NEJM original articles

Background. International recommendations advise against the use of intravenous rehydration therapy in children with severe acute malnutrition because of the concern about fluid overload, but evidence to support this concern is lacking. Given the high mortality associated with the current recommendations, the adoption of intravenous rehydration strategies might improve outcomes.

Methods. We conducted a factorial, open-label superiority trial in four countries in Africa. Children 6 months to 12 years of age with severe acute malnutrition with gastroenteritis and dehydration underwent randomization in a 2:1:1 ratio to one of three rehydration strategies: oral rehydration, plus intravenous boluses for shock; a rapid intravenous strategy that consisted of lactated Ringer's solution (100 ml per kilogram of body weight) administered over a period of 3 to 6 hours, with boluses for shock; or a slow intravenous strategy that consisted of the same solution administered over a period of 8 hours, with no boluses. The primary end point was death at 96 hours.

Results. A total of 272 children underwent randomization; 138 were assigned to the oral strategy, 67 to the rapid intravenous strategy, and 67 to the slow intravenous strategy. Participants were followed for 28 days. A nasogastric tube was used for oral rehydration in 126 of 135 participants (93%) in the oral group and in 82 of 126 (65%) in the intravenous groups. Intravenous boluses were administered at admission in 12 participants (9%) in the oral group, 7 (10%) in the rapid intravenous group, and none in the slow intravenous group. At 96 hours, 11 participants (8%) in the oral group and 9 (7%) in the intravenous groups (5 in the rapid group and 4 in the slow group) had died (risk ratio, 1.02; 95% confidence interval [CI], 0.41 to 2.52; P = 0.69). At 28 days, 17 participants (12%) in the oral group and 14 (10%) in the intravenous groups had died (hazard ratio, 0.85; 95% CI, 0.41 to 1.78). Serious adverse events occurred in 32 participants (23%) in the oral group, 14 (21%) in the rapid intravenous group, and 10 (15%) in the slow intravenous group. No evidence of pulmonary edema, heart failure, or fluid overload was noted.

Conclusions. Among children with severe acute malnutrition and gastroenteritis, no evidence of a difference in mortality at 96 hours was noted between oral and intravenous rehydration strategies. (Funded by the Joint Global Health Trials scheme and others; GASTROSAM Current Controlled Trials number, ISRCTN76149273.).

Background. Assessing the risk of radiation-induced hematologic cancer from medical imaging in children and adolescents might support informed decisions on the use of imaging.

Methods. We followed a retrospective cohort of 3,724,623 children born between 1996 and 2016 in six U.S. health care systems and Ontario, Canada, until the earliest of cancer or benign-tumor diagnosis, death, end of health care coverage, an age of 21 years, or December 31, 2017. Radiation doses to active bone marrow from medical imaging were quantified. Associations between hematologic cancers and cumulative radiation exposure (vs. no exposure), with a lag of 6 months, were estimated with the use of continuous-time hazards models.

Results. During 35,715,325 person-years of follow-up (mean, 10.1 years per person), 2961 hematologic cancers were diagnosed, primarily lymphoid cancers (2349 [79.3%]), myeloid cancers or acute leukemia (460 [15.5%]), and histiocytic- or dendritic-cell cancers (129 [4.4%]). The mean (±SD) exposure among children exposed to at least 1 mGy was 14.0±23.1 mGy overall (for comparison, 13.7 mGy was the exposure from one computed tomographic [CT] scan of the head) and 24.5±36.4 mGy among children with hematologic cancer. Cancer risk increased with cumulative dose, with a relative risk (vs. no exposure) of 1.41 (95% confidence interval [CI], 1.11 to 1.78) for 1 to less than 5 mGy, 1.82 (95% CI, 1.33 to 2.43) for 15 to less than 20 mGy, and 3.59 (95% CI, 2.22 to 5.44) for 50 to less than 100 mGy. The cumulative radiation dose to bone marrow was associated with an increased risk of all hematologic cancers (excess relative risk per 100 mGy, 2.54 [95% CI, 1.70 to 3.51; P<0.001]; relative risk for 30 vs. 0 mGy, 1.76 [95% CI, 1.51 to 2.05]) and most tumor subtypes. The excess cumulative incidence of hematologic cancers by 21 years of age among children exposed to at least 30 mGy (mean, 57 mGy) was 25.6 per 10,000. We estimated that, in our cohort, 10.1% (95% CI, 5.8 to 14.2) of hematologic cancers may have been attributable to radiation exposure from medical imaging, with higher risks from the higher-dose medical-imaging tests such as CT.

Conclusions. Our study suggests an association between exposure to radiation from medical imaging and a small but significantly increased risk of hematologic cancer among children and adolescents. (Funded by the National Cancer Institute and others.).

Background. Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an N-acetylgalactosamine-conjugated antisense oligonucleotide that targets the messenger RNA of apolipoprotein C-III, which inhibits triglyceride clearance.

Methods. In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change).

Results. A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups.

Conclusions. Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.).

Background. Clesrovimab is a long-acting investigational monoclonal antibody against site IV of the respiratory syncytial virus (RSV) fusion protein. Data regarding the safety and efficacy of clesrovimab in healthy infants are needed.

Methods. We randomly assigned healthy preterm and full-term infants entering their first RSV season in a 2:1 ratio to receive one intramuscular 105-mg dose of clesrovimab or placebo. The primary efficacy end point was RSV-associated medically attended lower respiratory infection (including at least one indicator of lower respiratory infection or disease severity) through 150 days after injection. A key secondary efficacy end point was RSV-associated hospitalization during the same period.

Results. A total of 3614 infants received an injection: 2412 infants received clesrovimab, and 1202 infants received placebo. Through day 150 after injection, RSV-associated medically attended lower respiratory infection occurred in 60 of 2398 infants in the clesrovimab group (incidence rate over 5-month period, 2.6%) and in 74 of 1201 infants in the placebo group (incidence rate over 5-month period, 6.5%), for an efficacy of 60.4% (95% confidence interval [CI], 44.1 to 71.9; P<0.001). RSV-associated hospitalization within 150 days was reported in 9 of 2398 infants in the clesrovimab group and in 28 of 1201 infants in the placebo group, for an efficacy of 84.2% (95% CI, 66.6 to 92.6; P<0.001). Serious adverse events were reported in 278 of 2409 infants (11.5%) in the clesrovimab group and 149 of 1202 infants (12.4%) in the placebo group.

Conclusions. In healthy preterm and full-term infants, a single dose of clesrovimab reduced the incidence of RSV-associated medically attended lower respiratory infection and RSV-associated hospitalization, with a safety profile similar to that of placebo. (Funded by Merck Sharp and Dohme; CLEVER ClinicalTrials.gov number, NCT04767373.).

Background. Poorly controlled hypertension is a common problem worldwide, particularly in low-resource settings.

Methods. We conducted an open-label, randomized, controlled trial of a home-based model of hypertension care in South Africa. Adults with hypertension were assigned to receive home-based care, which consisted of patient monitoring of blood pressure, home visits from a community health worker (CHW) for data collection and medication delivery, and remote nurse-led decision making supported by a mobile application (CHW group); enhanced home-based care, which consisted of the same intervention but with blood-pressure machines transmitting readings automatically (enhanced CHW group); or standard care with clinic-based management (standard-care group). The primary outcome was the systolic blood pressure at 6 months. Secondary outcomes were the systolic blood pressure at 12 months and hypertension control at 6 and 12 months. Safety outcomes included adverse events, deaths, and retention in care.

Results. A total of 774 adults underwent randomization. The mean age was 62 years; 76.0% of the participants were women, 13.6% had diabetes mellitus, and 46.5% had human immunodeficiency virus infection. The mean systolic blood pressure at 6 months was lower in the CHW group than in the standard-care group (difference, -7.9 mm Hg; 95% confidence interval [CI], -10.5 to -5.3; P<0.001) and was also lower in the enhanced CHW group than in the standard-care group (difference, -9.1 mm Hg; 95% CI, -11.7 to -6.4; P<0.001). The percentage of participants with hypertension control at 6 months was 32.5% in the standard-care group, as compared with 57.4% in the CHW group (relative risk, 1.76; 95% CI, 1.40 to 2.13) and 61.3% in the enhanced CHW group (relative risk, 1.89; 95% CI, 1.51 to 2.27). The improvements in systolic blood pressure and hypertension control with home-based care appeared to persist at 12 months. Severe adverse events and deaths occurred in 2.7% and 1.0% of the participants, respectively, and occurred in a similar percentage of participants across trial groups. Retention in care was observed in more than 95% of the participants in the CHW and enhanced CHW groups.

Conclusions. In South Africa, home-based hypertension care led to a significantly lower mean systolic blood pressure at 6 months than standard, clinic-based care. (Supported by the National Institutes of Health and others; IMPACT-BP ClinicalTrials.gov number, NCT05492955; South African National Clinical Trials Register number, DOH-27-112022-4895.).