Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain

TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and wide-spread expression. One of the critical functions of TRPV4 in this spectrum is its involvement in pain and inflammation. However, few small-molecule inhibitors of TRPV4 are available. Here we developed TRPV4-inhibitory molecules based on modifications of a known TRPV4-selective tool-compound, GSK205. We not only increased TRPV4-inhibitory potency, but surprisingly also generated two compounds that potently co-inhibit TRPA1, known to function as chemical sensor of noxious and irritant signaling. We demonstrate TRPV4 inhibition by these compounds in primary cells with known TRPV4 expression - articular chondrocytes and astrocytes. Importantly, our novel compounds attenuate pain behavior in a trigeminal irritant pain model that is known to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain-associated behavior in a model of acute pancreatitis - known to also rely on TRPV4 and TRPA1. Our results illustrate proof of a novel concept inherent in our prototype compounds of a drug that targets two functionally-related TRP channels, and thus can be used to combat isoforms of pain and inflammation in-vivo that involve more than one TRP channel. This approach could provide a novel paradigm for treating other relevant health conditions

Mixed methods study protocol for combining stakeholder-led rapid evaluation with near real-time continuous registry data to facilitate evaluations of quality of care in intensive care units [version 1; peer review: awaiting peer review]

BACKGROUND: Improved access to healthcare in low- and middle-income countries (LMICs) has not equated to improved health outcomes. Absence or unsustained quality of care is partly to blame. Improving outcomes in intensive care units (ICUs) requires delivery of complex interventions by multiple specialties working in concert, and the simultaneous prevention of avoidable harms associated with the illness and the treatment interventions. Therefore, successful design and implementation of improvement interventions requires understanding of the behavioural, organisational, and external factors that determine care delivery and the likelihood of achieving sustained improvement. We aim to identify care processes that contribute to suboptimal clinical outcomes in ICUs located in LMICs and to establish barriers and enablers for improving the care processes. METHODS: Using rapid evaluation methods, we will use four data collection methods: 1) registry embedded indicators to assess quality of care processes and their associated outcomes; 2) process mapping to provide a preliminary framework to understand gaps between current and desired care practices; 3) structured observations of processes of interest identified from the process mapping and; 4) focus group discussions with stakeholders to identify barriers and enablers influencing the gap between current and desired care practices. We will also collect self-assessments of readiness for quality improvement. Data collection and analysis will be performed in parallel and through an iterative process across eight countries: Kenya, India, Malaysia, Nepal, Pakistan, South Africa, Uganda and Vietnam. CONCLUSIONS: The results of our study will provide essential information on where and how care processes can be improved to facilitate better quality of care to critically ill patients in LMICs; thus, reduce preventable mortality and morbidity in ICUs. Furthermore, understanding the rapid evaluation methods that will be used for this study will allow other researchers and healthcare professionals to carry out similar research in ICUs and other health services

Using a Delphi process to determine optimal care for patients with pancreatic cancer

Aim Overall 5-year survival for pancreatic cancer is ~5%. Optimising the care that pancreatic cancer patients receive may be one way of improving outcomes. The objective of this study was to establish components of care which Australian health professionals believe important to optimally manage patients with pancreatic cancer. Methods Using a Delphi process, a multi-disciplinary panel of 250 health professionals were invited to provide a list of factors they considered important for optimal care of pancreatic cancer patients. They were then asked to score and then rescore (from one (no importance/disagree) to 10 (very important/agree) the factors. The mean and coefficient of variation scores were calculated and categorised into three levels of importance. Results Overall 63 (66% of those sent the final questionnaire; 25% of those initially invited) health professionals from 9 disciplines completed the final scoring of 55 statements/factors encompassing themes of presentation/staging, surgery and biliary obstruction, multi-disciplinary team details and oncology. Mean scores ranged from 3.7 to 9.7 with the highest related to communication and patient assessment. There was substantial intra- and inter- disciplinary variation in views about MDT membership and roles. Conclusion Overall the opinions of Australian health professionals reflect international guideline recommended care; however they identified a number of additional factors focusing on where patients should be treated, the importance of clear communication and the need for multi-disciplinary care which were not included in current clinical practice guidelines. Differences in priorities between specialty groups were also identified

The impact of rate and rhythm control strategies on quality of life for patients with atrial fibrillation: a protocol for a systematic review

Abstract Background Atrial fibrillation (AF) is the most common heart arrhythmia globally and it adversely affects the quality of life (QoL). Available rate and rhythm control strategies equally reduce mortality but may impact QoL differently. A number of systematic reviews have focused on the impact of specific strategies on QoL, though a 2006 review synthesized the evidence on the effect of all strategies on QoL, allowing for a clinically important comparison between the types of strategies. Many trials have been published since the review undertook the search in 2005; therefore, an update is needed. This systematic review aims to provide an update to the 2006 review on the impact of all rate and rhythm control strategies on QoL in people with AF. Methods The following four databases and three clinical trial registries will be searched for primary studies: CENTRAL, MEDLINE, Embase, CINAHL, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and ClinicalTrialsRegister.eu. No language restriction will be applied. The search will be limited to 2004 or later publication year to allow overlap with the search conducted by the 2006 review authors. Any randomized control trial that reports the QoL of adult (≥ 18 years) AF patients following an eligible rate or rhythm control intervention will be eligible for inclusion. Eligible interventions (and comparators) include pacing, atrioventricular node junction and bundle of HIS ablation, pharmacological therapy, radio frequency catheter ablation, cryoablation, pulmonary vein isolation, maze operation, pace maker implantation, and defibrillator implantation. Two reviewers will independently screen for eligible studies, extract the data using a piloted tool, and assess bias by QoL outcome using the RoB 2 tool. The suitability of conducting a meta-analysis will be assessed by the clinical and methodology similarities of included studies. If it is feasible, standardized mean differences will be pooled using a random-effects model and assessed appropriately. Discussion The findings from this review will allow for meaningful comparisons between various rate and rhythm control strategies regarding their impact on QoL. This review will be useful for a wide range of stakeholders and will be crucial for optimizing the overall wellbeing of AF patients. Systematic review registration PROSPERO CRD42021290542 </jats:sec

Cardiovascular Health and Atrial Fibrillation or Flutter: A Cross-Sectional Study from ELSA-Brasil.

BackgroundThe association between ideal cardiovascular health (ICVH) status and atrial fibrillation or flutter (AFF) diagnosis has been less studied compared to other cardiovascular diseases.ObjectiveTo analyze the association between AFF diagnosis and ICVH metrics and scores in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).MethodsThis study analyzed data from 13,141 participants with complete data. Electrocardiographic tracings were coded according to the Minnesota Coding System, in a centralized reading center. ICVH metrics (diet, physical activity, body mass index, smoking, blood pressure, fasting plasma glucose, and total cholesterol) and scores were calculated as proposed by the American Heart Association. Crude and adjusted binary logistic regression models were built to analyze the association of ICVH metrics and scores with AFF diagnosis. Significance level was set at 0.05.ResultsThe sample had a median age of 55 years and 54.4% were women. In adjusted models, ICVH scores were not significantly associated with prevalent AFF diagnosis (odds ratio [OR]:0.96; 95% confidence interval [95% CI]:0.80-1.16; p=0.70). Ideal blood pressure (OR:0.33; 95% CI:0.15-0.74; p=0.007) and total cholesterol (OR:1.88; 95% CI:1.19-2.98; p=0.007) profiles were significantly associated with AFF diagnosis.ConclusionsNo significant associations were identified between global ICVH scores and AFF diagnosis after multivariable adjustment in our analyses, at least partially due to the antagonistic associations of AFF with blood pressure and total cholesterol ICVH metrics. Our results suggest that estimating the prevention of AFF burden using global ICVH scores may not be adequate, and ICVH metrics should be considered in separate

A Protocol for a Pan-Canadian Prospective Observational Study on Active Surveillance or Surgery for Very Low Risk Papillary Thyroid Cancer

BackgroundThe traditional management of papillary thyroid cancer (PTC) is thyroidectomy (total or partial removal of the thyroid). Active surveillance (AS) may be considered as an alternative option for small, low risk PTC. AS involves close follow-up (including regularly scheduled clinical and radiological assessments), with the intention of intervening with surgery for disease progression or patient preference.MethodsThis is a protocol for a prospective, observational, long-term follow-up multi-centre Canadian cohort study. Consenting eligible adults with small, low risk PTC (&lt; 2cm in maximal diameter, confined to the thyroid, and not immediately adjacent to critical structures in the neck) are offered the choice of AS or surgery for management of PTC. Patient participants are free to choose either option (AS or surgery) and the disease management course is thus not assigned by the investigators. Surgery is provided as usual care by a surgeon in an institution of the patient’s choice. Our primary objective is to determine the rate of ‘failure’ of disease management in respective AS and surgical arms as defined by: i) AS arm – surgery for progression of PTC, and ii) surgical arm - surgery or other treatment for disease persistence or progression after completing initial treatment. Secondary outcomes include long-term thyroid oncologic and treatment outcomes, as well as patient-reported outcomes.DiscussionThe results from this study will provide long-term clinical and patient reported outcome evidence regarding active surveillance or immediate surgery for management of small, low risk PTC. This will inform future clinical trials in disease management of small, low risk papillary thyroid cancer.Registration detailsThis prospective observational cohort study is registered on clinicaltrials.gov (NCT04624477), but it should not be considered a clinical trial as there is no assigned intervention and patients are free to choose either AS or surgery

6-(4-(2-{2-[2-(2-Hydroxy-ethoxy)-ethoxy]-ethoxy}-ethyl)-10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione)

Microwave irradiation of maleimide with an excess of furan in water exclusively yields the corresponding exo-cycloadduct in good yield (87%) in 1 hour at 90 oC. Alkylation of the imido nitrogen with tetraethylene glycol under Mitsunobu conditions gives the ROMP monomer in 81% yield