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OBJECTIVES: To examine if receiving a pedometer along with an intervention toolkit is associated with increased physical activity, aerobic fitness and better self-rated health among individuals with low levels of physical activity or fitness. METHODS: The intervention was nested in the Danish Health Examination Survey (DANHES) and carried out in 2008. Participants were randomly assigned to either a pedometer group (n=326) or a control group (n=329). Physical activity, aerobic fitness, and self-rated health were measured at baseline and at 3-month follow-up, and differences were tested by Wilcoxons signed rank tests and Chi-squared tests. RESULTS: At follow-up, no significant differences in physical activity, aerobic fitness and self-rated health were found between the groups. However, the oldest participants in the pedometer group reported significantly more walking time compared to the controls (controls=368min/week, pedometer group=680min/week, P=0.05). Among participants who completed the intervention, a significant effect on total walking time was observed (median difference=225min/week, P=0.04). CONCLUSIONS: The results suggest that receiving a pedometer and along with an intervention toolkit can increase walking time in older individuals, but not in younger individuals. Thus, this type of intervention offers great potential for promoting physical activity in older individuals. Trial registration number: NCT01071811.Copyright © 2012 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Aim: To describe the design of the Danish National Health Survey (DNHS) 2023, participants' demographic characteristics and differences in demographic and selected health-related characteristics between respondents invited by web-mode and paper-mode., Methods: A sample of 25,000 residents in Denmark aged 16 years or above was invited to participate in the DNHS 2023 using a mixed-mode approach (web/paper mode). Web-mode invited were additionally invited to participate in an accelerometer study. The self-administered questionnaire included 83 questions about health, health behaviour and morbidity. Descriptive statistics were used to describe characteristics associated with response and invitation mode., Results: The response proportion was 40.8%. Non-response was more frequent among men, individuals of the youngest age groups, individuals with non-Western backgrounds, unmarried and individuals from densely populated areas. The response proportion was higher among web-mode invited (42.0%) than paper-mode invited (22.6%). Paper-mode invited respondents were more often women, aged 80 years or older, and widowed compared with web-mode invited respondents., Conclusions: The DNHS 2023 is a national health survey including adult residents in Denmark. Non-response was more pronounced among some subgroups; however, calibrated weights were calculated to minimise non-response bias. The survey is essential for public health surveillance and can be used in health planning and policy development. Furthermore, the data from the survey can be used for research on the population's health and health behaviour. For future waves of the DNHS, it should be considered whether resources should be used to invite people unsubscribed from digital-post due to the low response proportion., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: There is insufficient evidence to provide recommendations for leisure-time physical activity among workers across various occupational physical activity levels. This study aimed to assess the association of leisure-time physical activity with cardiovascular and all-cause mortality across occupational physical activity levels., Methods: This study utilized individual participant data from 21 cohort studies, comprising both published and unpublished data. Eligibility criteria included individual-level data on leisure-time and occupational physical activity (categorized as sedentary, low, moderate, and high) along with data on all-cause and/or cardiovascular mortality. A 2-stage individual participant data meta-analysis was conducted, with separate analysis of each study using Cox proportional hazards models (Stage 1). These results were combined using random-effects models (Stage 2)., Results: Higher leisure-time physical activity levels were associated with lower all-cause and cardiovascular mortality risk across most occupational physical activity levels, for both males and females. Among males with sedentary work, high compared to sedentary leisure-time physical activity was associated with lower all-cause (hazard ratios (HR) = 0.77, 95% Confidence interval(95%CI): 0.70-0.85) and cardiovascular mortality (HR = 0.76, 95%CI: 0.66-0.87) risk. Among males with high levels of occupational physical activity, high compared to sedentary leisure-time physical activity was associated with lower all-cause (HR = 0.84, 95%CI: 0.74-0.97) and cardiovascular mortality (HR = 0.79, 95%CI: 0.60-1.04) risk, while HRs for low and moderate levels of leisure-time physical activity ranged between 0.87 and 0.97 and were not statistically significant. Among females, most effects were similar but more imprecise, especially in the higher occupational physical activity levels., Conclusion: Higher levels of leisure-time physical activity were generally associated with lower mortality risks. However, results for workers with moderate and high occupational physical activity levels, especially women, were more imprecise. Our findings suggests that workers may benefit from engaging in high levels of leisure-time physical activity, irrespective of their level of occupational physical activity., Competing Interests: Competing interests The authors declare that they have no competing interests., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Objective: Health effects of different physical activity domains (ie, during leisure time, work and transport) are generally considered positive. Using Active Worker consortium data, we assessed independent associations of occupational and leisure-time physical activity (OPA and LTPA) with all-cause mortality., Design: Two-stage individual participant data meta-analysis., Data Source: Published and unpublished cohort study data., Eligibility Criteria: Working participants aged 18-65 years., Methods: After data harmonisation, we assessed associations of OPA and LTPA with all-cause mortality. In stage 1, we analysed data from each study separately using Cox survival regression, and in stage 2, we pooled individual study findings with random-effects modelling., Results: In 22 studies with up to 590 497 participants from 11 countries, during a mean follow-up of 23.1 (SD: 6.8) years, 99 743 (16%) participants died. Adjusted for LTPA, body mass index, age, smoking and education level, summary (ie, stage 2) hazard ration (HRs) and 95% confidence interval (95% CI) for low, moderate and high OPA among men (n=2 96 134) were 1.01 (0.99 to 1.03), 1.05 (1.01 to 1.10) and 1.12 (1.03 to 1.23), respectively. For women (n=2 94 364), HRs (95% CI) were 0.98 (0.92 to 1.04), 0.96 (0.92 to 1.00) and 0.97 (0.86 to 1.10), respectively. In contrast, higher levels of LTPA were inversely associated with mortality for both genders. For example, for women HR for low, moderate and high compared with sedentary LTPA were 0.85 (0.81 to 0.89), 0.78 (0.74 to 0.81) and 0.75 (0.65 to 0.88), respectively. Effects were attenuated when adjusting for income (although data on income were available from only 9 and 6 studies, for men and women, respectively)., Conclusion: Our findings indicate that OPA may not result in the same beneficial health effects as LTPA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Loneliness among nursing home residents is an increasing public health issue and consists of a combination of social, emotional, and existential loneliness. Cycling Without Age (CWA) involves taking nursing home residents on trishaw rides pedaled by trained volunteer 'pilots'. This study aims to explore nursing home residents' lived experiences of CWA and whether participation in CWA can mitigate experiences of loneliness., Methods: A qualitative phenomenological design was used. We conducted three observations and eight interviews: semi-structured interviews (n = 5) and informal interviews (n = 3) with passengers in CWA. Data were analyzed using reflexive thematic analysis., Results: Three themes were developed: 1. creating meaningful communities (related to the social mechanism connected to participating in CWA), 2. breaking the monotony of everyday life (related to how the passengers experience CWA as a meaningful activity), and 3. reconnecting to oneself (related to the meaningful experience the passengers have when they are connected to their local communities and reminiscence)., Conclusion: Taking part in CWA may mitigate loneliness, as passengers perceive it as being meaningful. These results strengthen the notion that participating in meaningful activities hold the potential to mitigate feelings of loneliness among nursing home residents.

Objectives: The World Health Organization (WHO) highlights parous women as a key population for monitoring trends of physical activity (PA). We aimed to estimate the proportion of Danish women non-adhering to WHO PA guidelines in parous women compared with nulliparous women and to describe leisure-time PA intensity in each of these groups., Study Design: Cross-sectional study., Methods: This population-based study builds on a sample of 27,668 women aged 16-40 years from the Danish National Health Survey 2021. These data were linked with childbirth data from the Danish National Birth Registry. The primary outcome was self-reported weekly hours of moderate to vigorous leisure-time PA (MVPA) dichotomized into: (i) adhering to WHO guidelines for MVPA or (ii) not adhering to WHO guidelines for MVPA. Binomial regression analysis was used to calculate prevalence proportions (PP) and prevalence proportion ratios (PPR)., Results: Of the 27,668 women, a total of 20,022 were included; 9338 (46.6%) parous women and 10,684 (53.4%) nulliparous women. The PP of women non-adhering to WHO PA guidelines was 63.8% (95% CI 62.9-64.8) for parous and 51.3% (95% CI 50.4-52.3) for nulliparous women, corresponding to a PPR of 1.24 (95% CI 1.21; 1.27)., Conclusions: The proportion of parous women who did not adhere to WHO PA guidelines for MVPA was 24% higher than that of nulliparous women. This highlights parous women as a subgroup of the adult population at increased risk of non-adherence to WHO PA guidelines. These findings call for future research to inform new strategies aiming to promote PA in parous women., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: During the past decades, social inequality in mortality has increased in several countries, including Denmark. Modifiable risk factors, such as smoking and harmful alcohol consumption, have been suggested to moderate the association between socioeconomic position and health-related outcomes. The present study aims to investigate the contribution of smoking- and alcohol-related deaths to the trends in educational inequality in mortality in Denmark 1995-2019 among individuals aged 30-74 years., Methods: Nationwide data on mortality and highest attained educational level divided into quartiles were derived from administrative registers. Alcohol-related mortality was directly estimated using information on alcohol-related deaths from death certificates. Smoking-related mortality was indirectly estimated using the Peto-Lopez method. The contribution of smoking- and alcohol-related deaths to the social inequality gap in mortality 1995-2019 was calculated., Results: Alongside a decrease in all-cause mortality in Denmark 1995-2019, absolute differences in the mortality rate (per 100 000 person-year) between the lowest and the highest educational quartile increased from 494 to 607 among men and from 268 to 376 among women. Among both men and women, smoking- and alcohol-related deaths explained around 60% of the social inequality in mortality and around 50% of the increase in mortality inequality., Conclusion: Smoking and harmful alcohol consumption continue to be important risk factors and causes of social inequality in mortality, with around half of the increase in Denmark 1995-2019 being attributable to smoking- and alcohol-related deaths. Future healthcare planning and policy development should aim at reducing social inequality in modifiable health risk behaviours and their negative consequences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19. Primary outcomes were the presence of (i) SARS-CoV-2 RNA in CSF via polymerase chain reaction (PCR), (ii) SARS-CoV-2 immunoglobulin G (IgG) anti-S receptor-binding-domain antibodies via the Euroimmun and Wantai assays and (iii) IgG autoantibodies against neuronal surface antigens using commercial cell- and tissue-based assays (Euroimmun). Secondary outcomes were (i) routine CSF investigations and (ii) correlation between SARS-CoV-2 antibody levels in CSF with serum levels, blood-brain barrier permeability and peripheral inflammation. We obtained CSF from 38 COVID-19 patients (mean age 56.5 ± 19.2 years, 53% women) who developed neurological and neuropsychiatric symptoms. CSF pleocytosis (>5 cells) was observed in 9/38 patients (23.7%), elevated CSF protein (>0.50 g/L) in 13/38 (34.2%) and elevated CSF/serum albumin ratio in 12/35 (34.3%). PCR for SARS-CoV-2 RNA in CSF was negative in all. SARS-CoV-2 CSF antibodies were detected in 15/34 (44.1%; Euroimmun assay) and 7/31 (22.6%; Wantai assay) individuals, but there were no signs of intrathecal SARS-CoV-2 IgG production. SARS-CoV-2 CSF antibodies were positively correlated with serum levels ( R = 0.93, P < 0.001), blood-brain barrier permeability ( R = 0.47, P = 0.006), peripheral inflammation ( R = 0.51, P = 0.002) and admission to the intensive care unit [odds ratio (OR) 17.65; 95% confidence interval (CI) 1.18-264.96; P = 0.04; n = 15]. Cell-based assays detected weakly positive NMDAR, LGI1 and CASPR2 antibodies in serum of 4/34 (11.8%) patients but not in CSF. The tissue-based assay showed anti-neuronal fluorescence in CSF from one individual, staining for Purkinje cells. In summary, whereas we did not detect active SARS-CoV-2 infection in the CSF, SARS-CoV-2 antibodies were prevalent. The absence of intrathecal antibody production points towards blood-brain barrier impairment as the origin of CSF SARS-CoV-2 antibodies. In contrast, CSF autoantibodies against neuronal surface antigens were rare. There was no evidence for a clinical correlate of these antibodies. We conclude that, rather than specific autoimmune neuronal injury, non-specific effects of critical illness including an impaired blood-brain barrier are more likely to contribute to neuro-COVID., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Patient and family-centred care (PFCC) is a healthcare model has been acknowledged as the central pillar in the paediatric health care that recognizes the family's role and experience in the health care delivery., Aims: This study investigated and compared the perception of PFCC from the perspective of staff and parents of hospitalized children and adolescents., Methods: A quantitative and comparative cross-sectional survey was used in a convenience sample of 105 staff and 116 parents, who completed the Brazilian versions of the Perceptions of Family Centred Care-Parent and Staff questionnaires, with additional questions on their characteristics. Descriptive and analytical statistics were used, as well as the Kruskal-Wallis and Mann-Whitney tests and Spearman's correlation coefficient., Results: Both parents and staff responses were positive and parents had significantly higher scores for 19 of the 20 items (p < 0.001). The item related to parental participation did not show any significant difference between the groups., Conclusion: The positive perception of PFCC for both groups is consistent with recommendations for expanded care that includes patient and family in healthcare settings. Parents' perception was more positive than staff perceptions of their delivery of family-centred care in hospital. The lowest score for the parent support subscale in both groups requires investigation., (© 2023 John Wiley & Sons Ltd.)

Diagnosis of a sleep disorders is multimodal. An overview is presented in this review. The medical history leads to a tentative diagnosis supported by questionnaires, sleep diary and objective methods. Examination may reveal upper airway problems in a patient suspected to have obstructive sleep apnoea or rigidity in an elderly patient with shouting during sleep, suggestive of rapid eye movement sleep behaviour disorder. The choice of diagnostic sleep test is based on the tentative diagnosis. Other tests (e.g., lumbar puncture, brain scan) may be indicated. Wearables pose the advantage of documenting the patients' habitual sleep and circadian rhythm.

Aims: The benefits associated with being physical active on mental health is well-established, but little is known on how rapid changes in physical activity are associated with mental health. This study investigated the association between changes in physical activity and mental health among Danish university students during the first COVID-19 lockdown., Methods: Online survey data were collected among 2,280 university students at the University of Southern Denmark and University of Copenhagen in May-June 2020 as part the "COVID-19 International Student Well-being Study." Multiple linear regressions were used to analyze associations between changes in physical activity and mental health (depression and stress scores) adjusted for potential socio-economic confounders., Results: During the first COVID-19 lockdown, 40% decreased their moderate and 44% their vigorous physical activity, while 16% increased their moderate and 13% their vigorous physical activity. Overall, students with a stable physical activity level had the lowest mean depressive and stress scores. Adjusted analyses showed that a decrease in vigorous and moderate physical activity level was significantly associated with a higher depression score (mean difference (vigorous): 1.36, p  < 0.001 and mean difference (moderate): 1.55, p  < 0.001). A decrease in vigorous physical activity and an increase in moderate physical activity was associated with a 1-point increase in the PSS-4 stress score ( p  < 0.001)., Conclusion: A substantial proportion of students changed their physical activity level during lockdown. Our findings emphasize the importance of staying physically active during COVID-19 lockdown. This knowledge might be important for relevant health authorities to bridle post-pandemic mental health challenges., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Petersen, Krüger, Guldager, Algren, Jervelund and Berg-Beckhoff.)

Background: In the EU, approx. 16.5% of the 20-34-year-olds are Not in Education, Employment or Training (NEET). Research shows that good health is an important progression factor towards employment, and daily physical activity as well as participation in sports has a positive effect on physical and mental health as well as in the development of life skill. However, there is an absence of studies investigating what role physical activity can play in the employment efforts. The aim of this study is to investigate experiences with physical activity in employment interventions and to describe the development of a health-promoting employment intervention with physical activity for young people aged 18-30 years who are NEET., Methods: The study combined an evidence-based approach with practice-based experiences. It included a Mapping of Danish employment interventions with physical activity for young people NEET, an overview of national reports and international literature, a workshop with leaders and employees from Danish municipalities, and fieldwork in four municipalities. Key findings were grouped thematically and were transformed into intervention content in a close dialog with relevant researchers and practitioners., Results: In general, physical activity was assessed as a meaningful method when working with young people NEET. A range of positive experiences was highlighted, including successful experiences, surplus of mental resources, new ways of meeting, and new social relations. Based on these findings, a 16-week health-promoting employment intervention, NEXT STEP, was developed with the following intervention components: (1) fixed boundaries, (2) body and physical activity, (3) social relations and network, and (4) life skills and future. NEXT STEP is designed to be implemented in Danish job centers., Conclusion: The study found the great potential of including physical activity in employment interventions for young people NEET. The planning and development of the intervention have reinforced a comprehensive evaluation; however, the first intervention in its entirety is ready for testing in a randomized feasibility trial., (© 2022. The Author(s).)

Bioimpedance (mfBIA) non-invasively assesses cellular muscle health. Our aim was to explore whether mfBIA captures abnormal cellular muscle health in patients with Parkinson's Disease (PD) and how such changes are modulated with the use of Parkinson's medication. In patients with PD (n = 20) mfBIA measurements were made of biceps brachii, triceps, and extensor carpi radialis longus muscles of the more affected arm whilst at rest, using a mobile mfBIA device (IMPEDIMED, Australia). mfBIA and assessment of motor symptoms were performed in a pragmatic off-medication state, as well as one and 3 h after oral intake of 200 mg levodopa. Age and sex-matched healthy subjects (HC; n = 20) served as controls. PD and HC mfBIA parameters were compared by applying an unpaired two-tailed adjusted t-test and ANOVA with Tukey's correction for multiple comparisons (p ≤ 0.05). The PD group consisted of 13 men (71 ± 17 years) and 7 women (65 ± 7 years). Independent of medication, internal (R i ) and external resistance (R e ) were found to be significantly higher, and membrane capacitance (Mc) significantly lower, in m.biceps brachii in PD subjects compared to HC. Center frequency (fc) was significantly higher in m.biceps brachii of PD subjects in the "medication-off" state. There was no difference between PD and HC in mfBIA parameters in the measured extensor muscles. The upper limb flexor muscle shows a difference in mfBIA parameters in PD compared to HC. mfBIA may be useful in the diagnosis and assessment of PD patients and is objective, non-invasive, reliable, and easy to use., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The 3,9-diazaspiro[5.5]undecane-based compounds 2027 and 018 have previously been reported to be potent competitive γ-aminobutyric acid type A receptor (GABA A R) antagonists showing low cellular membrane permeability. Given the emerging peripheral application of GABA A R ligands, we hypothesize 2027 analogs as promising lead structures for peripheral GABA A R inhibition. We herein report a study on the structural determinants of 2027 in order to suggest a potential binding mode as a basis for rational design. The study identified the importance of the spirocyclic benzamide, compensating for the conventional acidic moiety, for GABA A R ligands. The structurally simplified m -methylphenyl analog 1e displayed binding affinity in the high-nanomolar range ( K i = 180 nM) and was superior to 2027 and 018 regarding selectivity for the extrasynaptic α 4 βδ subtype versus the α 1 - and α 2 - containing subtypes. Importantly, 1e was shown to efficiently rescue inhibition of T cell proliferation, providing a platform to explore the immunomodulatory potential for this class of compounds.

Recreational activities may promote and maintain health and well-being, but empirical evidence is limited. The aim of this study was to explore socioeconomic variations in participation in recreational activities in the local community and to examine associations with health and well-being in the general population. Participants ≥ 16 years from the Danish Capital Region Health Survey, conducted in 2017 (N = 55,185, response rate 52.6%) were included. Participation in community-based recreational activities, self-rated health, quality of life, and health status was assessed by questionnaire. Socioeconomic variables (educational level, occupational and marital status) were obtained from national registers. Multiple logistic regression models were used to examine associations. Less than half of the population participated in community-based recreational activities. Individuals with a higher educational level were 55% more likely to participate in recreational activities compared to those with a lower educational level (OR = 1.55, CI:1.45-1.66). Individuals with a low educational level who participated in recreational activities, were more likely to have an excellent/good quality of life (OR = 2.03 (95% CI:1.86-2.21)) and an excellent/very good self-rated health (OR = 1.61 (95% CI:1.51-1.71)), than those who did not participate in recreational activities. Regardless of educational level, recreational activity participation was associated with better self-rated health and quality of life. Thus, to counter-balance social inequality in health, a focus on participation in recreational activities is important when planning community public health interventions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Aim: In ovarian cancer, methylated HOXA9 (meth-HOXA9) has been proposed as a relevant biomarker, however, its role in the carcinogenic development remains unknown. This study aimed at evaluating meth-HOXA9 as a diagnostic biomarker in ovarian cancer. Materials & methods: The meth-HOXA9 status was examined in 138 tissue specimens encompassing normal ovaries, benign- and borderline tumors, and ovarian cancer using droplet digital PCR. Results: Meth-HOXA9 was detected in 93% (82/88) and 88% (14/16) of ovarian cancer and borderline tumors, respectively. In patients with benign ovarian tumors meth-HOXA9 was detected in 17% (3/18). Using receiver operating characteristic (ROC) analysis meth-HOXA9 had a diagnostic accuracy of 98%. Conclusion: Meth-HOXA9 is highly cancer specific and could serve as a general diagnostic marker of ovarian malignancy.

Physical activity (PA) can improve physical, mental, and social health, leading to quality of life (QoL). However, some are unable to participate independently due to age-related impairments or disabilities. This study protocol presents the design, methods, outcomes, strengths and limitations of the study "When Movement Moves" (WMM). WMM investigates whether indirect PA in a social context, where persons are unable to participate independently, can result in outcomes similar to those of independent PA, by evaluating the effects of disabled's, elderly, volunteers', relatives' and nursing staff's participation in either the running programme (Team Twin) or cycling programme (Cycling Without Age). Both programmes seek to enhance QoL through indirect PA in a social context, making PA possible for elderly and disabled persons through PA conducted by abled-bodied volunteers. WMM is a multi-method 12-16-week pre/post evaluation with quality of life, physical, mental and social health as main outcomes. Pre/post measurements consist of questionnaires, clinical examinations, and physical and cognitive appraisal. Throughout, interviews and participant observations will be conducted. Combined results will provide essential knowledge on the effects and experiences of indirect PA. Explorative data will pave the way for further research. Findings may inform policies, guidelines and health promotion among the elderly and disabled.

The betaine/GABA transporter 1 (BGT1) is a member of the GABA transporter (GAT) family with still elusive function, largely due to a lack of potent and selective tool compounds. Based on modeling, we here present the design, synthesis and pharmacological evaluation of five novel conformationally restricted cyclic GABA analogs related to the previously reported highly potent and selective BGT1 inhibitor (1 S ,2 S ,5 R )-5-aminobicyclo[3.1.0]hexane-2-carboxylic acid (bicyclo-GABA). Using [ 3 H]GABA radioligand uptake assays at the four human GATs recombinantly expressed in mammalian cell lines, we identified bicyclo-GABA and its N -methylated analog ( 2 ) as the most potent and selective BGT1 inhibitors. Additional pharmacological characterization in a fluorescence-based membrane potential assay showed that bicyclo-GABA and 2 are competitive inhibitors, not substrates, at BGT1, which was validated by a Schild analysis for bicyclo-GABA (p K B value of 6.4). To further elaborate on the selectivity profile both compounds were tested at recombinant α 1 β 2 γ 2 GABA A receptors. Whereas bicyclo-GABA showed low micromolar agonistic activity, the N -methylated 2 was completely devoid of activity at GABA A receptors. To further reveal the binding mode of bicyclo-GABA and 2 binding hypotheses of the compounds were obtained from in silico -guided mutagenesis studies followed by pharmacological evaluation at selected BGT1 mutants. This identified the non-conserved BGT1 residues Q299 and E52 as the molecular determinants driving BGT1 activity and selectivity. The binding mode of bicyclo-GABA was further validated by the introduction of activity into the corresponding GAT3 mutant L314Q (38 times potency increase cf. wildtype). Altogether, our data reveal the molecular determinants for the activity of bicyclic GABA analogs, that despite their small size act as competitive inhibitors of BGT1. These compounds may serve as valuable tools to selectively and potently target BGT1 in order to decipher its elusive pharmacological role in the brain and periphery such as the liver and kidneys., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kickinger, Lie, Suemasa, Al-Khawaja, Fujiwara, Watanabe, Wilhelmsen, Falk-Petersen, Frølund, Shuto, Ecker and Wellendorph.)

Delta selective compound 2 (DS2; 4-chloro- N -[2-(2-thienyl)imidazo[1,2- a ]pyridin-3-yl]benzamide) is one of the most widely used tools to study selective actions mediated by δ -subunit-containing GABA A receptors. DS2 was discovered over 10 years ago, but despite great efforts, the precise molecular site of action has remained elusive. Using a combination of computational modeling, site-directed mutagenesis, and cell-based pharmacological assays, we probed three potential binding sites for DS2 and analogs at α 4 β 1 δ receptors: an α 4 (+) δ (-) interface site in the extracellular domain (ECD), equivalent to the diazepam binding site in αβγ 2 receptors, and two sites in the transmembrane domain (TMD) - one in the α 4 (+) β 1 (-) and one in the α 4 (-) β 1 (+) interface, with the α 4 (-) β 1 (+) site corresponding to the binding site for etomidate and a recently disclosed low-affinity binding site for diazepam. We show that mutations in the ECD site did not abrogate DS2 modulation. However, mutations in the TMD α 4 (+) β 1 (-) interface, either α 4 (S303L) of the α 4 (+) side or β 1 (I289Q) of the β 1 (-) side, convincingly disrupted the positive allosteric modulation by DS2. This was consistently demonstrated both in an assay measuring membrane potential changes and by whole-cell patch-clamp electrophysiology and rationalized by docking studies. Importantly, general sensitivity to modulators was not compromised in the mutated receptors. This study sheds important light on the long-sought molecular recognition site for DS2, refutes the misconception that the selectivity of DS2 for δ -containing receptors is caused by a direct interaction with the δ -subunit, and instead points toward a functional selectivity of DS2 and its analogs via a surprisingly well conserved binding pocket in the TMD. SIGNIFICANCE STATEMENT: δ-Containing GABA A receptors represent potential drug targets for the treatment of several neurological conditions with aberrant tonic inhibition, yet no drugs are currently in clinical use. With the identification of the molecular determinants responsible for positive modulation by the known compound delta selective compound 2, the ground is laid for design of ligands that selectively target δ -containing GABA A receptor subtypes, for better understanding of tonic inhibition, and ultimately, for rational development of novel drugs., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

γ-Aminobutyric acid (GABA) acting through heteropentameric GABA A receptors plays a pivotal role in the sleep-promoting circuitry. Whereas the role of the different GABA A receptor α-subunits in sleep regulation and in mediating the effect of benzodiazepines for treatment of insomnia is well-described, the β-subunits are less studied. Here we report the first study characterizing sleep in mice lacking the GABA A receptor β 1 -subunit (β 1 -/- mice). We show that β 1 -/- mice have a distinct and abnormal sleep phenotype characterized by increased delta power in non-rapid eye movement (NREM) sleep and decreased theta activity in rapid eye movement (REM) sleep compared to β 1 +/+ mice, without any change in the overall sleep-wake architecture. From GABA A receptor-specific autoradiography, it is further demonstrated that functional β 1 -subunit-containing GABA A receptors display the highest binding levels in the hippocampus and frontal cortex. In conclusion, this study suggests that the GABA A receptor β 1 -subunit does not play an important role in sleep initiation or maintenance but instead regulates the power spectrum and especially the expression of theta rhythm. This provides new knowledge on the complex role of GABA A receptor subunits in sleep regulation. In addition, β 1 -/- mice could provide a useful mouse model for future studies of the physiological role of delta and theta rhythms during sleep., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The aim was to examine the effects of replacing self-reported leisure-time sedentary behavior with sleep, light-to-moderate physical activity, or vigorous physical activity on incident diabetes among Danish adults using isotemporal substitution modeling. Participants ≥25 years from the Danish Capital Region Health Survey 2007 (N = 69 800, response rate 52.3%), 2010 (N = 95 150, response rate 52.3%), and 2013 (N = 95 150, response rate 43.5%) were included. Information on daily sleep duration, leisure-time sedentary behavior, and movement behaviors was collected by questionnaire. Information on incident diabetes was obtained from National registers. Analyses included Cox proportional hazards regression models and isotemporal substitution analyses, with time (in years) from baseline to incident diabetes or censoring December 31, 2017. Potential confounders, sex, age, BMI, ethnicity, education, smoking, inflammatory joint disease, perceived stress, physical and mental component scale and work status, were included. Out of N = 87 339 in the final study sample, n = 3007 had incident diabetes during a mean follow-up time of 7.4 years. Adults with incident diabetes included more men, higher mean age, and higher BMI, compared to respondents without incident diabetes. Theoretically substituting 30 minutes of leisure-time sedentary behavior with light-to-moderate PA (HR: 0.96; 95% CI: 0.94; 0.98) or with vigorous PA (HR: 0.82; 95% CI: 0.72; 0.94) decreased the risk of incident diabetes. We found no change in incident diabetes risk of substituting sedentary time with sleep (HR: 1.00; 95% CI: 0.97; 1.02). Substituting 30 minutes per day of leisure-time sedentary behavior with light-to-moderate or vigorous PA may significantly reduce the risk of incident diabetes among adults., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The purpose was to examine the correlation and association between a single-item question of self-rated physical fitness and objective measures of fitness and cardiometabolic risk factors in a large population-based study. Participants were 3441 men and women aged 18-85 years who filled in a questionnaire and participated in a clinical health examination in the Danish Health Examination Survey 2007-2008. Cardiorespiratory fitness was estimated by an indirect maximal exercise test. Muscle strength was measured by (a) sit-to-stand test, (b) handgrip strength, and (c) bent arm strength. Body mass index and fat percentage were used as measures for body composition. Associations were derived from regression analyses, correlations were calculated using Spearman's correlation test, and agreement was tested by kappa statistics. Within categories of self-rated physical fitness moving from lowest to highest, objectively measured cardiorespiratory fitness increased. Self-rated physical fitness was strongly correlated to cardiorespiratory fitness (r men  = 0.69 and r women  = 0.65) and moderately correlated to the sit-to-stand test (r men  = 0.49 and r women  = 0.48), bent arm strength (r = 0.45) and fat percentage (r = 0.46) among men, and handgrip strength among women (r =0.41). Mutually adjusted analysis showed a significant association between self-reported physical fitness and cardiorespiratory fitness for men and women and bent arm strength for women. The single-item question of physical fitness was correlated to cardiorespiratory fitness, muscle strength, and body composition. However, this study suggests that it mainly captures cardiorespiratory fitness. At the population level, the single-item question could be a useful tool to identify and monitor variation in fitness levels., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABA A Rs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, 30 , 35, and 36, were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6-16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABA A Rs in general.

Background and Purpose: The δ-subunit-containing GABA A receptors, α 4 β 1 δ and α 4 β 3 δ, in dentate gyrus granule cells (DGGCs) are known to exhibit both spontaneous channel openings (i.e. constitutive activity) and agonist-induced current. The functional implications of spontaneous gating are unclear. In this study, we tested the hypothesis that constitutively active α 4 β 1/3 δ receptors limit agonist efficacy., Experimental Approach: Whole-cell electrophysiological recordings of adult male rat and mouse hippocampal DGGCs were used to characterize known agonists and antagonists at δ-subunit-containing GABA A receptors. To separate constitutive and agonist-induced currents, different recording conditions were employed., Key Results: Recordings at either 24°C or 34°C, including the PKC autoinhibitory peptide (19-36) intracellularly, removed spontaneous gating by GABA A receptors. In the absence of spontaneous gating, DGGCs responded to the α 4 β 1/3 δ orthosteric agonist Thio-THIP with a four-fold increased efficacy relative to recording conditions favouring constitutive activity. Surprisingly, the neutral antagonist gabazine was unable to antagonize the current by Thio-THIP. Furthermore, a current was elicited by gabazine alone only when the constitutive current was silenced (EC 50 2.1 μM). The gabazine-induced current was inhibited by picrotoxin, potentiated by DS2, completely absent in δ -/- mice and reduced in β 1 -/- mice, but could not be replicated in human α 4 β 1/3 δ receptors expressed heterologously in HEK cells., Conclusion and Implications: Kinase activity infers spontaneous gating in α 4 β 1/3 δ receptors in DGGCs. This significantly limits the efficacy of GABA A agonists and has implications in pathologies involving aberrant excitability caused by phosphorylation (e.g. addiction and epilepsy). In such cases, the efficacy of δ-preferring GABA A ligands may be reduced., (© 2020 The British Pharmacological Society.)

Brain GABA Α receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human α 4 β 1 δ GABA Α receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABA Α receptors. The initial screening hit 2027 (IC 50 of 1.03 μM) was used for analogue search resulting in 018 (IC 50 of 0.088 μM). 018 was most potent at α 3,4,5 -subunit containing receptors, thus showing preference for forebrain-expressed extrasynaptic receptors. Schild analysis of 018 at recombinant human α 4 β 1 δ receptors and displacement of [ 3 H]muscimol binding in rat cortical homogenate independently confirmed a competitive profile. The antagonist profile of 018 was further validated by whole-cell patch-clamp electrophysiology, where kinetic studies revealed a slow dissociation rate and a shallow hill slope was observed. Membrane permeability studies showed that 2027 and 018 do not cross membranes, thus making the compounds less attractive for studying central GABA Α receptors effects, but conversely more attractive as tool compounds in relation to emerging peripheral GABA Α receptor-mediated effects of GABA e.g. in the immune system.

This study aimed to compare the prognostic value of quantitative measures of [ 18 F]-fluorodeoxyglucose positron emission tomography with integrated computed tomography (FDG-PET/CT) for the response monitoring of patients with metastatic breast cancer (MBC). In this prospective study, 22 patients with biopsy-verified MBC diagnosed between 2011 and 2014 at Odense University Hospital (Denmark) were followed up until 2019. A dual-time-point FDG-PET/CT scan protocol (1 and 3 h) was applied at baseline, when MBC was diagnosed. Baseline characteristics and quantitative measures of maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), corrected SUVmean (cSUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and corrected TLG (cTLG) were collected. Survival time was analyzed using the Kaplan-Meier method and was regressed on MTV, TLG, and cTLG while adjusting for clinicopathological characteristics. Among the 22 patients included (median age: 59.5 years), 21 patients (95%) died within the follow-up period. Median survival time was 29.13 months (95% Confidence interval: 20.4-40 months). Multivariable Cox proportional hazards regression analyses of survival time showed no influence from the SUVmean, cSUVmean, or SUVmax, while increased values of MTV, TLG, and cTLG were significantly associated with slightly higher risk, with hazard ratios ranging between 1.0003 and 1.004 ( p = 0.007 to p = 0.026). Changes from 1 to 3 h were insignificant for all PET measures in the regression model. In conclusion, MTV and TLG are potential prognostic markers for overall survival in MBC patients.

Introduction: The aim of the present study was to investigate the prognostic impact of intratumoral cytotoxic T cells, Natural Killer (NK) cells, neutrophils and PD-L1 expression in patients with epithelial ovarian cancer. Methods: All patients diagnosed with high-grade serous carcinoma (HGSC) in Denmark in 2005 were included in the study. Immunohistochemical staining for PD-L1, CD8, CD66b and CD57 was performed on tumor tissue from 283 patients. Cell densities were analyzed using a digital image analysis method. The primary endpoint was overall survival (OS). Results: The median OS for HGSC patients was 30 months. It was 45 months in patients with high level of CD57+ NK cells (≥10 cells/mm 2 ) compared with 29 month in patients with low level (<10 cells/mm 2 ) ( p  = .0310). The median OS was 37 and 25 months in patients with high vs. low level of CD8+ T cells (cutoff 80 cells/mm 2 ) ( p  = .0008). In multivariate analysis, high numbers of CD57+ NK cells and CD8+ T cells remained independent markers of favorable OS, adjusted hazard ratio (HR) 0.67; p  = .041, and HR 0.72; p  = .020, respectively. PD-L1 expression was associated with improved OS (37 months vs. 22 months, p  = .0006), but was only borderline significant in the multivariate analysis (HR 0.77, p  = .061). CD66b + neutrophils had no association with OS. Conclusions: In patients with HGSC tumor-infiltrating CD57+ NK cells and CD8+ T cells had favorable prognostic impact, while PD-L1 expression had borderline favorable prognostic significance. CD66b + neutrophils had no prognostic association. These findings may influence future immunotherapy development.

Gabazine, a γ-aminobutyric acid type A (GABA A ) receptor antagonist, has previously been reported to inhibit the binding of [ 3 H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance γ-hydroxybutyric acid (GHB). We herein report a study on the structural determinants of gabazine for binding to (i) the orthosteric binding site of the GABA A receptor and (ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2- b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogues with relatively high affinity ( K i 0.19-2.19 μM) and >50 times selectivity for the [ 3 H]NCS-382 over [ 3 H]muscimol binding sites. These results highlight that gabazine interacts with the high-affinity GHB and orthosteric GABA A receptor binding sites differently and that distinct analogues can be generated to select between them. To facilitate further in vivo studies, a promising prodrug candidate for brain delivery was identified.

Aims: This study aimed to test the hypotheses that a high total sitting time and vigorous physical activity in leisure time increase the risk of low back pain and herniated lumbar disc disease., Methods: A total of 76,438 adults answered questions regarding their total sitting time and physical activity during leisure time in the Danish Health Examination Survey 2007-2008. Information on low back pain diagnoses up to 10 September 2015 was obtained from The National Patient Register. The mean follow-up time was 7.4 years. Data were analysed using Cox regression analysis with adjustment for potential confounders. Multiple imputations were performed for missing values., Results: During the follow-up period, 1796 individuals were diagnosed with low back pain, of whom 479 were diagnosed with herniated lumbar disc disease. Total sitting time was not associated with low back pain or herniated lumbar disc disease. However, moderate or vigorous physical activity, as compared to light physical activity, was associated with increased risk of low back pain (HR = 1.16, 95% CI: 1.03-1.30 and HR = 1.45, 95% CI: 1.15-1.83). Moderate, but not vigorous physical activity was associated with increased risk of herniated lumbar disc disease., Conclusions: The results suggest that total sitting time is not associated with low back pain, but moderate and vigorous physical activity is associated with increased risk of low back pain compared with light physical activity.

Background: Women with a gynecologic cancer tend to be older, obese, and postmenopausal, characteristics that are associated with an increased risk for obstructive sleep apnea. However, there is limited investigation regarding the condition's prevalence in this population or its impact on postoperative outcomes. In other surgical populations, patients with obstructive sleep apnea have been observed to be at increased risk for adverse postoperative events., Objective: We sought to estimate the prevalence of obstructive sleep apnea among gynecologic oncology patients undergoing elective surgery and to investigate for a relationship between obstructive sleep apnea and postoperative outcomes., Study Design: Patients referred to an academic gynecologic oncology practice were approached for enrollment in this prospective, observational study. Patients were considered eligible for study enrollment if they were scheduled for a nonemergent inpatient surgery and could provide informed consent. Enrolled patients were evaluated for a preexisting diagnosis of obstructive sleep apnea. Those without a prior diagnosis were screened using the validated, 4-item STOP questionnaire (ie, Snore loudly, daytime Tiredness, Observed apnea, elevated blood Pressure). All patients who screened positive for obstructive sleep apnea were referred for polysomnography. The primary outcome was the prevalence of women with obstructive sleep apnea or those who screened at high risk for the condition. Secondary outcomes examined the correlation between body mass index (kg/m 2 ) with obstructive sleep apnea and assessed for a relationship between obstructive sleep apnea and postoperative outcomes., Results: Over a 22-month accrual period, 383 eligible patients were consecutively approached to participate in the study. A cohort of 260 patients were enrolled. A total of 33/260 patients (13%) were identified as having a previous diagnosis of obstructive sleep apnea. An additional 66/260 (25%) screened at risk for the condition using the STOP questionnaire. Of the patients who screened positive, 8/66 (12%) completed polysomnography, all of whom (8/8 [100%]) were found to have obstructive sleep apnea. The prevalence of previously diagnosed obstructive sleep apnea or screening at risk for the condition increased as body mass index increased (P < .001). Women with untreated obstructive sleep apnea and those who screened at risk for the condition were found to have an increased risk for postoperative hypoxemia (odds ratio, 3.5; 95% confidence interval, 1.8-4.7; P = .011) and delayed return of bowel function (odds ratio, 2.1; 95% confidence interval, 1.3-4.5; P = .009)., Conclusion: The prevalence of obstructive sleep apnea or screening at risk for the condition is high among women presenting for surgery with a gynecologic oncologist. Providers should consider evaluating a patient's risk for obstructive sleep apnea in the preoperative setting, especially when risk factors for the condition are present., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The purpose was to examine and compare the effects of replacing time spent sitting with standing at work on fat-free mass, fat mass and waist circumference using isotemporal substitution. Analyses were conducted on work hours on both cross-sectional and longitudinal data. The study included 223 persons from an intervention study aimed at reducing sitting time at work among office employees. Sitting, standing and anthropometry were measured objectively. Cross-sectional isotemporal substitution analyses were modelled on baseline data, while longitudinal analyses were modelled based on differences in sitting and standing time at work between baseline and 1-month follow-up in relation to differences in anthropometric measures between baseline and 3-months follow-up. Replacing one hour of sitting time with one hour of standing was associated with a 0.21 kg higher fat-free mass in the longitudinal analysis and 0.95 kg in the cross-sectional analysis. Fat mass was 0.32 kg lower in the longitudinal analysis and 0.61 kg lower in the cross-sectional analysis. Waist circumference decreased by 0.38 cm in the longitudinal analysis and 0.81 cm in the cross-sectional analysis. Both cross-sectional and longitudinal analyses showed an effect on body composition measures by replacing one hour of sitting with standing however, this effect was largest in the cross-sectional analyses. Trial registration ClinicalTrials.gov NCT01996176., Competing Interests: The authors have declared that no competing interests exist.

Background: Using self-reported surveys to monitor physical activity levels in the population require short items covering both time and intensity. The present study aims to 1) develop the Nordic Physical Activity Questionnaire-short from the original version of the NPAQ, 2) assess test-retest reliability and criterion validity of the NPAQ-short, and 3) test the NPAQ-short's ability to monitor compliance with the WHO recommendations on physical activity. In addition, we aimed to compare open and closed-ended answering modes for the NPAQ-short., Methods: A sample of 122 participants were included. The NPAQ-short comprised of two questions on weekly moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA). It was filled in twice, two weeks apart, in open- and closed-ended versions. Physical activity was measured objectively by an Actiheart accelerometer worn 24 h/day seven consecutive days. Spearman's rank correlation and Cohen's kappa were used to assess correlations between the test and retest results, and between the objective and the self-reported measures., Results: Valid data was available for 92 participants. Test-retest reliability showed Spearman's rho = 0.82 for MVPA and 0.80 for VPA. For the open-ended questions, the correlations between self-reported and objectively measured physical activity levels were Spearman's rho = 0.33 for MVPA and rho = 0.32 for VPA. For closed-ended questions, the kappa-coefficients were 0.17 for MVPA and 0.21 for VPA. When using objective and self-reported measures to monitor WHO's physical activity recommendations, the kappa correlations were 0.42 for open-ended and 0.34 for closed-ended answering modes., Conclusion: The NPAQ-short was found to be sufficiently reliable and valid to monitor physical activity levels in the population when using both open and closed-ended questions. However, using open-ended questions seems to be a better answering mode for self-reported surveys monitoring WHO's physical activity recommendations.

γ-Hydroxybutyric acid (GHB) is a neuroactive substance with specific high-affinity binding sites. To facilitate target identification and ligand optimization, we herein report a comprehensive structure-affinity relationship study for novel ligands targeting these binding sites. A molecular hybridization strategy was used based on the conformationally restricted 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and the linear GHB analog trans-4-hydroxycrotonic acid (T-HCA). In general, all structural modifications performed on HOCPCA led to reduced affinity. In contrast, introduction of diaromatic substituents into the 4-position of T-HCA led to high-affinity analogs (medium nanomolar K i ) for the GHB high-affinity binding sites as the most high-affinity analogs reported to date. The SAR data formed the basis for a three-dimensional pharmacophore model for GHB ligands, which identified molecular features important for high-affinity binding, with high predictive validity. These findings will be valuable in the further processes of both target characterization and ligand identification for the high-affinity GHB binding sites.

δ-Containing GABA A receptors are located extrasynaptically and mediate tonic inhibition. Their involvement in brain physiology positions them as interesting drug targets. There is thus a continued interest in establishing reliable recombinant expression systems for δ-containing GABA A receptors. Inconveniently, the recombinant expression of especially α 4 β 1/3 δ receptors has been found to be notoriously difficult, resulting in mixed receptor populations and/or stoichiometries and differential pharmacology depending on the expression system used. With the aim of developing a facile and robust 96-well format cell-based assay for extrasynaptic α 4 β 1/3 δ receptors, we have engineered and validated a HEK293 Flp-In™ cell line stably expressing the human GABA A δ-subunit. Upon co-transfection of α 4 and β 1/3 subunits, at optimized ratios, we have established a well-defined system for expressing α 4 β 1/3 δ receptors and used the fluorescence-based FLIPR Membrane Potential (FMP) assay to evaluate their pharmacology. Using the known reference compounds GABA and THIP, ternary α 4 β 1/3 δ and binary α 4 β 1/3 receptors could be distinguished based on potency and kinetic profiles but not efficacy. As expected, DS2 was able to potentiate only δ-containing receptors, whereas Zn 2+ had an inhibitory effect only at binary receptors. By contrast, the hitherto reported δ-selective compounds, AA29504 and 3-OH-2'MeO6MF, were non-selective. The expression system was further validated using patch clamp electrophysiology, in which the superagonism of THIP was confirmed. The established FMP assay set-up, based on transient expression of human α 4 and β 1/3 subunits into a δ-subunit stable HEK293 Flp-In™ cell line, portrays a simple 96-well format assay as a useful supplement to electrophysiological recordings on δ-containing GABA A receptors., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: Pediatric cardiac arrest carries a poor prognosis. Basic life support improves survival. Studies on pediatric basic life support (PBLS) training are sparse. The aim of our study was to investigate the effect of self-training in PBLS., Participants and Methods: We conducted a prospective controlled trial enrolling nurses from pediatric and maternity wards (n=29 in each group). Self-training, including a manikin and access to a web-based video on PBLS, was compared with a 2-h instructor-led course. Two weeks after training, all participants were tested in a mock scenario of pediatric cardiac arrest. Fifteen parameters equivalent to the steps in the PBLS algorithm - for example, effective ventilations, effective chest compressions, calling for help, and correct sequence of actions, were evaluated and rated dichotomously (1=approved or 0=not approved)., Results: No difference was observed in the baseline demographics between the self-training group and the instructor-led group. The participants in the self-training group accessed the website 2±1.5 times (mean±SD) and spent 41±25 min on the site. There was no significant difference between the two groups in the overall average score (10.5 in the self-training group vs. 10.0 in the instructor-led group, P=0.51) or in any of the 15 parameters. After the study, all participants felt that they had improved their skills and felt capable of performing PBLS., Conclusion: Self-training is not statistically different to instructor-led training in teaching PBLS. Self-evaluated confidence improved, but showed no difference between groups. PBLS may be disseminated through self-training.

Background: Increasing evidence suggests that smoking influences mental health negatively. This study investigated whether high tobacco consumption is causally related to psychological distress in a Mendelian randomization design, using a variant in the nicotine acetylcholine receptor gene CHRNA3-known to influence individual tobacco consumption-as instrumental variable for tobacco consumption., Methods: Data from 90 108 participants in the Copenhagen General Population Study was used. Exposures included self-reported cigarettes/day and pack years and the CHRNA3 rs1051730 genotype as instrumental variable for tobacco consumption. Three dimensions of psychological distress were studied: Stress, fatigue, and hopelessness. Analyses with the CHRNA3 genotype were stratified by smoking status., Results: Self-reported amount of smoking was associated with all three dimensions of psychological distress. For instance among participants smoking 30 cigarettes/day or more, the odds ratio (OR) for stress was 1.67 (95% confidence interval [CI] 1.47-1.89) compared to never-smokers. Corresponding ORs for fatigue and hopelessness were 2.18 (95% CI 1.92-2.47) and 3.08 (95% CI 2.62-3.62). Among current smokers, homozygotes and heterozygotes for the CHRNA3 genotype had higher tobacco consumption than noncarriers. Nevertheless, the CHRNA3 genotype was not associated with psychological distress neither in current nor in former or never-smokers. For instance among current smokers, the OR for stress was 1.02 (95% CI 0.91-1.15) among homozygotes compared to noncarriers of the CHRNA3 genotype., Conclusions: Though a strong association between tobacco consumption and psychological distress was found, there was no clear evidence that high tobacco consumption was causally related to psychological distress., Implications: Smoking is associated with several mental health outcomes and smoking cessation is associated with improved mental health. Causality in the association between smoking and mental health is difficult to establish using observational data. Using a genotype known to influence tobacco consumption as instrumental variable for amount of smoking, we found no clear evidence of a direct causal path between high tobacco consumption and psychological distress. Whatever causes the strong association between tobacco consumption and psychological distress, the co-occurrence is important to consider both in interventions for smoking prevention and cessation., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Accelerometers can obtain precise measurements of movements during the day. However, the individual activity pattern varies from day-to-day and there is limited evidence on measurement days needed to obtain sufficient reliability. The aim of this study was to examine variability in accelerometer derived data on sedentary behaviour and physical activity at work and in leisure-time during week days among Danish office employees., Methods: We included control participants (n = 135) from the Take a Stand! Intervention; a cluster randomized controlled trial conducted in 19 offices. Sitting time and physical activity were measured using an ActiGraph GT3X+ fixed on the thigh and data were processed using Acti4 software. Variability was examined for sitting time, standing time, steps and time spent in moderate-to-vigorous physical activity (MVPA) per day by multilevel mixed linear regression modelling., Results: Results of this study showed that the number of days needed to obtain a reliability of 80% when measuring sitting time was 4.7 days for work and 5.5 days for leisure time. For physical activity at work, 4.0 days and 4.2 days were required to measure steps and MVPA, respectively. During leisure time, more monitoring time was needed to reliably estimate physical activity (6.8 days for steps and 5.8 days for MVPA)., Conclusions: The number of measurement days needed to reliably estimate activity patterns was greater for leisure time than for work time. The domain specific variability is of great importance to researchers and health promotion workers planning to use objective measures of sedentary behaviour and physical activity., Trial Registration: Clinical trials NCT01996176 .

Objective:: to present the concept of needs according to different approaches to discuss the possibility of health care that incorporates a broader view of human vulnerabilities in health services., Methods:: the arguments are founded on nursing theorists who worked on the construction of frameworks relevant to care, based on needs and on philosophers who show the possibility of identifying the vulnerabilities of human beings, defending art as a therapeutic instrument that can promote health care., Conclusion:: although care can acquire a new dimension with the introduction of art, according to certain perspectives, philosophical studies on ethics and aesthetics should be resumed to identify human vulnerabilities that can in fact be compensated by sensible understanding of the outer world. To incorporate art in nursing care requires studies from theorists to be recovered, deepening concepts and working on empirical investigations for their adequate use.

GHB (γ-hydroxybutyric acid) is a compound endogenous to mammalian brain with high structural resemblance to GABA. GHB possesses nanomolar-micromolar affinity for a unique population of binding sites, but the exact nature of these remains elusive. In this study we utilized the highly selective GHB analogue, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) as a tritiated version ( 3 H-HOCPCA) to radioactively label the specific GHB high-affinity binding site and gain further insight into the density, distribution and developmental profile of this protein. We show that, in low nanomolar concentrations, 3 H-HOCPCA displays excellent signal-to-noise ratios using rodent brain autoradiography, which makes it a valuable ligand for anatomical quantification of native GHB binding site levels. Our data confirmed that 3 H-HOCPCA labels only the high-affinity specific GHB binding site, found in high density in cortical and hippocampal regions. The experiments revealed markedly stronger binding at pH 6.0 (K d 73.8 nM) compared to pH 7.4 (K d 2312 nM), as previously reported for other GHB radioligands but similar B max values. Using 3 H-HOCPCA we analyzed the GHB binding protein profile during mouse brain development. Due to the high sensitivity of this radioligand, we were able to detect low levels of specific binding already at E15 in mouse brain, which increased progressively until adulthood. Collectively, we show that 3 H-HOCPCA is a highly sensitive radioligand, offering advantages over the commonly used radioligand 3 H-NCS-382, and thus a very suitable in vitro tool for qualitative and quantitative autoradiography of the GHB high-affinity site., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: To test the hypothesis that total sitting time is associated with incident diabetes, after adjustment for physical activity and obesity., Methods: 72 608 Danish adults from the DANHES cohort reported their total sitting time in 2007-2008 and were followed-up for 5 years, in relation to register-based incident diabetes mellitus. Cox regression analyses were used, and the effect-modifying influence of obesity and physical activity assessed., Results: The age-sex adjusted HR for developing diabetes among those who sat 10+ h/day as compared to <6 h/day was 1.35 (95% CI 1.17 to 1.57). The relative risks were similar by gender, but were largely attenuated by adjustment for potential confounding factors including physical activity, and statistically non-significant for all categories of body mass index except the obese., Conclusions: The association between total sitting time and incident diabetes is substantially moderated by physical activity and obesity. Total sitting time remains a risk factor for diabetes only in inactive and obese populations., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Recent studies suggest that physical inactivity as well as sitting time are associated with metabolic syndrome. Our aim was to examine joint associations of leisure time physical activity and total daily sitting time with metabolic syndrome., Methods: Leisure time physical activity and total daily sitting time were assessed by self-report in 15,235 men and women in the Danish Health Examination Survey 2007-2008. Associations between leisure time physical activity, total sitting time and metabolic syndrome were investigated in logistic regression analysis., Results: Adjusted odds ratios (OR) for metabolic syndrome were 2.14 (95% CI: 1.88-2.43) amongst participants who were inactive in leisure time compared to the most active, and 1.42 (95% CI: 1.26-1.61) amongst those who sat for ≥10h/day compared to <6h/day. Within strata of leisure time physical activity, sitting time was positively associated with metabolic syndrome. For example, in the moderate to vigorous physical activity stratum, ORs were 1.31 (95% CI: 1.11-1.54) and 1.48 (95% CI: 1.16-1.88) in participants who sat 6-10 and ≥10h/day compared to <6h/day., Conclusion: Higher amounts of sitting time seem to be associated with a higher prevalence of metabolic syndrome, even amongst individuals who are physically active., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We revise the species of anoles occurring along the Pacific versant of Mexico west of the Isthmus de Tehuantepec in the states of Oaxaca, Guerrero, and Puebla. Based on our analyses of morphological and molecular genetic data, we recognize 21 species, six of which we describe as new (i.e., Anolis carlliebi sp. nov., A. immaculogularis sp. nov., A. nietoi sp. nov., A. sacamecatensis sp. nov., A. stevepoei sp. nov., and A. zapotecorum sp. nov.). Furthermore, we synonymize Anolis forbesi Smith & Van Gelder 1955 with Anolis microlepidotus Davis 1954. Of the recognized species, six have smooth ventral scales (i.e., Anolis dunni, A. gadovii, A. liogaster, A. omiltemanus, A. peucephilus, and A. taylori) and 14 have keeled ventral scales (i.e., A. boulengerianus, A. carlliebi, A. immaculogularis, A. megapholidotus, A. microlepidotus, A. nebuloides, A. nebulosus, A. nietoi, A. quercorum, A. sacamecatensis, A. stevepoei, A. subocularis, A. unilobatus, and A. zapotecorum). In one species, A. macrinii, the ventral scales vary from smooth to weakly keeled. For each species we provide color descriptions in life, color photographs in life, descriptions and illustration of hemipenis morphology (if available), description of external morphology, distribution maps based on the specimensexamined, comments on the conservation status, and natural history notes. Finally, we provide a dichotomous key for the identification of the 21 species of anoles occurring along the Pacific versant of Mexico west of the Isthmus de Tehuantepec in the states of Oaxaca, Guerrero, and Puebla.

We describe the new species Anolis peucephilus sp. nov. from the Pacific versant of southern Mexico. Anolis peucephilus differs from all congeners by having a combination of (1) smooth ventral scales; (2) usually a patch of three greatly enlarged supraocular scales; (3) extremely short hind legs, longest toe of adpressed hind leg reaching to a point between levels of axilla and ear opening, ratio shank length/snout-vent length 0.18-0.21; (4) circumnasal usually in contact with first supralabial; and (5) a large yellowish orange dewlap in males and a very small to small white dewlap in females. In external morphology, A. peucephilus is most similar to A. omiltemanus from which it differs by having even shorter hind legs with the longest toe of adpressed hind leg reaching to a point between levels of axilla and ear opening (versus usually to ear opening, occasionally to slightly beyond ear opening or to a point between shoulder and ear opening in A. omiltemanus), a slightly larger dewlap in females, to 64 mm2 (versus to 41 mm2 in A. omiltemanus), the circumnasal usually in contact with the first supralabial (versus those scales separated by the presence of a subnasal in A. omiltemanus), and 4-6 internasal scales in the new species (versus usually 6-7 in A. omiltemanus). Furthermore, A. peucephilus differs from A. omiltemanus in hemipenial morphology (no finger-like processus on asulcate side in A. peucephilus versus such a processus present in A. omiltemanus). Also, in a preliminary molecular genetic analysis of the mitochondrial CO1 gene fragment, A. peucephilus has a genetic distance of 11.5% from A. omiltemanus. Anolis peucephilus was collected at night while the lizards were sleeping in pine trees, 2-10 m above the ground.

Background: Occupational heavy lifting is known to impose a high cardiovascular strain, but the risk of ischemic heart disease (IHD) from occupational heavy lifting is unknown. The objective was to investigate the association between occupational heavy lifting and risk of IHD and all-cause mortality, and the influence of occupational and leisure time physical activity on this association., Methods: Data were analyzed from 1987, 1994, and 2000 from the Danish National Health Interview Surveys providing a sample of 6,692 working men and 5,921 working women aged 16-85 years without cardiovascular disease at baseline. Conventional risk factors for the outcomes IHD and all-cause mortality were controlled for in Cox analyses., Results: Among men, heavy lifting was associated with increased risk for IHD (hazard ratio (HR): 1.52, 95% Confidence interval (95% CI): 1.15, 2.02), while a decreased risk was associated with occupational (HR: 0.50, 95% CI: 0.37, 0.68) and leisure time (HR: 0.73, 95% CI: 0.56, 0.95) physical activity. Referencing men with high occupational physical activity and no heavy lifting, men with high occupational physical activity and heavy lifting did not have an increased risk (HR: 1.11, 95% CI:0.68, 1.82), while men with low occupational physical activity and heavy lifting had a substantial increased risk (HR: 2.56, 95% CI:1.52, 4.32). No significant associations were found for all-cause mortality or for females., Conclusion: These findings indicate an excessive risk for IHD from occupational heavy lifting among men, particularly among those with low occupational and leisure time physical activity.