NEJM evidence最新文献

Background: Minimally invasive pancreatoduodenectomy (MIPD) might accelerate postoperative recovery in patients with primary resectable neoplasm compared with open pancreatoduodenectomy (OPD), although the safety of MIPD remains debated. We aimed to assess whether MIPD is noninferior to OPD for overall complications and superior for time to functional recovery (TTFR).

Methods: We conducted an international, multicenter, patient-blinded randomized noninferiority trial in patients undergoing pancreatoduodenectomy for primary resectable pancreatic and periampullary neoplasm from high-volume centers. Patients were randomly assigned in a 2:1 ratio to undergo robot-assisted or laparoscopic MIPD versus OPD and were blinded to the procedure until postoperative day 5. The primary end point was overall complications within 90 days of surgery, as measured using the Comprehensive Complication Index (range 0-100, with higher scores indicating more severe complications). Noninferiority was tested using a margin of -7.5 points (one-sided 97.5% confidence interval [CI]; P<0.025 for noninferiority). The main secondary end point was TTFR, tested for superiority. Analyses were reported by the intention-to-treat principle.

Results: Overall, 288 patients were randomly assigned (190 MIPD [170 robot-assisted, 20 laparoscopic] and 98 OPD) in 14 centers. The mean Comprehensive Complication Index was 33.4±27.5 in the MIPD group versus 35.3±25.5 in the OPD group (mean difference, -1.9; 95% CI, -8.5 to 4.7; P=0.002 for nonferiority). In the MIPD group, the median TTFR was 7 days (95% CI, 6 to 8) versus 8 days (95% CI, 7 to 11) in the OPD group. The MIPD conversion rate to open surgery was 8.4%. Rates of postoperative pancreatic fistula were 22.6% versus 35.7% (relative risk 0.63; 95% CI, 0.43 to 0.91) and were 12.6% versus 22.7% (relative risk 0.57; 95% CI, 0.32 to 0.98) for surgical site infection after MIPD and OPD, respectively. Death by 90 days occurred in 4.7% of patients after MIPD versus 2.0% after OPD (relative risk 2.40; 95% CI, 0.51 to 11.30).

Conclusions: In patients with resectable pancreatic and periampullary neoplasm, MIPD was noninferior to OPD for 90-day overall complications (Funded by Intuitive Surgical and Fondazione Poliambulanza Istituto Ospedaliero; International Standard Randomised Controlled Trial Number Registry, ISRCTN27483786.).

Background: Human challenge trials evaluate protection from influenza exposure following vaccination but have not been reported for nucleoside-modified messenger ribonucleic acid (modRNA) influenza vaccines.

Methods: This phase 2a, double-blind trial randomly assigned healthy adults 18-55 years of age in a 1:1 ratio to receive either a modRNA or quadrivalent influenza vaccine (QIV) 30 days before an influenza A/H1N1 challenge. Control group participants from a separate trial were exposed to the same virus but were not vaccinated. Four primary efficacy end points were used to evaluate events from day 1 to 8 postchallenge. Two end points were the percentage of participants with laboratory-confirmed symptomatic influenza (grade 2 or higher) and the percentage with febrile influenza (with a temperature of at least 37.9°C). Influenza end points were compared between vaccine and control groups to calculate vaccine efficacy (VE [1 minus relative risk]). Two end points were the median differences between the vaccine and control groups for the area under the viral load (VL)-time curve (VL-AUC) and for peak VL. Vaccine safety end points were examined.

Results: The per-protocol cohort included 55, 48, and 52 participants in the modRNA, QIV, and control groups, respectively. Symptomatic influenza occurred in 0%, 4.2%, and 26.9% of participants in the modRNA, QIV, and control groups, respectively, with a VE of 100.0% (95% confidence interval [CI], 75.2% to 100.0%) for the modRNA vaccine and 84.5% (95% CI, 43.4% to 96.0%) for the QIV. Febrile influenza occurred in 0%, 0%, and 17.3% of participants in the modRNA, QIV, and control groups, respectively, with a VE of 100.0% (95% CI, 61.2% to 100.0%) for the modRNA vaccine and 100.0% (95% CI, 55.9% to 100.0%) for the QIV. The median differences in the VL-AUC between the vaccine and control groups were -88.66 for the modRNA (95% CI, -261.95 to -1.35) and -67.01 for the QIV (95% CI, -254.13 to -0.97). The median differences in peak VL between the vaccine and control groups were -4.52 for the modRNA vaccine (95% CI, -5.29 to 0.00) and -1.49 for the QIV (95% CI, -5.25 to 0.00). No serious adverse events were reported.

Conclusions: Following an influenza challenge, the modRNA vaccine was associated with greater VE and reduced VL compared with the control, without any serious adverse events. (Funded by hVIVO and Pfizer; clinical trial registration number, ISRCTN13789612.).

Background: Plaque psoriasis involving high-impact sites is difficult to treat. Icotrokinra, a targeted oral peptide that selectively binds interleukin-23 receptors, is a new treatment being investigated for this condition.

Methods: This phase 3, double-blind, placebo-controlled trial randomly assigned participants 12 years of age and over with plaque psoriasis {with a body surface area ≥1%; an Investigator's Global Assessment (IGA) score ≥2 [clear (0), minimal (1), mild (2), moderate (3), and severe (4)] for overall skin; and at least moderate psoriasis involving the scalp, genitalia, and/or hands and feet} to receive either icotrokinra 200 mg daily or placebo in a 2:1 ratio. The primary end point at week 16 was the proportion of participants achieving an overall IGA score of 0 or 1 and an improvement of 2 points or more from baseline (IGA score of 0 or 1), reported as the between-group difference adjusted for high-impact site involvement, geographic region, and body surface area category using Mantel-Haenszel weights. Absent/clear or minimal/almost clear scalp, genital, and/or hand and foot psoriasis at 16 weeks were secondary end points. Adverse events were recorded.

Results: The trial randomly assigned 311 participants (icotrokinra, n=208; placebo, n=103) with scalp (n=252: icotrokinra, n=167; placebo, n=85), genital (n=140: icotrokinra, n=98; placebo, n=42), and/or hand and foot (n=71: icotrokinra, n=48; placebo, n=23) psoriasis. The proportions of participants achieving an IGA score of 0 or 1 in the icotrokinra and placebo groups were 56.7% and 5.8%, respectively [adjusted difference, 51.1 percentage points; 95% confidence interval (CI), 42.1 to 58.8; P<0.001]. The proportions of icotrokinra-treated and placebo-treated participants achieving absence/clear or minimal/almost clear high-impact site psoriasis were as follows: scalp, 65.9% and 10.6% (difference, 55.5 percentage points; 95% CI, 44.8 to 64.4; P<0.001); genitalia, 76.5% and 21.4% (difference, 55.4 percentage points; 95% CI, 39.1 to 68.0; P<0.001); and hand and foot, 41.7% and 26.1% (difference, 16.7 percentage points; 95% CI, -6.2 to 36.8; P=0.144). Adverse events occurred among 50% and 42% of participants in the icotrokinra and placebo groups, respectively.

Conclusions: At 16 weeks, significantly higher proportions of participants 12 years of age and over with at least moderate psoriasis involving high-impact sites treated with icotrokinra versus placebo achieved clearance or minimal psoriasis in their skin overall and in the scalp and genital areas, but not in their hands and feet. No safety signals were identified. (Funded by Johnson & Johnson; ClinicalTrials.gov number, NCT06095102.).

AbstractIn the United States, community-acquired pneumonia (CAP) is estimated to be responsible for 1.2 million emergency department visits and 41,210 deaths annually. This review summarizes the epidemiology, pathophysiology, microbiology, diagnosis, microbiologic testing, pharmacotherapy, and long-term adverse health outcomes for CAP in adults.

AbstractIn comparative clinical investigations for nearly all disease types, patient responses - signifying clinically meaningful improvements in health or reductions in disease burden - are routinely employed as key end points for assessing treatment activity or efficacy. Trials typically use the response rate to summarize treatment effects, a metric with limitations for investigating the temporal profile of the effect. In this Clinical Trials Workshop, the authors present a novel approach for analyzing time to response and duration of response in clinical trials using, as an example, data from the JAVELIN Renal-101 trial of avelumab and axitinib versus sunitinib for treating renal cell carcinoma.

Background: Intrauterine devices (IUDs) are effective contraceptives but are also associated with a higher ectopic pregnancy risk than other contraceptive methods. This study assessed ectopic pregnancy risk with varying hormonal IUD dosages compared with copper IUDs.

Methods: We conducted a nationwide cohort study using data from the French National Healthcare Data System (SNDS) and identified first-time IUD dispensations from 2018 to 2022. The primary outcome was ectopic pregnancy occurrence within 1 year of the index date, set 1 month post IUD dispensing. We used propensity score-based weighting and Cox regression analysis to compare ectopic pregnancy risk among users of levonorgestrel 13.5-mg, 19.5-mg, and 52-mg IUDs versus copper IUDs.

Results: Between 2018 and 2022, 45,450 women received a levonorgestrel 13.5-mg IUD, 212,301 received a levonorgestrel 19.5-mg IUD, 244,871 received a levonorgestrel 52-mg IUD, and 1,033,505 received a copper IUD. The mean age (standard deviation) was 26.8 (7.8), 29.7 (8.1), and 35.2 (8.2) years among levonorgestrel 13.5-mg, 19.5-mg, and 52-mg IUD users, respectively, and 29.1 (6.9) years in copper IUD users. At 1 year, ectopic pregnancy occurred in 71 levonorgestrel 13.5-mg IUD users (incidence rate, 0.18 per 100 person-years; 95% confidence interval [CI], 0.14 to 0.23), 182 levonorgestrel 19.5-mg IUD users (incidence rate, 0.10 per 100 person-years; 95% CI, 0.08 to 0.11), 88 levonorgestrel 52-mg users (incidence rate, 0.04 per 100 person-years; 95% CI, 0.03 to 0.05), and 682 copper IUD users (incidence rate, 0.07 per 100 person-years; 95% CI, 0.07 to 0.08). Compared with copper IUD users, the hazard ratios for ectopic pregnancy with hormonal IUDs were 2.57 (95% CI, 1.92 to 3.43) for 13.5-mg users, 1.37 (95% CI, 1.15 to 1.62) for 19.5-mg users, and 0.62 (95% CI, 0.49 to 0.80) for 52-mg users.

Conclusions: In this nationwide cohort study comparing three doses of hormonal IUDs and copper IUDs, the highest dose (levonorgestrel 52 mg) was associated with the lowest risk of ectopic pregnancy within 1 year compared with copper IUDs, whereas the 13.5-mg hormonal IUD was associated with the highest risk. (Funded by the French National Fund for Health Insurance and the French National Agency for Medicines and Health Products Safety.).