Family Member Experiences in Intensive Care Units Care: Insights From a Family Involvement Tool Implementation Trial.

Family involvement is widely considered an important part of patient care in the intensive care unit. From professional health care organizations, government, and hospital associations, there has been a cultural shift toward family presence as part of a wider commitment to patient-centered care. At the same time, the meaning and impact of family involvement in the intensive care unit setting remain opaque and under-studied. This study employed an ethnographic approach to better understand family involvement in practice and from the perspective of health care professionals and family members by studying an implementation trial of a family involvement tool in two intensive care units over 2 years. The findings revealed that an expanded and self-defined role for family members as carers in the intensive care unit challenged the current configuration of the nurse patient/family relationship and that family members were aware of these dynamics. While the intensive care unit implementation teams were both motivated to implement a novel way of facilitating family involvement, the processual, organizational, and contextual factors in the intensive care units largely determined the possibilities of its application. This suggests that interventions should address the specific context in which they are employed.

Derivation and validation of the UCAP-Q case-finding questionnaire to detect undiagnosed asthma and COPD.

BACKGROUND: Many people with asthma and COPD remain undiagnosed. We developed and validated a new case-finding questionnaire to identify symptomatic adults with undiagnosed obstructive lung disease. METHODS: Adults in the community with no prior history of physician-diagnosed lung disease who self-reported respiratory symptoms were contacted via random-digit dialling. Pre- and post-bronchodilator spirometry was used to confirm asthma or COPD. Predictive questions were selected using multinomial logistic regression with backward elimination. Questionnaire performance was assessed using sensitivity, predictive values and area under the receiver operating characteristic curve (AUC). The questionnaire was assessed for test-retest reliability, acceptability and readability. External validation was prospectively conducted in an independent sample and predictive performance re-evaluated. RESULTS: A 13-item Undiagnosed COPD and Asthma Population Questionnaire (UCAP-Q) case-finding questionnaire to predict undiagnosed asthma or COPD was developed. The most appropriate risk cut-off was determined to be 6% for either disease. Applied to the derivation sample (n=1615), the questionnaire yielded a sensitivity of 92% for asthma and 97% for COPD; specificity of 17%; and an AUC of 0.69 (95% CI 0.64-0.74) for asthma and 0.82 (95% CI 0.78-0.86) for COPD. Prospective validation using an independent sample (n=471) showed sensitivities of 93% and 92% for asthma and COPD, respectively; specificity of 19%; with AUCs of 0.70 (95% CI 0.62-0.79) for asthma and 0.81 (95% CI 0.74-0.87) for COPD. AUCs for UCAP-Q were higher compared to AUCs for currently recommended case-finding questionnaires for asthma or COPD. CONCLUSIONS: The UCAP-Q demonstrated high sensitivities and AUCs for identifying undiagnosed asthma or COPD. A web-based calculator allows for easy calculation of risk probabilities for each disease.

Discovery and SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as 5-HT7/2 inhibitors leading to the identification of a clinical candidate.

We report here the synthesis and characterization of a dual 5-HT7 / 5-HT2 receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT7 and 5-HT2A receptor ligand having a pKi = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT2A and as an inverse agonist in an in vitro functional assay for 5-HT7. In a validated in vivo model for central 5-HT7 activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED50 = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~27 ng/ml. In a validated in vivo model for central 5-HT2A activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED50 = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT2A receptor binding sites in the frontal cortex of the rat brain with an ED50 in good agreement with the ED50 value for central functional effect mediated by 5-HT2A receptor (ED50 = 0.8 mg/kg, p.o., 1 h).

Population-based case-finding to identify subjects with undiagnosed asthma or COPD.

BACKGROUND: ∼5-10% of adults may have undiagnosed airflow obstruction. The objective of this study was to develop a population-based case-finding strategy to assess the prevalence of undiagnosed airflow obstruction (asthma or COPD) amongst adults with respiratory symptoms in Canada. METHODS: Adults without a previous history of asthma, COPD or lung disease were recruited using random digit-dialling and asked if they had symptoms of dyspnoea, cough, sputum or wheeze within the past 6 months. Those who answered affirmatively completed the Asthma Screening Questionnaire (ASQ), COPD-Diagnostic Questionnaire (COPD-DQ) and COPD Assessment Test (CAT). Those with an ASQ score of ≥6 or a COPD-DQ score of ≥20 underwent pre- and post-bronchodilator spirometry to diagnose asthma or COPD. RESULTS: 12 117 individuals were contacted at home and assessed for study eligibility. Of the 1260 eligible individuals, 910 (72%) enrolled and underwent spirometry. Ultimately, 184 subjects (20% of those enrolled) had obstructive lung disease (73 asthma and 111 COPD). Individuals found to have undiagnosed asthma or COPD had more severe respiratory symptoms and impaired quality of life compared with those without airflow obstruction. The ASQ, COPD-DQ, and CAT had ROC areas for predicting undiagnosed asthma or COPD of 0.49, 0.64 and 0.56, respectively. Four descriptive variables (age, BMI, sex and pack-years smoked) produced better receiver operating characteristic (ROC) values than the questionnaires (ROC area=0.68). CONCLUSION: 20% of randomly selected individuals who report respiratory symptoms in Canada have undiagnosed airflow obstruction due to asthma or COPD. Questionnaires could exclude subjects at low risk but lack the ability to accurately find subjects with undiagnosed disease.

Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.

Mobilizing a Whole Community: Policy and Strategy Implications of an Integrated Local System Response to a Global Health Crisis.

The East Toronto Health Partners (ETHP) include more than 50 organizations working collaboratively to create an integrated system of care in the east end of Toronto. This existing partnership proved invaluable as a platform for a rapid, coordinated local response to the COVID-19 pandemic. Months after the first wave of the pandemic began, with the daily numbers of COVID-19 cases finally starting to decline, leaders from ETHP provided preliminary reflections on two critical questions: (1) How were existing integration efforts leveraged to mobilize a response during the COVID-19 crisis? and (2) How can the response to the initial wave of COVID-19 be leveraged to further accelerate integration and better address subsequent waves and system improvements once the pandemic abates?

Program of Integrated Care for Patients with Chronic Obstructive Pulmonary Disease and Multiple Comorbidities (PIC COPD+): a randomised controlled trial.

We sought to evaluate the effectiveness of a multi-component, case manager-led exacerbation prevention/management model for reducing emergency department visits. Secondary outcomes included hospitalisation, mortality, health-related quality of life, chronic obstructive pulmonary disease (COPD) severity, COPD self-efficacy, anxiety and depression.Two-centre randomised controlled trial recruiting patients with ≥2 prognostically important COPD-associated comorbidities. We compared our multi-component intervention including individualised care/action plans and telephone consults (12-weekly then 9-monthly) with usual care (both groups). We used zero-inflated Poisson models to examine emergency department visits and hospitalisation; Cox proportional hazard model for mortality.We randomised 470 participants (236 intervention, 234 control). There were no differences in number of emergency department visits or hospital admissions between groups. We detected difference in emergency department visit risk, for those that visited the emergency department, favouring the intervention (RR 0.74, 95% CI 0.63-0.86). Similarly, risk of hospital admission was lower in the intervention group for those requiring hospital admission (RR 0.69, 95% CI 0.54-0.88). Fewer intervention patients died (21 versus 36) (HR 0.56, 95% CI 0.32-0.95). No differences were detected in other secondary outcomes.Our multi-component, case manager-led exacerbation prevention/management model resulted in no difference in emergency department visits, hospital admissions and other secondary outcomes. Estimated risk of death (intervention) was nearly half that of the control.

Endometrial biomarkers for the non-invasive diagnosis of endometriosis.

BACKGROUND: About 10% of reproductive-aged women suffer from endometriosis, which is a costly, chronic disease that causes pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but it is expensive and carries surgical risks. Currently, there are no non-invasive tests available in clinical practice that accurately diagnose endometriosis. This is the first diagnostic test accuracy review of endometrial biomarkers for endometriosis that utilises Cochrane methodologies, providing an update on the rapidly expanding literature in this field. OBJECTIVES: To determine the diagnostic accuracy of the endometrial biomarkers for pelvic endometriosis, using a surgical diagnosis as the reference standard. We evaluated the tests as replacement tests for diagnostic surgery and as triage tests to inform decisions to undertake surgery for endometriosis. SEARCH METHODS: We did not restrict the searches to particular study designs, language or publication dates. To identify trials, we searched the following databases: CENTRAL (2015, July), MEDLINE (inception to May 2015), EMBASE (inception to May 2015), CINAHL (inception to April 2015), PsycINFO (inception to April 2015), Web of Science (inception to April 2015), LILACS (inception to April 2015), OAIster (inception to April 2015), TRIP (inception to April 2015) and ClinicalTrials.gov (inception to April 2015). We searched DARE and PubMed databases up to April 2015 to identify reviews and guidelines as sources of references to potentially relevant studies. We also performed searches for papers recently published and not yet indexed in the major databases. The search strategies incorporated words in the title, abstract, text words across the record and the medical subject headings (MeSH). SELECTION CRITERIA: We considered published peer-reviewed, randomised controlled or cross-sectional studies of any size that included prospectively collected samples from any population of reproductive-aged women suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from each study and performed a quality assessment. For each endometrial diagnostic test, we classified the data as positive or negative for the surgical detection of endometriosis and calculated the estimates of sensitivity and specificity. We considered two or more tests evaluated in the same cohort as separate data sets. We used the bivariate model to obtain pooled estimates of sensitivity and specificity whenever sufficient data were available. The predetermined criteria for a clinically useful test to replace diagnostic surgery was one with a sensitivity of 94% and a specificity of 79%. The criteria for triage tests were set at sensitivity at or above 95% and specificity at or above 50%, which in case of negative results rules out the diagnosis (SnOUT test) or sensitivity at or above 50% with specificity at or above 95%, which in case of positive result rules in the diagnosis (SpIN test). MAIN RESULTS: We included 54 studies involving 2729 participants, most of which were of poor methodological quality. The studies evaluated endometrial biomarkers either in specific phases of the menstrual cycle or outside of it, and the studies tested the biomarkers either in menstrual fluid, in whole endometrial tissue or in separate endometrial components. Twenty-seven studies evaluated the diagnostic performance of 22 endometrial biomarkers for endometriosis. These were angiogenesis and growth factors (PROK-1), cell-adhesion molecules (integrins α3ß1, α4ß1, ß1 and α6), DNA-repair molecules (hTERT), endometrial and mitochondrial proteome, hormonal markers (CYP19, 17ßHSD2, ER-α, ER-ß), inflammatory markers (IL-1R2), myogenic markers (caldesmon, CALD-1), neural markers (PGP 9.5, VIP, CGRP, SP, NPY, NF) and tumour markers (CA-125). Most of these biomarkers were assessed in single studies, whilst only data for PGP 9.5 and CYP19 were available for meta-analysis. These two biomarkers demonstrated significant diversity for the diagnostic estimates between the studies; however, the data were too limited to reliably determine the sources of heterogeneity. The mean sensitivities and specificities of PGP 9.5 (7 studies, 361 women) were 0.96 (95% confidence interval (CI) 0.91 to 1.00) and 0.86 (95% CI 0.70 to 1.00), after excluding one outlier study, and for CYP19 (8 studies, 444 women), they were were 0.77 (95% CI 0.70 to 0.85) and 0.74 (95% CI 0.65 to 84), respectively. We could not statistically evaluate other biomarkers in a meaningful way. An additional 31 studies evaluated 77 biomarkers that showed no evidence of differences in expression levels between the groups of women with and without endometriosis. AUTHORS' CONCLUSIONS: We could not statistically evaluate most of the biomarkers assessed in this review in a meaningful way. In view of the low quality of most of the included studies, the findings of this review should be interpreted with caution. Although PGP 9.5 met the criteria for a replacement test, it demonstrated considerable inter study heterogeneity in diagnostic estimates, the source of which could not be determined. Several endometrial biomarkers, such as endometrial proteome, 17ßHSD2, IL-1R2, caldesmon and other neural markers (VIP, CGRP, SP, NPY and combination of VIP, PGP 9.5 and SP) showed promising evidence of diagnostic accuracy, but there was insufficient or poor quality evidence for any clinical recommendations. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and using any non-invasive tests should only be undertaken in a research setting. We have also identified a number of biomarkers that demonstrated no diagnostic value for endometriosis. We recommend that researchers direct future studies towards biomarkers with high diagnostic potential in good quality diagnostic studies.

Effect of perceptions of menstrual blood loss and menstrual pain on women's quality of life.

OBJECTIVES: The aim of the study was to explore Australian women's experiences of menstruation and effect on quality of life (QoL). METHODS: A representative sample of women recruited through a commercial social research sampling organisation completed a detailed online questionnaire about menstruation. Specific detailed questions were asked about perceptions of heavy menstrual bleeding (HMB) and menstrual pain. RESULTS: The questionnaire was completed by 1575 women aged 20-39 years. Most perceived their bleeding to be light (11.6%) or moderate (60.5%); 363 (22.5%) perceived it to be heavy and 86 (5.3%) very heavy. Women who experienced severe or very severe menstrual pain were significantly more likely to report periods as heavy or very heavy (p < .001). The prevalence ratios for being confined to bed during menstruation for women experiencing severe or very severe menstrual pain were 12.02 (95% CI: 5.71-25.31) and 15.93 (95% CI: 7.51-33.78), respectively, compared with women experiencing no pain. The prevalence ratios for being confined to bed were 1.58 (95% CI: 1.11-2.24) and 1.53 (95% CI: 1.04-2.25) for women with heavy or very heavy bleeding, respectively. Women who experienced severe or very severe menstrual pain associated with their HMB were >12 times more likely to be confined to bed for 0.5-1 day during menstruation than if they reported HMB without pain. CONCLUSION: Severe menstrual pain with HMB has a much more profound effect on all aspects of women's QoL than HMB alone; it accounts for more days in bed and for loss of productivity.

Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia.

Dual orexin receptor antagonists have been shown to promote sleep in various species, including humans. Emerging research indicates that selective orexin-2 receptor (OX2R) antagonists may offer specificity and a more adequate sleep profile by preserving normal sleep architecture. Here, we characterized JNJ-42847922 ([5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone), a high-affinity/potent OX2R antagonist. JNJ-42847922 had an approximate 2-log selectivity ratio versus the human orexin-1 receptor. Ex vivo receptor binding studies demonstrated that JNJ-42847922 quickly occupied OX2R binding sites in the rat brain after oral administration and rapidly cleared from the brain. In rats, single oral administration of JNJ-42847922 (3-30 mg/kg) during the light phase dose dependently reduced the latency to non-rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, whereas REM sleep was minimally affected. The reduced sleep onset and increased sleep duration were maintained upon 7-day repeated dosing (30 mg/kg) with JNJ-42847922, then all sleep parameters returned to baseline levels following discontinuation. Although the compound promoted sleep in wild-type mice, it had no effect in OX2R knockout mice, consistent with a specific OX2R-mediated sleep response. JNJ-42847922 did not increase dopamine release in rat nucleus accumbens or produce place preference in mice after subchronic conditioning, indicating that the compound lacks intrinsic motivational properties in contrast to zolpidem. In a single ascending dose study conducted in healthy subjects, JNJ-42847922 increased somnolence and displayed a favorable pharmacokinetic and safety profile for a sedative/hypnotic, thus emerging as a promising candidate for further clinical development for the treatment of insomnia.

Urinary biomarkers for the non-invasive diagnosis of endometriosis.

BACKGROUND: About 10% of reproductive-aged women suffer from endometriosis which is a costly chronic disease that causes pelvic pain and subfertility. Laparoscopy is the 'gold standard' diagnostic test for endometriosis, but it is expensive and carries surgical risks. Currently, there are no simple non-invasive or minimally-invasive tests available in clinical practice that accurately diagnoses endometriosis. OBJECTIVES: 1. To provide summary estimates of the diagnostic accuracy of urinary biomarkers for the diagnosis of pelvic endometriosis compared to surgical diagnosis as a reference standard.2. To assess the diagnostic utility of biomarkers that could differentiate ovarian endometrioma from other ovarian masses.Urinary biomarkers were evaluated as replacement tests for surgical diagnosis and as triage tests to inform decisions to undertake surgery for endometriosis. SEARCH METHODS: The searches were not restricted to particular study design, language or publication dates. We searched the following databases to 20 April - 31 July 2015: CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, LILACS, OAIster, TRIP and ClinicalTrials.gov (trial register). MEDION, DARE, and PubMed were also searched to identify reviews and guidelines as reference sources of potentially relevant studies. Recently published papers not yet indexed in the major databases were also sought. The search strategy incorporated words in the title, abstract, text words across the record and the medical subject headings (MeSH) and was modified for each database. SELECTION CRITERIA: Published peer-reviewed, randomised controlled or cross-sectional studies of any size were considered, which included prospectively collected samples from any population of reproductive-aged women suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). We included studies comparing the diagnostic test accuracy of one or more urinary biomarkers with surgical visualisation of endometriotic lesions. DATA COLLECTION AND ANALYSIS: Two authors independently collected and performed a quality assessment of the data from each study. For each diagnostic test, the data were classified as positive or negative for the surgical detection of endometriosis and sensitivity and specificity estimates were calculated. If two or more tests were evaluated in the same cohort, each was considered as a separate data set. The bivariate model was used to obtain pooled estimates of sensitivity and specificity whenever sufficient data sets were available. The predetermined criteria for a clinically useful urine test to replace diagnostic surgery was one with a sensitivity of 94% and a specificity of 79% to detect endometriosis. The criteria for triage tests were set at sensitivity of equal or greater than 95% and specificity of equal or greater than 50%, which in case of negative result rules out the diagnosis (SnOUT test) or sensitivity of equal or greater than 50% with specificity of equal or greater than 95%, which in case of positive result rules the diagnosis in (SpIN test). MAIN RESULTS: We included eight studies involving 646 participants, most of which were of poor methodological quality. The urinary biomarkers were evaluated either in a specific phase of menstrual cycle or irrespective of the cycle phase. Five studies evaluated the diagnostic performance of four urinary biomarkers for endometriosis, including three biomarkers distinguishing women with and without endometriosis (enolase 1 (NNE); vitamin D binding protein (VDBP); and urinary peptide profiling); and one biomarker (cytokeratin 19 (CK 19)) showing no significant difference between the two groups. All of these biomarkers were assessed in small individual studies and could not be statistically evaluated in a meaningful way. None of the biomarkers met the criteria for a replacement test or a triage test. Three studies evaluated three biomarkers that did not differentiate women with endometriosis from disease-free controls. AUTHORS' CONCLUSIONS: There was insufficient evidence to recommend any urinary biomarker for use as a replacement or triage test in clinical practice for the diagnosis of endometriosis. Several urinary biomarkers may have diagnostic potential, but require further evaluation before being introduced into routine clinical practice. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and diagnosis of endometriosis using urinary biomarkers should only be undertaken in a research setting.

Use of hormonal therapy is associated with reduced nerve fiber density in deep infiltrating, rectovaginal endometriosis.

OBJECTIVE: To study the density of nerve fibers in cases of deep infiltrating endometriosis (DIE) of the rectovaginal septum in relation to various clinical factors. DESIGN: A research laboratory-based study. SETTING: A tertiary center together with a research laboratory. METHODS: Archived DIE tissue samples from 45 women operated upon for rectovaginal septum DIE were re-examined histologically, and by immunohistochemistry. MAIN OUTCOME MEASURES: The effect of progestogens or combined oral contraceptives on the density of nerve fibers, and the expression of nerve growth factor (NGF) and its high-affinity receptor (tyrosine kinase receptor A, Trk-A). RESULTS: The use of hormonal therapy was associated with reduced densities of sympathetic, parasympathetic and sensory nerve fibers in DIE lesions. Density of total nerve fibers (with pan-neuronal marker PGP9.5) was significantly lower (p < 0.05) in lesions collected from hormone-treated women (8.6/mm², 4.2-20.8/mm²; median density, from 25th to 75th quartiles) compared with that in lesions from untreated women (24.9/mm², 11.2-34.9/mm²). DIE lesions stained strongly for NGF and its receptor Trk-A. Expression of NGF, but not of Trk-A, was significantly reduced during use of hormonal therapy. CONCLUSIONS: Use of hormonal therapy was associated with significantly reduced nerve fiber density in DIE lesions. This may be an important mechanism of action of hormonal therapy for controlling DIE pain symptoms. The expression of estrogen-regulated NGF and its receptor was only partially suppressed during the use of hormonal therapy, suggesting that local estrogen action is often maintained during conventional hormonal therapy in cases of DIE.

Detection of the pan neuronal marker PGP9.5 by immuno-histochemistry and quantitative PCR in eutopic endometrium from women with and without endometriosis.

PURPOSE: To assess endometrial gene as well as protein expression of neuroendocrine and supposedly endometriosis-associated product PGP9.5 and pain symptoms in women with endometriosis and controls undergoing laparoscopy, using molecular biological and immuno-histochemical approaches in the same patients. METHODS: Biopsy of eutopic endometrium from 29 patients by sharp curettage, and preparation of paraffin blocks. Determination of PGP9.5 gene expression and protein abundance using qPCR and immuno-histochemistry. RESULTS: qPCR; The PGP9.5 mRNA expression level between women with (N = 16) and without (N = 13) endometriosis was not different, regardless of pain symptoms or menstrual cycle phase. PGP9.5 expression was higher in women who reported pain compared to those who did not; however, this association was not statistically significant. The expression of PGP9.5 mRNA was higher in women with endometriosis and pain during the proliferative than in the secretory phase (P = 0.03). Furthermore, in the first half of the cycle, the abundance of the PGP9.5 transcript was also significantly higher in endometriosis patients compared to those without (P = 0.03). Immuno-histochemistry; Thirteen of the 16 endometriosis patients showed positive PGP9.5 immuno-reactivity in the endometrium, whereas no such signal was observed in women without endometriosis. The absolute number of nerve fibres per mm(2) in women with endometriosis was similar, regardless of the pain symptoms. CONCLUSIONS: PGP9.5 mRNA expression is increased in the proliferative phase of endometriotic women with pain. The presence of nerve fibres was demonstrated by a PGP9.5 protein signal in immuno-histochemistry and restricted to patients with endometriosis. Based on these results, however, there did not appear to be a direct association between the gene expression and protein abundance in women with and without endometriosis or those that experienced pain.

Effects of anemia and iron deficiency on quality of life in women with heavy menstrual bleeding.

OBJECTIVE: To assess the impact of anemia and iron deficiency on health-related quality of life (HRQoL) in women treated for heavy menstrual bleeding (HMB). DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Five university hospitals in Finland. SAMPLE: A total of 236 women referred for HMB. METHODS: Women were randomized to treatment with hysterectomy or a levonorgestrel-releasing intrauterine system. We defined groups based on women's pretreatment hemoglobin [hemoglobin <120 g/L (anemic) vs. hemoglobin ≥120 g/L (nonanemic)] and serum ferritin (ferritin <15 µg/L vs. ≥15 µg/L) concentrations. HRQoL was compared between groups at baseline, 6 and 12 months after treatment. Hemoglobin and ferritin were followed for 5 years. MAIN OUTCOME MEASURES: HRQoL was measured by the RAND 36-item health survey (RAND-36), 5-Dimensional EuroQol and two questionnaires of mental wellbeing. RESULTS: At baseline, 63 women (27%) were anemic and 140 (60%) were severely iron deficient (ferritin <15 µg/L). Only 8% of the anemic women had taken iron supplementation. Twelve months after treatment hemoglobin had increased in both hemoglobin groups, but was still significantly lower (p < 0.001) in initially anemic women (128 g/L) compared with nonanemic women (136 g/L). Twelve months after treatment three domain scores of RAND-36 increased more (energy, p = 0.002; physical functioning, p = 0.04; social functioning, p = 0.05), and anxiety (p = 0.02) and depression scores (p = 0.002) decreased more in anemic compared with nonanemic women. Serum ferritin took 5 years to reach normal levels. CONCLUSIONS: Improved HRQoL after treatment of HMB is associated with correction of anemia. Clinicians should actively screen for anemia in women with HMB and emphasize early iron substitution as an integral part of treatment.

Abnormal uterine bleeding: advantages of formal classification to patients, clinicians and researchers.

OBJECTIVE: To highlight the advantages of formal classification of causes of abnormal uterine bleeding from a clinical and scientific perspective. DESIGN: Review and recommendations for local implementation. SETTING: In the past, research in the field of menstrual disorders has not been funded adequately with respect to the impact of symptoms on individuals, healthcare systems and society. This was confounded by a diverse terminology, which lead to confusion between clinical and scientific groups, ultimately harming the underlying evidence base. To address this, a formal classification system (PALM-COEIN) for the causes of abnormal uterine bleeding has been published for worldwide use by FIGO (International Federation of Gynecology and Obstetrics). POPULATION AND MAIN OUTCOME MEASURES: This commentary explains problems created by the prior absence of such a system, the potential advantages stemming from its use, and practical suggestions for local implementation. RESULTS AND CONCLUSIONS: The PALM-COEIN classification is applicable globally and, as momentum gathers, will ameliorate recurrence of historic problems, and harmonise reporting of clinical and scientific research to facilitate future progress in women's health.

Female genital mutilation/cutting--towards abandonment of a harmful cultural practice.

Globally, the prevalence of, and support for, female genital mutilation/cutting (FGM/C) is declining. However, the entrenched sense of social obligation that propagates the continuation of this practice and the lack of open communication between men and women on this sensitive issue are two important barriers to abandonment. There is limited evidence on the role of men and their experiences in FGM/C. Marriageability of girls is considered to be one of the main driving forces for the continuation of this practice. In some countries, more men than women are advocating to end FGM/C. Moreover, men, as partners to women with FGM/C, also report physical and psychosexual problems. The abandonment process involves expanding a range of successful programs, addressing the human rights priorities of communities and providing power over their own development processes. Anecdotal evidence exists that FGM/C is practised amongst African migrant populations in Australia. The Australian Government supports a taskforce to improve community awareness and education, workforce training and evidence building. Internationally, an African Coordinating Centre for abandonment of FGM/C has been established in Kenya with a major global support group to share research, promote solidarity, advocacy and implement a coordinated and integrated response to abandon FGM/C.

Direct Health Care Costs Associated With a Multicomponent COPD Exacerbation Intervention.

BACKGROUND: Health care costs attributed to COPD have been estimated at $4.7 trillion globally in the next 30 years. With the global burden of COPD rising, identification of interventions that might lead to health care cost savings is an imperative. Although many studies report the effect of COPD self-management interventions on subject outcomes and health care utilization, few data describe their effect on health care costs. METHODS: Using data linkage and established case-costing methods with provincial Canadian health databases, we established public health care costs (acute and community) for 12 months following randomization for the 462 participants enrolled in our randomized controlled trial of the Program of Integrated Care for Patients with COPD and Multiple Comorbidities. RESULTS: Total median (interquartile range) in-hospital costs in the 12 months follow-up for all (intervention and control) 462 trial participants were CAD $4,769 ($417-16,834) (equivalent to US $3,566 [$312-12,588]). Total costs incurred in the community were higher at CAD $8,011 ($4,749-13,831) (equivalent to US $5,990 [$3,551-10,342]). Controlling for sex, income quintile, Johns Hopkins Aggregated Diagnosis Groups score, and living in an urban locality, we found lower community health care costs but no differences in acute care costs for participants receiving our multicomponent COPD exacerbation prevention management intervention compared to usual care. CONCLUSIONS: Controlling for important confounders, we found lower public community health care costs but no difference in acute health care costs with our multicomponent COPD exacerbation prevention management intervention compared to usual care. Community health care costs were almost double those incurred compared to acute health care costs. Given this finding, although most COPD exacerbation management interventions generally focus on reducing the use of acute care, interventions that enable health care cost savings in the community require further exploration.

Variation in near-surface soil temperature drives plant assemblage differentiation across aspect.

Quantifying assemblage variation across environmental gradients provides insight into the ecological and evolutionary mechanisms that differentiate assemblages locally within a larger climate regime. We assessed how vascular plant functional composition and diversity varied across microenvironment to identify ecological differences in assemblages in a mountainous fieldsite in northeastern Utah, USA. Then, we looked at how life-history strategies and information about phylogenetic differences affect the relationship between functional metrics and environment. We found less functionally dispersed assemblages that were shorter and more resource-conservative on south-facing slopes where intra-annual soil temperature was hotter and more variable. In contrast, we found more functionally dispersed assemblages, that were taller and more resource-acquisitive on north-facing slopes where intra-annual temperature was cooler and less variable. Herbaceous and woody perennials drove these trends. Additionally, including information about phylogenetic differences in a dispersion metric indicated that phylogeny accounts for traits we did not measure. At this fieldsite, soil temperature acts as an environmental filter across aspect. If soil temperature increases and becomes more variable, intra-annually, the function of north- versus south-facing assemblages may be at risk for contrasting reasons. On south-facing slopes, assemblages may not have the variance in functional diversity needed to respond to more intense, stressful conditions. Conversely, assemblages on north-facing slopes may not have the resource-conservative strategies needed to persist if temperatures become hotter and more variable intra-annually. Given these results, we advocate for the inclusion of aspect differentiation in studies seeking to understand species and assemblage shifts in response to changing climate conditions.

Antibacterial activity of Dioscorea bulbifera Linn. extract and its active component flavanthrinin against skin-associated bacteria.

BACKGROUND: Dioscorea bulbifera Linn. has been used for wound care in Thailand. However, a comprehensive evaluation of its antibacterial activity is required. This study aimed to investigate the antibacterial efficacy of D. bulbifera extract against skin-associated bacteria and isolate and characterize its active antibacterial agent, flavanthrinin. METHODS: Air-dried bulbils of D. bulbifera were pulverised and extracted with hexane, dichloromethane, ethyl acetate, methanol, ethanol, and distilled water; vacuum filtered; concentrated; freeze-dried; and stored at -20 ºC. Antibacterial activity of the extracts was assessed using microdilution techniques against several skin-associated bacteria. Thin-layer chromatography (TLC) bioautography was used to identify the active compounds in the extract, which were fractionated by column chromatography and purified by preparative TLC. The chemical structures of the purified compounds were analysed using nuclear magnetic resonance (NMR). The cytotoxicity of the extract and its active compounds was evaluated in Vero cells. RESULTS: The ethyl acetate extract exhibited distinct inhibition zones against bacteria compared to other extracts. Therefore, the ethyl acetate extract of D. bulbifera in the ethyl acetate layer was used for subsequent analyses. D. bulbifera extract exhibited antibacterial activity, with minimum inhibitory concentrations (MICs) of 0.78-1.56 mg/mL. An active compound, identified through TLC-bioautography, demonstrated enhanced antibacterial activity, with MICs of 0.02-0.78 mg/mL. NMR analysis identified this bioactive compound as flavanthrinin. Both D. bulbifera extract and flavanthrinin-containing fraction demonstrated potent antibacterial activity against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and S. epidermidis. The flavanthrinin containing fraction demonstrated low cytotoxicity against Vero cells, showing CC50 values of 0.41 ± 0.03 mg/mL. These values are lower than the MIC value, indicating that this fraction is safer than the initial ethyl acetate extract. CONCLUSIONS: Dioscorea bulbifera extract and its bioactive component flavanthrinin demonstrated significant antibacterial activity against the skin-associated bacteria Staphylococci, including MRSA. Flavanthrinin has potential as a complementary therapeutic agent for managing skin infections owing to its potent antibacterial effects and low cytotoxicity.

Translational evaluation of JNJ-18038683, a 5-hydroxytryptamine type 7 receptor antagonist, on rapid eye movement sleep and in major depressive disorder.

In rodents 5-hydroxytryptamine type 7 (5-HT(7)) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT(7) receptor antagonist, (3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683). In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration, and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers JNJ-18038683 prolonged REM latency and reduced REM sleep duration, demonstrating that the effect of 5-HT(7) blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drug-drug interaction could not be ruled out. In a double-blind, active, and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or escitalopram separated from placebo, indicating a failed study lacking assay sensitivity. Post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group Montgomery-Åsberg Depression Rating Scale (MADRS) < = 12] and from sites with no placebo response (MADRS > = 28) are removed, there was a clinically meaningful difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.