NEJM 2026-06-04｜本週新刊導讀

本期共 24 篇，其中 0 篇 OA。

本期主軸

本期 NEJM 的主軸不是單一疾病，而是「制度、介入、免疫與風險邊界」四條線並行。制度面聚焦美國醫療 corporatization、戰爭飢荒、種族化藥物與 Indigenous health curricula；介入面則以 AF 的 left atrial appendage closure、acute hypoxemic respiratory failure 的 high-flow oxygen、AML 全口服 HMA–venetoclax 為核心；免疫與移植面以 CAR T desensitization 挑戰高度 HLA sensitization；基因治療安全則由 AAV integration 相關 neuroepithelial tumor 提醒長期監測不能鬆懈。

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必讀導讀

Regulating Corporate Control in the U.S. Health Care System（Perspective）

這篇把 health care corporatization 拆成可監管的幾個機制，而不是把問題簡化成「private equity 壞」或「大型體系壞」。作者指出市場紀律在醫療中常失靈：病人不易比較品質，付款者與使用者分離，品質訊號滯後，導致 consolidation、vertical integration、site-of-service payment differential、340B margin 等政策結構可被用來獲利而未必改善照護。臨床端最相關的是，這些安排會影響人力配置、轉診導流、coding burden、服務可近性與安全文化。作者提出的監管路徑包括 ownership 與 related-party payment 透明化、serial acquisition 審查、反競爭合約限制、醫療機構財務脆弱性監測，以及降低因所有權型態而產生的付款套利。 常見誤判：把 corporatization 視為單一所有權問題，而忽略付款規則、反競爭結構與資訊不透明共同製造誘因。

War and Famine（Perspective）

這篇以 Gaza 兒童 wasting 的時間序列切入，將 famine 從政治事件拉回臨床與公共衛生問題。文中數字很尖銳：戰前 Gaza 5 歲以下兒童 wasting 約 1–2%，初期 aid blockade 期間升至 14% 以上，ceasefire 期間降到接近 5%，封鎖再起時 northern Gaza 最高達 28%；2025 年 7 月平均食物供應為 1394 kcal/person/day。作者強調，對醫師而言，mid-upper-arm circumference、RUTF、疫苗、感染治療、連續追蹤與 humanitarian access 都是臨床處置的一部分。這不是把政治帶入醫療，而是承認沒有 access 時，可治療的 severe acute malnutrition 會變成死亡。 常見誤判：把 humanitarian corridor 視為政治表態，而不是 severe malnutrition 與感染併發症治療所需的臨床條件。

Perversity in Medicine — When Vocation and Corporatization Clash（Perspective）

這是一篇高度主觀、但臨床共鳴強的敘事型 Perspective。作者用「領導者說了什麼」與「臨床醫師聽見什麼」的反差，描寫 corporate medicine 中 business growth、hospital acquisition、coding、tertiary expansion、outpatient neglect 與 clinician morale 的裂縫。重點不在證明每個 health system leader 都有惡意，而是指出當組織語言持續把 market position、census、billing、construction 與 expansion 放在 care relationship、primary care、psychiatry 與可近性之前，醫療的 vocation 會被消磨。臨床可帶走的是：burnout 不能只用 wellness program 處理，因為許多痛點是價值排序失衡。 常見誤判：把 clinician burnout 當成個人韌性不足，而非組織價值與臨床使命衝突造成的 moral injury。

BiDil — The Story of the Black Pill — ITT Episode 2.5（Perspective）

BiDil 的故事是 hydralazine–isosorbide dinitrate 從心衰竭藥物變成第一個 race-specific drug indication 的案例。文中呈現兩個張力：一方面，self-identified Black patients 在 trial 中有臨床受益訊號，且 Black cardiologists 希望改善心衰竭死亡不平等；另一方面，將 race 作為生物學藥物標籤強化了「race 等於 genetics」的錯誤敘事，也與專利、定價、行銷策略交織。臨床端最重要的教訓是：race 可作為 racism、access、exposure 與結構性差異的研究變項，但不應被當成遺傳 proxy；真正需要的是更細緻蒐集 socioeconomic status、racism exposure、housing、education 與 biologic markers。 常見誤判：把 self-identified race 當成可直接替代 genetics、mechanism 或 pharmacogenomics 的臨床變項。

Advancing Indigenous Health Equity in Medical School Curricula（Perspective）

這篇介紹 University of Washington School of Medicine 的 Indian Health Pathway。其價值在於它不是把 Indigenous health 做成一堂「文化敏感度」課，而是以 Tribal sovereignty、formal memorandum of understanding、Tribal liaison、Indigenous faculty、community engagement、scholarly project、Indian health primary care clerkship 與 traditional Indian medicine clerkship 組成長期教育結構。自 1992 年起已有 141 名學生完成 certificate，超過 50% 進入 primary care residency。對醫學教育者來說，這篇的 take-home 是：health equity curriculum 若沒有社群治理、雙向關係與臨床場域 immersion，容易停在象徵性內容。 常見誤判：把 Indigenous health education 等同於短期文化課程，而忽略 Tribal sovereignty、互惠關係與臨床場域責任。

Left Atrial Appendage Closure or Anticoagulation for Atrial Fibrillation（RCT）

CHAMPION-AF 納入 3000 名適合 anticoagulation 的 AF 病人，比較 Watchman Flx left atrial appendage closure 與 NOAC。3 年 primary efficacy endpoint（CV death、stroke、systemic embolism）為 5.7% vs. 4.8%，difference 0.9 percentage points，95% CI −0.8 to 2.6，達 noninferiority；non–procedure-related bleeding 為 10.9% vs. 19.0%，HR 0.55，95% CI 0.45 to 0.67，達 superiority。臨床解讀要保守：這支持在 selected anticoagulation-eligible AF 病人納入 shared decision-making，但不能等同於「器械全面取代 NOAC」。ischemic stroke/systemic embolism 數值方向、device-related thrombus、leak、post-implant antithrombotic regimen 與 5 年追蹤仍是關鍵。 常見誤判：把 noninferiority 解讀成完全等效或更優，進而把 LAA closure 視為多數 AF 病人的 first-line 替代方案。

High-Flow or Standard Oxygen in Acute Hypoxemic Respiratory Failure（RCT）

SOHO trial 納入 1110 名 ICU acute hypoxemic respiratory failure 病人，條件包括 PaO2:FIO2 ≤200、respiratory rate >25/min 與 pulmonary infiltrates。High-flow oxygen 未降低 day-28 mortality：14.6% vs. 14.6%，difference −0.05 percentage points，95% CI −4.21 to 4.10，P=0.98；但 day-28 intubation 較低：42.4% vs. 48.4%，difference −5.93 percentage points，95% CI −11.78 to −0.08。臨床上，HFNC 的價值可能在減少 intubation、改善呼吸功與 dyspnea，而不是直接降低死亡。這也提醒 ICU trials 的 endpoint 要對齊介入機制；mortality 很重要，但未必是每個氧氣介入最合適的 primary endpoint。 常見誤判：看到 intubation 下降就推論 mortality 必然下降，或看到 mortality 未下降就認定 HFNC 沒有臨床價值。

All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia（phase 1–2）

ASCERTAIN-V 評估 oral decitabine–cedazuridine 加 oral venetoclax，用於 ≥75 歲或不適合 intensive induction chemotherapy 的 newly diagnosed AML。研究沒有 randomized comparator；重點是 PK interaction、response 與安全性。結果顯示 decitabine–cedazuridine 與 venetoclax 沒有明顯 drug–drug interaction；phase 2b complete response 47%，CR/CRi 63%，median overall survival 15.5 months。毒性核心仍是 myelosuppression：grade ≥3 anemia 30%、neutropenia 26%、febrile neutropenia 25%，30-day mortality 3%、60-day mortality 10%。真正的臨床訊息不是「全口服等於輕鬆」，而是早期 marrow assessment、blast clearance 後縮短 venetoclax、azole dose adjustment、G-CSF 與密集 supportive care 必須內建。 常見誤判：把 all-oral AML regimen 當成低監測、低風險治療，而忽略 cytopenia、infection 與 adherence 管理。

Kidney Transplantation in Two Highly Sensitized Candidates after CAR T-Cell Therapy（phase 1 case series）

這是 highly sensitized kidney-transplant candidates 的 CAR T desensitization safety run-in cohort。兩名 cPRA ≥99.9% 候選人接受 CD19-targeted 與 BCMA-targeted CAR T cells，加上較溫和 lymphodepletion，並配合 plasmapheresis 與 low-dose IVIG。Patient 1 cPRA 從 99.998% 降至 99.516%，day 229 接受 deceased-donor kidney transplant，12 個月無 DSA rebound；Patient 2 cPRA 從 99.995% 降至 99.567%，day 93 transplant，7 個月無 DSA rebound。沒有 dose-limiting toxic effects。這不是可立即推廣的標準療法，但提供 proof-of-concept：細胞治療可把等待名單上幾乎無法配對的病人推進可移植範圍。 常見誤判：以 oncology CAR T 毒性想像移植 desensitization，或認為必須完全清除所有 plasma cells 才可能有臨床效益。

Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery（case report）

這篇是 AAV gene therapy 長期安全的重要警訊。5 歲男童因 severe MPSI 於 13 個月大接受 intracisternal magna AAV9 RGX-111，4 年後發現 intraventricular neuroepithelial tumor。腫瘤分子分析顯示 rearranged AAV vector elements clonal integration into PLAG1，產生 AAV–PLAG1 fusion transcript；PLAG1 expression 為 comparator CNS tumor cohort 的 298 倍，integrated structure 在 long-read sequencing 約 40% reads 中可見。腫瘤切除後 8 個月未見成長，且孩子 cognitive function 仍優於 severe MPSI natural history。臨床意義不是否定 AAV，而是要求 route、dose、promoter、target tissue proliferation 與長期監測更精細化。 常見誤判：把 AAV 視為 practically nonintegrating，因此短期安全通過後就不需要 insertional oncogenesis 監測。

Childhood Vaccine Hesitancy（clinical practice）

這篇 Clinical Practice 對兒童疫苗猶豫提供實用溝通框架。作者把 hesitancy 放在 spectrum 中間，而非等同 active antivaccine denial；多數家長仍想保護孩子，只是受安全疑慮、錯誤資訊、trust、social norm、access 與認知偏誤影響。臨床證據支持「presumptive recommendation」作為開場，再以 active listening、validation、permission to share information、motivational interviewing 或 empathetic refutational interviewing 處理特定疑慮。文中提醒：clinician recommendation 是最強 predictor，provider recommendation OR 3.4，on-site vaccination OR 2.9；但 facts alone 常不足。對 MMR-autism 類疑慮，重點是先保留關係，再清楚說明證據。 常見誤判：把 vaccine-hesitant parents 當成反疫苗運動者，或以為丟更多 facts 就能改變決策。

The Unusual Suspects（clinical problem-solving）

這個 CPS 的核心是「雙重診斷」。53 歲男性有 Crohn’s disease 與 psoriasis，使用 budesonide 與 dupilumab，因 headache、slurred speech、nausea、vomiting、jaundice 就醫。皮膚 Osler nodes、Janeway lesion、splinter hemorrhages、MSSA bacteremia、mitral vegetation 1.2 cm、mitral leaflet perforation、severe mitral regurgitation 與腦／腎 embolic infarcts 指向 infective endocarditis；但 ALT 遠高於 AST、bilirubin、ANA 1:320、anti–smooth-muscle IgG、IgG elevation 與 biopsy 的 interface hepatitis、plasma-cell infiltration 又指向 autoimmune hepatitis。停用／低劑量重啟 budesonide 可能揭露原先被壓住的 autoimmune hepatitis。治療以 antibiotics、prednisone、azathioprine 與 bioprosthetic mitral-valve replacement 收斂，16 個月肝酵素維持正常。 常見誤判：要求一個診斷解釋所有異常，因而把 severe hepatocellular injury 全歸因於 sepsis、alcohol 或 emboli。

Left Atrial Appendage Closure — Should Recommendations Be Expanded?（editorial）

這篇 editorial 對 CHAMPION-AF 給出必要的煞車。作者承認 LAA closure 對 selected patients 有吸引力，但指出 noninferiority margin 是 absolute scale，且 observed event rate 低於預期，使「排除較小但臨床相關差異」更困難。安全性方面，non–procedure-related bleeding 較低，但若納入 procedure-related major bleeding，差距沒有同樣明確；NOAC 種類比例、apixaban 安全 profile、device-related thrombus 4.8%、postimplant leak 與 LAA endocrine/hemodynamic function 都仍需理解。最實務的建議是 case-by-case shared decision-making，且在 operator financial incentives 存在時，可考慮獨立第三方協助決策溝通。 常見誤判：看到 CHAMPION-AF 達 noninferiority，就把 LAA closure 推成多數 AF 病人的常規替代。

Rethinking High-Flow Oxygen in Acute Hypoxemic Respiratory Failure（editorial）

這篇 editorial 幫 SOHO trial 重新定義期待：HFNC 不應被包裝成 unselected acute hypoxemic respiratory failure 的 mortality-reducing therapy，而是能改變 respiratory support pathway 的工具。它可能透過降低 inspiratory effort、改善 comfort、dead-space washout 與 oxygenation，減少一部分病人進入 invasive ventilation；而 invasive ventilation 本身會帶來 VAP、sedation complications、diaphragm dysfunction 與 ICU stay。文中特別指出 median time to intubation 類似，較不支持「HFNC 只是延遲該插管的病人」。臨床端應早用於合適病人，但不可因設備舒適而延誤 deterioration recognition。 常見誤判：將 mortality 作為唯一價值標準，或相反地，因 HFNC 讓病人舒服而放鬆 escalation criteria。

Virtual-Only or In-Person Interviews for Residency Applicants（clinical decisions）

這篇 Clinical Decisions 以兩方辯論處理 residency interviews。支持 virtual-only 的論點是降低 travel cost、opportunity cost、program burden 與碳排，且多數 applicant 對 virtual interviews 滿意；也可用 optional post-rank site visit 補足 program fit。支持回到 in-person 的論點是 virtual process 可能偏利大型名校，傷害 smaller/rural programs，加劇 application inflation 與 interview hoarding，也可能讓 lower socioeconomic status 申請者因網路、空間背景而被隱性評價。臨床教育管理上，這不是「省錢 vs 傳統」的二分，而是 match system design、equity、program fit 與 rural workforce 的權衡。 常見誤判：認為 virtual interviews 因省旅費就必然更公平，而忽略 application inflation、program visibility 與 digital divide。

Fasting, Glucocorticoids, and Breast Cancer（CIBR）

這篇 CIBR 討論 fasting 或 fasting-mimicking diet 如何可能增強 ER-positive breast cancer hormonal therapy。機轉重點在 fasting 引發 adrenal glucocorticoid production，活化 glucocorticoid receptor，可能與 progesterone receptor 類似，透過 chromatin occupancy 競爭抑制 ER alpha–dependent transcription，進一步增強 tamoxifen 效果。小鼠 xenograft 中 fasting 或 dexamethasone 加 tamoxifen 可增強 tumor-growth suppression；臨床試驗血清也看到 fasting-mimicking diet 後 cortisol 上升。但作者明確提醒：triple-negative breast cancer 中 glucocorticoid receptor 可能促進腫瘤，且 circulating steroid level 與 tumor tissue metabolism 未必一致。這支持 biomarker-guided dietary trials，而非一般化禁食建議。 常見誤判：把 fasting 當成不分 tumor biology 的通用抗癌輔助療法。

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指南/綜論/方法學（表格）

文章	type	導讀重點
Chyluria from a Lymphatic–Urinary Fistula	image case	Milky urine 加低 albumin 與極高 urinary triglyceride 指向 chyluria；lymphangiography 找到 lymphatic–urinary fistula，低脂飲食不足時 embolization 可改善。
Dysphagia Lusoria	image case	Cerebral palsy 病人的 choking 不一定全是 oropharyngeal dysphagia；endoscopy 的 pulsatile posterior esophageal compression 應想到 aberrant right subclavian artery。
Kidney Transplantation after Clearing Anti-HLA Antibodies with CD19 CAR T Cells	correspondence	單一 compassionate-use 個案顯示 CD19 CAR T 可使多名原不相容 donor 轉為相容；proof-of-principle 強，但仍不能外推為標準 desensitization。
Targeting of Wnt–β-Catenin Pathway in Recurrent Ameloblastoma	correspondence	APC frameshift、nuclear β-catenin 與 Wnt signature 的 recurrent ameloblastoma 對 zolucatetide 有 ongoing partial response，提示 BRAF-negative 仍可做 pathway-driven therapy。
Finerenone in Type 1 Diabetes and Chronic Kidney Disease	correspondence	來信聚焦 SGLT2/GLP-1 背景療法排除、potassium 監測、functional unblinding、eGFR dip 與 albuminuria surrogate；作者回應 6 個月不足以證明 hard renal outcomes。
Romiplostim versus Placebo for Chemotherapy-Induced Thrombocytopenia	correspondence	爭點是 oxaliplatin CIT 是否需 phenotype 分層，以及 endpoint 是否混合短期 rescue 與再挑戰後持續支撐；作者認為 primary endpoint 正是為捕捉兩者。
Polymyalgia Rheumatica	correspondence	Methotrexate 25 mg/week 新試驗顯示 glucocorticoid-free remission 訊號，但作者提醒 cumulative glucocorticoid dose 未降；另應在 refractory/atypical older men 搜尋 VEXAS mimic。
Chronic Myeloid Leukemia in Low- and Middle-Income Countries	correspondence	CML treatment-free remission 不應只看 TKI 年限；原作者說 ≥10 年是資源有限場域的初始保守策略，核心仍是 deep molecular response 與監測能力。

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臨床可帶走的 10 點

1. AF 病人談 LAA closure 時要講清楚 noninferiority。 CHAMPION-AF 支持 selected patients shared decision-making，不支持把 NOAC 全面換成 device。
2. HFNC 的主要價值可能是降低 intubation 與改善呼吸負荷，不是降低 28 天死亡。 需保留明確 escalation criteria。
3. 全口服 AML regimen 仍是高監測療法。 Venetoclax duration、azole interaction、marrow assessment、cytopenia 與 infection prevention 是成敗關鍵。
4. CAR T desensitization 正在打開高度 HLA sensitization 的新路徑。 但目前仍屬早期 proof-of-concept，不能跳過安全與感染風險評估。
5. AAV gene therapy 的長期監測不能只看短期 toxicity。 Rare integration-related oncogenesis 雖罕見，但 vector design、route、dose 與 tissue biology 都要納入風險評估。
6. Vaccine hesitancy 應先區分 hesitancy 與 denial。 Presumptive recommendation 加 empathy-based dialogue 比單純事實轟炸更可維持關係與提高接受度。
7. Sepsis 或 endocarditis 不一定能解釋所有 abnormal LFT。 自體免疫病背景、steroid withdrawal 與 biopsy 訊息可能揭露第二診斷。
8. Milky urine 要想到 chyluria。 Urine triglyceride、chylomicrons 與 lymphangiography 可把「看似腎病症候群」轉向 lymphatic–urinary fistula。
9. PMR-like syndrome 要反覆重新評估。 高齡男性、refractory、皮膚／軟骨／肺部表現或 vasculitis 線索應考慮 VEXAS。
10. 飲食介入癌症治療不能去生物標記化。 Fasting 對 ER-positive 與 triple-negative breast cancer 可能方向相反，不能用單一養生敘事處理。

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完整文章連結（按文章類型分組）

Perspective

• Regulating Corporate Control in the U.S. Health Care System — Perspective
• War and Famine — Perspective
• Perversity in Medicine — When Vocation and Corporatization Clash — Perspective
• BiDil — The Story of the Black Pill — ITT Episode 2.5 — Perspective
• Advancing Indigenous Health Equity in Medical School Curricula — Perspective

Original Article

• Left Atrial Appendage Closure or Anticoagulation for Atrial Fibrillation — RCT
• High-Flow or Standard Oxygen in Acute Hypoxemic Respiratory Failure — RCT
• All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia — phase 1–2
• Kidney Transplantation in Two Highly Sensitized Candidates after CAR T-Cell Therapy — phase 1 case series
• Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery — case report

Clinical Practice / Clinical Problem-Solving / Clinical Decisions / CIBR

• Childhood Vaccine Hesitancy — clinical practice
• The Unusual Suspects — clinical problem-solving
• Virtual-Only or In-Person Interviews for Residency Applicants — clinical decisions
• Fasting, Glucocorticoids, and Breast Cancer — CIBR

Images

• Chyluria from a Lymphatic–Urinary Fistula — image case
• Dysphagia Lusoria — image case

Editorial

• Left Atrial Appendage Closure — Should Recommendations Be Expanded? — editorial
• Rethinking High-Flow Oxygen in Acute Hypoxemic Respiratory Failure — editorial

Correspondence

• Kidney Transplantation after Clearing Anti-HLA Antibodies with CD19 CAR T Cells — correspondence
• Targeting of Wnt–β-Catenin Pathway in Recurrent Ameloblastoma — correspondence
• Finerenone in Type 1 Diabetes and Chronic Kidney Disease — correspondence
• Romiplostim versus Placebo for Chemotherapy-Induced Thrombocytopenia — correspondence
• Polymyalgia Rheumatica — correspondence
• Chronic Myeloid Leukemia in Low- and Middle-Income Countries — correspondence

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Article-level structured metadata

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  {
    "doi": "10.1056/NEJMp2415616",
    "title": "Regulating Corporate Control in the U.S. Health Care System",
    "type": "perspective",
    "is_oa": false,
    "population": null,
    "comparator": null,
    "primary_endpoint": null,
    "effect_size": "AMA physician-practice survey: private practice approximately 60% in 2012 to approximately 42% in 2024",
    "key_claim": "Regulation should make ownership and money flows visible, constrain anticompetitive consolidation, and reduce payment distortions that make consolidation profitable without care improvement.",
    "common_misconception": "Corporate ownership is a single problem solvable by banning one owner type."
  },
  {
    "doi": "10.1056/NEJMp2602465",
    "title": "War and Famine",
    "type": "perspective",
    "is_oa": false,
    "population": "Children younger than 5 years in Gaza; broader wartime civilian populations",
    "comparator": "Periods of blockade/severe aid restriction vs ceasefire or aid access",
    "primary_endpoint": "Prevalence of acute wasting and famine-related clinical consequences",
    "effect_size": "Prewar wasting 1–2%; above 14% during initial blockade; nearly 5% during ceasefire; as high as 28% in northern Gaza when blockade reestablished; July 2025 food availability 1394 kcal/person/day",
    "key_claim": "Famine prevention and malnutrition treatment are clinical duties requiring access, RUTF supply, vaccination, and continuity of care.",
    "common_misconception": "Humanitarian corridors are merely political advocacy rather than a clinical intervention."
  },
  {
    "doi": "10.1056/NEJMp2602962",
    "title": "Perversity in Medicine — When Vocation and Corporatization Clash",
    "type": "perspective",
    "is_oa": false,
    "population": "Clinicians, patients, and health system leaders in corporate medicine",
    "comparator": null,
    "primary_endpoint": null,
    "effect_size": null,
    "key_claim": "Corporate leadership language may conceal divergence between business priorities and the professional vocation of medicine, worsening trust, morale, and patient care.",
    "common_misconception": "Burnout is mainly an individual resilience problem, not an organizational moral-injury problem."
  },
  {
    "doi": "10.1056/NEJMp2601978",
    "title": "BiDil — The Story of the Black Pill — ITT Episode 2.5",
    "type": "perspective",
    "is_oa": false,
    "population": "Patients with heart failure, with focus on self-identified Black patients in the BiDil story",
    "comparator": "Race-based indication and marketing vs mechanism- or evidence-based prescribing not using race as genetic proxy",
    "primary_endpoint": null,
    "effect_size": "Small trial in self-identified Black patients reported 43% lower mortality",
    "key_claim": "BiDil illustrates how a potentially useful drug became tied to a biologically false and commercially useful race narrative.",
    "common_misconception": "Race can safely substitute for genetics or mechanism in drug labeling."
  },
  {
    "doi": "10.1056/NEJMp2605243",
    "title": "Advancing Indigenous Health Equity in Medical School Curricula",
    "type": "perspective",
    "is_oa": false,
    "population": "Medical students preparing to care for Indigenous communities in the WWAMI region",
    "comparator": null,
    "primary_endpoint": "Graduation with Indian Health Pathway certificate and downstream primary care placement",
    "effect_size": "141 graduates since 1992; more than 50% matriculate to primary care residencies",
    "key_claim": "Indigenous health education requires Tribal sovereignty, relationship infrastructure, Indigenous faculty, community engagement, and clinical immersion including traditional medicine.",
    "common_misconception": "Cultural competency can be delivered as a short content module without sovereignty or reciprocal community governance."
  },
  {
    "doi": "10.1056/NEJMoa2517213",
    "title": "Left Atrial Appendage Closure or Anticoagulation for Atrial Fibrillation",
    "type": "RCT",
    "is_oa": false,
    "population": "3000 patients with atrial fibrillation suitable for anticoagulation; mean age 71.7 years; mean CHA2DS2-VASc 3.5",
    "comparator": "Device-based left atrial appendage closure vs NOAC therapy",
    "primary_endpoint": "Composite of cardiovascular death, stroke, or systemic embolism at 3 years; non–procedure-related bleeding at 3 years",
    "effect_size": "Primary efficacy 5.7% vs 4.8%; difference 0.9 percentage points; 95% CI −0.8 to 2.6; P<0.001 for noninferiority. Non–procedure-related bleeding 10.9% vs 19.0%; HR 0.55; 95% CI 0.45 to 0.67; P<0.001 for superiority.",
    "key_claim": "Left atrial appendage closure was noninferior to NOACs for major thromboembolic/cardiovascular outcomes and reduced non–procedure-related bleeding at 3 years.",
    "common_misconception": "Noninferiority means LAA closure is equivalent or preferable for most anticoagulation-eligible AF patients."
  },
  {
    "doi": "10.1056/NEJMoa2516087",
    "title": "High-Flow or Standard Oxygen in Acute Hypoxemic Respiratory Failure",
    "type": "RCT",
    "is_oa": false,
    "population": "1110 ICU patients with acute hypoxemic respiratory failure; PaO2:FIO2 ≤200, respiratory rate >25/min, pulmonary infiltrates",
    "comparator": "High-flow nasal oxygen vs standard oxygen therapy",
    "primary_endpoint": "Death from any cause by day 28",
    "effect_size": "Day-28 mortality 14.6% vs 14.6%; difference −0.05 percentage points; 95% CI −4.21 to 4.10; P=0.98. Intubation by day 28 42.4% vs 48.4%; difference −5.93 percentage points; 95% CI −11.78 to −0.08.",
    "key_claim": "High-flow oxygen did not lower 28-day mortality but appeared to reduce intubation and improve early respiratory measures.",
    "common_misconception": "A reduction in intubation necessarily implies a mortality reduction."
  },
  {
    "doi": "10.1056/NEJMoa2510223",
    "title": "All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia",
    "type": "phase 1–2",
    "is_oa": false,
    "population": "189 patients with newly diagnosed AML age ≥75 years or ineligible for intensive chemotherapy",
    "comparator": "No randomized comparator; historical context of parenteral hypomethylating agent plus venetoclax",
    "primary_endpoint": "Venetoclax AUC0–24 and Cmax with/without decitabine–cedazuridine; complete response",
    "effect_size": "Phase 2b CR 47% (95% CI 36 to 57); CR or CRi 63% (95% CI 53 to 73); median OS 15.5 months (95% CI 7.6 to NE); grade ≥3 anemia 30%, neutropenia 26%, febrile neutropenia 25%; 30-day mortality 3%, 60-day mortality 10%.",
    "key_claim": "All-oral decitabine–cedazuridine plus venetoclax showed no drug–drug interaction and produced responses comparable to expected HMA–venetoclax activity, with important myelosuppression requiring schedule management.",
    "common_misconception": "All-oral AML therapy can be treated as low-monitoring outpatient therapy by default."
  },
  {
    "doi": "10.1056/NEJMoa2513428",
    "title": "Kidney Transplantation in Two Highly Sensitized Candidates after CAR T-Cell Therapy",
    "type": "phase 1 case series",
    "is_oa": false,
    "population": "Two kidney-transplant candidates with cPRA ≥99.9% in the safety run-in cohort",
    "comparator": "No comparator",
    "primary_endpoint": "Safety and antibody-reduction/desensitization sufficient to enable transplantation",
    "effect_size": "Patient 1 cPRA 99.998% to 99.516%, transplanted day 229, no DSA rebound at 12 months; Patient 2 cPRA 99.995% to 99.567%, transplanted day 93, no DSA rebound at 7 months; no dose-limiting toxic effects reported.",
    "key_claim": "Combined CD19- and BCMA-targeted CAR T-cell therapy can reduce anti-HLA antibodies enough to enable transplantation in very highly sensitized candidates.",
    "common_misconception": "CAR T desensitization must completely erase plasma-cell memory or protective antibodies to be clinically useful."
  },
  {
    "doi": "10.1056/NEJMoa2601608",
    "title": "Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery",
    "type": "case report",
    "is_oa": false,
    "population": "A 5-year-old boy with severe MPSI treated with intracisternal magna AAV9 gene therapy at 13 months of age",
    "comparator": "No comparator",
    "primary_endpoint": "Molecular attribution of tumor to AAV integration",
    "effect_size": "Tumor appeared 4 years after vector delivery; PLAG1 expression 298 times that in comparator CNS tumors; integrated AAV structure in 40% of reads; no tumor growth 8 months after resection",
    "key_claim": "Rare rearranged AAV integration into PLAG1 can plausibly drive human oncogenesis after CNS-directed AAV gene therapy.",
    "common_misconception": "AAV vectors are effectively nonintegrating, so long-term insertional oncogenesis monitoring is unnecessary."
  },
  {
    "doi": "10.1056/NEJMcp2516616",
    "title": "Childhood Vaccine Hesitancy",
    "type": "clinical practice",
    "is_oa": false,
    "population": "Children and parents encountered in routine vaccination visits",
    "comparator": "Presumptive recommendation and motivational interviewing vs open-ended or purely factual approaches",
    "primary_endpoint": "Vaccine acceptance and uptake",
    "effect_size": "Provider recommendation OR 3.4 (95% CI 2.5 to 4.6); on-site vaccination OR 2.9 (95% CI 2.3 to 3.7); HPV announcement training increased coverage by 5.4 percentage points (95% CI 1.1 to 9.7)",
    "key_claim": "Confident presumptive recommendations combined with respectful, empathy-based follow-up are central to managing vaccine hesitancy.",
    "common_misconception": "Vaccine-hesitant parents are the same as antivaccine activists and can be corrected by facts alone."
  },
  {
    "doi": "10.1056/NEJMicm2516914",
    "title": "Chyluria from a Lymphatic–Urinary Fistula",
    "type": "image case",
    "is_oa": false,
    "population": "56-year-old woman with leg swelling and milky urine",
    "comparator": null,
    "primary_endpoint": "Diagnostic identification and post-embolization clinical improvement",
    "effect_size": "Serum albumin 18 g/L; urinary protein-to-creatinine ratio 34,958; urinary triglyceride 1456 mg/dL; improvement at 3 months after embolization",
    "key_claim": "Milky urine with nephrotic-range protein loss can reflect chyluria from lymphatic–urinary fistula, treatable with embolization.",
    "common_misconception": "Milky urine should be presumed to be infection or lipiduria from nephrotic syndrome alone."
  },
  {
    "doi": "10.1056/NEJMicm2600585",
    "title": "Dysphagia Lusoria",
    "type": "image case",
    "is_oa": false,
    "population": "44-year-old man with cerebral palsy and 4 years of choking episodes while eating",
    "comparator": null,
    "primary_endpoint": "Imaging diagnosis and symptom course under nonsurgical management",
    "effect_size": "Aberrant right subclavian artery coursing posterior to esophagus; less frequent choking and maintained weight at 3 months",
    "key_claim": "Persistent dysphagia despite reflux and texture management should trigger evaluation for vascular compression such as dysphagia lusoria.",
    "common_misconception": "Dysphagia in cerebral palsy is always oropharyngeal or reflux-related."
  },
  {
    "doi": "10.1056/NEJMcps2506943",
    "title": "The Unusual Suspects",
    "type": "clinical problem-solving",
    "is_oa": false,
    "population": "53-year-old man with Crohn's disease and psoriasis presenting with jaundice and neurologic symptoms",
    "comparator": null,
    "primary_endpoint": "Final diagnostic synthesis and clinical response",
    "effect_size": "MSSA bacteremia; 1.2-cm mitral vegetation with severe mitral regurgitation; liver enzymes normalized and remained normal at 16 months after prednisone/azathioprine and valve surgery",
    "key_claim": "The case required dual diagnosis: staphylococcal endocarditis with emboli plus autoimmune hepatitis unmasked by interruption/reduction of budesonide.",
    "common_misconception": "One unifying infection diagnosis should explain both septic emboli and severe hepatocellular injury."
  },
  {
    "doi": "10.1056/NEJMe2603846",
    "title": "Left Atrial Appendage Closure — Should Recommendations Be Expanded?",
    "type": "editorial",
    "is_oa": false,
    "population": "Patients with atrial fibrillation eligible for NOAC therapy, interpreted through CHAMPION-AF and prior trials",
    "comparator": "LAA closure vs NOAC therapy",
    "primary_endpoint": "Interpretation of noninferiority, bleeding, stroke, and device-related uncertainty",
    "effect_size": "CHAMPION-AF primary efficacy 5.7% vs 4.8%; ischemic stroke or systemic embolism 3.2% vs 2.2%; device thrombus observed in 4.8% of imaged patients",
    "key_claim": "Data support selected case-by-case consideration of LAA closure, not a definitive claim that it is as efficacious as NOACs for most AF patients.",
    "common_misconception": "A positive noninferiority trial automatically justifies broad first-line device replacement of NOACs."
  },
  {
    "doi": "10.1056/NEJMe2602037",
    "title": "Rethinking High-Flow Oxygen in Acute Hypoxemic Respiratory Failure",
    "type": "editorial",
    "is_oa": false,
    "population": "ICU patients with acute hypoxemic respiratory failure in SOHO and related evidence",
    "comparator": "High-flow oxygen vs standard oxygen",
    "primary_endpoint": "Interpretation of mortality and intubation outcomes",
    "effect_size": "SOHO: 28-day mortality unchanged; intubation 42.4% vs 48.4%",
    "key_claim": "High-flow oxygen should be viewed as respiratory-support pathway modification rather than mortality-reducing therapy for unselected patients.",
    "common_misconception": "No mortality benefit means no clinically meaningful value."
  },
  {
    "doi": "10.1056/NEJMclde2508421",
    "title": "Virtual-Only or In-Person Interviews for Residency Applicants",
    "type": "clinical decisions",
    "is_oa": false,
    "population": "Residency applicants and residency training programs",
    "comparator": "Virtual-only residency interviews vs return to in-person interviews",
    "primary_endpoint": "Equity, cost, program fit, application inflation, and match-process quality",
    "effect_size": "Virtual interview satisfaction 83–89% in one seven-specialty evaluation; large-program directors 42% vs smaller-program directors 16% agreed virtual interviews sufficiently informed rank order",
    "key_claim": "Virtual-only interviews reduce costs and emissions but may worsen program-fit uncertainty, application inflation, and inequities for smaller or rural programs.",
    "common_misconception": "Virtual interviewing is automatically more equitable because it lowers travel costs."
  },
  {
    "doi": "10.1056/NEJMcibr2600647",
    "title": "Fasting, Glucocorticoids, and Breast Cancer",
    "type": "CIBR",
    "is_oa": false,
    "population": "Mouse xenograft models of breast cancer and serum samples from patients in fasting-mimicking diet trials",
    "comparator": "Tamoxifen with fasting or dexamethasone vs tamoxifen alone in mechanistic models",
    "primary_endpoint": "Mechanistic interaction between fasting, glucocorticoid receptor activation, and hormone therapy response",
    "effect_size": "No single clinical effect size reported in this commentary; mouse studies showed enhanced tumor-growth suppression with fasting or dexamethasone plus tamoxifen",
    "key_claim": "Fasting may augment endocrine therapy in ER-positive breast cancer through glucocorticoid-receptor signaling, but effects may differ in triple-negative disease and require biomarker-guided trials.",
    "common_misconception": "Fasting is a generic anticancer intervention independent of tumor steroid-receptor biology."
  },
  {
    "doi": "10.1056/NEJMc2517277",
    "title": "Kidney Transplantation after Clearing Anti-HLA Antibodies with CD19 CAR T Cells",
    "type": "correspondence",
    "is_oa": false,
    "population": "35-year-old woman with broad HLA sensitization awaiting second kidney transplant",
    "comparator": "No comparator",
    "primary_endpoint": "Compatibility conversion and graft function after CD19 CAR T",
    "effect_size": "Baseline virtual PRA 99.84%; probability of compatible ABO/HLA donor 0.08%; three living donors became compatible; creatinine 1.2 mg/dL by postoperative day 7; CAR T persisted 15 months",
    "key_claim": "Anti-CD19 CAR T can contract cross-reactive anti-HLA antibodies enough to enable transplantation in a single compassionate-use case.",
    "common_misconception": "Only plasma-cell targeting can meaningfully reduce alloantibody barriers."
  },
  {
    "doi": "10.1056/NEJMc2517783",
    "title": "Targeting of Wnt–β-Catenin Pathway in Recurrent Ameloblastoma",
    "type": "correspondence",
    "is_oa": false,
    "population": "29-year-old man with recurrent right mandible ameloblastoma and APC frameshift mutation",
    "comparator": "No comparator",
    "primary_endpoint": "Radiographic response to zolucatetide",
    "effect_size": "Ongoing partial response at 40 weeks; complete resolution of solid tumor component and cerebral edema; grade 1 or 2 aminotransferase and bilirubin increases",
    "key_claim": "Direct β-catenin–TCF pathway inhibition with zolucatetide may be active in Wnt-driven recurrent ameloblastoma.",
    "common_misconception": "BRAF-negative ameloblastoma has no rational targeted systemic option worth testing."
  },
  {
    "doi": "10.1056/NEJMc2604395",
    "title": "Finerenone in Type 1 Diabetes and Chronic Kidney Disease",
    "type": "correspondence",
    "is_oa": false,
    "population": "Patients with type 1 diabetes and CKD discussed in relation to FINE-ONE",
    "comparator": "Finerenone vs placebo; questions about background therapy and longer follow-up",
    "primary_endpoint": "Albuminuria reduction and interpretation of potassium/eGFR findings",
    "effect_size": "Hyperkalemia adverse event 10% by investigator report; potassium >5.5 mmol/L 11% by central laboratory data; follow-up 6 months",
    "key_claim": "Finerenone albuminuria reduction is promising, but long-term kidney outcomes, potassium handling, and generalizability need further study.",
    "common_misconception": "Albuminuria improvement alone proves durable kidney protection in type 1 diabetes CKD."
  },
  {
    "doi": "10.1056/NEJMc2604757",
    "title": "Romiplostim versus Placebo for Chemotherapy-Induced Thrombocytopenia",
    "type": "correspondence",
    "is_oa": false,
    "population": "Patients with persistent chemotherapy-induced thrombocytopenia in RECITE trial context",
    "comparator": "Romiplostim vs placebo; debate over oxaliplatin phenotype and endpoint structure",
    "primary_endpoint": "Chemotherapy modification due to persistent CIT and durable platelet support",
    "effect_size": null,
    "key_claim": "The exchange clarifies that CIT phenotyping matters, but authors defend the composite endpoint as capturing both initial recovery and prevention of recurrent CIT.",
    "common_misconception": "Any platelet rise after romiplostim proves durable chemotherapy-enabling benefit."
  },
  {
    "doi": "10.1056/NEJMc2604645",
    "title": "Polymyalgia Rheumatica",
    "type": "correspondence",
    "is_oa": false,
    "population": "Patients with polymyalgia rheumatica, especially new-onset disease and older men with refractory or atypical features",
    "comparator": "Methotrexate vs placebo; consideration of VEXAS syndrome as mimic",
    "primary_endpoint": "Glucocorticoid-free remission and diagnostic reassessment",
    "effect_size": "Methotrexate 25 mg/week trial: glucocorticoid-free remission at week 52 80% vs 46%; no cumulative glucocorticoid-dose reduction; VEXAS estimated 1 in 4000 men age ≥50",
    "key_claim": "Methotrexate deserves nuanced consideration, and refractory or atypical PMR in older men should prompt reassessment for VEXAS or other mimics.",
    "common_misconception": "All PMR-like syndromes in older adults are glucocorticoid-responsive PMR."
  },
  {
    "doi": "10.1056/NEJMc2605636",
    "title": "Chronic Myeloid Leukemia in Low- and Middle-Income Countries",
    "type": "correspondence",
    "is_oa": false,
    "population": "Patients with CML pursuing treatment-free remission in low- and middle-income countries",
    "comparator": "Eligibility based on ≥10 years TKI therapy vs criteria emphasizing depth and stability of molecular response",
    "primary_endpoint": "Treatment-free remission program eligibility and safe implementation",
    "effect_size": null,
    "key_claim": "The conservative ≥10-year TKI criterion was intentional for initial resource-limited implementation and should not be interpreted as universally required.",
    "common_misconception": "Long TKI duration alone is the determinant of safe treatment-free remission."
  }
]