Lancet
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Mitochondria are dynamic bioenergetic organelles whose maintenance requires around 1500 proteins from two genomes. Mutations in either the mitochondrial or nuclear genome can disrupt a plethora of cellular metabolic and homoeostatic functions. ⋯ New insights into both bioenergetic and biosynthetic mitochondrial functionalities have expedited the genetic diagnosis of primary mitochondrial disorders, and identified novel mitochondrial pathomechanisms and new targets for therapeutic intervention. As we enter this new era of mitochondrial medicine, underpinned by global unbiased approaches and multifaceted investigation of mitochondrial function, omics technologies will continue to shed light on unresolved mitochondrial questions, paving the way for improved outcomes for patients with mitochondrial diseases.
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Type 1 diabetes is a chronic autoimmune disease characterised by insulin deficiency and resultant hyperglycaemia. Knowledge of type 1 diabetes has rapidly increased over the past 25 years, resulting in a broad understanding about many aspects of the disease, including its genetics, epidemiology, immune and β-cell phenotypes, and disease burden. ⋯ However, wide gaps still exist in our understanding of type 1 diabetes and our ability to standardise clinical care and decrease disease-associated complications and burden. This Seminar gives an overview of the current understanding of the disease and potential future directions for research and care.
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Genome-wide association studies have implicated around 250 genomic regions in predisposition to type 2 diabetes, with evidence for causal variants and genes emerging for several of these regions. Understanding of the underlying mechanisms, including the interplay between β-cell failure, insulin sensitivity, appetite regulation, and adipose storage has been facilitated by the integration of multidimensional data for diabetes-related intermediate phenotypes, detailed genomic annotations, functional experiments, and now multiomic molecular features. ⋯ Despite rapid progress in the discovery of the highly polygenic architecture of type 2 diabetes, dominated by common alleles with small, cumulative effects on disease risk, these insights have been of little clinical use in terms of disease prediction or prevention, and have made only small contributions to subtype classification or stratified approaches to treatment. Successful development of academia-industry partnerships for exome or genome sequencing in large biobanks could help to deliver economies of scale, with implications for the future of genomics-focused research.
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Many clinical practice guidelines recommend similar approaches for the assessment and management of low back pain. Recommendations include use of a biopsychosocial framework to guide management with initial non-pharmacological treatment, including education that supports self-management and resumption of normal activities and exercise, and psychological programmes for those with persistent symptoms. Guidelines recommend prudent use of medication, imaging, and surgery. ⋯ The advances with the greatest potential are arguably those that align practice with the evidence, reduce the focus on spinal abnormalities, and ensure promotion of activity and function, including work participation. We have identified effective, promising, or emerging solutions that could offer new directions, but that need greater attention and further research to determine if they are appropriate for large-scale implementation. These potential solutions include focused strategies to implement best practice, the redesign of clinical pathways, integrated health and occupational interventions to reduce work disability, changes in compensation and disability claims policies, and public health and prevention strategies.