Associations between anemia and FGF23 in the CKiD study.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that plays a central role in chronic kidney disease-mineral bone disorder and is associated with CKD progression and cardiovascular morbidity. Factors related to CKD-associated anemia, including iron deficiency, can increase FGF23 production. This study aimed to assess whether anemia and/or iron deficiency are associated with increased circulating concentrations of FGF23 in the large, well-characterized Chronic Kidney Disease in Children (CKiD) study cohort. METHODS: Hemoglobin concentrations, iron parameters, C-terminal (total) FGF23, intact FGF23, and relevant covariables were measured in cross-sectional analysis of CKiD study subjects. RESULTS: In 493 pediatric patients with CKD (median [interquartile range] age 13 [9, 16] years), the median estimated glomerular filtration rate was 48 [35, 61] ml/min/1.73 m2, and 103 patients (21%) were anemic. Anemic subjects had higher total FGF23 concentrations than non-anemic subjects (204 [124, 390] vs. 109 [77, 168] RU/ml, p < 0.001). In multivariable linear regression modeling, anemia was independently associated with higher total FGF23, after adjustment for demographic, kidney-related, mineral metabolism, and inflammatory covariables (standardized ß (95% confidence interval) 0.10 (0.04, 0.17), p = 0.002). In the subset of subjects with available iron parameters (n = 191), iron deficiency was not associated with significantly higher total FGF23 concentrations. In the subgroup that had measurements of both total and intact FGF23 (n = 185), in fully adjusted models, anemia was significantly associated with higher total FGF23 (standardized ß (95% CI) 0.16 (0.04, 0.27), p = 0.008) but not intact FGF23 (standardized ß (95% CI) 0.02 (-0.12, 0.15), p = 0.81). CONCLUSIONS: In this cohort of pediatric patients with CKD, anemia was associated with increased total FGF23 levels but was not independently associated with elevated intact FGF23, suggesting possible effects on both FGF23 production and cleavage. Further studies are warranted to investigate non-mineral factors affecting FGF23 production and metabolism in CKD.

Association of the COVID-19 Pandemic on Treatment Times for ST-Elevation Myocardial Infarction: Observations from the Los Angeles County Regional System.

Previous studies have documented longer treatment times and worse outcomes for patients with ST-elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) during the COVID-19 pandemic. The objective of the present study was to evaluate the impact of the COVID-19 pandemic on treatment times and outcomes for patients with STEMI who underwent primary PCI within a regional system of care. This was a retrospective study using data from the Los Angeles County Emergency Medical Services Agency. Data on the emergency medical service activations were abstracted for patients with STEMI from March 19, 2020 to January 31, 2021, during the COVID-19 pandemic and for the same interval the previous year. All adult patients (≥18 years) with STEMI who underwent emergent coronary angiography were included. The primary end point was the first medical contact (FMC) to device time. The secondary end points included treatment time intervals, vascular complications, need for emergent coronary artery bypass surgery, length of hospital stay, and in-hospital mortality. During the study period, 3,017 patients underwent coronary angiography for STEMI, 1,893 patients pre-COVID-19 and 1,124 patients during COVID-19 (40% lower). A total of 2,334 patients (77%) underwent PCI. During the COVID-19 period, rates of PCI were significantly lower compared with the control period (75.1% vs 78.7%, p = 0.02). FMC to device time was shorter during the COVID-19 period compared with the control period (median 77.0 vs 81.0 minutes, p = 0.004). For patients with STEMI complicated by out-of-hospital cardiac arrest, FMC to device time was similar during the COVID-19 period compared with the control period (median 95.0 [33.0] vs 100.0 [40.0] minutes, p = 0.34). Vascular complications, the need for emergent bypass surgery, length of hospital stay, and in-hospital mortality were similar between the periods. In conclusion, in this large regional system of care, we found a relatively small but significant decrease in treatment times, yet overall, similar clinical outcomes for patients with STEMI who underwent primary PCI and were treated during the COVID-19 period compared with a control period. These findings suggest that mature cardiac systems of care were able to maintain efficient care despite the challenges of the COVID-19 pandemic.

Infusion Product TNFα, Th2, and STAT3 Activities Are Associated with Clinical Responses to Transgenic T-cell Receptor Cell Therapy.

Transgenic T-cell receptor (TCR) T cell-based adoptive cell therapies for solid tumors are associated with dramatic initial response rates, but there remain many instances of treatment failure and disease relapse. The association of infusion product cytokine profiles with clinical response has not been explored in the context of TCR T-cell therapy products. Single-cell antigen-dependent secretomic and proteomic analysis of preinfusion clinical TCR T-cell therapy products revealed that TNFα cytokine functionality of CD8+ T cells and phospho-STAT3 signaling in these cells were both associated with superior clinical responsiveness to therapy. By contrast, CD4+ T-helper 2 cell cytokine profiles were associated with inferior clinical responses. In parallel, preinfusion levels of IL15, Flt3-L, and CX3CL1 were all found to be associated with clinical response to therapy. These results have implications for the development of therapeutic biomarkers and identify potential targets for enrichment in the design of transgenic TCR T-cell therapies for solid tumors.

Impact of Age and Variant Time Period on Clinical Presentation and Outcomes of Hospitalized Coronavirus Disease 2019 Patients.

Objective: To evaluate the impact of age and COVID-19 variant time period on morbidity and mortality among those hospitalized with COVID-19. Patients and Methods: Patients from the American Heart Association's Get With The Guidelines COVID-19 cardiovascular disease registry (January 20, 2020-February 14, 2022) were divided into groups based on whether they presented during periods of wild type/alpha, delta, or omicron predominance. They were further subdivided by age (young: 18-40 years; older: more than 40 years), and characteristics and outcomes were compared. Results: The cohort consisted of 45,421 hospitalized COVID-19 patients (wild type/alpha period: 41,426, delta period: 3349, and omicron period: 646). Among young patients (18-40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.6; 95% CI, 1.3-2.1), major adverse cardiovascular events (MACE) (OR, 1.8; 95% CI, 1.3-2.5), and in-hospital mortality (OR, 2.2; 95% CI, 1.5-3.3) when compared with presentation during wild type/alpha. Among older patients (more than 40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.2; 95% CI, 1.1-1.3), MACE (OR, 1.5; 95% CI, 1.4-1.7), and in-hospital mortality (OR, 1.4; 95% CI, 1.3-1.6) when compared with wild type/alpha. Among older patients (more than 40 years), presentation during omicron associated with decreased odds of severe COVID-19 (OR, 0.7; 95% CI, 0.5-0.9) and in-hospital mortality (OR, 0.6; 95% CI, 0.5-0.9) when compared with wild type/alpha. Conclusion: Among hospitalized adults with COVID-19, presentation during a time of delta predominance was associated with increased odds of severe COVID-19, MACE, and in-hospital mortality compared with presentation during wild type/alpha. Among older patients (aged more than 40 years), presentation during omicron was associated with decreased odds of severe COVID-19 and in-hospital mortality compared with wild type/alpha.

Structural Factors in Health Care Associated With the Mental Health Needs of Black Women in California During the Perinatal Period.

OBJECTIVE: To identify structural factors associated with the receipt of mental health care treatment among Black women in California during pregnancy and after childbirth. DESIGN: Secondary analysis of data from the population-based Listening to Mothers in California survey. PARTICIPANTS: The sample included 194 non-Latina Black women in the postpartum period. METHODS: We used descriptive statistics, including differences between means and logistic regression, to conduct a series of bivariate analyses. RESULTS: 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. CONCLUSION: 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.

Recurrent High-Grade Squamous Intraepithelial Lesion After Loop Excision Procedure Versus Loop Procedure With Top Hat.

OBJECTIVE: To evaluate single-pass loop electrosurgical excision procedure (LEEP-SP) versus LEEP with top hat (LEEP-TH) in terms of treatment failure defined as high-grade squamous intraepithelial lesion (HSIL) cytology within 2 years' follow-up. METHODS: This single-institution cohort study used a prospectively collected cervical dysplasia database including all patients who underwent LEEP-SP or LEEP-TH for biopsy-proven cervical intraepithelial neoplasia between 2005 and 2019. RESULTS: Of 340 patients included, 178 underwent LEEP-SP and 162 LEEP-TH. The LEEP-TH patients were more likely to be older (mean age, 40.4 vs 36.5 years; p < .001) and have a positive preprocedure endocervical sampling (68.5% vs 11.8%; p < .001). Positive margins were found in 23 LEEP-SP (12.9%) and in 25 LEEP-TH (15.4%; p = .507). There was no significant difference in depth of excision between LEEP-SP (13.21 ± 23.19 mm) and LEEP-TH (17.37 ± 28.26 mm; p = .138). At 2 years, there was no difference in the rates of HSIL cytology (5.2% vs 6.3%; p = .698), any positive human papillomavirus test, or HSIL cytology (25% vs 15%; p = .284). The 57 patients undergoing repeat excision were more likely to be older (mean age, 40.95 vs 37.52 years; p = .023), have had a LEEP-TH (26.3% vs 73.7%; p < .001), and have initial cytologic HSIL (64.9% vs 35.0%; p < .001). CONCLUSIONS: In this single-institution study, there is no difference in the rate of recurrent HSIL in patients undergoing LEEP-SP versus LEEP-TH. A LEEP-TH may have limited additional benefit over a LEEP-SP in the treatment of cervical HSIL.

Hypophosphatemia Due to Increased Effector Cell Metabolic Activity Is Associated with Neurotoxicity Symptoms in CD19-Targeted CAR T-cell Therapy.

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.

Reconnecting Homeless Adolescents and Their Families: Correlates of Participation in a Family Intervention.

Behavioral family interventions are an effective way to intervene to prevent negative developmental outcomes for adolescents. Participation in family interventions encompasses behavioral and cognitive/attitudinal dimensions, among others, indicated by retention and engagement, respectively. Two dimensions of participation, retention and engagement, in a family intervention were examined in a sample of newly homeless adolescents and their parents or guardians. Correlates of participation included parents with more income and less perceived family conflict and adolescents with higher endorsement of depression, anxiety, somatization, obsessive-compulsive, phobic, and psychotic symptoms on the Brief Symptom Inventory (BSI). Stronger therapeutic alliance was correlated with being more distressed (i.e., lower income, more hostility), being a female adolescent participant, and having greater comfort discussing sex with parents. Furthermore, parents and adolescents with greater distress and thus greater need were more apt to finish the intervention. The finding that families who were experiencing more distress had higher alliance scores suggests that there is an additional need for development of interventions for families in crisis. Both participant and provider perceptions are also important in development of a strong therapeutic alliance. This study's findings have implications for further exploration of the development of cultural humility and improving mental health literacy among facilitators of behavioral interventions.

Adolescent Suicide Attempt Prevention: Predictors of Response to a Cognitive-Behavioral Family and Youth Centered Intervention.

OBJECTIVE: Suicide is a leading cause of adolescent death. Recent data support the efficacy of cognitive-behavioral treatments with strong family components for reducing suicide risk; however, not all youth benefit from current interventions. Identifying predictors of treatment response can inform treatment selection and optimize benefits. METHOD: This study examines predictors of response to a DBT-informed cognitive-behavioral family treatment (SAFETY), among 50 youth with recent suicide attempts/self-harm. Youth and parents were assessed at baseline and post-treatment. RESULTS: Results indicated medium-to-large effect sizes for SAFETY on youth suicidal behavior (SB; defined as suicide attempts, aborted attempts, and planning), depression, hopelessness, social adjustment, and parental depression. Classification tree analysis, with a correct classification rate of 93.3%, and follow-up logistic analyses indicated that 35% of youths reporting active SB at baseline reported active SB at post-treatment, whereas post-treatment SB was rare among youths whose active suicidality had resolved by the baseline assessment (5%). Among youths reporting baseline SB, those endorsing sleep problems were more likely to report post-treatment SB (53%) versus those without sleep problems (0%). CONCLUSIONS: These findings highlight the potential value of personalized treatment approaches based on pretreatment characteristics and the significance of baseline SB and sleep problems for predicting treatment response.

Randomized controlled trial of family-focused treatment for child depression compared to individual psychotherapy: one-year outcomes.

OBJECTIVE: Childhood-onset depression is associated with increased risk of recurrent depression and high morbidity extending into adolescence and adulthood. This multisite randomized controlled trial evaluated two active psychosocial treatments for childhood depression: family-focused treatment for childhood depression (FFT-CD) and individual supportive psychotherapy (IP). Aims were to describe effects through 52 weeks postrandomization on measures of depression, functioning, nondepressive symptoms, and harm events. METHODS: Children meeting criteria for depressive disorders (N = 134) were randomly assigned to 15 sessions of FFT-CD or IP and evaluated at mid-treatment for depressive symptoms and fully at roughly 16 weeks (after acute treatment), 32 weeks, and 52 weeks/one year. See clinicaltrials.gov: NCT01159041. RESULTS: Analyses using generalized linear mixed models confirmed the previously reported FFT-CD advantage on rates of acute depression response (≥50% Children's Depression Rating Scale reduction). Improvements in depression and other outcomes were most rapid during the acute treatment period, and leveled off between weeks 16 and 52, with a corresponding attenuation of observed group differences, although both groups showed improved depression and functioning over 52 weeks. Survival analyses indicated that most children recovered from their index depressive episodes by week 52: estimated 76% FFT-CD, 77% IP. However, by the week 52 assessment, one FFT-CD child and six IP children had suffered recurrent depressive episodes. Four children attempted suicide, all in the IP group. Other indicators of possible harm were relatively evenly distributed across groups. CONCLUSIONS: Results indicate a quicker depression response in FFT-CD and hint at greater protection from recurrence and suicide attempts. However, outcomes were similar for both active treatments by week 52/one year. Although community care received after acute treatment may have influenced results, findings suggest the value of a more extended/chronic disease model that includes monitoring and guidance regarding optimal interventions when signs of depression-risk emerge.

Association of NOD2 and IL23R with inflammatory bowel disease in Puerto Rico.

The Puerto Rico population may be modeled as an admixed population with contributions from three continents: Sub-Saharan Africa, Ancient America, and Europe. Extending the study of the genetics of inflammatory bowel disease (IBD) to an admixed population such as Puerto Rico has the potential to shed light on IBD genes identified in studies of European populations, find new genes contributing to IBD susceptibility, and provide basic information on IBD for the care of US patients of Puerto Rican and Latino descent. In order to study the association between immune-related genes and Crohn's disease (CD) and ulcerative colitis (UC) in Puerto Rico, we genotyped 1159 Puerto Rican cases, controls, and family members with the ImmunoChip. We also genotyped 832 subjects from the Human Genome Diversity Panel to provide data for estimation of global and local continental ancestry. Association of SNPs was tested by logistic regression corrected for global continental descent and family structure. We observed the association between Crohn's disease and NOD2 (rs17313265, 0.28 in CD, 0.19 in controls, OR 1.5, p = 9×10-6) and IL23R (rs11209026, 0.026 in CD, 0.0.071 in controls, OR 0.4, p = 3.8×10-4). The haplotype structure of both regions resembled that reported for European populations and "local" continental ancestry of the IL23R gene was almost entirely of European descent. We also observed suggestive evidence for the association of the BAZ1A promoter SNP with CD (rs1200332, 0.45 in CD, 0.35 in controls, OR 1.5, p = 2×10-6). Our estimate of continental ancestry surrounding this SNP suggested an origin in Ancient America for this putative susceptibility region. Our observations underscored the great difference between global continental ancestry and local continental ancestry at the level of the individual gene, particularly for immune-related loci.