NEJM Group

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 

Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death.     Whether treatment with semaglutide would mitigate these risks is unknown.    In the FLOW trial, researchers assessed whether the glucagon-like peptide 1 receptor agonist semaglutide was effective in preventing progression of kidney disease in patients with type 2 diabetes and chronic kidney disease.     3533 participants with type 2 diabetes and chronic kidney disease were randomly assigned to receive weekly subcutaneous semaglutide (1.0 mg) or placebo.     The primary outcome was major kidney disease events, a composite of the onset of kidney failure (initiation of dialysis, kidney transplantation, or an estimated glomerular filtration rate [eGFR] of <15 ml per minute per 1.73 m2), at least a 50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes.    Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease.    Read the full FLOW trial results and Plain Language Summary: https://nej.md/44U3slP    #ClinicalTrials #MedicalResearch 

Idiopathic infantile hypercalcemia has long been a clinical diagnosis of exclusion in infants when all other causes of hypercalcemia have been ruled out. In the age of widespread genetic testing, research has shown that many of these cases are caused by genetic variants in the vitamin D pathway that increase calcium absorption. Idiopathic infantile hypercalcemia can be caused by variants in several genes, but the most common is CYP24A1, the gene encoding the 24-hydroxylase enzyme. 24-Hydroxylase is responsible for converting 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to 24,25-dihydroxyvitamin D and 1,24,25-trihydroxyvitamin D (calcitroic acid), respectively, both of which are inactive and can be excreted through the kidneys (shown in figure). This excretion prevents the toxic effects of vitamin D, including the main associated complications — hypercalcemia and nephrocalcinosis.    Learn more in “A 10-Month-Old Boy with Vomiting and Hypercalcemia,” the latest Case Record of the Massachusetts General Hospital, by Christina Jacobsen, M.D., Ph.D., Harald Jüppner, M.D., and Deborah Mitchell, M.D.: https://nej.md/3Lnf73u 

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