N Engl J Med
· 2026 Jun · PMID 42269153
·
Publisher ↗
The global rise in anticoagulant use has increased the number of major bleeding events that warrant timely and effective pharmacologic reversal. Reversal strategies should be informed by the pharmacodynamic and pharmacok...The global rise in anticoagulant use has increased the number of major bleeding events that warrant timely and effective pharmacologic reversal. Reversal strategies should be informed by the pharmacodynamic and pharmacokinetic features of the anticoagulant and antidote, regulatory indications, quality of evidence, patient-specific factors, and availability of treatment options. Protamine sulfate neutralizes unfractionated heparin, whereas no specific antidotes exist for low-molecular-weight heparins or fondaparinux. Four-factor prothrombin complex concentrates effectively reverse vitamin K antagonists. Idarucizumab specifically reverses dabigatran, although delayed dabigatran rebound can occur. Andexanet alfa targets direct oral factor Xa inhibitors, but uncertainties regarding the efficacy-safety balance, monitoring, rebound, perioperative use, and cost have prompted off-label use of four-factor prothrombin complex concentrates, for which stronger evidence is needed. Key challenges remain, including determination of appropriate dosing, standardization and validation of laboratory monitoring, mitigation of thrombotic risk, and development of guidelines for perioperative treatment. Emerging agents aim to broaden targets and improve safety. Building high-quality evidence remains essential to advancing global, patient-centered anticoagulant and hemostatic care.
Liang L, She K, Ren C
… +15 more, Li R, Liao M, Tao Z, Liu F, Su J, Hu M, Yang Y, Wang X, Zhang CL, Bao L, Chen Q, Zhang K, Wei Y, Yang Y, Lu F
N Engl J Med
· 2026 Jun · PMID 42269152
·
Publisher ↗
BACKGROUND: X-linked retinoschisis is a recessive disease characterized by progressive macular degeneration and vision loss due to pathogenic variation in . METHODS: We administered a single subretinal injection of an AA...BACKGROUND: X-linked retinoschisis is a recessive disease characterized by progressive macular degeneration and vision loss due to pathogenic variation in . METHODS: We administered a single subretinal injection of an AAV8 vector containing human complementary DNA (scAAV8-hRS1) into one eye of patients 5 to 18 years of age who had X-linked retinoschisis. The primary end point was safety during the 52-week period after injection. Secondary end points included the change from baseline to week 52 in the best corrected visual acuity (BCVA), retinal structure (assessed with swept-source optical coherence tomography; SS-OCT), the function of photoreceptor and bipolar cells (assessed with full-field electroretinography), and macular sensitivity to light (assessed with microperimetry). RESULTS: A total of 12 patients were enrolled. The dose-escalation phase included two cohorts of 3 patients each who received scAAV8-hRS1 at a dose of 7.5×10 or 1×10 vector genomes. In the dose-expansion phase, 3 additional patients were enrolled in each cohort. Overall, 56 adverse events were reported during the 52 weeks after surgery. No patient was reported to have an adverse event of grade 3 or higher or ocular inflammation. A macular hole in the treated eye was observed at week 1 in 1 patient. The mean increase at week 52 in the BCVA was 10.8 letters among the treated eyes and 2.4 letters among the untreated eyes. SS-OCT imaging showed closure of the macular schisis cavity by week 13 in the treated eye in all 12 patients. The mean change at week 52 in central retinal thickness was -437.7 μm among the treated eyes and -17.2 μm among the untreated eyes; the outer retinal layers in the treated eyes of 9 patients were continuous at week 52. No clinically meaningful changes in the function of photoreceptor and bipolar cells or macular retinal sensitivity were observed in the treated eyes. CONCLUSIONS: In this study of subretinal gene therapy with scAAV8-hRS1 in 12 patients with X-linked retinoschisis, there were no reports of adverse events of grade 3 or higher or ocular inflammation. Further clinical testing of scAAV8-hRS1 is warranted. (Funded by the National Natural Science Foundation of China and others; Chinese Clinical Trial Registry number, ChiCTR2300076682.).
Gharahdaghi N, Yeh PJ, Ceron-Gutierrez L
… +47 more, Griffin H, Gordon H, Jayamanne C, Fracchia A, Chong AY, Walsh A, Brain O, Baker K, Kockelbergh H, Luo Y, Guevara Becerra M, Vadakethala K, Coy M, Kabiri L, Barnardo M, Dunachie S, Kronsteiner B, Adams A, Fowler D, Zhang Q, Fachal L, Anderson CA, Desoki R, Vestergaard MV, Larsen L, Wyatt NJ, Lees RD, Mulligan RJ, Dong C, Sharip MT, Faustini SE, Shields A, Pakpoor J, Naz B, Richter A, Satsangi J, Lamb CA, Parkes M, Powrie F, Mentzer AJ, Sazonovs A, Jess T, Klenerman P, Travis S, Hambleton S, Doffinger R, Uhlig HH
N Engl J Med
· 2026 Jun · PMID 42269151
·
Publisher ↗
BACKGROUND: Neutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD). The allel...BACKGROUND: Neutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD). The allele HLA-DRB1*01:03 is the strongest genetic risk factor for ulcerative colitis. METHODS: We used a cellular interleukin-10 reporter assay and a confirmatory competitive enzyme-linked immunosorbent assay to assess neutralizing interleukin-10 autoantibodies in serum samples obtained from patients with IBD in the Oxford and U.K. IBD BioResource cohorts and from persons without IBD (controls). An in vitro cytokine-release bioassay was performed in a subgroup of patients to assess interleukin-10, interleukin-23, interleukin-1β, tumor necrosis factor, and interleukin-6. We performed HLA association analysis using imputation and high-resolution sequencing. RESULTS: Interleukin-10-neutralizing autoantibodies were detected in 173 of 4909 patients with IBD (3.5%; 95% confidence interval [CI], 3.0 to 4.1) and in none of 1006 controls (P<0.001). High anti-interleukin-10 activity in serum was associated with a reduction in detectable interleukin-10 and with an exaggerated proinflammatory cytokine response, consistent with functional neutralization of interleukin-10 signaling. Anti-interleukin-10 seropositivity was strongly associated with HLA-DRB1*01:03 on the basis of imputed data from the Oxford cohort (odds ratio, 50.0; 95% CI, 16.4 to 152.3; P = 6.14×10) and the U.K. IBD BioResource cohort (odds ratio, 24.7; 95% CI, 14.5 to 42.1; P = 6.20×10) and in a high-resolution sequencing analysis of data from the Oxford cohort (odds ratio, 29.5; 95% CI, 12.2 to 71.1; P = 4.85×10). CONCLUSIONS: Neutralizing interleukin-10 autoantibodies were present in a subgroup of patients with IBD and were strongly associated with HLA-DRB1*01:03. (Funded by the National Institute for Health and Care Research and others.).
LOGICAL Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Hodgson CL, Mackle D
… +30 more, Mather AM, Bailey M, Beasley R, Beehre N, Bernard S, Brickell K, Crichton B, Deane AM, Eastwood G, Finfer S, Henderson S, Higgins AM, Hunt A, Kasza J, Lawrence C, Linke NJ, Litton E, McDonald CF, Moore J, Nichol AD, Olatunji S, Parke R, Peake S, Secombe P, Seppelt IM, Serpa Neto A, Trapani T, Turner A, Udy A, Young PJ
N Engl J Med
· 2026 Jun · PMID 42267831
·
Publisher ↗
BACKGROUND: In patients who are unresponsive after resuscitation from cardiac arrest, limiting oxygen exposure to that necessary to achieve acceptable oxygenation may increase the likelihood of survival with a favorable...BACKGROUND: In patients who are unresponsive after resuscitation from cardiac arrest, limiting oxygen exposure to that necessary to achieve acceptable oxygenation may increase the likelihood of survival with a favorable functional outcome. METHODS: We randomly assigned unresponsive adults receiving mechanical ventilation in the intensive care unit (ICU) after cardiac arrest to conservative or liberal oxygen therapy. In the two groups, the default lower limit of arterial oxygen saturation as measured by pulse oximetry (Spo) was 90%. In the conservative-oxygen group, the alarm for the upper limit of the Spo was set at 95%, and the fraction of inspired oxygen (Fio) was decreased to 0.21 provided that the Spo was above the lower limit. In the liberal-oxygen group, there were no measures limiting the upper Spo, but the minimum Fio permitted during mechanical ventilation was 0.3. The primary outcome was survival with a favorable functional outcome at 180 days, assessed with the Extended Glasgow Outcome Scale (GOS-E). Levels on the GOS-E range from 1 (death) to 8 ("upper good recovery"). We defined survival with a favorable functional outcome as a GOS-E level of 5 ("lower moderate disability") or higher. RESULTS: A total of 1840 patients were recruited from 53 ICUs in Australia, New Zealand, and Ireland, with 882 assigned to conservative oxygen therapy and 958 assigned to liberal oxygen therapy. A favorable functional outcome at 180 days was observed for 313 of 819 patients (38.2%) in the conservative-oxygen group and 353 of 890 patients (39.7%) in the liberal-oxygen group (relative risk, 0.97; 95% confidence interval, 0.87 to 1.09; P = 0.65). No adverse events were reported. CONCLUSIONS: Among unresponsive adults undergoing mechanical ventilation in the ICU after a cardiac arrest, the percentage who survived with a favorable functional outcome was not higher with conservative oxygen therapy than with liberal oxygen therapy. (Funded by the Health Research Council of New Zealand and others; LOGICAL Australian New Zealand Clinical Trials Registry number, ACTRN12621000518864.).
Connolly B, Dickson N, Campbell C
… +31 more, Bradley JM, O'Neill B, Agus A, Barker M, Bewley JS, Blackwood B, Borthwick M, Camporota L, Chikhani M, Clarke M, Dark P, Higgins L, Lambert P, Lunn T, McDowell C, McFarland M, McShane U, Mehta R, Messer B, Morton B, Patel N, Perkins GD, Rowley D, Shyamsundar M, Silversides JA, Sturmey G, Warburton J, Williams B, Lall R, McAuley DF, MARCH Trial Investigators
N Engl J Med
· 2026 Jun · PMID 42267821
·
Publisher ↗
BACKGROUND: Mucoactive agents are widely used in patients with acute respiratory failure despite limited evidence of their effectiveness or safety. METHODS: We conducted a multicenter, open-label, randomized trial with a...BACKGROUND: Mucoactive agents are widely used in patients with acute respiratory failure despite limited evidence of their effectiveness or safety. METHODS: We conducted a multicenter, open-label, randomized trial with a 2-by-2 factorial design that involved critically ill, mechanically ventilated participants 16 years of age or older with acute respiratory failure and difficult-to-clear secretions. All participants received usual care along with carbocisteine (750 mg three times daily enterally), 6% or 7% nebulized hypertonic saline (HTS) (4 ml four times daily), both interventions, or usual care alone for up to 28 days. The primary outcome was duration of mechanical ventilation (from randomization to first successful unassisted breathing). The primary comparisons were between any carbocisteine and no carbocisteine and between any HTS and no HTS, with each comparison comprising two treatment groups. RESULTS: A total of 1956 participants underwent randomization: 486 were assigned to carbocisteine, 485 to HTS, 492 to both treatments, and 493 to usual care alone (472, 474, 479, and 478, respectively, were included in the primary analysis). No evidence of treatment interaction was found (hazard ratio, 1.01, 95% confidence interval [CI], 0.83 to 1.22; P = 0.91). The median duration of mechanical ventilation was 186.1 hours (95% CI, 168.3 to 196.6) with carbocisteine and 172.7 hours (95% CI, 165.2 to 190.4) with no carbocisteine (adjusted hazard ratio, 0.96; 95% CI, 0.87 to 1.05; P = 0.34) and 184.5 hours (95% CI, 165.6 to 194.1) with HTS and 174.3 hours (95% CI, 166.9 to 192.7) with no HTS (adjusted hazard ratio, 1.00; 95% CI, 0.91 to 1.10; P = 0.98). Clinically important upper gastrointestinal bleeding occurred significantly more often with carbocisteine than with no carbocisteine (13 of 965 [1.4%] vs. 2 of 966 [0.2%]; risk ratio, 6.51; 95% CI, 1.47 to 28.76; P = 0.01). Bronchoconstriction leading to bronchodilator use occurred significantly more often with HTS than with no HTS (23 of 967 [2.4%] vs. 4 of 964 [0.4%]; risk ratio, 5.73; 95% CI, 1.99 to 16.52; P = 0.001), as did hypoxemia during nebulization (40 of 967 [4.1%] vs. 3 of 964 [0.3%]; risk ratio, 13.29; 95% CI, 4.12 to 42.83; P<0.001). One serious adverse reaction was reported in the combination group. CONCLUSIONS: Among critically ill patients with acute respiratory failure, neither carbocisteine nor HTS significantly reduced the duration of mechanical ventilation, and each was associated with harm. (Funded by the NIHR Health Technology Assessment Programme and the Belfast Health and Social Care Trust Charitable Trust Fund; MARCH ISRCTN Registry number, ISRCTN17683568.).
Houston BL, McIsaac DI, Breau RH
… +25 more, Kanji S, Greenstreet P, Andrews M, Avramescu S, Bagry HS, Balshaw R, Daya J, Duncan K, Harle CC, Jacobsohn E, Kerelska T, Pitz M, Komenda P, McIsaac S, Ramsay T, Saha T, Tinmouth A, Recio A, Szoke D, Tenenbein M, Slagerman S, Solvason D, Talarico R, Fergusson DA, Zarychanski R
N Engl J Med
· 2026 Jun · PMID 42267805
·
Publisher ↗
BACKGROUND: Whether a hospital policy of tranexamic acid administration for patients undergoing major noncardiac surgery safely reduces the need for red-cell transfusion is uncertain. METHODS: We conducted a multicenter,...BACKGROUND: Whether a hospital policy of tranexamic acid administration for patients undergoing major noncardiac surgery safely reduces the need for red-cell transfusion is uncertain. METHODS: We conducted a multicenter, double-blind, cluster-randomized, placebo-controlled trial involving patients undergoing noncardiac surgery who were at high risk for red-cell transfusion. Hospitals were randomly assigned at 4-week intervals to a hospital-wide policy of intraoperative tranexamic acid or placebo. The coprimary effectiveness and safety outcomes were transfusion of red cells during the index hospitalization and diagnosis of venous thromboembolism within 90 days, respectively. The safety outcome was assessed for noninferiority, with a prespecified noninferiority margin defined as an upper boundary of 1.46 for the 95% confidence interval of the relative risk. Analyses used mixed-effects models that accounted for the cluster-crossover design. RESULTS: A total of 8273 patients enrolled across 10 Canadian hospitals could be evaluated for the coprimary outcomes. Oncologic surgery accounted for 60.5% of the surgical procedures (5002 of 8273). The percentage of patients who received a red-cell transfusion during hospitalization was 7.4% (306 of 4156) in the tranexamic acid group and 9.8% (403 of 4117) in the placebo group (relative risk, 0.73; 95% confidence interval [CI], 0.61 to 0.86; adjusted difference, -2.7 percentage points; 95% CI, -4.2 to -1.4). Venous thromboembolism within 90 days occurred in 2.1% of patients (86 of 4128) in the tranexamic acid group and 2.1% of patients (85 of 4052) in the placebo group (relative risk, 0.96; 95% CI, 0.65 to 1.38; adjusted difference, -0.1 percentage points; 95% CI, -0.9 to 0.7), which met the criterion for noninferiority. CONCLUSIONS: Among patients undergoing major noncardiac surgery, a hospital policy of tranexamic acid administration resulted in a lower incidence of red-cell transfusion than placebo administration, and tranexamic acid was noninferior to placebo with regard to diagnosis of venous thromboembolism. (Funded by the Canadian Institutes of Health Research and others; TRACTION ClinicalTrials.gov number, NCT04803747.).
le Roux CW, Wharton S, Startseva E
… +22 more, Kloer IM, Hussain SA, Unseld A, Bozkurt B, Ard JD, Bays HE, Bogdański P, Ekinci EI, Jastreboff AM, Ji L, Ogawa W, Pedersen SD, Pietiläinen KH, Sattar N, Seufert J, Stenlöf K, van Beek AP, Vangoitsenhoven R, Brueckmann M, Younes R, Kaplan LM, SYNCHRONIZE-1 Investigators
N Engl J Med
· 2026 Jun · PMID 42253238
·
Publisher ↗
BACKGROUND: Although medications with glucagon-like peptide-1 (GLP-1) receptor agonist activity have transformed the management of obesity and shown substantial cardiometabolic benefits, unmet needs remain. Survodutide,...BACKGROUND: Although medications with glucagon-like peptide-1 (GLP-1) receptor agonist activity have transformed the management of obesity and shown substantial cardiometabolic benefits, unmet needs remain. Survodutide, an investigational glucagon receptor-GLP-1 receptor dual agonist, led to substantial weight reduction in a phase 2 trial involving adults with obesity without diabetes. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher, or 27 or higher with at least one obesity-related complication (excluding diabetes), in a 1:1:1 ratio to receive once-weekly survodutide administered subcutaneously at a dose adjusted up to 3.6 mg or 6.0 mg or placebo, in addition to counseling for lifestyle modification. The two primary end points were the percent change in body weight and a reduction in body weight of at least 5% from baseline to week 76. The primary efficacy analysis was conducted according to the treatment-regimen estimand, which incorporates the effects of any early discontinuation of survodutide or placebo, the use of protocol-prohibited obesity medications, and a prolonged dose-escalation period. RESULTS: Among 725 participants (241 in the 3.6-mg survodutide group, 242 in the 6.0-mg survodutide group, and 242 in the placebo group), the mean age was 47.1 years; 294 participants (40.6%) were men. At baseline, the mean BMI was 37.9, and the mean body weight was 108.8 kg. At week 76, the mean change in body weight from baseline according to the treatment-regimen estimand was -12.2% (95% confidence interval [CI], -13.6 to -10.8) in the 3.6-mg group, -13.0% (95% CI, -14.4 to -11.6) in the 6.0-mg group, and -5.4% (95% CI, -6.9 to -4.0) in the placebo group; 72.6%, 71.9% and 46.3% of the participants, respectively, had weight reduction of at least 5% (P<0.001 for all comparisons with placebo). The most common adverse events were gastrointestinal symptoms (typically mild to moderate), which occurred in 80.9% of the participants in the 3.6-mg group, in 89.7% of those in the 6.0-mg group, and in 47.9% of those in the placebo group. No deaths were reported. CONCLUSIONS: Survodutide led to significantly greater reductions in body weight than placebo in adults with obesity without diabetes. (Funded by Boehringer Ingelheim; SYNCHRONIZE-1 ClinicalTrials.gov number, NCT06066515.).