A major complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell–associated neurotoxicity syndrome (ICANS), which presents as aphasia, confusion, weakness, somnolence, seizures, and coma. This is similar to the neurologic manifestations of hypophosphatemia, which can result from sudden increases in metabolic demand for phosphorylated intermediates (e.g., refeeding syndrome and sepsis). Given these similarities, we investigated whether CAR T-cell effector metabolic activity is associated with increased extracellular phosphate consumption and a possible association between hypophosphatemia and ICANS. In vitro 4–1BB and CD28 CD19-targeted CAR T-cell effector activity was found to be associated with increased consumption of media phosphorus, which was temporally associated with increased single-cell effector secretomic activity and increased phosphorus-dependent metabolic demand of the CAR T cells. A clinical cohort of 77 patients treated with CD19-targeted CAR T-cell therapy demonstrated a significant anticorrelation between serum phosphorus and ICANS incidence and severity, with earlier onset of hypophosphatemia after CAR T-cell infusion more likely to result in neurotoxicity. These results imply phosphorous level monitoring could alert to the development of ICANS in clinical scenarios. See related Spotlight by Tobin et al., p. 1422

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to decrease blood glucose levels, promote weight loss, and prevent cardiovascular events. However, evidence is limited regarding their effect on dementia, although emerging observational studies, some with serious methodological limitations, have suggested large reductions in dementia associated with GLP-1RAs that may not be entirely causally related. To compare the effect of GLP-1RAs versus dipeptidyl peptidase-4 inhibitors (DPP4is) as second-line therapy for type 2 diabetes on risk for dementia among older adults. Target trial emulation. United States from January 2016 to December 2020. Medicare fee-for-service beneficiaries aged 66 years or older with diabetes who used metformin and did not have dementia at baseline and initiated GLP-1RAs or DPP4is between January 2017 and December 2018. Onset of dementia was defined as 1 year before the date of a new dementia diagnosis. Risks were calculated at 30 months in GLP-1RA and DPP4i groups matched in a 1:2 ratio on an estimated propensity score and compared via ratios and differences. Among 2418 patients initiating GLP-1RAs and 4836 matched patients initiating DPP4is, the mean age was 71 years, and 55% were female. Over a median follow-up of 1.9 years, the outcome occurred in 96 patients in the GLP-1RA group and 217 in the DPP4i group. The estimated risk difference at 30 months was -0.93 (95% CI, -2.33 to 0.23) percentage points, and the estimated risk ratio was 0.83 (95% CI, 0.61 to 1.05). The estimated risk ratios were 0.64 (95% CI, 0.46 to 0.93) and 1.22 (95% CI, 0.74 to 1.66) among those younger than 75 years and aged 75 years or older, respectively. Potential residual confounding (no data on body mass index, glycemic control, or duration of diabetes), outcome misclassification, and short follow-up. Among older adults with diabetes, no clear evidence was found that the incidence of dementia differed overall between patients using GLP-1RAs versus DPP4is. Under conventional statistical criteria, an effect of GLP-1RAs between a 39% decrease and a 5% increase in risk for dementia was highly compatible with the data, although estimates differed by age. Randomized trials are needed to quantify the effect of GLP-1RAs on dementia. Gregory Annenberg Weingarten, GRoW @ Annenberg.

To identify structural factors associated with the receipt of mental health care treatment among Black women in California during pregnancy and after childbirth. Secondary analysis of data from the population-based Listening to Mothers in California survey. The sample included 194 non-Latina Black women in the postpartum period. We used descriptive statistics, including differences between means and logistic regression, to conduct a series of bivariate analyses. Most respondents (84.4%, n = 163) reported symptoms of perinatal mood and anxiety disorders prenatally, and half (50% n = 97) reported symptoms of perinatal mood and anxiety disorders in the postpartum period. Only 12.3% to 14.6% of those who reported symptoms received mental health care treatment. Furthermore, 21.2% (n = 38) of respondents were not screened for postpartum depression. Respondents with private insurance coverage were more likely to report receipt of mental health care after childbirth (OR = 4.6; 95% confidence interval [1.5, 13.5]) compared to respondents with public insurance coverage. Our results suggest a high prevalence of unmet mental health needs among non-Latina Black women who lived in California during the perinatal period. Practitioners in clinical settings may be more likely to make referrals to mental health care for women with private insurance coverage in the postpartum period.

Background: Although suicide is a leading cause of death among children, the optimal approach for using health care data sets to detect suicide-related emergencies among children is not known. Objective: This study aimed to assess the performance of suicide-related International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes and suicide-related chief complaint in detecting self-injurious thoughts and behaviors (SITB) among children compared with clinician chart review. The study also aimed to examine variations in performance by child sociodemographics and type of self-injury, as well as develop machine learning models trained on codified health record data (features) and clinician chart review (gold standard) and test model detection performance. Methods: A gold standard classification of suicide-related emergencies was determined through clinician manual review of clinical notes from 600 emergency department visits between 2015 and 2019 by children aged 10 to 17 years. Visits classified with nonfatal suicide attempt or intentional self-harm using the Centers for Disease Control and Prevention surveillance case definition list of ICD-10-CM codes and suicide-related chief complaint were compared with the gold standard classification. Machine learning classifiers (least absolute shrinkage and selection operator–penalized logistic regression and random forest) were then trained and tested using codified health record data (eg, child sociodemographics, medications, disposition, and laboratory testing) and the gold standard classification. The accuracy, sensitivity, and specificity of each detection approach and relative importance of features were examined. Results: SITB accounted for 47.3% (284/600) of the visits. Suicide-related diagnostic codes missed nearly one-third (82/284, 28.9%) and suicide-related chief complaints missed more than half (153/284, 53.9%) of the children presenting to emergency departments with SITB. Sensitivity was significantly lower for male children than for female children (0.69, 95% CI 0.61-0.77 vs 0.84, 95% CI 0.78-0.90, respectively) and for preteens compared with adolescents (0.66, 95% CI 0.54-0.78 vs 0.86, 95% CI 0.80-0.92, respectively). Specificity was significantly lower for detecting preparatory acts (0.68, 95% CI 0.64-0.72) and attempts (0.67, 95% CI 0.63-0.71) than for detecting ideation (0.79, 95% CI 0.75-0.82). Machine learning–based models significantly improved the sensitivity of detection compared with suicide-related codes and chief complaint alone. Models considering all 84 features performed similarly to models considering only mental health–related ICD-10-CM codes and chief complaints (34 features) and models considering non–ICD-10-CM code indicators and mental health–related chief complaints (53 features). Conclusions: The capacity to detect children with SITB may be strengthened by applying a machine learning–based approach to codified health record data. To improve integration between clinical research informatics and child mental health care, future research is needed to evaluate the potential benefits of implementing detection approaches at the point of care and identifying precise targets for suicide prevention interventions in children.

We developed and tested MivacunaLA/MyshotLA, a community-informed mobile phone intervention, to increase COVID-19 vaccination among Latino parents/caretakers of minors in under-resourced areas of Los Angeles by addressing misinformation and building trust. We recruited Latino parents/caregivers with at least one unvaccinated child in East and South Los Angeles in the summer of 2021 and evaluated MivacunaLA as a randomized controlled trial with a wait-list control group. A difference-in-difference analysis showed Latino parents/caregivers that participated in MivacunaLA (n = 246), in comparison to the control group, were 15 percentage points more likely (p = 0.04) to report vaccination of minors aged 12–17 years, and 12 percentage points more likely (p = 0.03) to report a positive intention to vaccinate minors aged 2–11 years (when COVID-19 vaccines became available). Mobile phone-delivered digital interventions using videos and culturally tailored educational material to promote COVID-19 vaccine confidence can be an effective way to combat misinformation and deliver timely information to marginalized communities. Community-based participatory research approaches are crucial to advance health equity among minority communities, especially immigrant Spanish-speaking underserved communities.

Adoptive transfer of genetically engineered T cells expressing a tumor-antigen-specific transgenic T cell receptor (TCR) can result in clinical responses in a variety of malignancies. However, these responses are frequently short-lived, and patients typically relapse within several months. This phenomenon is largely due to poor persistence of the transgenic T cells, as well as a progressive loss of their functionality and terminal differentiation in vivo. This underscores the need for cell therapy approaches able to sustain the initial antitumor efficacy and lead to long-term antitumor efficacy. Herein, we report the use of tandem cell therapies involving autologous T cells and hematopoietic stem cells engineered to express the NY-ESO-1 TCR for the treatment of solid tumors in a first-in-human phase I clinical trial (NCT03240861). This therapy is shown to be safe, feasible, and leads to initial tumor regression activity. T cell progeny from the HSC progenitors is shown to provide circulating transgenic NY-ESO-1 TCR-T cells, which display tumor-antigen-specific antitumor functionality, without any evidence of anergy or exhaustion. These results demonstrate the utility of transgenic HSCs to generate a self-renewing source of tumor-specific cellular immunotherapy in human participants. Clinicaltrials.gov: NCT NCT03240861