Project description:Atherosclerosis is a chronic inflammatory disorder of the vasculature where cholesterol accumulates in the arterial wall stimulating infiltration of immune cells. This plays an important role in plaque formation, as well as complications caused by its build up. Pro-inflammatory cytokines and chemokines are implicated throughout the progression of the disease and different therapies that aim to resolve this chronic inflammation, reduce cardiovascular (CV) events and improve clinical outcomes have been tested. The results from the pivotal CANTOS trial show that targeting the pro-inflammatory cytokine IL-1β successfully reduces the incidence of secondary CV events. This review briefly assesses the role of inflammation in atherosclerosis, providing a picture of the multiple players involved in the process and offering a perspective on targeting inflammation to prevent atherosclerotic CV events, as well as focusing on the results of the latest Phase III clinical trials.
Project description:BackgroundThe updated national guidelines for cardiovascular risk assessment and lipid modification in the UK and US expand the indications for statin therapy in primary prevention to adults with moderate risk of cardiovascular disease (CVD) but many adults at high CVD risk remain untreated in both countries. We set out to identify treatment gaps in English and American adults at moderate and high risk of cardiovascular disease (CVD), and to estimate the number of CVD events that would be prevented from expanding statin therapy to those who are currently untreated.MethodsWe used nationally representative samples of 10,375 English adults and 7,687 US adults aged 40-75 years and free of existing CVD from the Health Survey for England 2009-2013, and the National Health and Nutrition Examination Survey 2007-2012 in the US. We used the risk algorithms and the risk thresholds for statin therapy recommended by each country's national guideline to categorize the survey participants into moderate-risk (≥10% to <20% 10-year risk of CVD in England and ≥7.5% to <20% risk in the US) or high-risk (≥20%risk) and simulated the number of events that would be prevented from expansion of statin therapy to those currently untreated.ResultsClose to half of adults at high CVD risk in England (46.0%) and the US (49.7%) were not receiving statins. Expanding statin use to 1.45 million high-risk adults in England would save 101,000 (95% CI = 81,000-120,000) CVD events in the next 10 years compared with 128,000 (103,000-154,000) CVD events that would be prevented from expanding treatment to 3.64 million untreated moderate-risk adults. In the US, expanding statin use to 5.27 million untreated high-risk adults would save 384,000 (305,000-461,000) CVD events over 10 years compared with 616,000 (493,000-738,000) CVD events that would be prevented from treating 20.29 million untreated moderate-risk adults.ConclusionsIn both England and the US, expanding statin therapy to untreated moderate-risk adults would prevent a comparable number of events as expanding statin use to a much smaller number of currently untreated high-risk adults. A large potential for CVD prevention remains from improving coverage of statin therapy among high-risk adults.
Project description:IntroductionThere has been a growing recognition on the importance of diversity in clinical trials. Existing research has highlighted a significant demographic imbalance. Amidst this renewed focus on diversity, it is crucial to acknowledge that Asia comprises over half of the world's population. Given the region's demographic significance, we sought to compare various characteristics and growth rates for trials with sites in Asia against those without any sites in Asia.MethodsWe performed comprehensive analyses of industry-sponsored phase 2 and 3 oncology trials registered at Clinicaltrials.gov, using drugs or biologics as investigational agents and executed between 1 January 2018 and 31 December 2022. We applied the compound annual growth rate (CAGR) as an analytical tool to track the trial growth rates over this 5-year period.ResultsWe identified 894 industry-sponsored phase 2 and 3 cancer studies with available study location data. Out of these, 415 trials (46.42%) had study sites in Asia. Notably, these trials with sites in Asia were also more likely to be phase 3 trials (39.76% vs 6.47%, p < 0.001), include female and paediatric populations, and be randomised trials. Interestingly, lung and stomach cancers were more commonly studied in these trials, while myeloma was less commonly studied. The number of trial sites for liver cancer was not significantly higher for Asia, even though the incidence of the disease is much higher in this region. Despite an overall declining trend in the number of clinical trials in the last 5 years, we observed a transitional positive increase in the CAGR from 2020 to 2021 for trials with sites in Asia. However, East Asia, specifically China, exhibited a disproportionate overrepresentation in these trials.ConclusionsThere are notable characteristics of clinical trials with sites in Asia. Comprehending these disparities may aid in the strategic planning to enhance a balanced representation of ethnicities in trials.
Project description:The investigational NEDD8-activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single-agent azacitidine in patients with higher-risk myelodysplastic syndrome (higher-risk MDS), higher-risk chronic myelomonocytic leukemia (higher-risk CMML), or low-blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia-inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug-related and disease-related intrinsic and extrinsic factors. A PubMed literature review (January 2000-November 2019) supported similarity in epidemiology of higher-risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose-escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug-related and disease-related intrinsic and extrinsic factors supported design of an Asia-inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia-inclusive MRCTs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Azacitidine is the standard of care for myelodysplastic syndromes/low-blast acute myeloid leukemia (AML) across Western and East Asian patients. The first-in-class small-molecule inhibitor of NEDD8-activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS? By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian-inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug-related and disease-related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These analyses provide scientific rationale for Asia-inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia-inclusive multiregional clinical trials.
Project description:BackgroundThe Health Management Information System (HMIS) is crucial for evidence-based policy-making, informed decision-making during planning, implementation and evaluation of health programs; and for appropriate use of resources at all levels of the health system. This study explored the gaps and factors influencing HMIS in the context of a changing health sector in Tanzania.MethodsA cross sectional descriptive study was conducted in 11 heath facilities in Kilombero district between January and February 2008. A semi-structured questionnaire was used to interview 43 health workers on their knowledge, attitude, practice and factors for change on HMIS and HMIS booklets from these facilities were reviewed for completeness.ResultsOf all respondents, 81% had never been trained on HMIS, 65% did not properly define this system, 54% didn't know who is supposed to use the information collected and 42% did not use the collected data for planning, budgeting and evaluation of services provision. Although the attitude towards the system was positive among 91%, the reviewed HMIS booklets were never completed in 25% - 55% of the facilities. There were no significant differences in knowledge, attitude and practice on HMIS between clinicians and nurses. The most common type of HMIS booklets which were never filled were those for deliveries (55%). The gaps in the current HMIS were linked to lack of training, inactive supervision, staff workload pressure and the lengthy and laborious nature of the system.ConclusionsThis research has revealed a state of poor health data collection, lack of informed decision-making at the facility level and the factors for change in the country's HMIS. It suggests need for new innovations including incorporation of HMIS in the ongoing reviews of the curricula for all cadres of health care providers, development of more user-friendly system and use of evidence-based John Kotter's eight-step process for implementing successful changes in this system.
Project description:Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare, autosomal-recessive, acid ceramidase (ACDase) deficiency disorders caused by ASAH1 gene mutations. Currently, 73 different mutations in the ASAH1 gene have been described in humans. These mutations lead to reduced ACDase activity and ceramide (Cer) accumulation in many tissues. Presenting as divergent clinical phenotypes, the symptoms of FD vary depending on central nervous system (CNS) involvement and severity. Classic signs of FD include, but are not limited to, a hoarse voice, distended joints, and lipogranulomas found subcutaneously and in other tissues. Patients with SMA-PME lack the most prominent clinical signs seen in FD. Instead, they demonstrate muscle weakness, tremors, and myoclonic epilepsy. Several ACDase-deficient mouse models have been developed to help elucidate the complex consequences of Cer accumulation. In this review, we compare clinical reports on FD patients and experimental descriptions of ACDase-deficient mouse models. We also discuss clinical presentations, potential therapeutic strategies, and future directions for the study of FD and SMA-PME.
Project description:Well-characterized disparities in clinical research have disproportionately affected patients of color, particularly in underserved communities. To tackle these barriers, Genentech formed the External Council for Advancing Inclusive Research, a 14-person committee dedicated to developing strategies to increase clinical research participation. To help improve the recruitment and retention of patients of color, this article chronicles our efforts to tangibly address the clinical research barriers at the system, study, and patient levels over the last four years. These efforts are one of the initial steps to fully realize the promise of personalized health care and provide increased patient benefit at less cost to society. Instead of simply acknowledging the problem, here we illuminate the collaborative and multilevel strategies that have been effective in delivering meaningful progress for patients.
Project description:As the world faces the health crisis of a global pandemic-with healthcare protocols in overhaul, and patients and care teams experiencing unprecedented levels of stress and unpredictability-we predict that current knowledge gaps in maternal health will inevitably have a lasting impact on the health of women giving birth now and in the near future. Since we are decades away from closing the knowledge gaps we need filled today, we recommend shifting thinking toward a comprehensive conceptual model that merges knowledge of stress physiology, neurobiology, and pregnancy physiology. The model we present here, the Maternal Reactive Scope Model, is an expansion of the Reactive Scope Model built upon the concept of Homeostasis and Allostasis. The model provides a framework to consider pathways and interactions across physiological systems to attribute a physiological basis for considering stress exposure and bridge research gaps on mechanisms to measure or target for treatment. Our intention is to provide an adaptable, heuristic framework for discussion of research considerations and new healthcare models that aim to provide the best care for new mothers during and after the COVID-19 pandemic.
Project description:BackgroundCardiovascular diseases (CVDs) are the leading cause of deaths and disability in Nepal. Health systems can improve CVD health outcomes even in resource-limited settings by directing efforts to meet critical system gaps. This study aimed to identify Nepal's health systems gaps to prevent and manage CVDs.MethodsWe formed a task force composed of the government and non-government representatives and assessed health system performance across six building blocks: governance, service delivery, human resources, medical products, information system, and financing in terms of equity, access, coverage, efficiency, quality, safety and sustainability. We reviewed 125 national health policies, plans, strategies, guidelines, reports and websites and conducted 52 key informant interviews. We grouped notes from desk review and transcripts' codes into equity, access, coverage, efficiency, quality, safety and sustainability of the health system.ResultsNational health insurance covers less than 10% of the population; and more than 50% of the health spending is out of pocket. The efficiency of CVDs prevention and management programs in Nepal is affected by the shortage of human resources, weak monitoring and supervision, and inadequate engagement of stakeholders. There are policies and strategies in place to ensure quality of care, however their implementation and supervision is weak. The total budget on health has been increasing over the past five years. However, the funding on CVDs is negligible.ConclusionGovernments at the federal, provincial and local levels should prioritize CVDs care and partner with non-government organizations to improve preventive and curative CVDs services.
Project description:Various studies have highlighted the importance of ethnic differences. The consideration of ethnic differences in the field of individualized pharmacotherapy is imperative. Therefore, various organizations and networks across countries should aim to conduct multicountry and multiregional clinical trials (MRCTs). If there is solid evidence available to evaluate the existence of ethnic differences between the same regional areas, it will lead to an increase in the efficiency of drug development. The purpose of this paper was to compare the approval dosing regimen among four Asian countries (Korea, Japan, China, and Taiwan) and elucidate the readiness and current status of the implementation of the International Conference on Harmonization (ICH) E17 guidelines on MRCTs. Reducing unnecessary clinical trials via multinational clinical trials in East Asian countries is also suggested. The approved dosing regimens for some drugs in the four Asian countries were similar; however, some differences might be caused by differences in legislation, even though there were no ethnic differences. This indicates that there are several roles to be expected of the Asia Clinical Pharmacology study network for exploratory MRCTs, which would lead to the accumulation of evidence for MRCTs, ultimately accelerating the efficiency of drug development in East Asian countries. The exposure of the new treatment to the necessary patients through collaborative research coordination and simultaneous multinational subject recruitment would serve its role in providing East Asia with specific personalized medicine with a high treatment success rate.