Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial.

Importance: Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial. Objective: To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023. Interventions: Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days. Results: Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital. Conclusion and Relevance: In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg. Trial Registration: ClinicalTrials.gov Identifier: NCT04425031.

Molecular Determinants Underlying Delta Selective Compound 2 Activity at δ-Containing GABAA Receptors.

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 GABAA 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 ß 1 δ receptors: an α 4 (+) δ (-) interface site in the extracellular domain (ECD), equivalent to the diazepam binding site in αßγ 2 receptors, and two sites in the transmembrane domain (TMD) - one in the α 4 (+) ß 1 (-) and one in the α 4 (-) ß 1 (+) interface, with the α 4 (-) ß 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 (+) ß 1 (-) interface, either α 4(S303L) of the α 4 (+) side or ß 1(I289Q) of the ß 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 GABAA 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 GABAA receptor subtypes, for better understanding of tonic inhibition, and ultimately, for rational development of novel drugs.

GABAA receptor ß1 -subunit knock-out mice show increased delta power in NREM sleep and decreased theta power in REM sleep.

γ-Aminobutyric acid (GABA) acting through heteropentameric GABAA receptors plays a pivotal role in the sleep-promoting circuitry. Whereas the role of the different GABAA receptor α-subunits in sleep regulation and in mediating the effect of benzodiazepines for treatment of insomnia is well-described, the ß-subunits are less studied. Here we report the first study characterizing sleep in mice lacking the GABAA receptor ß1 -subunit (ß1-/- mice). We show that ß1-/- 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 ß1+/+ mice, without any change in the overall sleep-wake architecture. From GABAA receptor-specific autoradiography, it is further demonstrated that functional ß1 -subunit-containing GABAA receptors display the highest binding levels in the hippocampus and frontal cortex. In conclusion, this study suggests that the GABAA receptor ß1 -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 GABAA receptor subunits in sleep regulation. In addition, ß1-/- mice could provide a useful mouse model for future studies of the physiological role of delta and theta rhythms during sleep.

A simple echocardiographic score to rule out cardiac amyloidosis.

BACKGROUND: Early diagnosis of cardiac amyloidosis (CA) is warranted to initiate specific treatment and improve outcome. The amyloid light chain (AL) and inferior wall thickness (IWT) scores have been proposed to assess patients referred by haematologists or with unexplained left ventricular (LV) hypertrophy, respectively. These scores are composed of 4 or 5 variables, respectively, including strain data. METHODS: Based on 2 variables common to the AL and IWT scores, we defined a simple score named AMYLoidosis Index (AMYLI) as the product of relative wall thickness (RWT) and E/e' ratio, and assessed its diagnostic performance. RESULTS: In the original cohort (n = 251), CA was ultimately diagnosed in 111 patients (44%). The 2.22 value was selected as rule-out cut-off (negative likelihood ratio [LR-] 0.0). In the haematology subset, AL CA was diagnosed in 32 patients (48%), with 2.36 as rule-out cut-off (LR- 0.0). In the hypertrophy subset, ATTR CA was diagnosed in 79 patients (43%), with 2.22 as the best rule-out cut-off (LR- 0.0). In the validation cohort (n = 691), the same cut-offs proved effective: indeed, there were no patients with CA in the whole population or in the haematology or hypertrophy subsets scoring < 2.22, <2.36 or < 2.22, respectively. CONCLUSIONS: The AMYLI score (RWT*E/e') may have a role as an initial screening tool for CA. A < 2.22 value excludes the diagnosis in patients undergoing a diagnostic screening for CA, while a < 2.36 and a < 2.22 value may be better considered in the subsets with suspected cardiac AL amyloidosis or unexplained hypertrophy, respectively.

Self-rated physical fitness and measured cardiorespiratory fitness, muscular strength, and body composition.

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 (rmen  = 0.69 and rwomen  = 0.65) and moderately correlated to the sit-to-stand test (rmen  = 0.49 and rwomen  = 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.

Should leisure-time sedentary behavior be replaced with sleep or physical activity for prevention of diabetes?

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.

Favorable prognostic impact of Natural Killer cells and T cells in high-grade serous ovarian carcinoma.

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/mm2) compared with 29 month in patients with low level (<10 cells/mm2) (p = .0310). The median OS was 37 and 25 months in patients with high vs. low level of CD8+ T cells (cutoff 80 cells/mm2) (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.

Professionals' experiences with palliative care and collaboration in relation to a randomised clinical trial: a qualitative interview study.

BACKGROUND: International evidence on the outcome of generalist versus specialist palliative care provision in palliative care trajectories is limited and varied. In general, intervention studies can influence the organisation of palliative care practice and professional collaborations. However, randomised clinical trials in palliative care rarely consider the organisational significance of the studies, as experienced by the professionals involved. DOMUS is the abbreviation for a Danish intervention study designed as a randomised clinical trial, investigating an accelerated transition from oncological to specialist palliative care at home for patients with incurable cancer. Alongside conducting the palliative care intervention study, we wanted to discover the perspectives of the healthcare professionals involved. AIM: To explore the organisational significance of the DOMUS intervention study as experienced by the professionals involved. DESIGN: A qualitative interview study, using thematic content analysis and inspired by organisational theory. SETTING/PARTICIPANTS: Thirty-eight professionals from four units involved in the DOMUS intervention study took part in 10 groups and six individual interviews. RESULTS: The DOMUS randomised clinical trial intervention influenced and sometimes disrupted both the ways of organising, collaborating and practising palliative care, and patients' and relatives' understanding of their own situation. It did this by (1) referring a broader palliative care target group to specialist palliative care, leading to (2) different palliative care needs, professional tasks, and perceived impact on (3) the organisation of palliative care and (4) professional collaboration. CONCLUSION: Professionals involved in the DOMUS palliative care intervention found that the study had organisational significance, with an influence on professionals, patients and relatives. Specialist palliative care in Denmark is devoted organisationally and professionally to patients with severe or complex palliative care needs. Hence, new ways of organising palliative care for people in the earlier stages of their disease are needed.

Screening individuals' experiences of colonoscopy and colon capsule endoscopy; a mixed methods study.

BACKGROUND: The standard investigation in colorectal cancer screening (optical colonoscopy [OC]) has a less invasive alternative with the colon capsule endoscopy (CCE). The experiences of screening individuals are needed to support a decision aid (DA) and to provide a patient view in future health technology assessments (HTA). We aimed to explore the experiences of CCE at home and OC in an outpatient clinic by screening participants who experienced both investigations on the same bowel preparation. METHODS: In a mixed methods study, Danish screening individuals with a positive immunological fecal occult blood test (FIT) were consecutively included and underwent both CCE and OC in the same bowel preparation. They answered questionnaires about discomfort during CCE, delivered at home, and during a following OC in the outpatient clinic. Data were calculated in percentages and Wilcoxon signed rank test was used for comparisons. Among the 253 included patients, 10 participants were selected for a semi-structured interview about their experiences of the two examinations. The analysis and interpretation of the transcribed data were inspired by Ricoeur. RESULTS: Questionnaire data were received from 239 participants and revealed significant less discomfort during the CCE than the OC. Interview data included explained discomfort elements in two categories: 'The examination' and 'The setting'. Compared to OC, the CCE was experienced with less pain, embarrassment and invasiveness, but presented challenges and disadvantages as well, i.e., a large camera capsule to swallow, a longer waiting time for test results after CCE and an additional OC, if pathologies were found. The home setting for CCE delivery made the participants feel less like they were ill or patients less restricted and that they received more personal care, but could induce technical challenges. CONCLUSION: In screening individuals, CCE at home was associated with significantly less discomfort compared to OC at a hospital, and multiple reasons for this was identified.

Total sitting time, leisure time physical activity and risk of hospitalization due to low back pain: The Danish Health Examination Survey cohort 2007-2008.

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.

Validation of the NPAQ-short - a brief questionnaire to monitor physical activity and compliance with the WHO recommendations.

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.

Does High Tobacco Consumption Cause Psychological Distress? A Mendelian Randomization Study.

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.

Carotid-Ventricular Coupling During Exercise: A Pilot Study.

OBJECTIVES: To evaluate carotid elasticity and left ventricular elastance during a graded bicycle semisupine exercise test in patients with known or suspected coronary artery disease and compare them with a control group of healthy young volunteers. METHODS: Thirty-six elderly patients and 18 young healthy volunteers were recruited. The right carotid diameter was estimated by an automatic system applied to B-mode sonographic sequences, central mean blood and pulse pressures by radial artery tonometry, and cardiac volumes by 2-dimensional transthoracic echocardiography; from these direct measurements, the carotid cross-sectional distensibility coefficient and left ventricular elastance index were obtained. Analyses were performed at rest, at peak stress, and during the recovery phase. RESULTS: The elderly patients included 20 men (mean age ± SD, 61 ± 8 years); the volunteers included 9 men (mean age, 34 ± 3 years). The mean blood pressure (at rest: patients, 97 ± 7 mm Hg; controls, 93 ± 9 mm Hg; not significant) increased similarly in both groups during exercise and decreased during the recovery phase. The diameter was higher in patients than controls (7.5 ± 1.1 versus 6.2 ± 0.5 mm) and increased significantly with exercise only in the latter group (at peak: 6.5 ± 0.6 mm; P < .05). The distensibility coefficient and elastance index were lower in patients than controls during the test phases [at rest: 24.5 ± 10.2 versus 60.8 ± 21.3 × 10(-3)/kPa and 3.6 ± 1.4 versus 1.6 ± 0.8 mm Hg/(mL/m(2))] and mostly changed in the controls, showing a decreased distensibility coefficient (peak: 40.6 ± 15.1 × 10(-3)/kPa) and an increased elastance index [peak: 5.9 ± 2.8 mm Hg/(mL/m(2))]. CONCLUSIONS: In older patients with multiple cardiovascular risk factors or established coronary artery disease, an abnormal carotid-ventricular adaptation to exercise was observed when compared to young healthy individuals.

Total sitting time and the risk of incident diabetes in Danish adults (the DANHES cohort) over 5†years: a prospective study.

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.

Total sitting time and risk of myocardial infarction, coronary heart disease and all-cause mortality in a prospective cohort of Danish adults.

BACKGROUND: Evidence suggests that sitting time is adversely associated with health risks. However, previous epidemiological studies have mainly addressed mortality whereas little is known of the risk of coronary heart disease. This study aimed to investigate total sitting time and risk of myocardial infarction, coronary heart disease incidence and all-cause mortality. METHODS: In the Danish Health Examination Survey (DANHES) conducted in 2007-2008 we tested the hypothesis that a higher amount of daily total sitting time is associated with greater risk of myocardial infarction, coronary heart disease and all-cause mortality. The study population consisted of 71,363 men and women aged 18-99 years without coronary heart disease. Participants were followed for myocardial infarction, coronary heart disease and mortality in national registers to August 10, 2012. Cox regression analyses were performed with adjustment for potential confounders and multiple imputation for missing values. RESULTS: During a mean follow-up period of 5.4 years 358 incident cases of myocardial infarction, 1,446 of coronary heart disease, and 1,074 deaths from all causes were registered. The hazard ratios associated with 10 or more hours of daily sitting compared to less than 6 hours were 1.38 (95% CI: 1.01, 1.88) for myocardial infarction, 1.07 (95% CI: 0.91, 1.27) for coronary heart disease and 1.31 (95% CI: 1.09, 1.57). Compared to sitting less than 6 hours per day and being physically active in leisure time, the hazard ratios of sitting more than 10 hours per day and also being physically inactive in leisure time were 1.80 (95% CI: 1.15, 2.82) for myocardial infarction, 1.42 (95% CI: 1.11, 1.81) for coronary heart disease, and 2.29 (95% CI: 1.82, 2.89) for all-cause mortality. CONCLUSIONS: The results suggest that a higher amount of daily total sitting time is associated with all-cause mortality, particularly among inactive adults. In relation to coronary heart, disease results were less clear. This paper adds new evidence to the limited data on the evidence of sitting time and cardiovascular disease and mortality.

Joint association of physical activity in leisure and total sitting time with metabolic syndrome amongst 15,235 Danish adults: a cross-sectional study.

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.

Echocardiographic derived forward left ventricular output improves risk prediction in systolic heart failure.

BACKGROUND AND AIMS: Though widely used to classify heart failure (HF) patients, the prognostic role of left ventricular ejection fraction (LVEF) is debated. We hypothesized that the echocardiographic measures of forward LV output, being more representative of cardiac hemodynamics, may improve risk prediction in a large cohort of HF patients with systolic dysfunction. METHODS: Consecutive stable HF patients with LVEF <50% on guideline-recommended therapies undergoing an echocardiography including the evaluation of forward LV output (i.e., LV outflow tract velocity-time integral [LVOT-VTI], stroke volume index [SVi], and cardiac index [CI]) over a 6-year period, were selected and followed-up for the endpoint of cardiac and all-cause death. RESULTS: Among the 1,509 patients analyzed (71±12 years, 75% males, LVEF 35±9%), 328 (22%) died during a median 28-month (14-40) follow-up, 165 (11%) of which for cardiac causes. At multivariable regression analysis, LVOT-VTI (<0.001), SVi (p<0.001), and CI (p<0.001), but not LVEF (p>0.05), predicted cardiac and all-cause death. The optimal prognostic cut-offs for LVOT-VTI, SVi, and CI were 15 cm, 38 mL/m2, and 2 L/min/m2, respectively. Adding each of these measures to a multivariable risk model (including clinical, biohumoral, and echocardiographic markers) improved risk prediction (p<0.001). Among the different measures of forward LV output, CI was less accurate than LVOT-VTI and SVi. CONCLUSION: The echocardiographic evaluation of forward LV output improves risk prediction in HF patients across a wide LVEF spectrum over other well-established clinical, biohumoral, and echocardiographic prognostic markers.

Standard operating procedures for female genital sexual pain.

INTRODUCTION: Female genital sexual pain (GSP) is a common, distressing complaint in women of all ages that is underrecognized and undertreated. Definitions and terminology for female GSP are currently being debated. While some authors have suggested that GSP is not per se a sexual dysfunction, but rather a localized genial pain syndrome, others adhere to using clearly sexually related terms such as dyspareunia and vaginismus. AIM: The aims of this brief review are to present definitions of the different types of female GSP. Their etiology, incidence, prevalence, and comorbidity with somatic and psychological disorders are highlighted, and different somatic and psychological assessment and treatment modalities are discussed. METHODS: The Standard Operating Procedures (SOP) committee was composed of a chair and five additional experts. No corporate funding or remuneration was received. The authors agreed to survey relevant databases, journal articles and utilize their own clinical experience. Consensus was guided by systematic discussions by e-mail communications. MAIN OUTCOME/RESULTS: There is a clear lack of epidemiological data defining female GSP disorders and a lack of evidence supporting therapeutic interventions. However, this international expert group will recommend guidelines for management of female GSP. CONCLUSIONS: GSP disorders are complex. It is recommended that their evaluation and treatment are performed through comprehensive somato-psychological multidisciplinary approach.

Cognitive impairment and polidistrectual atherosclerotic disease in chylomicronemia syndrome: a case report.

A case of chylomicronemia syndrome is reported in a 72-year-old male with distinctive features of chronic pancreatic damage, severe hypertriglyceridemia, polidistrectual atherosclerosis and premature cognitive impairment. Although the patient had a positive history for recurrent episodes of pancreatitis the characteristic lesions of the hyperchylomicronemia syndrome, such as eruptive xanthomas and lipemia retinalis, were not present and splenomegaly could not be documented due to a previous post-traumatic splenectomy. Based on clinical phenotype, an apolipoprotein C-II deficiency was excluded by a fresh plasma infusion test, in which clarification of the patient plasma was not obtained. The absence of changes in the lipoprotein electrophoretic plasma after heparin infusion can be secondary to a lipoprotein lipase deficiency, a rare genetic disorder with an incidence of one per million. In relation to the resistance to diet and drugs, plasma exchange therapy was performed. After 3 years of this treatment there was no significant progression of atherosclerosis.