Current Evidence Gaps Research Articles

Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity.

Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is US Food and Drug Administration approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1 year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate, another hepatotoxic antiepileptic drug, through an unknown mechanism. With the growing popularity of CBD in the consumer market, an improved understanding of the safety risks associated with CBD is needed to ensure public health. This review details current efforts to describe CBD pharmacokinetics and mechanisms of hepatotoxicity using both pharmacokinetic models and in vitro models of the liver. In addition, current evidence and knowledge gaps related to intracellular mechanisms of CBD-induced hepatotoxicity are described. The authors propose future directions that combine systems-based models with markers of CBD-induced hepatotoxicity to understand how CBD pharmacokinetics may influence the adverse effect profile and risk of liver injury for those taking CBD. SIGNIFICANCE STATEMENT: This review describes current pharmacokinetic modeling approaches to capture the metabolic clearance and safety profile of cannabidiol (CBD). CBD is an increasingly popular natural product and US Food and Drug Administration-approved antiepileptic drug known to cause clinically significant enzyme-mediated drug interactions and hepatotoxicity at therapeutic doses. CBD metabolism, pharmacokinetics, and putative mechanisms of CBD-induced liver injury are summarized from available preclinical data to inform future modeling efforts for understanding CBD toxicity.

Infertility in the Pacific: A crucial component of the sexual and reproductive health and rights agenda.

Across Pacific Island countries, women and men are disproportionately affected by several risk factors for infertility, including sexually transmissible infections, complications from unsafe abortions, postpartum sepsis, obesity, diabetes, tobacco smoking and excessive alcohol consumption. Despite this, little is known about community awareness of infertility, behavioural risk factors, the lived experiences of infertile couples or the contexts in which they access fertility care. In this opinion piece we discuss the current evidence and gaps in evidence regarding infertility in Pacific Island countries and the importance of locally tailored approaches to preventing infertility and the provision of fertility care.

Discrimination against HIV/AIDS patients and associated factors among women in East African countries: using the most recent DHS data (2015–2022)

IntroductionThe biggest health problem in East Africa is the human immunodeficiency virus (HIV). Combating stigma and discrimination related to HIV/AIDS is a key goal of many international organizations in their efforts to ensure universal access to HIV/AIDS prevention, treatment, care, and support programs. However, previous studies in various regions of Africa have shown that the prevalence of discriminatory attitudes related to HIV/AIDS is particularly high. Furthermore, there is a current evidence gap in the region. Therefore, the aim of this study was to determine the prevalence of discriminatory attitude toward HIV/AIDS patients, and its associated factors among women in East African countries.MethodsThe data we utilized were gathered from the most recent Demographic and Health Surveys (DHS), which were carried out in east African nations between 2016 and 2022. We integrated DHS data from ten countries into our investigation. For our analysis, a weighted sample of 139,812 women overall was employed. The analysis used multiple logistic regressions. The adjusted odds ratio and its 95% confidence interval were then shown, and components with binary logistic regression p values of less than or equal to 0.2 and < 0.05 were regarded as significant predictors of discrimination against HIV/AIDS patients.ResultsIn this study, 32.73% (95% CI 34.48–32.97) of respondents had a discriminatory attitude toward HIV/AIDS patients. In the multiple logistic regression analysis, being in the older age groups, having a better education level, being from a wealthy household, having employment status, having ANC follow-up, institutional delivery, mass media exposure, and having female household heads were associated with higher odds of not having a discriminatory attitude toward HIV/AIDS patients. However, being unmarried and living far from the health facilities were associated with higher odds of discriminatory attitudes toward HIV/AIDS patients.ConclusionThis study concluded that women in East Africa still had a very discriminatory attitude toward HIV/AIDS patients. The good news for East Africa is that prevalence has decreased when compared to earlier findings. Improving women's empowerment, maternal health services, and health facilities' accessibility are crucial.

FROM PATHOPHYSIOLOGY TO POTENTIAL INTERVENTIONS: INVESTIGATING THE INTRICATE DYNAMICS OF POLYCYSTIC OVARY SYNDROME, AGING, AND FERTILITY

Polycystic ovary syndrome (PCOS) and age-related decline in fertility are complex issues affecting women’s reproductive health. This review aims to explore the intricate dynamics between PCOS, aging, and fertility, and examine potential interventions for improved clinical outcomes. It delves into the pathophysiology of PCOS, highlighting hormonal imbalances, metabolic disturbances, and the impact on ovarian function and follicular development. Concurrently, age-related changes in female fertility are discussed, including ovarian reserve decline, hormonal shifts, and alterations in egg quality and uterine environment. Emphasizing the overlapping mechanisms, shared pathways are elucidated such as hormonal dysregulation, insulin resistance, hyperandrogenism, and inflammation. Additionally, the clinical implications of diagnosing and managing PCOS in aging women are addressed, as well as fertility preservation options and assisted reproductive techniques. Furthermore, potential interventions and therapeutic strategies are explored, encompassing lifestyle modifications, pharmacological interventions, and emerging technologies. By comprehensively reviewing the current evidence and research gaps, this article provides valuable insights into the interplay between PCOS, aging, and fertility, paving the way for optimized clinical approaches and future advancements.

Determining the research priorities for emergency care within the Western Cape province of South Africa: A consensus study

IntroductionLow- and middle-income countries (LMICs) are disproportionally affected by conditions requiring emergency care but there are limited contextually appropriate studies performed within these settings involving the patient population and healthcare systems they aim to benefit. Over the past five years, researchers in the Western Cape of South Africa have produced approximately 20 % of all emergency care publications from Africa, yet no agreed list of research priorities exists. Establishing research priorities, via recognised consensus methods, can ensure that efforts and resources in LMICs are more appropriately targeted to the need. MethodUsing a modified Delphi study, we invited a range of public and private representatives from different professional emergency care cadres within the Western Cape to identify current evidence gaps and consensus research priorities across the four areas of the WHO Emergency Care Systems framework: scene care, prehospital care, facility-based care, and the emergency care system itself. We then purposively selected eleven experts holding key academic and management positions to form a panel and perform a nominal group technique process to discuss these identified research priorities and establish a final list of priority research questions. ResultForty of the sixty-six (61 %) emergency care professionals invited contributed to the Delphi phase of the study, with representation from all professional cadres. After deduplication, 154 research topics were identified in the first round. In the second round, 94 (61 %) topics were considered research priorities by at least 80 % of participants. Following the nominal group technique discussion, 26 questions were established as consensus research priorities having been ranked as a top ten priority by over 50 % of panellists. ConclusionWe were able to successfully collate expert opinion and identify existing emergency care knowledge gaps within the Western Cape province of South Africa. Key topics identified for future work included questions on current health-seeking behaviour, dispatch, interfacility transfer, and staff burnout.

PP147 What Does Real World Evidence (RWE) Offer Health Technology Assessment (HTA) Procedures In Australia?

IntroductionMedical device health technology assessment (HTA) in Australia is largely coordinated by the Medical Services Advisory Committee (MSAC). Its remit to improve the public’s health by deciding where to allocate public healthcare funding, can be enhanced by considering real world evidence (RWE). Existing data sources have limitations that can be addressed through RWE, including coverage of Australian patient populations who may not meet trial eligibility criteria, and long-term follow-up through data linkage and datasets. We partnered with a university to explore what information could be gained from an analysis of linked administrative patient data, with a view to addressing current evidence gaps and/or limitations. The findings can be used as a source of local data to define patient populations, estimate actual costs of care, and enable more comprehensive economic modeling to inform medical device HTA.MethodsThe University-developed New South Wales Cardiovascular Cohort dataset, comprising person-level longitudinal NSW administrative data for all patients admitted to hospital with a cardiovascular diagnosis from 2001 onwards, linked to national Medicare Benefits Schedule and Pharmaceutical Benefits Scheme claims data, was interrogated.ResultsWorking with RWE is resource intensive in terms of time and costs. The potential of these data was revealed as the research progressed. It was possible to continually refine the data analyzed and reported,as well as expand the data requested. Varied expertise is required to accurately analyze the administrative datasets, particularly clinical classification skills and expertise in methods for causal inference using observational data. Findings from this study will enable the refinement of information for MSAC submissions, including identifying the most relevant patient population and reporting comprehensive costs, beyond an admitted hospital setting. The data will enhance engagement with clinicians and refine messaging, for example regarding patient risk factors.ConclusionsRWE enhances Australian HTA applications. Local data, extended periods of time and insights not apparent from a focus on admitted hospital episodes can be revealed. Data can be refined during the process for specificity and applicability.

Epidemiology and clinical outcomes of light-chain amyloidosis in Sweden: A nationwide population-based study.

This study evaluated data from six Swedish national registries to fill current evidence gaps on the epidemiology, clinical burden, and overall survival (OS) associated with light-chain (AL) amyloidosis. Patients newly diagnosed with AL amyloidosis were identified using six linked Swedish nationwide population-based registers. For each case, individuals from the general population were selected and matched with a maximum ratio of 1:5 based on age, sex, calendar year, and county. 846 patients newly diagnosed with AL amyloidosis and 4227 demographically matched individuals were identified. From 2011 to 2019, annual AL amyloidosis incidence increased from 10.5 to 15.1 cases per million. At baseline, patients with AL amyloidosis had a significantly higher disease burden including higher rates of cardiac and renal failure relative to the comparison group. Among patients with AL amyloidosis, 21.5% had incident heart failure and 17.1% had incident renal failure after initial diagnosis. Median OS for patients with AL amyloidosis was 56 months versus not reached in the matched general population comparison group. The incidence of newly diagnosed AL amyloidosis in Sweden increased over time with AL amyloidosis being associated with a higher risk of cardiac/renal failure and all-cause mortality compared with the general population.

Redo-TAVR: Essential Concepts, Updated Data and Current Gaps in Evidence.

Within the last two decades, transcatheter aortic valve replacement (TAVR) has transformed the treatment strategy for symptomatic severe aortic stenosis (AS), representing a less invasive alternative to traditional open-chest surgery. With time, advances in device features, imaging planning, and implantation techniques have contributed to an improvement in safety as well as a reduction in procedural complications. This has led to the expansion of TAVR to lower-risk patients, where TAVR has shown favorable outcomes compared to surgical aortic valve replacement (SAVR). As TAVR expands to younger and lower-risk patients with longer life expectancies, the need for reintervention for failing transcatheter heart valves is expected to increase. Redo-TAVR has gained increasing relevance in the lifetime management of AS as one of the treatment strategies available for structural valve dysfunction (SVD). However, some issues are associated with this approach, including coronary re-access and the risk of coronary obstruction. In this review, we provide essential concepts to properly select candidates for Redo-TAVR, updated data on clinical outcomes and complication rates, and current gaps in evidence.

Integration of real-world evidence from different data sources in health technology assessment.

Real-world evidence (RWE) is being increasingly used by a wide range of stakeholders involved in the therapeutic product lifecycle but remains underutilized in the health technology assessment (HTA) process. RWE aims to fill the current evidence gaps, reduce the uncertainty around the benefits of medical technologies, and better understand the long-term impact of health technologies in real-world conditions. Despite the minimal use of RWE in some elements of HTA, there has been a larger push to further utilize RWE in the HTA processes. HTA bodies, as other stakeholders, work towards developing more robust means to leverage RWE from various data sources in the HTA processes. However, these agencies need to overcome important challenges before the broader incorporation of RWE into their routine practice. This paper aims to explore the extensive integration of RWE utilizing diverse sources of RWD. We discuss the utilization of RWE in HTA processes, considering aspects such as when, where, and how RWE can be effectively applied. Additionally, we seek the potential challenges and barriers associated with the utilization of different data sources.

Delphi panel to obtain clinical consensus about using long-acting injectable antipsychotics to treat first-episode and early-phase schizophrenia: treatment goals and approaches to functional recovery

BackgroundSchizophrenia is mostly a chronic disorder whose symptoms include psychosis, negative symptoms and cognitive dysfunction. Poor adherence is common and related relapse can impair outcomes. Long-acting injectable antipsychotics (LAIs) may promote treatment adherence and decrease the likelihood of relapse and rehospitalization. Using LAIs in first-episode psychosis (FEP) and early-phase (EP) schizophrenia patients could benefit them, yet LAIs have traditionally been reserved for chronic patients.MethodsA three-step modified Delphi panel process was used to obtain expert consensus on using LAIs with FEP and EP schizophrenia patients. A literature review and input from a steering committee of five experts in psychiatry were used to develop statements about patient population, adverse event management, and functional recovery. Recruited Delphi process psychiatrists rated the extent of their agreement with the statements over three rounds (Round 1: paper survey, 1:1 interview; Rounds 2–3: email survey). Analysis rules determined whether a statement progressed to the next round and the level of agreement deemed consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists assess their previous responses in the context of those of the overall group.ResultsThe Delphi panelists were 17 psychiatrists experienced in treating schizophrenia with LAIs, practicing in seven countries (France, Italy, US, Germany, Spain, Denmark, UK). Panelists were presented with 73 statements spanning three categories: patient population; medication dosage, management, and adverse events; and functional recovery domains and assessment. Fifty-five statements achieved ≥ 80% agreement (considered consensus). Statements with low agreement (40-79%) or very low agreement (< 39%) concerned initiating dosage in FEP and EP patients, and managing loss of efficacy and breakthrough episodes, reflecting current evidence gaps. The panel emphasized benefits of LAIs in FEP and EP patients, with consensus that LAIs can decrease the risk of relapse, rehospitalization, and functional dysfunction. The panel supported links between these benefits and multidimensional longer-term functional recovery beyond symptomatic remission.ConclusionsFindings from this Delphi panel support the use of LAIs in FEP and EP schizophrenia patients regardless of disease severity, number of relapses, or social support status. Gaps in clinician knowledge make generating evidence on using LAIs in FEP and EP patients critical.

Understanding an epidemiological view of a retrospective audit of medication errors in an intensive care unit

BackgroundMedication errors in the intensive care setting continue to occur at significant rates and are often associated with adverse events and potentially life-threatening repercussions. Aim/objectiveThe aim of this study was to (i) determine the frequency and severity of medication errors reported in the incident management reporting system; (ii) examine the antecedent events, their nature, the circumstances, risk factors, and contributing factors leading to medication errors; and (iii) identify strategies to improve medication safety in the intensive care unit (ICU). MethodA retrospective, exploratory, descriptive design was selected. Retrospective data were collected from the incident report management system and electronic medical records over a 13-month period from a major metropolitan teaching hospital ICU. ResultsA total of 162 medication errors were reported during a 13-month period, of which, 150 were eligible for inclusion. Most medication errors occurred during the administration (89.4%) and dispensing phases (23.3%). The highest reported errors included incorrect doses (25.3%), incorrect medications (12.7%), omissions (10.7%), and documentation errors (9.3%). Narcotic analgesics (20%), anaesthetics (13.3%), and immunomodifiers (10.7%) were the most frequently reported medication classes associated with medication errors. Prevention strategies were found to be focussed on active errors (67.7%) as opposed to latent errors (32.3%) and included various and infrequent levels of education and follow-up. Active antecedent events included action-based errors (39%) and rule-based errors (29.5%), whereas latent antecedent events were most associated with a breakdown in system safety (39.3%) and education (25%). ConclusionThis study presents an epidemiological view and understanding of medication errors in an Australian ICU. This study highlighted the preventable nature of most medication errors in this study. Improving administration-checking procedures would prevent the occurrence of many medication errors. Approaches aimed at both individual- and organisational-level improvements are recommended to address administration errors and inconsistent medication-checking procedures. Areas for further research include determining the most effective system developments for improving administration-checking procedures and verifying the risk and prevalence of immunomodifier administration errors in the ICU as this is an area not reported previously in the literature. In addition, the impact of single- versus two-person checking procedures on medication errors in the ICU should be prioritised to address current evidence gaps.

Delphi-Based Expert Consensus Statements for the Management of Percutaneous Radiofrequency Neurotomy in the Treatment of Lumbar Facet Joint Syndrome.

A modified Delphi strategy was implemented for obtaining recommendations that could be useful in the management of percutaneous radiofrequency treatment of lumbar facet joint syndrome, as the literature on the argument was poor in quality. An Italian research team conducted a comprehensive literature search, defined the investigation topics (diagnosis, treatment, and outcome evaluation), and developed an explorative semi-structured questionnaire. They also selected the members of the panel. After an online meeting with the participants, the board developed a structured questionnaire of 15 closed statements (round 1). A five-point Likert scale was used and the cut-off for consensus was established at a minimum of 70% of the number of respondents (level of agreement ≥ 4, agree or strongly agree). The statements without consensus were rephrased (round 2). Forty-one clinicians were included in the panel and responded in both rounds. After the first round, consensus (≥ 70%) was obtained in 9 out of 15 statements. In the second round, only one out of six statements reached the threshold. The lack of consensus was observed for statements concerning the use of imaging for a diagnosis [54%, median 4, interquartile range (IQR) 3-5], number of diagnostic blocks (37%, median 4, IQR 2-4), bilateral denervation (59%, median 4, IQR 2-4), technique and number of lesions (66%, median 4, IQR 3-5), and strategy after denervation failure (68%, median 4, IQR 3-4). Results of the Delphi investigations suggest that there is a need to define standardized protocols to address this clinical problem. This step is essential for designing high-quality studies and filling current gaps in scientific evidence.

Nutraceutical alternatives to red yeast rice extract/monacolin K for moderate hypercholesterolaemia: Current evidence and knowledge gaps: Nutraceuticals and hypercholesterolaemia

The nutraceutical approach to moderate hypercholesterolaemia is an interesting option in the context of appropriate conditions associated with low cardiovascular risk, and red yeast rice (RYR) extract is one of the most utilized products in this field. Monacolin k, its main active component, reduces serum LDL-C levels via inhibition of β-Hydroxy β-methylglutaryl-CoA reductase, similarly to statins. In 2011, EFSA approved the claim regarding monacolin k from RYR extract and maintenance of normal cholesterol levels. However, in 2018, EFSA issued a warning about potential adverse effects of this nutraceutical and, in 2022, the European Commission published a Regulation with several limitations of its use. Therefore, current research and development efforts are aiming at assessing efficacy and safety of other known and novel nutraceutical products which may benefit patients with moderate hypercholesterolaemia. These active agents range from phytosterols, probiotics and berberine to bergamot, cabbage and artichoke extracts and soy protein. Moreover, plant extracts from traditional medicine, for example from African countries, are also a subject of study in this direction. The full clinical exploitation of many of them, however, still requires robust clinical evidence, which should be the objective of future research.

Fluid Management for Critically Ill Patients with Acute Kidney Injury Receiving Kidney Replacement Therapy: An International Survey.

In critically ill patients receiving KRT, high ultrafiltration rates and persistent fluid accumulation are associated with adverse outcomes. The purpose of this international survey was to evaluate current practices and evidence gaps related to fluid removal with KRT in critically ill patients. This was a multinational, web-based survey distributed by seven networks comprising nephrologists and intensivists. Physicians involved in the care of critically ill patients were invited to complete a 39-question survey about fluid management practices on KRT. The survey was distributed from September 2021 to December 2021. There were 757 respondents from 96 countries (response rate of 65%). Most respondents practiced adult medicine (89%) and worked in an academic center (69%). The majority (91%) reported aiming for a 0.5- to 2-L negative fluid balance per day when fluid removal is indicated, although there was important variability in what respondents considered a safe maximal target. Intensivists were more likely than nephrologists to use adjunct volume status assessment methods ( i.e. , ultrasound, hemodynamic markers, and intra-abdominal pressure), while nephrologists were more likely to deploy cointerventions aimed at improving tolerance to fluid removal ( i.e. , osmotic agents and low-temperature dialysate). There was a broad consensus that rapid decongestion should be prioritized when fluid accumulation is present, but the prevention of hypotension was also reported as a competing priority. A majority (77%) agreed that performing trials that compare fluid management strategies would be ethical and clinically relevant. We have identified multiple areas of variability in current practice of fluid management for patients receiving KRT. Most nephrologists and intensivists agreed that several knowledge gaps related to fluid removal strategies should be investigated in future randomized controlled trials.

Hydroxyurea treatment for sickle cell anemia during pregnancy and lactation: Current evidence and knowledge gaps.

Sickle cell anemia (SCA) is a life-threatening genetic condition contributing to high-risk pregnancies affecting both the mother and fetus. With improved management of children with SCA, this life-threatening hematological disorder has evolved into a chronic disease of adults, and consequently parenthood has now become a possible and important life goal for many patients. Providing continuous management with healthy red blood cell function and avoiding SCA-associated complications, such as pain crises, acute chest syndrome, and stroke, are crucial for a healthy pregnancy. Despite its excellent safety profile in non-pregnant adults and children, and based on theoretical concerns derived from data using animal models and supraphysiological dosing, hydroxyurea is currently contraindicated for pregnant and lactating women with SCA. Clinical experience of hydroxyurea use during pregnancy is increasingly reported, however, and has shown inconsistent results of fetal or infant adverse effects. How the hydroxyurea exposure level may correlate with pregnancy outcomes is still unclear. Accordingly, efforts should be made to systemically evaluate exposure and safety of hydroxyurea treatment during pregnancy and lactation. Novel approaches such as physiologically based pharmacokinetic (PBPK) modeling, coupled with the ex vivo human placental cotyledon perfusion assay, provide opportunities to understand hydroxyurea exposure not only in pregnant women but also in the developing fetus. Combined with animal data, research using these approaches might be able to define safe and effective hydroxyurea dosing regimens for pregnant and lactating women with SCA, when the benefits of continuing hydroxyurea treatment likely outweigh the risks of non-treatment, by avoiding substantial morbidity and even mortality for both mothers and infants.

Oral Immunotherapy in Food Allergy: Where Are We Now?

Food allergy (FA) has become more prevalent and problematic in the last 2 decades, and it poses important individual, social, and economic burdens. Besides treating reactions induced by accidental exposure and periodic evaluation for acquiring natural tolerance, the primary management approach is still allergen avoidance as a global standard. However, an active therapeutic approach that can raise the reaction threshold or accelerate tolerance is needed. This review aimed to provide an overview and the latest evidence of oral immunotherapy (OIT), which has recently been used in the active treatment of FA. FA immunotherapy, particularly OIT, is gaining considerable interest, and substantial effort has been made to integrate this active treatment into clinical practice. Consequently, growing evidence has been obtained regarding the efficacy and safety of OIT, particularly for allergens such as peanuts, eggs, and milk. However, several issues need to be addressed regarding the availability, safety, and long-term effects of this intervention. In this review, we summarize currently available information regarding tolerance-inducing immune mechanisms of OIT, data on efficacy and safety, gaps in current evidence, and ongoing research to develop new therapeutic molecules in order to enhance safety.

Consumer experiences of long-term oral nicotine replacement therapy and related health information-seeking: A qualitative study.

Nicotine replacement therapy (NRT) delivers a therapeutic dose of nicotine to support smoking cessation, and is currently approved for short-term use (typically ≤12 weeks). Yet, research on real-world over-the-counter NRT use indicates that some consumers continue to use these products long-term. This study sought to understand consumers' experiences of long-term oral NRT use, including self-reported reasons for continued use, and health information-seeking regarding long-term use. In-depth semi-structured telephone interviews were conducted between May and June 2021 with 21 current and former NRT consumers aged ≥18 years from across Australia, with oral NRT use of ≥1 year. Interviews were thematically analysed using the Framework Method. The majority of participants reported achieving NRT-assisted smoking cessation and related health benefits (e.g. respiratory health, improved physical appearance). However, nearly all participants reported experiencing addiction to oral NRT, with many attributing their long-term use to dependence on these products. Participants reported low engagement with NRT health information sources; just half reported consulting with a health professional regarding their long-term NRT use, and some reported negative experiences when health professional advice was sought (e.g. perceptions of not being taken seriously, perceived lack of health professional knowledge). Less than half of participants accurately identified the duration of use recommended in NRT consumer medicine information, and some reported actively dismissing this information. Findings highlight consumers' perceived benefits of continued NRT use whilst also identifying two key concerns - the addictive potential of oral NRT, and low health information-seeking and health professional engagement regarding long-term use. While oral NRT is indisputably safer than tobacco smoking, public health strategies to raise consumer and health professional awareness about the safe use of NRT, which acknowledge the current evidence gap regarding safety and efficacy of long-term use, are needed to maximise their benefits as a harm reduction strategy for smoking cessation.

Health economics of health justice partnerships: A rapid review of the economic returns to society of promoting access to legal advice.

Welfare legal problems and inadequate access to support services follow both the socioeconomic and the health inequalities gradients. Health Justice Partnership (HJP) is an international practitioner-led movement which brings together legal and healthcare professionals to address the root causes of ill health from negative social determinants. The aim of this paper was to identify the current evidence base for the cost-effectiveness of HJP or comparable welfare advice services. A rapid review format was used, with a literature search of PubMed, CINAHL, ASSIA, PsycINFO, Medline, Cochrane Library, Global Health and Web of Science identifying 496 articles. After removal of duplicates, 176 papers were screened on titles and abstracts, and 20 papers met the eligibility criteria. Following a full-text screening, a further 14 papers were excluded due to lack of economic evaluations. Excluded papers' reference lists were scanned, with a further 3 further papers identified which met the inclusion criteria. A final pool of nine studies were included in this review. Studies focused on the financial benefit to service users, with only three studies reporting on cost effectiveness of the interventions. Only one study reported on the economic impact of change of health in service users and one study reported on changes in health service use. This review highlights the current evidence gap in evaluating the cost-effectiveness of adequate access to free legal welfare advice and representation. We propose that an interdisciplinary research agenda between health economics and legal-health services is required to address this research gap.

Public Health Measures to Address the Impact of Climate Change on Population Health-Proceedings from a Stakeholder Workshop.

Background: The World Health Organization identified climate change as the 21st century’s biggest health threat. This study aimed to identify the current knowledge base, evidence gaps, and implications for climate action and health policymaking to address the health impact of climate change, including in the most underserved groups. Methods: The Horizon-funded project ENBEL (‘Enhancing Belmont Research Action to support EU policy making on climate change and health’) organised a workshop at the 2021-European Public Health conference. Following presentations of mitigation and adaptation strategies, seven international researchers and public health experts participated in a panel discussion linking climate change and health. Two researchers transcribed and thematically analysed the panel discussion recording. Results: Four themes were identified: (1) ‘Evidence is key’ in leading the climate debate, (2) the need for ‘messaging about health for policymaking and behaviour change’ including health co-benefits of climate action, (3) existing ‘inequalities between and within countries’, and (4) ‘insufficient resources and funding’ to implement national health adaptation plans and facilitate evidence generation and climate action, particularly in vulnerable populations. Conclusion: More capacity is needed to monitor health effects and inequities, evaluate adaptation and mitigation interventions, address current under-representations of low- or middle-income countries, and translate research into effective policymaking.

Inflammasome Activation in Parkinson's Disease.

Chronic sterile inflammation and persistent immune activation is a prominent pathological feature of Parkinson’s disease (PD). Inflammasomes are multi-protein intracellular signaling complexes which orchestrate inflammatory responses in immune cells to a diverse range of pathogens and host-derived signals. Widespread inflammasome activation is evident in PD patients at the sites of dopaminergic degeneration as well as in blood samples and mucosal biopsies. Inflammasome activation in the nigrostriatal system is also a common pathological feature in both neurotoxicant and α-synuclein models of PD where dopaminergic degeneration occurs through distinct mechanisms. The NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome has been shown to be the primary driver of inflammatory neurotoxicity in PD and other neurodegenerative diseases. Chronic NLRP3 inflammasome activation is triggered by pathogenic misfolded α-synuclein aggregates which accumulate and spread over the disease course in PD. Converging lines of evidence suggest that blocking inflammasome activation could be a promising therapeutic strategy for disease modification, with both NLRP3 knockout mice and CNS-permeable pharmacological inhibitors providing robust neuroprotection in multiple PD models. This review summarizes the current evidence and knowledge gaps around inflammasome activation in PD, the pathological mechanisms by which persistent inflammasome activation can drive dopaminergic degeneration and the therapeutic opportunities for disease modification using NLRP3 inhibitors.