Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases1. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof of concept studies involving abnormally fertilized human zygotes2 were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. Following optimisation, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.

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Chronic disease (care) management (CDM) is a patient-centered model of care that involves longitudinal care delivery; integrated, and coordinated primary medical and specialty care; patient and clinician education; explicit evidence-based care plans; and expert care availability. The model, incorporating mental health and specialty addiction care, holds promise for improving care for patients with substance dependence who often receive no care or fragmented ineffective care. We describe a CDM model for substance dependence and discuss a conceptual framework, the extensive current evidence for component elements, and a promising strategy to reorganize primary and specialty health care to facilitate access for people with substance dependence. The CDM model goes beyond integrated case management by a professional, colocation of services, and integrated medical and addiction care-elements that individually can improve outcomes. Supporting evidence is presented that: 1) substance dependence is a chronic disease requiring longitudinal care, although most patients with addictions receive no treatment (eg, detoxification only) or short-term interventions, and 2) for other chronic diseases requiring longitudinal care (eg, diabetes, congestive heart failure), CDM has been proven effective. Keywordschronic disease management; addiction; primary care; linkage; addiction treatment; chronic care model; recovery Substance (alcohol and drug) dependence is a chronic disease for which many affected adults receive no intervention or detoxification without subsequent treatment. Like other chronic diseases (eg, diabetes, congestive heart failure), substance dependence has no cure and is characterized by relapses requiring longitudinal care. Medical and psychiatric comorbidities are the rule rather than the exception. As a result, care delivery can be complex both for clinicians and patients. In the United States, systems of care for substance dependence (both alcohol and drug) are rarely integrated with those for medical and psychiatric illnesses. Specialty alcohol and drug treatment is efficacious, but many patients do not access available treatment for substance dependence problems after detoxification or medical care. Others enter NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript specialty addiction treatment but do not receive medical or psychiatric care. Some have called to expand the frame of health services research on addictions to include services outside the specialty treatment sector, including behavioral care integrated into primary care. [1][2][3] Although primary care settings provide the venue for longitudinal, comprehensive, and coordinated care, their potential to effectively treat addiction and related comorbidities has not been realized; medical, mental health, and addiction treatment are not coordinated. Primary care settings, with reorganization and appropriate service elements, hold the promise of simultaneously improving physical and psychiatric health while decreasing substan...