Switchable assembly and function of antibody complexes in vivo using a small molecule.

The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics. These properties have been coopted in a number of synthetic formats, such as antibody-drug conjugates, bispecific antibodies, or Fc-fusion proteins to generate novel biologic drug modalities. Historically, these new therapies have been generated by covalently linking multiple molecular moieties through chemical or genetic methods. This irreversible fusion of different components means that the function of the molecule is static, as determined by the structure. Here, we report the development of a technology for switchable assembly of functional antibody complexes using chemically induced dimerization domains. This approach enables control of the antibody's intended function in vivo by modulating the dose of a small molecule. We demonstrate this switchable assembly across three therapeutically relevant functionalities in vivo, including localization of a radionuclide-conjugated antibody to an antigen-positive tumor, extension of a cytokine's half-life, and activation of bispecific, T cell-engaging antibodies.

Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade.

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5 Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.

Consequences of Low eGFR either before or early after Kidney Donation.

In the general population, decreases in glomerular filtration rate (GFR) are associated with subsequent development of chronic kidney disease (CKD), cardiovascular disease (CVD), and death. It is unknown if low estimated GFR (eGFR) before or early after kidney donation was also associated with these risks. 1699 living donors (LDs) had both pre- and early (4-10 weeks) postdonation eGFR. We studied the relationships between eGFR, age at donation, and the time to sustained eGFR<45 (CKD Stage 3b) and <30 mL/min/1.73m2 (CKD Stage 4), hypertension, diabetes mellitus (DM), CVD, and death. Median follow-up was 12 (IQR, 6-21) years. Twenty-year event rates were 5.8% eGFR<45 mL/min/1.73m2; 1.2% eGFR<30 mL/min/1.73m2; 29.0% hypertension; 7.8% DM; 8.0% CVD; and 5.2% death. Median time to eGFR<45 (N=79) was 17 years; eGFR<30 (N=22), 25 years. Both low pre- and early postdonation eGFR were associated with eGFR<45 (p<0.0001) and eGFR<30 (p<0.006); however, the primary driver of risk for all ages was low postdonation (rather than predonation) eGFR. Pre- and postdonation eGFR were not associated with hypertension, DM, CVD, or death. Low pre- and early postdonation eGFR are risk factors for developing eGFR<45 mL/min/1.73m2 (CKD Stage 3b) and <30 mL/min/1.73m2 (CKD Stage 4), but not CVD, hypertension, DM, or death. SIGNIFICANCE STATEMENT: Although the vast majority of living kidney donors do well, some develop low GFR and kidney failure. Understanding risk factors for these events impacts donor acceptance and long-term donor care. We show that low predonation eGFR and low eGFR at approximately 6 weeks postdonation are risk factors for development of CKD Stages 3b and 4, with increased risk concentrated in those with early postdonation eGFR <50 ml/min/m2. Low pre- or postdonation eGFR were not associated with increased risk for mortality, cardiovascular disease, diabetes, or hypertension. Early postdonation eGFR <50 ml/min/m2 should lead to increased long-term follow-up of living donor kidney function.

Race, rituximab, and relapse in TTP.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Should children receive a kidney transplant before 2 years of age?

BACKGROUND: The optimal age of kidney transplantation for infants and toddlers with kidney failure is unclear. We aimed to evaluate the patient survival associated with kidney transplantation before 2 years of age versus remaining on the waitlist until ≥2 years. METHOD: We used the Scientific Registry of Transplant Recipients to identify all children added to the deceased-donor waitlist before 2 years of age between 1/1/2000 and 4/30/2020. For each case aged <2 years at transplant, we created a control group comprising all candidates on the waitlist on the case's transplant date. Patient survival was evaluated using sequential Cox regression. Dialysis-free time was defined as graft survival time for cases and the sum of dialysis-free time on the waitlist and graft survival time for controls. RESULTS: We observed similar patient survival for posttransplant periods 0-3 and 4-12 months but higher survival for period >12 months for <2-year decreased-donor recipients (aHR: 0.32; 95% CI: 0.13-0.78; p = .01) compared with controls. Similarly, patient survival was higher for <2-year living-donor recipients for posttransplant period >12 months (aHR: 0.21; 95% CI: 0.06-0.73; p = .01). The 5-year dialysis-free survival was higher for <2-year deceased- (difference: 0.59 years; 95% CI: 0.23-0.93) and living-donor (difference: 1.84 years; 95% CI: 1.31-2.25) recipients. CONCLUSION: Kidney transplantation in children <2 years of age is associated with improved patient survival and reduced dialysis exposure compared with remaining on the waitlist until ≥2 years.

Kidney transplant outcomes in children with simultaneous versus sequential heart-kidney transplants.

BACKGROUND: Heart transplant recipients frequently require kidney transplantation for concomitant advanced chronic kidney disease. Data on simultaneous (heart and kidney transplants performed simultaneously) versus sequential (heart transplant performed before kidney) heart-kidney transplants in children are limited. Herein, we compare kidney transplant outcomes between the two groups. METHOD: We used the Scientific Registry of Transplant Recipients to identify all pediatric (age <21 years) heart transplant recipients who also received a kidney transplant within 10 years of the heart transplant. We divided the study cohort into simultaneous heart-kidney and sequential heart-kidney recipients. We compared patient and death-censored graft survival using the Cox regression, adjusting for age at kidney transplant, sex, race, pre-transplant dialysis, donor type, and prior kidney transplant. We evaluated delayed graft function (defined as dialysis within the first week posttransplant) using logistic regression. RESULTS: Our analysis cohort included 165 recipients (86 simultaneous and 79 sequential). The incidence of delayed graft function was higher in simultaneous recipients (22.4 vs. 7.7%, p=0.017), but the difference lost statistical significance on multivariable analysis. We found no difference in patient survival (aHR 0.97; 95% CI 0.39, 2.41; p=0.95) after kidney transplant but higher death-censored kidney graft survival in sequential heart-kidney recipients compared with simultaneous heart-kidney recipients (aHR 4.26; 95% CI 1.21, 14.9; p=0.02). CONCLUSION: Sequential heart-kidney transplants are associated with higher death-censored kidney allograft survival in children compared with simultaneous heart-kidney transplants.

Neurodevelopmental profile of infants and toddlers awaiting a kidney transplant.

BACKGROUND: Infants and toddlers with kidney failure are susceptible to neurodevelopmental delays due to medical comorbidities and rapid brain development in early childhood. However, research on the neuropsychological development of this patient population has been limited over the past 10 years. METHODS: We performed a retrospective study to evaluate the neurodevelopmental functioning of infants/toddlers with kidney failure who completed the Bayley Scales of Infant and Toddler Development (3rd and 4th Edition) as part of a pretransplant evaluation between 2010 and 2022 (n = 23; Mage = 18 months, SD = 8.53; 16 males) using t-tests, linear model, and Pearson correlations. RESULTS: Mean Bayley scores of participants were below normative means for cognition (M = 86.74, 95% CI = 80.53-92.94, p < 0.001), language (M = 79.20, 95% CI = 73.32-85.08, p < 0.001), and motor (M = 78.00, 95% CI = 70.15-85.85, p < 0.001) domains. After adjusting for prematurity and epilepsy, patients on dialysis had significantly lower cognitive (78.7 vs. 93.8; p = 0.001) and motor scores (67.1 vs. 85.5; p = 0.01) compared to no dialysis. Pretransplant cognitive scores were positively correlated with posttransplant Full-Scale IQ (r(8) = 0.65 p = 0.04), verbal comprehension (r(8) = 0.75 p = 0.02), and fluid reasoning (r(7) = 0.68 p = 0.045). Similarly, pretransplant language scores were positively correlated with posttransplant Full-Scale IQ (r(7) = 0.74 p = 0.03) and verbal comprehension (r(7) = 0.73 p = 0.03). Of the 16 participants who reached age > 5 years during the study period, seven were diagnosed with a neurodevelopmental disorder, including three with autism spectrum disorder. CONCLUSIONS: Infants and toddlers with kidney failure are at risk of developmental delays and later neurodevelopmental disorders. Dialysis is associated with cognitive and motor delays independent of prematurity and epilepsy.

New Morbidities During Critical Illness and Associated Risk of ICU Readmission: Virtual Pediatric Systems Cohort, 2017-2020.

OBJECTIVES: To describe change in Functional Status Scale (FSS) associated with critical illness and assess associated development of new morbidities with PICU readmission. DESIGN: Retrospective, cross-sectional cohort study using the Virtual Pediatric Systems (VPS; Los Angeles, CA) database. SETTING: One hundred twenty-six U.S. PICUs participating in VPS. SUBJECTS: Children younger than 21 years old admitted 2017-2020 and followed to December 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 40,654 patients, 86.2% were classified as having good function or mild dysfunction before illness. Most patients did not have a change in their FSS category during hospitalization. Survival with new morbidity occurred most in children with baseline good/mild dysfunction (8.7%). Hospital mortality increased across categories of baseline dysfunction. Of 39,701 survivors, 14.2% were readmitted within 1 year. Median time to readmission was 159 days. In multivariable, mixed-effects Cox modeling, time to readmission was most associated with discharge functional status (hazard ratio [HR], 5.3 [95% CI, 4.6-6.1] for those with very severe dysfunction), and associated with lower hazard in those who survived with new morbidity (HR, 0.7 [95% CI, 0.6-0.7]). CONCLUSIONS: Development of new morbidities occurs commonly in pediatric critical illness, but we failed to find an association with greater hazard of PICU readmission. Instead, patient functional status is associated with hazard of PICU readmission.

School Connectedness and Adolescent E-cigarette Susceptibility in an Urban Sample of Middle and High School Students.

Adolescent school connectedness generally protects from risk behaviors such as tobacco use; however, its relationship to e-cigarette use is unclear. This study examines the relationship between adolescent school connectedness and e-cigarette susceptibility in a diverse longitudinal sample. This secondary analysis of a school-based intervention surveyed 608 middle (66%) and high school (34%) students from 10 schools at 3 time points over 1 year. At baseline, respondents had a mean age of 14 years, 54% were female, and 71% were BIPOC (Black, Indigenous, People of Color). Logistic regression models examined unadjusted and adjusted associations between school connectedness (both baseline and concurrent) and e-cigarette susceptibility over time. E-cigarettes represented the most prevalent form of current nicotine-containing product use in spring 2019 (2.3%), and most respondents reported no e-cigarette susceptibility (69%). E-cigarette susceptibility remained relatively stable during the study. Higher baseline school connectedness levels were associated with lower odds of e-cigarette susceptibility over time. Similarly, higher concurrent school connectedness scores were associated with lower odds of e-cigarette susceptibility over time: spring 2019 (OR, 0.39; 95% CI, 0.32, 0.47), fall 2019 (OR, 0.49; 95% CI, 0.34, 0.72), and spring 2020 (OR, 0.64; 95% CI, 0.47, 0.87). Findings were similar for middle and high school students and did not differ significantly after adjusting for other covariates. Adolescents' school connectedness appears to protect from e-cigarette susceptibility over time, underscoring the importance of promoting positive school experiences to reduce adolescent risk e-cigarette use.

Invasive haemodynamics predict outcomes in paediatric pulmonary artery hypertension.

BACKGROUND: Invasive haemodynamics are often performed for initiating and guiding pulmonary artery hypertension therapy. Little is known about the predictive value of invasive haemodynamic indices for long-term outcomes in children with pulmonary artery hypertension. We aimed to evaluate invasive haemodynamic data to help predict outcomes in paediatric pulmonary artery hypertension. METHODS: Patients with pulmonary artery hypertension who underwent cardiac catheterisation (2006-2019) at a single centre were included. Invasive haemodynamic data from the first cardiac catheterisation and clinical outcomes were reviewed. The combined adverse outcome was defined as pericardial effusion (due to right ventricle failure), creation of a shunt for pulmonary artery hypertension (atrial septal defect or reverse Pott's shunt), lung transplant, or death. RESULTS: Among 46 patients with a median [interquartile range (IQR)] age of 13.2 [4.1-44.7] months, 76% had CHD. Median mean pulmonary artery pressure was 37 [28-52] mmHg and indexed pulmonary vascular resistance was 6.2 [3.6-10] Woods units × m2. Median pulmonary artery pulsatility index was 4.0 [3.0-4.7] and right ventricular stroke work index was 915 [715-1734] mmHg mL/m2. After a median follow-up of 2.4 years, nine patients had a combined adverse outcome (two had a pericardial effusion, one underwent atrial level shunt, one underwent reverse Pott's shunt, and six died). Patients with an adverse outcome had higher systolic and mean pulmonary artery pressures, higher diastolic and transpulmonary pressure gradients, higher indexed pulmonary vascular resistance, higher pulmonary artery elastance, and higher right ventricular stroke work index (p < 0.05 each). CONCLUSION: Invasive haemodynamics (especially mean pulmonary artery pressure and diastolic pressure gradient) obtained at first cardiac catheterisation in children with pulmonary artery hypertension predicts outcomes.

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Chemoenzymatic Syntheses of Fluorine-18-Labeled Disaccharides from [18F] FDG Yield Potent Sensors of Living Bacteria In Vivo.

Chemoenzymatic techniques have been applied extensively to pharmaceutical development, most effectively when routine synthetic methods fail. The regioselective and stereoselective construction of structurally complex glycans is an elegant application of this approach that is seldom applied to positron emission tomography (PET) tracers. We sought a method to dimerize 2-deoxy-[18F]-fluoro-d-glucose ([18F]FDG), the most common tracer used in clinical imaging, to form [18F]-labeled disaccharides for detecting microorganisms in vivo based on their bacteria-specific glycan incorporation. When [18F]FDG was reacted with ß-d-glucose-1-phosphate in the presence of maltose phosphorylase, the α-1,4- and α-1,3-linked products 2-deoxy-[18F]-fluoro-maltose ([18F]FDM) and 2-deoxy-2-[18F]-fluoro-sakebiose ([18F]FSK) were obtained. This method was further extended with the use of trehalose (α,α-1,1), laminaribiose (ß-1,3), and cellobiose (ß-1,4) phosphorylases to synthesize 2-deoxy-2-[18F]fluoro-trehalose ([18F]FDT), 2-deoxy-2-[18F]fluoro-laminaribiose ([18F]FDL), and 2-deoxy-2-[18F]fluoro-cellobiose ([18F]FDC). We subsequently tested [18F]FDM and [18F]FSK in vitro, showing accumulation by several clinically relevant pathogens including Staphylococcus aureus and Acinetobacter baumannii, and demonstrated their specific uptake in vivo. Both [18F]FDM and [18F]FSK were stable in human serum with high accumulation in preclinical infection models. The synthetic ease and high sensitivity of [18F]FDM and [18F]FSK to S. aureus including methicillin-resistant (MRSA) strains strongly justify clinical translation of these tracers to infected patients. Furthermore, this work suggests that chemoenzymatic radiosyntheses of complex [18F]FDG-derived oligomers will afford a wide array of PET radiotracers for infectious and oncologic applications.

A method for comparing multiple imputation techniques: A case study on the U.S. national COVID cohort collaborative.

Healthcare datasets obtained from Electronic Health Records have proven to be extremely useful for assessing associations between patients' predictors and outcomes of interest. However, these datasets often suffer from missing values in a high proportion of cases, whose removal may introduce severe bias. Several multiple imputation algorithms have been proposed to attempt to recover the missing information under an assumed missingness mechanism. Each algorithm presents strengths and weaknesses, and there is currently no consensus on which multiple imputation algorithm works best in a given scenario. Furthermore, the selection of each algorithm's parameters and data-related modeling choices are also both crucial and challenging. In this paper we propose a novel framework to numerically evaluate strategies for handling missing data in the context of statistical analysis, with a particular focus on multiple imputation techniques. We demonstrate the feasibility of our approach on a large cohort of type-2 diabetes patients provided by the National COVID Cohort Collaborative (N3C) Enclave, where we explored the influence of various patient characteristics on outcomes related to COVID-19. Our analysis included classic multiple imputation techniques as well as simple complete-case Inverse Probability Weighted models. Extensive experiments show that our approach can effectively highlight the most promising and performant missing-data handling strategy for our case study. Moreover, our methodology allowed a better understanding of the behavior of the different models and of how it changed as we modified their parameters. Our method is general and can be applied to different research fields and on datasets containing heterogeneous types.

Language barriers and kidney transplantation in children.

BACKGROUND: Understanding disparities in pediatric kidney transplants is important to provide equitable care. We compared transplant outcomes between English-speaking (ES) and interpreter-needing (IN) pediatric kidney transplant recipients. METHODS: Through retrospective review, primary kidney transplant recipients, 0-21 years transplanted between 2005 and 2019, were divided into ES and IN cohorts. Continuous and categorical variables were compared using Wilcoxon rank-sum, Welch two-sample t-test, and chi-squared analyses. Patient survival, graft survival, and rejection-free survival were evaluated using Kaplan-Meier methods and Cox regression. Days hospitalized were evaluated using negative binomial regression. RESULTS: Our sample included 211 ES and 37 IN transplant recipients. Compared with the ES, the IN cohort was older at transplant (14.56 vs. 11.03 years; p < 0.01), had more time between kidney failure and transplant (0.9 vs. 0.3 years; p < 0.01), and more often received deceased over living donor transplants (78.4% vs. 30.4%; p < 0.01). Multivariate Cox proportional-hazard models evaluating adjusted 5-year patient survival demonstrated decreased 5-year post-transplant survival in the IN cohort (aHR = 10.10, 95% CI: 1.5, 66.8; p = 0.02). We did not identify differences in 5-year death-censored graft survival (aHR = 0.57; 95% CI: 0.14, 2.4; p = 0.4) nor rejection-free survival (aHR = 0.8; 95% CI: 0.4, 1.5; p = 0.5). We found significantly fewer hospitalization events in the IN cohort during the first year post-transplant (aRR: 0.62; 95% CI: 0.4, 0.9; p = 0.01) but no difference 5-year post-transplant. The IN cohort had more missed outpatient appointments (10.4% vs. 2.8%; p = 0.03) and undetectable serum immunosuppressant levels (mean: 3.8% vs. 1.3%; p = 0.02) 5 years post-transplant. CONCLUSIONS: Pediatric kidney transplant recipients requiring interpreter services for healthcare delivery demonstrate fewer post-transplant interactions with their healthcare team (fewer hospitalizations and more no-show visits) and lower 5-year patient survival compared with recipients not requiring interpreters. A higher resolution version of the Graphical abstract is available as Supplementary information.

Prolonged Elevations of Factor VIII and von Willebrand Factor Antigen After Multisystem Inflammatory Syndrome in Children.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a late systemic inflammatory response to a recent mild or asymptomatic coronavirus disease of 2019 infection. The pathophysiology is incompletely understood but it often features significant coagulopathy along with cardiac and endothelial dysfunction. Endothelial inflammation has been primarily described in acute coronavirus disease of 2019 infection, with less characterization in MIS-C. Here we describe novel findings of nearly universal severe and prolonged factor VIII (FVIII) and von Willebrand factor antigen elevations in an institutional cohort of patients with MIS-C ages younger than or 21 years old (N=31). All patients had elevated acute phase reactants and D-dimer at presentation and met published criteria for MIS-C. FVIII was high at presentation in 97% of patients but continued to rise during the ensuing weeks of treatment to a mean 429%, peaking on median day 17 of illness as an outpatient. FVIII levels were >600% in multiple patients. von Willebrand factor antigen was measured less frequently but showed similar trends. These escalations occurred amidst resolving cardiac dysfunction and acute phase reactant normalization and despite patients receiving multimodal anti-inflammatory treatments and aspirin and enoxaparin thromboprophylaxis. No thrombotic events occurred. Endothelial dysfunction represented by very elevated FVIII levels may persist longer than other acute phase reactants may reflect.

Correlation between non-invasive to invasive right-heart data in paediatric heart transplant patients.

BACKGROUND: Paediatric studies have shown serum N-terminal pro b-type natriuretic peptide levels to be a valuable tool in the surveillance of myocardial function and an early biomarker for rejection in transplant patients. The correlation between low mean right atrial pressure and increased inferior vena cava collapsibility index is well studied in adults. Our study aims to assess correlation between non-invasive measurements (serum N-terminal pro b-type natriuretic peptide, inferior vena cava dimensions collapsibility, tricuspid regurgitation, and left ventricular remodelling index to invasive mean right atrial pressure in paediatric heart transplant patients). METHODS: A single centre, retrospective chart review of the paediatric transplant patients from 0 to 21 years of age was performed between 2015 and 2017. Thirty-nine patients had complete data which includes cardiac catheterisation, transthoracic echocardiogram, and serum N-terminal pro b-type natriuretic peptide levels done within a two weeks of interval. RESULTS: A higher inferior vena cava collapsibility index correlated with a lower mean right atrial pressure (r = -0.21, p = 0.04) and a larger inferior vena cava diameter in expiration indexed to body surface area (IVCmax/BSA0.5) correlated with a higher mean right atrial pressure (r = 0.29, p = 0.01). There was a correlation between elevated N-terminal pro b-type natriuretic peptide and inferior vena cava collapsibility index (r = -0.38, p = 0.0001), IVCmax/BSA0.5 (r = 0.25, p = 0.0002), and mean right atrial pressure (r = 0.6, p = 0.0001). CONCLUSION: Serum N-terminal pro b-type natriuretic peptide levels correlated to non-invasive measurements (inferior vena cava collapsibility index and IVCmax/BSA0.5) and to the invasive mean right atrial pressure. Non-invasive (IVC-CI IVCmax/BSA0.5) correlates with elevated mean right atrial pressure in this population. Together, these may serve as a reliable surveillance tool in assessing right heart filling pressures and cardiac function within the paediatric heart transplant patient.

Neuroimaging and biomarker evidence of neurodegeneration in asthma.

BACKGROUND: Epidemiologic studies have shown that Alzheimer's disease (AD) and related dementias (ADRD) are seen more frequently with asthma, especially with greater asthma severity or exacerbation frequency. OBJECTIVE: To examine the changes in brain structure that may underlie this phenomenon, we examined diffusion-weighted magnetic resonance imaging (dMRI) and blood-based biomarkers of AD (phosphorylated tau 181, p-Tau181), neurodegeneration (neurofilament light chain, NfL), and glial activation (glial fibrillary acidic protein, GFAP). METHODS: dMRI data were obtained in 111 individuals with asthma, ranging in disease severity from mild to severe, and 135 healthy controls. Regression analyses were used to test the relationships between asthma severity and neuroimaging measures, as well as AD pathology, neurodegeneration, and glial activation, indexed by plasma p-Tau181, NfL, and GFAP, respectively. Additional relationships were tested with cognitive function. RESULTS: Asthma participants had widespread and large-magnitude differences in several dMRI metrics, which were indicative of neuroinflammation and neurodegeneration, and which were robustly associated with GFAP and, to a lesser extent, NfL. The AD biomarker p-Tau181 was only minimally associated with neuroimaging outcomes. Further, asthma severity was associated with deleterious changes in neuroimaging outcomes, which in turn were associated with slower processing speed, a test of cognitive performance. CONCLUSIONS: Asthma, particularly when severe, is associated with characteristics of neuroinflammation and neurodegeneration, and may be a potential risk factor for neural injury and cognitive dysfunction. There is a need to determine how asthma may affect brain health and whether treatment directed toward characteristics of asthma associated with these risks can mitigate these effects.

Improving modeling of low-altitude particulate matter emission and dispersion: A cotton gin case study.

Monitoring and modeling of airborne particulate matter (PM) from low-altitude sources is becoming an important regulatory target as the adverse health consequences of PM become better understood. However, application of models not specifically designed for simulation of PM from low-altitude emissions may bias predictions. To address this problem, we describe the modification and validation of an air dispersion model for the simulation of low-altitude PM dispersion from a typical cotton ginning facility. We found that the regulatory recommended model (AERMOD) overestimated pollutant concentrations by factors of 64.7, 6.97 and 7.44 on average for PM2.5, PM10, and TSP, respectively. Pollutant concentrations were negatively correlated with height (p < 0.05), distance from source (p < 0.05) and standard deviation of wind direction (p < 0.001), and positively correlated with average wind speed (p < 0.001). Based on these results, we developed dispersion correction factors for AERMOD and cross-validated the revised model against independent observations, reducing overestimation factors to 3.75, 1.52 and 1.44 for PM2.5, PM10 and TSP, respectively. Further reductions in model error may be obtained from use of additional observations and refinement of dispersive correction factors. More generally, the correction permits the validated adjustment and application of pre-existing models for risk assessment and development of remediation techniques. The same approach may also be applied to improve simulations of other air pollutants and environmental conditions of concern.

Health topics emerged from brief-motivational interviewing: A randomized clinical trial.

OBJECTIVE: The goal of this study was to analyse transcription of audio recordings to determine health topics that emerged from brief-motivational interviewing (MI) compared to traditional oral hygiene instructions (OHI). METHODS: Fifty-eight periodontal maintenance patients were randomized to a brief-MI or traditional OHI group for a longitudinal 1-year clinical trial. Both groups received four patient education sessions per their assigned group. Audio recordings were transcribed and coded. The overarching themes and subthemes emerged were quantified and reported as the number of instances per participant. Global scores and behavioural counts were compared across baseline, 4, 8, and 12-month research visits using mixed-effect models. RESULTS: Of the six overarching themes, the brief-MI group evoked more topics toward total health. Oral home care behaviours (15 vs. 10.2) and oral diseases/conditions (3.3 vs. 1.9) were discussed more in the brief-MI group compared to the traditional OHI group. This positive outcome for the average number of times a health topic was discussed in the brief-MI group compared to the traditional OHI group continued for the remaining major themes: lifestyle behaviours (1.0 vs. 0.4), nutrition (2.6 vs. 0.8), emotional/mental health (1.8 vs. 0.8) and general health (1.2 vs. 0.4). CONCLUSION: This study identified that brief-MI was a more successful communication approach to increase discussions of oral home care behaviours, oral diseases/conditions, lifestyle behaviours, nutrition, emotional/mental health and general health compared to traditional OHI in individuals with periodontitis.

Mucus Plugs in Asthma at CT Associated with Regional Ventilation Defects at 3He MRI.

Background Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. Purpose To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 (3He) MRI. Materials and Methods In this secondary analysis of a Health Insurance Portability and Accountability Act-compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized 3He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. Results Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th-75th percentile, 7.3%-38.3%) versus 1.4% (25th-75th percentile, 0.1%-5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th-75th percentile, 7.1%-18.9%) versus 3.1% (25th-75th percentile, 1.1%-4.4%) in those without plugs (P < .001). Conclusion Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.