Lancet
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Review
The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches.
With the 2019 breakthrough in the development of highly effective modulator therapy providing unprecedented clinical benefits for over 90% of patients with cystic fibrosis who are genetically eligible for treatment, this rare disease has become a front runner of transformative molecular therapy. This success is based on fundamental research, which led to the identification of the disease-causing CFTR gene and our subsequent understanding of the disease mechanisms underlying the pathogenesis of cystic fibrosis, working together with a continuously evolving clinical research and drug development pipeline. ⋯ We review progress in (and the remaining obstacles to) pharmacological approaches to rescue CFTR function, and novel strategies for improved symptomatic therapies for cystic fibrosis, including how these might be applicable to common lung diseases, such as bronchiectasis and chronic obstructive pulmonary disease. Finally, we discuss the promise of genetic therapies and gene editing approaches to restore CFTR function in the lungs of all patients with cystic fibrosis independent of their CFTR genotype, and the unprecedented opportunities to transform cystic fibrosis from a fatal disease to a treatable and potentially curable one.
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Following discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989 and subsequent elucidation of the varied CFTR protein abnormalities that result, a new era of cystic fibrosis management has emerged-one in which scientific principles translated from the bench to the bedside have enabled us to potentially treat the basic defect in the majority of children and adults with cystic fibrosis, with a resultant burgeoning adult cystic fibrosis population. However, the long-term effects of these therapies on the multiple manifestations of cystic fibrosis are still under investigation. ⋯ Furthermore, establishing appropriate disease measures to assess efficacy in the youngest potential trial participants and in those whose post-modulator lung function is in the typical range for people without chronic lung disease is essential for continued drug development. Finally, recognising that a health outcome gap has been created for some people and widened for others who are not eligible for, cannot tolerate, or do not have access to modulators is important.
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Hepatitis C virus (HCV) is a hepatotropic RNA virus that can cause acute and chronic hepatitis, with progressive liver damage resulting in cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In 2016, WHO called for the elimination of HCV infection as a public health threat by 2030. Despite some progress, an estimated 57 million people were living with HCV infection in 2020, and 300 000 HCV-related deaths occur per year. The development of direct-acting antiviral therapy has revolutionised clinical care and generated impetus for elimination, but simplified and broadened HCV screening, enhanced linkage to care, and higher coverage of treatment and primary prevention strategies are urgently required.
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Across multiple pandemics, global health governance institutions have struggled to secure the compliance of states with international legal and political commitments, ranging from data sharing to observing WHO guidance to sharing vaccines. In response, governments are negotiating a new pandemic treaty and revising the International Health Regulations. Achieving compliance remains challenging, but international relations and international law research in areas outside of health offers insights. ⋯ Drawing on human rights, trade, finance, tobacco, and environmental law, we categorise compliance mechanisms as police patrol, fire alarm, or community organiser models. We show that, to date, current and proposed global health law incorporates only a few of the mechanisms that have shown to be effective in other areas. We offer six specific, politically feasible mechanisms for new international agreements that, together, could create compliance pressures to shift state behaviour.
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Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. ⋯ Stryker and Amsterdam University Medical Centers, University of Amsterdam.