NEJM Group

ANNA-1, an antibody directed against an intracellular antigen, is associated with a highly destructive CD8+ T-cell–mediated process, which rapidly leads to brain atrophy and severe neurologic disability.     Figure 4 from the case shows mechanisms underlying ANNA-1 paraneoplastic autoimmune encephalitis.    Apoptotic tumor cells release onconeural antigens — shared proteins between the nervous system and cancers such as small-cell lung cancer, a neuroendocrine cancer (Panel A). The released antigens, such as antineuronal nuclear antibody type 1 (ANNA-1) antigen, are taken up by dendritic cells, which then travel to regional lymph nodes, where they activate CD4+ helper T cells, CD8+ cytotoxic T cells, naive B cells, and memory B cells. Naive and memory B cells mature into plasma cells, which produce neural autoantibodies (ANNA-1, also known as anti-Hu autoantibody) that can be detected in the blood (serum) and cerebrospinal fluid. In the brain, CD8+ cytotoxic T cells that are primed against the ANNA-1 antigen detect the protein, which has been loaded into major histocompatibility complex molecules on the surface of neurons, and release cytotoxic enzymes (Panel B), such as granzymes and perforin, which damage the neurons (Panel C), leading to irreversible brain atrophy.    Learn more in the latest Case Records of the Massachusetts General Hospital by Eric E. Smith, M.D., M.P.H., Saurabh Rohatgi, M.D., Jenny Linnoila, M.D., Ph.D., and Maria Martinez-Lage, M.D.: https://nej.md/4feA9iJ 

Untreated human immunodeficiency virus (#HIV) infection markedly increases the risk of tuberculosis, which remains the most common cause of hospitalization and death globally among people with HIV infection in the era of antiretroviral therapy (ART). Challenges related to diagnosing #Tuberculosis in people with HIV infection can result in diagnostic delays. Drug–drug interactions and immune reconstitution inflammatory syndrome (IRIS) complicate cotreatment of tuberculosis and HIV infection. Short regimens of rifapentine-based preventive therapy are effective, but access to these regimens is limited. A new review covers recent advances in research and international guidelines, with a focus on clinical issues in adults living in countries where the HIV and tuberculosis disease burden is high.    Read the Review Article “HIV-Associated Tuberculosis” by Graeme Meintjes, M.B., ChB., Ph.D., M.P.H., and Gary Maartens, M.B., Ch.B.: https://nej.md/3LCGmHD 

Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited.    In the TRACE-III trial, researchers investigated the efficacy and safety of intravenous tenecteplase administered 4.5 to 24 hours after the onset of stroke in patients who had had ischemic stroke and did not have access to thrombectomy.    516 patients with ischemic stroke due to anterior-circulation large-vessel occlusion who had salvageable tissue 4.5 to 24 hours after the onset of stroke were assigned to receive intravenous tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) or standard medical treatment.    The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death.    In Chinese patients with ischemic stroke who did not have access to thrombectomy, tenecteplase administered 4.5 to 24 hours after the onset of stroke resulted in a higher percentage of patients with no disability at 90 days than standard medical treatment.    Read the full TRACE-III trial results and Plain Language Summary: https://nej.md/4bZ0peT    #ClinicalTrials #MedicalResearch 

𝗙𝗮𝗰𝘁𝗼𝗿 𝗩𝗜𝗜𝗜 is a large glycoprotein synthesized in liver sinusoidal and vascular endothelial cells that participates in the coagulation cascade. The active form of factor VIII (factor VIIIa), generated by the action of thrombin (activated factor II), is a cofactor for the serine protease factor IXa within the intrinsic tenase complex. The intrinsic tenase complex is essential for the generation of thrombin, the final enzyme of the coagulation cascade necessary for clot formation (so thrombin is activated by factor VIIIa; in an amplification reaction, it also activates factor VIII). In the circulation, the large majority of factor VIII molecules are bound to von Willebrand factor, which is necessary for its stability. Membrane-dependent assembly of the intrinsic tenase complex requires release of factor VIII from von Willebrand factor. Abnormalities of the factor VIII gene (located on the X chromosome) cause hemophilia A, a bleeding disorder. Conversely, factor VIII levels can double, triple, or quadruple during acute-phase responses and pregnancy, increasing the risk of thrombosis. To learn more about this NEJM Illustrated Glossary term, read the editorial “Bioengineered Factor VIII — More Innovation for Hemophilia A” by Pratima Chowdary, M.D., from the Royal Free London NHS Foundation Trust: https://nej.md/3Y6RTWY    Explore more terms: https://nej.md/glossary  

“It was a small nodule. He had noticed it on the lateral aspect of his left wrist, just where his watch strap lay. No pain nor discoloration, 1 cm in diameter, subcutaneous, firm and mobile,” writes Martin H. Ellis, M.D., in a new Perspective. “Being a 20-year-old medical student in his clinical years, he knew exactly what the diagnosis was: occasionally, the links of his metal watch strap would pull at the hairs on his wrist, so this bump was no more than a granuloma secondary to watch-strap–induced trauma. No treatment necessary. Case closed.    “‘Not so,’ said his mother when she came to visit from out of town. And after some cajoling and persuading, he dutifully went off to see his family doctor, who promptly referred him to a general surgeon. One cursory examination and not much of a medical history later, a date was set for excision. The procedure was uncomplicated, and the pathology report read, ‘Nodular fasciitis, clear margins.’ No treatment necessary. Case closed.    “Not so. Six months later, my patient noticed that the lump had recurred in the linear 3-cm surgical scar on his forearm. He was now in his fifth year of medical school and had completed a surgical rotation, so he took himself directly off to ‘his’ surgeon. A cursory examination, some tut-tutting, a date for excision, a simple procedure. The pathology report was forthcoming: ‘Nodular fasciitis, clear margins.’ No treatment necessary. Case closed.”    Despite his growing knowledge of medicine and special access to care as a medical student and then a resident, a patient’s condition is repeatedly misdiagnosed, forcing him to be persistent and self-reliant. Read the Perspective “My First Patient” by Martin H. Ellis, M.D., from the Meir Medical Center and Tel Aviv University: https://nej.md/3xGYtcg 

The August 2024 issue of NEJM Catalyst Innovations in Care Delivery, guest edited by Nicholas Stine MD, includes an in-depth look at the San Francisco Health Systems Collaborative, which convened during the Covid-19 pandemic to align and coordinate medical surge planning and response. Read the article: https://nej.md/3SbFAoz    Here are more highlights from the August issue:     𝗖𝗔𝗦𝗘 𝗦𝗧𝗨𝗗𝗜𝗘𝗦  💡 “Think. Test. Treat TB” in Action: An Innovative Primary Care and Public Health Partnership to Improve Tuberculosis Prevention and Care https://nej.md/4cJgeXl    🤝 Knocking Down Public Health and Health Care Silos: An Innovative Covid-19 Health Equity Response https://nej.md/4cXPu5T    📊 Pediatric Asthma Surveillance System (PASS): Community-Facing Disease Monitoring for Health Equity https://nej.md/4fguBV0    𝗩𝗜𝗘𝗪𝗣𝗢𝗜𝗡𝗧𝗦  🌐 Public Health and Care Delivery — a Common Destiny https://nej.md/3Wp4BiD    𝗔𝗥𝗧𝗜𝗖𝗟𝗘𝗦  🩺 Strengthening the Provision of Abortion and Sexual and Reproductive Health Care Post-𝘋𝘰𝘣𝘣𝘴: An Initiative of the Philadelphia Department of Public Health https://nej.md/3RXrib4    🗽 New York City’s Rapid Response to the 2022 Mpox Outbreak https://nej.md/469k35L    𝗖𝗢𝗠𝗠𝗘𝗡𝗧𝗔𝗥𝗬  💻 Plugging Public Health Data into the Health IT Ecosystem to Protect National Health https://nej.md/3Wokrdi    𝗜𝗡𝗦𝗜𝗚𝗛𝗧𝗦 𝗥𝗘𝗣𝗢𝗥𝗧   🚑 Public Health and Care Delivery: Similar Missions, Separate Paths https://nej.md/469vn1D    𝗙𝗥𝗢𝗠 𝗧𝗛𝗘 𝗘𝗗𝗜𝗧𝗢𝗥𝗦   🌉 How to Bridge Public Health and Care Delivery https://nej.md/3Sb7otv    Explore the current issue: https://nej.md/4f4TDGi    #CareDelivery 

Dr. Ken Wu, a pediatrician and NEJM editorial fellow from 2019 to 2020, reflects on his NEJM editorial fellowship experience and the impact it has had on his career.    Sound interesting? NEJM is looking for physicians at any career stage to apply for a one-year, full-time, paid editorial fellowship beginning in July 2025.     Several fellows will be selected for the 2025–26 year; applications are due by Thursday, August 1, 2024.    For more reflections from prior NEJM fellows and for more information, visit https://nej.md/421foPx 

Insomnia disorder is characterized by dissatisfaction with sleep quality or duration associated with difficulty falling or staying asleep and substantial distress or daytime impairments. The disorder is a sleep disturbance that occurs 3 nights or more per week, persists for more than 3 months, and is not the result of inadequate opportunities for sleep. It frequently co-occurs with other medical conditions (e.g., pain) and psychiatric disorders (e.g., depression), as well as other sleep disorders (e.g., restless legs syndrome and sleep apnea).    The assessment and diagnosis of insomnia rests on a careful history to document symptoms, course, co-occurring conditions, and other contributing factors. A 24-hour history of sleep–wake behaviors may identify additional behavioral and environmental targets for intervention (shown in figure). Patient-reported assessment tools and sleep diaries can provide valuable information about the nature and severity of insomnia symptoms, help screen for other sleep disorders, and monitor treatment progress.    Learn more in the Clinical Practice article “Management of Insomnia” by Charles Morin, PhD, and Daniel J. Buysse, MD, from Université Laval and the University of Pittsburgh: https://nej.md/3zMCiBW 

The past decade has witnessed phenomenal progress in the therapeutic options available for persons with hemophilia A and B, conditions characterized by deficiencies in coagulation factor VIII and factor IX, respectively. In NEJM, Malec et al. describe a study of efanesoctocog alfa, a bioengineered human factor VIII recombinant protein, to treat children with severe hemophilia A. The modifications introduced to factor VIII were based on comprehensive knowledge of its high-affinity interaction with von Willebrand factor (VWF), which protects factor VIII from premature breakdown and rapid clearance. The bioengineering approach disrupts this interaction, stabilizes unbound factor VIII, and extends its half-life.    In children, the factor VIII protein has a shorter half-life than in adults, and intravenous administration of coagulation factors is particularly challenging owing to poor venous access. In this context, a notable outcome in the study by Malec et al. is the achievement of once-weekly prophylaxis in children with sustained factor VIII levels through the week, which augurs well for protection in the context of delayed or missed doses.    A new editorial describes the science behind the treatment of children with hemophilia A with efanesoctocog alfa, a bioengineered recombinant factor VIII protein.    Read the editorial “Bioengineered Factor VIII — More Innovation for Hemophilia A” by Pratima Chowdary, M.D., from the Royal Free London NHS Foundation Trust: https://nej.md/3Y6RTWY    𝗙𝗨𝗥𝗧𝗛𝗘𝗥 𝗥𝗘𝗔𝗗𝗜𝗡𝗚  Original Article by Lynn Malec, M.D., et al., from Versiti Inc., the Medical College of Wisconsin, and elsewhere: Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A https://nej.md/3y5zCyP    #MedicalResearch 

A 𝘀𝗺𝗮𝗹𝗹-𝗺𝗼𝗹𝗲𝗰𝘂𝗹𝗲 𝗱𝗿𝘂𝗴 is a chemical compound with a low molecular weight (typically 0.1 to 0.6 kD). Small-molecule drugs are smaller than biologic drugs, such as monoclonal antibodies (typically 150 kD) and oligonucleotides (typically 4 to 10 kD). Because of their small size, they can penetrate the cell membrane and bind intracellular targets. They are generally more stable than biologic drugs and can be administered orally. Learn about small-molecule drugs that resulted in unprecedented improvements in the health of many persons with #CysticFibrosis in a review by Hartmut Grasemann, M.D., and Felix Ratjen, M.D.: https://nej.md/40f40k1