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Abstract Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using GWAS summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [ORSD] = 0.97; 95% confidence interval [CI]: 0.95–0.99, p = 0.006), methionine (ORSD= 0.97; 95%CI: 0.94-1.00, p = 0.031), stearic acid (ORSD= 0.93; 95%CI: 0.87–0.99, p = 0.027), carnitine = (ORSD=1.01; 95% CI: 1.00-1.03, p = 0.027), hippuric acid (ORSD= 1.02; 95%CI: 1.00-1.04, p = 0.038) and 3-methylhistidine (ORSD= 1.05; 95%CI: 1.01–1.10, p = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78–0.99, p = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80–0.96, p = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis.

Abstract Background Swine flu might serve as a model for challenges that primary care faces during pandemics. This study examined changes in the numbers and diagnoses of general practitioner (GP) visits during and after the Swine flu pandemic in Vantaa, a Finnish city, and how GP activities recovered after the pandemic. Putative sex and age group differences were also evaluated. Methods The study was an observational retrospective study. The monthly number of patient visits to primary care GPs by women and men in age groups 0–19, 20–64 and 65 + years was recorded before, during and two years after the Swine flu pandemic. The recorded diagnoses were also examined. The investigation period was from 2008 to 2012. Results The numbers of monthly visits to primary care decreased from 12 324 (mean) to 10 817 in women and from 8563 to 7612 in men during the first six months of the Swine flu, returning to the original level afterwards. This decrease was thus slightly more prominent in women. However, as the size of the population increased during the follow-up period, the actual number of GP visits adjusted for the size of population remained at a decreased level for two years after the Swine flu. This decrease was observed especially in office-hours visits of men (from 3692 to 3260) and women (from 6301 to 5428) of 20–64 years. Swine flu did not alter the number of visits to the primary care Emergency Department. The proportion of visits with diagnostic recordings of common infectious diseases mostly decreased during the Swine flu. Only a minor impact on the distribution of recordings of chronic diagnoses was found. Conclusion A pandemic, such as Swine flu, may decrease office-hours visits to primary care GPs. This in turn may lead to activities of primary care being adjusted downward for a long time following the pandemic. Especially the age group 20–64 years may be affected. This risk should be considered when recovery from the COVID-19 pandemic begins. Swine flu did not affect the proportion of consultations of chronic diseases, but the number of diagnoses of common infectious diseases had diminished.

This is a register-based study that examines the distribution of diagnoses made by general practitioners (GPs) in the public primary health care of the city of Vantaa, Finland. Data were gathered from the electronic health record (EHR) system and consisted of every record entered into the EHR system between 1 January 2016 and 31 December 2018. Both absolute numbers and relative proportions of the 10th edition of International Classification of Diseases (ICD-10) diagnosis recordings were reported and calculated. Among GP visits, the 88 most common diagnoses covered 75% of all diagnoses. The most common diagnoses were related to the musculoskeletal (3.8%, ICD code M54) and respiratory systems (6.0%, ICD-10 code J06). Primary health care GP services were mostly used by children (age 65 years). Health examinations – mostly children’s and maternity clinics appointments/visits – covered 20% of the GP office visits. Women between the ages 15–79 years had relatively more GP visits compared to men. The 88 most commonly recorded diagnoses covered the majority of the GP visits. Health examinations for the healthy were an important part of GPs’ work. In an urban Finnish city, GP services were predominantly used by children and older adults.

Abstract Purpose High levels of physical activity have been documented in eating disorder patients. Our aim was to examine whether adolescent leisure-time physical activity is prospectively associated with eating disorders in adolescence and young adulthood. Methods Finnish twins born in 1983–1987 reported their physical activity frequency at ages 12, 14, and 17. A subsample of participants underwent structured, retrospective interviews for eating disorders at the mean age of 22.4 years. Associations between female twins’ physical activity and future eating disorders (571–683 twins/wave) were investigated with the Cox proportional hazards model. To illustrate the physical activity similarity of the co-twins in a twin pair, we used cross-tabulation of eating disorder–discordant twin pairs (13–24 pairs/wave). Results After adjusting for several covariates, we found no statistically significant longitudinal association between physical activity and eating disorders. This applied when all eating disorders were combined but also when assessed separately as restrictive and non-restrictive eating disorders. Co-twins’ physical activity in adolescence tended to be similar irrespective of their future eating disorder, supporting the results of the regression analysis. Conclusion We observed no evidence of adolescent physical activity frequency being prospectively associated with eating disorders in female twins. Further longitudinal studies with larger sample sizes and more detailed physical activity data are needed. Level of evidence: III, evidence obtained from cohort or case–control analytic studies.

Objective This study compared the costs and nursing time associated with the delivery of continuous infusion of antibiotics via elastomeric infusion pumps (EIP) versus conventional intermittent infusion (CII) across different care pathways.Design Retrospective real-world data informed a cost comparison analysis that compared costs and nursing hours between infusion of antibiotics via EIP versus CII across eight care pathways in inpatient or outpatient care during infection episodes. Real-world data were obtained from patients treated within a year with parenteral antimicrobial therapy in Päijät-Häme Region, Finland.Setting Inpatient care with hospital admission and outpatient care at hospital at home in Päijät-Häme Region in Finland.Participants 3778 patients with a total of 4214 infection episodes treated with intravenous antimicrobial therapy.Interventions Eight treatment strategies with various combinations of EIP and CII administered in inpatient or outpatient care.Primary and secondary outcome measures Direct costs and nursing time.Results Skin and soft tissue infections accounted for the highest number of episodes treated with EIP overall (30.8%; 74 out of 240 episodes) and in outpatient care specifically (53.3%; 128 out of 240 episodes). Compared with inpatient care costs with CII (€4590 per episode), treating skin and soft tissue infections in outpatient care with EIP or CII incurred only 24% (€1104) and 35% (€1620) of the costs, respectively. Across all treatment strategies and infections studied, the use of EIP consistently required less nursing time. The highest nursing time in the outpatient care was observed in sepsis episodes treated with CII (37 hours with CII vs 7 hours with EIP per episode).Conclusion Delivery of antimicrobial therapy using continuous infusions with EIP instead of CII can significantly decrease the nursing time and cost in both inpatient and outpatient care. For skin and soft tissue infections and sepsis, the utilisation of EIP is a cost-saving option in outpatient care compared with the use of CII.

Background Partial or complete thymectomy is routinely performed in paediatric open-heart surgeries when treating congenital heart defects. Whether or not thymectomised children require systematic immunological monitoring later in life is unknown. The objective of this study was to investigate the effects of preoperatively and postoperatively used antibiotics, hospitalisation and surgical complications on self-reported immunological vulnerability in paediatric patients with early thymectomy to better recognise the patients who could benefit from immunological follow-up in the future.Methods We conducted a retrospective cohort study, including 98 children and adolescents aged 1–15 years, who had undergone an open-heart surgery and thymectomy in infancy and who had previously answered a survey regarding different immune-mediated symptoms and diagnoses. We performed a comprehensive chart review of preoperative and postoperative factors from 1 year preceding and 1 year following the open-heart surgery and compared the participants who had self-reported symptoms of immunological vulnerability to those who had not.Results The median age at primary open-heart surgery and thymectomy was 19.5 days in the overall study population (60% men, n=56) and thymectomies mainly partial (80%, n=78). Broad-spectrum antibiotics were more frequently used preoperatively in participants with self-reported immunological vulnerability (OR=3.05; 95% CI 1.01 to 9.23). This group also had greater overall use of antibiotics postoperatively (OR=3.21; 95% CI 1.33 to 7.76). These findings were more pronounced in the subgroup of neonatally operated children. There was no statistically significant difference in the duration of intensive care unit stay, hospitalisation time, prevalence of severe infections, surgical complications or glucocorticoid use between the main study groups.Conclusion Antimicrobial agents were more frequently used both preoperatively and postoperatively in thymectomised children with self-reported immunological vulnerability after thymectomy. Substantial use of antimicrobial agents early in life should be considered a potential risk factor for increased immunological vulnerability when evaluating the significance of immune-mediated symptom occurrence in thymectomised paediatric patients.

Abstract Background Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database. Results We discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12–1.23], p = 1.5 × 10–9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80–7.17], p = 7.0 × 10–10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09–1.21], p = 7.1 × 10–9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11–1.20], p = 1.5 × 10–9) which is in significant LD with rs2316327. Conclusions Our results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.

Abstract Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142− /low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142− /low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.

Abstract Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1R189W demonstrated longer thin filaments than GFP-TMOD1wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1R189W showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant’s effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.

Abstract Background Testicular germ cell tumours (TGCTs) are the most common malignancy in men aged 15–40 years, with increasing incidence worldwide. About 33 ~ 50% of the patients present with metastatic disease at diagnosis. TGCT survivors experience short- and long-term sequelae, including cancer-related fatigue (CRF). Physical activity (PA) has established effects on reducing CRF and other sequelae and improving health-related quality of life (HRQoL). However, its impact on TGCT survivors has so far received little attention. The gut microbiota plays a crucial role in various physiological functions, including cognition and metabolism, and may mediate the effects of PA on CRF and other sequelae, but this has not been investigated in randomized controlled trials. Methods This national, multicentre, phase-III trial will evaluate the impact of a one-year supervised PA program on CRF and other short- and long-term sequelae in metastatic TGCT patients receiving cisplatin-based chemotherapy combined with etoposide+/-bleomycin. It will also investigate potential mediating effects of the gut microbiota and its metabolites involved in the gut-brain axis on the relationship between PA and CRF and other sequelae. A total of 236 men ≥ 18 years of age with metastatic TGCT (seminoma and non-seminoma) will be enrolled before starting first-line chemotherapy in several French hospitals. The primary (CRF) and secondary (cognitive/psychological/metabolic sequelae, HRQoL, etc.) outcomes and gut microbiota and relevant metabolites will be assessed at inclusion, during and at the end of the one-year intervention, and annually until 10 years since inclusion to assess long-term sequelae, more specifically CRF, cardiovascular toxicities, and second primary cancer occurrence in this population. Discussion This trial will provide comprehensive and novel insights into the effects of a long-term supervised PA program on CRF and other sequelae in metastatic TGCT patients receiving first-line chemotherapy. It will also contribute to understanding the potential role of the gut microbiota and its metabolites in mediating the effects of PA on these outcomes. The findings of this study will help the development of effective PA interventions to improve the health of TGCT survivors and may have implications for other cancer populations as well. Trial registration The study was registered on ClinicalTrials.gov (NCT05588700) on 20 Oct. 2022.

Untargeted metabolomic profiling through liquid chromatography-mass spectrometry (LC-MS) measures a vast array of metabolites within biospecimens, advancing drug development, disease diagnosis, and risk prediction. However, the low throughput of LC-MS poses a major challenge for biomarker discovery, annotation, and experimental comparison, necessitating the merging of multiple datasets. Current data pooling methods encounter practical limitations due to their vulnerability to data variations and hyperparameter dependence. Here, we introduce GromovMatcher, a flexible and user-friendly algorithm that automatically combines LC-MS datasets using optimal transport. By capitalizing on feature intensity correlation structures, GromovMatcher delivers superior alignment accuracy and robustness compared to existing approaches. This algorithm scales to thousands of features requiring minimal hyperparameter tuning. Manually curated datasets for validating alignment algorithms are limited in the field of untargeted metabolomics, and hence we develop a dataset split procedure to generate pairs of validation datasets to test the alignments produced by GromovMatcher and other methods. Applying our method to experimental patient studies of liver and pancreatic cancer, we discover shared metabolic features related to patient alcohol intake, demonstrating how GromovMatcher facilitates the search for biomarkers associated with lifestyle risk factors linked to several cancer types.

Wildfires present severe threats to various aspects of ecosystems, human settlements, and the environment. Early detection plays a critical role in minimizing the destructive consequences of wildfires. This study introduces an innovative approach for smoke-based wildfire detection in Boreal forests by combining the YOLO V5 algorithm and transfer learning. YOLO V5 is renowned for its real-time performance and accuracy in object detection. Given the scarcity of labelled smoke images specific to wildfire scenes, transfer learning techniques are employed to address this limitation. Initially, the generalisability of smoke as an object is examined by utilising wildfire data collected from diverse environments for fine-tuning and testing purposes in Boreal forest scenarios. Subsequently, Boreal forest fire data is employed for training and fine-tuning to achieve high detection accuracy and explore benchmarks for effective local training data. This approach minimises extensive manual labelling efforts while enhancing the accuracy of smoke-based wildfire detection in Boreal forest environments. Experimental results validate the efficacy of the proposed approach. The combined YOLO V5 and transfer learning framework demonstrates a high detection accuracy, making it a promising solution for automated wildfire detection systems. Implementing this methodology can potentially enhance early detection and response to wildfires in Boreal forest regions, thereby contributing to improved disaster management and mitigation strategies.

Background: Antipsychotics are effective in controlled environments for treatment of schizophrenia. However, there is hardly any research on the effects of antipsychotics in years-long follow-ups in antipsychotic trials. In addition, study samples of the antipsychotic trials differ quite notably from the day-to-day clinical treatment population. In this study, we aimed to compare the population-based Northern Finland Birth Cohort 1966 (NFBC1966) population to the samples in antipsychotic trials using typical inclusion and exclusion criteria found in randomized clinical trials (RCTs). We also compared long-term outcomes of individuals with schizophrenia meeting and not meeting inclusion criteria for clinical trials. Method: We gathered clinical antipsychotic trials and their inclusion and exclusion criteria. These inclusion and exclusion criteria were compared to the data of NFBC1966 to find out how many of the 54 participants in NFBC1966 34-year follow-up would meet these criteria, and how representative outcomes of the clinical antipsychotic trials are compared to a longitudinal population-based sample. Result: Depending on how strict the inclusion and exclusion criteria of the RCTs were, 10.5 to 24.6 per cent of the participants in the NFBC1966 34-year follow-up could have been included in RCTs using the criteria. Notably, 42.1 per cent of the participants in the NFBC1966 would be excluded without considering PANSS as inclusion criteria. There was no statistically significant difference in the distribution of PANSS and SOFAS scores between the included and excluded groups in longitudinal analysis. However, in the distribution of hospital treatment days in the groups included and excluded by criteria of RCTs, there was a statistically significant difference between the groups. Conclusions: Over one-third of the participants of this population sample could have been excluded from clinical trials without even considering psychotic symptoms as an inclusion criterion.

AbstractObjective This study aimed to examine primary health care (PHC) service utilization and mortality in older patients with type 2 diabetes (T2D) with or without comorbidities.Design and setting A cohort study in PHC in the city of Vantaa, Finland. Follow-up period was set between the years 2011 and 2018.Subjects PHC patients aged 60 years or more with a T2D were included.Main outcome measures Service utilization was defined as the number of face-to-face appointments and telephone contacts between a patient and general practitioner (GP) or nurse. The presence of comorbidities was defined using the Charlson Comorbidity Index (CCI). Mortality was assessed using hazard ratio (HR) and standardized mortality ratio (SMR).Results In total, 11,020 patients were included and followed for 71,596 person years. Mean age of the women and men in the beginning of follow-up were 71 and 69 years, respectively. The patients in the study cohort had a mean of eight appointments per person year to the GPs or nurses. Patients with T2D with comorbidities had more appointments than patients with T2D without comorbidities (incidence rate ratio (IRR) 1.44 [95% CI 1.39–1.49]). Increase in the number of all appointments reduced mortality in patients with T2D with and without comorbidities. Between patients with T2D with comorbidities and patients with T2D without comorbidities, the age and sex adjusted HR for death was 1.50 (95% CI 1.39–1.62). The SMR was higher in patients with T2D with comorbidities (1.83 [95% CI 1.74–1.92]) than in patients with T2D without comorbidities (0.91 [95% CI 0.86–0.96]).Conclusions In older patients with T2D, the presence of comorbidities was associated with increased use of PHC services and increased mortality. Increase in the number of appointments was associated with reduced mortality in patients with T2D with or without comorbidities.Key PointsIn older patients with T2D, it has not been studied whether and to what extend multimorbidity affects use of PHC services and mortality.The presence of comorbidities according to the Charlson Comorbidity Index (CCI) was associated with increased use of PHC services.The number of appointments to GPs or nurses was associated with reduced mortality in patients with T2D with or without comorbidities according to the CCI.

Abstract Background Cardiovascular diseases (CVDs) are prevalent in older people, but few studies focus on developmental patterns in CVD medication directly after transition to statutory retirement. We thus aimed to identify trajectories of CVD medication after retirement, and their sociodemographic, work and health-related determinants. Methods We used complete register data of former employees of the City of Helsinki, Finland. All who reached their statutory retirement in 2000–2013, with five-year follow-up data (n = 6,505, 73% women), were included. Trajectories of CVD medication were identified with group-based trajectory modelling using data from Finnish Social Insurance Institution’s reimbursement register. Sociodemographic, work and health-related determinants of trajectory group membership were analysed using multinomial logistic regression. Results Six trajectories of CVD medication were distinguished: "constant low" (35%), “late increase” (6%), “early increase” (5%), "constant high" (39%), "high and decreasing " (8%), and "low and decreasing” (7%). The majority (74%) of the retirees fell into the "constant low" and "constant high" categories. Lower occupational class and increased pre-retirement sickness absence were associated with the "constant high" trajectory. Further, those with lower educational attainment were more prone to be in the “early increase” trajectory. Conclusions Individuals in lower socioeconomic positions or with a higher number of pre-retirement sickness absence may be considered at higher risk and might benefit from early interventions, e.g. lifestyle interventions and interventions targeting working conditions, or more frequent monitoring.

Abstract Background The ageing work force is heterogeneous, following distinct development in work ability. This study aims to identify trajectories of long-term sickness absence (SA) in later careers and to examine potentially modifiable factors associated with the development of SA. Methods Data comprised of municipal employees of the city of Helsinki aged 50–60 years during 2004–2018 (N = 4729, 80% women). The developmental trajectories of long-term (> 10 working days) SA were examined with Group-based trajectory modelling (GBTM) using SA records of the Social Insurance Institution of Finland during 2004–2018. All-cause and diagnosis-specific (mental disorder– and musculoskeletal disease–related) SA days were analysed. The association of social and health-related factors with trajectory membership was examined using multinomial logistic regression (odds ratios and 95% confidence intervals). Results A model with three trajectories was selected for both all-cause and diagnosis-specific SA. Regarding all-cause long-term SA trajectories, 42% had no long-term SA, 46% had low levels of SA, and 12% had a high rate of SA during follow-up. Lower occupational class, reporting smoking, overweight or obesity, moderate or low leisure-time physical activity, and sleep problems were associated with a higher likelihood of belonging to the trajectory with a high rate of SA in both all-cause and diagnosis-specific models. Conclusions Most ageing employees have no or little long-term SA. Modifiable factors associated with trajectories with more SA could be targeted when designing and timing interventions in occupational healthcare.

Summary: Background: Altered lipid metabolism is a hallmark of cancer development. However, the role of specific lipid metabolites in colorectal cancer development is uncertain. Methods: In a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined associations between pre-diagnostic circulating concentrations of 97 lipid metabolites (acylcarnitines, glycerophospholipids and sphingolipids) and colorectal cancer risk. Circulating lipids were measured using targeted mass spectrometry in 1591 incident colorectal cancer cases (55% women) and 1591 matched controls. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between concentrations of individual lipid metabolites and metabolite patterns with colorectal cancer risk. Findings: Of the 97 assayed lipids, 24 were inversely associated (nominally p

Smoking, alcohol consumption, obesity, and physical inactivity are key lifestyle risk factors for cancer. Previously these have been mostly examined singly or combined as an index, assuming independent and equivalent effects to cancer risk. The aim of our study was to systematically examine the joint pairwise and interactive effects of these lifestyle factors on the risk of a first solid primary cancer in a multi-cohort prospective setting.We used pooled data from seven Finnish health survey studies during 1972–2015, with 197,551 participants diagnosed with 16,373 solid malignant primary tumors during follow-up. Incidence of any cancer was analyzed separately without and with lung cancers using Poisson regression with main and interaction effects of key lifestyle factors.When excluding lung cancer, the highest risk of any cancer in men was observed for smokers with a BMI of ≥25 kg/m2 (HR 1.36, 95 % CI 1.25–1.48) and in women for smokers consuming alcohol (HR 1.22, 1.14–1.30). No statistically significant interactions between any studied risk factor pairs were observed. When including lung cancer, the highest HRs among men were observed for smokers who consume alcohol (HR 1.72, 1.57–1.89) and among women for smokers who were physically inactive (HR 1.38, 1.27–1.49).Smoking combined with other lifestyle factors at any exposure level resulted in highest pairwise risks, both in men and women. These results highlight the importance of smoking prevention, but also the importance of preventing obesity and reducing alcohol consumption.

PurposeIn the palliated single ventricle anomalies, a considerable amount of the aortic flow may be absorbed by the systemic-pulmonary collateral flow (SPCF), which can be noninvasively assessed by cardiac magnetic resonance (CMR). The aims of this study were to (1) identify factors associated with SCPF in pediatric single ventricle patients, and (2) establish a cutoff values indicating an association between SCPF and a reduction in antegrade pulmonary flow.MethodsA retrospective single-tertiary-center cohort study included 158 consecutive CMR studies of patients with a single ventricle. In the uni- and multivariable analysis, SPCF was presented as a percentage of the total pulmonary venous flow (SPCF%PV). The minimal clinically important difference in QP/QS ratios was estimated as ≥0.50, and an optimal cutoff value was defined using the receiver operating characteristic (ROC) curve.ResultsSPCF%PV was significantly smaller in the post-total cavopulmonary connection (TCPC) group than in the pre-TCPC patients (p

Abstract Background . Decreased work ability due to mental disorders is a growing concern in Europe. We studied the role of work-family conflicts in association with long-term sickness absence due to mental disorders (LTSA-MD). Methods . Baseline data were extracted from the Helsinki Health Study for women aged 40 to 55 in full-time work in 2001 − 2002 (N = 2386). Questionnaire responses were linked with register data from the Social Insurance Institution of Finland on SA spells due to mental disorders during 2004–2010. We studied an overall question on satisfaction with combining work and family (WFS) and composite scores of work-to-family conflicts (WTFC) and family-to-work-conflicts (FTWC), and their components in association with the first certified SA spell (≥ 12 calendar days) due to a mental disorder during the follow-up. We performed Cox regression analyses with hazard ratios (HR) and their 95% confidence intervals (CI) adjusted for sociodemographic factors, work schedule, perceived mental and physical strenuousness at work, and self-rated health. First, we examined all participants, and second, only those who reported no prior mental disorder. Results . Poor work-family satisfaction (WFS) was associated with subsequent LTSA-MD, adjusting for all covariates (HR 1.60; 95% CI 1.10–2.16). Both high WTFC (1.64; 1.15–2.23), and high FTWC (1.43; 1.02–2.00) increased the probability of LTSA-MD in the full model. When participants with prior mental disorder were excluded, the association between poor WFS and WTFC with LTSA-MD retained while that between FTWC and LTSA-MD attenuated; however, two items of the FTWC were still associated with LTSA-MD: ‘Family worries and problems distract you from your work’ and ‘Family matters prevent you from sleeping enough to do your job well’. Of the WTFC items, the following remained associated with LTSA-MD: ‘Problems at work make you irritable at home’ and ‘Your job takes so much energy you do not feel up to doing things that need attention at home’. The experience of decreased time for work or family did not associate with LTSA-MD. Conclusions . Among female municipal employees, dissatisfaction with combining work and family and both work-to-family and family-to-work conflicts were associated with subsequent long-term sickness absence due to mental disorders.

Abstract Background Pain conditions and poorer mental health are associated with work disability. However, few studies have examined the association of concurrent pain and poorer mental health with sickness absence among younger employees. We examined separate and joint associations of chronic pain, multisite pain, and mental health with total and long-term all-cause sickness absence days among younger Finnish municipal employees. Methods The Young Helsinki Health-study data were collected in 2017 from 19–39-year-old employees of the City of Helsinki, Finland. Chronic (≥ 3 months) and multisite (≥ 2 body sites) pain and mental health (RAND-36 emotional wellbeing subscale dichotomized by median score) were self-reported (n = 3911). Chronic pain, multisite pain and mental health were analyzed separately and combined. Register data on total (≥ 1 workdays) and long-term (≥ 11 workdays) sickness absence days during the following year were obtained. Negative binomial regression analyses were performed with sociodemographic, socioeconomic, and health-related factors as confounders. Gender interaction and synergistic indices were examined. Results Chronic multisite pain was associated with long-term sickness absence days (rate ratio [RR] 2.51, 95% CI 1.17–5.42). Chronic pain (RR 5.04, 95% CI 2.14–11.87) and multisite pain (RR 4.88, 95% CI 2.30–10.33) were associated with long-term sickness absence days among employees with poorer mental health. There was a synergistic interaction between gender and multisite pain for total sickness absence days (synergy index 1.80, 95% CI 1.27–2.54), with stronger associations among women. Conclusions Chronic and multisite pain are associated with long-term sickness absence among younger employees, particularly among women and employees with concurrent poorer mental health. Consideration of this knowledge at workplaces and in healthcare could help to identify and support employees at increased risk of later sickness absence.

Abstract Background Women undergoing induction of labour (IOL) more often have poor childbirth experience compared to women with spontaneous onset of labour (SOL). For understanding and optimizing childbirth experience in IOL, we investigated the subjective maternal reasons and perceptions leading to poor childbirth experience in IOL compared to SOL, as well as the background factors and delivery outcomes associated with the poor experience. Methods Two-year retrospective cohort study included 836/19442 deliveries (4.3%) with poor childbirth experience in induced or spontaneous onset at term in Helsinki University Hospital. Poor childbirth experience occurred in 389/5290 (7.4%) cases of IOL and in 447/14152 (3.2%) of SOL. Childbirth experience was measured after delivery using Visual Analog Scale (VAS) score, with poor experience defined as VAS

The intricate relationship between electrons and the crystal lattice is a linchpin in condensed matter, traditionally described by the Fröhlich model encompassing the lowest-order lattice-electron coupling. Recently developed quantum acoustics, emphasizing the wave nature of lattice vibrations, has enabled the exploration of previously uncharted territories of electron–lattice interaction not accessible with conventional tools such as perturbation theory. In this context, our agenda here is two-fold. First, we showcase the application of machine learning methods to categorize various interaction regimes within the subtle interplay of electrons and the dynamical lattice landscape. Second, we shed light on a nebulous region of electron dynamics identified by the machine learning approach and then attribute it to transient localization, where strong lattice vibrations result in a momentary Anderson prison for electronic wavepackets, which are later released by the evolution of the lattice. Overall, our research illuminates the spectrum of dynamics within the Fröhlich model, such as transient localization, which has been suggested as a pivotal factor contributing to the mysteries surrounding strange metals. Furthermore, this paves the way for utilizing time-dependent perspectives in machine learning techniques for designing materials with tailored electron–lattice properties.

Recent theoretical investigations have revealed unconventional transport mechanisms within high Brillouin zones of two-dimensional superlattices. Electrons can navigate along channels we call superwires, gently guided without brute force confinement. Such dynamical confinement is caused by weak superlattice deflections, markedly different from the static or energetic confinement observed in traditional wave guides or one-dimensional electron wires. The quantum properties of superwires give rise to elastic dynamical tunneling, linking disjoint regions of the corresponding classical phase space, and enabling the emergence of several parallel channels. This paper provides the underlying theory and mechanisms that facilitate dynamical tunneling assisted by chaos in periodic lattices. Moreover, we show that the mechanism of dynamical tunneling can be effectively conceptualized through the lens of a paraxial approximation. Our results further reveal that superwires predominantly exist within flat bands, emerging from eigenstates that represent linear combinations of conventional degenerate Bloch states. Finally, we quantify tunneling rates across various lattice configurations and demonstrate that tunneling can be suppressed in a controlled fashion, illustrating potential implications in future nanodevices.

Endogenous sex hormones and DNA methylation both play important roles in various diseases. However, their interplay is largely unknown. A deeper understanding of their interrelationships could provide new insights into the pathology of disease development. We, therefore, investigated associations between circulating sex hormones, sex hormone binding globulin (SHBG), and DNA methylation in blood, using samples from 77 men (65 with repeated samples), from the population-based Northern Sweden Health and Disease Study (NSHDS). DNA methylation was measured in buffy coat using the Infinium Methylation EPIC BeadChip (Illumina). Sex hormone (oestradiol, oestrone, testosterone, androstenedione, dehydroepiandrosterone, and progesterone) and SHBG concentrations were measured in plasma using a high-performance liquid chromatography tandem mass spectrometry (LC/MS-MS) method and an enzyme-linked immunoassay, respectively. Associations between sex hormones, SHBG, and DNA methylation were estimated using both linear regression and mixed-effects models. Additionally, we used the comb-p method to identify differentially methylated regions based on nearby P values. We identified one novel CpG site (cg14319657), at which DNA methylation was associated with dehydroepiandrosterone, surpassing a genome-wide significance level. In addition, more than 40 differentially methylated regions were associated with levels of sex hormones and SHBG and several of these mapped to genes involved in hormone-related diseases. Our findings support a relationship between circulating sex hormones and DNA methylation and suggest that further investigation is warranted, both for validation, further exploration and to gain a deeper understanding of the mechanisms and potential consequences for health and disease.

Abstract Background Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming. Methods Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings. Results Forty-seven CpGs were associated with rapid weight growth at suggestive p-value

Abstract Background Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment. Methods Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC–QTOF-MS metabolomics, targeted LC–MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment. Results Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism. Conclusions Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies. Trial registration ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.

Abstract Background Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. Methods We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. Results Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. Conclusions These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.

Background: In Finland, there have been various strategies attempting to provide access to GPs. The 'restricted-List General Practitioner model' (rLGP) was launched in primary health care (PHC) in the city of Vantaa after the 'named General Practitioner model' (nGP) failed to provide sufficient access to GPs. This was done to improve access to GP appointments for those most needing care. Aim: To evaluate the impact of the transition from nGP to rLGP on access to non-urgent scheduled appointments among patients aged ≥75 years. Design & setting: A register-based follow-up study in public PHC in Vantaa, Finland. Method: The study focused on patients aged ≥75 years who used PHC from 2004–2008. It looked at the number of non-urgent and urgent scheduled appointments, patient contacts, home visits, PHC emergency department appointments, and cancelled appointments, which were recorded 7 years before and after the transition from nGP to rLGP in 2011 and adjusted to patient-years. Non-urgent appointments were booked to the patient’s own nGP or rLGP in public PHC, whereas urgent appointments could be to any GP. Results: The number of non-urgent scheduled appointments to GPs was halved during the time of nGP, before launching the rLGP. Simultaneously, the number of urgent scheduled appointments more than tripled. The number of both started to plateau a year before the rLGP was launched. The number of both non-urgent and urgent scheduled appointments remained mainly at that level after rLGP was implemented. Conclusion: The rLGP model was unsuccessful in improving access to non-urgent scheduled appointments to GPs.