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.

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.

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.

Co-designed and consensus based development of a quality improvement checklist of patient and family-centered actionable processes of care for adults with persistent critical illness.

PURPOSE: Few quality improvement tools specific to patients with persistent or chronic critical illness exist to aid delivery of high-quality care. Using experience-based co-design methods, we sought consensus from key stakeholders on the most important actionable processes of care for inclusion in a quality improvement checklist. METHODS: Item generation methods: systematic review, semi-structured interviews (ICU survivors and family) members, touchpoint video creation, and semi-structured interviews (ICU clinicians). Consensus methods: modified online Delphi and a virtual meeting using nominal group technique methods. RESULTS: We enrolled 138 ICU interprofessional team, patients, and family members. We obtained consensus on a quality improvement checklist comprising 11 core domains: patient and family involvement in decision-making; patient communication; physical comfort and complication prevention; promoting self-care and normalcy; ventilator weaning; physical therapy; swallowing; pharmacotherapy; psychological issues; delirium; and appropriate referrals. An additional 27 actionable processes are contained within 6 core domains that provide more specific direction on the actionable process to be targeted. CONCLUSIONS: Using a highly collaborative and methodologically rigorous process, we generated a quality improvement checklist of actionable processes to improve patient and family-centred care considered important by key stakeholders. Future research is needed to understand optimal implementation strategies and impact on outcomes and experience.

Disease burden in individuals with symptomatic undiagnosed asthma or COPD.

BACKGROUND: The actual burden of COPD and asthma may be much higher than appreciated, since a large proportion of individuals are not diagnosed. Our study objective was to compare health care utilization, burden of symptoms and quality of life in subjects with self-reported respiratory symptoms who were subsequently found to have undiagnosed airflow obstruction compared to those having no airflow obstruction. METHODS: This cross-sectional case-finding study used data from the Undiagnosed COPD and Asthma Population (UCAP) study. Adult subjects with respiratory symptoms who had no history of diagnosed lung disease were recruited in a two-step case-finding process using random digit-dialling of land lines and cell phones located within a 90-min radius of 16 Canadian study sites. Participants were assessed for COPD, asthma or no airflow obstruction using pre- and post-bronchodilator spirometry based on American Thoracic Society diagnostic criteria. RESULTS: 1660 participants were recruited, of these 1615 had adequate spirometry and 331 (20.5%) subjects met spirometry criteria for undiagnosed asthma or COPD. Subjects with undiagnosed asthma or COPD had increased respiratory symptoms as assessed by the COPD Assessment Test (CAT), and higher St. George's Respiratory Questionnaire (SGRQ) scores indicating worse health-related quality of life, compared to subjects with no airflow obstruction. No between-group differences were found in health care utilization or work or school absenteeism. CONCLUSION: Undiagnosed asthma and COPD are common in Canadian adults experiencing breathing problems and are associated with a greater burden of symptoms and poorer health-related quality of life. These results suggest that patients may benefit from early identification and treatment of undiagnosed asthma and COPD.

Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform.

d-Serine is a coagonist of the N-methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.

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.

Mortality, Health Care Use, and Costs of Weaning Center Survivors and Matched Prolonged ICU Stay Controls.

BACKGROUND: Quantification of long-term survival, health care utilization, and costs of prolonged ventilator dependence informs patient/family decision-making, health care policy, and understanding of specialized weaning centers (SWCs) as alternate care models. Our objective was to compare survival trajectory, health care utilization, and costs of SWC survivors with a matched cohort of ≥ 21-d-stay ICU patients. METHODS: This was a retrospective longitudinal (12 y) case-control study linking to health administrative databases with matching on age, sex, Charlson comorbidity index, income quintiles, and days in ICU and hospital in preceding 12 months. RESULTS: We matched 201 SWC subjects to 201 prolonged ICU survivors (402-subject cohort); 42% had a Charlson score of > 4. Risk of death at 12 months was lower in SWC subjects (hazard ratio [HR] 0.70 [95% CI 0.54-0.91]) adjusting for length of hospital admission (HR 1.02 [95% CI 1.00-1.04]) and number of care location transfers (HR 0.84 [95% CI 0.75-0.93]). By follow-up end, more SWC subjects died, 149 (73%) versus 127 (62%). We found no difference in discharge to home. At 12 months, acute health care utilization was comparable for the entire cohort, except hospital readmission rates (median interquartile range [IQR] 2 [1-3) vs 1 [1-2] d). Median (IQR) cost 12 months after unit discharge was CAD $68,165 ($19,894-$153,475). 12-month costs were higher in the SWC survivors (CAD $82,874 [$29,942-$224,965] vs CAD $55,574 [$6,572-$128,962], P < .001). SWC survivors had higher community health care utilization. Regression modeling demonstrated cost was associated with stay and care transfers but not SWC admission. Over 12-y follow-up, health care utilization and costs were higher in SWC survivors. CONCLUSIONS: SWC admission may confer some medium-term survival advantage; however, this may be influenced by selection bias associated with admission criteria.

The effect of SARS-CoV-2 on the nervous system: a review of neurological impacts caused by human coronaviruses.

The COVID-19 pandemic has affected millions of people worldwide. While coronaviruses typically have low rates of neurotropic effects, the massive transmission of SARS-CoV-2 suggests that a substantial population will suffer from potential SARS-CoV-2-related neurological disorders. The rapid and recent emergence of SARS-CoV-2 means little research exists on its potential neurological effects. Here we analyze the effects of similar viruses to provide insight into the potential effects of SARS-CoV-2 on the nervous system and beyond. Seven coronavirus strains (HCoV-OC43, HCoV-HKU1, HCoV-229E, HCoV-NL63, SARS-CoV, MERS-CoV, SARS-CoV-2) can infect humans. Many of these strains cause neurological effects, such as headaches, dizziness, strokes, seizures, and critical illness polyneuropathy/myopathy. Certain studies have also linked coronaviruses with multiple sclerosis and extensive central nervous system injuries. Reviewing these studies provides insight into the anticipated effects for patients with SARS-CoV-2. This review will first describe the effects of other coronaviruses that have caused severe disease (SARS-CoV, MERS-CoV) on the nervous system, as well as their proposed origins, non-neurological effects, and neurological infection mechanisms. It will then discuss what is known about SARS-CoV-2 in these areas with reference to the aforementioned viruses, with the goal of providing a holistic picture of SARS-CoV-2.

Defining and Redefining Family Involvement in Practice: An Implementation Trial of a Locally Adaptable Patient-Centered Professional Development Tool in Two Ontario Intensive Care Units.

ABSTRACT: Research on best practices for family member involvement has shown that such involvement improves care quality in critical care settings and helps to reduce medical errors leading to adverse events. Although many critical care units promote the principle of "patient-centered care" and family member involvement, there can be a significant gap between knowledge about these processes and their translation into practice. This article is based on an implementation trial of a patient and family involvement knowledge-based tool that involves an educational component for frontline health care workers. By combining ethnographic observation, semistructured interviews, focus groups, and document analysis, we were able to not only examine health care provider views on family involvement but also explore the areas of tension that arose in practice because the introduction of the family involvement tool exposed local factors that shaped the conditions of possibility of family involvement. In particular, unspoken preferences, assumptions, and concerns about family involvement were brought to the fore because this intervention disrupted well-entrenched power dynamics related to family involvement and professional boundaries. Through this ethnographic research, we found that the concept of patient-centered care is not uncontroversial among health care providers and that the form of its practice was largely up for individual interpretation. Interventions and policies that aim to promote patient-centered and family-centered care would benefit from addressing the ways in which these ideas affect the work of different health care professionals and incorporating nursing concerns around family involvement.

Evaluation of 3D-printer settings for producing personal protective equipment.

Aim: COVID-19 resulted in a shortage of personal protective equipment. Community members united to 3D-print face shield headbands to support local healthcare workers. This study examined factors altering print time and strength. Materials & methods: Combinations of infill density (50%, 100%), shell thickness (0.8, 1.2 mm), line width (0.2 mm, 0.4 mm), and layer height (0.1 mm, 0.2 mm) were evaluated through tensile testing, finite element analysis, and printing time. Results: Strength increased with increased infill (p < 0.001) and shell thickness (p < 0.001). Layer height had no effect on strength. Increasing line width increased strength (p < 0.001). Discussion: Increasing layer height and line width decreased print time by 50 and 39%, respectively. Increased shell thickness did not alter print time. These changes are recommended for printing.

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

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 IC50 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.

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).

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?

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

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.

Best Practices for Counseling Adolescents about the Etonogestrel Implant.

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.

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.

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.

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.

Diagnosing adenomyosis: an integrated clinical and imaging approach.

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.

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.