Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Understanding and Improving the Price-Quality Relationship in Rwanda's Coffee Sector

EXECUTIVE SUMMARY At 15 years old, specialty coffee is a relatively new sub-sector of Rwanda’s long-standing coffee industry. As such, structures and policies to maximize coffee quality are still evolving and have room for improvement. The problem examined in this report includes the obstacles preventing the sector from reaching the Government of Rwanda’s (GOR’s) stated goal of 80 percent high quality coffee coffee instead of only 55 percent, (the status quo in 2017). The approach used by the author is to demonstrate and quantify the effects of not reaching the quality targets from three perspectives: that of the producer, the exporter, and the GOR. The models indicate that producers lost 125 RWF/kg cherry sold in the time period considered, exporters had 43 percent lower profits than might have been possible, and the country missed an estimated $2.6 million in foreign exchange, just in 2016. The damage from potato taste defect is estimated at$.30 - $2.00 per pound FOB for exported green coffee, depending on the quality level.* These estimated, unrealized gains provide the impetus to examine possible solutions. Five case studies of exemplary East African coffee organizations give concrete examples of how some cooperatives and private companies have invested to improve cherry purchasing practices and improve quality. At the end, marketing and policy recommendations are offered to support further increases in the value of Rwanda’s coffee. * Potato taste defect is a taste defect occurring in coffee in Rwanda’s region. It creates a musty, vegetal taste, like a raw potato, in the brewed coffee

ESTIMATING FARMER COST OF PRODUCTION FOR FULLY-WASHED COFFEE IN RWANDA

The purpose of this research report is to provide a clear understanding of the methodology used by the Africa Great Lakes Region Coffee Support project (AGLC) to determine the cost of production (CoP) for coffee farmers in Rwanda. In documenting how the CoP data were collected and the estimates derived, users will be equipped to use the findings of this research confidently and appropriately as they incorporate them into planning and decision making in the coffee sector. It is intended for this report to also assist research purposes and program implementation elsewhere in the Africa Great Lakes region and beyond

ESTIMATING FARMER COST OF PRODUCTION FOR FULLY-WASHED COFFEE IN RWANDA

The purpose of this research report is to provide a clear understanding of the methodology used by the Africa Great Lakes Region Coffee Support project (AGLC) to determine the cost of production (CoP) for coffee farmers in Rwanda. In documenting how the CoP data were collected and the estimates derived, users will be equipped to use the findings of this research confidently and appropriately as they incorporate them into planning and decision making in the coffee sector. It is intended for this report to also assist research purposes and program implementation elsewhere in the Africa Great Lakes region and beyond

DETERMINANTS OF FARMER INVESTMENT IN COFFEE PRODUCTION: FINDING A PATH TO SUSTAINABLE GROWTH IN RWANDA’S COFFEE SECTOR

Coffee production has been at the core of farm family livelihoods in Rwanda for many generations and today it serves as source of cash income for over 355,000 households across the country. Since 2001, the coffee value chain has seen a transformation in quality (fully-washed coffee) and is now well-established in specialty coffee markets around the globe. With the construction of 245 washing stations, the processing segments of the sector have prospered. Dry mills and export companies, both domestic and international, have similarly emerged during this period. While the value-added from this transformation has benefited Rwanda, those at the base, the coffee producers, have shared the least in the new prosperity

Incentivizing Farmer Investments for Sustainable Growth in Rwanda’s Coffee Sector

Coffee production has been at the core of farm family livelihoods in Rwanda for many generations. Today it remains a primary source of cash income for over 355,000 households across the country (NAEB 2016b). Since 2001, the coffee value chain has enjoyed a renaissance and has emerged as the darling of specialty coffee markets and consumers around the globe. The processing side of the sector has thrived with the construction of 245 privately and cooperatively funded washing stations in every coffee growing region of the country. Dry mills and export companies, both domestic and international, have likewise opened for business. There has been tremendous value added in the industry’s transformation

THE ROLE OF COOPERATIVES ON ADOPTION OF BEST MANAGEMENT PRACTICES AND PRODUCTIVITY IN RWANDA’S COFFEE SECTOR

Agricultural cooperatives operate under the notion that smallholder farmers are better off working collectively. Rwanda’s coffee sector has experienced a significant transformation over the past two decades, which includes farmers coming together to establish cooperative coffee washing stations (CWSs). Our data and analysis show that these collectives provide farmers with a myriad of services that include economic, agronomic and social benefits. We find that cooperative membership affects adoption of specific practices, most notably pesticide application. This finding, however cannot be generalized to all best management practices as we find that membership is not associated with uptake of some practices (like fertilizer use) and in some instances it can contribute to a lower likelihood of adoption. Among other differences, we find that cooperative members attain higher levels of productivity, however our analysis cannot confirm this to be a causal relationship. We note that collective action in Rwanda’s coffee sector needs additional research attention, as these types of farmer associations don’t always thrive or provide the same level of services that their members expect. We derive implications of our findings and identify areas in need of further inquiry