Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Adipokines are possible risk markers for aortic stenosis requiring surgery.

OBJECTIVES: Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR). DESIGN: In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents. RESULTS: Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92-1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08-1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82-1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64-0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI). CONCLUSIONS: The adipokine leptin may promote the development of AS.

Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population.

BACKGROUND: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population. METHODS: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data. RESULTS: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population. CONCLUSIONS: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement.

BACKGROUND: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. METHODS: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. RESULTS: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. CONCLUSIONS: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

Arterial hypertension and diastolic blood pressure associate with aortic stenosis.

OBJECTIVES: Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis (AS) and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on AS development requiring surgery among patients without concomitant coronary artery disease (CAD) and stratified for age. DESIGN: This study included 322 patients, who had prior to surgery for AS participated in population-based surveys, and 131 of them had no visible CAD upon preoperative coronary angiogram. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension (or measured blood pressure and antihypertensive medication), cholesterol levels, diabetes, body mass index (BMI), and smoking. RESULTS: In patients without CAD, future surgery for AS was associated with arterial hypertension and elevated levels of diastolic blood pressure in patients younger than 60 years at surgery (odds ratio [95% confidence interval]), (3.40 [1.45-7.93] and 1.60 [1.09-2.37], respectively), and with only impaired fasting glucose tolerance in patients 60 years or older at surgery (3.22 [1.19-8.76]). CONCLUSION: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for AS requiring surgery in subjects below 60 years of age. Strict blood pressure control in this group is strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk factors for developing AS requiring surgery need further investigations. Notably, elevated fasting glucose levels were related to AS requiring surgery in older adults without concomitant CAD.

Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis.

Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFRcystatin C and eGFRcreatinine and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFRcystatin C and eGFRcreatinine. A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFRcystatin C and eGFRcreatinine was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

Campylobacter jejuni-associated perimyocarditis: two case reports and review of the literature.

BACKGROUND: Campylobacter spp. are among the most common bacterial causes of gastroenteritis world-wide and mostly follow a benign course. We report two cases of Campylobacter jejuni-associated perimyocarditis, the first two simultaneous cases published to date and the third and fourth cases over all in Sweden, and a review of the literature. CASE PRESENTATION: A previously healthy 24-yo male (A) presented at the Emergency Department(ED) with recent onset of chest pain and a 3-day history of abdominal pain, fever and diarrhoea. The symptoms began within a few hours of returning from a tourist visit to a central European capital. Vital signs were stable, the Electrocardiogram(ECG) showed generalized ST-elevation, laboratory testing showed increased levels of C-reactive protein(CRP) and high-sensitive Troponin T(hsTnT). Transthoracic echocardiogram (TTE) was normal, stool cultures were positive for C Jejuni and blood cultures were negative. Two days after patient A was admitted to the ED his travel companion (B), also a previously healthy male (23-yo), presented at the same ED with almost identical symptoms: chest pain precipitated by a few days of abdominal pain, fever and diarrhoea. Patient B declared that he and patient A had ingested chicken prior to returning from their tourist trip. Laboratory tests showed elevated CRP and hsTnT but the ECG and TTE were normal. In both cases, the diagnosis of C jejuni-associated perimyocarditis was set based on the typical presentation and positive stool cultures with identical strains. Both patients were given antibiotics, rapidly improved and were fully recovered at 6-week follow up. CONCLUSION: Perimyocarditis is a rare complication of C jejuni infections but should not be overlooked considering the risk of heart failure. With treatment, the prognosis of full recovery is good but several questions remain to be answered regarding the pathophysiology and the male preponderance of the condition.

Involving parents of children treated for cancer in Sweden as public contributors to inform the design and conduct of an evaluation of internet-administered self-help for parents of children treated for cancer: a protocol.

INTRODUCTION: Public contribution in research can facilitate the design and conduct of meaningful research, resulting in feasible and sustainable solutions to healthcare challenges. However, the evidence concerning the acceptability, feasibility, and impact of public contribution in research is limited. We will embed a mixed-method examination of public contribution activities into the CHANGE trial. The overall aim of the CHANGE trial is to evaluate the efficacy and cost-effectiveness of an internet-administered, guided, low-intensity cognitive behavioral therapy-based self-help intervention (EJDeR) plus treatment as usual (TAU) versus TAU for symptoms of depression and/or Generalized Anxiety Disorder in a superiority randomized controlled trial with an internal pilot phase. In this protocol we describe how we aim to: (1) involve parents of children treated for cancer in the managing and undertaking, analysis and interpretation, and dissemination phases of the CHANGE trial; and (2) examine the acceptability, feasibility, and perceived impact of Parent Advisory Board contribution to the trial from the perspective of board members and public contribution coordinators. METHODS: We will recruit around six parents of children treated for cancer to the Parent Advisory Board. Board members will contribute throughout the trial during online workshops and steering group meetings. An impact log will be used during workshops to record activities and examine the perceived impact of activities according to board members and public contribution coordinators, including anticipated and unanticipated changes to the research process and potential benefits and harms. Activities will be reported using the Guidance for Reporting Involvement of Patients and the Public checklist. We will conduct semi-structured interviews with board members and public contribution coordinators 6 months after the board is established and at the end of the trial to examine the acceptability, feasibility, and perceived impact of public contribution activities. We will also conduct interviews with board members and public contribution coordinators who withdraw participation. Findings will be reported in accordance with the Standards for Reporting Qualitative Research checklist. DISCUSSION: We hope adding public contribution to the CHANGE trial will provide guidance on how to embed public contribution in research and add to the evidence base concerning the impact of public contribution.

Involving the public in research can help improve research. However, we do not know so much about what impact it has. Here, we describe how we will involve parents of children treated for cancer in the CHANGE trial and how we will examine the impact of their contribution.Even years after end of treatment parents can experience difficult emotions, such as depression and anxiety. We have therefore developed an internet-administered self-help intervention called EJDeR for parents of children treated for cancer. In the CHANGE trial we will evaluate whether EJDeR reduces parent's depression and anxiety.We will recruit around six parents to a Parent Advisory Board. Board members will help us to: (1) manage and undertake the CHANGE trial including designing trial procedures e.g., participant-facing material and interview guides; and to steer the trial e.g., discuss trial progress and produce research updates; (2) interpret findings; and (3) plan how to communicate findings to parents and the surrounding community.Board members will participate in online workshops. We will record all activities and whether, and if so how, activities are perceived to impact on the CHANGE trial. Board members will also participate in steering meetings with members of our research team. We will interview board members and public contribution coordinators about their experiences working with us and contributing to the CHANGE trial. We hope this approach will help us and other researchers to understand the potential impact of public contribution on research.

E-therapists' views on the acceptability and feasibility of an internet-administered, guided, low-intensity cognitive behavioural therapy intervention for parents of children treated for cancer: A qualitative study.

Background: Childhood cancer treatment completion can be a period of vulnerability for parents and is associated with mental health difficulties such as depression and anxiety. We developed an internet-administered, guided, low-intensity cognitive behavioural therapy-based self-help intervention (EJDeR) for parents delivered on the U-CARE-portal (Portal). The acceptability and feasibility of EJDeR and study procedures were examined using a single-arm feasibility trial (ENGAGE). Results indicated that EJDeR and ENGAGE study procedures are acceptable and feasible, however, a need for clinical and technical modifications to EJDeR and refinements to ENGAGE study procedures was identified. Objectives: This study aimed to explore the acceptability and feasibility of EJDeR and ENGAGE study procedures from the perspective of e-therapists to inform clinical and technical modifications to EJDeR and refinements to study procedures prior to progression to a superiority randomised controlled trial. Methods: We conducted semi-structured interviews with 10 e-therapists. Data were analysed using manifest content analysis. Results: We identified three categories relating to the acceptability and feasibility of EJDeR: (a) Support to e-therapists (subcategories: Clinical supervision and Technical difficulties); (b) Guidance to parents (subcategories: Support protocols and Synchronous communication); and (c) Content (subcategories: Relevancy of the intervention and Pacing of the intervention). We identified four categories relating to the acceptability and feasibility of study procedures: (a) Recruitment and training of e-therapists (subcategories: Definition of the role and Training program); (b) Retention of parents (subcategories: Parent suitability and screening and Frequency of weekly Portal assessments); (c) Retention of e-therapists (subcategories: Administrative requirements and Communication with the research team); and (d) The Portal. Conclusions: EJDeR and study procedures were considered acceptable and feasible, however, clinical and technical modifications and refinements to study procedures were suggested to enhance acceptability and feasibility. Results may also inform implementation considerations for both EJDeR and other similar digital psychological interventions. Trial registration number: ISRCTN 57233429.

Sex differences in prevalence and characteristics of imaging detected atherosclerosis - a population-based study.

AIMS: Men are more likely to suffer a myocardial infarction than women, but population-based studies on sex differences in imaging detected atherosclerosis are lacking. The aims were to assess sex differences in prevalence of imaging detected coronary and carotid atherosclerosis, as well as multivariable adjusted associations between sex and atherosclerosis. METHODS AND RESULTS: Participants aged 50-65, recruited from the general population to the Swedish Cardiopulmonary bioImage Study (SCAPIS), were included in this population-based cross-sectional study. Comprehensive diagnostics, including coronary computed tomography angiography and carotid ultrasound, were performed. The image findings were any coronary atherosclerosis, coronary stenosis ≥50%, segment involvement score (SIS) ≥4, coronary artery calcium score (CACS) ≥100, and any ultrasound-detected carotid plaque.In 25,580 participants (50% women), men had more hypertension (20.3% vs 17.0%), hyperlipidaemia (9.0% vs 5.5%), and diabetes (8.5% vs 4.7%). The prevalence was 56.2% vs 29.5% for any coronary atherosclerosis (p<0.01), 9.0% vs 2.3% for coronary stenosis ≥50% (p<0.01), 20.2% vs 5.3% for SIS≥4 (p<0.01), 18.2% vs 5.6% for CACS≥100 (p<0.01), and 60.9% vs 48.7% for carotid plaque (p<0.01), in men vs women, respectively. Multivariable adjustment only marginally changed these associations: odds ratios [OR] (95% confidence interval [CI]): 2.75 (2.53-2.99) for coronary atherosclerosis, 2.88 (2.40-3.45) for coronary stenosis ≥50%, 3.99 (3.50-4.55) for SIS≥4, 3.29 (2.88-3.75), for CACS≥100, and 1.57 (1.45-1.70) for carotid plaque. CONCLUSION: Men had higher prevalence of imaging detected carotid and coronary atherosclerosis with prevalence in women aged 65 corresponding to men 10-14 years younger. The associations remained after extensive multivariable adjustment.

Inhaled ciclesonide in adults hospitalised with COVID-19: a randomised controlled open-label trial (HALT COVID-19).

OBJECTIVE: To assess the efficacy of inhaled ciclesonide in reducing the duration of oxygen therapy (an indicator of time to clinical improvement) among adults hospitalised with COVID-19. DESIGN: Multicentre, randomised, controlled, open-label trial. SETTING: 9 hospitals (3 academic hospitals and 6 non-academic hospitals) in Sweden between 1 June 2020 and 17 May 2021. PARTICIPANTS: Adults hospitalised with COVID-19 and receiving oxygen therapy. INTERVENTION: Inhaled ciclesonide 320 µg two times a day for 14 days versus standard care. MAIN OUTCOME MEASURES: Primary outcome was duration of oxygen therapy, an indicator of time to clinical improvement. Key secondary outcome was a composite of invasive mechanical ventilation/death. RESULTS: Data from 98 participants were analysed (48 receiving ciclesonide and 50 receiving standard care; median (IQR) age, 59.5 (49-67) years; 67 (68%) men). Median (IQR) duration of oxygen therapy was 5.5 (3-9) days in the ciclesonide group and 4 (2-7) days in the standard care group (HR for termination of oxygen therapy 0.73 (95% CI 0.47 to 1.11), with the upper 95% CI being compatible with a 10% relative reduction in oxygen therapy duration, corresponding to a <1 day absolute reduction in a post-hoc calculation). Three participants in each group died/received invasive mechanical ventilation (HR 0.90 (95% CI 0.15 to 5.32)). The trial was discontinued early due to slow enrolment. CONCLUSIONS: In patients hospitalised with COVID-19 receiving oxygen therapy, this trial ruled out, with 0.95 confidence, a treatment effect of ciclesonide corresponding to more than a 1 day reduction in duration of oxygen therapy. Ciclesonide is unlikely to improve this outcome meaningfully. TRIAL REGISTRATION NUMBER: NCT04381364.

Survival after surgery of the ascending aorta: a matched cohort study.

OBJECTIVES: Surgery of ascending aortic aneurysms is performed prophylactically or acute. The expected survival after surgery is uncertain. The goal of this study was to compare mortality in people with aortic surgery with matched controls. METHODS: All patients undergoing ascending aortic surgery at Umeå University Hospital from 1988 to 2012, who previously participated in 1 of 3 population-based health surveys, were matched to 2 randomly selected controls from the same health survey and followed until death or until censoring on 24 August 2017, whichever came first. Mortality was calculated using the Kaplan-Meier method and the log-rank test. Cox regression analyses were made for all-cause mortality, adjusted for traditional cardiovascular risk factors. Deaths during the first 90 days after surgery and at >90 days postoperatively were studied separately. RESULTS: The median follow-up time was 9.2 years. A total of 61 of 189 patients and 51 of 370 controls died [hazard ratio (HR) 2.77, 95% confidence interval (CI) 1.91-4.01]. Mortality was increased during the first 90 days post-surgery (HR 43.4, 95% CI 5.83-323), as well as after the first 90 days (HR 1.90, 95% CI 1.25-2.88) and after acute surgery (HR 6.05, 95% CI 2.92-12.56) as well as after elective surgery (HR 2.10, 95% CI 1.35-3.27). Among 57 surgical patients with information about cause of death, 23 (40%) died of aortic disease. CONCLUSIONS: During follow-up, more patients died than matched controls. Findings were consistent when adjusting for traditional cardiovascular risk factors and across subgroups. Both short-term and long-term postoperative deaths were increased as well.

Troponin T but not C reactive protein is associated with future surgery for aortic stenosis: a population-based nested case-referent study.

AIMS: High-sensitivity troponin T (hs-TnT) and high-sensitivity C reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). This study evaluated if hs-TnT and hs-CRP associate with myocardial mass, and risk of future surgery for AS. METHODS: In total, 336 patients (48% women) with surgery for AS with previous participation in large population surveys were identified. Preoperatively, myocardial mass and the presence of coronary artery disease (CAD) were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma from the baseline survey. Conditional logistic regression analysis was used to estimate the risk (OR (95% CI)) related to one (natural logarithm) SD increase in hs-TnT and hs-CRP. Kaplan-Mayer and Cox regression analyses were used to evaluate time to surgery. RESULTS: Median age (IQR) was 59.8 (10.3) years at survey, and median time between survey and surgery was 10.9 (9.3) years. Hs-TnT was independently associated with surgery for AS (1.24 (1.06-1.44)) irrespective of CAD, whereas Hs-CRP was not (1.05 (0.90-1.22)). Elevated hs-TnT levels at survey associated with shorter time to surgery (p<0.001), and with increased myocardial mass (p=0.002). Hs-CRP did not associate with time to surgery or with myocardial mass. CONCLUSIONS: Hs-TnT-but not hs-CRP-was associated with increased risk of-and shorter time to-future surgery for AS. Hs-TnT associated with myocardial mass at surgery which indicates that hs-TnT could be a potential biomarker for determining intervention.

Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis.

Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.

[Management of malaria in Sweden]. / Handläggning av malaria ­ ur ett svenskt perspektiv.

Malaria is a potentially severe infection and time to treatment can be decisive for the outcome. Febrile patients returning from travel in endemic areas should therefore be promptly investigated for malaria. This review focuses on the acute management of malaria in Sweden. The disease is diagnosed in travellers, migrants and temporary visitors from malaria-endemic countries. Malaria is a relatively rare infection in Sweden, with approximately 150 imported cases per year in a population of 10 million. Health care delay is a risk of more severe disease. Children, pregnant women, elderly, and individuals from endemic areas who lived in Sweden for a long time as well as those with comorbidities are at increased risk of severe malaria. Microscopy is used for diagnosis and determination parasite density; rapid diagnostic tests are supportive diagnostic tools. First-line treatment for severe malaria is intravenous artesunate and for uncomplicated P. falciparum malaria artemether-lumefantrine (AL) or chloroquine in cases with non-P. falciparum infections from areas without known resistance. Treatment failures have been observed in non-immune travelers treated with AL, and patients should be recommended to seek care in the event of new fever. Being a relative rare disease in Sweden, management of malaria is performed at specialized centers with infectious disease specialists.

Macrolide and fluoroquinolone resistance in Mycoplasma genitalium in two Swedish counties, 2011-2015.

Mycoplasma genitalium, causing non-gonococcal non-chlamydial urethritis and associated with cervicitis, has developed antimicrobial resistance (AMR) to both the macrolide azithromycin (first-line treatment) and the fluoroquinolone moxifloxacin (second-line treatment). Our aim was to estimate the prevalence of resistance, based on genetic AMR determinants, to these antimicrobials in the M. genitalium population in two Swedish counties, Örebro and Halland, 2011-2015. In total, 672 M. genitalium positive urogenital samples were sequenced for 23S rRNA and parC gene mutations associated with macrolide and fluoroquinolone resistance, respectively. Of the samples, 18.6% and 3.2% in Örebro and 15.2% and 2.7% in Halland contained mutations associated with macrolide and fluoroquinolone resistance, respectively. The predominating resistance-associated mutations in the 23S rRNA gene was A2059G (n = 39) in Örebro and A2058G (n = 13) and A2059G (n = 13) in Halland. The most prevalent possible resistance-associated ParC amino acid alterations were S83I (n = 4) in Örebro and S83N (n = 2) in Halland. Resistance-associated mutations to both macrolides and fluoroquinolones were found in 0.7% of samples. Our findings emphasize the need for routine AMR testing, at a minimum for macrolide resistance, of all M. genitalium-positive samples and regular national and international surveillance of AMR in M. genitalium, to ensure effective patient management and rational antimicrobial use.

Traditional Cardiovascular Risk Factors and Their Relation to Future Surgery for Valvular Heart Disease or Ascending Aortic Disease: A Case-Referent Study.

BACKGROUND: Risk factors for developing heart valve and ascending aortic disease are based mainly on retrospective data. To elucidate these factors in a prospective manner, we have performed a nested case-referent study using data from large, population-based surveys. METHODS AND RESULTS: A total of 777 patients operated for heart valve disease or disease of the ascending aorta had previously participated in population-based health surveys in Northern Sweden. Median time (interquartile range) from survey to surgery was 10.5 (9.0) years. Primary indications for surgery were aortic stenosis (41%), aortic regurgitation (12%), mitral regurgitation (23%), and dilatation/dissection of the ascending aorta (17%). For each case, referents were allocated, matched for age, sex, and geographical area. In multivariable models, surgery for aortic stenosis was predicted by hypertension, high cholesterol levels, diabetes mellitus, and active smoking. Surgery for aortic regurgitation was associated with a low cholesterol level, whereas a high cholesterol level predicted surgery for mitral regurgitation. Hypertension, blood pressure, and previous smoking predicted surgery for disease of the ascending aorta whereas diabetes mellitus was associated with reduced risk. After exclusion of cases with coronary atherosclerosis, only the inverse associations between cholesterol and aortic regurgitation and between diabetes mellitus and disease of the ascending aorta remained. CONCLUSIONS: This is the first truly prospective study of traditional cardiovascular risk factors and their association with valvular heart disease and disease of the ascending aorta. We confirm the strong association between traditional risk factors and aortic stenosis, but only in patients with concomitant coronary artery disease. In isolated valvular heart disease, the impact of traditional risk factors is varying.

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease.

BACKGROUND: Aortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS. METHODS AND RESULTS: We identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni- and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07-1.55]), but not in 132 patients without CAD (1.04 [0.83-1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16-1.76]) but not in those without CAD (0.87 [0.69-1.10]). CONCLUSIONS: High levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

Development of an adenoviral vector system with adenovirus serotype 35 tropism; efficient transient gene transfer into primary malignant hematopoietic cells.

BACKGROUND: A paucity of coxsackie adenovirus receptor (CAR) hampers the adenovirus serotype 5 (Ad5)-based vector-mediated gene transfer into malignant hematopoietic cells. Fiber-retargeted adenoviral vectors with species B tropism can potentially bypass the CAR requirement and facilitate efficient gene transfer into malignant hematopoietic cells. METHODS: For feasible generation of fiber-retargeted adenoviral vectors, we have modified the versatile AdEasy system with a chimeric fiber gene encoding the Ad5 fiber tail domain and Ad35 fiber shaft and knob domains. An Ad5-based vector encoding the green fluorescent protein (GFP) gene under the control of the PGK promoter with Ad35 fiber receptor specificity was generated (Ad5F35-GFP). The Ad5F35-GFP vector-mediated gene transfer efficiency was compared with a fiber non-modified Ad5-GFP vector, which also encodes the GFP gene under the control of the PGK promoter. RESULTS: We demonstrated that a variety of Ad5-refractory malignant myeloid and B lymphoid cell lines were highly permissive to the Ad5F35-GFP vector infection. Importantly, primary chronic myeloid leukemic (CML) cells and chronic lymphocytic leukemia (CLL) B cells were superiorly transduced by the Ad5F35-GFP vector at a multiplicity of infection (MOI) of 100 compared with the Ad5-GFP vector. CONCLUSIONS: Our study will facilitate the generation of fiber-retargeted adenoviral vectors and enable transient genetic manipulation of primary malignant hematopoietic cells.