Publications by authors named "Ian Fraser"

200 Publications

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

J Med Chem 2021 Apr 17;64(7):3658-3676. Epub 2021 Mar 17.

Reviral Ltd., Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2FX, U.K.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01882DOI Listing
April 2021

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

Healthc Q 2020 Oct;23(3):15-23

FCFP, is the physician lead for Health Access Thorncliffe Park and chair of EasT-FPN in Toronto, ON.

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?
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http://dx.doi.org/10.12927/hcq.2020.26338DOI Listing
October 2020

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

Bioorg Med Chem Lett 2021 01 7;31:127669. Epub 2020 Nov 7.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.

We report here the synthesis and characterization of a dual 5-HT / 5-HT 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-HT and 5-HT receptor ligand having a pK = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT and as an inverse agonist in an in vitro functional assay for 5-HT. In a validated in vivo model for central 5-HT activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED = 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-HT activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT receptor binding sites in the frontal cortex of the rat brain with an ED in good agreement with the ED value for central functional effect mediated by 5-HT receptor (ED = 0.8 mg/kg, p.o., 1 h).
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http://dx.doi.org/10.1016/j.bmcl.2020.127669DOI Listing
January 2021

Comparison of Rapid to Standard Volumetric Modulated Arc Therapy for Palliative Radiotherapy in Lung Cancer Patients.

Cureus 2020 Aug 26;12(8):e10055. Epub 2020 Aug 26.

Radiation Oncology, British Columbia Cancer Agency, Vancouver, CAN.

Patients with incurable lung cancer often present with debilitating symptoms that require urgent palliative radiotherapy. Volumetric modulated arc therapy (VMAT) provides several dosimetric advantages compared to basic non-conformal techniques, but involves complex planning resulting in a slower turn-around time for treatment. A simplified planning technique known as 'rapid VMAT' was developed with an aim to deliver palliative treatment to patients within 48 hours. The purpose of this study was to prospectively compare the dosimetric quality of rapid VMAT plans to standard VMAT plans. Fourteen consecutive rapid VMAT cases were re-planned de novo as per standard VMAT planning guidelines. Planning target volume (PTV) and organs at risk (OARs) were then compared. PTV coverage and dose to OARs including the spinal canal, lung, heart, and esophagus were similar between rapid and standard VMAT. Each plan was ready for treatment within 48 hours of the CT simulation. This study describes an expedited process for which palliative radiotherapy can be delivered to lung tumors with a similar robust quality that is provided for curative intent VMAT radiotherapy plans.
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http://dx.doi.org/10.7759/cureus.10055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520402PMC
August 2020

Best Practices for Counseling Adolescents about the Etonogestrel Implant.

J Pediatr Adolesc Gynecol 2020 Oct 2;33(5):448-454. Epub 2020 Jul 2.

Sexual Health Service, New Crofte Centre, Newcastle upon Tyne, UK.

Among young persons, ease of use, high efficacy, and high acceptability makes the etonogestrel contraceptive implant an important choice for this age group. Adolescent-friendly, patient-centered counseling considers the patient's cognitive development, the influence of friends and family, as well as their own preferences and values. Age-appropriate language, graphics, and models are useful to explain contraceptive options and relevant side effects. Effectiveness, reversibility, safety, noncontraceptive benefits, and side effects are important attributes and should be discussed when teens are choosing a contraceptive method. In this review we describe suggested best practices for counseling adolescents about the etonogestrel implant so they can make informed, prudent decisions about using this contraceptive method.
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http://dx.doi.org/10.1016/j.jpag.2020.06.022DOI Listing
October 2020

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

Eur Respir J 2020 06 18;55(6). Epub 2020 Jun 18.

The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada

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.
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http://dx.doi.org/10.1183/13993003.00024-2020DOI Listing
June 2020

Support needs and health-related quality of life of family caregivers of patients requiring prolonged mechanical ventilation and admission to a specialised weaning centre: A qualitative longitudinal interview study.

Intensive Crit Care Nurs 2020 Jun 27;58:102808. Epub 2020 Feb 27.

Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Canada; Division of Respirology, Department of Medicine, Michael Garron Hospital & University of Toronto, Toronto, Canada; Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College, London, United Kingdom.

Objectives: Family caregivers of patients requiring prolonged mechanical ventilation may experience physical and psychological morbidity associated with a protracted intensive care unit experience. Our aim was to explore potentially modifiable support needs and care processes of importance to family caregivers of patients requiring prolonged mechanical ventilation and transition from the intensive care unit to a specialised weaning centre.

Research Methodology/design: A longitudinal qualitative descriptive interview study. Data was analysed using directed content analysis.

Setting: A 6-bed specialised weaning centre in Toronto, Canada.

Findings: Eighteen family caregivers completed interviews at weaning centre admission (100%), and at two-weeks (40%) and three-months after discharge (22%) contributing 29 interviews. Caregivers were primarily women (61%) and spouses (50%). Caregivers perceived inadequate informational, emotional, training, and appraisal support by health care providers limiting understanding of prolonged ventilation, participation in care and decision-making, and readiness for weaning centre transition. Participants reported long-term physical and psychological health changes including alterations to sleep, energy, nutrition and body weight.

Conclusions: Deficits in informational, emotional, training, and appraisal support of family caregivers of prolonged mechanical ventilation patients may increase caregiver burden and contribute to poor health outcomes. Strategies for providing support and maintaining family caregiver health-related quality of life are needed.
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http://dx.doi.org/10.1016/j.iccn.2020.102808DOI Listing
June 2020

Diagnosing adenomyosis: an integrated clinical and imaging approach.

Hum Reprod Update 2020 04;26(3):392-411

Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy.

Background: Adenomyosis is a benign uterine disorder where endometrial glands and stroma are pathologically demonstrated within the uterine myometrium. The pathogenesis involves sex steroid hormone abnormalities, inflammation, fibrosis and neuroangiogenesis, even though the proposed mechanisms are not fully understood. For many years, adenomyosis has been considered a histopathological diagnosis made after hysterectomy, classically performed in perimenopausal women with abnormal uterine bleeding (AUB) or pelvic pain. Until recently, adenomyosis was a clinically neglected condition. Nowadays, adenomyosis may also be diagnosed by non-invasive techniques, because of imaging advancements. Thus, a new epidemiological scenario has developed with an increasing number of women of reproductive age with ultrasound (US) or magnetic resonance imaging (MRI) diagnosis of adenomyosis. This condition is associated with a wide variety of symptoms (pelvic pain, AUB and/or infertility), but it is also recognised that some women are asymptomatic. Furthermore, adenomyosis often coexists with other gynecological comorbidities, such as endometriosis and uterine fibroids, and the diagnostic criteria are still not universally agreed. Therefore, the diagnostic process for adenomyosis is challenging.

Objective And Rationale: We present a comprehensive review on the diagnostic criteria of adenomyosis, including clinical signs and symptoms, ultrasound and MRI features and histopathological aspects of adenomyotic lesions. We also briefly summarise the relevant theories on adenomyosis pathogenesis, in order to provide the pathophysiological background to understand the different phenotypes and clinical presentation. The review highlights the controversies of multiple existing criteria, summarising all of the available evidences on adenomyosis diagnosis. The review aims also to underline the future perspective for diagnosis, stressing the importance of an integrated clinical and imaging approach, in order to identify this gynecological disease, so often underdiagnosed.

Search Methods: PubMed and Google Scholar were searched for all original and review articles related to diagnosis of adenomyosis published in English until October 2018.

Outcomes: The challenge in diagnosing adenomyosis starts with the controversies in the available pathogenic theories. The difficulties in understanding the way the disease arises and progresses have an impact also on the specific diagnostic criteria to use for a correct identification. Currently, the diagnosis of adenomyosis may be performed by non-invasive methods and the clinical signs and symptoms, despite their heterogeneity and poor specificity, may guide the clinician for a suspicion of the disease. Imaging techniques, including 2D and 3D US as well as MRI, allow the proper identification of the different phenotypes of adenomyosis (diffuse and/or focal). From a histological point of view, if the diagnosis of diffuse adenomyosis is straightforward, in more limited disease, the diagnosis has poor inter-observer reproducibility, leading to extreme variations in the prevalence of disease. Therefore, an integrated non-invasive diagnostic approach, considering risk factors profile, clinical symptoms, clinical examination and imaging, is proposed to adequately identify and characterise adenomyosis.

Wider Implications: The development of the diagnostic tools allows the physicians to make an accurate diagnosis of adenomyosis by means of non-invasive techniques, representing a major breakthrough, in the light of the clinical consequences of this disease. Furthermore, this technological improvement will open a new epidemiological scenario, identifying different groups of women, with a dissimilar clinical and/or imaging phenotypes of adenomyosis, and this should be object of future research.
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http://dx.doi.org/10.1093/humupd/dmz049DOI Listing
April 2020

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.

J Pharmacol Exp Ther 2020 03 9;372(3):339-353. Epub 2019 Dec 9.

Janssen Research & Development, LLC, San Diego, California.

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.
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http://dx.doi.org/10.1124/jpet.119.262139DOI Listing
March 2020

Patterns of Radiotherapy Utilization for Lung Cancer Patients with Brain Metastases: A Population-based Analysis.

Cureus 2019 Sep 7;11(9):e5591. Epub 2019 Sep 7.

Radiation Oncology, British Columbia Cancer Agency, Prince George, CAN.

Introduction: Brain metastases occur in 15%-20% of lung cancer patients. Recently, studies have suggested that whole-brain radiotherapy (WBRT) may not prolong survival for a subset of patients, and is associated with significant side-effects. Furthermore, it is hypothesized that radiotherapy is often given near the end-of-life when the potential for benefit is minimal. Therefore, this study investigates how frequently radiotherapy for brain metastases is given near the end-of-life in a population-based cohort.

Materials And Methods: All lung cancer patients who received radiotherapy in British Columbia for brain metastases in 2014-2015 were identified. Patient and treatment characteristics were collected and analyzed to assess associations with death within 90 days of first radiation treatment.

Results: In total, 740 patients were identified, with a total of 826 courses of brain radiation. The 90-day mortality rate was 40% (n=330). Multivariable analysis demonstrated higher odds for age (odds ratio (OR) = 1.04, 95% confidence interval (CI) 1.02-1.05), Eastern Cooperative Oncology Group (ECOG) performance score of 2 or higher (OR = 1.59, 95% CI 1.09-2.31) and squamous cell carcinoma (OR = 2.10, 95% CI 1.13-3.90) and lower odds for initial systemic therapy (OR = 0.48, 95% CI 0.34-0.68), more than five fractions of radiotherapy (OR = 0.25, 95% CI 0.16-0.39) and stereotactic radiation (OR = 0.29, 95% CI 0.13-0.65).

Conclusion: In our population-based study, WBRT is given in 86% of radiotherapy courses for brain metastases from lung cancer. Of these patients, 40% received treatment near the end-of-life. We identified several factors associated with shortened survival. Using these factors and already established prognostic tools, WBRT utilization should be decreased in the future, improving individualized treatment for patients with brain metastases from lung cancer.
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http://dx.doi.org/10.7759/cureus.5591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820896PMC
September 2019

Palliative thoracic radiotherapy near the end of life in lung cancer: A population-based analysis.

Lung Cancer 2019 09 22;135:97-103. Epub 2019 Feb 22.

Department of Surgery, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, 11th Floor, Vancouver, British Columbia, V5Z 1M9, Canada; Radiation Therapy Program, BC Cancer - Prince George (Centre for the North), 1215 Lethbridge Street, Prince George, British Columbia, V2M 7E9, Canada. Electronic address:

Objectives: Palliative thoracic radiotherapy (RT) can improve quality of life for patients with advanced lung cancer, but treatment can be associated with acute toxicity and symptomatic relief may take several weeks. The optimal fractionation schedule is not known. Delivery of RT near the end of life (EOL) is an emerging indicator of poor quality care. The aim of this study was to determine utilization of palliative thoracic RT in the last 4 weeks of life, and factors associated with its use, in patients with incurable lung cancer in a population-based healthcare system.

Materials And Methods: All patients with lung cancer in British Columbia treated with palliative thoracic RT in 2014 and 2015 were identified. Associations between starting a course of palliative thoracic RT within 4 weeks of death and patient/treatment characteristics were assessed using univariate and multivariate logistic regression analysis.

Results: 1676 courses of palliative thoracic RT were delivered to 1584 lung cancer patients. Median survival was 20 weeks. 12% of palliative thoracic RT courses were delivered in the last 4 weeks of life, with short fractionation schedules and simple RT planning techniques used more frequently near EOL. Of RT courses delivered in the last 4 weeks of life 89% were courses of 1 - 5 fractions, 75% were completed as prescribed and 94% involved simple 1-2 field RT techniques. Receipt of RT in the last 4 weeks of life was associated with male gender, younger age, poor performance status, metastatic disease, small cell carcinoma histology and no prior chemotherapy.

Conclusion: Further study and standardization of quality indicators for palliative RT utilization near EOL is required. Whilst clarification occurs, physicians should consider the prognosis of patients with incurable lung cancer and the realistic expectation of benefit from palliative thoracic RT when considering treatment indications and fractionation schedules.
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http://dx.doi.org/10.1016/j.lungcan.2019.02.024DOI Listing
September 2019

Bleeding profile associated with 1-year use of the segesterone acetate/ethinyl estradiol contraceptive vaginal system: pooled analysis from Phase 3 trials.

Contraception 2019 12 6;100(6):438-444. Epub 2019 Aug 6.

Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Objectives: To describe bleeding patterns among users of the segesterone acetate (SA) and ethinyl estradiol (EE) contraceptive vaginal system (CVS), and identify factors associated with unscheduled bleeding/spotting (B/S).

Study Design: We pooled results from two multicenter, single-arm, open-label, pivotal, phase 3 studies of the SA/EE CVS conducted in 17 US and 7 international sites. Participants (age 18-40 years; BMI ≤29 kg/m) followed a 21/7-day in/out schedule of CVS use for up to 13 cycles and recorded vaginal bleeding daily in paper diaries. Scheduled and unscheduled B/S were summarized by cycle. We used multiple logistic regression to identify factors associated with unscheduled bleeding/spotting, based on the first 4 cycles only.

Results: Analysis included data from 2070 participants (16,408 cycles). Ninety-eight percent documented scheduled B/S [mean (SD): 4.9 (1.1) days/cycle)]. Absence of scheduled B/S was 5-8% of women/cycle. Unscheduled B/S ranged from 13.2% to 21.7% of women per cycle. Few women (1.8%) discontinued prematurely due to unacceptable bleeding. Black women were more likely to report unscheduled B/S than White women [Adjusted odds ratio (AOR) = 1.49, 95% confidence interval (CI) = 1.14-1.94]. Women with fewer years of schooling [
Conclusions: Participants using the SA/EE CVS up to 13 cycles reported good cycle control. Discontinuation due to unacceptable bleeding was very low. Further research into demographic/other differences with reported unscheduled bleeding is warranted.

Implications: Since good cycle control is a key factor influencing contraceptive selection, adherence and continuation of combined hormonal contraceptives, the favorable bleeding profiles experienced by women during the SA/EE CVS clinical trials provide reassuring information for prospective users.
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http://dx.doi.org/10.1016/j.contraception.2019.07.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893119PMC
December 2019

Can initial vaginal bleeding patterns in etonogestrel implant users predict subsequent bleeding in the first 2 years of use?

Contraception 2019 10 6;100(4):264-268. Epub 2019 Jun 6.

University of California, Davis, Sacramento, CA 95817, USA.

Objectives: To evaluate if a simple method for characterizing vaginal bleeding patterns in etonogestrel contraceptive implant users can predict subsequent patterns and bleeding-related discontinuation over the first 2 years of use.

Study Design: We reanalyzed phase 3 study bleeding data for non-breastfeeding participants from the United States, Europe, Russia and Chile during the first 2 years of implant use to characterize and correlate bleeding patterns. We used 90-day reference periods with period 1.1 starting at Day 29 and ending at Day 118. We dichotomized bleeding patterns as "favorable" (amenorrhea, infrequent bleeding and normal frequency bleeding without prolonged bleeding) or "unfavorable' (prolonged and/or frequent bleeding) and tracked user groups based on these bleeding patterns in reference period 1.1 through Year 1 and from Year 1 through Year 2, respectively.

Results: We evaluated data from 537 and 428 women with up to 1 and 2 years use, respectively. Of the 325 (60.5%) women with favorable bleeding in reference period 1.1, 275 (84.6%) reported favorable bleeding also in reference period 2, 197 (60.6%) reported favorable bleeding throughout Year 1, and favorable bleeding in 75-85% of reference periods in Year 2. Among 212 (39.5%) women with unfavorable bleeding in reference period 1.1, 118 (55.7%) continued with unfavorable bleeding in reference period 2, while about 40%-50% reported favorable patterns in RP 2, 3 and/or 4. Initial favorable bleeding resulted in lower discontinuation rates than initial unfavorable bleeding in years 1 (3.7% vs 12.7%, p≪.0001) and 2 (2.5% vs 16.5%, p≪.0001).

Conclusion: Implant users with favorable bleeding in the first reference period are likely to continue with favorable bleeding over the next 2 years. Initial bleeding patterns predict overall continuation rates in years 1 and 2. Implications Statement When evaluating vaginal bleeding in any 90-day reference period over 2 years of etonogestrel implant use, approximately 80% of women with favorable and 40% with unfavorable bleeding patterns will have favorable bleeding in the next reference periods. These findings can facilitate counseling regarding bleeding for women using the etonogestrel implant.
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http://dx.doi.org/10.1016/j.contraception.2019.05.017DOI Listing
October 2019

Antibacterial activity of cuminaldehyde on food-borne pathogens, the bioactive component of essential oil from Cuminum cyminum L. collected in Thailand.

J Complement Integr Med 2019 May 25;16(4). Epub 2019 May 25.

Department of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand.

Background Cuminum cyminum L., commonly known as cumin, has been traditionally used in Thai traditional medicine and traditional food flavoring. The present study investigated the chemical composition, antimicrobial activity against all tested major food-borne pathogenic bacteria, and bioactive components of essential oil extracted from C. cyminum L. collected in Thailand. Methods The main components of the essential oil were investigated by gas chromatography-mass spectrometry (GC-MS) technique. Antibacterial activities against Bacillus cereus, Staphylococcus aureus, Escherichia coli, and Salmonella Typhi were investigated by disk diffusion and microdilution method. The presence of the biologically active antibacterial components was also confirmed by the thin-layer chromatography (TLC)-bioautography. Results The main components of the essential oil investigated by GC-MS were cuminaldehyde (27.10%), beta-pinene (25.04%) and gamma-terpinene (15.68%). The essential oil exhibited antibacterial activity against B. cereus, S. aureus, E. coli and S. Typhi. The essential oil showed the strongest antimicrobial activity against B. cereus with a comparable inhibition zone to tetracycline. TLC confirmed the presence of biologically active antibacterial component in the essential oil against all tested food-borne bacteria. It is further demonstrated that cuminaldehyde was the most active compound in TLC-bioautography which inhibited all of tested bacteria. Conclusions Essential oil extracted from C. cyminum L. exhibited antibacterial activity against all tested major food-borne pathogenic bacteria. Cuminaldehyde is a major bioactive component. Our results suggest that the essential oil extracted from C. cyminum L. could be applied as an alternative natural preservative to control food-borne disease and have the potential for further development of new antibacterial agents.
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http://dx.doi.org/10.1515/jcim-2018-0195DOI Listing
May 2019

Characterization of a Selective, Orally Available, and Brain Penetrant Small Molecule GPR139 Agonist.

Front Pharmacol 2019 21;10:273. Epub 2019 Mar 21.

Janssen Research & Development, LLC, San Diego, CA, United States.

Recently, our group along with another demonstrated that GPR139 can be activated by L-phenylalanine (L-Phe) and L-tryptophan (L-Trp) at physiologically relevant concentrations. GPR139 is discretely expressed in brain, with highest expression in medial habenula. Not only are the endogenous ligands catecholamine/serotonin precursors, but GPR139 expressing areas can directly/indirectly regulate the activity of catecholamine/serotonin neurons. Thus, GPR139 appears expressed in an interconnected circuit involved in mood, motivation, and anxiety. The aim of this study was to characterize a selective and brain penetrant GPR139 agonist (JNJ-63533054) in relevant models. JNJ-63533054 was tested for its effect on c-fos activation in the habenula and dorsal striatum. microdialysis experiments were performed in freely moving rats to measure basal levels of serotonin or dopamine (DA) in prefrontal cortex (mPFC) and nucleus accumbens (NAc). Finally, the compound was profiled in behavioral models of anxiety, despair, and anhedonia. The agonist (10-30 mg/kg, p.o.) did not alter c-fos expression in medial habenula or dorsal striatum nor neurotransmitter levels in mPFC or NAc. JNJ-63533054 (10 mg/kg p.o.) produced an anhedonic-like effect on urine sniffing, but had no significant effect in tail suspension, with no interaction with imipramine, no effect on naloxone place aversion, and no effect on learned helplessness. In the marble burying test, the agonist (10 mg/kg p.o.) produced a small anxiolytic-like effect, with no interaction with fluoxetine, and no effect in elevated plus maze (EPM). Despite GPR139 high expression in medial habenula, an area with connections to limbic and catecholaminergic/serotoninergic areas, the GPR139 agonist had no effect on c-fos in medial habenula. It did not alter catecholamine/serotonin levels and had a mostly silent signal in models commonly associated with these pathways. The physiological function of GPR139 remains elusive.
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http://dx.doi.org/10.3389/fphar.2019.00273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437111PMC
March 2019

Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation.

Contraception 2019 06 1;99(6):323-328. Epub 2019 Mar 1.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.

Objectives: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily.

Study Design: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive days and removed it for 7 days of each 28-day cycle. Four studies used the final manufactured CVS, including a 1-year pharmacokinetic study, two 1-year phase 3 trials and a second-year treatment extension study. We assessed safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies.

Results: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m] received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of use. Women using the final CVS most commonly reported adverse events of headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%) and abdominal pain (n=225, 10%). Few (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29 kg/m (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions in 4259 (19.5%) cycles and complete expulsions in 1509 (7%) cycles, most frequently in the initial cycle [499/2050 (24.3%) and 190/2050 (9.3%), respectively]. Safety-focused studies revealed no safety concerns.

Conclusion: The 1-year SA/EE CVS has an acceptable safety profile. Additional studies are warranted in obese women at higher risk of VTE.

Implications: This 1-year contraceptive vaginal system represents a new long-term, user-controlled and procedure-free option with a safety profile similar to other combination hormonal contraceptives. The same precautions currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.
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http://dx.doi.org/10.1016/j.contraception.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357828PMC
June 2019

Corrigendum to "The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions" [Int J Gynecol Obstet 143(2018) 393-408.].

Int J Gynaecol Obstet 2019 02 27;144(2):237. Epub 2018 Nov 27.

School of Women's and Children's Health, Royal Hospital for Women, University of New South Wales, Randwick, New South Wales, Australia.

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http://dx.doi.org/10.1002/ijgo.12709DOI Listing
February 2019

Emergency Room Safer Transfer of Patients (ER-STOP): a quality improvement initiative at a community-based hospital to improve the safety of emergency room patient handovers.

BMJ Open 2018 12 14;8(12):e019553. Epub 2018 Dec 14.

Department of Medicine, Division of Respirology, University of Toronto and Michael Garron Hospital, Michael Garron Hospital, Toronto, Ontario, Canada.

Objectives: Ensure early identification and timely management of patient deterioration as essential components of safe effective healthcare. Prompted by analyses of incident reports and deterioration events, a multicomponent organisational rescue from danger system was redesigned to decrease unexpected inpatient deterioration.

Design: Quality improvement before-after unblinded trial.

Setting: 430-bed Canadian community teaching hospital.

Participants: All admitted adult medical-surgical patients in a before-after 12-month interventional study.

Intervention: Locally validated checklist (Modified Early Warning Score+urinary catheter in situ+nurse concern) with an intentional pause and explicit management options was deployed as a modification of an existing ward transfer of accountability fax report in the emergency department (ED).

Results: Following deployment of Emergency Room Safer Transfer of Patients (ER-STOP), the risk of an unexpected CCRT (critical care response team) response within 24 hours of admission from ED to adult medical and surgical wards was significantly decreased (OR 4.1, 95% CI 2.17 to 7.77). Mean (±SD) ED wait times (5.66±1.54vs 5.74±1.04 hours, p=0.30), intensive care unit admission rate (3.84%, n=233vs 4.61%, n=278, p=0.06) and cardiac care unit admission rate (9.51%, n=577vs 9.60%, n=579, p=0.198) were unchanged.

Conclusions: ER-STOP improvement was out of proportion to the predictive value of the checklist component suggesting that effectiveness of this low-cost sustainable tool was related to increased situational awareness, empowering a culture of patient safety and repurposing of an adjacent ED medical short-stay unit use. Local adaptation within existing processes is essential to successful safety outcomes.
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http://dx.doi.org/10.1136/bmjopen-2017-019553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303585PMC
December 2018

Transdifferentiating Astrocytes Into Neurons Using ASCL1 Functionalized With a Novel Intracellular Protein Delivery Technology.

Front Bioeng Biotechnol 2018 21;6:173. Epub 2018 Nov 21.

Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.

Cellular transdifferentiation changes mature cells from one phenotype into another by altering their gene expression patterns. Manipulating expression of transcription factors, proteins that bind to DNA promoter regions, regulates the levels of key developmental genes. Viral delivery of transcription factors can efficiently reprogram somatic cells, but this method possesses undesirable side effects, including mutations leading to oncogenesis. Using protein transduction domains (PTDs) fused to transcription factors to deliver exogenous transcription factors serves as an alternative strategy that avoids the issues associated with DNA integration into the host genome. However, lysosomal degradation and inefficient nuclear localization pose significant barriers when performing PTD-mediated reprogramming. Here, we investigate a novel PTD by placing a secretion signal sequence next to a cleavage inhibition sequence at the end of the target transcription factor-achaete scute homolog 1 (ASCL1), a powerful regulator of neurogenesis, resulting in superior stability and nuclear localization. A fusion protein consisting of the amino acid sequence of ASCL1 transcription factor with this novel PTD added can transdifferentiate cerebral cortex astrocytes into neurons. Additionally, we show that the synergistic action of certain small molecules improves the efficiency of the transdifferentiation process. This study serves as the first step toward developing a clinically relevant transdifferentiation strategy for converting astrocytes into neurons.
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http://dx.doi.org/10.3389/fbioe.2018.00173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258721PMC
November 2018

The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions.

Int J Gynaecol Obstet 2018 Dec 10;143(3):393-408. Epub 2018 Oct 10.

School of Women's and Children's Health, Royal Hospital for Women, University of New South Wales, Randwick, NSW, Australia.

Background: The International Federation of Gynecology and Obstetrics (FIGO) systems for nomenclature of symptoms of normal and abnormal uterine bleeding (AUB) in the reproductive years (FIGO AUB System 1) and for classification of causes of AUB (FIGO AUB System 2; PALM-COEIN) were first published together in 2011. The purpose was to harmonize the definitions of normal and abnormal bleeding symptoms and to classify and subclassify underlying potential causes of AUB in the reproductive years to facilitate research, education, and clinical care. The systems were designed to be flexible and to be periodically reviewed and modified as appropriate.

Objectives: To review, clarify, and, where appropriate, revise the previously published systems.

Methodology And Outcome: To a large extent, the process has been an iterative one involving the FIGO Menstrual Disorders Committee, as well as a number of invited contributions from epidemiologists, gynecologists, and other experts in the field from around the world between 2012 and 2017. Face-to-face meetings have been held in Rome, Vancouver, and Singapore, and have been augmented by a number of teleconferences and other communications designed to evaluate various aspects of the systems. Where substantial change was considered, anonymous voting, in some instances using a modified RAND Delphi technique, was utilized.
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http://dx.doi.org/10.1002/ijgo.12666DOI Listing
December 2018

Stereotactic body radiation therapy for lung, spine and oligometastatic disease: current evidence and future directions.

Ann Transl Med 2018 Jul;6(14):283

Department of Radiation Oncology, British Columbia Cancer Agency (BCCA), Vancouver, Canada.

Stereotactic body radiation therapy (SBRT) also referred to as stereotactic ablative radiotherapy (SABR), is a technique which has emerged over the past two decades due to improvements in radiation technology. Unlike conventional external beam radiotherapy (cEBRT) which traditionally delivers radiation in small doses [approximately 2 Gray (Gy) per fraction] over several weeks, SBRT, typically delivered in one to eight fractions, is a technique whereby potentially ablative doses of radiotherapy (usually 7.5-20 Gy per fraction) can be delivered with steeper dose gradients and sub millimetre precision, minimising risk to surrounding normal tissues. The potential benefits of excellent tumor control with low toxicity has led to the increasing use of SBRT in a number of clinical situations. Due to compelling evidence, SBRT is now the treatment of choice for medically inoperable patients with peripherally located stage I non-small cell lung cancer (NSCLC). Controversy remains however as to its efficacy and safety for central or ultra-central lung tumors. The evidence base supporting the use of SBRT as a novel treatment for spinal metastases and oligometastases is rapidly expanding but challenges remain in these difficult patient populations. In an era where targeted therapy and improved systemic treatments for stage IV cancer have resulted in increased disease-free survival, and our knowledge of the oligometastatic state is ever expanding, using SBRT to treat metastatic disease and gain durable local control is increasingly desirable. Several randomized trials are currently underway and are sure to provide valuable information on the benefit and utility of SBRT across many tumor sites including early-stage NSCLC, spinal metastases and oligometastatic disease. Recognizing the evolving role of SBRT in clinical practice, this paper provides a critical review of recent developments in each of these areas particularly highlighting the challenges facing clinicians and discusses potential areas for future research.
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http://dx.doi.org/10.21037/atm.2018.06.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068327PMC
July 2018

Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.

Neuropsychopharmacology 2018 12 9;43(13):2586-2596. Epub 2018 Jul 9.

Janssen Research & Development, LLC. Neuroscience Therapeutic Area, San Diego, CA, 92131, USA.

Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.
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http://dx.doi.org/10.1038/s41386-018-0141-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224414PMC
December 2018

Impact and management of iron deficiency and iron deficiency anemia in women's health.

Expert Rev Hematol 2018 09 1;11(9):727-736. Epub 2018 Aug 1.

g Department of Internal Medicine , American University of Beirut Medical Center , Beirut , Lebanon.

Introduction: Iron deficiency and iron deficiency anemia are highly prevalent among women throughout their lives. Some females are particularly vulnerable to iron deficiency/iron deficiency anemia, including those with heavy menstrual bleeding (HMB) and pregnant/postpartum women. Despite the high prevalence of iron deficiency/iron deficiency anemia in women, the condition is still underdiagnosed and therefore undertreated, with serious clinical consequences. Areas covered: The following review examines the impact of iron deficiency and iron deficiency anemia on clinical outcomes and quality of life in women from adolescence to post-menopause, paying particular attention to guidelines and current recommendations for diagnostic tests and management. Expert commentary: There are numerous adverse health consequences of an iron-deficient state, affecting all aspects of the physical and emotional health and well-being of women. Guidelines must be developed to help clinicians better identify and treat women at risk of iron deficiency or iron deficiency anemia, particularly those with HMB, or who are pregnant or postpartum. Replacement therapy with oral or intravenous iron preparations is the mainstay of treatment for iron deficiency/iron deficiency anemia, with red blood cell transfusion reserved for emergency situations. Each iron therapy type is associated with benefits and limitations which impact their use.
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http://dx.doi.org/10.1080/17474086.2018.1502081DOI Listing
September 2018

Contraceptive practices and menstrual patterns in women aged 18-50 years awaiting bariatric surgery.

BMJ Sex Reprod Health 2018 Jun 15. Epub 2018 Jun 15.

Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland, Tyne and Wear, UK;

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http://dx.doi.org/10.1136/bmjsrh-2018-200091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225510PMC
June 2018

Feasibility of the electrolarynx for enabling communication in the chronically critically ill: The EECCHO study.

J Crit Care 2018 10 12;47:109-113. Epub 2018 Jun 12.

Sunnybrook Health Sciences Centre and Sunnybrook Research Institute, 2075 Bayview Ave, Toronto M4N 3M5, Canada; University of Toronto, 155 College St, Toronto M5T 1P8, Canada.

Purpose: To assess feasibility of producing intelligible and comprehensible speech with an electrolarynx; measure anxiety, communication ease, and satisfaction before/after electrolarynx training; and identify barriers/facilitators.

Methods: We included tracheostomized adults from 3 units following commands, reading English, and mouthing words. On enrolment, we measured anxiety, ease, and satisfaction with communication. We gave electrolarynx instruction for ≤5 days then 2 independent raters assessed intelligibility, sentence comprehensibility (9-point difficulty scale), and Electrolarynx Effectiveness Score (EES), and re-evaluated anxiety, communication ease, and satisfaction. Interviews explored barriers/facilitators.

Measurements And Main Results: We recruited 24 participants (Jan2015-Dec2016). Mean (SD) intelligibility was 45%(18%) words correct: 57%(21%) when facing. Mean comprehension difficulty was 6.4(2.0) overall, indicating moderate difficulty (5.5(2.5) scored visualizing). Mean EES was 2.9(1.0) (3 = improved lip-reading through recognizable sounds). Anxiety decreased from median 3.8 to 2.0 (P = .007). Communication was rated easier (median 15 vs 12, P = .04) whereas satisfaction remained similar (P = .06). Facilitators included device friendliness, patient independence, and word intelligibility. Barriers were patient weakness, difficulty positioning the device, and limited sentence as opposed to word intelligibility.

Conclusion: The electrolarynx may aid intelligible speech for some tracheostomized patients if the communication partner can visualize the users face, and reduce anxiety and make patient perceived communication easier.
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http://dx.doi.org/10.1016/j.jcrc.2018.06.013DOI Listing
October 2018

Blood microvasculature and lymphatic densities in endometrial polyps and adjacent and distant endometrium.

SAGE Open Med 2018 12;6:2050312118761287. Epub 2018 Mar 12.

Discipline of Obstetrics, Gynaecology and Neonatology, The University of Sydney, Sydney, NSW, Australia.

Objective: Endometrial polyps are localised growths of endometrial tissue containing glands, stroma and blood vessels, covered with epithelium. The reported prevalence of endometrial polyps is dependent upon the population being studied and the uterine imaging technique utilised. The light microscopy literature provides very little information regarding their microvasculature and lymphatic systems; however, a plethora of ultrasound data demonstrating single central arteries in most medium- or large-sized endometrial polyps are well documented.

Methods: Archived formalin-fixed paraffin-embedded blocks of endometrial curettings were retrieved from files for women with confirmed endometrial polyps ( = 20) and women with normal endometrium (control endometrium;  = 32). Immunohistochemistry was performed with the antibodies CD31 (blood vessels) and D2-40 (lymphatics). Blood vessels and lymphatics were quantified in endometrial polyps and adjacent, distant and control endometrium.

Results: CD31 and D2-40 staining was present in all specimens, although there were no significant differences in blood vessel ((3,70) = 2.36,  = 0.079) and lymphatic ((3,70) = 0.16,  = 0.920) densities between endometrial polyps as well as adjacent, distant and control endometrium. There were also no significant differences in women with endometrial polyp-associated bleeding and those with no bleeding. In relation to infertility, there were no significant differences found in blood and lymphatic densities between women with endometrial polyps who were infertile and those with endometrial polyps who were fertile.

Conclusion: Small blood vessel wall and perivascular structures rather than the distribution of vessels may be associated with abnormal bleeding.
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http://dx.doi.org/10.1177/2050312118761287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858742PMC
March 2018

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

Eur Respir J 2018 01 11;51(1). Epub 2018 Jan 11.

Medical Health Service, Michael Garron Hospital, Toronto, ON, Canada.

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 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.
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http://dx.doi.org/10.1183/13993003.01567-2017DOI Listing
January 2018

A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate.

J Med Chem 2018 01 20;61(1):207-223. Epub 2017 Dec 20.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01279DOI Listing
January 2018

4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate.

J Med Chem 2017 06 25;60(11):4559-4572. Epub 2017 May 25.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00408DOI Listing
June 2017

Severe symptomatic hyponatremia associated with the use of polyethylene glycol-based bowel preparation.

Endocrinol Diabetes Metab Case Rep 2017 23;2017. Epub 2017 Feb 23.

Epworth HealthCare, Melbourne, Victoria, Australia.

Summary: Colonoscopy is a useful tool in modern medicine and is increasingly employed for both diagnostic and treatment reasons. However, its effectiveness is highly reliant on the quality of bowel cleansing. Among different bowel-cleansing agents available, PEG (polyethylene glycol) is considered to be the safest cleansing agent, especially in relation to fluid and electrolyte problems. We present here a case of severe symptomatic hyponatremia that developed after the use of PEG for an elective colonoscopy. This case highlights that despite the use of PEG-based preparations, life-threatening fluid and electrolyte disturbances can still occur in patients with risk factors, such as old age, use of thiazide diuretics and SSRIs, chronic kidney disease, heart failure and a history of electrolyte problems. These patients should be closely monitored when undertaking bowel cleansing and should receive prompt care in the event of complications, to avoid permanent neurological sequelae and death. Rapid correction of sodium levels in patients requiring treatment of hyponatremia should be avoided to prevent complications such as osmotic demyelination syndrome.

Learning Points: PEG is considered to be the safest bowel-cleansing agents among different options available, but it can still cause significant side effects in susceptible individuals.Those at risk of developing adverse events include elderly individuals, patients with chronic kidney disease, heart failure or previous history of electrolyte problems and those taking thiazide diuretics and SSRIs.All such patients should be closely monitored i.e. have their metabolic profile checked prior to the commencement of bowel cleansing and a low threshold should be kept for the initiation of investigations and treatment in case of development of symptoms.Medications with a potential of causing fluid and electrolytes such as thiazide diuretics and SSRIs should be withheld while patient is undertaking bowel preparation.Hyponatremia in a hospitalized patient can be multifactorial, and the treatment principles are based on duration of onset, presence of symptoms and patients volume status.Overzealous correction of sodium levels during treatment of hyponatremia can result in serious complications such as osmotic demyelination syndrome.
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http://dx.doi.org/10.1530/EDM-16-0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404463PMC
February 2017