Demonstrating Benefit-Risk Profiles of Novel Therapeutic Strategies in Kidney Transplantation: Opportunities and Challenges of Real-World Evidence.

While great progress has been made in transplantation medicine, long-term graft failure and serious side effects still pose a challenge in kidney transplantation. Effective and safe long-term treatments are needed. Therefore, evidence of the lasting benefit-risk of novel therapies is required. Demonstrating superiority of novel therapies is unlikely via conventional randomized controlled trials, as long-term follow-up in large sample sizes pose statistical and operational challenges. Furthermore, endpoints generally accepted in short-term clinical trials need to be translated to real-world (RW) care settings, enabling robust assessments of novel treatments. Hence, there is an evidence gap that calls for innovative clinical trial designs, with RW evidence (RWE) providing an opportunity to facilitate longitudinal transplant research with timely translation to clinical practice. Nonetheless, the current RWE landscape shows considerable heterogeneity, with few registries capturing detailed data to support the establishment of new endpoints. The main recommendations by leading scientists in the field are increased collaboration between registries for data harmonization and leveraging the development of technology innovations for data sharing under high privacy standards. This will aid the development of clinically meaningful endpoints and data models, enabling future long-term research and ultimately establish optimal long-term outcomes for transplant patients.

Economic burden and quality of life of caregivers of patients with sickle cell disease in the United Kingdom and France: a cross-sectional study.

BACKGROUND: Sickle cell disease (SCD), a genetic blood disorder that affects red blood cells and oxygen delivery to body tissues, is characterized by haemolytic anaemia, pain episodes, fatigue, and end-organ damage with acute and chronic dimensions. Caring for patients with SCD imposes a high burden on informal caregivers. This study aims to capture the impact on health-related quality of life (HRQoL) and economic burden of caregiving for patients with SCD. METHODS: Validated instruments of HRQoL (EQ-5D-5L, Carer Quality of Life-7 dimensions [CarerQol-7D]) and productivity (Work Productivity and Activity Impairment Questionnaire: Specific Health Problem [WPAI: SHP]) were administered via a cross-sectional online survey to caregivers in the United Kingdom (UK) and France. Demographics, HRQoL, and economic burden data were analyzed using descriptive statistics. Economic burden was determined using country-specific minimum and average wage values. Subgroup analysis examined caregivers with and without SCD. RESULTS: Sixty-nine caregivers were recruited (UK, 43; France, 26), 83% were female, and 22% had SCD themselves. The mean (SD) caregiver EQ-5D-5L score was 0.66 (0.28) (UK, 0.62; France, 0.73), and the mean CarerQol-7D score was 80.69 (24.40) (UK, 78.72 [25.79]; France, 83.97 [22.01]). Mental health problems were reported in 72% and 70% of caregivers measured using the EQ-5D-5L and CarerQol-7D, respectively. Financial problems were reported by 68% of caregivers, with mean annual minimum wage productivity losses of £4209 and €3485, increasing to £5391 and €9319 for average wages. Sensitivity analysis determined additional HRQoL decrements for caregivers with and without, SCD. CONCLUSION: Caring for patients with SCD impacts the HRQoL and economic burden of caregivers. Further research to support the complex needs of SCD caregivers is required.

Caregivers play an important role in the lives of the people with sickle cell disease that they care for; however, their mental and physical health and their finances can be affected, particularly if their ability to work is impacted. The extent to which caring for a person with sickle cell disease impacts caregivers is not fully understood. In this study, 69 caregivers of a family member, partner, or friend with sickle cell disease in the United Kingdom or France completed an online survey to share their experiences about how caring for someone with sickle cell disease can impact a caregiver's quality of life and financial well-being. Caregiving negatively affected the quality of life of caregivers compared with people in the general population and caused a large financial and social burden. Around 70% of caregivers reported having mental health problems, 68% reported financial problems, and lost work hours and lost income were not uncommon. More research is needed to understand the specific needs of caregivers of people with sickle cell disease and how best to support them.

Effects of l-arginine supplementation associated with continuous or interval aerobic training on chronic heart failure rats.

OBJECTIVE: Chronic heart failure (CHF) is related with exercise intolerance and impaired nitric oxide (NO) production, which can lead to several functional capacity alterations. Considering the possible superiority of aerobic interval training compared to continuous training and the capacity of l-arginine to restore the NO pathway, the aim of the present study was to investigate whether these treatments are beneficial to exercise capacity, muscle mass preservation and hemodynamic, inflammatory and oxidative stress parameters in CHF rats. METHODS: Thirty-eight male Wistar rats post 6weeks of myocardial infarction (MI) surgery were randomly assigned into 6 CHF groups: sedentary (SED, n=6); SED+Arg (n=7); ACT (n=8); ACT+Arg (n=5); AIT (n=7); AIT+Arg (n=5). Exercise test capacity (ETC) was performed pre and post 8weeks of intervention. Supplemented rats received Arg (1g/kg) by oral gavage (7×/week). Exercise training was performed on a rat treadmill (5×/week). Hemodynamic variables, tissue collection, congestion, inflammatory cytokines, and oxidative parameters were evaluated at the end of protocols. RESULTS: All trained groups showed a superior exercise capacity compared to SED groups on the post-intervention test (p<0.0001). Pulmonary congestion was attenuated in AIT and AIT+Arg compared with the SED group (p<0.05). Left ventricular end-diastolic pressure (LVEDP) was lower in ACT+Arg, AIT, and AIT+Arg groups than SED group (p<0.05). Association of AIT with Arg supplementation was able to improve hemodynamic responses (left ventricular systolic pressure (LVSP), systolic blood pressure (SBP), +dP/dtmax, and -dP/dtmax (p<0.05), likewise, decrease muscular and renal lipid peroxidation and tumor necrosis factor (TNF)-α, and increase interleukin (IL)-10/TNF-α plasmatic levels (p<0.01). Groups that associated aerobic exercise with Arg supplementation (ACT+Arg and AIT+Arg) revealed higher gastrocnemius mass compared to the SED group (p<0.01). CONCLUSIONS: Both aerobic training protocols were capable to improve aerobic capacity, and the association with Arg supplementation was important to attenuate muscle loss. Moreover, interval training associated with Arg supplementation elicits greater improvements in hemodynamic parameters, contributing to reduction in pulmonary congestion, and demonstrated particular responses in the inflammatory profile and in the antioxidant status.