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This article presents data collected using online surveys conducted in Norway, Tasmania (Australia) and Iceland, with the aim of exploring public perceptions of the salmon aquaculture industry in each country. A total of 2085 survey participants provided responses, with 1183 from Norway, 406 from Tasmania, and 496 from Iceland. The survey encompassed various aspects of attitudes towards and perceptions of the aquaculture industry. Participants were asked questions regarding their environmental concerns, trust in governance and management, and knowledge of the aquaculture industry in their respective country. Additionally, attitudes towards the industry were explored using questions related to preferences regarding information sources, perceptions of industry contributions, distribution of economic benefits, financial significance in local community, sustainability, and acceptance and tolerance of industry production. Respondents were also given the opportunity to provided text comments regarding the areas in which they thought the industry should become more sustainable. Demographic data on the respondents were collected, directly from the participants and from existing panel data from the survey company. However, the dataset excludes information on residence on the local level (postal code) to ensure anonymity of the respondents. The survey design was created by the SoLic-project (2019-2022, supported by the Research Council of Norway, no. 295114), drawing on the social license literature and the team's extensive research experience on topics related to the aquaculture industry, social acceptance, and legitimacy. The dataset presented in the article combines raw survey data with additional analysis data derived from grouping answer options or recoding data variables. The data provided in this article offers a valuable resource for researchers, industry representatives, public authorities, and other parties interested in salmon aquaculture. It enables comparative analyses and further investigations into public perceptions in Norway, Tasmania, and Iceland. This dataset can be used to explore a wide range of topics and extend the research conducted by the SoLic project team., (© 2024 The Author(s).)

Purpose: To review and describe the development, methods and cohort of the lumbosacral part of the Norwegian registry for spine surgery (NORspine)., Methods: NORspine was established in 2007. It is government funded, covers all providers and captures consecutive cases undergoing operations for degenerative disorders. Patients' participation is voluntary and requires informed consent. A set of baseline-, process- and outcome-variables (3 and 12 months) recommended by the International Consortium for Health Outcome Measurement is reported by surgeons and patients. The main outcome is the Oswestry disability index (ODI) at 12 months., Results: We show satisfactory data quality assessed by completeness, timeliness, accuracy, relevance and comparability. The coverage rate has been 100% since 2016 and the capture rate has increased to 74% in 2021. The cohort consists of 60,647 (47.6% women) cases with mean age 55.7 years, registered during the years 2007 through 2021. The proportions > 70 years and with an American Society of Anaesthesiologists' Physical Classification System (ASA) score > II has increased gradually to 26.1% and 19.3%, respectively. Mean ODI at baseline was 43.0 (standard deviation 17.3). Most cases were operated with decompression for disc herniation (n = 26,557, 43.8%) or spinal stenosis (n = 26,545, 43.8%), and 7417 (12.2%) with additional or primary fusion. The response rate at 12 months follow-up was 71.6%., Conclusion: NORspine is a well-designed population-based comprehensive national clinical quality registry. The register's methods ensure appropriate data for quality surveillance and improvement, and research., (© 2023. The Author(s).)

Clinically, unique markers in fetal membrane cells may contribute to the search for biomarkers for preterm prelabor rupture of the fetal membranes (pPROM) in maternal blood. pPROM is associated with overwhelming inflammation and premature cellular senescence causing "biological microfractures" of the fetal membranes. We hypothesize that these pathological processes are associated with the shedding of fetal membrane cells into the maternal circulation. The aim of this study was to identify markers expressed exclusively in fetal membrane cells to facilitate their isolation, characterization, and determination of biomarker potential in maternal blood. We have (1), by their transcriptomic profile, identified markers that are upregulated in amnion and chorion tissue compared to maternal white blood cells, and (2), by immunohistochemistry, confirmed the localization of the differentially expressed proteins in fetal membranes, placenta, and the placental bed of the uterus. RNA sequencing revealed 31 transcripts in the amnion and 42 transcripts in the chorion that were upregulated. Among these, 22 proteins were evaluated by immunohistochemistry. All but two transcripts were expressed both on mRNA and protein level in at least one fetal membrane cell type. Among these remaining 20 proteins, 9 proteins were not significantly expressed in the villous and extravillous trophoblasts of the placenta.

Marine aquaculture has the potential to increase its contribution to the global food system and provide valuable ecosystem services, but appropriate planning, licensing and regulation systems must be in place to enable sustainable development. At present, approaches vary considerably throughout the world, and several national and regional investigations have highlighted the need for reforms if marine aquaculture is to fulfil its potential. This article aims to map and evaluate the challenges of planning and licensing for growth of sustainable marine aquaculture. Despite the range of species, production systems and circumstances, this study found a number of common themes in the literature; complicated and fragmented approaches to planning and licensing, property rights and the licence to operate, competition for space and marine spatial planning, emerging species and diversifying marine aquaculture production (seaweed production, Integrated Multi-Trophic Aquaculture [IMTA], nutrient and carbon offsetting with aquaculture, offshore aquaculture and co-location and multiuse platforms), and the need to address knowledge gaps and use of decision-support tools. Planning and licensing can be highly complicated, so the UK is used as a case study to show more detailed examples that highlight the range of challenges and uncertainty that industry, regulators and policymakers face across interacting jurisdictions. There are many complexities, but this study shows that many countries have undergone, or are undergoing, similar challenges, suggesting that lessons can be learned by sharing knowledge and experiences, even across different species and production systems, rather than having a more insular focus., Competing Interests: The authors have no conflicts of interest to disclose., (© 2023 The Authors. Reviews in Aquaculture published by John Wiley & Sons Australia, Ltd.)

The Dengue Virus (DENV) non-structural protein 3 (NS3) is a multi-functional protein critical in the viral life cycle. The DENV NS3 is comprised of a serine protease domain and a helicase domain. The helicase domain itself acts as a molecular motor, either translocating in a unidirectional manner along single-stranded RNA or unwinding double-stranded RNA, processes fueled by the hydrolysis of nucleoside triphosphates. In this brief review, we summarize our contributions and ongoing efforts to uncover the thermodynamic and mechanistic functional properties of the DENV NS3 as an NTPase and helicase., Competing Interests: Conflict of interestThe authors declare no competing interests., (© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Fijiviruses replicate and package their genomes within viroplasms in a process involving RNA-RNA and RNA-protein interactions. Here, we demonstrate that the 24 C-terminal residues (C-arm) of the P9-1 major viroplasm protein of the mal de Río Cuarto virus (MRCV) are required for its multimerization and the formation of viroplasm-like structures. Using an integrative structural approach, the C-arm was found to be dispensable for P9-1 dimer assembly but essential for the formation of pentamers and hexamers of dimers (decamers and dodecamers), which favored RNA binding. Although both P9-1 and P9-1ΔC-arm catalyzed ATP with similar activities, an RNA-stimulated ATPase activity was only detected in the full-length protein, indicating a C-arm-mediated interaction between the ATP catalytic site and the allosteric RNA binding sites in the (do)decameric assemblies. A stronger preference to bind phosphate moieties in the decamer was predicted, suggesting that the allosteric modulation of ATPase activity by RNA is favored in this structural conformation. Our work reveals the structural versatility of a fijivirus major viroplasm protein and provides clues to its mechanism of action. IMPORTANCE The mal de Río Cuarto virus (MRCV) causes an important maize disease in Argentina. MRCV replicates in several species of Gramineae plants and planthopper vectors. The viral factories, also called viroplasms, have been studied in detail in animal reovirids. This work reveals that a major viroplasm protein of MRCV forms previously unidentified structural arrangements and provides evidence that it may simultaneously adopt two distinct quaternary assemblies. Furthermore, our work uncovers an allosteric communication between the ATP and RNA binding sites that is favored in the multimeric arrangements. Our results contribute to the understanding of plant reovirids viroplasm structure and function and pave the way for the design of antiviral strategies for disease control.

Objective: Despite its worldwide use, reviews of oxytocin for labor augmentation include mainly studies from high-income countries. Meanwhile, oxytocin is a potentially harmful medication and risks may be higher in low-resource settings. We conducted a systematic review and meta-analysis of practices, benefits, and risks of oxytocin for labor augmentation in low- and lower-middle-income countries., Data Sources: PubMed, Embase, PsycINFO, Index Medicus, Cochrane, and Google Scholar were searched for publications until January 1, 2022., Study Eligibility Criteria: All studies evaluating oxytocin augmentation rates were included. To investigate benefits and risks, randomized and quasi-randomized trials comparing oxytocin augmentation with placebo or no oxytocin were included. To explore risks more broadly, cohort and case-control studies were also included., Methods: Data were extracted and quality-assessed by 2 researchers using a modified Newcastle-Ottawa scale. Generic inverse variance outcome and a random-effects model were used. Adjusted or crude effect measures with 95% confidence intervals were used., Results: In total, 42 studies were included, presenting data from 885 health facilities in 25 low- and lower-middle-income countries (124,643 women). Rates of oxytocin for labor augmentation varied from 0.7% to 97.0%, exceeding 30% in 14 countries. Four studies investigated timing of oxytocin for augmentation and found that 89.5% (2745) of labors augmented with oxytocin did not cross the partograph's action line. Four cohort and 7 case-control studies assessed perinatal outcomes. Meta-analysis revealed that oxytocin was associated with: stillbirth and day-1 neonatal mortality (relative risk, 1.45; 95% confidence interval, 1.02-2.06; N=84,077; 6 studies); low Apgar score (relative risk, 1.54; 95% confidence interval, 1.21-1.96; N=80,157; 4 studies); neonatal resuscitation (relative risk, 2.69; 95% confidence interval, 1.87-3.88; N=86,750; 3 studies); and neonatal encephalopathy (relative risk, 2.90; 95% confidence interval, 1.87-4.49; N=1383; 2 studies). No studies assessed effects on cesarean birth rate and uterine rupture., Conclusion: This review discloses a concerning level of oxytocin use, including in labors that often did not fulfill criteria for dystocia. Although this finding is limited by confounding by indication, oxytocin seems associated with increased perinatal risks, which are likely mediated by inadequate fetal monitoring. We call for cautious use on clear indications and robust implementation research to support evidence-based guidelines for labor augmentation, particularly in low-resource settings., (© 2022 The Authors.)

Parkinson's disease, Multiple System Atrophy, and Lewy Body Dementia are incurable diseases called α-synucleinopathies as they are mechanistically linked to the protein, α-synuclein (α-syn). α-syn exists in different structural forms which have been linked to clinical disease distinctions. However, sleeping disorders (SDs) are common in the prodromal phase of all three α-synucleinopathies, which suggests that sleep-controlling neurons are affected by multiple forms of α-syn. To determine whether a structure-independent neuronal impact of α-syn exists, we compared and contrasted the cellular effect of three different α-syn forms on neurotransmitter-defined cells of two sleep-controlling nuclei located in the brainstem: the laterodorsal tegmental nucleus and the pedunculopontine tegmental nucleus. We utilized size exclusion chromatography, fluorescence spectroscopy, circular dichroism spectroscopy and transmission electron microscopy to precisely characterize ​​timepoints in the α-syn aggregation process with three different dominating forms of this protein (monomeric, oligomeric and fibril) and we conducted an in-depth investigation of the underlying neuronal mechanism behind cellular effects of the different forms of the protein using electrophysiology, multiple-cell calcium imaging, single-cell calcium imaging and live-location tracking with fluorescently-tagged α-syn. Interestingly, α-syn altered membrane currents, enhanced firing, increased intracellular calcium and facilitated cell death in a structure-independent manner in sleep-controlling nuclei, and postsynaptic actions involved a G-protein-mediated mechanism. These data are novel as the sleep-controlling nuclei are the first brain regions reported to be affected by α-syn in this structure-independent manner. These regions may represent highly important targets for future neuroprotective therapy to modify or delay disease progression in α-synucleinopathies., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The divergence of plumage color genes contributes to songbird radiation. However, the mechanisms by which color gene divergence counteracts gene flow to maintain reproductive isolation during the formation of new species boundaries remain elusive. The hybrid zone between Setophaga occidentalis (SOCC) and S. townsendi (STOW) in the Cascade Range provides a natural observatory to investigate potential behavioral mechanisms underlying divergent selection on color genes. Recently, we found that selection within a single gene block associated with plumage color variation has maintained a stable and narrow hybrid zone. Here, we investigated the potential role of plumage signals in moderating a behavioral mechanism of selection. Specifically, we assessed whether two plumage traits are associated with body size among breeding males and if trait mismatch predicted aggressive behavior within hybrid and parental individuals in response to simulated territorial intrusion. The two plumage signals, cheek and flank coloration, though associated with the same gene block, reflect opposing dominance of SOCC and STOW alleles. We found that both plumage traits significantly predict the body size in the territorial sex (i.e. males). The opposing dominance of the single color gene block resulted in plumage signal discordance in heterozygotes, which in turn was associated with reduced hybrid territorial performance, an important proxy of fitness in this system. Taken together, these observations point to a single-locus-two-alleles mechanism of incompatibility in shaping a natural species boundary in the early stage of speciation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

Study Question: To what extent is exposure to cellular telephones associated with male fertility?, Summary Answer: Overall, we found little association between carrying a cell phone in the front pants pocket and male fertility, although among leaner men (BMI <25 kg/m2), carrying a cell phone in the front pants pocket was associated with lower fecundability., What Is Known Already: Some studies have indicated that cell phone use is associated with poor semen quality, but the results are conflicting., Study Design, Size, Duration: Two prospective preconception cohort studies were conducted with men in Denmark (n = 751) and in North America (n = 2349), enrolled and followed via the internet from 2012 to 2020., Participants/materials, Setting, Methods: On the baseline questionnaire, males reported their hours/day of carrying a cell phone in different body locations. We ascertained time to pregnancy via bi-monthly follow-up questionnaires completed by the female partner for up to 12 months or until reported conception. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs) for the association between male cell phone habits and fecundability, focusing on front pants pocket exposure, within each cohort separately and pooling across the cohorts using a fixed-effect meta-analysis. In a subset of participants, we examined selected semen parameters (semen volume, sperm concentration and sperm motility) using a home-based semen testing kit., Main Results and the Role of Chance: There was little overall association between carrying a cell phone in a front pants pocket and fecundability: the FR for any front pants pocket exposure versus none was 0.94 (95% CI: 0.0.83-1.05). We observed an inverse association between any front pants pocket exposure and fecundability among men whose BMI was <25 kg/m2 (FR = 0.72, 95% CI: 0.59-0.88) but little association among men whose BMI was ≥25 kg/m2 (FR = 1.05, 95% CI: 0.90-1.22). There were few consistent associations between cell phone exposure and semen volume, sperm concentration, or sperm motility., Limitations, Reasons for Caution: Exposure to radiofrequency radiation from cell phones is subject to considerable non-differential misclassification, which would tend to attenuate the estimates for dichotomous comparisons and extreme exposure categories (e.g. exposure 8 vs. 0 h/day). Residual confounding by occupation or other unknown or poorly measured factors may also have affected the results., Wider Implications of the Findings: Overall, there was little association between carrying one's phone in the front pants pocket and fecundability. There was a moderate inverse association between front pants pocket cell phone exposure and fecundability among men with BMI <25 kg/m2, but not among men with BMI ≥25 kg/m2. Although several previous studies have indicated associations between cell phone exposure and lower sperm motility, we found few consistent associations with any semen quality parameters., Study Funding/competing Interest(s): The study was funded by the National Institutes of Health, grant number R03HD090315. In the last 3 years, PRESTO has received in-kind donations from Sandstone Diagnostics (for semen kits), Swiss Precision Diagnostics (home pregnancy tests), Kindara.com (fertility app), and FertilityFriend.com (fertility app). Dr. L.A.W. is a fibroid consultant for AbbVie, Inc. Dr. H.T.S. reports that the Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to and administered by Aarhus University. None of these studies are related to the current study. Dr. M.L.E. is an advisor to Sandstone Diagnostics, Ro, Dadi, Hannah, and Underdog. Dr. G.J.S. holds ownership in Sandstone Diagnostics Inc., developers of the Trak Male Fertility Testing System. In addition, Dr. G.J.S. has a patent pending related to Trak Male Fertility Testing System issued., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: One of the main concerns using low-dose (LD) CT for evaluation of patients with suspected intestinal obstruction or pneumoperitoneum is the potential need to make an additional standard-dose (SD) CT scan (retake) due to insufficient diagnostic accuracy of the LD CT., Purpose: To determine the frequency of retakes and evaluate the diagnostic accuracy of LD CT for the assessment of intestinal obstruction and pneumoperitoneum., Material and Methods: This retrospective study registered all LD CT scans over a one-year period at Aarhus University Hospital, Denmark in patients with suspected intestinal obstruction or perforation, comprising a total of 643 LD CT scans. A retake was defined as a SD CT scan of the abdomen and pelvis performed with or without intravenous contrast within 72 h after the initial LD CT due to either continued suspicion of intestinal obstruction or perforation or due to unclarified secondary findings. The sensitivity and specificity of LD CT for diagnosing intestinal obstruction and pneumoperitoneum compared to the discharge diagnoses of the scanned patients were determined., Results: The frequency of retakes was 3%. The overall LD CT sensitivity and specificity for assessment of patients with suspected intestinal obstruction and pneumoperitoneum was 83% and 99%, respectively, but higher in certain subgroups., Conclusions: LD CT led to few retakes and had a high diagnostic accuracy for diagnosing intestinal obstruction and pneumoperitoneum. Thus, LD CT can be recommended as the examination of choice in patients with suspected intestinal obstruction or perforation in order to reduce radiation dose., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Foundation Acta Radiologica 2021.)

Marine spatial planning (MSP) has rapidly become the most widely used integrated, place-based management approach in the marine environment. Monitoring and evaluation of MSP is key to inform best practices, adaptive management and plan iteration. While standardised evaluation frameworks cannot be readily applied, accounting for evaluation essentials such as the definition of evaluation objectives, indicators and stakeholder engagement of stakeholders is a prerequisite for meaningful evaluation outcomes. By way of a literature review and eleven practical MSP case studies, we analysed present day trends in evaluation approaches and unravelled the adoption of evaluation essentials for three categories for monitoring and evaluation for plan making, plan outcomes, and policy implementation. We found that at a global scale the focus of MSP evaluation has shifted over the past decade from evaluating predominantly plan outcomes towards the evaluation of plan making. Independent of the scope of the evaluation, evaluation approaches varied greatly from formal and structured processes, building for instance on MSP goals and objectives, to informal processes based on stakeholder interviews. We noted a trend in the adoption of formalised approaches where MSP evaluations have increasingly become linked to MSP policy goals and objectives. However, the enhanced use of MSP objectives and indicators did not result in a more straightforward reporting of outcomes, e.g. such as the achievement of specific MSP objectives. Overall, we found weak linkages between defined MSP objectives, indicators and available monitoring data. While the apparent shift towards a focus on objectives is promising, we highlight the need of fit-for-purpose monitoring data to enable effective evaluation of those objectives. Hence, effective MSP and adaptive management processes require customised and concurrent monitoring and evaluation strategies and procedures. We argue that evaluation processes would also benefit from a better understanding of the general environmental, socio-economic and socio-cultural effects of MSP. Therefore, to understand better environmental effects of MSP, we praise that forthcoming MSP processes need to deepen the understanding and considerations of cause-effect pathways between human activities and changes of ecosystem state through the adoption of targeted cumulative effects assessments., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein α-synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated α-synuclein-mediated damage to substantia nigra (SN) neurons, up to a decade before motor symptom appearance, patients exhibit sleep disorders (SDs). Therefore, we hypothesized that α-synuclein, which can be present in monomeric, fibril, and other forms, has deleterious cellular actions on sleep-control nuclei., Objective: We investigated whether native monomer and fibril forms of α-synuclein have effects on neuronal function, calcium dynamics, and cell-death-induction in two sleep-controlling nuclei: the laterodorsal tegmentum (LDT), and the pedunculopontine tegmentum (PPT), as well as the motor-controlling SN., Methods: Size exclusion chromatography, Thioflavin T fluorescence assays, and circular dichroism spectroscopy were used to isolate structurally defined forms of recombinant, human α-synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of α-synuclein were determined on LDT, PPT, and SN neurons using electrophysiology, calcium imaging, and neurotoxicity assays., Results: In LDT and PPT neurons, both forms of α-synuclein induced excitation and increased calcium, and the monomeric form heightened putatively excitotoxic neuronal death, whereas, in the SN, we saw inhibition, decreased intracellular calcium, and monomeric α-synuclein was not associated with heightened cell death., Conclusion: Nucleus-specific differential effects suggest mechanistic underpinnings of SDs' prodromal appearance in PD. While speculative, we hypothesize that the monomeric form of α-synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction.

Study Question: Does male alcohol consumption affect fecundability?, Summary Answer: In data pooled across Danish and North American preconception cohort studies, we found little evidence of an association between male alcohol consumption and reduced fecundability., What Is Known Already: Experimental and clinical studies have shown that alcohol affects male reproductive physiology, mainly by altering male reproductive hormones and spermatogenesis. However, few epidemiologic studies have examined the association between alcohol consumption and male fertility., Study Design, Size, Duration: Data were collected from two ongoing prospective preconception cohort studies: the Danish 'SnartForaeldre' (SF) study (662 couples) and the North American 'Pregnancy Study Online' (PRESTO) (2017 couples). Participants included in the current analysis were enrolled from August 2011 through June 2019 (SF) and from June 2013 through June 2019 (PRESTO)., Participants/materials, Setting, Methods: Eligible men were aged ≥18 years in SF and ≥21 years in PRESTO, in a stable relationship with a female partner and not using contraception or receiving fertility treatment. In both cohorts, alcohol consumption/serving size was self-reported as number of beers (330 mL/12 oz.), glasses of white or red wine (120 mL/4 oz. each), dessert wine (50 mL/2 oz.) and spirits (20 mL/1.5 oz.). Overall alcohol consumption was categorized as none, 1-5, 6-13 and ≥14 standard servings per week. Total menstrual cycles at risk were calculated using data from female partners' follow-up questionnaires, which were completed every 8 weeks until self-reported pregnancy or 12 menstrual cycles, whichever came first. Analyses were restricted to couples that had been trying to conceive for ≤6 cycles at study entry. Proportional probability regression models were used to compute fecundability ratios (FRs) and 95% confidence interval (CIs). We adjusted for male and female age, female partner's alcohol consumption, intercourse frequency, previous history of fathering a child, race/ethnicity, education, BMI, smoking and consumption of sugar-sweetened beverages and caffeine., Main Results and the Role of Chance: The cumulative proportion of couples who conceived during 12 cycles of follow-up were 1727 (64.5%). The median (interquartile range) of total male alcohol consumption was 4.5 (2.0-7.8) and 4.1 (1.0-8.6) standard servings per week in the SF and PRESTO cohorts, respectively. In pooled analyses, adjusted FRs for male alcohol consumption of 1-5, 6-13 and ≥14 standard servings per week compared with no alcohol consumption were 1.02 (95% CI: 0.90-1.17), 1.10 (95% CI: 0.96-1.27) and 0.98 (95% CI: 0.81-1.18), respectively. For SF, adjusted FRs of 1-5, 6-13 and ≥14 standard servings per week compared with no alcohol consumption were 0.97 (95% CI: 0.73-1.28), 0.81 (95% CI: 0.60-1.10) and 0.82 (95% CI: 0.51-1.30), respectively. For PRESTO, adjusted FRs of 1-5, 6-13 and ≥14 standard servings per week compared with no alcohol consumption were 1.02 (95% CI: 0.88-1.18), 1.20 (95% CI: 1.03-1.40) and 1.03 (95% CI: 0.84-1.26), respectively., Limitations, Reasons for Caution: Male alcohol consumption was ascertained at baseline only, and we did not distinguish between regular and binge drinking. In addition, we had insufficient numbers to study the effects of specific types of alcoholic beverages. As always, residual confounding by unmeasured factors, such as dietary factors and mental health, cannot be ruled out. Comorbidities thought to play a role in the reproductive setting (i.e. cancer, metabolic syndrome) were not considered in this study; however, the prevalence of cancer and diabetes was low in this age group. Findings for the highest categories of alcohol consumption (6-13 and ≥14 servings/week) were not consistent across the two cohorts., Wider Implications of the Findings: Despite little evidence of an association between male alcohol consumption and reduced fecundability in the pooled analysis, data from the Danish cohort might indicate a weak association between reduced fecundability and consumption of six or more servings per week., Study Funding/competing Interest(s): This study was supported by the National Institutes of Health (R01-HD060680, R01-HD086742, R21-HD050264, R21-HD072326, R03-HD090315), the Novo Nordisk Foundation, Oticon Fonden, Politimester J.P.N. Colind og hustru Asmine Colinds mindelegat and Erna og Peter Houtveds studielegat. PRESTO receives in-kind donations from FertilityFriend.com, Kindara.com, Swiss Precision Diagnostics and Sandstone Diagnostics for the collection of data pertaining to fertility. Dr Wise serves as a consultant on uterine leiomyomata for AbbVie.com. All other authors declare no conflict of interest., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: While metformin is the first-line pharmacological treatment of diabetes mellitus type 2, this drug is not considered safe to use in pregnant women because of its unknown consequences for the fetus. In this study, we aimed to investigate the biodistribution of metformin in the pregnant chinchilla, a species exhibiting placental characteristics comparable with the pregnant woman. Furthermore, we aimed to investigate the expression of metformin transporters in humans and chinchillas, respectively, in order to evaluate the pregnant chinchilla as a novel animal model for the use of metformin in pregnancy., Methods: Three chinchillas in the last part of gestation were injected with [ 11 C]-metformin and scanned by PET/CT for 70 minutes to visualize the distribution. To investigate the difference in expression of placenta transporters between humans and chinchillas, PCR was performed on samples from five chinchilla placentae and seven human placentae., Results: Dynamic PET with [ 11 C]-metformin showed that the metformin distribution in chinchillas was similar to that in nonpregnant humans, with signal from kidneys, liver, bladder, and submandibular glands. Conversely, no radioactive signal was observed from the fetuses, and no metformin was accumulated in the chinchilla fetus when measuring the SUV. PCR of placental mRNA showed that the human placentae expressed OCT3, whereas the chinchilla placentae expressed OCT1., Conclusion: Since metformin did not pass the placenta barrier in the pregnant chinchilla, as it is known to do in humans, we do not suggest the chinchilla as a future animal model of metformin in pregnancies.

Purpose: Owing to its noninvasive nature, hyperpolarized MRI may improve delineation of myocardial metabolic derangement in heart disease. However, consistency may depend on the changeable nature of cardiac metabolism in relation to whole-body metabolic state. This study investigates the impact of feeding status on cardiac hyperpolarized MRI in a large animal model resembling human physiology., Methods: Thirteen 30-kg pigs were subjected to an overnight fast, and 5 pigs were fed a carbohydrate-rich meal on the morning of the experiments. Vital parameters and blood samples were registered. All pigs were then scanned by hyperpolarized [1- 13 C]pyruvate cardiac MRI, and results were compared between the 2 groups and correlated with circulating substrates and hormones., Results: The fed group had higher blood glucose concentration and mean arterial pressure than the fasted group. Plasma concentrations of free fatty acids (FFAs) were decreased in the fed group, whereas plasma insulin concentrations were similar between groups. Hyperpolarized MRI showed that fed animals had increased lactate/pyruvate, alanine/pyruvate, and bicarbonate/pyruvate ratios. Metabolic ratios correlated negatively with FFA levels., Conclusion: Hyperpolarized MR can identify the effects of different metabolic states on cardiac metabolism in a large animal model. Unlike previous rodent studies, all metabolic derivatives of pyruvate increased in the myocardium of fed pigs. Carbohydrate-rich feeding seems to be a feasible model for standardized, large animal hyperpolarized MRI studies of myocardial carbohydrate metabolism., (© 2018 International Society for Magnetic Resonance in Medicine.)

Introduction of hyperpolarized magnetic resonance in preclinical studies and lately translation to patients provides new detailed in vivo information of metabolic flux in organs. Hyperpolarized magnetic resonance based on 13 C enriched pyruvate is performed without ionizing radiation and allows quantification of the pyruvate conversion products: alanine, lactate and bicarbonate in real time. Thus, this methodology has a promising potential for in vivo monitoring of energetic alterations in hepatic diseases. Using 13 C pyruvate, we investigated the metabolism in the porcine liver before and after intravenous injection of glucose. The overall mean lactate to pyruvate ratio increased significantly after the injection of glucose whereas the bicarbonate to pyruvate ratio was unaffected, representative of the levels of pyruvate entering the tricarboxylic acid cycle. Similarly, alanine to pyruvate ratio did not change. The increased lactate to pyruvate ratio over time showed an exponential correlation with insulin, glucagon and free fatty acids. Together, these data, obtained by hyperpolarized 13 C magnetic resonance spectroscopy and by blood sampling, indicate a hepatic metabolic shift in glucose utilization following a glucose challenge. Our findings demonstrate the capacity of hyperpolarized 13 C magnetic resonance spectroscopy for quantifying hepatic substrate metabolism in accordance with well-known physiological processes. When combined with concentration of blood insulin, glucagon and free fatty acids in the blood, the results indicate the potential of hyperpolarized magnetic resonance spectroscopy as a future clinical method for quantification of hepatic substrate metabolism., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Objective: To assess the extent to which lubricant use during intercourse is associated with time to pregnancy (TTP)., Design: Prospective cohort study., Setting: Denmark and North America., Population: A total of 6467 women aged 18-49 years who were not using contraception or fertility treatment., Methods: We pooled data from two continuing prospective cohort studies of pregnancy planners in Denmark (2011-2017) and North America (2013-2017). Female participants completed bimonthly questionnaires for 12 months or until they reported pregnancy. After restricting the study to women without a history of infertility who had been trying to conceive for six or fewer cycles at enrollment, 6467 women were retained for analysis. Self-reported lubricant use was categorised as water-based/not pH balanced, water-based/pH balanced 'fertility friendly', silicone-based, oil-based, or a combination of these. We used proportional probability models to calculate fecundability ratios (FRs) and 95% confidence intervals (95% CIs) for the association between lubricant use and fecundability, after adjusting for cohort and sociodemographic and lifestyle factors., Main Outcome Measure: Fecundability., Results: At baseline, 17.5% of participants reported the use of lubricants, most commonly water-based/not pH balanced (11.4%). Compared with non-use of lubricants, FRs were 1.02 (95% CI 0.93-1.11) for water-based/not pH-balanced lubricant use, 1.01 (95% CI 0.86-1.18) for water-based/pH balanced 'fertility friendly' lubricant use, 1.23 (95% CI 0.94-1.61) for oil-based lubricant use, and 1.27 (95% CI 0.93-1.73) for silicone-based lubricant use. Associations between oil-based lubricant use and fecundability were inconsistent across subgroups of study cohort, age, parity, and intercourse frequency., Conclusions: Lubricant use was not associated with reduced fecundability in the preconception cohorts of pregnancy planners studied., Tweetable Abstract: Lubricant use during intercourse was not associated with time to pregnancy in a study of pregnancy planners., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Introduction: The provision of healthcare for patients with inflammatory arthritis occurs in the context of somewhat conflicting targets, values and drivers. Therefore, there is a need for introducing 'value-based healthcare' defined as the value of patient relevant health outcomes in relation to costs. This term is a central part of tomorrow's healthcare sector, especially for rheumatic diseases, yet the transition is a huge challenge, as it will impact the development, delivery and assessment of healthcare., Aims: The aim of this study is to compare medical and patient evaluated impact of the traditional settlement and financing production (DAGS) controlled healthcare setting with a value-based and patient-centred adjunctive to standard care., Methods and Analysis: Patients with inflammatory arthritis receiving treatment in routine care at the outpatient clinics in the Capital Region of Denmark will prospectively and consecutively be enrolled in a Non-Intervention-Study framework providing a pragmatic value-based management model. A Danish reference cohort, used for comparison will be collected as part of routine clinical care. The enrolment period will be from 1 June 2018 until 31December 2023. Baseline and follow-up visits will be according to routine clinical care. Registry data will be obtained directly from patients and include personal, clinical and outcomes information. The study results will be reported in accordance with the STROBE statement., Ethics and Dissemination: The study has been notified to the Danish Data Protection Agency and granted authorisation for the period June 2018 to January 2025 (pending). Informed consent will be obtained from all patients before enrolment in the study. The study is approved by the ethics committee, Capital Region of Denmark (H-18013158). Results of the study will be disseminated through publication in international peer-reviewed journals., Competing Interests: Competing interests: TSJ has received fees for speaking by Abbvie, Roche, UCB, Novartis, Biogen, Eli Lilly and Pfizer. HG has received fees for speaking by MSD and Pfizer, LEK has received fees for speaking and consultancy by Pfizer, AbbVie, Amgen, UCB, Celgene, BMS, MSD, Novartis, Eli Lilly and Janssen Pharmaceuticals., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Despite an intensive screening activity, the incidence of cervical cancer in Denmark has remained stable for the last 15 years, while regional differences have increased. To search for explanations, we investigated possible weaknesses in the screening program., Material and Methods: Data on the screen-targeted women were retrieved from Statistics Denmark. Data on screening activity were retrieved from the annual reports from 2009 to 2015 on quality of cervical screening. Coverage was calculated as proportion of screen-targeted women with at least one cytology sample within recommended time intervals. Insufficient follow-up was calculated as proportion of abnormal and unsatisfactory samples not followed up within recommended time intervals. Diagnostic distribution was calculated for samples with a satisfactory cytology diagnosis., Results: Coverage remained stable at 75%-76% during the study period. Annually, approximately 100,000 women are screened before they are eligible for invitation, and 600,000 invitations and reminders are issued resulting in screening of 200,000 women. In 2009, 21% of abnormal and unsatisfactory samples were not followed up within the recommended time interval; a proportion that had decreased to 15% in 2015. Overall, 11% of satisfactory samples with a cytology diagnosis were abnormal, but with surprising variation from 6% to 15% across regions., Discussion: The success of a screening program depends first of all on coverage and timely follow-up of abnormal findings. Our analysis indicated that the currently high incidence of cervical cancer in Denmark may partly be due to low screening coverage. Also worrisome is a high proportion of non-timely follow-up of abnormal findings. Innovative ways to improve coverage and follow-up are urgently needed.

Objective: To determine cost functions that describe the dynamics of costs of HIV treatment and care in Ghana by CD4 cell count at treatment initiation and over time on antiretroviral therapy (ART)., Design: We used detailed longitudinal healthcare utilization data from clinical health records of HIV-infected patients at seven Ghanaian ART clinics to estimate cost functions of treatment and care by CD4 cell count at treatment initiation and time on ART., Methods: We developed two linear regression models; one with individual random effects to determine the relationship between CD4 cell count at ART initiation and costs of treatment and care, and one with individual fixed effects to determine the causal effect of time in care on costs of treatment and care., Results: Costs for treatment and care were lowest (-7.9 US$) for patients with CD4 cell counts of at least 350 cells/μl at ART initiation, compared with patients with 50 cells/μl or less at ART initiation, yet the difference was not significant. The per-patient costs peaked during the first 6 months on ART at 112.6 US$, and significantly decreased by 70% after 4 years on treatment., Conclusion: Our findings show that an accurate analysis of resource needs of HIV treatment and care should take into account that healthcare costs for HIV-infected people are dynamic rather than constant. The cost functions derived from our study are valuable input for cost-effectiveness analyses and research allocation exercises for HIV treatment in sub-Saharan Africa.

Cardiac metabolism has received considerable attention in terms of both diagnostics and prognostics, as well as a novel target for treatment. As human trials involving hyperpolarized magnetic resonance in the heart are imminent, we sought to evaluate the general feasibility of detection of an imposed shift in metabolic substrate utilization during metabolic modulation with glucose-insulin-potassium (GIK) infusion, and thus the limitations associated with this strategy, in a large animal model resembling human physiology. Four [1- 13 C]pyruvate injections did not alter the blood pressure or ejection fraction over 180 min. Hyperpolarized [1- 13 C]pyruvate conversion showed a generally high reproducibility, with intraclass correlation coefficients between the baseline measurements at 0 and 30 min as follows: lactate to pyruvate, 0.85; alanine to pyruvate, 1.00; bicarbonate to pyruvate, 0.83. This study demonstrates that hyperpolarized [1- 13 C]pyruvate imaging is a feasible technique for cardiac studies and shows a generally high reproducibility in fasted large animals. GIK infusion increases the metabolic conversion of pyruvate to its metabolic derivatives lactate, alanine and bicarbonate, but with increased variability., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: During cesarean delivery in patients with placenta previa, hemorrhaging after removal of the placenta is often challenging. In this condition, the extraordinarily high concentration of tissue factor at the placenta site may constitute a principle of treatment as it activates coagulation very effectively. The presumption, however, is that tissue factor is bound to activated factor VII., Objective: We hypothesized that topical application of recombinant activated factor VII at the placenta site reduces bleeding without affecting intravascular coagulation., Study Design: We included 5 cases with planned cesarean delivery for placenta previa. After removal of the placenta, the surgeon applied a swab soaked in recombinant activated factor VII containing saline (1 mg in 246 mL) to the placenta site for 2 minutes; this treatment was repeated once if the bleeding did not decrease sufficiently. We documented the treatment on video recordings and measured blood loss. Furthermore, we determined hemoglobin concentration, platelet count, international normalized ratio, activated partial thrombin time, fibrinogen (functional), factor VII:clot, and thrombin generation in peripheral blood prior to and 15 minutes after removal of the placenta. We also tested these blood coagulation variables in 5 women with cesarean delivery planned for other reasons. Mann-Whitney test was used for unpaired data., Results: In all 5 cases, the uterotomy was closed under practically dry conditions and the median blood loss was 490 (range 300-800) mL. There were no adverse effects of recombinant activated factor VII and we did not measure factor VII to enter the circulation. Neither did we observe changes in thrombin generation, fibrinogen, activated partial thrombin time, international normalized ratio, and platelet count in the peripheral circulation (all P values >.20)., Conclusion: This study indicates that in patients with placenta previa, topical recombinant activated factor VII may diminish bleeding from the placenta site without initiation of systemic coagulation., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Several parameters are important when choosing the most appropriate animal to model human obstetrics, including gestation period, number of fetuses per gestation and placental structure. The domesticated long-tailed chinchilla ( Chinchilla lanigera ) is a well-suited and appropriate animal model of pregnancy that often will carry only one offspring and has a long gestation period of 105-115 days. Furthermore, the chinchilla placenta is of the haemomonochorial labyrinthine type and is therefore comparable to the human villous haemomonochorial placenta. This proof-of-concept study demonstrated the feasibility in laboratory settings, and demonstrated the potential of the pregnant chinchilla as an animal model for obstetric research and its potential usefulness for non-invasive measurements in the placenta. We demonstrate measurements of the placental and fetal metabolism (demonstrated in vivo by hyperpolarized MRI and in vitro by qPCR analyses), placental vessels (demonstrated ex vivo by contrast-enhanced CT angiography) and overall anatomy (demonstrated in vivo by whole-body CT)., Competing Interests: We declare we have no competing interests.

Study Design: Hospital-based cohort study at Spinal Cord Injury Centre of Western Denmark (VCR)., Objective: To examine the overall survival and mortality over time adjusted for age at the time of injury and gender., Methods: Review of medical records of traumatic spinal cord injury (TSCI) patients admitted at VCR between 1990 and 2012. The patients were followed up until death, emigration or end of study (December 2014). Survival and mortality rate ratios (MRRs) with 95% confidence intervals (CI) were estimated for sub-groups defined by year of injury (1990-1994, 1995-1999, 2000-2004, 2005-2009 and 2010-2012). Mortality was analysed using Cox proportional hazard regression. Adjustment for gender and age at injury was performed (restricted cubic splines)., Results: In total, 665 patients (males 82%) were followed; 136 (20%) patients died during the observation period. Two-year survival varied from 93% in 2005-2009 to 98% in 2000-2004. Using 1990-1994 as a reference, the adjusted MRRs varied between 1.22 (CI: 0.43; 3.42) and 0.48 (CI: 0.13; 2.71). The 5- and 10-year survival varied between 85% (2005-2009) and 95% (1990-1994), and between 77% (2005-2009) and 91% (1990-1994), respectively. No trend over time was observed either for 2-, 5- or 10-year survival. Men's mortality did not differ consistently from that of women. Except for the most recent time period, the overall survival after TSCI was higher among those aged <60 years at time of injury., Conclusion: Survival after TSCI in Denmark did not change considerably from 1990 to 2014, and there seemed to be no gender difference. Mortality was highest among patients above 60 years of age at injury.

Intrarenal hypoxia is an acknowledged factor contributing to the development of diabetic nephropathy. Hyperbaric oxygen (HBO) therapy is a well-known adjuvant treatment for several medical conditions, such as decompression sickness, infections, and wound healing. The underlying metabolic response of HBO is largely unknown. In this study, we investigated the effect of HBO on the intrarenal metabolic alteration in diabetes. Hyperpolarized [1- 13 C]pyruvate MRI was performed to assess intrarenal energy metabolism in normoglycemic controls and short-term (2 weeks) streptozotocin-induced diabetic rats with and without HBO for five consecutive days. HBO therapy blunted intrarenal lactate production, 3 days after the therapy, in both normoglycemic controls and diabetic rats without affecting either lactate dehydrogenase mRNA expression or activity. HBO therapy reduced lactate formation in both normoglycemic and hyperglycemic rats. These findings support hyperpolarized [1- 13 C]pyruvate MRI as a novel method for monitoring HBO therapy via the pyruvate to lactate conversion., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Renal ischemia-reperfusion injury is the state of which a tissue experiences injury after a phase of restrictive blood supply and recirculation. Ischemia-reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) in several disease states, including kidney transplantation, sepsis, and hypovolemic shock. The most common methods to evaluate AKI are creatinine clearance, plasma creatinine, blood urea nitrogen, or renal histology. However, currently, there are no precise methods to directly assess renal injury state noninvasively. Hyperpolarized 13 C-pyruvate MRI enables noninvasive accurate quantification of the in vivo conversion of pyruvate to lactate, alanine, and bicarbonate. In the present study, we investigated the in situ alterations of metabolic conversion of pyruvate to lactate, alanine, and bicarbonate in a unilateral I/R-I rat model with 30 min and 60 min of ischemia followed by 24 h of reperfusion. The pyruvate conversion was unaltered compared with sham in the 30 min I/R-I group, while a significant reduced metabolic conversion was found in the postischemic kidney after 60 min of ischemia. This indicates that after 30 min of ischemia, the kidney maintains normal metabolic function in spite of decreased kidney function, whereas the postischemic kidney after 60 min of ischemia show a generally reduced metabolic enzyme activity concomitant with a reduced kidney function. We have confidence that these findings can have a high prognostic value in prediction of kidney injury and the outcome of renal injury., (Copyright © 2017 the American Physiological Society.)

Jan Hontelez and colleagues argue that the cost-effectiveness studies of HIV treatment scale-up need to include health system constraints to be more informative.

Depressive symptoms are common in multiple psychiatric disorders and are frequent sequelae of trauma. A dimensional conceptualization of depression suggests that symptoms should be associated with a continuum of deficits in specific neural circuits. However, most prior investigations of abnormalities in functional connectivity have typically focused on a single diagnostic category using hypothesis-driven seed-based analyses. Here, using a sample of 105 adult female participants from three diagnostic groups (healthy controls, n=17; major depression, n=38; and post-traumatic stress disorder, n=50), we examine the dimensional relationship between resting-state functional dysconnectivity and severity of depressive symptoms across diagnostic categories using a data-driven analysis (multivariate distance-based matrix regression). This connectome-wide analysis identified foci of dysconnectivity associated with depression severity in the bilateral amygdala. Follow-up seed analyses using subject-specific amygdala segmentations revealed that depression severity was associated with amygdalo-frontal hypo-connectivity in a network of regions including bilateral dorsolateral prefrontal cortex, anterior cingulate and anterior insula. In contrast, anxiety was associated with elevated connectivity between the amygdala and the ventromedial prefrontal cortex. Taken together, these results emphasize the centrality of the amygdala in the pathophysiology of depressive symptoms, and suggest that dissociable patterns of amygdalo-frontal dysconnectivity are a critical neurobiological feature across clinical diagnostic categories.

Unlabelled: Perceived stress is associated with several adverse health outcomes; however, little is known about the impact of stress on fracture risk. In this population-based cohort study, persons with high perceived stress have an increased 5-year risk of any osteoporotic fracture, in particular hip fracture., Introduction: We conducted a population-based cohort study in Denmark to examine the association between perceived stress and risk of subsequent osteoporotic fracture., Methods: A 2006 population-based health survey in the Central Danish Region (with 1.25 million inhabitants) was used to identify 7943 persons who were 55 years or older on the survey date and completed the Perceived Stress Scale. Individuals were categorized into two groups: high level of stress and low level of stress (including no stress). We obtained information on all osteoporotic fractures through linkage to the Danish National Registry of Patients. We used Cox regression to compute hazard ratios (HRs) with 95 % confidence interval (CI) adjusted for a number of lifestyle factors, socioeconomic data, perceived general health, and prescription history, comparing high- and low-stress persons., Results: A total of 1799 persons (22.6 %) reported high level of perceived stress, whereas 6144 (77.4 %) reported low level or no stress. The 5-year risk of any osteoporotic fracture was 7.4 and 5.4 % in persons with high and low perceived stress, respectively, corresponding to adjusted HR of 1.37 (CI 1.00-1.89). The adjusted HR for hip fracture within 5 years associated with high perceived stress was 1.68 (CI 1.04-2.72). The associations weakened with increasing follow-up time., Conclusions: Persons with high perceived stress have an increased risk of any osteoporotic fracture, in particular risk of hip fracture within 5 years of stress assessment even after adjusting for differences in lifestyle, comorbidities, osteoporosis presence, medication use, and socioeconomic status at the time of stress level evaluation. The association attenuated after longer follow-up time.

Early diabetic nephropathy is largely undetectable before substantial functional changes have occurred. In the present study, we investigated the distribution of electrolytes and urea in the early diabetic kidney in order to explore whether pathophysiological and metabolic changes appear concomitantly with a decreased sodium and urea gradient. By using hyperpolarized (13)C urea it was possible to measure the essential intrarenal electrolyte gradients and the acute changes following furosemide treatment. No differences in either intrarenal urea or sodium gradients were observed in early diabetes compared to healthy controls. These results indicate that the early metabolic and hypertrophic changes occurring in the diabetic kidney prelude the later functional alterations in diabetic kidney function, thus driving the increased metabolic demand commonly occurring in the diabetic kidney., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Background/objectives: Periconceptional folic acid (FA) supplementation reduces the risk of neural tube defects and has been associated with ovulatory function. However, only two studies have associated supplementation with multivitamins (MVs) that contained FA with increased pregnancy rates. We aimed to examine the association between FA supplementation (obtained either through single FA tablets or through MVs) and fecundability., Subjects/methods: A prospective cohort study of 3895 Danish women who were planning a pregnancy between 2007 and 2011. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) in relation to FA supplementation (either through single FA tablets or MV) using a proportional probabilities regression model, with adjustment for potential socio-demographic, reproductive and lifestyle confounders. In stratified analyses, we also estimated FR with 95% CI in relation to FA supplementation for women with regular and irregular cycles, respectively, and for women with short (<27 days), medium (27-29 days) and long cycles (⩾30 days), respectively., Results: FA supplementation was associated with increased fecundability (FR=1.15, 95% CI=1.06-1.25), compared with non-use. The adjusted FRs for FA supplement use relative to non-use were 1.35 (95% CI=1.12-1.65) and 1.11 (95% CI=1.01-1.22) for women with irregular and regular cycles, respectively, and 1.36 (95% CI=0.95-1.95), 1.10 (95% CI=0.98-1.22) and 1.24 (95% CI=1.10-1.41) for women with short (<27 days), medium (27-29 days) and long cycles (⩾30 days), respectively., Conclusions: FA supplementation was associated with increased fecundability, and this association appeared to be stronger among women with irregular cycles and among women with either short or long cycle length.

Study Design: Hospital-based incidence study., Objectives: To assess the incidence of traumatic spinal cord injuries (TSCIs) and TSCI incidence trends in relation to cause, age, gender, level and completeness of injury., Setting: Spinal Cord Injury Centre of Western Denmark., Methods: We reviewed medical records of TSCI patients admitted between 1 January 1990 and 31 December 2012. Proportions, incidence rates and incidence rate ratios were calculated for five time periods; 1990-94, 1995-99, 2000-04, 2005-09 and 2010-12, and were stratified on age, gender, cause, level and completeness of TSCI. TSCI incidence was calculated as the number of new cases divided by person-years at risk., Results: Included were 691 patients (males 81.9%). Within the study period, median age at time of injury rose from 29.0 to 47.5 years. The overall annual TSCI incidence during the study period 1990-94 to 2010-12 was 10.2 per million person-years at risk and varied from 8.3 to 11.8. The proportion of transport-related injuries fell from 56.9% in the first to 36.8% in the most recent time period. Fall-related injuries rose from 11.1 to 35.5%. The proportion of incomplete tetraplegia increased from 32.0% in the first to 40.5% in the last time period., Conclusions: The overall TSCI incidence is low and remained stable from 1990 to 2012. The proportion of transport-related injuries fell, while age at time of injury and proportion of fall-related injuries and proportion with incomplete tetraplegia all increased.

Study Question: Is caffeine and caffeinated beverage consumption associated with the risk of spontaneous abortion (SAB)?, Summary Answer: While preconceptional caffeine consumption was not materially associated with an increased risk of SAB, consumption during early pregnancy was associated with a small increased risk of SAB, although the relation was not linear., What Is Known Already: Caffeine has been hypothesized as a risk factor for SAB since the 1980s; however, results from previous studies have been conflicting., Study Design, Size, Duration: This prospective cohort study included 5132 Danish women planning pregnancy and enrolled from 2007 to 2010., Participants/materials, Setting, Methods: Participants were women who conceived after entry into the Snart-Gravid cohort and who were aged 18-40, in a stable relationship with a male partner, and did not use fertility treatments to conceive. Women reported their daily caffeine and caffeinated beverage consumption on questionnaires before conception and during early pregnancy. All exposure measurements were prospective with respect to outcome ascertainment. We estimated hazard ratios (HRs) of SAB for categories of caffeine consumption in milligrams (mg) per day and the corresponding 95% confidence intervals (CIs) using Cox proportional hazards regression models with gestational weeks as the time scale., Main Results and the Role of Chance: There were 732 women (14.3%) who were identified as having a SAB. In the preconceptional period, caffeine consumption was not materially associated with SAB risk (HR comparing ≥300 with <100 mg/day: 1.09; 95% CI: 0.89, 1.33). In early pregnancy, the HRs for 100-199, 200-299 and ≥300 mg/day of caffeine consumption were 1.62 (95% CI: 1.19, 2.22), 1.48 (95% CI: 1.03, 2.13) and 1.23 (95% CI: 0.61, 2.46), respectively, compared with that for <100 mg/day., Limitations, Reasons for Caution: The observed results may be affected by non-differential exposure misclassification, reverse causation and residual confounding., Wider Implications of the Findings: This is the largest study to date of prospectively measured, preconception caffeine consumption and risk of SAB. We were able to reduce the likelihood of differential left truncation bias and recall bias present in other analyses., Study Funding/competing Interests: Snart-Gravid was funded by the NICHD (R21-050264). Dr. Hahn's work was funded in part by the BU Reproductive, Perinatal, and Pediatric Epidemiology Training Grant NIH #T32HD052458. There are no competing interests., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: What is the magnitude of the association between a woman's gestational age at her own birth and her fecundability (cycle-specific probability of conception)?, Summary Answer: We found a 62% decrease in fecundability among women born <34 weeks of gestation relative to women born at 37-41 weeks of gestation, whereas there were few differences in fecundability among women born at later gestational ages., What Is Known Already: One study, using retrospectively collected data on time-to-pregnancy (TTP), and self-reported data on gestational age, found a prolonged TTP among women born <37 gestational weeks (preterm) and with a birthweight ≤1500 g. Other studies of women's gestational age at birth and subsequent fertility, based on data from national birth registries, have reported a reduced probability of giving birth among women born <32 weeks of gestation., Study Design, Size, Duration: We used data from a prospective cohort study of Danish pregnancy planners ('Snart-Gravid'), enrolled during 2007-2011 and followed until 2012. In all, 2814 women were enrolled in our study, of which 2569 had complete follow-up., Participants/materials, Setting, Methods: Women eligible to participate were 18-40 years old at study entry, in a relationship with a male partner, and attempting to conceive. Participants completed a baseline questionnaire and up to six follow-up questionnaires until the report of pregnancy, discontinuation of pregnancy attempts, beginning of fertility treatment, loss to follow-up or end of study observation after 12 months., Main Results and the Role of Chance: Among women born <34 gestational weeks, the cumulative probability of conception was 12, 28 and 48% within 3, 6 and 12 cycles, respectively. Among women born at 37-41 weeks of gestation, cumulative probability of conception was 47, 67 and 84% within 3, 6 and 12 cycles, respectively. Relative to women born at 37-41 weeks' gestation, women born <34 weeks had decreased fecundability (fecundability ratio (FR) 0.38, 95% confidence interval (CI): 0.17-0.82). Our data did not suggest reduced fecundability among women born at 34-36 weeks of gestation or at ≥42 weeks of gestation (FR 1.03, 95% CI: 0.80-1.34, and FR 1.13, 95% CI: 0.96-1.33, respectively)., Limitations, Reasons for Caution: Data on gestational age, obtained from the Danish Medical Birth Registry, were more likely to be based on date of last menstrual period than early ultrasound examination, possibly leading to an overestimation of gestational age at birth. Such overestimation, however, would not explain the decrease in fecundability observed among women born <34 gestational weeks. Another limitation is that the proportion of women born before 34 weeks of gestation was low in our study population, which reduced the precision of the estimates., Wider Implications of the Findings: By using prospective data on TTP, our study elaborates on previous reports of impaired fertility among women born preterm, suggesting that women born <34 weeks of gestation have reduced fecundability., Study Funding/competing Interests: The study was supported by the National Institute of Child Health and Human Development (R21-050264), the Danish Medical Research Council (271-07-0338), and the Health Research Fund of Central Denmark Region (1-01-72-84-10). The authors have no competing interests to declare., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: Is the prevalence of psychological stress and moderate/severe depression higher for women with recurrent pregnancy loss (RPL) than pregnancy planners trying to conceive naturally?, Summary Answer: Both psychological stress and major depression are significantly more common among women with RPL than in those trying to conceive naturally., What Is Known Already: RPL has a significant emotional impact on couples, especially the woman. Previous studies have shown inconclusive results., Study Design, Size, Duration: In this cross-sectional study, we compared the prevalence of stress and depression among 301 women with RPL and 1813 women attempting to conceive naturally. We defined RPL as three or more pregnancy losses before 12 weeks' gestation. RPL patients were enrolled from 2010 to 2013 and the comparison group from 2011 to 2014., Participants/materials, Setting, Methods: RPL patients completed an online questionnaire before their first consultation at the Danish RPL Unit. In addition, we included data from a comparison group of 1813 women who participated in the Soon Parents Study (www.SnartForældre.dk). The Major Depression Index (MDI) was used to assess symptoms of depression, and Cohen's Perceived Stress Scale (PSS) was used to measure stress. Relevant demographic data were also retrieved., Main Results and the Role of Chance: Of the RPL patients, 26 (8.6%) had a score on the MDI corresponding to moderate/severe depression, as did 40 (2.2%) of the women in Soon Parents Study (adjusted odds ratio (OR) 5.53 (95% confidence interval (CI): 2.09; 14.61)). A high stress level, defined as ≥19 on the PSS scale, was reported by 124 (41.2%) of the patients and 420 (23.2%) in the comparison group (adjusted OR 1.59 (95% CI 1.03; 2.44))., Limitations, Reasons for Caution: We used online questionnaires, and have no interview data. We were unaware if any of the women in the comparison group suffer from RPL., Wider Implications of the Findings: This study should entail a heightened awareness of mental distress among care providers for women with RPL., Study Funding/competing Interests: No specific funding was sought for this study. The Soon Parents Study is funded by National Institute of Child Health and Human Development (R01 HD060680-01A4). No authors have competing interests to declare., Trial Registration Number: N/A., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: About half a million people in South Africa are deprived of antiretroviral therapy (ART), and there is little systematic knowledge on who they are - e.g. by severity of disease, sex, or socio-economic status (SES). We performed a systematic review to determine the current quantitative evidence-base on equity in utilization of ART among HIV-infected people in South Africa., Method: We conducted a literature search based on the Cochrane guidelines. A study was included if it compared for different groups of HIV infected people (by sex, age, severity of disease, area of living, SES, marital status, ethnicity, religion and/or sexual orientation (i.e. equity criteria)) the number initiating/adhering to ART with the number who did not. We considered ART utilization inequitable for a certain criterion (e.g. sex) if between groups (e.g. men versus women) significant differences were reported in ART initiation/adherence., Results: Twelve studies met the inclusion criteria. For sex, 2 out of 10 studies that investigated this criterion found that men are less likely than women to utilize ART, while the other 8 found no differences. For age, 4 out of 8 studies found inequities and reported less utilization for younger people. For area of living, 3 out of 4 studies showed that those living in rural areas or certain provinces have less access and 2 out of 6 studies looking at SES found that people with lower SES have less access. One study which looked at the marital status found that those who are married are less likely to utilize ART. For severity of disease, 5 out of 6 studies used more than one outcome measure for disease stage and reported within their study contradicting results. One of the studies reported inconclusive findings for ethnicity and no study had looked at religion and sexual orientation., Conclusion: It seems that men, young people, those living in certain provinces or rural areas, people who are unemployed or with a low educational level, and those being unmarried have less access to ART. As studies stem from different contexts and use different methods conclusions should be taken with caution.

Proton pump inhibitors (PPIs) are increasingly used in reflux disease treatment also among pregnant women. Hypospadias prevalence is increasing and the birth defect is diagnosed in 0.3%-0.8% of male births, but the association with maternal PPI use during pregnancy is virtually unknown. Therefore, we decided to estimate the hypospadias risk in male offspring after maternal PPI use during pregnancy. We used Danish nationwide registries to conduct a population-based prevalence study including all live-born boys from 1997 through 2009. Maternal PPI use was classified according to exposure time: early pregnancy (30 days before conception through the end of the first trimester) and entire pregnancy (30 days before and throughout pregnancy). Outcome was defined as a hospital hypospadias diagnosis recorded any time after delivery. We calculated prevalence ratios and 95% confidence intervals associating maternal PPI use with hypospadias in male offspring using Cox proportional hazard regression analysis and adjusted for confounding factors. We identified a total of 430,569 live-born boys of whom 2926 were exposed to maternal PPI use during early pregnancy. Among the exposed boys, 20 (0.7%) were diagnosed with hypospadias, whereas 2683 (0.6%) of the nonexposed had hypospadias (adjusted prevalence ratio = 1.1; 95% confidence interval, 0.7-1.7). A total of 5227 boys were exposed during the entire pregnancy, and 32 (0.6%) had hypospadias corresponding to a prevalence ratio of 1.0 (95% confidence interval, 0.7-1.4). The subanalysis restricted to omeprazole exposure showed similar results. We thus conclude that maternal PPI use during pregnancy was not associated with hypospadias in boy offspring.

Objective: The initiation of treatment for women with threatening preterm labor requires effective distinction between true and false labor. The electrohysterogram (EHG) has shown great promise in estimating and classifying uterine activity. However, key issues remain unresolved and no clinically usable method has yet been presented using EHG. Recent studies have focused on the propagation velocity of the EHG signals as a potential discriminator between true and false labor. These studies have estimated the propagation velocity of individual spikes of the EHG signals. We therefore focus on estimating the propagation velocity of the entire EHG burst recorded during a contraction in two dimensions., Study Design: EHG measurements were performed on six women in active labor at term, and a total of 35 contractions were used for the estimation of propagation velocity. The measurements were performed using a 16-channel two-dimensional electrode grid. The estimates were calculated with a maximum-likelihood approach., Results: The estimated average propagation velocity was 2.18 (±0.68) cm/s. No single preferred direction of propagation was found., Conclusion: The propagation velocities estimated in this study are similar to those reported in other studies but with a smaller intra- and inter-patient variation. Thus a potential tool has been established for further studies on true and false labor contractions.

Background: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage., Methods: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP., Findings: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per μL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per μL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective., Interpretation: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets., Funding: Bill & Melinda Gates Foundation, WHO., (Copyright © 2014 Eaton et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by .. All rights reserved.)

Background: New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly., Methods: We used multiple independent mathematical models in four settings-South Africa, Zambia, India, and Vietnam-to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered 'very cost-effective' if the $/DALY was less than the country's per capita gross domestic product (GDP; South Africa: $8040, Zambia: $1425, India: $1489, Vietnam: $1407) and 'cost-effective' if $/DALY was less than three times per capita GDP., Findings: In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from $237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to $749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to $241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective., Interpretation: Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets., Funding: The Bill and Melinda Gates Foundation and World Health Organization.

South Africa, the country with the largest HIV epidemic worldwide, has been scaling up treatment since 2003 and is rapidly expanding its eligibility criteria. The HIV treatment programme has achieved significant results, and had 1.8 million people on treatment per 2011. Despite these achievements, it is now facing major concerns regarding (i) efficiency: alternative treatment policies may save more lives for the same budget; (ii) equity: there are large inequalities in who receives treatment; (iii) feasibility: still only 52% of the eligible population receives treatment.Hence, decisions on the design of the present HIV treatment programme in South Africa can be considered suboptimal. We argue there are two fundamental reasons to this. First, while there is a rapidly growing evidence-base to guide priority setting decisions on HIV treatment, its included studies typically consider only one criterion at a time and thus fail to capture the broad range of values that stakeholders have. Second, priority setting on HIV treatment is a highly political process but it seems no adequate participatory processes are in place to incorporate stakeholders' views and evidences of all sorts.We propose an alternative approach that provides a better evidence base and outlines a fair policy process to improve priority setting in HIV treatment. The approach integrates two increasingly important frameworks on health care priority setting: accountability for reasonableness (A4R) to foster procedural fairness, and multi-criteria decision analysis (MCDA) to construct an evidence-base on the feasibility, efficiency, and equity of programme options including trade-offs. The approach provides programmatic guidance on the choice of treatment strategies at various decisions levels based on a sound conceptual framework, and holds large potential to improve HIV priority setting in South Africa.

Objective: Electrohysterographic assessment of the propagation velocity of uterine depolarization has been introduced as a promising predictor of preterm labor. Therefore, the objectives of this study were to characterize the uterine electrohysterographic signals during labor and to determine the propagation velocity and propagation direction of electrohysterographic signals., Design: Descriptive study., Setting: Department of Obstetrics and Gynecology, Aarhus University Hospital, Denmark., Population: Eight women in active labor at term., Methods: Electrohysterograms (three channels) were recorded using surface electrodes placed abdominally along the vertical median axis with an inter-electrode distance of 6.5-11.2 cm. In total, 89 contractions were analyzed., Results: Electrohysterographic characteristics: The duration of the contractions was 61.0 ± 18.0 s (mean ± SD). The median frequency of the power spectrum density was 0.51 (0.44; 0.51) Hz (median; 10th; 90th percentile). The greatest signal magnitude was obtained by the electrode in the centermost position. The propagation velocity: 2.15 (0.66; 13.8) cm/s in the upper part and 1.53 (0.58; 6.7) cm/s in the lower part of the uterus. Propagation direction: Both downward (58%) and upward (42%) propagation of the electrohysterographic signals occurred. Moreover, downward and upward propagations were recorded simultaneously in the upper and lower part of the uterus, suggesting a multidirectional propagation pattern., Conclusions: Labor contractions, expressed by electrohysterographic signals, propagate both in the downward and upward direction, a phenomenon that must be taken into account when determining the propagation velocity for preterm labor diagnostics., (© 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

Mammography screening is offered healthy women, and a high standard on professional and organizational level is mandatory not only in the screening programme but even in the diagnostic work-up and treatment. The main goal is to achieve a substantial reduction in disease specific mortality, but it is not possible to evaluate the effect on mortality until several years later, and continuously monitoring of the quality of all aspects of a screening programme is necessary. Based on other European guidelines, 11 quality indicators have been defined, and guidelines concerning organizational requirements for a Danish screening programme as well as recommendations for the radiographic and radiological work have been drawn up.

Objective: To review the progress made over the past decade with regard to the treatment of enuresis and encopresis, as well as advances in the understanding of etiological mechanisms., Method: Separate computerized literature (English language only) searches of Medline and PsycINFO databases were conducted under the parameter of enuresis and children-adolescents, as well as encopresis and children-adolescents., Results: There has been a substantial decrease in published research concerning the use of imipramine to treat enuresis compared with the prior two decades, accompanied by a corresponding increase in the number of papers concerning desmopressin acetate (DDAVP), which has become the primary pharmacological treatment. Genetic studies of large pedigrees have further confirmed the importance of heritable factors. With regard to encopresis, the research has focused primarily on pathophysiological factors related to the colon and anal sphincter., Conclusions: The widespread use of DDAVP has been the primary addition to treatment strategies over the past decade. The bell-and-pad method of conditioning, the only major treatment that has enduring benefit after being withdrawn, is the most cost-effective and appears to be underutilized. Research into etiological mechanisms has focused primarily on the mechanism of action of DDAVP and advances in the understanding of genetic factors. Advances in the treatment and etiological understanding of encopresis have been less impressive.

Large coronary arteries undergo marked circumferential and axial deformations due to changes in blood pressure and gross movements of the ventricular wall during systole and diastole. The present study was designed to investigate 1) whether axial stretch of large coronary arteries influences the sensitivity to vasoconstrictors, 2) the mechanisms mediating stretch-dependent changes in vascular sensitivity. Endothelium-denuded cylindrical segments from large porcine coronary arteries were studied under isometric conditions using a balloon-based impedance planimetric technique. In segments subjected to a pressure of 60 mmHg, 20% axial stretch caused a left-ward shift of the concentration-response curves for K+ and 5-hydroxytryptamine (5-HT). Enhancement of vascular sensitivity to 5-HT induced by axial stretch was observed also in maximally K+-depolarized coronary arteries. Protein kinase C inhibition by calphostin C (1 microM) slightly decreased the spontaneous resting tone at 60 mmHg and inhibited the leftward shift of the concentration-response curve for 5-HT elicited by axial stretch. These results suggest that axial stretch of the vessel wall enhances the sensitivity of coronary arteries to vasoconstrictors by a protein kinase C-dependent mechanism.

After i.v. and oral administration of nimodipine the concentration-time profiles of the drug and its enantiomers were studied in seven patients with subarachnoid hemorrhage. Concentrations of nimodipine, (+)-(R)-, and (-)-(S)-nimodipine were analyzed using a new stereoselective high-performance liquid chromatographic method. During the first 3 h after oral administration the concentrations of (+)-(R)- and (-)-(S)-nimodipine were significantly different, the (-)-(S)-enantiomer being found in much lesser concentrations compared to the (+)-(R)-enantiomer. The results indicate that if uptake from the gastrointestinal system is equal for the two enantiomers, then (-)-(S)-nimodipine is metabolized at a much faster rate compared to (+)-(R)-nimodipine after oral administration of the drug in patients with subarachnoid bleeding. After i.v. administration; no significant differences between the concentrations of the (-)-(S) and the (+)-(R) isomers were demonstrated., (Copyright 2000 Wiley-Liss, Inc.)

The purpose of the study was to investigate the influence of preactivation, wall tension and geometry on the reactivity of porcine coronary arteries to nifedipine and extracellular Ca(2+) in vitro. Porcine large coronary arteries were mounted as ring and cylindrical preparations and studied by wire- and balloon-based techniques. The sensitivity and maximal responses to nifedipine were more pronounced in 25 mM K(+) compared to 10 microM prostaglandin F(2alpha)-contracted preparations. Vascular sensitivity to nifedipine and Ca(2+) was enhanced under isometric compared to isobaric conditions. Under isometric conditions in the presence of 25 mM K(+), coronary rings were more sensitive to nifedipine, but less sensitive to Ca(2+) compared to cylindrical segments. In cylindrical segments, circumferential and axial tension increases augmented the extracellular Ca(2+)-dependent spontaneous resting tone and the sensitivity to extracellular Ca(2+). Coronary rings showed no resting tone at various resting tensions. These results suggest that preactivation, wall tension and vessel geometry are important determinants of Ca(2+)-influxes via nifedipine-sensitive voltage-gated Ca(2+) channels. Furthermore, axial wall tension appears to be a modulator of nifedipine-insensitive transmembrane Ca(2+)-influx that may play a role for the tone and reactivity in large coronary arteries.