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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.

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.

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.

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.

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.

Objectives Unhealthy behaviours are associated with increased sickness absence (SA), but few studies have considered person-oriented approach in these associations. Using latent class analysis, we examined clustering of unhealthy behaviours among Finnish municipal employees and their associations with subsequent SA.Design A prospective register-linkage study.Setting Unhealthy behaviours (low leisure-time physical activity, non-daily fruit and vegetable consumption, insufficient sleep, excessive alcohol use and tobacco use) were derived from the Helsinki Health Study questionnaire survey, collected in 2017 among 19- to 39-year-old employees of the City of Helsinki, Finland.Participants A total of 4002 employees (81% women) of the City of Helsinki, Finland.Primary outcome measures The questionnaire data were prospectively linked to employer’s SA register through March 2020. Associations between latent classes of unhealthy behaviours and subsequent SA (1–7 days/8+ days/all lengths) were examined using negative binomial regression.Results Among women, a three-class latent class model was selected: (1) few unhealthy behaviours (84%), (2) excessive alcohol and tobacco use (12%) and (3) several unhealthy behaviours (5%). Women belonging to classes 2 and 3 had increased SA rates compared with those in class 1, regardless of the length of SA spells. Among men, a 2-latent class model was selected: (1) few unhealthy behaviours (53%) and (2) several unhealthy behaviours (47%). Men belonging to class 2 had increased rates of 1–7 days’ SA compared with men in class 1.Conclusions This study suggests that preventive actions aiming to reduce employees’ SA should consider simultaneously several unhealthy behaviours. Targeted interventions may benefit of identifying the clustering of these behaviours among occupational groups.

Summary: Background: Vaginal microbiota and its potential contribution to preterm birth is under intense research. However, only few studies have investigated the vaginal microbiota in later stages of pregnancy or at the onset of labour. Methods: We used 16S rRNA gene amplicon sequencing to analyse cross-sectional vaginal swab samples from 324 Finnish women between 37–42 weeks of gestation, sampled before elective caesarean section, at the onset of spontaneous labour, and in pregnancies lasting ≥41 weeks of gestation. Microbiota data were combined with comprehensive clinical data to identify factors associated with microbiota variation. Findings: Vaginal microbiota composition associated strongly with advancing gestational age and parity, i.e. presence of previous deliveries. Absence of previous deliveries was a strong predictor of Lactobacillus crispatus dominated vaginal microbiota, and the relative abundance of L. crispatus was higher in late term pregnancies, especially among nulliparous women. Interpretation: This study identified late term pregnancy and reproductive history as factors underlying high abundance of gynaecological health-associated L. crispatus in pregnant women. Our results suggest that the vaginal microbiota affects or reflects the regulation of the duration of gestation and labour onset, with potentially vast clinical utilities. Further studies are needed to address the causality and the mechanisms on how previous labour, but not pregnancy, affects the vaginal microbiota. Parity and gestational age should be accounted for in future studies on vaginal microbiota and reproductive outcomes. Funding: This research was supported by EU H2020 programme Sweet Crosstalk ITN (814102), Academy of Finland, State Research Funding, and University of Helsinki.

Objectives To determine the association between the rate of labour induction and caesarean delivery.Design Medical Birth Register-based study. We used data from the nationwide Medical Birth Register collecting data on delivery outcomes on all births from 22+0 weeks and/or birth weight of at least 500 g.Setting Finland.Participants 663 024 live births in Finland from 2008 to 2019.Main outcome measures The rates of labour induction and caesarean delivery.Results The rate of labour induction increased from 17.8% to 30.3%; p

Objective First birth and labor induction are risk factors for negative childbirth experiences. As labor inductions are increasing, research into this high-risk group’s childbirth experiences is important. We aimed to investigate whether nulliparity or factors related to labor induction, labor, and delivery explain the association. Methods This was a prospective study of 711 women undergoing labor induction at Helsinki University Hospital, Finland, between January 1, 2019, and January 31, 2020. The participants answered the Childbirth Experience Questionnaire (CEQ) after delivery (response rate 69.4%). The patient characteristics and delivery outcomes were collected from patient records. We analyzed the results for nulliparous and parous women. Results The mean CEQ scores were 2.9 (SD 0.5) for nulliparous women (n = 408) and 3.2 (SD 0.5) for parous women (n = 303), on a scale of 1–4; higher scores represent more positive experiences. However, 7.3% of the women had negative childbirth experiences (8.8% nulliparous; 5.3% parous, p = 0.08). Negative experiences were associated with a cesarean section (OR 6.7, 95% CI 1.8–9.3, p < 0.001) and a hemorrhage ≥ 1500 ml in vaginal delivery (OR 2.8, 95% CI 1.1–7.5, p = 0.03). In the separate CEQ domains analyses, nulliparity was associated with negative experiences in the “Own Capacity” domain (OR 1.6, 95% CI 1.0–2.4, p = 0.03). Cervical ripening, oxytocin use, and daytime delivery were associated with negative experiences in at least one domain, whereas epidural or spinal analgesia was regarded positively in two domains and negatively in one. Conclusions Nulliparous women undergoing labor induction risk negative childbirth experiences mainly due to labor and delivery-related factors, similar to parous women. Their perceptions of their capacity and preparedness for labor and delivery should be enhanced antenatally. An effective labor induction protocol promoting as high a rate of vaginal delivery as possible and preparedness to promptly respond to postpartum hemorrhage are key for avoiding negative childbirth experiences.

A variety of oxytocin regimens are used for labor induction and augmentation. Considering the increasing rates of labor induction, it is important to assess the most optimal oxytocin regimen without compromising maternal and fetal safety. The aim of this study was to compare delivery outcomes of low-dose and high-dose oxytocin induction protocols. This retrospective cohort study of 487 women comparing low-dose oxytocin protocol (n = 280) and high-dose oxytocin protocol (n = 207) in labor induction following cervical ripening by balloon catheter was performed in Helsinki University Hospital after implementation of a new oxytocin induction protocol. The study included two six-month cohorts from 2016 and 2019. Women with vital singleton pregnancies ≥37 gestational weeks, cephalic presentation, and intact amniotic membranes were included. The primary outcome was the rate of vaginal delivery. The secondary outcomes were the rates of maternal and neonatal infections, postpartum hemorrhage, umbilical artery blood pH-value, admission to neonatal intensive care, and induction-to-delivery interval. Statistical analyses were performed by using IBM SPSS Statistics for Windows (Armonk, NY, USA). The rate of vaginal delivery was higher [69.9% (n = 144) vs. 47.9% (n = 134); p

Objectives To identify groups of municipal employees between the ages of 20 and 34 years with distinct utilisation trajectories of primary care services provided by occupational health service (OHS), measured as the annual number of OHS visits, and to identify demographic and socioeconomic risk factors that distinguish employees in the high utilisation trajectory group(s).Methods The present study is a retrospective register-based cohort study. All municipal employees of the City of Helsinki, Finland, aged 20–34 in the Helsinki Health Study, recruited from 2004 to 2013, with follow-up data for 4 years were included in the study (n=9762). The outcome measure was group-based trajectories of OHS utilisation, identified with a group-based trajectory analysis. The demographic and socioeconomic variables used to predict the outcome were age, first language, educational level and occupational class. The analyses were stratified by gender.Results A large proportion of the young employees do not use OHS. Trajectory groups of ‘No visits’ (50%), ‘Low/increasing’ (18%), ‘Low/decreasing’ (22%) and ‘High/recurrent’ (10%) use were identified. We found occupational class differences in OHS utilisation patterns showing that lower occupational classes had a higher propensity for ‘High/recurrent’ OHS utilisation for both genders.Conclusions Preventive measures should be targeted particularly to the trajectory groups of ‘Low/increasing’ and ‘High/recurrent’ in order to intervene early. In addition, OHS utilisation should be closely monitored among the two lowest occupational classes. More research with longitudinal OHS data is needed.

BackgroundThere is increasing evidence that childhood socioeconomic position and childhood adversities influence adult health. However, the potential contribution of these factors to disability retirement is poorly understood. This study aimed to examine the associations between childhood adversities, parental education and disability retirement.MethodsData on parental education and childhood adversities were derived from the Helsinki Health Study baseline survey, conducted in 2000-02 among 40- to 60-year old employees of the City of Helsinki, Finland. Data on disability retirement and their diagnoses were obtained from the Finnish Centre of Pensions and followed until the end of 2016. The analyses included 5992 employees. The associations of parental education and childhood adversities with disability retirement due to any cause, musculoskeletal diseases and mental disorders were analysed using Cox regression analysis.ResultsLow parental education was associated with an increased risk of disability retirement due to any cause (maternal education: HR 1.74, 95% CI 1.16-2.62; paternal education: 1.86, 1.38-2.51) and due to musculoskeletal diseases (maternal education: 4.44, 1.66-11.92; paternal education: 3.81, 2.02-7.17). However, adjustment for own education mainly abolished the associations. Economic difficulties in the childhood family, parental alcohol problems and having been bullied at school or by peers increased the risk of disability retirement due to all studied diagnostic groups, whereas parental death or divorce had no effect. Childhood illness (1.53, 1.20-1.95) and parental mental illness (1.68, 1.28-2.20) were associated with disability retirement due to any cause and due to mental disorders (1.65, 1.05-2.59; 3.60, 2.46-5.26). The associations between childhood adversities and disability retirement remained after adjustment for own education, whereas working conditions, and weight and health behaviours somewhat attenuated the associations.ConclusionsParental education and childhood adversities contributed to disability retirement even in midlife. Policy actions investing in children's well-being might promote work ability in midlife.

Poor childhood family conditions have a long-term effect on adult mental health, but the mechanisms behind this association are unclear. Our aim was to study the pathways from problematic family relationships in adolescence to midlife psychological distress via disadvantages in early adulthood. Participants of a Finnish cohort study at the age of 16 years old in 1983 were followed up at ages 22, 32 and 42 years old (N = 1334). Problems in family relationships were measured with poor relationship with mother and father, lack of parental support in adolescent's individuation process and poor home atmosphere, and mental health was assessed using Kessler's Psychological Distress Scale (K10). We analyzed the indirect effects of adolescent family relations on mental health at age 42 years old via various disadvantages (somatic and psychological symptoms, relationship/marital status, low education/unemployment and heavy drinking) at ages 22 and 32 years old. Problematic adolescent family relationships were associated with midlife psychological distress in women (0.19; 95% CI 0.11, 0.26) and men (0.13; 95% CI 0.04, 0.21). However, after adjustment for adolescent psychological symptoms, the association was only significant for women (0.12; 95% CI 0.04, 0.20). Poor family relationships were associated with various disadvantages in early adulthood. The association from poor family relationships (16 years old) to psychological distress (42 years old) was in part mediated via psychological symptoms in women (0.03; 95% CI 0.01, 0.04) and men (0.02; 95% CI 0.00, 0.04) and in women also via heavy drinking in early adulthood (0.02; 95% CI 0.00, 0.03). Adolescent family relationships have a role in determining adult mental health. Targeted support addressing psychological well-being and hazardous drinking for adolescents with problematic family relationships might prevent disadvantages in early adulthood, and further prevent poor midlife mental health.

BackgroundPhysical inactivity is a major public health problem associated with increased mortality risk. It is, however, poorly understood whether vigorous physical activity is more beneficial for reducing mortality risk than activities of lower intensity. The aim of this study was to examine associations of the intensity and volume of leisure-time physical activity with all-cause mortality among middle-aged women and men while considering sociodemographic and health related factors as covariates.MethodsQuestionnaire survey data collected in 2000-02 among 40-60-year-old employees of the City of Helsinki (N = 8960) were linked with register data on mortality (74% gave permission to the linkage) providing a mean follow-up time of 12-years. The analysis included 6429 respondents (79% women). The participants were classified into three groups according to intensity of physical activity: low moderate, high moderate and vigorous. The volume of physical activity was classified into three groups according to tertiles. Cox regression analysis was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for all-cause mortality.ResultsDuring the follow up 205 participants died. Leisure-time physical activity was associated with reduced risk of mortality. After adjusting for covariates the vigorous group (HR = 0.54, 95% CI 0.34-0.86) showed a reduced risk of mortality compared with the low moderate group whereas for the high moderate group the reductions in mortality risk (HR = 0.72, 95% CI 0.48-1.08) were less clear. Adjusting for the volume of physical activity did not affect the point estimates. Higher volume of leisure-time physical activity was also associated with reduced mortality risk; however, adjusting for the covariates and the intensity of physical activity explained the differences.ConclusionsFor healthy middle-aged women and men who engage in some physical activity vigorous exercise may provide further health benefits preventing premature deaths.

Low oxygen tension (hypoxia) contributes critically to pluripotency of human embryonic stem cells (hESCs) by preventing spontaneous differentiation and supporting self-renewal. However, it is not well understood how hESCs respond to reduced oxygen availability and what are the molecular mechanisms maintaining pluripotency in these conditions. In this study we characterized the transcriptional and molecular responses of three hESC lines (H9, HS401 and HS360) on short (2 hours), intermediate (24 hours) and prolonged (7 days) exposure to low oxygen conditions (4% O2). In response to prolonged hypoxia the expression of pluripotency surface marker SSEA-3 was increased. Furthermore, the genome wide gene-expression analysis revealed that a substantial proportion (12%) of all hypoxia-regulated genes in hESCs, were directly linked to the mechanisms controlling pluripotency or differentiation. Moreover, transcription of MYC oncogene was induced in response to continuous hypoxia. At the protein level MYC was stabilized through phosphorylation already in response to a short hypoxic exposure. Total MYC protein levels remained elevated throughout all the time points studied. Further, MYC protein expression in hypoxia was affected by silencing HIF2α, but not HIF1α. Since MYC has a crucial role in regulating pluripotency we propose that induction of sustained MYC expression in hypoxia contributes to activation of transcriptional programs critical for hESC self-renewal and maintenance of enhanced pluripotent state.

Stable positioning between a measurement probe and its target from sub- to few micrometer scales has become a prerequisite in precision metrology and in cellular level measurements from biological tissues. Here we present a 3D stabilization system based on an optoelectronic displacement sensor and custom piezo-actuators driven by a feedback control loop that constantly aims to zero the relative movement between the sensor and the target. We used simulations and prototyping to characterize the developed system. Our results show that 95% attenuation of movement artifacts is achieved at 1 Hz with stabilization performance declining to ca. 70% attenuation at 10 Hz. Stabilization bandwidth is limited by mechanical resonances within the displacement sensor that occur at relatively low frequencies, and are attributable to the sensor's high force sensitivity. We successfully used brain derived micromotion trajectories as a demonstration of complex movement stabilization. The micromotion was reduced to a level of ∼1 µm with nearly 100 fold attenuation at the lower frequencies that are typically associated with physiological processes. These results, and possible improvements of the system, are discussed with a focus on possible ways to increase the sensor's force sensitivity without compromising overall system bandwidth.

OBJECTIVE: Self-rated health is a generic health indicator predicting mortality, many diseases, and need for care. We examined self-rated health as a predictor of subsequent disability retirement, and ill-health and working conditions as potential explanations for the association. METHODS: Self-rated health and the covariates were obtained from the Helsinki Health Study baseline mail surveys in 2000-2002 conducted among municipal employees aged 40-60 years (n = 6525). Data for disability retirement events (n = 625) along with diagnoses were linked from the Finnish Centre for Pensions, with a follow-up by the end of 2010. Hazard ratios (HR) and their 95% confidence intervals (CI) were calculated using competing risks models. RESULTS: Less than good self-rated health predicted disability retirement due to all causes among both women (HR = 4.60, 95% CI = 3.84-5.51) and men (HR = 3.83, 95% CI = 2.64-5.56), as well as due to musculoskeletal diseases (HR = 5.17, 95% CI = 4.02-6.66) and mental disorders (HR = 4.80, 95% CI = 3.50-6.59) among women and men pooled. Ill-health and physical working conditions partly explained the found associations, which nevertheless remained after the adjustments. Among the measures of ill-health limiting long-standing illness explained the association most in all-cause disability retirement and disability retirements due to musculoskeletal diseases, whereas common mental disorders explained the association most in disability retirements due to mental health disorders. Among working conditions physical work load and hazardous exposures at work explained the association most, although much less than ill-health. CONCLUSIONS: Self-rated health is a strong predictor of disability retirement. This can be partly explained by ill-health and working conditions. Poor self-rated health provides a useful marker for increased risk of work disability and subsequent disability retirement.

To examine the epidemiology of anorexia nervosa in men, we screened Finnish male twins born in 1975-79.Men (N = 2122) from FinnTwin16 birth cohorts were screened for lifetime eating disorders by a questionnaire. The screen positives (N = 18), their male co-twins (N = 10) and those with lifetime minimum BMI< or =17.5 (N = 21) were administered the Structured Clinical Interview for DSM-IV anorexia nervosa. The incidence rate of anorexia nervosa for the presumed peak age of risk (10-24y) was 15.7 per 100,000 person-years; its lifetime prevalence was 0.24%. All probands had recovered from eating disorders, but suffered from substantial psychiatric comorbidity, which also manifested in their co-twins. Additionally, male co-twins displayed significant dissatisfaction with body musculature, a male-specific feature of body dysmorphic disorder.Anorexia nervosa in males in the community is more common, transient and accompanied by more substantial comorbidity than previously thought.