The article "Solving the Puzzle of Long Covid" by Ziyad Al-Aly and Eric Topol discusses the ongoing challenges and progress in understanding and managing Long Covid, a condition affecting millions worldwide. Long Covid is characterized by a range of post-acute and long-term health issues, with symptoms varying across different demographics. The disease is likely multifaceted, with multiple subtypes and potential risk factors. Mechanisms include viral persistence, immune dysregulation, mitochondrial dysfunction, and microbiome imbalance. Vaccines and antivirals have shown promise in reducing the risk of Long Covid, but their effectiveness and safety need further evaluation, especially in younger and healthier adults. Reinfections can exacerbate the condition, and the lack of consensus on definitions and clinical endpoints hinders research and treatment development. The article emphasizes the need for multidisciplinary care, expanded access to specialty clinics, and innovative approaches to biomarker development. It also highlights the importance of addressing Long Covid denialism and improving surveillance systems to better understand and manage the condition. The authors call for urgent efforts to develop treatments and preventions, emphasizing the need for well-powered randomized controlled trials and nonpharmaceutical interventions to reduce infection and reinfection rates.The article "Solving the Puzzle of Long Covid" by Ziyad Al-Aly and Eric Topol discusses the ongoing challenges and progress in understanding and managing Long Covid, a condition affecting millions worldwide. Long Covid is characterized by a range of post-acute and long-term health issues, with symptoms varying across different demographics. The disease is likely multifaceted, with multiple subtypes and potential risk factors. Mechanisms include viral persistence, immune dysregulation, mitochondrial dysfunction, and microbiome imbalance. Vaccines and antivirals have shown promise in reducing the risk of Long Covid, but their effectiveness and safety need further evaluation, especially in younger and healthier adults. Reinfections can exacerbate the condition, and the lack of consensus on definitions and clinical endpoints hinders research and treatment development. The article emphasizes the need for multidisciplinary care, expanded access to specialty clinics, and innovative approaches to biomarker development. It also highlights the importance of addressing Long Covid denialism and improving surveillance systems to better understand and manage the condition. The authors call for urgent efforts to develop treatments and preventions, emphasizing the need for well-powered randomized controlled trials and nonpharmaceutical interventions to reduce infection and reinfection rates.