Implementation of climate adaptation in the public health sector in Europe: qualitative thematic analysis.

BACKGROUND: Adaptation, to reduce the health impacts of climate change, is driven by political action, public support and events (extreme weather). National adaptation policies or strategies are limited in addressing human health risks and implementation of adaptation in the public health community is not well understood. AIM: To identify key issues in climate change adaptation implementation for public health in Europe. METHODS: Key informant interviews with decision-makers in international, national and local city governments in 19 European countries. Participants were recruited if a senior decision-maker working in public health, environmental health or climate adaptation. INTERVIEWS ADDRESSED: Barriers and levers for adaptation, policy alignment, networks and evidence needs. RESULTS: Thirty-two interviews were completed between June and October 2021 with 4 international, 5 national and 23 city/local government stakeholders. Respondents reported inadequate resources (funding, training and personnel) for health-adaptation implementation and the marginal role of health in adaptation policy. A clear mandate to act was key for implementation and resource allocation. Limited cross-departmental collaboration and poor understanding of the role of public health in climate policy were barriers to implementation. CONCLUSIONS: Across Europe, progress is varied in implementation of climate adaptation in public health planning. Providing appropriate resources, training, knowledge mobilization and supporting cross-departmental collaboration and multi-level governance will facilitate adaptation to protect human health.

The 2020 report of The Lancet Countdown on health and climate change: responding to converging crises.

TRANSLATIONS: For the Chinese, French, German, and Spanish translations of the abstract see Supplementary Materials section.

The Payer License Agreement, or "Netflix model," for hepatitis C virus therapies enables universal treatment access, lowers costs and incentivizes innovation and competition.

BACKGROUND AND AIMS: High unit prices of treatments limit access. For epidemics like that of hepatitis C virus (HCV), reduced treatment access increases prevalence and incidence, making the infectious disease increasingly difficult to manage. The objective of the current study was to construct and test an alternative pricing model, the Payer License Agreement (PLA), and determine whether it could improve outcomes, cut costs and incentivize innovation versus the current unit-based pricing model. METHODS: We built and used computational models of hepatitis C disease progression, treatment, and pricing in historical and future scenarios and quantitatively analyzed their economic and epidemiological impact in three high-income countries. RESULTS: This study had three key results regarding HCV treatment. First, if the PLA model had been implemented when interferon-free direct-acting antiviral (DAA) combinations launched, the number of patients treated and cured would have more than doubled in the first three years, while the liver-related deaths (LRDs) would have decreased by around 40%. Second, if the PLA model had been implemented beginning in 2018, the year that several Netflix-like payment models were under implementation, the number of treated and cured patients would nearly double, and the LRDs would decline by more than 55%. Third, implementing the PLA model would result in a decline in total payer costs of more than 25%, with an increase to pharmaceutical manufacturer revenues of 10%. These results were true across the three healthcare landscapes studied, the USA, the UK and Italy, and were robust against variations to critical model parameters through sensitivity analysis. CONCLUSIONS AND RELEVANCE: These results suggest that implementation of the PLA model in high-income countries across a variety of health system contexts would improve patient outcomes at lower payer cost with more stable revenue for pharmaceutical manufacturers. Health policy-makers in high-income countries should consider the PLA model for application to more cost-effective management of HCV, and explore its application for other infectious diseases with curative therapies available now or soon.

The Pleckstrin homology like domain family member, TDAG51, is temporally regulated during skeletal muscle regeneration.

The capacity for skeletal muscle to repair from daily insults as well as larger injuries is a vital component to maintaining muscle health over our lifetime. Given the importance of skeletal muscle for our physical and metabolic well-being, identifying novel factors mediating the growth and repair of skeletal muscle will thus build our foundational knowledge and help lead to potential therapeutic avenues for muscle wasting disorders. To that end, we investigated the expression of T-cell death associated gene 51 (TDAG51) during skeletal muscle repair and studied the response of TDAG51 deficient (TDAG51-/-) mice to chemically-induced muscle damage. TDAG51 mRNA and protein expression within uninjured skeletal muscle is almost undetectable but, in response to chemically-induced muscle damage, protein levels increase by 5 days post-injury and remain elevated for up to 10 days of regeneration. To determine the impact of TDAG51 deletion on skeletal muscle form and function, we compared adult male TDAG51-/- mice with age-matched wild-type (WT) mice. Body and muscle mass were not different between the two groups, however, in situ muscle testing demonstrated a significant reduction in force production both before and after fatiguing contractions in TDAG51-/- mice. During the early phases of the regenerative process (5 days post-injury), TDAG51-/- muscles display a significantly larger area of degenerating muscle tissue concomitant with significantly less regenerating area compared to WT (as demonstrated by embryonic myosin heavy chain expression). Despite these early deficits in regeneration, TDAG51-/- muscles displayed no morphological deficits by 10 days post injury compared to WT mice. Taken together, the data presented herein demonstrate TDAG51 expression to be upregulated in damaged skeletal muscle and its absence attenuates the early phases of muscle regeneration.

Global prevalence of hepatitis C virus in children in 2018: a modelling study.

BACKGROUND: Hepatitis C virus (HCV) prevalence estimates for adults and high-risk groups have been widely published, but the disease burden in children is poorly understood. Direct-acting antiviral drugs, which are considered to be highly effective curative therapies for HCV, are now approved for paediatric patients as young as 3 years. Reliable prevalence estimates for this population are needed to inform scale-up of treatment and national strategies. This analysis combines past modelling and epidemiological work in 104 countries and territories to estimate global HCV prevalence in children in 2018. METHODS: In this modelling study, a comprehensive literature review for articles published between Jan 1, 2000, and March 31, 2019, was used to determine historical HCV prevalence estimates in children in all 249 countries and territories of the world. We identified published HCV prevalence estimates for children aged 0-18 years who are not at high risk of HCV infection in 39 countries and territories and inputted them into dynamic Markov disease-burden models to estimate viraemic HCV prevalence in 2018. For 25 of them, which had complete data, available information on HCV prevalence in children was used to build regression models to predict paediatric prevalence in an additional 65 countries and territories that had country-specific or territory-specific data about predictors only. Regression models were created for each 5-year paediatric age cohort from 0 to 19 years, considering several predictor variables. The data and forecasts from the 104 countries and territories for which data were available were used to calculate HCV prevalence by Global Burden of Disease region, which was then applied to the remaining 145 countries and territories to generate a global estimate. FINDINGS: The global estimate for viraemic prevalence in the paediatric population aged 0-18 years was 0·13% (95% uncertainty interval 0·08-0·16), corresponding to 3·26 million (2·07-3·90) children with HCV in 2018. HCV prevalence increased with age in all countries and territories. HCV prevalence in women of childbearing age was the strongest predictor of HCV prevalence in children aged 0-4 years (p<0·0001). Prevalence of HCV in adults was significantly associated with HCV prevalence in children aged 5-19 years (p<0·0001), and the proportion of HCV infections in people who inject drugs was significantly associated with HCV prevalence in children aged 15-19 years (p=0·036). INTERPRETATION: Most studies on HCV prevalence in children focus on high-risk groups and highly endemic geographic areas. Our analysis provides global prevalence estimates of HCV in the paediatric population. Treatment in paediatric patients requires different clinical and population health management optimisation than in adults. Because of this heterogeneity, country-specific or territory-specific and age-specific HCV prevalence estimates can help countries and territories to improve national HCV elimination strategies. FUNDING: Gilead Sciences, John C Martin Foundation, and private donors.

Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice.

Those with diabetes invariably develop complications including cardiovascular disease (CVD). To reduce their CVD risk, diabetics are generally prescribed cholesterol-lowering 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (i.e., statins). Statins inhibit cholesterol biosynthesis, but also reduce the synthesis of a number of mevalonate pathway intermediates, leading to several cholesterol-independent effects. One of the pleiotropic effects of statins is the reduction of the anti-fibrinolytic hormone plasminogen activator inhibitor-1 (PAI-1). We have previously demonstrated that a PAI-1 specific inhibitor alleviated diabetes-induced delays in skin and muscle repair. Here we tested if statin administration, through its pleiotropic effects on PAI-1, could improve skin and muscle repair in a diabetic rodent model. Six weeks after diabetes onset, adult male streptozotocin-induced diabetic (STZ), and WT mice were assigned to receive control chow or a diet enriched with 600 mg/kg Fluvastatin. Tibialis anterior muscles were injured via Cardiotoxin injection to induce skeletal muscle injury. Punch biopsies were administered on the dorsal scapular region to induce injury of skin. Twenty-four days after the onset of statin therapy (10 days post-injury), tissues were harvested and analyzed. PAI-1 levels were attenuated in statin-treated diabetic tissue when compared to control-treated tissue, however no differences were observed in non-diabetic tissue as a result of treatment. Muscle and skin repair were significantly attenuated in Fluvastatin-treated STZ-diabetic mice as demonstrated by larger wound areas, less mature granulation tissue, and an increased presence of smaller regenerating muscle fibers. Despite attenuating PAI-1 levels in diabetic tissue, Fluvastatin treatment impaired cutaneous healing and skeletal muscle repair in STZ-diabetic mice.

Myostatin inhibition therapy for insulin-deficient type 1 diabetes.

While Type 1 Diabetes Mellitus (T1DM) is characterized by hypoinsulinemia and hyperglycemia, persons with T1DM also develop insulin resistance. Recent studies have demonstrated that insulin resistance in T1DM is a primary mediator of the micro and macrovascular complications that invariably develop in this chronic disease. Myostatin acts to attenuate muscle growth and has been demonstrated to be elevated in streptozotocin-induced diabetic models. We hypothesized that a reduction in mRNA expression of myostatin within a genetic T1DM mouse model would improve skeletal muscle health, resulting in a larger, more insulin sensitive muscle mass. To that end, Akita diabetic mice were crossed with Myostatin(Ln/Ln) mice to ultimately generate a novel mouse line. Our data support the hypothesis that decreased skeletal muscle expression of myostatin mRNA prevented the loss of muscle mass observed in T1DM. Furthermore, reductions in myostatin mRNA increased Glut1 and Glut4 protein expression and glucose uptake in response to an insulin tolerance test (ITT). These positive changes lead to significant reductions in resting blood glucose levels as well as pronounced reductions in associated diabetic symptoms, even in the absence of exogenous insulin. Taken together, this study provides a foundation for considering myostatin inhibition as an adjuvant therapy in T1DM as a means to improve insulin sensitivity and blood glucose management.

Skeletal muscle as a therapeutic target for delaying type 1 diabetic complications.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease targeting the pancreatic beta-cells and rendering the person hypoinsulinemic and hyperglycemic. Despite exogenous insulin therapy, individuals with T1DM will invariably develop long-term complications such as blindness, kidney failure and cardiovascular disease. Though often overlooked, skeletal muscle is also adversely affected in T1DM, with both physical and metabolic derangements reported. As the largest metabolic organ in the body, impairments to skeletal muscle health in T1DM would impact insulin sensitivity, glucose/lipid disposal and basal metabolic rate and thus affect the ability of persons with T1DM to manage their disease. In this review, we discuss the impact of T1DM on skeletal muscle health with a particular focus on the proposed mechanisms involved. We then identify and discuss established and potential adjuvant therapies which, in association with insulin therapy, would improve the health of skeletal muscle in those with T1DM and thereby improve disease management- ultimately delaying the onset and severity of other long-term diabetic complications.

Inhibition of PAI-1 Via PAI-039 Improves Dermal Wound Closure in Diabetes.

Diabetes impairs the ability to heal cutaneous wounds, leading to hospitalization, amputations, and death. Patients with diabetes experience elevated levels of plasminogen activator inhibitor 1 (PAI-1), regardless of their glycemic control. It has been demonstrated that PAI-1-deficient mice exhibit improved cutaneous wound healing, and that PAI-1 inhibition improves skeletal muscle repair in mice with type 1 diabetes mellitus, leading us to hypothesize that pharmacologically mediated reductions in PAI-1 using PAI-039 would normalize cutaneous wound healing in streptozotocin (STZ)-induced diabetic (STZ-diabetic) mice. To simulate the human condition of variations in wound care, wounds were aggravated or minimally handled postinjury. Following cutaneous injury, PAI-039 was orally administered twice daily for 10 days. Compared with nondiabetic mice, wounds in STZ-diabetic mice healed more slowly. Wound site aggravation exacerbated this deficit. PAI-1 inhibition had no effect on dermal collagen levels or wound bed size. PAI-039 treatment failed to improve angiogenesis in the wounds of STZ-diabetic mice and blunted angiogenesis in the wounds of nondiabetic mice. Importantly, PAI-039 treatment significantly improved epidermal cellular migration and wound re-epithelialization compared with vehicle-treated STZ-diabetic mice. These findings support the use of PAI-039 as a novel therapeutic agent to improve diabetic wound closure and demonstrate the primary mechanism of its action to be related to epidermal closure.

Early oxidative shifts in mouse skeletal muscle morphology with high-fat diet consumption do not lead to functional improvements.

Short-term consumption of a high-fat diet (HFD) can result in an oxidative shift in adult skeletal muscle. However, the impact of HFD on young, growing muscle is largely unknown. Thus, 4-week-old mice were randomly divided into sedentary HFD (60% kcal from fat), sedentary standard chow (control), or exercise-trained standard chow. Tibialis anterior (TA) and soleus muscles were examined for morphological and functional changes after 3 weeks. HFD consumption increased body and epididymal fat mass and induced whole body glucose intolerance versus control mice. Compared to controls, both HFD and exercise-trained TA muscles displayed a greater proportion of oxidative fibers and a trend for an increased succinate dehydrogenase (SDH) content. The soleus also displayed an oxidative shift with increased SDH content in HFD mice. Despite the aforementioned changes, palmitate oxidation rates were not different between groups. To determine if the adaptive changes with HFD manifest as a functional improvement, all groups performed pre- and postexperiment aerobic exercise tests. As expected, exercise-trained mice improved significantly compared to controls, however, no improvement was observed in HFD mice. Interestingly, capillary density was lower in HFD muscles; a finding which may contribute to the lack of functional differences seen with HFD despite the oxidative shift in skeletal muscle morphology. Taken together, our data demonstrate that young, growing muscle exhibits early oxidative shifts in response to a HFD, but these changes do not translate to functional benefits in palmitate oxidation, muscle fatigue resistance, or whole body exercise capacity.