To the Editor Ms DeCleene and colleagues presented a methodologically robust analysis of obesity prevalence in the US from 1990 to 2022, with forecasts through 2035. Their analytic strategy leveraged modeling techniques from the Global Burden of Disease project, which has produced highly reliable estimates of disease burden in the US and globally. However, the current use of this approach for US obesity forecasting relies on the assumption that pre-2022 trends will continue, absent exogenous shocks. The rapid proliferation of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) represents an already demonstrated example of such a shock.
Science Journals
To the Editor Dr Ali and colleagues reported no additional analgesic benefit from adding acetaminophen (paracetamol) or hydromorphone to ibuprofen for children with acute musculoskeletal injuries. In all groups, the ibuprofen dose was 10 mg/kg and the acetaminophen dose was 15 mg/kg, with pain assessed 60 minutes after drug administration. Pain scores did not differ between ibuprofen monotherapy and either combination (ibuprofen plus acetaminophen or ibuprofen plus hydromorphone).
To the Editor Dr Ali and colleagues reported results from 2 randomized clinical trials evaluating whether adding acetaminophen (paracetamol) or hydromorphone to ibuprofen improves analgesia for children with acute nonoperative musculoskeletal injury. In pooled analyses, pain scores at 60 minutes were similar across groups, whereas adverse events were more frequent with hydromorphone. These findings are timely given pediatric opioid stewardship policies and recent clinical guidance that encourages nonopioid-first strategies and cautious outpatient opioid prescribing for acute pain in children.
In Reply Drs Yin and Zhang query what impact clinically relevant heterogeneity of participants with severe pain scores might have on study conclusions for the No OUCH trials. Study exclusion criteria ensured children requiring intranasal or intravenous opioid analgesia for severe pain would not be included in this study of oral analgesia. Indeed, the study participants’ mean baseline pain severity score of 6.4 to 6.5 (SD, 1.7-1.9), which at its upper limits was still only at the cusp of severe pain (defined as 8-10/10), included the group in whom clinicians often consider escalation beyond ibuprofen. We agree with Yin and Zhang that all children with mild to moderately severe pain should receive oral analgesia. However, our study was specifically designed to understand the incremental benefit of adding other analgesics to ibuprofen for children with moderately severe pain, rather than those with severe pain. Stratification by injury type demonstrated no clinically or statistically significant difference between study groups and across injury types (fracture vs sprain vs dislocation) consistent with prior studies of children’s fractures and other musculoskeletal injuries that have not reported any benefit with either combination therapy or opioids alone. We plan to report functional outcomes according to injury type in a future article, in which we will consider stratification by pain severity if the data support such analysis.
To the Editor Dr Williams and colleagues reported a rapid recovery with extended ultraoxygenated preservation (REUP) technique for adult donation after circulatory death (DCD) heart transplant that avoids both preimplant donor heart reanimation and ex situ machine perfusion, with encouraging early outcomes (30-day survival, 96%; severe primary graft dysfunction, 4%). In settings where thoracoabdominal normothermic regional perfusion is restricted—often reflecting deceased donor rule concerns and variable institutional policies—a cold-preservation strategy that does not require reanimation could have important practical implications.
Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by <i>GBA1</i> mutations, leading to defective acid β-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate the human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells of nGD patients with <i>GBA1</i><sup>L444P/P415R</sup> and <i>GBA1</i><sup>L444P/RecNcil</sup> mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology. <i>GBA1</i> mutation correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of <i>GBA1</i> mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unraveling disease mechanisms and accelerating the discovery of therapies for patients with nGD.
Neonatal opioid withdrawal syndrome (NOWS) remains a consequential downstream effect of the ongoing opioid epidemic in the US. Although we have improved both access and approach to medical management of opioid use disorder in pregnancy, exposure confers a risk of withdrawal to the infant, regardless of type of exposure or presence of medical supervision. Infants with opioid withdrawal syndrome continue to experience prolonged hospitalization, separation from caregivers, and significant additional opioid exposure. The burden is substantial: tens of thousands of infants are affected annually, and hospitalizations for NOWS continue to consume significant health care resources. Dozens of publications have addressed which medications should be used in the management of NOWS, but there remains a surprising dearth of comparative evidence informing how these medications should be implemented.
This crossover randomized clinical trial examines the effect of symptom-based dosing vs scheduled opioid taper on time to medical readiness for discharge in infants with neonatal opioid withdrawal syndrome treated with the Eat, Sleep, Console approach.
Intraflagellar transport (IFT) is a fundamental process driving ciliogenesis in most eukaryotic organisms. IFT172, the largest protein of the IFT complex, plays a crucial role in cilium formation, and several disease-causing IFT172 variants have been identified in ciliopathy patients. While IFT172 is tethered to the IFT-B complex via its N-terminal domains, the function of its C-terminal domains has remained elusive. Here, using both human and <i>Chlamydomonas reinhardtii</i> IFT172, we reveal that the C-terminal part of IFT172 interacts with IFT-A complex subunits, providing a molecular basis for the role of IFT172 in bridging IFT-A and IFT-B complexes. We determine the crystal structure of the C-terminal part of IFT172, uncovering a conserved U-box-like domain often found in E3 ubiquitin ligases. This domain exhibits ubiquitin-binding properties, and IFT172 undergoes ubiquitin conjugation in vitro, an activity that is reduced in the C1727R patient ciliopathy variant. We use CRISPR-engineered RPE-1 cells to demonstrate that the U-box-like domain is essential for IFT172 protein stability and proper cilium formation. Notably, RPE-1 cells with heterozygous deletion of the U-box domain show altered TGF-β signaling responses, particularly in SMAD2 phosphorylation levels and AKT activation. Our findings suggest that IFT172, beyond its structural role in bridging IFT-A and IFT-B complexes within IFT trains, harbors a conserved U-box-like domain with potential involvement in ciliary ubiquitination processes and signaling, providing new insights into the molecular mechanisms underlying IFT172-related ciliopathies.
This Viewpoint discusses breaking up health care conglomerates to decrease the cost of health care insurance.
This JAMA Insights discusses strategies for lifestyle modifications and managing adverse effects for individuals with obesity receiving incretin-based therapies for weight loss.
In this narrative essay, an anesthesiologist and the parents of a child he treated describe the extraordinary effort to save a 6-year-old’s life.
Ketamine infusions may help treat major depressive episodes during the acute phase, according to a study published in JAMA Psychiatry.
This narrative review discusses the pathophysiology, epidemiology, clinical presentation, diagnosis, and treatment of male hypogonadism.
Approximately 116 million people in the US and 1.4 billion worldwide have hypertension. In the US, among people aged 40 to 59 years, approximately 53% have hypertension, and among people 60 years and older, 71.6% have hypertension. Hypertension is a major risk factor for cardiovascular morbidity and mortality, and lowering blood pressure in people with hypertension meaningfully reduces this risk. In a network meta-analysis of 42 randomized clinical trials and 144 220 people with hypertension, systolic blood pressure lowering by 10, 20, or 30 mm Hg to achieve a treatment goal of 120 to 124 mm Hg was associated with reductions in cardiovascular disease events of 29%, 42%, and 54%, respectively. Most people with hypertension require multiple antihypertensive medications to effectively control their blood pressure.
This study uses American Hospital Association Annual Survey data to examine current trends in hospital-led payvider models.
This network meta-analysis of short-term randomized clinical trials examines adverse effects and treatment discontinuation associated with blood pressure–lowering therapies and their combinations, by drug class and regimen.
This Viewpoint discusses the US Supreme Court’s decision in Chiles v Salazar and offers suggestions for state professional regulation that protect patient safety and autonomy while respecting constitutional boundaries.
To the Editor We read with interest the Tenecteplase for Acute Non–Large Vessel Occlusion in the Extended Time Window (OPTION) trial, which evaluated intravenous tenecteplase administered between 4.5 hours and 24 hours after ischemic stroke onset in patients selected by computed tomographic (CT) perfusion imaging. Although the study addresses an important question in acute stroke care, its findings warrant cautious interpretation in light of safety considerations and clinical context.
In Reply We thank Dr Morelli and colleagues for their thoughtful comments about the OPTION trial.
This study assessed whether a symptom-based dosing strategy for opioid treatment reduces time to medical readiness for discharge compared with scheduled opioid taper in infants with neonatal opioid withdrawal syndrome (NOWS) cared for with the Eat, Sleep, Console approach (ESC) or Finnegan-based care, which focuses on detailed scoring of the signs of withdrawal.
The size and shape of cytoskeletal bundles, essential regulators of cell function, emerge from collective filament assembly rather than precise size-control mechanisms.
High multiplicity of infection (MOI), the number of genetically distinct parasite strains co-infecting a host, characterizes falciparum malaria and other infectious diseases under high transmission. High MOI in <i>Plasmodium falciparum</i> accompanies high prevalence of asymptomatic infection despite high exposure, creating a large transmission reservoir that challenges intervention. This pattern is enabled by parasite immune evasion through extensive antigenic diversity. The force of infection (FOI), the number of new infections acquired by an individual host over a given time interval, is the dynamic counterpart of MOI and a key epidemiological parameter for monitoring antimalarial interventions. FOI is difficult and costly to measure, especially in high-transmission regions, requiring cohort studies or model-based inference from repeated cross-sectional surveys. Here, we apply queuing theory to estimate FOI from MOI with two approaches: a two-moment approximation and Little’s Law. We illustrate these methods using MOI estimates obtained under sparse sampling schemes with the ‘<i>var</i>coding’ approach. Both methods rely on infection duration data from naive malaria therapy patients and are therefore suitable for subpopulations with limited immunity, such as toddlers. We evaluate their performance using output from a stochastic agent-based model and apply the methods to an interrupted time-series study in northern Ghana, before and immediately after a three-round transient indoor residual spraying intervention. By accounting for sampling limitations with a Bayesian framework and bootstrap imputation, both methods yield good and replicable FOI estimates across various simulated scenarios. Their application to the surveys of 1- to 5-year-old children in Ghana indicates a larger than 70% reduction in annual FOI immediately after intervention.
Single-pill combination therapy for hypertension remains uncommon and in fact has decreased over time, according to a study published in the Journal of the American College of Cardiology.
This Medical News article discusses a new study that found weakened heart muscle cell contractions in patients with heart failure with preserved ejection fraction and very high body mass index.