Time to diagnosis and determinants of diagnostic delays of people living with a rare disease: results of a Rare Barometer retrospective patient survey.

Timely diagnosis is one of the most serious challenges faced by people living with a rare disease (PLWRD), and this study estimates that in Europe, the average total diagnosis time (TDT) is close to 5 years. We investigated the duration of the TDT for PLWRD in Europe, the difficulties associated with their diagnosis odyssey and the main determinants of diagnosis delays for all rare diseases (RD). We conducted a survey of PLWRD and their families using Rare Barometer, the survey initiative of EURORDIS-Rare Diseases Europe. In geographical Europe, we surveyed 6507 people living with 1675 RD in 41 countries. We then performed a descriptive analysis and ordinal logistic regressions to identify the main determinants of diagnosis delays. Average TDT is 4.7 years. 56% of respondents were diagnosed more than 6 months after a first medical contact. The main determinants of diagnosis delays are symptom onset before 30 years of age, especially during childhood (OR = 3.11; 95% CI: 2.4-4.0) and adolescence (OR = 4.79; 95% CI: 3.7-6.2), being a woman (OR = 1.22; 95% CI:1.1-1.4), living in Northern Europe (OR = 2.15; 95% CI:1.8-2.6) or Western Europe (OR = 1.96; 95% CI:1.6-2.3), the number of healthcare professionals consulted (OR = 5.15; 95% CI:4.1-6.4), misdiagnosis (OR = 2.48; 95% CI:2.1-2.9), referral to a centre of expertise (OR = 1.17; 95% CI:1.0-1.3), unmet needs for psychological support (OR = 1.34; 95% CI:1.2-1.5) and financial support (OR = 1.16; 95% CI:1.0-1.3), having a genetic disease (OR = 1.33; 95% CI:1.1-1.5) and a family history of an RD (OR = 1.36; 95% CI:1.1-1.6). These determinants can inform policies and actions to improve access to diagnosis for all PLWRD.

TRIFLURIDINE/TIPIRACIL (FTD/TPI) with or without bevacizumab in previously treated patients with esophago-gastric adenocarcinoma, a randomised phase III trial.

Background: Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to compare the efficacy of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil monotherapy in pre-treated patients with metastatic esophago-gastric adenocarcinoma. Methods: This investigator-initiated, open-label, randomized trial enrolled patients with metastatic esophago-gastric adenocarcinoma. The main inclusion criteria were patients with pre-treated metastatic esophago-gastric adenocarcinoma, and WHO performance status 0 or 1. Participants were randomly assigned (1:1) to receive oral trifluridine-tipiracil (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Randomisation was stratified by sex and treatment line. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2018-004845-18. Findings: From Oct 1, 2019, to Sept 30, 2021, 103 patients were enrolled and randomly assigned to trifluridine-tipiracil (n = 53) or trifluridine-tipiracil plus bevacizumab (n = 50). The clinical cut-off date was March 1st, 2023, after a median follow-up of 36.6 months. Median progression-free survival was 3.1 months (95% CI 2.0-4.3) in the trifluridine-tipiracil group vs 3.9 months (3.0-6.3) in the trifluridine-tipiracil plus bevacizumab group (hazard ratio 0.68, 95% CI 0.46-1.02; p = 0.058). The most frequent grade 3 or worse adverse event was neutropenia, observed in 26 (49%) patients in the trifluridine-tipiracil group vs 23 patients (46%) in the trifluridine-tipiracil plus bevacizumab group. At least one hospitalization was observed in 21 patients (40%) in the trifluridine-tipiracil group and 22 patients (44%) in the trifluridine-tipiracil plus bevacizumab group. No deaths were deemed treatment related. Interpretation: In patients with pre-treated metastatic esophago-gastric cancer, trifluridine-tipiracil plus bevacizumab, compared to trifluridine-tipiracil monotherapy, did not significantly prolong progression-free survival. The combination of trifluridine-tipiracil with bevacizumab was well tolerated without increase in severe neutropenia and no new safety signals. Funding: Servier, Roche.

Interprofessional diagnostic management teams: a scoping review protocol.

BACKGROUND: Diagnostic errors are a major problem in healthcare. In 2015, the report "Improving Diagnosis in Health Care" by the National Academies of Sciences, Engineering, and Medicine (NASEM) stated that it is likely that most people will experience at least one diagnostic error in their lifetime. The report suggests implementing diagnostic management teams, including patients and their relatives, diagnosticians, and healthcare professionals who support the diagnostic process, to limit diagnostic error and improve patient safety. Implementing interprofessional diagnostic management teams (IDMT), however, is not an easy task due to the complexity of the diagnostic processes and the traditional organization of healthcare with divided departments and healthcare professional who operate in different geographic locations. As this topic is still emerging, a scoping review is ideal to determine the scope of the body of literature on IDMT, indicate the volume of literature and studies available and identify any gaps in knowledge. In a long-term perspective, this scoping review will contribute to prevent diagnostic errors and improve patient safety, for adults and children with physical health issues. METHODS: We will conduct this scoping review in accordance with the JBI methodology and report it based on the PRISMA-ScR. We will systematically search six databases (EMBASE, PubMed, CINAHL, Academic Search Premier, SCOPUS and Web of Science) for papers published between 1985 and 2023 that describe the use of interprofessional diagnostic management teams. The participants included will be adults and children seeking diagnostic care for physical health issues. The concept studied will be interprofessional diagnostic management teams, and the context will be the diagnostic process in the healthcare system. Studies examining the diagnostic process in psychiatry, odontology or complementary medicine will be excluded. Data extraction, including key study characteristics and findings, will be done by two reviewers independently. Any disagreement will be resolved by discussion and eventually by including the two remainder reviewers. DISCUSSION: To our knowledge, this will be the first scoping review regarding IDMT and the derived effects on diagnostic safety and can therefore be a very important contribution to improve patient safety significantly during the diagnostic process. PROTOCOL REGISTRATION: The project is registered at Open Science Framework (OSF) with ID: osf.io/kv2n6.

Colchicine twice a day for hand osteoarthritis (COLOR): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Colchicine has been suggested for osteoarthritis treatment, but evidence is contradictory. We aimed to investigate colchicine's efficacy and safety compared with placebo in people with hand osteoarthritis. METHODS: In this single-centre, double-blind, randomised, placebo-controlled trial we recruited adults with symptomatic hand osteoarthritis and finger pain of at least 40 mm on a 100 mm visual analogue scale from an outpatient clinic in Denmark. The hand with the most severe finger pain at inclusion was the target hand. Participants were randomly assigned (1:1) to 0·5 mg colchicine or placebo taken orally twice a day for 12 weeks, stratified by BMI (≥30 kg/m2), sex, and age (≥75 years). Participants, outcome assessors, and data analysts were masked to treatment allocation. The primary endpoint was change from baseline to week 12 in target hand finger pain, assessed on a 100 mm visual analogue scale with a pre-specified minimal clinically important difference of 15 mm, in the intention-to-treat population. Safety was assessed at week 12 in the intention-to-treat population. The study was registered with ClinicalTrials.gov, NCT04601883, and with EudraCT, 2020-002803-20. FINDINGS: Between Jan 15, 2021, and March 3, 2022, 186 people were screened for eligibility, and 100 were randomly assigned to receive colchicine (n=50) or placebo (n=50). Participants had a mean age of 70·9 (SD 7·5) years, 69 (69%) of 100 were women and 31 (31%) were men. All participants completed the study. The mean change from baseline to week 12 in finger pain were -13·9 mm (SE 2·8) in the colchicine group and -13·5 mm (2·8) in the placebo group, with a between-group difference (colchicine vs placebo) of -0·4 mm (95% CI -7·6 to 6·7; p=0·90). In the colchicine group, there were 76 adverse events in 36 (72%) of 50 participants and one serious adverse advent (migraine attack leading to hospital admission). In the placebo group, there were 42 adverse events in 22 (44%) of 50 participants and two serious adverse events (cholecystitis and elevated alanine aminotransferase concentrations, in the same patient). INTERPRETATION: In people with painful hand osteoarthritis, treatment with 0·5 mg of colchicine twice day for 12 weeks did not effectively relieve pain, and treatment with colchicine was associated with more adverse events. FUNDING: The Oak Foundation, IMK Almene Fond, Minister Erna Hamilton's Scholarship for Science and Art, AP Moller and Wife Chastine McKinney Moller's Foundation for Medical Science Advancement, The Danish Medical Association, the Velux Foundation, Aase and Ejnar Danielsen's Foundation, and Director Emil C Hertz and Wife Inger Hertz's foundation.

The Cultural Psychology of Religiosity, Spirituality, and Secularism in Adolescence.

Cultural psychology has raised awareness of religiosity, spirituality, and secularism in people's psychological lives. This article takes a cultural-developmental approach by examining the development of religiosity, spirituality, and secularism among culturally diverse adolescents. At the outset, an explanation is provided as to why the valid study of peoples' psychological lives necessitates taking culture into account, and of key implications for theory and methodology. Throughout research on adolescent religiosity, spirituality, and secularism is described, including studies on conceptions of God, afterlife beliefs, the development of an Ethic of Divinity in moral reasoning, recent increases in spirituality and secularism, and the impact of globalization on worldviews and religiously-based puberty rituals. While the focus is on adolescents, the article includes relevant research with children and emerging adults. Concrete future research directions are proposed, including a call to address the extent to which effects of religion on adolescents are dependent on culture and globalization.

Cognitive behavior therapy in early psychosis with a focus on depression and low self-esteem: A randomized controlled trial.

BACKGROUND: Patients in early phases of psychosis often struggle with depressive symptoms and low self-esteem. The main aims of the present study were to examine whether cognitive behavior therapy (CBT) compared to treatment as usual (TAU) would reduce depressive symptoms (primary outcome) and increase self-esteem (secondary outcome). Furthermore, we wanted to examine whether CBT reduces symptoms measured with the PANSS (positive, negative, cognitive, or excited symptoms) or increases general functioning compared to TAU. METHODS: A total of 63 early psychosis patients were included and randomly assigned to receive either CBT (maximum 26 sessions) or TAU for a period of up to six months. A linear mixed model was used for longitudinal analysis, with a focus on whether patients in the CBT group or the TAU group changed differently to one another between the baseline and 15-month follow-up. RESULTS: There were no differences between the CBT group and TAU group regarding improvements in depressive symptoms measured with the Calgary Depression Scale for Schizophrenia (P = 0.188) or self-esteem measured with the Rosenberg Self-Esteem Scale (P = 0.580). However, patients in the CBT group improved significantly more on negative symptoms (P = 0.002) and social functioning (P = 0.001). CONCLUSIONS: We did not find CBT to be more effective than TAU in reducing depressive symptoms or increasing self-esteem in patients with early psychosis. However, CBT seems to improve negative symptoms and functioning. These results still need to be replicated in further studies as the present one was merely an exploratory analysis. ClinicalTrials.gov Identifier: NCT01511406.

Sources, distribution and fate of microfibres on the Great Barrier Reef, Australia.

Marine microdebris, in particular microplastics (plastics <5 mm), has become an issue of international concern due to its prevalence, persistence and potential adverse impacts on marine ecosystems. Informing source reduction based on ecological effects requires an understanding of the origin, distribution and characteristics of microdebris and the interactions with marine organisms. Here we show widespread contamination of the central Great Barrier Reef environment with microdebris, with microfibres comprising 86% of all items detected. Microdebris intake by coral reef fish was non-random, with chemical composition, shape and colour differing significantly from that detected in surface waters. Furthermore, the origin of microdebris contamination in surface waters is non-random with riverine discharge a likely source for microdebris detected at inshore, but not at offshore reef locations. Our findings demonstrate the complexities associated with determining marine microdebris exposure and fate, and assist in improving future ecological assessments and prioritizing source reduction.

The fate of microplastics during uptake and depuration phases in a blue mussel exposure system.

We present a blue mussel exposure system where the fate of microplastics (polystyrene beads) is tracked during exposure and depuration phases. This enabled the establishment of a complete mass balance. Quantification of beads in mussels was done with a novel enzymatic digestion protocol. We found a similar relative distribution of beads for 2 environmentally realistic concentrations (5 and 100 beads L-1 ) and no substantial egestion of particles within 2 h of depuration. Environ Toxicol Chem 2019;38:99-105. © 2018 SETAC.

Classification of marine microdebris: A review and case study on fish from the Great Barrier Reef, Australia.

Marine debris, and in particular plastic pollution, is ubiquitous throughout global marine environments. Here, we present a classification of marine microdebris (i.e. debris between 0.1 µm and <5 mm) tailored to represent synthetic, semi-synthetic and naturally-derived items. The specific aim of this classification is to introduce a level of consistency in the higher-level characterisation of marine microdebris, thereby improving the overall reporting on marine microdebris contamination. We first conducted an extensive literature review on the accumulation of ingested debris in fish to identify discrepancies in marine microdebris reporting as a basis for the new classification. The review reveals the diverse nature of ingested marine microdebris, including items that are non-plastic but often incorrectly reported on as microplastics. We then applied our classification to a case study on wild-caught juvenile coral trout, Plectropomus spp., from the Great Barrier Reef World Heritage Area, Australia. This first report on accumulation of ingested marine debris in commercial fish on the reef demonstrates a high frequency of occurrence and a prevalence of semi-synthetic and naturally-derived fibres. Based on our findings, we offer recommendations on potential improvements for the classification presented, ultimately contributing to a more realistic assessment of the ecological risks of marine microdebris.

Effect of once-weekly semaglutide on the counterregulatory response to hypoglycaemia in people with type 2 diabetes: A randomized, placebo-controlled, double-blind, crossover trial.

AIMS: To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D). METHODS: In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L). RESULTS: The mean (range) participant age was 54.2 (41-64) years, body mass index 29.4 (23.3-36.1) kg/m2 , glycated haemoglobin 60.8 (44.3-83.6) mmol/mol (7.7 [6.2-9.8]%), and diabetes duration 4.5 (0.3-13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval -7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide. CONCLUSIONS: Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.

The Delivery of Health Promotion and Environmental Health Services; Public Health or Primary Care Settings?

The WHO Regional Office for Europe developed a set of public health functions resulting in the ten Essential Public Health Operations (EPHO). Public health or primary care settings seem to be favorable to embrace all actions included into EPHOs. The presented paper aims to guide readers on how to assign individual health promotion and environmental health services to public health or primary care settings. Survey tools were developed based on EPHO 2, 3 and 4; there were six key informant surveys out of 18 contacted completed via e-mails by informants working in Denmark on health promotion and five face-to-face interviews were conducted in Australia (Melbourne and Victoria state) with experts from environmental health, public health and a physician. Based on interviews, we developed a set of indicators to support the assignment process. Population or individual focus, a system approach or one-to-one approach, dealing with hazards or dealing with effects, being proactive or reactive were identified as main element of the decision tool. Assignment of public health services to one of two settings proved to be possible in some cases, whereas in many there is no clear distinction between the two settings. National context might be the one which guides delivery of public health services.

A Randomized Trial Investigating the Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Semaglutide Once-Weekly in Healthy Male Japanese and Caucasian Subjects.

INTRODUCTION: Semaglutide is a glucagon-like peptide-1 analogue for once-weekly subcutaneous treatment of type 2 diabetes. This trial compared the pharmacokinetics, pharmacodynamics, and safety of semaglutide in Japanese and Caucasian subjects. METHODS: In this single-center, double-blind, parallel-group, 13-week trial, 44 healthy male subjects (22 Japanese, 22 Caucasian) were randomized within each race to semaglutide 0.5 mg (n = 8), 1.0 mg (n = 8), placebo 0.5 mg (n = 3) or 1.0 mg (n = 3). The primary endpoint was semaglutide exposure at steady state [area under the curve (AUC0-168h)]. RESULTS: Steady-state exposure of semaglutide was similar for both populations: AUC0-168h estimated race ratio (ERR), Japanese/Caucasian: 0.5 mg, 1.06; 1.0 mg, 0.99; maximum concentration (Cmax) ERR: 0.5 mg, 1.06; 1.0 mg, 1.02. Exposure after the first dose (0.25 mg) was slightly higher in Japanese versus Caucasian subjects (AUC0-168h ERR 1.11; Cmax ERR 1.14). Dose-dependent increases in AUC0-168h and Cmax occurred in both populations. Accumulation was as expected, based on the half-life (t1/2, ~ 1 week) and dosing interval of semaglutide. Significant body weight reductions were observed with semaglutide 0.5 mg and 1.0 mg in Japanese (both p ≤ 0.05) and Caucasian (both p ≤ 0.05) subjects versus placebo. No new safety issues were identified. CONCLUSIONS: The pharmacokinetic, pharmacodynamic, and safety profiles of semaglutide were similar in Japanese and Caucasian subjects, suggesting that no dose adjustment is required for the clinical use of semaglutide in Japanese subjects. FUNDING: Novo Nordisk A/S, Denmark. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02146079. Japanese trial registration number JapicCTI-142550.

Pharmacokinetics and tolerability of semaglutide in people with hepatic impairment.

AIMS: To investigate whether the pharmacokinetic characteristics of semaglutide were altered in people with hepatic impairment, assessed using Child-Pugh criteria, vs those with normal hepatic function. METHODS: In this multicentre, open-label, parallel-group trial (sponsor Novo Nordisk, ClinicalTrials.gov ID NCT02210871), four groups of participants with normal hepatic function (n = 19) or mild (n = 8), moderate (n = 10) or severe (n = 7) hepatic impairment received a single, subcutaneous dose of 0.5 mg semaglutide. Semaglutide plasma concentrations were assessed frequently for 35 days after dosing. The primary endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-∞ ). No effect of hepatic impairment was declared if the 90% confidence interval (CI) for the between-group ratio (hepatic impairment/normal function) was within the interval 0.70 to 1.43. RESULTS: Semaglutide exposure was similar across all groups, with AUC0-∞ treatment ratios for mild impairment/normal function of 0.95 (90% CI 0.77, 1.16), moderate impairment/normal function 1.02 (90% CI 0.93, 1.12), and severe impairment/normal function 0.97 (90% CI 0.84, 1.12). The maximum plasma semaglutide concentration (Cmax ) did not appear to be influenced by hepatic function, with mild impairment/normal function treatment ratios of 0.99 (90% CI 0.80, 1.23), moderate impairment/normal function 1.02 (90% CI 0.88, 1.18) and severe impairment/normal function 1.15 (90% CI 0.89, 1.48; sensitivity analysis excluding one extreme semaglutide concentration: 1.05 [90% CI 0.88, 1.25]). In all, 10 participants reported 12 mild or moderate non-serious adverse events. No unexpected safety or tolerability issues were observed. CONCLUSIONS: Semaglutide exposure did not appear to be affected by hepatic impairment, suggesting that dose adjustment may not be necessary in patients with hepatic impairment. Semaglutide was well tolerated and there were no unexpected safety issues.

Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species.

Semaglutide is a human glucagon-like peptide-1 analogue in clinical development for the treatment of type 2 diabetes. The absorption, metabolism and excretion of a single 0.5mg/450µCi [16.7MBq] subcutaneous dose of [3H]-radiolabelled semaglutide was investigated in healthy human subjects and compared with data from nonclinical studies. Radioactivity in blood, plasma, urine and faeces was determined in humans, rats and monkeys; radioactivity in expired air was determined in humans and rats. Metabolites in plasma, urine and faeces were quantified following profiling and radiodetection. The blood-to-plasma ratio and pharmacokinetics of both radiolabelled semaglutide-related material and of semaglutide (in humans only) were assessed. Intact semaglutide was the primary component circulating in plasma for humans and both nonclinical species, accounting for 69-83% of the total amount of semaglutide-related material, and was metabolised prior to excretion. Recovery of excreted radioactivity was 75.1% in humans, 72.1% in rats and 58.2% in monkeys. Urine and faeces were shown to be important routes of excretion, with urine as the primary route in both humans and animals. Semaglutide was metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain, and metabolism was not confined to specific organs. Intact semaglutide in urine accounted for 3.1% of the administered dose in humans and less than 1% in rats; it was not detected in urine in monkeys. The metabolite profiles of semaglutide in humans appear to be similar to the profiles from the nonclinical species investigated.

Pharmacokinetic Properties of Liraglutide as Adjunct to Insulin in Subjects with Type 1 Diabetes Mellitus.

BACKGROUND: The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D. METHODS: Subjects (18-64 years; body mass index 20.0-28.0 kg/m2; glycated hemoglobin ≤9.5 %) were randomized 1:1:1 to 0.6, 1.2, or 1.8 mg liraglutide/placebo. Each group underwent two 4-week treatment periods (liraglutide then placebo or placebo then liraglutide) separated by a 2- to 3-week washout. Both trial drugs were administered subcutaneously, once daily, as adjunct to insulin. A stepwise hypoglycemic clamp was performed at the end of each treatment period (data reported previously). Pharmacokinetic endpoints were derived from liraglutide concentration-time curves after the final dose and exposure was compared with data from previous trials in healthy volunteers and subjects with T2D. RESULTS: The pharmacokinetic properties of liraglutide in T1D were comparable with those observed in healthy volunteers and subjects with T2D. Area under the steady-state concentration-time curve (AUC) and maximum plasma concentration data were consistent with dose proportionality of liraglutide. Comparison of dose-normalized liraglutide AUC suggested that exposure in T1D, when administered with insulin, is comparable with that observed in T2D. CONCLUSIONS: Liraglutide, administered as adjunct to insulin in subjects with T1D, shows comparable pharmacokinetics to those in subjects with T2D. ClinicalTrials.gov Identifier: NCT01536665.

The Moral Reasoning of U.S. Evangelical and Mainline Protestant Children, Adolescents, and Adults: A Cultural-Developmental Study.

This cultural-developmental interview study examined moral reasoning in relation to religious culture (evangelical, mainline Protestants), age (children, adolescents, adults), and moral issue (public, private; N = 120). Compared to adolescents and adults, children used more Ethic of Autonomy and less Ethic of Community reasoning. With age, differences between religious cultures became pronounced. Mainline adults invoked an Ethic of Divinity for private issues. Evangelical adolescents and adults used this ethic frequently, but more for public than private issues. These and other findings indicate that evangelical and mainline Protestants diverge on what should be society's moral lingua franca, and cast new and nuanced light on America's "culture wars." Results furthermore highlight comodulation of development and culture that requires life course research on moral reasoning.

Standardised Resting Time Prior to Blood Sampling and Diurnal Variation Associated with Risk of Patient Misclassification: Results from Selected Biochemical Components.

BACKGROUND: According to current recommendations, blood samples should be taken in the morning after 15 minutes' resting time. Some components exhibit diurnal variation and in response to pressures to expand opening hours and reduce waiting time, the aims of this study were to investigate the impact of resting time prior to blood sampling and diurnal variation on biochemical components, including albumin, thyrotropin (TSH), total calcium and sodium in plasma. METHODS: All patients referred to an outpatient clinic for blood sampling were included in the period Nov 2011 until June 2014 (opening hours: 7am-3pm). Each patient's arrival time and time of blood sampling were registered. The impact of resting time and the time of day for all components was analysed using simple linear regression. The "maximum allowable bias" was used as quality indicator for the change in reference interval. RESULTS: Significant diurnal variation was found for albumin (n = 15,544; p<2×10-16), TSH (n = 20,019; p<2×10-16), calcium (n = 13,588; p = 2.8×10-12) and sodium (n = 51,917; p<2×10-16). Further significant influence for resting time was found for albumin (p = 2.6×10-4), TSH (p = 0.004), calcium (p = 8.9×10-7) and sodium (p = 8.7×10-16). Only TSH and albumin were clinically significantly influenced by diurnal variation. Resting time had no clinically significant effect. CONCLUSIONS: We found no need for resting 15 minutes prior to blood sampling. However, diurnal variation was found to have a significant and considerable impact on TSH and, to a minor degree, albumin. This has to be taken into account to ensure that reference intervals provided by the laboratory are valid on a 24-hour basis.