Potassium rhythms couple the circadian clock to the cell cycle.

Circadian (~24 h) rhythms are a fundamental feature of life, and their disruption increases the risk of infectious diseases, metabolic disorders, and cancer1-6. Circadian rhythms couple to the cell cycle across eukaryotes7,8 but the underlying mechanism is unknown. We previously identified an evolutionarily conserved circadian oscillation in intracellular potassium concentration, [K+]i9,10. As critical events in the cell cycle are regulated by intracellular potassium11,12, an enticing hypothesis is that circadian rhythms in [K+]i form the basis of this coupling. We used a minimal model cell, the alga Ostreococcus tauri, to uncover the role of potassium in linking these two cycles. We found direct reciprocal feedback between [K+]i and circadian gene expression. Inhibition of proliferation by manipulating potassium rhythms was dependent on the phase of the circadian cycle. Furthermore, we observed a total inhibition of cell proliferation when circadian gene expression is inhibited. Strikingly, under these conditions a sudden enforced gradient of extracellular potassium was sufficient to induce a round of cell division. Finally, we provide evidence that interactions between potassium and circadian rhythms also influence proliferation in mammalian cells. These results establish circadian regulation of intracellular potassium levels as a primary factor coupling the cell- and circadian cycles across diverse organisms.

Critical physiotherapy: a ten-year retrospective.

Critical physiotherapy has been a rapidly expanding field over the last decade and could now justifiably be called a professional sub-discipline. In this paper we define three different but somewhat interconnected critical positions that have emerged over the last decade that share a critique of physiotherapy's historical approach to health and illness, while also diverging in the possibilities for new forms of practice and thinking. These three positions broadly align with three distinctive philosophies: approaches that emphasize lived experience, social theory, and a range of philosophies increasingly referred to as the "posts". In this paper we discuss the origins of these approaches, exploring the ways they critique contemporary physiotherapy thinking and practice. We offer an overview of the key principles of each approach and, for each in turn, suggest readings from key authors. We conclude each section by discussing the limits of these various approaches, but also indicate ways in which they might inform future thinking and practice. We end the paper by arguing that the various approaches that now fall under the rubric of critical physiotherapy represent some of the most exciting and opportune ways we might (re)think the future for the physiotherapy profession and the physical therapies more generally.

Men's Experiences With Managing Type 2 Diabetes and Their Encounters With Health Professionals: A Scoping Review.

Type 2 diabetes is on the rise globally, and previous research has identified gender as one known risk factor for developing this disease. Gender has also been reported to affect patients' experiences of managing type 2 diabetes. However, little is known of men's specific experiences with type 2 diabetes, as research with a gendered focus has concentrated more on women's experiences with the disease. This scoping review explores how research has addressed men's experiences of managing type 2 diabetes and their encounters with health professionals. The review consists of an iterative process, involving six steps: identification of the research questions, identification of relevant studies, study selection, charting the data, collating and summarizing results, and consultation with external stakeholders. Through the process, 28 publications were identified, which indicate a gap in research on patients' experiences with type 2 diabetes. The majority of the identified studies focuses on men from an ethnic minority due to their poorer health outcomes. However, a knowledge gap regarding men belonging to an ethnic or racial majority warrants further attention, as studies indicate that men who share similar social economic status face similar barriers to improving the management of type 2 diabetes. There is little discussion of how the gendered dynamics in encounters between patients and health professionals affect the management of type 2 diabetes. This review suggests a need for further research that explores how practices of masculinities, that is, the normative practices guiding men's behavior, intersect with men's experiences with type 2 diabetes in a broader perspective.

'Skeletal Age' for mapping the impact of fracture on mortality.

Background: Fragility fracture is associated with an increased risk of mortality, but mortality is not part of doctor-patient communication. Here, we introduce a new concept called 'Skeletal Age' as the age of an individual's skeleton resulting from a fragility fracture to convey the combined risk of fracture and fracture-associated mortality for an individual. Methods: We used the Danish National Hospital Discharge Register which includes the whole-country data of 1,667,339 adults in Denmark born on or before January 1, 1950, who were followed up to December 31, 2016 for incident low-trauma fracture and mortality. Skeletal age is defined as the sum of chronological age and the number of years of life lost (YLL) associated with a fracture. Cox's proportional hazards model was employed to determine the hazard of mortality associated with a specific fracture for a given risk profile, and the hazard was then transformed into YLL using the Gompertz law of mortality. Results: During the median follow-up period of 16 years, there had been 307,870 fractures and 122,744 post-fracture deaths. A fracture was associated with between 1 and 7 years of life lost, with the loss being greater in men than women. Hip fractures incurred the greatest loss of life years. For instance, a 60-year-old individual with a hip fracture is estimated to have a skeletal age of 66 for men and 65 for women. Skeletal Age was estimated for each age and fracture site stratified by gender. Conclusions: We propose 'Skeletal Age' as a new metric to assess the impact of a fragility fracture on an individual's life expectancy. This approach will enhance doctor-patient risk communication about the risks associated with osteoporosis. Funding: National Health and Medical Research Council in Australia and Amgen Competitive Grant Program 2019.

Osteoporosis is a 'silent disease' which often has no immediate symptoms but gradually weakens bones and makes them more likely to break. A bone fracture caused by osteoporosis in people over the age of 50 is linked to long-term health decline and in some cases, even early death. However, poor communication of the mortality risk to patients has led to a low uptake of treatment, resulting in a crisis of osteoporosis management. The impact of a fracture on life expectancy is typically conveyed to patients and the public in terms of probability (how likely something is to occur) or the relative risk of death compared to other groups. However, statements such as "Your risk of death over the next 10 years is 5% if you have suffered from a bone fracture" can be difficult to comprehend and can lead to patients underestimating the gravity of the risk. With the aim of devising a new way of conveying risks to patients, Tran et al. analyzed the relationship between fracture and lifespan in over 1.6 million individuals who were 50 years of age or older. The findings showed that one fracture was associated with losing up to 7 years of life, depending on gender, age and fracture site. Based on this finding, Tran et al. proposed the idea of 'skeletal age' as a new metric for quantifying the impact of a fracture on life expectancy. Skeletal age is the sum of the chronological age of a patient and the estimated number of years of life lost following a fracture. For example, a 60-year-old man with a hip fracture is predicted to lose an estimated 6 years of life, resulting in a skeletal age of around 66. Therefore, this individual has the same life expectancy as a 66-year-old person that has not experienced a fracture. Skeletal age can also be used to quantify the benefit of osteoporosis treatments. Some approved treatments substantially reduce the likelihood of post-fracture death and translating this into skeletal age could help communicate this to patients. For instance, telling patients that "This treatment will reduce your skeletal age by 2 years" is easier to understand than "This treatment will reduce your risk of death by 25%". Given the current crisis of osteoporosis management, adopting skeletal age as a new measure of how the skeleton declines after a fracture could enhance doctor-patient communication regarding treatment options and fracture risk assessment. Tran et al. are now developing an online tool called 'BONEcheck.org' to enable health care professionals and the public to calculate skeletal age. Future work should investigate the effectiveness of this new metric in conveying risk to patients, compared with current methods.

Association of Multimorbidity and Excess Mortality After Fractures Among Danish Adults.

Importance: Limited knowledge about interactions among health disorders impedes optimal patient care. Because comorbidities are common among patients 50 years and older with fractures, these fractures provide a useful setting for studying interactions among disorders. Objective: To define multimorbidity clusters at the time of fracture and quantify the interaction between multimorbidity and fracture in association with postfracture excess mortality. Design, Setting, and Participants: This nationwide cohort study included 307 870 adults in Denmark born on or before January 1, 1951, who had an incident low-trauma fracture between January 1, 2001, and December 31, 2014, and were followed up through December 31, 2016. Data were analyzed from February 1 to March 31, 2022. Main Outcomes and Measures: Fracture and 32 predefined chronic diseases recorded within 5 years before the index fracture were identified from the Danish National Hospital Discharge Register. Death was ascertained from the Danish Register on Causes of Death. Latent class analysis was conducted to identify multimorbidity clusters. Relative survival analysis was used to quantify excess mortality associated with the combination of multimorbidity and fractures at specific sites. Results: Among the 307 870 participants identified with incident fractures, 95 372 were men (31.0%; mean [SD] age at fracture, 72.3 [11.2] years) and 212 498 were women (69.0%; mean [SD] age at fracture, 74.9 [11.2] years). During a median of 6.5 (IQR, 3.0-11.0) years of follow-up, 41 017 men (43.0%) and 81 727 women (38.5%) died. Almost half of patients with fractures (42.9%) had at least 2 comorbidities. Comorbidities at fracture were categorized as low-multimorbidity (60.5% in men and 66.5% in women), cardiovascular (23.7% in men and 23.5% in women), diabetic (5.6% in men and 5.0% in women), malignant (5.1% in men and 5.0% in women), and mixed hepatic and/or inflammatory (5.1% in men only) clusters. These clusters distinguished individuals with advanced, complex, or late-stage disease from those with earlier-stage disease. Multimorbidity and proximal or lower leg fractures were associated with increased mortality risk, with the highest excess mortality found in patients with hip fracture in the malignant cluster (1-year excess mortality: 40.8% [95% CI: 38.1%-43.6%]). The combination of multimorbidity and fracture compounded the association with mortality, conferring much greater risk than either alone. Conclusions and Relevance: Concomitant illnesses were common and clustered into distinct multimorbidity clusters that were associated with excess postfracture mortality. The compound contribution of multimorbidity to postfracture excess mortality highlights the need for more comprehensive approaches in these high-risk patients. The analytical approach applied to fracture could also be used to examine other sentinel health events.

Cost Effectiveness of Patient Self-Managed Warfarin Compared with Direct Oral Anticoagulants in Atrial Fibrillation: An Economic Evaluation in a Danish Healthcare Sector Setting.

BACKGROUND: Patient self-managed anticoagulant treatment with warfarin (PSM) has been proposed as an alternative to direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF); however, direct evidence on the cost effectiveness of PSM compared with DOACs is lacking. We aimed to evaluate the cost effectiveness of PSM versus DOACs for NVAF patients in the Danish healthcare setting using a model-based cost-utility analysis. METHODS: A cost-utility analysis was performed using a decision-analytic model including two treatment alternatives: continuous PSM and DOACs. The analysis was performed from an extended Danish healthcare sector perspective, including patient-paid costs of medication related to the anticoagulant treatment, with a lifetime horizon. Inputs for the model comprised of probabilities of events, costs in Danish estimates, when possible, and effect in utilities. The probabilities of events are primarily based on real-life data from a direct comparison of PSM and DOACs. The results are presented as the incremental cost-effectiveness ratio (ICER) with an assumed cost-effectiveness threshold of £20,000/quality-adjusted life-year (QALY). Both deterministic and probabilistic sensitivity analyses were performed to investigate the robustness of the results. RESULTS: The base-analysis showed that PSM was dominant, with a decreased cost of £8495 and an increased QALY accumulation of 0.23 per patient (ICER = -£36,935/QALY). All deterministic sensitivity analyses indicated that PSM was dominant or at least cost effective. The probabilistic sensitivity analysis showed that 95% of the iterations were cost effective. CONCLUSIONS: The present study found that PSM is dominant (i.e., both more effective and cost saving) compared with DOACs, adding to the scarce evidence of the comparative cost effectiveness of PSM and DOACs in NVAF.

Patient-centeredness in Physiotherapy - A literature mapping review.

BACKGROUND AND PURPOSE: Research on patient-centeredness within physiotherapy points to a need for clarification about what the concept entails in science and practice and how research positions itself within health care. Thus, the aim is to systematically map the characteristics of research on patient-centeredness in physiotherapy and critically discuss the dominant understandings within. METHODS: A systematic research mapping was carried out, based on searches in leading bibliographic databases. Four categories were selected in order to characterize the research field: focus, design, theoretical approach and inherent logic. FINDINGS: Of 5,324 studies, 101 were included in the final mapping, pointing to a limited amount of research. The papers included were published in 47 different journals. Two major research foci emerges: one testing or developing technologies (tools) to promote patient-centeredness and one exploring patients' or professionals' experiences related to physiotherapy practice. Most papers reported on empirical research and there seems to be a dearth of conceptual papers. The theoretical approaches applied were mainly psychological, pedagogical and biomedical. The papers included were divided into equal amounts of studies carried out within inherent logics of causality and complexity. CONCLUSION: The mapping suggests an incipient awareness of patient-centeredness within the research field of physiotherapy. Empirical studies dominate the field, whereas conceptual and critical papers seem in need of wider acknowledgment. The research field is divided into two mutually disconnected trends: one concerned with understanding the complexity of clinical practice and patients' experiences of treatment and illness, and another trend concerned with solving "the problem" of patient involvement.

Social inequality in type 2 diabetes mellitus in the Faroe Islands: a cross-sectional study.

Aims: The Faroe Islands is considered a homogeneous society and has a low Gini coefficient, but the knowledge about the social distribution of health and disease is sparse. In a large population-based sample we investigated: (a) the association between socioeconomic position defined by level of education and the prevalence of type 2 diabetes mellitus by self-report in the Faroe Islands; and (b) to what degree lifestyle factors mediate the association. Methods: We used cross-sectional data from the population-based Public Health Survey Faroes 2015 (n=1095). We present odds ratios for type 2 diabetes mellitus by socioeconomic position from logistic regression models. In our main model we adjusted for potential confounders and in a secondary model we additionally adjusted for potential mediating lifestyle factors. Results: Individuals with middle and low levels of education display higher odds ratios of type 2 diabetes mellitus of 2.80 (95% confidence interval 1.32-5.92) and 4.65 (95% confidence interval 1.93-11.17) in adjusted analysis, respectively, compared to their counterparts with high education. After adjustment for potentially mediating lifestyle factors the estimates were attenuated slightly, but a significant statistical association remained, with lifestyle-related mediating factors in total explaining 21% for middle education and 34% for low education participants. Conclusions: Our results demonstrate that there may be a social gradient in the distribution of type 2 diabetes mellitus in the Faroe Islands, and that the association is partly mediated by lifestyle factors.

Pre-vaccination vulnerability and suspected adverse events following HPV vaccination. A case-control study nested in the Danish national birth cohort.

Previous studies have indicated that girls experiencing suspected adverse events (AE) following HPV vaccination were more vulnerable prior to vaccination. However, no study has previously investigated differences in vulnerability using prospectively collected self-reported measures of vulnerability. The objective of this study therefore was to describe the distribution of biological and psychosocial indicators of vulnerability in girls referred to a hospital setting due to suspected adverse events and compare it with a sample of non-referred HPV vaccinated girls. The study was conducted as a case control study based within the Danish National Birth Cohort. Cases were defined as HPV vaccinated girls referred to a hospital setting between 2015 and 2017 due to suspected adverse events (n = 80), and 5 controls were randomly selected from the remaining source population, matched to cases on age at vaccination, region of residence and year of vaccination. The final study population consisted of 480 girls. Prior exposures were based on information gathered from an 11 year follow up of the DNBC and included information on self-rated health, frequent health complaints, medication use, bullying, stressful life events and physical activity. Conditional logistic regression analysis was used to estimate the association between each exposure and referral. The percentage of individuals in the exposed category of each exposure was generally higher for cases than controls. Particularly, the odds of being referred were higher for those with low self-rated health compared to high (OR [95%-CI] 2.43 [1.07-5.5]1), those being bullied (OR 3.19 [1.17-8.73]), and those who had taken medication (OR 2.22 [1.32-3.67]). Overall, these results indicated that girls experiencing suspected AE following HPV vaccination were more vulnerable prior to vaccination.

Measuring expression heterogeneity of single-cell cytoskeletal protein complexes.

Multimeric cytoskeletal protein complexes orchestrate normal cellular function. However, protein-complex distributions in stressed, heterogeneous cell populations remain unknown. Cell staining and proximity-based methods have limited selectivity and/or sensitivity for endogenous multimeric protein-complex quantification from single cells. We introduce micro-arrayed, differential detergent fractionation to simultaneously detect protein complexes in hundreds of individual cells. Fractionation occurs by 60 s size-exclusion electrophoresis with protein complex-stabilizing buffer that minimizes depolymerization. Proteins are measured with a ~5-hour immunoassay. Co-detection of cytoskeletal protein complexes in U2OS cells treated with filamentous actin (F-actin) destabilizing Latrunculin A detects a unique subpopulation (~2%) exhibiting downregulated F-actin, but upregulated microtubules. Thus, some cells may upregulate other cytoskeletal complexes to counteract the stress of Latrunculin A treatment. We also sought to understand the effect of non-chemical stress on cellular heterogeneity of F-actin. We find heat shock may dysregulate filamentous and globular actin correlation. In this work, our assay overcomes selectivity limitations to biochemically quantify single-cell protein complexes perturbed with diverse stimuli.

Discovery of a Potent Adenine-Benzyltriazolo-Pleuromutilin Conjugate with Pronounced Antibacterial Activity against MRSA.

Conjugation of pleuromutilin is an attractive strategy for the development of novel antibiotics and the fight against multiresistant bacteria as the class is associated with low rates of resistance and cross-resistance development. Herein, the preparation of 35 novel (+)-pleuromutilin conjugates is reported. Their design was based on a synthetically more efficient benzyl adaption of a potent lead but still relied on the Cu(I)-catalyzed alkyne-azide [3 + 2] cycloaddition for conjugation onto pleuromutilin. Their antibacterial activity was evaluated against the multiresistant Staphylococcus aureus strain USA300 for which they displayed moderate to excellent activity. Compound 35, bearing a para-benzyladenine substituent, proved particularly potent against USA300 and additional strains of MRSA and displayed as importantly no cytotoxicity in four mammalian cell lines. Structure-activity relationship analysis revealed that the purine 6-amino is essential for high potency, likely because of strong hydrogen bonding with the RNA backbone of C2469, as suggested by a molecular model based on the MM-GBSA approach.

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis.

BACKGROUND: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. METHODS AND FINDINGS: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. CONCLUSIONS: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.

Weekly variation in markers of cardiometabolic health - the possible effect of weekend behavior - a cross-sectional study.

BACKGROUND: Adolescents' health-related behavior varies from weekday to weekend. Only few studies, however, have examined to which degree such variation will affect markers of cardiometabolic health. Therefore, the primary aim of this study is to examine if markers of cardiometabolic health differ between different days of the week in adolescents. METHODS: This cross-sectional school-based study included up to 581 participants, 11-17 years old. Markers of metabolic health were insulin, glucose, triglyceride, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) and blood pressure. Linear mixed regression modelling was used to examine the cardiometabolic profile across weekdays. RESULTS: Significant declining trends were observed across the week in adolescents' levels of cardiometabolic health markers. Lower levels of insulin (16.1%), glucose (2.6%) and triglyceride (24.7%) were observed on Fridays compared to Mondays (p ≤ 0.006). Gradual improvement in measurement profiles across weekdays was less apparent for HDL-C, LDL-C, systolic blood pressure and diastolic blood pressure (P ≥ 0.06). Analyses stratified by sex suggested a more noticeable pattern of gradual improvement across weekdays in boys than in girls. CONCLUSION: Significantly lower levels of insulin, glucose and triglyceride were observed in adolescents on Fridays compared to Mondays. However, when sex specific analyses were performed significant profile variations were only observed across the week in boys. More research is needed to better understand which behavioral factors in particular seem to influence weekly variation in markers of cardiometabolic health - especially since such variation potentially will have an impact on how assessments of markers of cardiometabolic health optimally should be planned, standardized and carried out, both in research and in medical practice.

Two-Fluorophore Mobile Phone Imaging of Biplexed Real-Time NAATs Overcomes Optical Artifacts in Highly Scattering Porous Media.

Nucleic acid amplification tests (NAATs) are common in laboratory and clinical settings because of their low time to result and exquisite sensitivity and specificity. Laboratory NAATs include onboard positive controls to reduce false negatives and specialized hardware to enable real-time fluorescence detection. Recent efforts to translate NAATs into at-home tests sacrifice one or more of the benefits of laboratory NAATs, such as sensitivity, internal amplification controls (IACs), or time to result. In this manuscript, we describe a mobile-phone-based strategy for real-time imaging of biplexed NAATs in paper. The strategy consisted of: (1) using mobile phones with multipass excitation and emission filters on the flash and camera to image the signal from distinct fluorophore-labeled probe types in a biplexed NAAT in a glass fiber membrane; and (2) analyzing the differential fluorescence signal between the red and green color channels of phone images to overcome a strong evaporation-induced optical artifact in heated glass fiber pads due to changes in the refractive index. We demonstrated that differential fluorescence imaging enabled low limits of detection (316 copies of methicillin-resistant Staphylococcus aureus DNA) in our lab's "MD NAAT" platform, even in biplexed isothermal strand displacement amplification reactions containing 100k copies of coamplifying IAC DNA templates. These results suggest that two-fluorophore mobile phone imaging may enable translating the benefits of extant laboratory-based, real-time NAATs to the point of care.

Dietary and Circulating Fatty Acids and Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case-control analysis. RESULTS: A positive association was found between ovarian cancer and intake of industrial trans elaidic acid [HR comparing fifth with first quintileQ5-Q1 = 1.29; 95% confidence interval (CI) = 1.03-1.62; P trend = 0.02, q-value = 0.06]. Dietary intakes of n-6 linoleic acid (HRQ5-Q1 = 1.10; 95% CI = 1.01-1.21; P trend = 0.03) and n-3 α-linolenic acid (HRQ5-Q1 = 1.18; 95% CI = 1.05-1.34; P trend = 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertileT3-T1 = 1.39; 95% CI = 0.99-1.94; P trend = 0.06) and α-linolenic acids (ORT3-T1 = 1.30; 95% CI = 0.98-1.72; P trend = 0.06). CONCLUSIONS: Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer. IMPACT: If causal, eliminating industrial trans-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.

Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort.

A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.

Is telehealthcare for heart failure patients cost-effective? An economic evaluation alongside the Danish TeleCare North heart failure trial.

OBJECTIVE: This study aimed to assess the cost-effectiveness of telehealthcare in heart failure patients as add-on to usual care. DESIGN: A cost-utility analysis was conducted from a public payer perspective alongside the randomised controlled TeleCare North trial. SETTING: The North Denmark Region, Denmark. PARTICIPANTS: The study included 274 heart failure patients with self-reported New York Heart Association class II-IV. INTERVENTIONS: Patients in the intervention group were provided with a Telekit consisting of a tablet, a digital blood pressure monitor, and a scale and were instructed to perform measurements one to two times a week. The responsibility of the education, instructions and monitoring of the heart failure (HF) patients was placed on municipality nurses trained in HF and telemonitoring. Both groups received usual care. OUTCOME MEASURES: Cost-effectiveness was reported as incremental net monetary benefit (NMB). A micro-costing approach was applied to evaluate the derived savings in the first year in the public health sector. Quality-adjusted life-years (QALY) gained were estimated using the EuroQol 5-Dimensions 5-Levels questionnaire at baseline and at a 1-year follow-up. RESULTS: Data for 274 patients were included in the main analysis. The telehealthcare solution provided a positive incremental NMB of £5164. The 1-year adjusted QALY difference between the telehealthcare solution and the usual care group was 0.0034 (95% CI: -0.0711 to 0.0780). The adjusted difference in costs was -£5096 (95% CI: -8736 to -1456) corresponding to a reduction in total healthcare costs by 35%. All sensitivity analyses showed the main results were robust. CONCLUSIONS: The TeleCare North solution for monitoring HF was highly cost-effective. There were significant cost savings on hospitalisations, primary care contacts and total costs. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02860013.

Pre- and post-diagnostic intake of whole grain and dairy products and breast cancer prognosis: the Danish Diet, Cancer and Health cohort.

PURPOSE: Fiber rich foods and dairy products have been suggested to be associated with breast cancer prognosis, though existing research is limited and either report on pre- or post-diagnostic dietary intake in relation to breast cancer prognosis. We investigated the associations between intake of whole grain (WG) and dairy products assessed both pre- and post-diagnostically in relation to breast cancer prognosis. METHODS: A total of 1965 women from the Diet, Cancer and Health cohort who were diagnosed with breast cancer between baseline (1993-1997) and December 2013 were included and followed for a median of 7 years after diagnosis. During follow-up, 309 women experienced breast cancer recurrence and 460 women died, of whom 301 died from breast cancer. Dietary assessment by food frequency questionnaires was obtained up to three times, pre- and post-diagnostic, over a period of 18 years. Cox proportional hazard models were used to estimate hazard ratios. RESULTS: No associations were observed between pre- or post-diagnostic intake of total WG or total dairy products and breast cancer prognosis. A high pre-diagnostic intake of oatmeal/muesli was associated with lower all-cause mortality (HR 0.76, 95% CI 0.59-0.99), whereas high post-diagnostic intake of rye bread was associated with higher breast cancer-specific mortality (HR 1.29, 95% CI 1.02-1.63). A generally high intake of cheese was associated with a higher recurrence rate. CONCLUSION: Pre-diagnostic intake of oatmeal/muesli was associated with lower all-cause mortality, and post-diagnostic intake of rye bread was associated with higher breast cancer specific mortality.

Development and validation of circulating CA125 prediction models in postmenopausal women.

BACKGROUND: Cancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker. METHODS: We developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses' Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC. RESULT: The linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset. CONCLUSIONS: The linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 levels, which may contribute to reducing false positive tests using CA125 as screening biomarker.