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Societal Impact Statement Can modern breeding technologies, such as genome editing, contribute to reduced pesticide usage? This question has been accentuated by a recent legal proposal to exempt genome‐edited plants from the strict regulations applied to classical genetically modified (GM) crops within the European Union (EU). Using official statistics on crop cultivation and pesticide usage for two example crops commonly grown in Sweden, we calculate that cereal farmers collectively could save up to 70 million € in pesticide usage for wheat alone and that a late blight‐resistant potato could reduce pesticide usage by over 80% provided that the EU legislation is amended. Summary The European Commission has set goals to reduce the use of chemical pesticides, and one way to meet these goals in the agricultural sector is to breed disease‐resistant crops. Here, we ask whether modern breeding technologies, for example, genome editing using site‐directed nucleases, can contribute to these goals. This question has been accentuated by recent legal proposals in the European Union (EU) and several other jurisdictions worldwide to exempt genome‐edited plants from the strict regulations often applied to classical genetically modified (GM) crops. Using official statistics on crop cultivation and pesticide usage for two example crops commonly grown in Sweden (wheat and potato), we show that cereal farmers collectively could potentially save up to 70 million € in pesticide usage for wheat alone and that a late blight‐resistant potato could reduce pesticide usage by over 80% provided that the EU legislation is amended. Given the immense potential of genome‐edited crops, we further discuss details in the legal proposal currently being negotiated in the EU on the so‐called new genomic techniques that includes both genome editing and targeted insertions of cisgenes. Although promising, we argue that several technical limitations in the legal proposal will, if implemented, hamper the development of disease‐resistant crops and make the suggested legislation less future‐proof.

Abstract Objective A growing body of evidence suggests patients with late‐onset seizures are at an increased risk of stroke, but the potential for reducing cardiovascular morbidity through risk factor screening and management is unknown. We aim to determine whether individuals with new‐onset unprovoked seizures after middle age should undergo vascular risk assessment. The long follow‐up needed to assess stroke risk and the known benefit of vascular risk factor modification make a standard RCT logistically and ethically challenging. Instead, we propose and have developed a protocol for a cluster project assessing the effect of vascular risk factor screening in an intervention trial as well as a cohort study. Methods Participating neurology clinics will implement standard cardiovascular risk factor assessment into the routine evaluation for individuals aged ≥50 years attending their first specialized consultation after an unprovoked seizure, excluding those with progressive brain disease. The project has two interlinked components: a prospective single group trial, in which risk factor assessment is performed and subsequent management is followed for one year; and a register‐based cohort study examining the long‐term effects of the intervention on a system level by comparing patients attending initial consultations in the 2 years after start of the study, with patients seen in the four preceding years at the same clinics. Analysis The primary outcome of the intervention trial is the proportion of patients receiving subsequent pharmacological treatment. The primary outcome of the cohort study is the incidence of acute stroke in the Swedish Stroke Register. Ethics and Dissemination Swedish Ethical Review Authority approval (which is valid for 2 years only) will be sought when funding is obtained. The results will be disseminated through peer‐reviewed scientific publications. Registration Details The study will be registered at clinicaltrials.gov. Plain Language Summary A first seizure in a middle‐aged or older person indicates a higher risk of stroke. It is not known whether investigating and treating blood pressure, blood cholesterol, or similar risk factors after a first seizure is an effective way to prevent stroke. A traditional clinical study would need too many patients and it would be unethical not to treat the control group. We have designed a study in which participating neurology departments change their practice to test and treat vascular risk factors. Patients are then compared to historic controls using registered data.

Abstract Aims This study aimed to characterize a contemporary population with subtypes of incident or prevalent heart failure (HF) based on reduced (HFrEF), mildly reduced, or preserved (HFpEF) left ventricular ejection fraction (LVEF) and to assess how outcomes, healthcare, treatments, and healthcare costs vary between each subtype of incident HF. Methods and results Using Swedish data from the CardioRenal and Metabolic disease Heart Failure (CaReMe HF) study, updated to cover a more recent time period, this population‐based study characterized patients from Stockholm County, Sweden, with incident HF (patients with a first HF diagnosis between 1 January 2015 and 31 December 2019) or prevalent HF (patients with a first HF diagnosis before 1 January 2020). Patients with incident HF had LVEF measured by echocardiography within ±90 days of their first HF diagnosis, and patients with prevalent HF within 5 years prior to the index date. The 13 375 patients with prevalent HF (39.2% women, mean age 73.9 years) had multiple comorbidities (cardiovascular diseases, chronic kidney disease, diabetes, and cancer). These were already highly prevalent at the time of the first HF diagnosis in the 8042 patients with incident HF (40.5% women, mean age 72.3 years). Patients with incident HFpEF received less specialist HF care at outpatient secondary care facilities following their first HF diagnosis than those with incident HFrEF. Patients with HFrEF had higher risks of complications and exerted a higher burden, in terms of care for and costs of HF, on the healthcare system. Conclusions This study of contemporary patients with incident HF demonstrates that those with HFpEF and HFrEF differ considerably in terms of clinical presentation, prognosis, and care, highlighting a potential to improve HF outcomes.

Background Coronary atherosclerosis detected by imaging is a marker of elevated cardiovascular risk. However, imaging involves large resources and exposure to radiation. The aim was, therefore, to test whether nonimaging data, specifically data that can be self‐reported, could be used to identify individuals with moderate to severe coronary atherosclerosis. Methods and Results We used data from the population‐based SCAPIS (Swedish CardioPulmonary BioImage Study) in individuals with coronary computed tomography angiography (n=25 182) and coronary artery calcification score (n=28 701), aged 50 to 64 years without previous ischemic heart disease. We developed a risk prediction tool using variables that could be assessed from home (self‐report tool). For comparison, we also developed a tool using variables from laboratory tests, physical examinations, and self‐report (clinical tool) and evaluated both models using receiver operating characteristic curve analysis, external validation, and benchmarked against factors in the pooled cohort equation. The self‐report tool (n=14 variables) and the clinical tool (n=23 variables) showed high‐to‐excellent discriminative ability to identify a segment involvement score ≥4 (area under the curve 0.79 and 0.80, respectively) and significantly better than the pooled cohort equation (area under the curve 0.76, P

Background Heart failure guidelines have recently introduced a narrow category with mildly reduced left ventricular ejection fraction (LVEF) (heart failure with mildly reduced ejection fraction; LVEF 41%–49%) between the previous categories of reduced (heart failure with reduced ejection fraction; LVEF ≤40%) and preserved (heart failure with preserved ejection fraction; LVEF ≥50%) ejection fraction. Grouping of continuous measurements into narrow categories can be questioned if their variability is high. Methods and Results We constructed a cohort of all 9716 new cases of chronic heart failure with an available LVEF in Stockholm, Sweden, from January 1, 2015, until December 31, 2020. All values of LVEF were collected over time, and patients were followed up until death, moving out of Stockholm, or end of study. Mixed models were used to quantify within‐person variance in LVEF, and multistate Markov models, with death as an absorbing state, to quantify the stability of LVEF categories. LVEF values followed a normal distribution. The SD of the within‐person variance in LVEF over time was 7.4%. The mean time spent in any LVEF category before transition to another category was on average

Abstract Axonal loss is the main cause of irreversible disability in multiple sclerosis (MS). Serum neurofilament light (sNfL) is a biomarker of axonal disintegration. In this nested case–control study, blood samples from 519 presymptomatic persons (age range 4–39 years) who later received an MS diagnosis showed higher sNfL concentrations than 519 matched controls (p

Background The study aimed to show the relationship between a large number of circulating metabolites and subsequent cardiovascular disease (CVD) and subclinical markers of CVD in the general population. Methods and Results In 2278 individuals free from CVD in the EpiHealth study (aged 45–75 years, mean age 61 years, 50% women), 790 annotated nonxenobiotic metabolites were measured by mass spectroscopy (Metabolon). The same metabolites were measured in the PIVUS (Prospective Investigation of Vasculature in Uppsala Seniors) study (n=603, all aged 80 years, 50% women), in which cardiac and carotid artery pathologies were evaluated by ultrasound. During a median follow‐up of 8.6 years, 107 individuals experienced a CVD (fatal or nonfatal myocardial infarction, stroke, or heart failure) in EpiHealth. Using a false discovery rate of 0.05 for age‐ and sex‐adjusted analyses and P

Background A significant proportion of patients with ST‐segment–elevation myocardial infarction (MI) have no standard modifiable cardiovascular risk factors (SMuRFs) and have unexpected worse 30‐day outcomes compared with those with SMuRFs. The aim of this article is to examine outcomes of patients with non–ST‐segment–elevation MI in the absence of SMuRFs. Methods and Results Presenting features, management, and outcomes of patients with non–ST‐segment–elevation MI without SmuRFs (hypertension, diabetes, hypercholesterolemia, smoking) were compared with those with SmuRFs in the Swedish MI registry SWEDEHEART (Swedish Web‐System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies; 2005–2018). Cox proportional hazard models were used. Out of 99 718 patients with non–ST‐segment–elevation MI, 11 131 (11.2%) had no SMuRFs. Patients without SMuRFs had higher all‐cause and cardiovascular mortality at 30 days (hazard ratio [HR], 1.20 [95% CI, 1.10–1.30], P

Background Renin‐angiotensin aldosterone system (RAAS) inhibitor—COVID‐19 studies, observational in design, appear to use biased methods that can distort the interaction between RAAS inhibitor use and COVID‐19 risk. This study assessed the extent of bias in that research and reevaluated RAAS inhibitor—COVID‐19 associations in studies without critical risk of bias. Methods and Results Searches were performed in MEDLINE, EMBASE, and CINAHL databases (December 1, 2019 to October 21, 2021) identifying studies that compared the risk of infection and/or severe COVID‐19 outcomes between those using or not using RAAS inhibitors (ie, angiotensin‐converting enzyme inhibitors or angiotensin II type‐I receptor blockers). Weighted hazard ratios (HR) and 95% CIs were extracted and pooled in fixed‐effects meta‐analyses, only from studies without critical risk of bias that assessed severe COVID‐19 outcomes. Of 169 relevant studies, 164 had critical risks of bias and were excluded. Ultimately, only two studies presented data relevant to the meta‐analysis. In 1 351 633 people with uncomplicated hypertension using a RAAS inhibitor, calcium channel blocker, or thiazide diuretic in monotherapy, the risk of hospitalization (angiotensin‐converting enzyme inhibitor: HR, 0.76; 95% CI, 0.66–0.87; P

Objective We aimed to determine relationships between objectively measured nightly sleep, sedentary behavior (SB), light physical activity (LPA), and moderate to vigorous physical activity (MVPA) with risk factors for cardiovascular disease (CVD) in patients with early rheumatoid arthritis (RA). Furthermore, we aimed to estimate consequences for these risk factors of theoretical displacements of 30 minutes per day in one behavior with the same duration of time in another. Methods This cross‐sectional study included 78 patients with early RA. Nightly sleep, SB, LPA, and MVPA were assessed by a combined heart rate and accelerometer monitor. Associations with risk factors for CVD were analyzed using linear regression models and consequences of reallocating time between the behaviors by isotemporal substitution modeling. Results Median (Q1‐Q3) nightly sleep duration was 4.6 (3.6‐5.8) hours. Adjusted for monitor wear time, age, and sex, 30‐minutes‐longer sleep duration was associated with favorable changes in the values β (95% confidence interval [CI]) for waist circumference by −2.2 (−3.5, −0.9) cm, body mass index (BMI) by −0.9 (−1.4, −0.4) kg/m2, body fat by −1.5 (−2.3, −0.8)%, fat‐free mass by 1.6 (0.8, 2.3)%, sleeping heart rate by −0.8 (−1.5, −0.1) beats per minute, and systolic blood pressure by −2.5 (−4.0, −1.0) mm Hg. Thirty‐minute decreases in SB, LPA, or MVPA replaced with increased sleep was associated with decreased android fat and lower systolic blood pressure levels. Replacement of SB or LPA with MVPA yielded lower BMIs. Conclusion Shorter sleep during the night is common among patients with early RA and is associated with adverse risk factors for CVD.

Abstract Aims Wild type transthyretin amyloidosis (ATTRwt) has gained interest during recent years due to better diagnostic tools and the emergence of treatment options. Little is known about the prevalence of the disease. We aimed to investigate the prevalence in a heart failure population with myocardial hypertrophy. Methods and results All patients with an ICD code of heart failure living within the catchment area of Umeå University hospital and intraventricular septum >14 mm were offered screening with 3,3‐diphosphono‐1,2‐propanodicarboxylic acid (DPD) scan and a clinical work up. Out of 2238 patients with heart failure, 174 patients were found to have a septum >14 mm. Ten patients were already diagnosed with hereditary ATTR cardiomyopathy, 12 patients had ATTRwt cardiomyopathy, 12 patients had known HCM, one patient had AL amyloidosis, and four patients had already undergone a negative DPD scan (DPD uptake grade 0 and 1) within the last 3 years. This left 134 patients who we tried to contact for screening, but 48 patients had either died or declined to participate. Out of 86 screened patients, 13 had a DPD uptake of grade 2 or 3 without other amyloid disease making the total number of patients with ATTRwt in this population 25. Conclusions Approximately 20% of investigated patients in a cohort with heart failure and increased myocardial wall thickness has ATTRwt. Calculated for the whole population of heart failure patients, the prevalence is just over 1.1%. Comparing this number to the total population would give an estimated prevalence of 1:6000.

Abstract Introduction Herpes simplex virus (HSV) may be involved in Alzheimer's disease (AD) pathophysiology. The antiviral valacyclovir inhibits HSV replication. Methods This phase‐II pilot trial involved valacyclovir administration (thrice daily, 500 mg week 1, 1000 mg weeks 2–4) to persons aged ≥ 65 years with early‐stage AD, anti‐HSV immunoglobulin G, and apolipoprotein E ε4. Intervention safety, tolerability, feasibility, and effects on Mini‐Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarkers were evaluated. Results Thirty‐two of 33 subjects completed the trial on full dosage. Eighteen percent experienced likely intervention‐related mild, temporary adverse events. CSF acyclovir concentrations were mean 5.29 ± 2.31 μmol/L. CSF total tau and neurofilament light concentrations were unchanged; MMSE score and CSF soluble triggering receptor expressed on myeloid cells 2 concentrations increased (P = .02 and .03). Discussion Four weeks of high‐dose valacyclovir treatment was safe, tolerable, and feasible in early‐stage AD. Our findings may guide future trial design.

Objectives. To estimate the incidence and prevalence of multiple sclerosis (MS) in Malmö municipality in southwestern Sweden. Materials and Methods. Multiple sources were used in the case identification process. Case ascertainment was assessed by medical chart review including examinations such as magnetic resonance imaging, cerebrospinal fluid analyses, and relevant laboratory tests. Cases were classified according to the 2010 McDonald’s diagnostic criteria. Onset-adjusted prevalence and a definition of onset symptoms were applied. Results. The crude incidence of MS in 2001-2010 in Malmö municipality was 5.3/100,000 (95% confidence interval (CI): 4.5 to 6.2). There was a relapsing onset in 90.5% of cases. The female to male ratio was 1.8. The onset-adjusted prevalence for Dec 2010 was 133/100,000 (95% CI, 120 to 146) with a female to male ratio of 2.1. Conclusions. This is the first population-based epidemiological study in Skåne, the most southwestern part of Sweden showing a high incidence and prevalence. We found a lower incidence than expected according to previous nationwide figures, probably due to methodological differences between the studies. Our findings support the presence of a north-south gradient of MS prevalence in Sweden.

Abstract In a subarctic climate, the seasonal shifts in temperature, precipitation, and plant cover drive the temporal changes in the microbial communities in the topsoil, forcing soil microbes to adapt or decline. Many organisms, such as mound‐building ants, survive the cold winter owing to the favorable microclimate in their nest mounds. We have previously shown that the microbial communities in the nest of the ant Formica exsecta are significantly different from those in the surrounding bulk soil. In the current study, we identified taxa, which were consistently present in the nests over a study period of three years. Some taxa were also significantly enriched in the nest samples compared with spatially corresponding reference soils. We show that the bacterial communities in ant nests are temporally stable across years, whereas the fungal communities show greater variation. It seems that the activities of the ants contribute to unique biochemical processes in the secluded nest environment, and create opportunities for symbiotic interactions between the ants and the microbes. Over time, the microbial communities may come to diverge, due to drift and selection, especially given the long lifespan (up to 30 years) of the ant colonies.

Background Considering the widespread risk of collider bias and confounding by indication in previous research, the associations between renin‐angiotensin aldosterone system (RAAS) inhibitor use and COVID‐19 remain unknown. Accordingly, this study tested the hypothesis that RAAS inhibitors influence the summation effect of COVID‐19 and its progression to severe outcomes. Methods and Results This nationwide cohort study compared all residents of Sweden, without prior cardiovascular disease, in monotherapy (as of January 1, 2020) with a RAAS inhibitor to those using a calcium channel blocker or a thiazide diuretic. Comparative cohorts were balanced using machine‐learning‐derived propensity score methods. Of 165 355 people in the analysis (51% women), 367 were hospitalized or died with COVID‐19 (246 using a RAAS inhibitor versus 121 using a calcium channel blocker or thiazide diuretic; Cox proportional hazard ratio [HR], 0.97; 95% CI, 0.74–1.27). When each outcome was assessed separately, 335 people were hospitalized with COVID‐19 (HR, 0.92; 95% CI, 0.70–1.22), and 64 died with COVID‐19 (HR, 1.22; 95% CI, 0.68–2.19). The severity of COVID‐19 outcomes did not differ between those using a RAAS inhibitor and those using a calcium channel blocker or thiazide diuretic (ordered logistic regression odds ratio, 1.01; 95% CI, 0.89–1.14). Conclusions Despite potential limitations, this study is among the best available evidence that RAAS inhibitor use in primary prevention does not increase the risk of severe COVID‐19 outcomes; presenting strong data from which scientists and policy makers alike can base, with greater confidence, their current position on the safety of using RAAS inhibitors during the COVID‐19 pandemic.

Background The aim is to study common etiological pathways for 3 major cardiovascular diseases (CVD), as reflected in multiple proteins. Methods and Results Eighty‐four proteins were measured using the proximity extension technique in 870 participants in the PIVUS (Prospective Investigation of Uppsala Seniors Study) cohort on 3 occasions (age 70, 75, and 80 years). The sample was followed for incident myocardial infarction, ischemic stroke or heart failure. The same proteins were measured in an independent validation sample, the ULSAM (Uppsala Longitudinal Study of Adult Men) cohort in 595 participants at age 77. During a follow‐up of up to 15 years in PIVUS and 9 years in ULSAM, 222 and 167 individuals experienced a CVD. Examining associations with the 3 outcomes separately in a meta‐analysis of the 2 cohorts, 6 proteins were related to incident myocardial infarction, 25 to heart failure, and 8 proteins to ischemic stroke following adjustment for traditional risk factors. Growth differentiation factor 15 and tumor necrosis factor‐related apoptosis‐inducing ligand receptor 2 were related to all 3 CVDs. Including estimated glomerular filtration rate in the models attenuated some of these relationships. Fifteen proteins were related to a composite of all 3 CVDs using a discovery/validation approach when adjusting for traditional risk factors. A selection of 7 proteins by lasso in PIVUS improved discrimination of incident CVD by 7.3% compared with traditional risk factors in ULSAM. Conclusions We discovered and validated associations of multiple proteins with incident CVD. Only a few proteins were associated with all 3 diseases: myocardial infarction, ischemic stroke, and heart failure.

Abstract Aims We aimed to investigate whether metabolomic profiling of blood can lead to novel insights into heart failure pathogenesis or improved risk prediction. Methods and results Mass spectrometry‐based metabolomic profiling was performed in plasma or serum samples from three community‐based cohorts without heart failure at baseline (total n = 3924; 341 incident heart failure events; median follow‐up ranging from 4.6 to 13.9 years). Cox proportional hazard models were applied to assess the association of each of the 206 identified metabolites with incident heart failure in the discovery cohorts Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) (n = 920) and Uppsala Longitudinal Study of Adult Men (ULSAM) (n = 1121). Replication was undertaken in the independent cohort TwinGene (n = 1797). We also assessed whether metabolites could improve the prediction of heart failure beyond established risk factors (age, sex, body mass index, low‐density and high‐density lipoprotein cholesterol, triglycerides, lipid medication, diabetes, systolic and diastolic blood pressure, blood pressure medication, glomerular filtration rate, smoking status, and myocardial infarction prior to or during follow‐up). Higher circulating urobilin and lower sphingomyelin (30:1) were associated with incident heart failure in age‐adjusted and sex‐adjusted models in the discovery and replication sample. The hazard ratio for urobilin in the replication cohort was estimated to 1.29 per standard deviation unit, 95% confidence interval (CI 1.03–1.63), and for sphingomyelin (30:1) to 0.72 (95% CI 0.58–0.89). Results remained similar after further adjustment for established heart failure risk factors in meta‐analyses of all three cohorts. Urobilin concentrations were inversely associated with left ventricular ejection fraction at baseline in the PIVUS cohort (β = −0.70, 95% CI −1.03 to −0.38). No major improvement in risk prediction was observed when adding the top 2 metabolites (C‐index 0.787, 95% CI 0.752–0.823) or nine Lasso‐selected metabolites (0.790, 95% CI 0.754–0.826) to a modified Atherosclerosis Risk in Communities heart failure risk score model (0.780, 95% CI 0.745–0.816). Conclusions Our metabolomic profiling of three community‐based cohorts study identified associations of circulating levels of the haem breakdown product urobilin, and sphingomyelin (30:1), a cell membrane component involved in signal transduction and apoptosis, with incident heart failure.

Abstract Background Immunotherapy for patients with microsatellite‐instable (MSI‐H) tumors or BRAF‐inhibitors combination treatment for BRAF‐mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population‐based studies of these molecular changes are warranted. Methods A population‐based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression‐free survival (PFS) were estimated. Results Here, 40/583 (7%) tumor samples were MSI‐H and 120/591 (20%) were mutBRAF; 87% of MSI‐H tumors were mutBRAF (non‐Lynch). Elderly (>75 years) had more often MSI‐H (10% vs 6%) and MSI‐H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first‐line chemotherapy was all significantly lower in patients with MSI‐H compared to patients with microsatellite stable tumors. MSI‐H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P

Background The molecular mechanisms involved in atrial fibrillation are not well known. We used plasma metabolomics to investigate if we could identify novel biomarkers and pathophysiological pathways of incident atrial fibrillation. Methods and Results We identified 200 endogenous metabolites in plasma/serum by nontargeted ultra‐performance liquid chromatography coupled to time‐of‐flight mass spectrometry in 3 independent population‐based samples (TwinGene, n=1935, mean age 68, 43% females; PIVUS [Prospective Investigation of the Vasculature in Uppsala Seniors], n=897, mean age 70, 51% females; and ULSAM [Uppsala Longitudinal Study of Adult Men], n=1118, mean age 71, all males), with available data on incident atrial fibrillation during 10 to 12 years of follow‐up. A meta‐analysis of ULSAM and PIVUS was used as a discovery sample and TwinGene was used for validation. In PIVUS, we also investigated associations between metabolites of interest and echocardiographic indices of myocardial geometry and function. Genome‐wide association studies were performed in all 3 cohorts for metabolites of interest. In the meta‐analysis of PIVUS and ULSAM with 430 incident cases, 4 metabolites were associated with incident atrial fibrillation at a false discovery rate

Abstract To what extent and how do men and women differ in their attitudes about poaching? Although research suggests that women can be more concerned about environmental degradation than men, inquiries about communities in protected areas are ambiguous: women are disproportionately affected by anti‐poaching laws and can have greater motivations to violate rules. We conducted a large‐scale survey in communities within the Great Limpopo Transfrontier Park in Mozambique, South Africa, and Zimbabwe and explored attitudes regarding; concern about resources, rule compliance, poaching, and anti‐poaching activities. Although women's attitudes generally are not divergent from men's, we find some differences among nonelectrified households and those with a dependence on resources; these women are less likely to condemn commercial poaching and less willing to engage in anti‐poaching activities. Men in poorer households are more likely to know a poacher. We identify a need of further understanding the causes behind gender differences in conservation attitudes.

Abstract Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low‐CIP2A‐expressing tumors had more frequently moderate or excellent response to long‐course (C)RT than patients with high‐CIP2A‐expressing tumors. They also had higher 36‐month disease‐specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long‐course (C)RT in rectal cancer patients.

BackgroundThe knowledge of the impact of cardiovascular risk factors at different ages has mainly been based on different studies performed at different ages. This study aimed to investigate the change in impact of traditional cardiovascular risk factors over the aging process in subjects followed for 4 decades. Methods and ResultsIn the ULSAM (Uppsala Longitudinal Study of Adult Men) study, 2322 men originally investigated in 1970 to 1974 have been followed regarding cardiovascular diseases until the end of 2013. This cohort has been investigated physically at ages 50, 60, 70, 77, and 82 years regarding body mass index, low‐density lipoprotein‐ and high‐density lipoprotein‐cholesterol, triglycerides, systolic blood pressure and diastolic blood pressure, fasting glucose, and smoking. These data were used to model the interactions between risk factors and age regarding incident myocardial infarction (n=540), ischemic stroke (n=343), or heart failure (n=397). Significant interactions were observed between age and the set of traditional risk factors regarding all 3 outcomes (P

Background: Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting., Methods: In this nested case-control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead-based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression., Results: Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV-6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8-8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0-2.9)., Conclusions: To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: High levels of 25-hydroxyvitamin D 3 (25[OH]D 3 ) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D 3 is regulated by its main plasma carrier, vitamin D-binding protein (DBP). Free 25(OH)D 3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D 3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D 3 and DBP as risk factors for MS., Methods: A nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D 3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D 3 was approximated as free vitamin D 3 index: (25[OH]D 3 /DBP) × 10 3 . MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs)., Results: Serum samples from 660 pairs of matched cases and controls were included. At <20 years of age, high levels of free vitamin D 3 index were associated with a lower risk of MS (highest vs. lowest quintile: OR = 0.37, 95% CI = 0.15-0.91, p for trend across quintiles = 0.04). At age 30-39 years, high levels of DBP were associated with a lower MS risk (highest vs. lowest quintile: OR = 0.36, 95% CI = 0.15-0.85, p for trend = 0.02)., Conclusions: These findings support the hypothesis that high levels of free 25(OH)D 3 at a young age reduce the risk of MS later in life. They also implicate a role for DBP in MS etiology., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology., Methods: A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP)., Results: Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65)., Conclusions: Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS., Methods: In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals., Results: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7)., Conclusions: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS., (© 2020 The Authors. European Journal of Neurology Published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To investigate the cumulative delivery rate for women completing three fresh embryo transfer cycles or giving birth after the first or second transfer cycle in an in vitro fertilization program with a single embryo transfer (SET) policy., Setting: Privately run infertility clinic in southern Sweden (Skåne region)., Population: Four hundred fifty-three consecutive, unselected public patients beginning an ovum pick-up cycle between July 2002 and June 2004., Method: Retrospective, observational study., Main Outcome Measure: Cumulative delivery rates., Results: Of 370 women who completed the study with up to three fresh ET cycles (90% SETs), 244 women (66%) progressed to delivery. Among the deliveries were three sets of twins (1%), one dizygotic. Cumulative delivery rates showed significant differences relative to age <36 (71%) and >or=36 years (47%), and delivery rates relative to rank of ET cycle (first and second vs. third ET cycle - 35, 34, and 21% delivery rates, respectively)., Conclusions: The 66% cumulative delivery rate is in accordance with rates in similar observational studies and in estimation studies, in which predominantly two embryos were used for transfer. The multiple delivery rate was low. We suggest that repeated SET cycles can be implemented on a large scale even in a primarily unselected patient population without compromising the outcome.

Cytokines have a central role in multiple sclerosis (MS) pathogenesis and may contribute to the aetiology of MS. A polymorphism in the IFNA17 gene with an allele carrying a pre-mature stop codon has been suggested to convey a 26-fold increased risk for MS. We investigated the possible association between this polymorphism and MS using population-based samples from a genetically well-characterized population. The IFNA17 gene variant was found in 2.8% of 327 MS cases and 3.3% of 698 referents (P = 0.64). Thus, our study does not support an association between the IFNA17 allele and risk for MS.

Background: To evaluate the relationship between age and poor ovarian response to pregnancy and cancellation rate after IVF stimulation., Methods: Poor ovarian response was defined as 37 years, who were poor responders, had a significantly lower pregnancy rate per OPU (3.0%) compared to normal to high responders in the same age group (22.1%, p<0.05). Also, 43.6% of women >37 years, who were classified as poor responders, did not receive an embryo transfer (ET), compared to 13.2% of normal to high responders in this age group (p<0.05). Poor responders who were 37 years, who receive high doses of FSH have a significantly poorer treatment outcome than can be explained by either age or FSH dose alone., Conclusions: Poor ovarian response after IVF stimulation requires thorough counselling prior to OPU, regardless of the woman's age. In poor responders >37 years of age, especially those who require high FSH doses, we suggest that the decision whether or not to proceed to OPU should include the couple after thorough counselling, even though the chance of successful outcome is extremely low.

Ovarian follicles were aspirated at midcycle from 193 women admitted to the hospital because of infertility or for legal sterilization. Eighteen women had not received prior hormone stimulation and 175 had been stimulated either with Clomiphene citrate and hCG with hCG alone. Preovulatory oocytes could not be obtained from any of the women in the non-stimulated group, but were obtained from 86 (49%) in the stimulated group. Of these 86, oocytes from 63 women were cultured successfully and from 47 (75%) cleavage occurred. The most advanced stages observed were about 10-cell embryos, but no attempts were made to culture them further. Almost all the oocytes which cleaved were obtained from women in whom the progesterone level started to rise from the basal level within 24 hours of the operation. Eight cleaved oocytes were taken for transmission electron microscopy (TEM). Early cleavage stages showed spheroidal mitochondria with a few peripheral cristae, while the number of elongated mitochondria with transverse cristae increased in later stages. Mitochondria-vesicle complexes, consisting of a vesicle filled with a dense substance and surrounded by 5-15 mitochondria, were observed in early (but not in more advanced) embryos. The complex is probably part of a transport system from the nucleus to the mitochondria. In the later stages, a type of granulated vesicle appeared. Thus, some changes occurred in tact with the degree of development, while no differences could be seen between oocytes with differing cleavage rates.