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Background The leukodystrophy “Vanishing White Matter” (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase. Clinical trials in VWM pose serious challenges, as VWM has an episodic disease course; disease phenotype is highly heterogeneous and predictable only for early onset; and study power is limited by the small patient numbers. To address these challenges and accelerate therapy delivery, the VWM Consortium, a group of academic clinicians with expertise in VWM, decided to develop a core protocol to function as a template for trials, to improve trial design and facilitate sharing of control data, while permitting flexibility regarding other trial details. Overall aims of the core protocol are to collect safety, tolerability, and efficacy data for treatment assessment and marketing authorization. Methods To develop the core protocol, the VWM Consortium designated a committee, including clinician members of the VWM Consortium, family and patient group advocates, and experts in statistics, clinical trial design and alliancing with industries. We drafted three age-specific protocols, to stratify into more homogeneous patient groups, of ages ≥ 18 years, ≥ 6 to < 18 years and < 6 years. We chose double‐blind, randomized, placebo-controlled design for patients aged ≥ 6 years; and open-label non-randomized natural-history-controlled design for patients < 6 years. The protocol describes study populations, age-specific endpoints, inclusion and exclusion criteria, study schedules, sample size determinations, and statistical considerations. Discussion The core protocol provides a shared uniformity across trials, enables a pool of shared controls, and reduces the total number of patients necessary per trial, limiting the number of patients on placebo. All VWM clinical trials are suggested to adhere to the core protocol. Other trial components such as choice of primary outcome, pharmacokinetics, pharmacodynamics, and biomarkers are flexible and unconstrained by the core protocol. Each sponsor is responsible for their trial execution, while the control data are handled by a shared research organization. This core protocol benefits the efficiency of parallel and consecutive trials in VWM, and we hope accelerates time to availability of treatments for VWM. Trial registration NA. From a scientific and ethical perspective, it is strongly recommended that all interventional trials using this core protocol are registered in a clinical trial register.

This paper is one of three synthesis documents produced via an integrated assessment (IA) that aims to increase understanding of artisanal and small-scale gold mining (ASGM) in Ghana. Given the complexities surrounding ASGM, an integrated assessment (IA) framework was utilized to analyze socio-economic, health, and environmental data, and co-develop evidence-based responses with stakeholders. This paper focuses on the causes, status, trends, and consequences of ecological issues related to ASGM activity in Ghana. It reviews dozens of studies and thousands of samples to document evidence of heavy metals contamination in ecological media across Ghana. Soil and water mercury concentrations were generally lower than guideline values, but sediment mercury concentrations surpassed guideline values in 64% of samples. Arsenic, cadmium, and lead exceeded guideline values in 67%, 17%, and 24% of water samples, respectively. Other water quality parameters near ASGM sites show impairment, with some samples exceeding guidelines for acidity, turbidity, and nitrates. Additional ASGM-related stressors on environmental quality and ecosystem services include deforestation, land degradation, biodiversity loss, legacy contamination, and potential linkages to climate change. Though more research is needed to further elucidate the long-term impacts of ASGM on the environment, the plausible consequences of ecological damages should guide policies and actions to address the unique challenges posed by ASGM.