Connor J Lewis, Precilla D'Souza, Jean M Johnston, Maria T Acosta, Cristan Farmer, Eva H Baker, Anna Crowell, Yoliann Mojica, Sumaiya Ashraf, Lisa Joseph, Gilbert Vézina, Zenaide Quezado, Muhammad H Yousef, Zeynep Vardar, Mohammed Salman Shazeeb, Manuela Corti, Meghan Blackwood, Kirsten Coleman, Rita Batista, Audrey Thurm, Erika De Boever, William A Gahl, Barry J Byrne, Terence R Flotte, Xuntian Jiang, Amanda L Gross, Allison M Keeler, Heather Gray-Edwards, Douglas R Martin, Miguel Sena-Esteves, Cynthia J Tifft
Background: GM1 gangliosidosis, caused by biallelic variants in GLB1, results from deficiency of lysosomal β-galactosidase, which degrades GM1 ganglioside. This fatal neurodegenerative disease currently has no effective therapy.
Methods: In a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns.
Results: Nine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline.
Conclusions: In this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures. (Funded by the National Human Genome Research Institute and others; ClinicalTrials.gov number, NCT03952637.).
{"title":"AAV9 Gene Therapy in Type II GM1 Gangliosidosis - A Phase 1-2 Trial.","authors":"Connor J Lewis, Precilla D'Souza, Jean M Johnston, Maria T Acosta, Cristan Farmer, Eva H Baker, Anna Crowell, Yoliann Mojica, Sumaiya Ashraf, Lisa Joseph, Gilbert Vézina, Zenaide Quezado, Muhammad H Yousef, Zeynep Vardar, Mohammed Salman Shazeeb, Manuela Corti, Meghan Blackwood, Kirsten Coleman, Rita Batista, Audrey Thurm, Erika De Boever, William A Gahl, Barry J Byrne, Terence R Flotte, Xuntian Jiang, Amanda L Gross, Allison M Keeler, Heather Gray-Edwards, Douglas R Martin, Miguel Sena-Esteves, Cynthia J Tifft","doi":"10.1056/NEJMoa2510935","DOIUrl":"https://doi.org/10.1056/NEJMoa2510935","url":null,"abstract":"<p><strong>Background: </strong>GM1 gangliosidosis, caused by biallelic variants in <i>GLB1</i>, results from deficiency of lysosomal β-galactosidase, which degrades GM1 ganglioside. This fatal neurodegenerative disease currently has no effective therapy.</p><p><strong>Methods: </strong>In a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns.</p><p><strong>Results: </strong>Nine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline.</p><p><strong>Conclusions: </strong>In this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures. (Funded by the National Human Genome Research Institute and others; ClinicalTrials.gov number, NCT03952637.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":" ","pages":""},"PeriodicalIF":78.5,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146151265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Otto Metzger,Sumithra Mandrekar,Shom Goel,Joseph Gligorov,Elgene Lim,Eva Ciruelos,Sibylle Loibl,Travis Dockter,Xavier Gonzàlez Farré,Prudence A Francis,Filipa Lynce,Jane Lanzillotti,Carter DuFrane,Anna Wall,Carrie Strand,Ian Krop,Ines Vaz-Luis,Debu Tripathy,Sherene Loi,Aleix Prat,Matthew Goetz,Santiago Escrivá-de-Romaní,David Porter,Jennifer Spoenlein,Daniel G Stover,Sagar Sardesai,Pierre Heudel,Maria Koehler,Cynthia Huang Bartlett,Ariadna Holynskyj,Prashanth Gopalakrishna,Eric Gauthier,Suzette Delaloge,Kathy Miller,Eric P Winer,Luca Gianni,Ann H Partridge,Angela DeMichele,Lisa A Carey
BACKGROUNDDual anti-human epidermal growth factor receptor 2 (HER2) therapy plus chemotherapy followed by maintenance treatment with HER2-targeted and endocrine therapies is standard first-line treatment for hormone-receptor-positive, HER2-positive metastatic breast cancer. On the basis of preclinical and clinical data, the addition of palbociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) may overcome resistance to both endocrine and HER2-directed therapies.METHODSIn this phase 3, open-label, randomized trial, we enrolled patients with hormone-receptor-positive, HER2-positive metastatic breast cancer who did not have disease progression after four to eight cycles of chemotherapy plus HER2-targeted therapy. Patients were randomly assigned in a 1:1 ratio to receive maintenance HER2-targeted and endocrine therapies with or without palbociclib. The primary end point was investigator-assessed progression-free survival. Secondary end points included the objective response, clinical benefit, safety, and overall survival.RESULTSA total of 518 patients underwent randomization: 261 were assigned to receive palbociclib and 257 to receive standard therapy. At a median follow-up of 53.5 months, patients in the palbociclib group had significantly longer progression-free survival than those in the standard-therapy group (median duration, 44.3 months vs. 29.1 months; hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; two-sided P = 0.02). Grade 3 and 4 adverse events, predominantly from neutropenia, occurred in 79.7% and 10.0% of the patients, respectively, in the palbociclib group, as compared with 30.6% and 3.6% of the patients, respectively, in the standard-therapy group.CONCLUSIONSThe addition of palbociclib to maintenance anti-HER2 and endocrine therapies led to a significant improvement in progression-free survival over standard therapy, with increased toxic effects, mainly neutropenia. (Funded by Pfizer and others; PATINA ClinicalTrials.gov number, NCT02947685.).
{"title":"Palbociclib for Hormone-Receptor-Positive, HER2-Positive Advanced Breast Cancer.","authors":"Otto Metzger,Sumithra Mandrekar,Shom Goel,Joseph Gligorov,Elgene Lim,Eva Ciruelos,Sibylle Loibl,Travis Dockter,Xavier Gonzàlez Farré,Prudence A Francis,Filipa Lynce,Jane Lanzillotti,Carter DuFrane,Anna Wall,Carrie Strand,Ian Krop,Ines Vaz-Luis,Debu Tripathy,Sherene Loi,Aleix Prat,Matthew Goetz,Santiago Escrivá-de-Romaní,David Porter,Jennifer Spoenlein,Daniel G Stover,Sagar Sardesai,Pierre Heudel,Maria Koehler,Cynthia Huang Bartlett,Ariadna Holynskyj,Prashanth Gopalakrishna,Eric Gauthier,Suzette Delaloge,Kathy Miller,Eric P Winer,Luca Gianni,Ann H Partridge,Angela DeMichele,Lisa A Carey","doi":"10.1056/nejmoa2511218","DOIUrl":"https://doi.org/10.1056/nejmoa2511218","url":null,"abstract":"BACKGROUNDDual anti-human epidermal growth factor receptor 2 (HER2) therapy plus chemotherapy followed by maintenance treatment with HER2-targeted and endocrine therapies is standard first-line treatment for hormone-receptor-positive, HER2-positive metastatic breast cancer. On the basis of preclinical and clinical data, the addition of palbociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) may overcome resistance to both endocrine and HER2-directed therapies.METHODSIn this phase 3, open-label, randomized trial, we enrolled patients with hormone-receptor-positive, HER2-positive metastatic breast cancer who did not have disease progression after four to eight cycles of chemotherapy plus HER2-targeted therapy. Patients were randomly assigned in a 1:1 ratio to receive maintenance HER2-targeted and endocrine therapies with or without palbociclib. The primary end point was investigator-assessed progression-free survival. Secondary end points included the objective response, clinical benefit, safety, and overall survival.RESULTSA total of 518 patients underwent randomization: 261 were assigned to receive palbociclib and 257 to receive standard therapy. At a median follow-up of 53.5 months, patients in the palbociclib group had significantly longer progression-free survival than those in the standard-therapy group (median duration, 44.3 months vs. 29.1 months; hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; two-sided P = 0.02). Grade 3 and 4 adverse events, predominantly from neutropenia, occurred in 79.7% and 10.0% of the patients, respectively, in the palbociclib group, as compared with 30.6% and 3.6% of the patients, respectively, in the standard-therapy group.CONCLUSIONSThe addition of palbociclib to maintenance anti-HER2 and endocrine therapies led to a significant improvement in progression-free survival over standard therapy, with increased toxic effects, mainly neutropenia. (Funded by Pfizer and others; PATINA ClinicalTrials.gov number, NCT02947685.).","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"42 1","pages":"451-462"},"PeriodicalIF":158.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen J Ryan,Øystein Kalsnes Jørstad,Mona Skjelland,Maiju Pesonen,Claus Z Simonsen,Toke Bek,Rolf Ankerlund Blauenfeldt,Petra Ijäs,Arja Laitinen,Andrej Khanevski,Jørgen Krohn,Eyvind Rødahl,Robin Lemmens,Jelle Demeestere,Catherine Cassiman,Ingvild Nakstad,Kristin Evensen,Tiril Sandell,Steffen Hamann,Thomas C Truelsen,Louisa M Christensen,Sverre Rosenbaum,Vaidas Matijošaitis,Reda Žemaitienė,Hanne Ellekjær,Erlend Almaas,Dordi Austeng,Michael V Mazya,Frank Traïsk,Pauli Ylikotila,Ulpu Salmi,Kristian N Jenssen,Håvard Lisether,Cathrine Breivik,Kristina Devik,Lasse-Marius Elden Honningsvåg,Jurgita Valaikienė,Andrius Cimbalas,Vetle Nilsen Malmberg,Espen Anderson,Ansar Roy,Thor Håkon Skattør,Kristian Lundsgaard Kraglund,Christina Kefaloykos,Inge Christoffer Olsen,Peter Vanacker,Daniel Strbian,Morten C Moe,Anne Hege Aamodt,
BACKGROUNDCentral retinal artery occlusion can result in permanent vision loss. Effective treatment is lacking.METHODSWe conducted a phase 3, double-blind, double-dummy, randomized, controlled trial involving adults with acute, nonarteritic central retinal artery occlusion who had symptom onset within 4.5 hours before treatment. Patients were assigned, in a 1:1 ratio, to receive intravenous tenecteplase (at a dose of 0.25 mg per kilogram of body weight) and oral placebo or intravenous placebo and oral aspirin (at a dose of 300 mg). The primary end point was vision recovery, defined as a best corrected visual acuity (BCVA) in the affected eye at 30 days of up to 0.7 logMAR (logarithm of the minimum angle of resolution; equivalent to ≥20/100). Key secondary visual end points were a BCVA of up to 0.5 logMAR (equivalent to ≥20/63), mean improvement in BCVA, and perimetry score at 30 days. Key safety end points included symptomatic intracranial hemorrhage, major bleeding, and death.RESULTSA total of 78 patients at 16 sites in six countries underwent randomization, with 40 assigned to receive tenecteplase and 38 to receive aspirin. At 30 days, 8 patients (20%) in the tenecteplase group and 9 patients (24%) in the aspirin group had vision recovery (risk difference, -3.7 percentage points; 95% confidence interval, -22.0 to 14.7; P = 0.69). The outcomes with regard to the secondary visual end points did not differ substantially between the groups. There was a greater incidence of adverse events in the tenecteplase group, including one fatal intracranial hemorrhage.CONCLUSIONSIntravenous tenecteplase administered within 4.5 hours after onset of central retinal artery occlusion did not result in significantly greater vision recovery at 30 days than oral aspirin but was associated with serious safety concerns. (Funded by Oslo University Hospital and others; TenCRAOS ClinicalTrials.gov number, NCT04526951; EU Clinical Trials number, 2024-517606-29-00.).
{"title":"A Randomized Trial of Tenecteplase in Acute Central Retinal Artery Occlusion.","authors":"Stephen J Ryan,Øystein Kalsnes Jørstad,Mona Skjelland,Maiju Pesonen,Claus Z Simonsen,Toke Bek,Rolf Ankerlund Blauenfeldt,Petra Ijäs,Arja Laitinen,Andrej Khanevski,Jørgen Krohn,Eyvind Rødahl,Robin Lemmens,Jelle Demeestere,Catherine Cassiman,Ingvild Nakstad,Kristin Evensen,Tiril Sandell,Steffen Hamann,Thomas C Truelsen,Louisa M Christensen,Sverre Rosenbaum,Vaidas Matijošaitis,Reda Žemaitienė,Hanne Ellekjær,Erlend Almaas,Dordi Austeng,Michael V Mazya,Frank Traïsk,Pauli Ylikotila,Ulpu Salmi,Kristian N Jenssen,Håvard Lisether,Cathrine Breivik,Kristina Devik,Lasse-Marius Elden Honningsvåg,Jurgita Valaikienė,Andrius Cimbalas,Vetle Nilsen Malmberg,Espen Anderson,Ansar Roy,Thor Håkon Skattør,Kristian Lundsgaard Kraglund,Christina Kefaloykos,Inge Christoffer Olsen,Peter Vanacker,Daniel Strbian,Morten C Moe,Anne Hege Aamodt, ","doi":"10.1056/nejmoa2508515","DOIUrl":"https://doi.org/10.1056/nejmoa2508515","url":null,"abstract":"BACKGROUNDCentral retinal artery occlusion can result in permanent vision loss. Effective treatment is lacking.METHODSWe conducted a phase 3, double-blind, double-dummy, randomized, controlled trial involving adults with acute, nonarteritic central retinal artery occlusion who had symptom onset within 4.5 hours before treatment. Patients were assigned, in a 1:1 ratio, to receive intravenous tenecteplase (at a dose of 0.25 mg per kilogram of body weight) and oral placebo or intravenous placebo and oral aspirin (at a dose of 300 mg). The primary end point was vision recovery, defined as a best corrected visual acuity (BCVA) in the affected eye at 30 days of up to 0.7 logMAR (logarithm of the minimum angle of resolution; equivalent to ≥20/100). Key secondary visual end points were a BCVA of up to 0.5 logMAR (equivalent to ≥20/63), mean improvement in BCVA, and perimetry score at 30 days. Key safety end points included symptomatic intracranial hemorrhage, major bleeding, and death.RESULTSA total of 78 patients at 16 sites in six countries underwent randomization, with 40 assigned to receive tenecteplase and 38 to receive aspirin. At 30 days, 8 patients (20%) in the tenecteplase group and 9 patients (24%) in the aspirin group had vision recovery (risk difference, -3.7 percentage points; 95% confidence interval, -22.0 to 14.7; P = 0.69). The outcomes with regard to the secondary visual end points did not differ substantially between the groups. There was a greater incidence of adverse events in the tenecteplase group, including one fatal intracranial hemorrhage.CONCLUSIONSIntravenous tenecteplase administered within 4.5 hours after onset of central retinal artery occlusion did not result in significantly greater vision recovery at 30 days than oral aspirin but was associated with serious safety concerns. (Funded by Oslo University Hospital and others; TenCRAOS ClinicalTrials.gov number, NCT04526951; EU Clinical Trials number, 2024-517606-29-00.).","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"71 1","pages":"442-450"},"PeriodicalIF":158.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CORE Principles in the Management of Severe Hypertriglyceridemia.","authors":"Pamela B Morris","doi":"10.1056/nejme2517580","DOIUrl":"https://doi.org/10.1056/nejme2517580","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"73 1","pages":"509-510"},"PeriodicalIF":158.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Seeing It Through - Lessons from a Retinal Stroke Trial.","authors":"Matthew Schrag,Brian Mac Grory","doi":"10.1056/nejme2514614","DOIUrl":"https://doi.org/10.1056/nejme2514614","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"217 1","pages":"511-512"},"PeriodicalIF":158.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peripheral artery disease affects approximately 236 million persons worldwide and is diagnosed with an ankle-brachial index of less than 0.90. Among older persons, 3.3% of those without peripheral artery disease, 18.1% with mild disease, and 52.0% with severe disease could not complete a 6-minute walk test without resting. To prevent cardiovascular events in persons with peripheral artery disease, intensive cholesterol-lowering medications (statins), antiplatelet medications or low-dose aspirin with rivaroxaban, blood-pressure lowering to less than 130/80 mm Hg, and semaglutide are recommended, along with sodium-glucose cotransporter 2 inhibitors in patients with diabetes. Supervised walking exercise and structured home-based walking exercise each improve walking ability in persons with peripheral artery disease. Revascularization in the legs should be reserved for those with persistent disease symptoms that do not respond to exercise.
外周动脉疾病影响全球约2.36亿人，诊断为踝肱指数小于0.90。在老年人中，3.3%没有外周动脉疾病的人、18.1%患有轻度疾病的人和52.0%患有严重疾病的人不能在不休息的情况下完成6分钟步行测试。为了预防外周动脉疾病患者的心血管事件，推荐使用强化降胆固醇药物（他汀类药物）、抗血小板药物或低剂量阿司匹林联合利伐沙班、血压降至低于130/80 mm Hg和西马鲁肽，以及糖尿病患者的钠-葡萄糖共转运蛋白2抑制剂。有监督的步行锻炼和有组织的家庭步行锻炼均可改善外周动脉疾病患者的步行能力。腿部血运重建术应该留给那些对运动没有反应的持续性疾病症状的患者。
{"title":"Peripheral Artery Disease in the Legs.","authors":"Mary M McDermott","doi":"10.1056/nejmcp2501200","DOIUrl":"https://doi.org/10.1056/nejmcp2501200","url":null,"abstract":"Peripheral artery disease affects approximately 236 million persons worldwide and is diagnosed with an ankle-brachial index of less than 0.90. Among older persons, 3.3% of those without peripheral artery disease, 18.1% with mild disease, and 52.0% with severe disease could not complete a 6-minute walk test without resting. To prevent cardiovascular events in persons with peripheral artery disease, intensive cholesterol-lowering medications (statins), antiplatelet medications or low-dose aspirin with rivaroxaban, blood-pressure lowering to less than 130/80 mm Hg, and semaglutide are recommended, along with sodium-glucose cotransporter 2 inhibitors in patients with diabetes. Supervised walking exercise and structured home-based walking exercise each improve walking ability in persons with peripheral artery disease. Revascularization in the legs should be reserved for those with persistent disease symptoms that do not respond to exercise.","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"38 1","pages":"486-496"},"PeriodicalIF":158.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shreya Shrestha,Tyler Brown,Jacqueline T Chu,M Lauren Donnelly-Morell
{"title":"Case 4-2026: An 80-Year-Old Woman with Cough and Hypoxemia.","authors":"Shreya Shrestha,Tyler Brown,Jacqueline T Chu,M Lauren Donnelly-Morell","doi":"10.1056/nejmcpc2513543","DOIUrl":"https://doi.org/10.1056/nejmcpc2513543","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"120 1 1","pages":"498-507"},"PeriodicalIF":158.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
George Karandinos,Mia Giuriato,José R Zubizarreta,Katherine A Koh,Peter T Masiakos,Zirui Song,Chana A Sacks
BACKGROUNDEvery year, approximately 20,000 youths lose a parent to firearm injury in the United States. Many more youths have parents who sustain nonfatal firearm injuries. The effect of parents' firearm injuries on their children's health and health care is poorly understood.METHODSUsing U.S. commercial health insurance claims data from the 2007-2022 period, we identified youths, 1 to 19 years of age, whose parents had received treatment for firearm injury (exposure). Each youth with exposure was matched with up to five control youths on the basis of year, month, youth sex, metropolitan statistical area, state, insurance plan type, and prescription drug coverage; mean values of age and a risk score predicting future health care use (to provide a proxy for health status) were balanced. The primary outcome was a diagnosis of psychiatric disorder among youths, assessed as a rate, which was defined as the number of youths with at least one related insurance claim in a given month, divided by the total number of youths. Secondary outcomes included substance use disorder diagnosis, health care use, and medical spending. After matching, we estimated the difference in differences in outcomes between the exposure group and the control group 12 months before the parental injury through 12 months after the injury, using a least-squares regression model with adjustment for age and risk score.RESULTSWe examined 3790 youths with exposure and 18,535 matched controls. The mean age of the youths was 10.7 years, and 51.5% were male. Parental firearm injury was associated with 8.4 additional psychiatric diagnoses (95% confidence interval [CI], 4.8 to 12.0) per 1000 youths and 23.1 additional mental health visits (95% CI, 8.2 to 38.1) per 1000 youths as compared with control, averaged over the year. This associated increase in the exposure group was largest for diagnoses of trauma-related disorders, including post-traumatic stress disorder, with an additional 8.5 diagnoses (95% CI, 6.0 to 10.9) per 1000 youths as compared with control, averaged over the year. No apparent changes relative to control were observed in rates of other diagnoses, medical encounters, procedures, and services or in medical spending.CONCLUSIONSParents' firearm injuries were associated with increases in rates of psychiatric disorders and mental health visits among their children. (Funded by the National Institute for Health Care Management and the National Institute of Mental Health.).
{"title":"Mental Health Outcomes in Children after Parental Firearm Injury.","authors":"George Karandinos,Mia Giuriato,José R Zubizarreta,Katherine A Koh,Peter T Masiakos,Zirui Song,Chana A Sacks","doi":"10.1056/nejmsa2502702","DOIUrl":"https://doi.org/10.1056/nejmsa2502702","url":null,"abstract":"BACKGROUNDEvery year, approximately 20,000 youths lose a parent to firearm injury in the United States. Many more youths have parents who sustain nonfatal firearm injuries. The effect of parents' firearm injuries on their children's health and health care is poorly understood.METHODSUsing U.S. commercial health insurance claims data from the 2007-2022 period, we identified youths, 1 to 19 years of age, whose parents had received treatment for firearm injury (exposure). Each youth with exposure was matched with up to five control youths on the basis of year, month, youth sex, metropolitan statistical area, state, insurance plan type, and prescription drug coverage; mean values of age and a risk score predicting future health care use (to provide a proxy for health status) were balanced. The primary outcome was a diagnosis of psychiatric disorder among youths, assessed as a rate, which was defined as the number of youths with at least one related insurance claim in a given month, divided by the total number of youths. Secondary outcomes included substance use disorder diagnosis, health care use, and medical spending. After matching, we estimated the difference in differences in outcomes between the exposure group and the control group 12 months before the parental injury through 12 months after the injury, using a least-squares regression model with adjustment for age and risk score.RESULTSWe examined 3790 youths with exposure and 18,535 matched controls. The mean age of the youths was 10.7 years, and 51.5% were male. Parental firearm injury was associated with 8.4 additional psychiatric diagnoses (95% confidence interval [CI], 4.8 to 12.0) per 1000 youths and 23.1 additional mental health visits (95% CI, 8.2 to 38.1) per 1000 youths as compared with control, averaged over the year. This associated increase in the exposure group was largest for diagnoses of trauma-related disorders, including post-traumatic stress disorder, with an additional 8.5 diagnoses (95% CI, 6.0 to 10.9) per 1000 youths as compared with control, averaged over the year. No apparent changes relative to control were observed in rates of other diagnoses, medical encounters, procedures, and services or in medical spending.CONCLUSIONSParents' firearm injuries were associated with increases in rates of psychiatric disorders and mental health visits among their children. (Funded by the National Institute for Health Care Management and the National Institute of Mental Health.).","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"3 1","pages":"475-485"},"PeriodicalIF":158.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daniel M Fernandes,Alejandro Llanos-Lizcano,Florian Brück,Victoria Oberreiter,Kadir T Özdoğan,Olivia Cheronet,Michaela Lucci,Albert Beckers,Patrick Pétrossians,Alfredo Coppa,Ron Pinhasi,Adrian F Daly
{"title":"A 12,000-Year-Old Case of NPR2-Related Acromesomelic Dysplasia.","authors":"Daniel M Fernandes,Alejandro Llanos-Lizcano,Florian Brück,Victoria Oberreiter,Kadir T Özdoğan,Olivia Cheronet,Michaela Lucci,Albert Beckers,Patrick Pétrossians,Alfredo Coppa,Ron Pinhasi,Adrian F Daly","doi":"10.1056/nejmc2513616","DOIUrl":"https://doi.org/10.1056/nejmc2513616","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"42 1","pages":"513-515"},"PeriodicalIF":158.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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