further research is needed to investigate potential mechanisms underlying the interactions presented in this study.

Summary This study examines the association between the ASA physical status classification score at hip fracture surgery and severe postoperative complications in patients aged 60 and older. Among both men and women, ASA scores consistently predict a wide range of complications including infections, cardiovascular complications, hospital readmissions, and death. Introduction Hip fractures are common in aging populations and associated with poor prognosis. This study examines how the American Society of Anaesthesiologists (ASA) physical status classification is related to severe complications among hip fracture patients including infections, cardiovascular diseases, hospital readmissions, and death. Methods Based on a linkage of the Swedish National Inpatient Register with the Swedish National Registry for Hip Fractures (RIKSHÖFT), this study includes patients aged 60+ with first hip fracture between 1998 and 2017. We estimated associations between ASA score and complications during the hospital stay and during 1 year after hip fracture using multivariable-adjusted logistic regression and Cox proportional hazard regression. Results The study population included 170,193 hip fracture patients of which 24% died and 39% were readmitted to hospital within 1 year. The most common complications were urinary tract infections, pneumonia, second hip fractures, and heart failure. Among both men and women, higher ASA scores were consistently associated with higher risks for all complications included in this study. The strongest associations were observed for heart failure, myocardial infarction, pneumonia, and death. Conclusion ASA scores are routinely assessed in clinical practice and predict a wide range of postoperative complications among hip fracture patients. Since many complications may be preventable through adequate drug treatment, rehabilitation, and risk awareness, future studies should examine the mechanisms linking ASA scores to complication risk in order to improve preventive strategies. Particularly, the high risk of cardiovascular complications among patients with high ASA scores deserves clinical and scientific attention. Supplementary Information The online version contains supplementary material available at 10.1007/s00198-021-05956-w.

ObjectiveIt has been debated whether the different clinical disease courses in multiple sclerosis (MS) are the consequence of different pathogenic mechanisms, with distinct risk factors, or if all MS clinical phenotypes are variations of similar underlying disease mechanisms. We aimed to study environmental risk factors and their interactions with human leucocyte antigen DRB1*15:01 with regards to relapsing-onset and progressive-onset MS.MethodsWe used two Swedish population-based case–control studies, including 7520 relapsing-onset cases, 540 progressive-onset cases and 11 386 controls matched by age, sex and residential area. Logistic regression was used to estimate ORs with 95% CIs for associations between the different MS phenotypes and a number of environmental and lifestyle factors. Interaction between the DRB1*15:01 allele and environmental risk factors was evaluated on the additive scale.ResultsAll environmental and lifestyle factors associated with risk of developing MS apply to both relapsing-onset and progressive-onset disease. Smoking, obesity and Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibody levels were associated with increased risk of both MS phenotypes, whereas snuff use, alcohol consumption and sun exposure were associated with reduced risk. Additive interactions between DRB1*15:01 and smoking, obesity, EBNA-1 antibody levels and sun exposure, respectively, occurred to increase MS risk regardless of the clinical phenotype.InterpretationOur finding that the same environmental and lifestyle factors affect both relapsing-onset and progressive-onset MS supports the notion that the different clinical phenotypes share common underlying disease mechanisms.

Background and purpose — Studies regarding hip fractures in young patients are rare since the patient population is small. We assessed clinical outcomes 4 months after hip fracture in patients < 50 years of age and whether there were differences between sexes and different age groups. Patients and methods — We included adult patients < 50 years with a hip fracture between January 1, 2014 and December 31, 2018. Baseline data were extracted from the Swedish Registry for Hip Fracture Patients and Treatment (RIKSHÖFT) and mortality data was obtained from Statistics Sweden. The outcome variables were change of walking ability, pain in fractured hip, use of analgesics, living conditions, and mortality rate at 4 months. Results — Of the 905 patients included, 72% were men and femoral neck fractures were most common (58%). 4 months after surgery, 23% used a walking aid and 7% reported severe pain. Women reported slightly more pain and higher usage of analgesics. Patients aged 40–49 reported higher usage of analgesics than patients aged 15–39, although the latter group reported more pain. Nearly all of those who lived independently before fracture did so at 4 months. The mortality rate was < 1%. Interpretation — Most patients did not use any walking aid and few had severe pain at 4 months. Furthermore, a hip fracture is not a life-threatening event in a patient < 50 years. The living conditions did not change for those who lived independently before the fracture.

ObjectiveWe aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for HLA-DRB1*15:01.MethodsUsing population-based case–control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale.ResultsThe effect of each DRB1*15:01 allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between DRB1*15:01 and each assessed environmental factor was of similar magnitude regardless of the number of DRB1*15:01 alleles, although ORs were affected. When any of the environmental factors were present in DRB1*15:01 carriers without the protective A*02:01 allele, a three-way interaction occurred and rendered high ORs, especially among DRB1*15:01 homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity).ConclusionsThe strikingly increased MS risk among DRB*15:01 homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.

Helplessness and hopelessness are transdiagnostic and aggravating factors of mental ill health, but their relation with somatization is not well documented. The main objectives were to identify somatic symptoms that are particularly associated with helplessness, referred to as somatic symptoms of helplessness (SS-He), and hopelessness, referred to as somatic symptoms of hopelessness (SS-Ho), determine increased risk of helplessness and hopelessness if having these symptoms and a certain number of these symptoms, and determine sensitivity and specificity in identifying helplessness and hopelessness based on number of these symptoms in a general Swedish sample. Population-based data from validated questionnaire instruments were used from 3,210 participants who constituted case groups of helplessness and hopelessness, and corresponding reference groups. Among 15 common somatic symptoms, five SS-He (e.g., feeling tired/having low energy) and five SS-Ho (e.g., dizziness) were identified, showing increased risk of helplessness and hopelessness that ranged from the factor 1.73 to 2.58 and from 1.44 to 1.92, respectively, which decreased considerably when controlled for depression and anxiety. The risk of helplessness increased by the factor 1.49 for each additional SS-He, and by 1.38 for each SS-Ho. A cutoff of two/three or more SS-He showed a sensitivity of 81.7/63.7% and a specificity of 40.6/61.4% in identifying helplessness, and 77.4/54.6% and 40.4/66.1%, respectively, in identifying hopelessness based on two/three or more SS-Ho. Primary care clinicians may consider further investigation of helplessness and hopelessness as well as depression and anxiety if presenting with these symptoms.

Studies using cotinine levels to define smokers have generally failed to detect an association between smoking and multiple sclerosis (MS). Using a Swedish population-based case-control study, we show that associations in relation to MS risk and progression differ considerably depending on how smoking is measured. The risk of conversion into secondary progressive disease was increased among smokers when self-reported smoking history, but not presumed cotinine levels, was used to define smokers. Defining smoking by cotinine levels without distinguishing between different sources of nicotine may lead to severely biased estimates of the association between smoking and both MS risk and progression.

Publisher's version (útgefin grein), Background: Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative. Methods: Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets. Results: Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined "seronegative"RA, associated with worse clinical outcome. Conclusions: "Seronegative"RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2-/IgM RF- patients with a high need for active treatment., This work was supported by grants from the Swedish Research Council (2017-01696); King Gustav V:s 80-year foundation (FAI-2016-0273); the EU funded consortia TRIGGER (FP7-Health-2013-306029); and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BeTheCure (grant n° 115142), and RTCure (grant n° 777357). Open access funding provided by Karolinska Institute.

Timing and indication for pulmonary valve replacement (PVR) in patients with repaired Tetralogy of Fallot (rToF) and pulmonary regurgitation (PR) are uncertain. To improve understanding of pumping mechanics, we investigated atrioventricular coupling before and after surgical PVR. Cardiovascular magnetic resonance was performed in patients ( n = 12) with rToF and PR > 35% before and after PVR and in healthy controls ( n = 15). Atrioventricular plane displacement (AVPD), global longitudinal peak systolic strain (GLS), atrial and ventricular volumes, and caval blood flows were analyzed. Right ventricular (RV) AVPD and RV free wall GLS were lower in patients before PVR compared with controls ( P < 0.0001; P < 0.01) and decreased after PVR ( P < 0.0001 for both). Left ventricular AVPD was lower in patients before PVR compared with controls ( P < 0.05) and decreased after PVR ( P < 0.01). Left ventricular GLS did not differ between patients and controls ( P > 0.05). Right atrial reservoir volume and RV stroke volume generated by AVPD correlated in controls ( r = 0.93; P < 0.0001) and patients before PVR ( r = 0.88; P < 0.001) but not after PVR. In conclusion, there is a clear atrioventricular coupling in patients before PVR that is lost after PVR, possibly because of loss of pericardial integrity. Impaired atrioventricular coupling complicates assessment of ventricular function after surgery using measurements of longitudinal function. Changes in atrioventricular coupling seen in patients with rToF may be energetically unfavorable, and long-term effects of surgery on atrioventricular coupling is therefore of interest. Also, AVPD and GLS cannot be used interchangeably to assess longitudinal function in rToF. NEW & NOTEWORTHY There is a clear atrioventricular coupling in patients with Tetralogy of Fallot (ToF) and pulmonary regurgitation before surgical pulmonary valve replacement (PVR) that is lost after operation, possibly because of loss of pericardial integrity. The impaired atrioventricular coupling complicates assessment of ventricular function after surgery when using measurements of longitudinal function. Left ventricular atrioventricular plane displacement (AVPD) found differences between patients and controls and changes after PVR that longitudinal strain could not detect. This indicates that AVPD and strain cannot be used interchangeably to assess longitudinal function in repaired ToF.

Aging is associated with a progressive decline in skeletal muscle mass, strength and function (sarcopenia). We have investigated whether a mixture of algae oil (25%) and extra virgin olive oil (75%) could exert beneficial effects on sarcopenia. Young (3 months) and old (24 months) male Wistar rats were treated with vehicle or with the oil mixture (OM) (2.5 mL/kg) for 21 days. Aging decreased gastrocnemius weight, total protein, and myosin heavy chain mRNA. Treatment with the OM prevented these effects. Concomitantly, OM administration decreased the inflammatory state in muscle, it prevented the increase of pro-inflammatory interleukin-6 (IL-6) and the decrease in anti-inflammatory interleukin-10 (IL-10) in aged rats. The OM was not able to prevent aging-induced alterations in either the insulin-like growth factor I/protein kinase B (IGF-I/Akt) pathway or in the increased expression of atrogenes in the gastrocnemius. However, the OM prevented decreased autophagy activity (ratio protein 1A/1B-light chain 3 (LC3b) II/I) induced by aging and increased expression of factors related with muscle senescence such as histone deacetylase 4 (HDAC-4), myogenin, and IGF-I binding protein 5 (IGFBP-5). These data suggest that the beneficial effects of the OM on muscle can be secondary to its anti-inflammatory effect and to the normalization of HDAC-4 and myogenin levels, making this treatment an alternative therapeutic tool for sarcopenia.

Previous studies have observed an inverse association between alcohol consumption and multiple sclerosis (MS) risk. We aimed to investigate possible interactions between alcohol consumption, MS-associated human leukocyte antigen (HLA) genes and smoking regarding MS risk. We used a Swedish population-based case–control study (2059 incident cases, 2887 controls) matched by age, sex, and residential area. Subjects with different genotypes and alcohol consumption habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals using logistic regression models. Interaction on the additive scale between non-drinking and both genotype and smoking were assessed by calculating the attributable proportion due to interaction (AP). There was a dose-dependent inverse association between alcohol consumption and MS risk (p for trend

Objective To study white-coat hypertension (WCHT, blood pressure ≥140/90 mmHg in a clinic and normal blood pressure

Inflammation induces a wide response of the neuroendocrine system, which leads to modifications in all the endocrine axes. The hypothalamic–growth hormone (GH)–insulin-like growth factor-1 (IGF-1) axis is deeply affected by inflammation, its response being characterized by GH resistance and a decrease in circulating levels of IGF-1. The endocrine and metabolic responses to inflammation allow the organism to survive. However, in chronic inflammatory conditions, the inhibition of the hypothalamic–GH–IGF-1 axis contributes to the catabolic process, with skeletal muscle atrophy and cachexia. Here, we review the changes in pituitary GH secretion, IGF-1, and IGF-1 binding protein-3 (IGFBP-3), as well as the mechanism that mediated those responses. The contribution of GH and IGF-1 to muscle wasting during inflammation has also been analyzed.

Background and purpose — Having patients self-evaluate the outcome is an important part of the follow-up after knee arthroplasty. The Forgotten Joint Score-12 (FJS-12) introduced joint awareness as a new approach, suggested to be sensitive enough to differentiate well-functioning patients. This study evaluated the Swedish translation of the FJS-12 and investigated the validity, reliability, and interpretability in patients undergoing knee arthroplasty Patients and methods — We included 109 consecutive patients 1 year after primary knee arthroplasty to assess construct validity (Pearson’s correlation coefficient, r), internal consistency (Cronbach’s alpha [CA]), floor and ceiling effects, and score distribution. The Knee injury and Osteoarthritis Outcome Score (KOOS) was the comparator instrument for the analyses. Further, 31 patients preoperatively and 22 patients postoperatively were included to assess test–retest reliability (intraclass correlation coefficient [ICC]). Results — Construct validity was moderate to excellent (r = 0.62–0.84). The FJS-12 showed a high degree of internal consistency (CA = 0.96). The ICC was good preoperatively (0.76) and postoperatively (0.87). Ceiling effects were 2.8% in the FJS-12 and ranging between 0.9% and 10% in the KOOS. Interpretation — The Swedish translation of the FJS-12 showed good validity and reliability and can be used to assess outcome after knee arthroplasty. Moreover, the FJS-12 shows promising results in its ability to differentiate well-functioning patients. Future studies on unidimensionality, scale validity, interpretability, and responsiveness are needed for a more explicit analysis of the psychometric properties.

Background and Objectives: The prevalence of multiple sclerosis (MS) differs between different regions of Iran. This study aimed to investigate changes in prevalence and incidence rates of MS in ten ethnic and cultural zones of Iran set by the Ministry of Health and Medical Education. Materials and Methods: Information on MS incidence and prevalence was obtained from the national registry of MS during the study period 2006–2013. Demographic data were acquired from the Statistical Centre of Iran. Results: A rising trend of MS prevalence was observed in Iran, and overall, the prevalence of MS increased by 3.67% per year. The highest prevalence rates of MS, and the most dramatic increase in MS prevalence, occurred in the central areas of Iran. However, during the 7-year period, the prevalence gradually increased also in southern and western areas. Conclusion: The prevalence and incidence of MS have been rapidly increasing in all regions of Iran, especially from central to western and southern regions.

Background Biliary complications during pregnancy is an important issue. The aim of this study was to examine if there is an increased risk to perform cholecystectomy during pregnancy in patients with previous bariatric surgery in comparison to other females subjected to cholecystectomy. Methods The Nationwide Swedish Registry for Gallstone Surgery (GallRiks) and the Scandinavian Obesity Surgery Registry (SOReg) were combined. Female patients 18–45 years old were included. The study group was patients with a history of bariatric surgery whom were pregnant at the time of cholecystectomy. This group was compared with pregnant patients without previous bariatric surgery and non-pregnant with and without previous bariatric surgery. Results In total, 21,314 patients were included and 292 underwent surgery during pregnancy. From 1282 patients identified in both registers, 16 patients were pregnant at the time of cholecystectomy. Acute cholecystectomy was performed in 5922 (28%) non-pregnant and 199 (68%) pregnant (p p = 0.031) and length of stay (p = 0.043), but no differences were seen when only comparing patients with an acute indication for surgery. There was no difference in complications comparing pregnant patients with previous bariatric surgery with non-pregnant, both with and without previous bariatric surgery. Conclusions Cholecystectomy during pregnancy in patients with previous bariatric surgery seems to be safe. The increased risk seen in the non-pregnant group after previous bariatric surgery is not seen in pregnancy, possibly due to an optimization of the circumstances at surgery.

Background and purpose — The incidence of manipulation under anesthesia (MUA) after knee arthroplasty surgery has been reported to vary between 0.5% and 10%. We evaluated the incidence of MUA after primary knee arthroplasty in Sweden, the demographics of the patients and the risk of revision. Patients and methods — Between 2009 and 2013, 64,840 primary total and unicompartmental knee arthroplasties (TKA and UKA) were registered in the Swedish Knee Arthroplasty Register (SKAR). MUAs performed between 2009 and 2014 were identified through the in- and outpatient registers of the Swedish National Board of Health and Welfare. Pertinent data were verified through medical records and patient demographics and revisions were obtained from the SKAR. Results — 1,258 MUAs were identified. Of these, 1,078 were 1st-time MUAs, performed within 1 year after the primary knee arthroplasty. The incidence of MUA was 1.7% and the incidence varied between hospitals from 0% to 5%. The majority were performed after TKA (98%), in younger patients (65% < 65 years), women (64%), and relatively healthy persons (88% had ASA ≤ 2). The cumulative risk of revision at 10 years was 10% (95% CI 8.6–12), similar for men and women. Interpretation — In Sweden, MUA is a rather uncommon measure after knee arthroplasty, especially after UKA. The CRR at 10 years was doubled compared to the general knee arthroplasty population. The frequency of the procedure varies between hospitals but in general it is performed more frequently in healthier and younger patients.

Background: Patients with certain autoimmune diseases (AID) have an increased risk of developing diffuse large B-cell lymphoma (DLBCL). However, the occurrence of AID in patients with DLBCL as well ...

Summary Limited visualization of the fetal heart and vessels by fetal ultrasound due to suboptimal fetal position, patient habitus and skeletal calcification may lead to missed diagnosis, overdiagnosis and parental uncertainty. Counselling and delivery planning may in those cases also be tentative. The recent fetal cardiac magnetic resonance (CMR) reconstruction method utilizing tiny golden‐angle iGRASP (iterative Golden‐angle RAdial Sparse Parallel MRI) allows for cine imaging of the fetal heart for use in clinical practice. This case describes an unbalanced common atrioventricular canal where limited ultrasound image quality and visibility of the aortic arch precluded confirming or ruling out presence of a ventricular septal defect. Need of prostaglandins or neonatal intervention was thus uncertain. Cardiovascular magnetic resonance imaging confirmed ultrasound findings and added value by ruling out a significant ventricular septal defect and diagnosing arch hypoplasia. This confirmed the need of patient relocation for delivery at a paediatric cardiothoracic surgery centre and prostaglandins could be initiated before the standard postnatal ultrasound. The applied CMR method can thus improve diagnosis of complicated fetal cardiac malformation and has direct clinical impact.

BACKGROUND Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein-Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA-1 antibody levels regarding MS risk. METHODS We used a population-based case-control study involving 2017 incident cases of MS and 2443 matched controls. We used logistic regression models to calculate the odds ratios of MS with 95% confidence intervals (CIs) in subjects with different sun exposure habits and EBNA-1 status. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). RESULTS Low sun exposure acted synergistically with high EBNA-1 antibody levels (AP 0.2, 95% CI 0.03-0.3) in its association to increased MS risk. The interaction was present regardless of HLA-DRB1*15:01 status. CONCLUSIONS Low sun exposure may either directly, or indirectly by affecting vitamin D levels, synergistically reinforce pathogenic mechanisms, such as aspects of the adaptive immune response, related to MS risk conveyed by EBV infection.

Olive-derived products, such as virgin olive oil (EVOO) and/or olive leaf extracts (OLE), exert anti-inflammatory, insulin-sensitizing and antihypertensive properties and may be useful for stabilizing omega 3 fatty acids (n-3 PUFA) due to their high content in antioxidant compounds. In this study, the addition of OLE 4:0.15 (w/w) to a mixture of algae oil (AO) rich in n-3 PUFA and EVOO (25:75, w/w) prevents peroxides formation after 12 months of storage at 30◦C. Furthermore, the treatment with the oil mixture (2.5 mL/Kg) and OLE (100 mg/Kg) for 24 month old Wistar rats in 21 days improved the lipid profile, increased the HOMA-IR and decreased the serum levels of miRNAs 21 and 146a. Treatment with this new nutraceutical also prevented age-induced insulin resistance in the liver, gastrocnemius and visceral adipose tissue by decreasing the mRNA levels of inflammatory and oxidative stress markers. Oil mixture + OLE also attenuated the age-induced alterations in vascular function and prevented muscle loss by decreasing the expression of sarcopenia-related markers. In conclusion, treatment with a new nutraceutical based on a mixture of EVOO, AO and OLE is a useful strategy for improving the stability of n-3 PUFA in the final product and to attenuate the cardiometabolic and muscular disorders associated with aging., This project was funded by the call “Doctorados Industriales 2017” (IND2017/BIO7701), a grant from the Community of Madrid (Spain). This program aims to promote the effective collaboration between universities and companies and provides funding for both the development of the research project in the university and the company and to hire a Ph.D. student (Daniel González- Hedström) for three years by the company (Pharmactive Biotech Products S.L.). The Community of Madrid also funded the contract of María de la Fuente-Fernández through the Youth Employment Program (PEJ-2018-AI/SAL-11315)

Aging is associated with increased visceral adiposity and a decrease in the amount of brown adipose tissue and muscle mass, known as sarcopenia, which results in the development of metabolic alterations such as insulin resistance. In this study, we aimed to analyze whether 3-week supplementation with a phenolic-rich olive leaf extract (OLE) to 24 months-old male Wistar rats orally (100 mg/kg) attenuated the aging-induced alterations in body composition and insulin resistance. OLE treatment increased brown adipose tissue and attenuated the aging-induced decrease in protein content and gastrocnemius weight. Treatment with OLE prevented the aging-induced increase in the expression of PPAR-γ in visceral and brown adipose tissues, while it significantly increased the expression of PPAR-α in the gastrocnemius of old rats and reduced various markers related to sarcopenia such as myostatin, HDAC-4, myogenin and MyoD. OLE supplementation increased insulin sensitivity in explants of gastrocnemius and epididymal visceral adipose tissue from aged rats through a greater activation of the PI3K/Akt pathway, probably through the attenuation of inflammation in both tissues. In conclusion, supplementation with OLE prevents the loss of muscle mass associated with aging and exerts anti-inflammatory and insulin-sensitizing effects on adipose tissue and skeletal muscle.

Highlights • Prostheses result in lower pain than osteosyntheses in pathological hip fractures. • Surgeons in sarcoma centers generally use prostheses for pathological hip fractures. • Both methods use similar healthcare resources and effectively restore ambulation., Aims How endoprosthetic replacement compares to osteosynthesis in the treatment of pathologic hip fractures as far as functional outcome and use of healthcare resources is concerned remains largely unknown. We aimed to investigate this in a nationwide registry. Methods We analyzed the functional outcome after surgery for a pathological fracture of the hip in terms of post-operative pain and ambulatory capacity. The preferred surgical method depending on the level of the treating unit was also examined. Furthermore, we documented the length of hospital stay and the patterns of discharge and compared them between these two methods. Results Patients operated with an endoprosthesis reported significantly lower pain at follow-up. Both methods (endoprosthetic replacement and osteosynthesis) were equally effective in restoring the ambulatory capacity and demanded a similar length of stay in hospital. Orthopaedic surgeons working in hospitals with dedicated sarcoma teams were more likely to use a prosthesis rather than osteosynthesis, when compared to surgeons working at other university hospitals or emergency hospitals. Conclusion Endoprosthetic replacement results in a better functional outcome in terms of post-operative pain without consuming more healthcare resources. Orthopaedic surgeons working in hospitals with sarcoma centers are more likely to use prostheses as compared to surgeons working at hospitals where dedicated musculoskeletal oncology teams are not available.

Key Points Question Does fetal cardiovascular magnetic resonance improve prenatal diagnosis of complex congenital heart defects when fetal echocardiography is insufficient? Findings In this cohort study of 31 fetuses referred for fetal cardiovascular magnetic resonance imaging, additional clinically useful information regarding cardiovascular anatomy and function was obtained in 84% of referred cases, covering a wide spectrum of congenital heart defects. This information affected choice of mode of delivery, planning of early postnatal care, and parental counseling. Meaning These findings suggest that fetal cardiovascular magnetic resonance imaging can add important diagnostic information and affect clinical decision-making and parental counseling., This cohort study assesses the clinical utility of fetal cardiovascular magnetic resonance imaging when fetal echocardiography could not visualize all relevant anatomy., Importance Prenatal diagnosis of complex congenital heart defects reduces mortality and morbidity in affected infants. However, fetal echocardiography can be limited by poor acoustic windows, and there is a need for improved diagnostic methods. Objective To assess the clinical utility of fetal cardiovascular magnetic resonance imaging in cases in which fetal echocardiography could not visualize all relevant anatomy. Design, Setting, and Participants This cohort study was conducted between January 20, 2017, and June 29, 2020, at Skåne University Hospital (Lund, Sweden), a tertiary center for pediatric cardiology and thoracic surgery. Participants were fetuses referred for fetal cardiovascular magnetic resonance examination by a pediatric cardiologist after an inconclusive echocardiograph. Exposures Fetal cardiovascular magnetic resonance examination requested by the patient’s pediatric cardiologist. Main Outcomes and Measures Any change in patient management because of diagnostic information gained from fetal cardiovascular magnetic resonance imaging. Results A total of 31 fetuses underwent cardiovascular magnetic resonance examination at a median gestational age of 36 weeks (range, 31-39 weeks). Overall, fetal cardiovascular magnetic resonance imaging had clinical utility, affecting patient management and/or parental counseling in 26 cases (84%). For aortic arch anatomy including signs of coarctation (20 fetuses), fetal cardiovascular magnetic resonance imaging added diagnostic information in 16 cases (80%). For assessment of univentricular vs biventricular outcome in borderline left ventricle, unbalanced atrioventricular septal defect, and pulmonary atresia with intact ventricular septum (15 fetuses), fetal cardiovascular magnetic resonance imaging visualized intracardiac anatomy and ventricular function, allowing assessment of outcome in 13 cases (87%). In 4 fetuses with hypoplastic left heart syndrome, fetal cardiovascular magnetic resonance imaging helped delivery planning in 3 cases (75%). Finally, fetal cardiovascular magnetic resonance imaging provided valuable information for parental counseling in 21 cases (68%). Conclusions and Relevance In this cohort study, fetal cardiovascular magnetic resonance imaging added clinically useful information to what was available from echocardiography. These findings suggest that fetal CMR has the potential to affect clinical decision-making in challenging cases of congenital heart defects with inconclusive data from echocardiography. Fetal cardiovascular magnetic resonance imaging showed an association with clinical decision-making, including mode of delivery and early postnatal care, as well as with parental counseling.

We investigate the importance of adult children and/or cohabitation with a partner for older hip fracture patients' probability of independent living, public home care use and hospital readmission. Data from 35,066 Swedish hip fracture patients between 2012 and 2017, aged 65 years, and living at home at the time of the fracture in the Swedish Registry for Hip Fracture Patients and Treatment were linked with national registers. We applied adjusted logistic regression models and Cox proportional hazard models. In total, 959 (4.0%) women and 817 (7.3%) men had no adult children, 13,384 (56.0%) women and 3,623 (32.5%) men had no cohabiting partner and 2,780 (11.6%) women and 1,389 (12.5%) men neither had a cohabiting partner nor adult children. In comparison with women and men who had both a cohabiting partner and adult children, those without a cohabiting partner (i.e. only adult children) and those who neither had a cohabiting partner nor adult children had significantly lower probabilities of returning home (at discharge and after 4 months). They also had a greater probability of both receiving home care and having an increase in the amount of home care they receive. Having a close next of kin and hospital readmission were not associated. In conclusion, absence of a close next of kin, specifically a cohabiting partner, reduces the chance of return to independent living and increases the use of home care after a hip fracture hospitalisation. The findings highlight the importance of family support for older adults living situation after a hip fracture.

Background Hospital length of stay (LoS) is believed to be associated with higher mortality in hip fracture patients; however, previous research has shown conflicting results. We aimed to explore the association between LoS and 4-month mortality in different groups of hip fracture patients. Methods The study population in this Swedish register-based cohort study was 47 811 patients 65 years or older with a first hip fracture during 2012–2016, followed up for 4 months after discharge. LoS was categorized by cubic splines, and the association between LoS and mortality was analyzed with Cox regression models, adjusted for sociodemographic- and health-related factors. Results Mean LoS was 11.2 ± 5.9 days and 12.3% of the patients died within 4 months. Both a shorter and a longer LoS, compared to the reference 9–12 days, were associated with higher mortality (hazard ratio [95% confidence interval]): 2–4 days 2.15 (1.98–2.34), 5–8 days 1.58 (1.47–1.69), and 24+ days 1.29 (1.13–1.46). However, in fully adjusted models, only the association with a long LoS remained: 13–23 days 1.08 (1.00–1.17) and 24+ days 1.42 (1.25–1.61). Stratifying by living arrangement revealed that the increased risk for a short LoS was driven by the group living in care homes. For patients living at home, a short LoS was associated with lower risk: 0.65 (0.47–0.91) and 0.85 (0.74–0.98) for 2–4 and 5–8 days, respectively. Conclusions A long LoS after a hip fracture is associated with increased 4-month mortality risk even after considering patient characteristics. The association between mortality and a short LoS, however, is explained by individuals coming from care homes (with higher mortality risk), being discharged early.

Introduction Despite advances in new surgical techniques and improvements in medical care of the last decades a considerable number of patients will not regain their ability to walk after a hip fracture. Aims To further identify risk factors associated with non-walking 4-months after a hip fracture. Material and Methods Register-based, longitudinal study with a 4-month follow-up. The collected data from the Swedish hip fracture registry, RIKSHOFT, contained all hip fracture between 2013-01-01–2015-12-31 in Sweden. All patients older than 50 years with a non-pathological fracture and who were able to walk before the fracture were included. The association of sex, age, general health, dementia and type of discharge with complete loss of walking after a hip fracture were investigated using a multivariate analysis. Results Included were 23,759 patients. At the 4-month follow-up, 10% were unable to walk. Twenty-five per cent of patients with dementia lost their ability to walk compared to 7% of those with no cognitive dysfunction. Adjusted odds ratio (OR) for factors associated with loss of walking ability were; discharge to institutionalized care rather than their own home or a rehabilitation unit (OR=1.91; 95% CI=1.67-2.18), dementia (OR=1.80; 95% CI=1.57-2.06), male gender (OR=1.59; 95% CI=1.40-1.81) and ASA score grade III-V (OR=1.37; 95% CI=1.20-1.55) but not age (OR=1.01; 95% CI=1.00-1.02). Conclusions An important factor associated with a complete loss of walking ability after a hip fracture is the discharge to institutionalized care. This factor might be influenced either by favouring rehabilitation units or by improving the rehabilitation protocols.

Background Charlson Comorbidity Index (CCI) has been suggested to be associated with mortality in hip fracture patients, to the same extent as more expensive and time-consuming tools. However, even CCI might be too time-consuming in a clinical setting. Aim To investigate whether the American Society of Anaesthesiologists score (ASA score), a simple grading from the anaesthesiologist’s examination, is comparable with CCI in the association with 1-year mortality after a hip fracture. Methods The study population was patients 60 + years registered in the Swedish Hip Fracture Registry with a first-time hip fracture between 1997 and 2017 (N = 165,596). The outcome was 1-year mortality, and the exposures were ASA score and CCI. The association between comorbidity and mortality was described with Kaplan–Meier curves and analyzed with Cox proportional hazards models. Results The Kaplan–Meier curves showed a stepwise increase in mortality for increasing values of both ASA and CCI. The Hazard Ratios (HRs) for the highest ASA (4–5) were 3.8 (95% Confidence Interval 3.5–4.2) for women and 3.2 (2.8–3.6) for men in the fully adjusted models. Adjusted HRs for the highest CCI (4 +) were 3.6 (3.3–3.9) for women and 2.5 (2.3–2.7) for men. Reference was the lowest score value for both tools. The correlation between the tools was moderate. Conclusions Both ASA and CCI show a similar stepwise association with 1-year mortality in hip fracture patients, despite measuring different factors and capturing different individuals at risk. Since the ASA score is already accessible for health care staff, it might be preferable to aid in prioritizing vulnerable hip fracture patients at risk of adverse outcomes.

Summary Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure., Graphical abstract, Highlights • The hypothalamic gliovascular interface is dynamically remodeled during obesity • Circulating leptin couples hypercaloric states with hypothalamic microangiopathy • Leptin-induced astroglial HIF1α-VEGF drives angiogenesis in the hypothalamus • VEGF in astrocytes promotes the development of arterial hypertension during obesity, Here, Gruber et al. show that during diet-induced obesity in mice there is a profound remodeling of the gliovascular interface in the hypothalamus, resulting in arterial hypertension. This process is driven by elevated leptin levels and upregulation of a HIF1α-VEGF signaling axis in local astrocytes.

Olive leaves are rich in bioactive substances which exert anti-inflammatory, antioxidant, insulin-sensitizing and antihypertensive effects. The aim of this study was to analyze the possible beneficial effects of an olive leaf extract (OLE) rich in secoiridoids and phenolic compounds on the aging-induced metabolic and vascular alterations. Three experimental groups of rats were used: 3-month-old rats, 24-month-old rats and 24-month-old rats supplemented 21 days with OLE (100 mg/kg). Administration of OLE to aged rats decreased the weight of adrenal glands and prevented the aging-induced loss of body weight and muscle mass. In the serum, OLE reduced the circulating levels of LDL-cholesterol and IL-6 and increased the concentrations of leptin and adiponectin. In the liver OLE attenuated the decreased gene expression of SOD-1, GSR, GCK and GSK-3β and reduced the aging-induced overexpression of NOX-4, Alox-5, iNOS and TNF-α. In aorta segments, OLE prevented endothelial dysfunction and vascular insulin resistance and improved vasoconstriction in response to KCl and NA. Improvement in vascular function was associated with the attenuation of the alterations in the gene expression of COX-2, IL-6, GPx, NOX-1 and IL-10. In conclusion, OLE exerts anti-inflammatory and antioxidant effects in aged rats and attenuates the alterations in vascular function associated with aging., This project was funded by the call “Doctorados Industriales 2017” (IND2017/BIO7701), a grant from Community of Madrid (Spain). This program aims to promote the effective collaboration between Universities and Companies and provides funding for both, the development of the research project in the University and the Company, and to hire a PhD student (Daniel González-Hedström) over a three-year period by the Company (Pharmactive Biotech Products S.L.). Community of Madrid also funded the contract of María de la Fuente-Fernández through the Youth Employment Program (PEJ-2018-AI/SAL-11315).

Routine follow-up for diffuse large B-cell lymphoma have been shortened to 2 years when event-free survival at 24 months (EFS24) emerged as a new milestone. In the present study, we aimed to determine whether the achievement of this milestone affected overall survival (OS). We compared OS to that of an age- and sex-matched population, analysed other factors governing OS, and reviewed the causes of death. Data were collected from the Swedish Cancer Registry and from individual patient's records. We included 1169 adult patients from five counties between the years 2001 and 2014. The median (range) age was 64·6 (18-91) years, 56·6% were men and the median follow-up was 82·3 months. For early stages, the achievement of EFS12 did not improve OS. More than two-thirds of the patients (n = 837, 71·6%) achieved EFS24, of which 190 (22·7%) died during follow-up. Lymphoma (20%), cardiovascular disease (22·4%) and malignancies (16%) contributed to causes of death. Patients aged 60 years significantly affected OS after EFS24 compared with the standard population. We concluded that follow-up beyond EFS24 should be considered for patients aged >60 years. Amal Abu Sabaa and Charlott Mörth share first authorship

[Ethnopharmacological relevance] Marjoram (Origanum majorana L.) is an herb traditionally used as a medicine in different countries, as Morocco and Iran, because of its beneficial cardiovascular effects. Some studies suggest that these effects are due, at least in part, to the presence of phenolic compounds such as rosmarinic acid (RA) and luteolin., [Aim of the study] To analyze the possible cardiprotective effects of a marjoram extract (ME) reducing myocardial damage after coronary ischemia-reperfusion (IR) and its possible antihypertensive effects reducing the response of aorta segments to the vasoconstrictors noradrenaline (NA) and endothelin-1 (ET-1)., [Materials and methods] Male Wistar rats (300g) were used. After sacrifice, the heart was immediately removed and mounted in a perfusion system (Langendorff). The aorta was carefully dissected and cut in 2 mm segments to perform vascular reactivity experiments., [Results] In the heart, ME perfusion after IR reduced heart rate and prevented IR-induced decrease of cardiac contractility, possibly through vasodilation of coronary arteries and through the upregulation of antioxidant markers in the myocardium that led to reduced apoptosis of cardiomyocytes. In the aorta, ME decreased the vasoconstrictor response to NA and ET-1 and exerted a potent anti-inflammatory and antioxidant effect. Neither RA nor 6-hydroxi-luteolin-O-glucoside, major compounds of this ME, were effective in improving cardiac contractility after IR or attenuating vasoconstriction to NA and ET-1 in aorta segments., [Conclusion] In conclusion, ME reduces the myocardial damage induced by IR and the contractile response to vasoconstrictors in the aorta. Thus, it may be useful for the treatment of cardiovascular diseases such as myocardial infarction and hypertension., This study has been funded by Grants from Community of Madrid awarded to Daniel González-Hedström (IND2017/BIO7701) and María de la Fuente-Fernández (PEJ-2018-AI/SAL-11315).

Background and Aim Caloric restriction (CR) improves insulin sensitivity and is one of the dietetic strategies most commonly used to enlarge life and to prevent aging-induced cardiovascular alterations. The aim of this study was to analyze the possible beneficial effects of caloric restriction (CR) preventing the aging-induced insulin resistance in the heart of male Wistar rats. Methods and results Three experimental groups were used: 3 months old rats (3m), 24 months old rats (24m) and 24 months old rats subjected to 20% CR during their three last months of life (24m-CR). After sacrifice hearts were mounted in a perfusion system (Langendorff) and heart function in basal conditions and in response to accumulative doses of insulin (10−9-10−7 M), in the presence or absence of Wortmannin (10−6 M), was recorded. CR did not attenuate the aging-induced decrease in coronary artery vasodilation in response to insulin administration, but it prevented the aging-induced downregulation of cardiac contractility (dp/dt) through activation of the PI3K/Akt intracellular pathway. Insulin stimulated in a greater extent the PI3K/Akt pathway vs the activation of the MAPK pathway and increased the protein expression of IR, GLUT-4 and eNOS in the hearts of 3m and 24m-CR rats, but not in the hearts of 24m rats. Furthermore, CR prevented the aging induced increase in endothelin-1 protein expression in myocardial tissue. Conclusion In conclusion CR partially improves cardiac insulin sensitivity and prevents the aging induced decrease in myocardial contractility in response to insulin administration through activation of PI3K/Akt pathway.

Background and purpose — Waiting time to surgery for patients with hip fractures and its potential association with mortality has been frequently studied with the hypothesis that longer waiting time is associated with adverse outcomes. However, despite numerous studies, there is no consensus regarding which time frames are appropriate, and whether some patients are more vulnerable to waiting than others. We explored the association between waiting time to surgery and short-term mortality and whether sex, age, surgical method, and comorbidity (ASA) modified this association. Patients and methods — This is a nationwide cohort study of 59,675 patients undergoing hip fracture surgery between January 1, 2013 and December 31, 2017 with a 4-month follow-up of mortality. Data were extracted from the Swedish Registry for Hip Fracture Patients and Treatment (RIKSHÖFT) and mortality was obtained from Statistics Sweden. Results — Unadjusted analyses revealed an association between waiting more than 24 hours for surgery and increased mortality, primarily for women. However, when stratifying for ASA grade, an association persisted only among patients with ASA 3 and 4. Furthermore, the absolute differences in mortality risk between those waiting less or longer than 24 hours were small. Age, fracture type, and surgical method did not modify the association between waiting time and mortality. Interpretation — This study suggests that there may be a need for new guidelines, which take into account the heterogeneity of the patient population.

Background According to the European evidence-based consensus, published by European Crohn's and Colitis Organization (ECCO), diseases of the pancreas are included as extra-intestinal manifestations in IBD in the forms of acute pancreatitis (AP), chronic pancreatitis (CP), autoimmune pancreatitis (AIP), pancreatic duct abnormalities and pancreatic exocrine insufficiency (PEI). Presence of pancreatic autoantibodies directed against the exocrine of the pancreas has been reported in about one-third of CD. However, association between CD and PEI is not fully elucidated. Methods Patients with a diagnosis of CD were recruited at the Department for Digestive Diseases at Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Fecal elastase-1 (FE-1) measurements were performed using the enzyme-linked immunosorbent assay (ELISA) method. Results There were 20 patients included in the study, 13 (65%) males and 7 (35%) females, mean age 48.3±1.4 years (range 29-67 years). Mean duration of CD was 15.7±2.1 years (range 1-40 years). There were 11 (55%) patients without history of bowel surgery and 9 (45%) patients after ileocecal resection. FE-1 test was normal in all patients, among them 15 (75%) patients with the values of FE-1>500. Conclusions Fecal elastase-1 level was normal in all patients with CD strongly indicated absence of PEI in this group of patients.

Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system, characterized by localized areas of inflammation, demyelination, and axonal loss. It is widely accepted that su...

BACKGROUND AND PURPOSE A femoral neck fracture (FNF) may have long term effects on the patient's health related quality of life (HRQoL) and mortality, especially in patients younger than 70 years. These long-term effects are unknown since most studies have a short follow-up. The aim of this study was to investigate self-assessed hip function, HRQoL and factors associated with 10-years mortality after a FNF. PATIENTS AND METHODS A prospective multicenter study with a 10-year follow-up of patients aged 20-69 years with a displaced and non-displaced FNF treated with closed reduction and internal fixation. The self-administered questionnaires EuroQol 5 Dimension (EQ-5D) and Hip Disability Outcome Score (HOOS) were used. Results of EQ-5D and HOOS was compared to sex and age matched general population data of Sweden. All patients that were deceased had their death date recorded. Factors associated with mortality were assessed by regression analysis of the baseline data including age, gender, harmful alcohol consumption according to AUDIT, co-morbidity measured by ASA-grade, body mass index, osteoporosis measured by dual energy x-ray absorptiometry (DXA) and smoking. Prevalence of co-morbidities and smoking was compared to general population data. RESULTS From initial 182 included patients, 55 were deceased at 10-year follow-up, 4 were deregistered from public record and 35 declined participations. A total of 88 patients participated through self-administrated questionnaires. There were no significant differences in HOOS between gender and fracture type and the results were equivalent to general population data. The EQ-5D continued to improve compared to a 24-month follow-up (p = 0.006) but did not recover to pre-fracture level (p

The cause of obesity in narcolepsy type 1 (NT1) patients is not fully understood. The present study investigated if a reduced physical activity could explain weight gain in NT1. Seventy-nine patients were included in this retrospective study and divided into an NT1 group (n = 56) and a non-NT1 group (n = 23), including NT2 and idiopathic hypersomnia (IH). Accelerometry-derived measures of physical activity, total energy expenditure and skin temperature were collected from patients during seven consecutive days without medication. In addition, results from multiple sleep latency tests and the Epworth Sleepiness Scale questionnaire, body weight, height and CSF orexin/hypocretin were acquired. Three measurements of physical activity, including metabolic equivalent of task (MET), the average time of physical activity and step count, were compared without differences between groups. Neither could we find a significant difference in total energy expenditure or skin temperature. Thus, by analysing accelerometric data, we could not find any differences in the amount of physical activity or total energy expenditure explaining overweight in NT1.

Intracardiac hemodynamic forces have been proposed to influence remodeling and be a marker of ventricular dysfunction. We aimed to quantify the hemodynamic forces in patients with repaired tetralogy of Fallot (rToF) to further understand the pathophysiological mechanisms as this could be a potential marker for pulmonary valve replacement (PVR) in these patients. Patients with rToF and pulmonary regurgitation (PR) > 20% ( n = 18) and healthy control subjects ( n = 15) underwent MRI, including four-dimensional flow. A subset of patients ( n = 8) underwent PVR and MRI after surgery. Time-resolved hemodynamic forces were quantified using 4D-flow data and indexed to ventricular volume. Patients had higher systolic and diastolic left ventricular (LV) hemodynamic forces compared with control subjects in the lateral-septal/LV outflow tract ( P = 0.011 and P = 0.0031) and inferior-anterior ( P < 0.0001 and P < 0.0001) directions, which are forces not aligned with blood flow. Forces did not change after PVR. Patients had higher RV diastolic forces compared with control subjects in the diaphragm-right ventricular (RV) outflow tract (RVOT; P < 0.001) and apical-basal ( P = 0.0017) directions. After PVR, RV systolic forces in the diaphragm-RVOT direction decreased ( P = 0.039) to lower levels than in control subjects ( P = 0.0064). RV diastolic forces decreased in all directions ( P = 0.0078, P = 0.0078, and P = 0.039) but were still higher than in control subjects in the diaphragm-RVOT direction ( P = 0.046). In conclusion, patients with rToF and PR had LV hemodynamic forces less aligned with intraventricular blood flow compared with control subjects and higher diastolic RV forces along the regurgitant flow direction in the RVOT and that of tricuspid inflow. Remaining force differences in the LV and RV after PVR suggest that biventricular pumping does not normalize after surgery. NEW & NOTEWORTHY Biventricular hemodynamic forces in patients with repaired tetralogy of Fallot and pulmonary regurgitation were quantified for the first time. Left ventricular hemodynamic forces were less aligned to the main blood flow direction in patients compared with control subjects. Higher right ventricular forces were seen along the pulmonary regurgitant and tricuspid inflow directions. Differences in forces versus control subjects remain after pulmonary valve replacement, suggesting that altered biventricular pumping does not normalize after surgery.

The etiology of multiple sclerosis (MS) involves multifaceted interactions between genetic loci and environmental factors. Smoking is an important risk factor for MS that overall increases the risk of the disease with approximately 50%. However, the precise effects of smoking on MS development vary considerably in different contexts and in different populations. This review focuses on the influence of smoking on MS risk and its interaction with genetics in MS etiology. The possible biological mechanisms are presented in this paper. Further research is needed to establish the mechanisms of causality and to explore preventive strategies.

ObjectiveWe hypothesize that different sources of lung irritation may contribute to elicit an immune reaction in the lungs and subsequently lead to multiple sclerosis (MS) in people with a genetic susceptibility to the disease. We aimed to investigate the influence of exposure to organic solvents on MS risk, and a potential interaction between organic solvents and MS risk human leukocyte antigen (HLA) genes.MethodsUsing a Swedish population-based case-control study (2,042 incident cases of MS and 2,947 controls), participants with different genotypes, smoking habits, and exposures to organic solvents were compared regarding occurrence of MS, by calculating odds ratios with 95% confidence intervals using logistic regression. A potential interaction between exposure to organic solvents and MS risk HLA genes was evaluated by calculating the attributable proportion due to interaction.ResultsOverall, exposure to organic solvents increased the risk of MS (odds ratio 1.5, 95% confidence interval 1.2–1.8, p = 0.0004). Among both ever and never smokers, an interaction between organic solvents, carriage of HLA-DRB1*15, and absence of HLA-A*02 was observed with regard to MS risk, similar to the previously reported gene-environment interaction involving the same MS risk HLA genes and smoke exposure.ConclusionThe mechanism linking both smoking and exposure to organic solvents to MS risk may involve lung inflammation with a proinflammatory profile. Their interaction with MS risk HLA genes argues for an action of these environmental factors on adaptive immunity, perhaps through activation of autoaggressive cells resident in the lungs subsequently attacking the CNS.

BACKGROUND Platelet microparticles (PMPs) are subcellular procoagulant vesicles released upon platelet activation. In people with clinical diseases, alterations in PMP concentrations have been extensively investigated, but few canine studies exist. OBJECTIVES This study aims to validate a canine flow cytometric protocol for PMP quantification and to assess the influence of calcium on PMP concentrations. METHODS Microparticles (MP) were quantified in citrated whole blood (WB) and platelet-poor plasma (PPP) using flow cytometry. Anti-CD61 antibody and Annexin V (AnV) were used to detect platelets and phosphatidylserine, respectively. In 13 healthy dogs, CD61+ /AnV- concentrations were analyzed with/without a calcium buffer. CD61+ /AnV- , CD61+ /AnV+ , and CD61- /AnV+ MP quantification were validated in 10 healthy dogs. The coefficient of variation (CV) for duplicate (intra-assay) and parallel (inter-assay) analyses and detection limits (DLs) were calculated. RESULTS CD61+ /AnV- concentrations were higher in calcium buffer; 841,800 MP/μL (526,000-1,666,200) vs without; 474,200 MP/μL (278,800-997,500), P

Background:The role of psychosocial conditions on the disease course of rheumatoid arthritis (RA) is getting increased attention. In our previous study, low social support and low decision latitude at work were associated with known modifiable risk factors for RA disease development, such as smoking and low educational level (1). Further, smoking and low educational level have previously been shown to be associated with worse RA disease outcome (2-4). Whether psychosocial characteristics are related to RA disease outcome needs further investigation.Objectives:To investigate the relationship between two psychosocial characteristics: low social support and low decision latitude at work, and achievement of remission in patients with RA.Methods:At inclusion in the Swedish EIRA study, incident RA cases (N=3724) and controls (N=5937), matched for age, sex and residential area, responded to a questionnaire including questions on social support and decision latitude at work. The answers were recoded into separate scores and the distribution of the scores among controls were used to define the exposures. Low social support and low decision latitude at work, respectively, among patients, were set as the level corresponding to the lowest quartile among controls, and were compared with scores corresponding to the remaining three quartiles.The outcome, disease activity score 28-joint count (DAS28) remission, defined as DAS28Logistic regression was used to evaluate the association between low social support or low decision latitude at work, respectively, and the chance of remission at the time-points 3 months, 12 months and 60 months after inclusion. All results were adjusted for age, sex and residential area and the fully adjusted models were also adjusted for smoking, obesity, physical activity and educational level.Results:Low social support (n=655) was associated with a reduced chance for remission at all three time points in the model adjusted for age, sex and residential area; OR 3 months 0.77 (95% CI 0.61-0.97), OR 12 months 0.78 (95% CI 0.64-0.95) OR 60 months 0.77 (95% CI 0.59-0.99). This association was diminished after further adjustment. After stratifying for sex, this association was enhanced in women but inverse among men (Figure 1).No association between low decision latitude at work (n=166) and chance for remission was observed neither in the analyses stratified for matching variables, nor in the full model. This result was only marginally changed after stratifying for sex (Figure 1).Conclusion:Low social support was associated with lower chance of remission in early RA, but the association was not independent of other risk factors for worse outcome (smoking, physical activity, obesity and low educational level).The interrelationship between social stressors and previously known risk factors for worse outcome highlights the importance of supportive actions at many levels to increase the possibility for the individual to make healthy decisions.References:[1]Hedenstierna. et al. Scand J Rheumatol. 2021:1-5.[2]Saevarsdottir, et al. Ann Rheum Dis. 2011;70(3):469-75.[3]Saevarsdottir, et al. Arthritis Rheum. 2011;63(1):26-36.[4]Jiang, et al. Arthritis Res Ther. 2015;17:317.Figure 1.Odds ratios for assiciation between social stressors and DAS 28 remissionAcknowledgements:We want to thank all the participants of the EIRA study and the clinical collaborators for their valuable contribution. We also want to thank the staff for their dedicated work with the data collection.Disclosure of Interests:None declared

Background and purpose Prospective studies on patient related outcome in patients Patients and methods 182 patients, 20–69 years with a FNF treated with internal fixation were prospectively included in a multicenter study. Follow up included radiographic and clinical examination at 4, 12 and 24 months. Collected data were hip function using Harris Hip Score (HHS), HRQoL (EQ-5D and SF-36), fracture healing and re-operations. Results At 24 months, HHS was good or excellent in 73% of the patients with a displaced fracture and 85% of the patients with a non-displaced fracture (p = 0.15). Of the patients with displaced fracture (n = 120), 23% had a non-union (NU) and 15% had an avascular necrosis (AVN) with a 28% re-operation rate. None of the patients with non-displaced fracture (n = 50) had an NU, 12% had a radiographic AVN and 8% needed a re-operation. The mean EQ-5Dindex in patients with displaced fracture decreased from 0.81 to 0.59 at 4 months, 0.63 at 12 months and 0.65 at 24 months (p Interpretation Two thirds of the patients with displaced femoral neck fracture healed after one operation and three quarters reported good or excellent functional outcome at 24 months. However, they did not regain their pre-fracture level of HRQoL.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p −16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p −16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Dysphagia is a common and severe toxicity after oncological treatment of head and neck cancer (HNC). The study aim was to investigate relationships between patient-reported dysphagia and clinically measured swallowing function in HNC after modern curative radiotherapy with or without chemotherapy to identify possible alarm symptoms for clinically manifest dysphagia. Patients with tumors of the tonsil, base of tongue, hypopharynx, and larynx treated in 2007–2015 were assessed for dysphagia post-treatment by telephone interview and videofluoroscopy (VFS). A study-specific categorized symptom score was used to determine patient-reported dysphagia (DESdC = presence of Drinking, Eating, Swallowing difficulties, and Coughing when eating/drinking (any combination); scores between 0 and 4 with 0 = no symptom); the penetration–aspiration scale (PAS) to determine swallowing function by VFS. Swallowing difficulties were defined as DESdC ≥ 1 and PAS ≥ 2. Relationships between clinically relevant cut-offs for DESdC and PAS were determined by Pearson’s correlation coefficient (Pr). Swallowing difficulties according to DESdC were reported by 89% of the patients and according to PAS by 60% at a median of 7 months post-treatment. Averaged correlations between DESdC score 1/2/3/4 and PAS were 0.16/0.10/0.27/0.18. Almost one in two patients with DESdC score ≥3 had severe swallowing difficulties according to PAS. Correlations between individual DESdC:s were highest for swallowing and eating (Pr = 0.53) and lowest for swallowing and coughing (Pr = 0.11). Our data suggest that if a patient reports having swallowing difficulties, it is likely that he or she also has eating difficulties but not necessarily coughing problems when eating/drinking. However, if all these three symptoms are reported, it is likely that the patient will present with moderate or severe impaired swallowing function according to PAS and thus should be referred for further evaluation and treatment.

Melanocortin 1 receptor (MC1R) and BRAF are common mutations in melanoma. Through different pathways, they each regulate the expression of PGC-1α, which is a key factor in the regulation of mitochondrial biogenesis and the antioxidant response. Our aim was to study the importance of the different regulatory characteristics of MC1R and BRAF on the pathways they regulate in melanoma. For this purpose, ROS production, levels of gene expression and enzymatic activities were analyzed in HBL and MeWo, with wild-type MC1R and BRAF, and A375 cells with mutant MC1R and BRAF. HBL cells showed a functional MC1R-PGC-1α pathway and exhibited the lowest ROS production, probably because of a better mitochondrial pool and the presence of UCP2. On the other hand, MeWo cells showed elevated levels of PGC-1α but also high ROS production, similar to the A375 cells, along with an activated antioxidant response and significantly low levels of UCP2. Finally, A375 cells are mutant for BRAF, and thus showed low levels of PGC-1α. Consequently, A375 cells exhibited poor mitochondrial biogenesis and function, and no antioxidant response. These results show the importance of the activation of the MC1R-PGC-1α pathway for mitochondrial biogenesis and function in melanoma development, as well as BRAF for the antioxidant response regulated by PGC-1α. J. Cell. Biochem. 118: 4404-4413, 2017. © 2017 Wiley Periodicals, Inc.

Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case–control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8–14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity. Electronic supplementary material The online version of this article (doi:10.1007/s10654-017-0250-2) contains supplementary material, which is available to authorized users.