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Esophagectomy is a complex and complication laden procedure. Despite centralization, variations in perioparative strategies reflect a paucity of evidence regarding optimal routines. The use of nasogastric (NG) tubes post esophagectomy is typically associated with significant discomfort for the patients. We hypothesize that immediate postoperative removal of the NG tube is non-inferior to current routines. All Nordic Upper Gastrointestinal Cancer centers were invited to participate in this open-label pragmatic randomized controlled trial (RCT). Inclusion criteria include resection for locally advanced esophageal cancer with gastric tube reconstruction. A pretrial survey was undertaken and was the foundation for a consensus process resulting in the Kinetic trial, an RCT allocating patients to either no use of a NG tube (intervention) or 5 days of postoperative NG tube use (control) with anastomotic leakage as primary endpoint. Secondary endpoints include pulmonary complications, overall complications, length of stay, health related quality of life. A sample size of 450 patients is planned (Kinetic trial: https://www.isrctn.com/ISRCTN39935085). Thirteen Nordic centers with a combined catchment area of 17 million inhabitants have entered the trial and ethical approval was granted in Sweden, Norway, Finland, and Denmark. All centers routinely use NG tube and all but one center use total or hybrid minimally invasive-surgical approach. Inclusion began in January 2022 and the first annual safety board assessment has deemed the trial safe and recommended continuation. We have launched the first adequately powered multi-center pragmatic controlled randomized clinical trial regarding NG tube use after esophagectomy with gastric conduit reconstruction. [ABSTRACT FROM AUTHOR]

Background Colorectal cancer is the third most common malignancy worldwide and is strongly linked to lifestyle and environmental risk factors. Although several drinking-water disinfection by-products are confirmed rodent carcinogens, the evidence in humans for carcinogenicity associated with these by-products, including colorectal cancer, is still inconclusive. Methods We assessed the association of long-term exposure to trihalomethanes (THMs), the most prevalent disinfection by-products in chlorinated drinking water, with incidence of colorectal cancer in 58 672 men and women in 2 population-based cohorts. Exposure was assessed by combining long-term information of residential history with drinking water–monitoring data. Participants were categorized according to no exposure, low exposure (<15 µg/L), and high exposure (≥15 µg/L). Incident cases of colorectal cancer were ascertained by use of the Swedish National Cancer Register. Results During an average follow-up of 16.8 years (988 144 person-years), 1913 cases of colorectal cancer were ascertained (1176 cases in men and 746 in women, respectively). High THM concentrations in drinking water (≥15 µg/L) were associated with increased risk of colorectal cancer in men (hazard ratio = 1.26, 95% confidence interval = 1.05-1.51) compared with no exposure. When subsites were assessed, the association was statistically significant for proximal colon cancer (hazard ratio = 1.59, 95% confidence interval = 1.11 to 2.27) but not for distal colon cancer or rectal cancer. In women, we observed overall no association of THMs with colorectal cancer. Conclusion These results add further evidence that disinfection by-products in drinking water may be a possible risk factor for proximal colon cancer in men. This observation was made at THM concentrations lower than those in most previous studies. [ABSTRACT FROM AUTHOR]

Anastomotic defect (AD) after esophagectomy can lead to severe complications with need for surgical or endoscopic intervention. Early detection enables early treatment and can limit the consequences of the AD. As of today, there are limited methods to predict AD. In this study, we have used microdialysis (MD) to measure local metabolism at the intrathoracic anastomosis. Feasibility and possible diagnostic use were investigated. Sixty patients planned for Ivor Lewis esophagectomy were enrolled. After construction of the anastomosis, surface MD (S-MD) probes were attached to the outer surface of the esophageal remnant and the gastric conduit in close vicinity of the anastomosis and left in place for 7 postoperative days (PODs). Continuous sampling of local tissue concentrations of metabolic substances (glucose, lactate, and pyruvate) was performed postoperatively. Outcome, defined as AD or not according to Esophagectomy Complications Consensus Group definitions, was recorded at discharge or at first postoperative follow up. Difference in concentrations of metabolic substances was analyzed retrospectively between the two groups by means of artificial neural network technique. S-MD probes can be attached and removed from the gastric tube reconstruction without any adverse events. Deviating metabolite concentrations on POD 1 were associated with later development of AD. In subjects who developed AD, no difference in metabolic concentrations between the esophageal and the gastric probe was recorded. The technical failure rate of the MD probes/procedure was high. S-MD can be used in a clinical setting after Ivor Lewis esophagectomy. Deviation in local tissue metabolism on POD 1 seems to be associated with development of AD. Further development of MD probes and procedure is required to reduce technical failure. [ABSTRACT FROM AUTHOR]

Background Despite newer treatments with immunosuppressive agents, there still exists a considerable morbidity and mortality risk among patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Since 1994 the European Vasculitis Society (EUVAS) has aimed for an improved outcome for patients with AAV, conducting several prospective randomized controlled trials (RCTs). The aim for the present study was to further evaluate the long-term survival of patients with AAV included in seven RCTs conducted by the EUVAS as well as to identify potential prognostic factors. Methods Long-term follow-up data were collected from questionnaires sent to the principal investigators of the original RCTs (1995–2012): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC, comprising 848 patients, all newly diagnosed with AAV. Relative survival estimates are presented for the study cohorts. Demographic, clinical and laboratory characteristics at trial entry were studied as potential prognostic factors in multivariable models. Results A total of 478 (56%) patients had granulomatosis with polyangiitis (GPA) and 370 (44%) had microscopic polyangiitis (MPA) with a mean age at diagnosis of 58 ± 14 years. The median follow-up time was 8 years (interquartile range 2.9–13.6). During the observation period there were 305 deaths and the main causes were infections (26%), cardiovascular disease (14%) and malignancies (13%). When compared with a matched cohort (regarding country, age group and sex) from the background population there were 14.2% more deaths among our cohort of AAV patients at 5 years, 19.9% at 10 years, 28.8% at 15 years and 36.3% at 20 years. The excess mortality occurred in all age groups. The estimated median survival time (from diagnosis) was 17.8 years (95% confidence interval 15.7–20). Among variables measured at baseline, advanced age, male sex, low estimated glomerular filtration rate and low platelet count were identified as predictors of death in a multivariate Cox model. Conclusions Patients with AAV still have an increased risk of mortality compared with the general population despite newer therapeutic regimens. Treatment complications and organ damage are the main causes of limited survival and infections remain the leading cause of mortality among patients with AAV. [ABSTRACT FROM AUTHOR]

Aims: We conducted observational and Mendelian randomization (MR) analyses to explore the associations between blood proteins and risk of peripheral artery disease (PAD). Methods and results: The observational cohort analyses included data on 257 proteins estimated in fasting blood samples from 12 136 Swedish adults aged 55–94 years who were followed up for incident PAD via the Swedish Patient Register. Mendelian randomization analyses were undertaken using cis-genetic variants strongly associated with the proteins as instrumental variables and genetic association summary statistic data for PAD from the FinnGen study (11 924 cases and 288 638 controls) and the Million Veteran Program (31 307 cases and 211 753 controls). The observational analysis, including 86 individuals diagnosed with incident PAD during a median follow-up of 6.6-year, identified 13 proteins [trefoil factor two, matrix metalloproteinase-12 (MMP-12), growth differentiation factor 15, V-set and immunoglobulin domain-containing protein two, N-terminal prohormone brain natriuretic peptide, renin, natriuretic peptides B, phosphoprotein associated with glycosphingolipid-enriched microdomains one, C-C motif chemokine 15, P-selectin, urokinase plasminogen activator surface receptor, angiopoietin-2, and C-type lectin domain family five member A] associated with the risk of PAD after multiple testing correction. Mendelian randomization analysis found associations of T-cell surface glycoprotein CD4, MMP-12, secretoglobin family 3A member 2, and ADM with PAD risk. The observational and MR associations for T-cell surface glycoprotein CD4 and MMP-12 were in opposite directions. Conclusion: This study identified many circulating proteins in relation to the development of incident PAD. Future studies are needed to verify our findings and assess the predictive and therapeutic values of these proteins in PAD. Graphical abstract [ABSTRACT FROM AUTHOR]

Aims Sleep duration has been associated with cardiovascular disease, however the effect of sleep on peripheral artery disease (PAD) specifically remains unestablished. We conducted observational and Mendelian randomization (MR) analyses to assess the associations of sleep duration and daytime napping with PAD risk. Methods and results Sleep traits were assessed for associations with incident PAD using cohort analysis among 53 416 Swedish adults. Replicated was sought in a case-control study of 28 123 PAD cases and 128 459 controls from the veterans affairs Million Veteran Program (MVP) and a cohort study of 452 028 individuals from the UK Biobank study (UKB). Two-sample Mendelian randomization (MR) was used for casual inference-based analyses of sleep-related traits and PAD (31 307 PAD cases 211 753 controls). Observational analyses demonstrated a U-shaped association between sleep duration and PAD risk. In Swedish adults, incident PAD risk was higher in those with short sleep [<5 h; hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.31–2.31] or long sleep (≥8 h; HR 1.24; 95% CI 1.08–1.43), compared to individuals with a sleep duration of 7 to <8 h/night. This finding was supported by the analyses in MVP and UKB. Observational analysis also revealed positive associations between daytime napping (HR 1.32, 95% CI 1.18–1.49) with PAD. MR analysis supported an inverse association between sleep duration [odds ratio (OR) per hour increase: 0.79, 95% CI, 0.55, 0.89] and PAD and an association between short sleep and increased PAD (OR 1.20, 95% CI, 1.04–1.38). Conclusion Short sleep duration was associated with an increased risk of PAD. [ABSTRACT FROM AUTHOR]

Background A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. Methods Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n  = 13 856 including 6031 individuals in the external validation cohort), from France (n  = 4429, including 964 Black Europeans), from Brazil (n  = 100) and from Africa (n  = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. Results In White Europeans (n  = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of –0.6 and –3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. Conclusion In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study. [ABSTRACT FROM AUTHOR]

Background Differences in the performance of estimated glomerular filtration rate (eGFR) equations have been attributed to the mathematical form of the equations and to differences between patient demographics and measurement methods. We evaluated differences in serum creatinine (SCr) and eGFR in cohorts matched for age, sex, body mass index (BMI) and measured GFR (mGFR). Methods White North Americans from Minnesota (n  = 1093) and the Chronic Renal Insufficiency Cohort (CRIC) (n  = 1548) and White subjects from the European Kidney Function Consortium (EKFC) cohort (n  = 7727) were matched for demographic patient characteristics (sex, age ± 3 years, BMI ± 2.5 kg/m2) and renal function (mGFR ± 3 ml/min/1.73 m2). SCr was measured with isotope dilution mass spectrometry (IDMS)-traceable assays in the Minnesota and EKFC cohorts and with non-standardized SCr assays recalculated to IDMS in the CRIC. The Minnesota cohort and CRIC shared a common method to measure GFR (renal clearance of iothalamate), while the EKFC cohort used a variety of exogenous markers and methods, all with recognized sufficient accuracy. We compared the SCr levels and eGFR predictions [for Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and EKFC equations] of patients fulfilling these matching criteria. Results For 305 matched individuals, mean SCr (mg/dL) was not different between the Minnesota and EKFC cohorts (females 0.83 ± 0.20 versus 0.86 ± 0.23, males 1.06 ± 0.23 versus 1.12 ± 0.37; P  > .05) but significantly different from the CRIC [females 1.13 ± 0.23 (P  < .0001), males 1.42 ± 0.31 (P  < .0001)]. The CKD-EPI equations performed better than the EKFC equation in the CRIC, while the opposite was true in the Minnesota and EKFC cohorts. Conclusion Significant differences in SCr concentrations between the Minnesota and EKFC cohorts versus CRIC were observed in subjects with the same level of mGFR and equal demographic characteristics and can be explained by the difference in SCr calibration. [ABSTRACT FROM AUTHOR]

Background: Frailty assessment in the Swedish health system relies on the Clinical Frailty Scale (CFS), but it requires training, in-person evaluation, and is often missing in medical records. We aimed to develop an electronic frailty index (eFI) from routinely collected electronic health records (EHRs) and assess its association with adverse outcomes in hospitalized older adults.Methods: EHRs were extracted for 18 225 patients with unplanned admissions between 1 March 2020 and 17 June 2021 from 9 geriatric clinics in Stockholm, Sweden. A 48-item eFI was constructed using diagnostic codes, functioning and other health indicators, and laboratory data. The CFS, Hospital Frailty Risk Score, and Charlson Comorbidity Index were used for comparative assessment of the eFI. We modeled in-hospital mortality and 30-day readmission using logistic regression; 30-day and 6-month mortality using Cox regression; and length of stay using linear regression.Results: Thirteen thousand one hundred and eighty-eight patients were included in analyses (mean age 83.1 years). A 0.03 increment in the eFI was associated with higher risks of in-hospital (odds ratio: 1.65; 95% confidence interval: 1.54-1.78), 30-day (hazard ratio [HR]: 1.43; 1.38-1.48), and 6-month mortality (HR: 1.34; 1.31-1.37) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the highest area under receiver operating characteristic curve for in-hospital mortality of 0.813. Higher eFI was associated with longer length of stay, but had a rather poor discrimination for 30-day readmission.Conclusions: An EHR-based eFI has robust associations with adverse outcomes, suggesting that it can be used in risk stratification in hospitalized older adults. [ABSTRACT FROM AUTHOR]

Motivation Network-based disease modules have proven to be a powerful concept for extracting knowledge about disease mechanisms, predicting for example disease risk factors and side effects of treatments. Plenty of tools exist for the purpose of module inference, but less effort has been put on simultaneously utilizing knowledge about regulatory mechanisms for predicting disease module hub regulators. Results We developed MODalyseR, a novel software for identifying disease module regulators and reducing modules to the most disease-associated genes. This pipeline integrates and extends previously published software packages MODifieR and ComHub and hereby provides a user-friendly network medicine framework combining the concepts of disease modules and hub regulators for precise disease gene identification from transcriptomics data. To demonstrate the usability of the tool, we designed a case study for multiple sclerosis that revealed IKZF1 as a promising hub regulator, which was supported by independent ChIP-seq data. Availability and implementation MODalyseR is available as a Docker image at https://hub.docker.com/r/ddeweerd/modalyser with user guide and installation instructions found at https://gustafsson-lab.gitlab.io/MODalyseR/. Supplementary information Supplementary data are available at Bioinformatics Advances online. [ABSTRACT FROM AUTHOR]

Objective: Female childhood cancer survivors (CCS) are at risk of several late effects, such as metabolic syndrome (MetS) and premature ovarian insufficiency (POI). The objective is to study if POI is associated with risk of MetS and increased cardiovascular risk in CSS. Design: A cross-sectional study with a median time since the cancer di agnosis of 25 (12-41) years. Patients and controls were recruited from the South Medical Region of Sweden. Methods: The study included 167 female CCS, median age 34 (19-57) years, diagnosed with childhood cancer at median age 8.4 (0.1-17.9) years together with 164 controls, matched for age, sex, ethnicity, residence, and smoking habits. All subjects were examined with fasting glucose, insulin, HbA1c, and lipid profile. Fat mass was calculated with dualenergy X-ray absorptiometry (DXA), and questionnaires for medic ation were obtained. Detailed information of cancer treatment was available. Results: POI was present in 13% (22/167) among CCS (hypothalamic/pituit ary cause excluded) and in none among controls. MetS was present in 14% (24/167) among all CCS (P = 0.001), in 23% (5/22) of those with POI (P < 0.001), compared with 4% (6/164) among controls. OR for MetS in all CCS compared with controls was 4.4 (95% CI: 1.8, 11.1) (P = 0.002) and among CCS with POI the OR was 7.7 (CI: 2.1, 28.1) (P = 0.002). Conclusion: The prevalence of MetS was higher in females treated for child hood cancer compared with controls, and the presence of POI significantly increased the risk of developi ng MetS. [ABSTRACT FROM AUTHOR]

Spectacular long‐distance migration has evolved repeatedly in animals enabling exploration of resources separated in time and space. In birds, these patterns are largely driven by seasonality, cost of migration, and asymmetries in competition leading most often to leapfrog migration, where northern breeding populations winter furthest to the south. Here, we show that the highly aerial common swift Apus apus, spending the nonbreeding period on the wing, instead exhibits a rarely found chain migration pattern, where the most southern breeding populations in Europe migrate to wintering areas furthest to the south in Africa, whereas the northern populations winter to the north. The swifts concentrated in three major areas in sub‐Saharan Africa during the nonbreeding period, with substantial overlap of nearby breeding populations. We found that the southern breeding swifts were larger, raised more young, and arrived to the wintering areas with higher seasonal variation in greenness (Normalized Difference Vegetation Index) earlier than the northern breeding swifts. This unusual chain migration pattern in common swifts is largely driven by differential annual timing and we suggest it evolves by prior occupancy and dominance by size in the breeding quarters and by prior occupancy combined with diffuse competition in the winter. [ABSTRACT FROM AUTHOR]

Summary: Children diagnosed with a combination of type 1 diabetes (T1D) and celiac disease (CD) show a dysregulated T helper type 1 (Th1)/Th17 response. Besides the cellular involvement, several soluble immune markers are involved in the autoimmune process of both T1D and CD. Only few studies have examined the peripheral pattern of different cytokines, chemokines and acute‐phase proteins (APP) in children with combined T1D and CD. To our knowledge, no studies have evaluated the serum levels of adipocytokines and matrix metalloproteinases (MMPs) in this context. The purpose of the present study was to acquire more knowledge and to gain deeper understanding regarding the peripheral immunoregulatory milieu in children with both T1D and CD. The study included children diagnosed with both T1D and CD (n = 18), children with T1D (n = 27) or CD (n = 16) and reference children (n = 42). Sera were collected and analysis of 28 immune markers (cytokines, chemokines, APPs, adipocytokines and MMPs) was performed using the Luminex technique. The major findings showed that children with a double diagnosis had lower serum levels of interleukin (IL)‐22, monocyte chemoattractant protein (MIP)‐1α, monocyte chemoattractant protein (MCP)‐1, procalcitonin, fibrinogen, visfatin and matrix metalloproteinase (MMP)‐2. These results indicate a suppressed immune profile in children with combined T1D and CD, including Th17 cytokines, chemokines, APPs, adipocytokines and MMPs. We conclude that, besides cytokines and chemokines, other immune markers, e.g. APPs, adipocytokines and MMPs, are of importance for further investigations to elucidate the heterogeneous immune processes present in patients diagnosed with T1D in combination with CD. [ABSTRACT FROM AUTHOR]

Background There are differences in esophageal cancer care across different regions in Sweden. According to Swedish national guidelines, all patients diagnosed with these tumors should be individually evaluated by regional multidisciplinary cancer conferences (MCCs) to be recommended the best possible treatment. The aim of the study was to investigate differences between the regional MCCs in Sweden regarding clinical staging and recommended treatment. Method Representatives for all six regional MCCs were invited to contribute with ten retrospective consecutive cases each. After anonymization radiological investigations were presented, along with the original case-specific medical history, anew at all participating regional MCCs. Each MCCs' clinical Tumor Nodal Metastasis classification (cTNM) and treatment recommendation (curative, palliative or best supportive care) were compared between MCCs as well as with the original assessment. Results Five regional MCCs joined the study. Out of 50 available cases the majority were assessed anew in addition to the previous original assessment. There was not consensus among the regional MCCs regarding clinical T-stage in 42 cases (84%), clinical N-stage in 33 cases (66%), and for clinical M-stage in 16 cases (32%). In 37 cases (74%) a positron emission tomography-computed tomography (PET-CT) was available. Differences in appraisal of cTNM were not associated with PET-CT availability. The MCCs agreed on treatment recommendations in 26/50 cases (52%). Discussion The study shows differences, both in assessment of cTNM as well as treatment recommendations at different MCCs. A patient recommended curative treatment by one MCC could be suggested palliative care by another. To achieve more equal care for esophageal cancer patients in Sweden it is essential to increase consensus on cTNM and recommended treatment. [ABSTRACT FROM AUTHOR]

Vector navigation, i.e. maintaining a constant heading for a given amount of time, is hypothesized to provide a viable basis for the navigational feats of a number of long-distance animal migrants. Since animals following this strategy are subject to drift by wind or by ocean current, performing long migrations relying on vector navigation is particularly challenging. We tested whether vector navigation could be involved in the migrations of green turtles (Chelonia mydas) that migrate between the remote Ascension Island and Brazil. To this aim, a novel approach was followed using individual-based numerical models to simulate migratory trajectories of virtual turtles that were compared to actual routes reconstructed by satellite. Simulated postnesting migrations from Ascension revealed that weak currents enabled modeled turtles to reach the Brazilian coast, but only for a limited range of headings around due West. This conclusion was corroborated by comparing modeled trajectories with the actual routes of previously tracked turtles, with a beeline vector navigation strategy providing the best fit, although a true-navigation strategy directed to the landfall site produced similar results. Finally, we tested if a vector navigational strategy was feasible for the prebreeding migration from Brazil towards Ascension, but modeled routes mostly failed to reach the island or a larger area around it, with individuals drifting away under the influence of currents. We conclude that Ascension turtles can take advantage of vector navigation when migrating towards a wide target like the Brazilian coast, while the demanding prebreeding migration likely requires more complex navigational systems. [ABSTRACT FROM AUTHOR]

Background. Early treatment is pivotal for favorable outcome in acute bacterial meningitis (ABM). Lumbar puncture (LP) is the diagnostic key. The aim was to evaluate the effect on outcome of adherence to European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), and Swedish guidelines regarding neuroimaging before LP. Methods. The cohort comprised 815 adult ABM patients in Sweden registered prospectively between 2008 and 2015. Primary endpoint was in-hospital mortality and secondary endpoint was favorable outcome at 2-6 months of follow-up. Results. Indications for neuroimaging before LP existed in 7%, 32%, and 65% according to Swedish, ESCMID, and IDSA guidelines, respectively. The adjusted odds ratio (aOR) was 0.48 (95% confidence interval [CI], .26-.89) for mortality and 1.52 (95% CI, 1.08-2.12) for favorable outcome if Swedish guidelines were followed. ESCMID guideline adherence resulted in aOR of 0.68 (95% CI, .38-1.23) for mortality and 1.05 (95% CI, .75-1.47) for favorable outcome. Following IDSA recommendations resulted in aOR of 1.09 (95% CI, .61-1.95) for mortality and 0.59 (95% CI, .42-.82) for favorable outcome. Performing prompt vs neuroimaging- preceded LP was associated with aOR of 0.38 (95% CI, .18-.77) for mortality and 2.11 (95% CI, 1.47-3.00) for favorable outcome. The beneficial effect of prompt LP was observed regardless of mental status and immunosuppression. Conclusions. Adherence to Swedish guidelines in ABM is associated with decreased mortality and increased favorable outcome in contrast to adherence to ESCMID or IDSA recommendations. Our findings support that impaired mental status and immunocompromised state should not be considered indications for neuroimaging before LP in patients with suspected ABM. [ABSTRACT FROM AUTHOR]

It is well established that differences in migratory behavior between populations of songbirds have a genetic basis but the actual genes underlying these traits remains largely unknown. In an attempt to identify such candidate genes we de novo assembled the genome of the willow warbler Phylloscopus trochilus, and used whole‐genome resequencing and a SNP array to associate genomic variation with migratory phenotypes across two migratory divides around the Baltic Sea that separate SW migrating P. t. trochilus wintering in western Africa and SSE migrating P. t. acredula wintering in eastern and southern Africa. We found that the genomes of the two migratory phenotypes lack clear differences except for three highly differentiated regions located on chromosomes 1, 3, and 5 (containing 146, 135, and 53 genes, respectively). Within each migratory phenotype we found virtually no differences in allele frequencies for thousands of SNPs, even when comparing geographically distant populations breeding in Scandinavia and Far East Russia (>6000 km). In each of the three differentiated regions, multidimensional scaling‐based clustering of SNP genotypes from more than 1100 individuals demonstrates the presence of distinct haplotype clusters that are associated with each migratory phenotype. In turn, this suggests that recombination is absent or rare between haplotypes, which could be explained by inversion polymorphisms. Whereas SNP alleles on chromosome 3 correlate with breeding altitude and latitude, the allele distribution within the regions on chromosomes 1 and 5 perfectly matches the geographical distribution of the migratory phenotypes. The most differentiated 10 kb windows and missense mutations within these differentiated regions are associated with genes involved in fatty acid synthesis, possibly representing physiological adaptations to the different migratory strategies. The ∼200 genes in these regions, of which several lack described function, will direct future experimental and comparative studies in the search for genes that underlie important migratory traits. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32 496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer. [ABSTRACT FROM AUTHOR]

Birds migrating between distant locations regularly perform long continuous flights lasting several days. What compass mechanism they use is still a mystery. Here, we use a novel approach, applying an individual-based model, taking compass mechanisms based on celestial and geomagnetic information and wind into account simultaneously, to investigate what compass mechanism likely is used during long continuous flights and how wind drift or compensation affects the resulting tracks. We found that for the 6 cases of long continuous migration flights, the magnetoclinic route could best explain the route selection in all except one case compared with the alternative compass mechanisms. A flight strategy correcting for wind drift resulted most often in routes ending up closest to the predicted destinations. In only half of the cases could a time-compensated sun compass explain the migration routes observed with sufficient precision. Migration from Europe to the Siberian tundra was especially challenging to explain by one compass mechanism alone, suggesting a more complex navigation strategy. Our results speak in favor of a magnetic compass based on the angle of inclination used by birds during continuous long-distance migration flights, but also a capacity to detect and correct for drift caused by winds along the route. [ABSTRACT FROM AUTHOR]

In many migratory birds, males precede females during migration and arrival at the breeding sites. Three proximate mechanisms are proposed to explain this phenomenon of protandry: males 1) winter closer to breeding sites, 2) start spring migration earlier, and/or 3) migrate faster than females. So far, the relative contribution of these mechanisms to protandry is unknown. The present study investigated the importance of each of the 3 proximate mechanisms of protandry for a songbird migrant wintering in Africa, the northern wheatear (Oenanthe oenanthe). Two subspecies co-occur in Europe on migration, of which the leucorhoa northern wheatears breeding from Iceland to Canada have to cross the North Atlantic, whereas the nominate form breeding in Europe does not face any significant sea barrier. We show that the leucorhoa subspecies had a significantly higher degree of protandry at stopover sites across Europe than the oenanthe subspecies (-6 vs. -2 days). Leucorhoa northern wheatear's higher degree of protandry was associated with a larger age effect, in which old males preceded young males, and greater sex-specific differences in wing shape and refueling yielding higher migration speeds in males than females. In oenanthe northern wheatears, light-level geolocators revealed that males did not winter closer to the breeding sites or migrate faster than females, but initiated spring migration earlier. Our results demonstrate that the significance of the mechanisms causing protandry can differ between related taxa and highlight the importance of the advancement in male arrival date with age as a potential factor shaping the degree of protandry. [ABSTRACT FROM AUTHOR]

Type 1 diabetes ( T1D) and coeliac disease are both characterized by an autoimmune feature. As T1D and coeliac disease share the same risk genes, patients risk subsequently developing the other disease. This study aimed to investigate the expression of T helper ( Th), T cytotoxic ( Tc) and regulatory T cells ( Treg) in T1D and/or coeliac disease children in comparison to healthy children. Subgroups of T cells ( Th : CD4+ or Tc : CD8+); naive ( CD27+CD28+CD45RA+CCR7+), central memory ( CD27+CD28+CD45RA− CCR7+), effector memory (early differentiated; CD27+CD28+CD45RA− CCR7− and late differentiated; CD27− CD28− CD45RA− CCR7−), terminally differentiated effector cells ( TEMRA; CD27− CD28− CD45RA+CCR7−) and Treg ( CD4+CD25+FOXP3+CD127−) cells, and their expression of CD39, CD45RA, CD101 and CD129, were studied by flow cytometry in T1D and/or coeliac disease children or without any of these diseases (reference group). Children diagnosed with both T1D and coeliac disease showed a higher percentage of TEMRA CD4+ cells ( P < 0·05), but lower percentages of both early and late effector memory CD8+ cells ( P < 0·05) compared to references. Children with exclusively T1D had lower median fluorescence intensity ( MFI) of forkhead box protein 3 ( FoxP3) ( P < 0·05) and also a lower percentage of CD39+ and CD45RA+ within the Treg population ( CD4+CD25+FOXP3+CD127−) ( P < 0·05). Children with exclusively coeliac disease had a higher MFI of CD101 ( P < 0·01), as well as a higher percentage of CD129+ ( P < 0·05), in the CD4+CD25hi lymphocyte population, compared to references. In conclusion, children with combined T1D and coeliac disease have a higher percentage of differentiated CD4+ cells compared to CD8+ cells. T1D children show signs of low CD39+/CD45RA+ Treg cells that may indicate loss of suppressive function. Conversely, children with coeliac disease show signs of CD101+/CD129+ Treg cells that may indicate suppressor activity. [ABSTRACT FROM AUTHOR]

Background and aim The Nordic countries have similar health care systems and registries simplifying epidemiological research. Differences in treatment traditions can, however, hamper the possibility to assess results and to harmonize control arms in joint randomized trials. In the process to set up a Nordic multi-center randomized trial regarding use of nasogastric tube (NG-tube) decompression after esophagectomy, we aimed to investigate perioperative routines in 12 University Hospitals in Sweden, Denmark, Norway and Finland. Methods All Nordic University Hospitals were contacted regarding a Nordic randomized controlled trial exploring effects and complications associated with the use of nasogastric tube use after esophagectomy for cancer. Those who chose to join the trial were sent a questionnaire regarding surgical and perioperative routines. Results Twelve centers with a combined catchment area of 16 million inhabitants and an annual volume of 400 esophagectomies joined the trial network. All but one used totally minimally invasive or hybrid surgical approach. All 12 centers reported routine use of NG-tube and 5 employed continuous suction. The NG-tube was removed between 3 and 7 days postoperatively. A routine pylorus drainage procedure was reported from two centers. Jejunostomy was used universally in 5 centers and selectively in 6 centers. One center did not use jejunostomy. Conclusion Differences in perioperative care after esophagectomy is apparent in the Nordic countries, highlighting the need for high-level evidence regarding these practices. A unified approach may facilitate clinical trial initiatives. There is a paucity of evidence regarding optimal NG-tube use after esophagectomy for cancer and a randomized trial investigating this issue is under way. [ABSTRACT FROM AUTHOR]

Motivation Complex diseases are due to the dense interactions of many disease-associated factors that dysregulate genes that in turn form the so-called disease modules, which have shown to be a powerful concept for understanding pathological mechanisms. There exist many disease module inference methods that rely on somewhat different assumptions, but there is still no gold standard or best-performing method. Hence, there is a need for combining these methods to generate robust disease modules. Results We developed MODule IdentiFIER (MODifieR), an ensemble R package of nine disease module inference methods from transcriptomics networks. MODifieR uses standardized input and output allowing the possibility to combine individual modules generated from these methods into more robust disease-specific modules, contributing to a better understanding of complex diseases. Availability and implementation MODifieR is available under the GNU GPL license and can be freely downloaded from https://gitlab.com/Gustafsson-lab/MODifieR and as a Docker image from https://hub.docker.com/r/ddeweerd/modifier. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background Anastomotic leakage (AL) after oesophageal surgery is a serious complication, leading to increased postoperative mortality. Early detection and treatment is essential. The aim of this study was to investigate if inflammatory serum parameters in the early postoperative course after oesophageal cancer surgery, could predict development of an AL. Methods All patients in Sweden with AL after thoraco-abdominal surgery for oesophageal or gastroesophageal junction cancer from 2006–01-01 to 2017–01-31 were collected from the Swedish National Registry for esophageal and gastric cancer (NREV). Two matched controls for each AL-patient were also selected from the registry. Pre-, per- and postoperative variables were collected from NREV. The following parameters were collected from patient charts: number of days from surgery to AL, diagnostic modality, method of treatment, serum levels of C-reactive protein (CRP), White blood cell count (WBC) and serum-Albumin taken on postoperative day 1 to 7 (POD1–7). Thoracic- and cervical anastomosis were analysed separately. Perioperative data and inflammatory markers were compared between controls and AL-patients. Receiver Operating Characteristic (ROC) curves was constructed to identify optimal cut-off values and a multivariate analysis was performed to identify independent risk factors. Results A total of 155 patients with AL and 307 controls (n = 462) were analysed. In patients with thoracic anastomosis median levels of CRP and WBC were significantly different on POD 2–7 and on POD 4–7 comparing AL-patients to controls. In patients with cervical anastomosis there was a significant difference in WBC levels on POD 1–7. ROC-curve analysis identified CRP on POD3 (cut-off 221) and POD4 (cut-off 203) as the best candidates for predicting AL in patients with a thoracic anastomosis, displaying an area under curve of 0.754 (Sensitivity 59%, Specificity 83%) and 0.731 (Sensitivity: 57%, Specificity 82%). Conclusion In this nation-wide register study we found that a model combining S-CRP levels on POD 3 and POD 4 after a thoraco-abdominal esophagectomy, could identify patients with increased risk of anastomotic leakage several days before it was diagnosed. However, since the sensitivity of this test is relatively low for predicting AL, it must be assessed in a larger clinical context. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]