Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.

Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca2+ uptake properties to support their unique physiological functions.

Upadacitinib Induction and Maintenance Therapy for Crohn's Disease.

BACKGROUND: Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn's disease. METHODS: In two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn's disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn's Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]). RESULTS: A total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib. CONCLUSIONS: Upadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn's disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.).

Making sense of artificial intelligence and large language models-including ChatGPT-in pediatric hematology/oncology.

ChatGPT and other artificial intelligence (AI) systems have captivated the attention of healthcare providers and researchers for their potential to improve care processes and outcomes. While these technologies hold promise to automate processes, increase efficiency, and reduce cognitive burden, their use also carries risks. In this commentary, we review basic concepts of AI, outline some of the capabilities and limitations of currently available tools, discuss current and future applications in pediatric hematology/oncology, and provide an evaluation and implementation framework that can be used by pediatric hematologist/oncologists considering the use of AI in clinical practice.

Coronavirus Disease 2019 mRNA Vaccination Appears Safe in Pediatric Patients With Hypersensitivity to Polyethylene Glycolated Escherichia coli L-asparaginase.

Polyethylene glycol-asparaginase (PEGAsp) is an established component of acute leukemia therapy. Hypersensitivity reactions to PEGAsp occur in 10% to 15% of patients, with polyethylene glycol suggested as the antigenic culprit. As coronavirus disease 2019 (COVID-19) mRNA vaccines contain polyethylene glycol, the safety of administration of these vaccines to patients with prior PEGAsp hypersensitivity has been questioned. Between December 21, 2020 and March 3, 2022, 66 patients with acute leukemia and PEGAsp allergy received COVID-19 vaccination. No patients (0/66 0%, 95% CI: 0%-5.4%) experienced an allergic reaction to the vaccine. COVID-19 mRNA vaccination appears to be safe in pediatric and young adult patients with acute lymphoblastic leukemia with PEGAsp allergy.

Upadacitinib Therapy Reduces Ulcerative Colitis Symptoms as Early as Day 1 of Induction Treatment.

BACKGROUND & AIMS: We evaluated the efficacy of once-daily (QD) upadacitinib 45 mg, an oral, reversible Janus kinase inhibitor, on early symptomatic improvement for ulcerative colitis (UC). Post hoc analyses were performed on pooled data from 2 replicate, phase 3, multicenter induction trials, U-ACHIEVE Induction and U-ACCOMPLISH, to determine the earliest time point of efficacy onset. METHODS: Diary entry data through 14 days from the first dose of placebo or upadacitinib 45 mg QD were analyzed for daily improvement in UC symptoms (stool frequency, rectal bleeding, abdominal pain, and bowel urgency). Changes in inflammatory markers, high-sensitivity C-reactive protein (hs-CRP), and fecal calprotectin (FCP) were assessed at week 2 and quality of life (QoL) at weeks 2 and 8. Regression analysis determined the association between changes in UC symptoms and the likelihood of achieving clinical remission/response per Adapted Mayo score at week 8. RESULTS: Overall, 988 patients (n = 328 placebo, n = 660 upadacitinib) were analyzed. Patients treated with upadacitinib demonstrated significant improvements vs placebo in all UC symptoms between days 1 and 3 and maintained through day 14. A >50% reduction from baseline in hs-CRP and FCP levels was achieved by 75.7% and 48.2% of patients, respectively (P < .001 vs placebo). Increased rates of clinical remission/response per Partial Mayo score from week 2 (26.9%/59.4% upadacitinib 45 mg QD vs 4.3%/22.3% placebo, P < .001) and significant improvements in QoL at weeks 2 and 8 were observed. Early improvement in stool frequency and bowel urgency by day 3 and reductions in hs-CRP and FCP by week 2 were significantly associated with clinical remission/response at week 8. CONCLUSIONS: Upadacitinib 45 mg QD provided rapid relief of UC symptoms from day 1. CLINICALTRIALS: gov: U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026).

Data standards in pediatric oncology: Past, present, and future.

In this commentary, we highlight the central role that data standards play in facilitating data-driven efforts to advance research in pediatric oncology. We discuss the current state of data standards for pediatric oncology and propose five steps to achieve an improved future state with benefits for clinicians, researchers, and patients.

Implementation science in pediatric oncology: A narrative review and future directions.

Implementation science (IS) has garnered attention within oncology, and most prior IS work has focused on adult, not pediatric, oncology. This narrative review broadly characterizes IS for pediatric oncology. It includes studies through 2020 using the following search terms in PubMed, Ovid Medline, and Cochrane: "implementation science," "pediatric," "childhood," "cancer," and "oncology." Systematic review was not performed due to the limited number of heterogeneous studies. Of 216 articles initially reviewed, nine were selected as specific to IS and pediatric oncology. All nine examined oncologic supportive care, cancer prevention, or cancer control. The supportive care focus is potentially due to the presence of cooperative study groups such as the Children's Oncology Group, which efficiently drive cancer-directed therapy changes through clinical trials. Future IS within pediatric oncology should embrace this ecosystem and focus on cancer control interventions that benefit patients across multiple cancer types and patients treated outside cooperative group studies.

Evaluation of an automated pediatric malnutrition screen using anthropometric measurements in the electronic health record: a quality improvement initiative.

PURPOSE: Malnutrition related to undernutrition in pediatric oncology patients is associated with worse outcomes including increased morbidity and mortality. At a tertiary pediatric center, traditional malnutrition screening practices were ineffective at identifying cancer patients at risk for undernutrition and needing nutrition consultation. METHODS: To efficiently identify undernourished patients, an automated malnutrition screen using anthropometric data in the electronic health record (EHR) was implemented. The screen utilized pediatric malnutrition (undernutrition) indicators from the 2014 Consensus Statement of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition with corresponding structured EHR elements. The time periods before (January 2016-August 2017) and after (September 2017-August 2018) screen implementation were compared. Process metrics including nutrition consults, timeliness of nutrition assessments, and malnutrition diagnoses documentation were assessed using statistical process control charts. Outcome metrics including change in nutritional status at least 3 months after positive malnutrition screen were assessed with the Cochran-Armitage trend test. RESULTS: After automated malnutrition screen implementation, all process metrics demonstrated center line shifts indicating special cause variation. For patient admissions with a positive screen for malnutrition of any severity level, no significant improvement in status of malnutrition was observed after 3 months (P = .13). Sub-analysis of patient admissions with screen-identified severe malnutrition noted improvement in degree of malnutrition after 3 months (P = .02). CONCLUSIONS: Select 2014 Consensus Statement indicators for pediatric malnutrition can be implemented as an automated screen using structured EHR data. The automated screen efficiently identifies oncology patients at risk of malnutrition and may improve clinical outcomes.

Proteolytic control of the mitochondrial calcium uniporter complex.

The mitochondrial calcium uniporter is a Ca2+-activated Ca2+ channel complex mediating mitochondrial Ca2+ uptake, a process crucial for Ca2+ signaling, bioenergetics, and cell death. The uniporter is composed of the pore-forming MCU protein, the gatekeeping MICU1 and MICU2 subunits, and EMRE, a single-pass membrane protein that links MCU and MICU1 together. As a bridging subunit required for channel function, EMRE could paradoxically inhibit uniporter complex formation if expressed in excess. Here, we show that mitochondrial mAAA proteases AFG3L2 and SPG7 rapidly degrade unassembled EMRE using the energy of ATP hydrolysis. Once EMRE is incorporated into the complex, its turnover is inhibited >15-fold. Protease-resistant EMRE mutants produce uniporter subcomplexes that induce constitutive Ca2+ leakage into mitochondria, a condition linked to debilitating neuromuscular disorders in humans. The results highlight the dynamic nature of uniporter subunit assembly, which must be tightly regulated to ensure proper mitochondrial responses to intracellular Ca2+ signals.

A robustness metric for biological data clustering algorithms.

BACKGROUND: Cluster analysis is a core task in modern data-centric computation. Algorithmic choice is driven by factors such as data size and heterogeneity, the similarity measures employed, and the type of clusters sought. Familiarity and mere preference often play a significant role as well. Comparisons between clustering algorithms tend to focus on cluster quality. Such comparisons are complicated by the fact that algorithms often have multiple settings that can affect the clusters produced. Such a setting may represent, for example, a preset variable, a parameter of interest, or various sorts of initial assignments. A question of interest then is this: to what degree do the clusters produced vary as setting values change? RESULTS: This work introduces a new metric, termed simply "robustness", designed to answer that question. Robustness is an easily-interpretable measure of the propensity of a clustering algorithm to maintain output coherence over a range of settings. The robustness of eleven popular clustering algorithms is evaluated over some two dozen publicly available mRNA expression microarray datasets. Given their straightforwardness and predictability, hierarchical methods generally exhibited the highest robustness on most datasets. Of the more complex strategies, the paraclique algorithm yielded consistently higher robustness than other algorithms tested, approaching and even surpassing hierarchical methods on several datasets. Other techniques exhibited mixed robustness, with no clear distinction between them. CONCLUSIONS: Robustness provides a simple and intuitive measure of the stability and predictability of a clustering algorithm. It can be a useful tool to aid both in algorithm selection and in deciding how much effort to devote to parameter tuning.

Health-related Google searches performed by parents of pediatric oncology patients.

BACKGROUND: Little is known about the specific information parents of children with cancer search for online. Understanding the content of parents' searches over time could offer insight into what matters most to parents and identify knowledge gaps that could inform more comprehensive approaches to family education and support. METHODS: We describe parents' health-related Google searches starting six months before cancer diagnosis and extending through the date of study enrollment, which was at least one month after initiating cancer treatment. Searches were obtained retrospectively and grouped into health-related and non-health-related categories. The median time to parent enrollment from date of cancer diagnosis was 264 days. RESULTS: Parents searched for health-related topics more frequently than the general population (13% vs 5%). Health-related searches increased in the months preceding the child's cancer diagnosis and most commonly pertained to symptoms and logistics, "directions to hospital." Health-related search volume peaked about a month after cancer diagnosis when general health-related searches were present in addition to cancer-specific searches. Eighteen percent of health-related searches were cancer specific, and of these cancer-specific searches, 54% pertained to support, for example "cancer quote for son." CONCLUSIONS: Google search content offers insight into what matters to parents of cancer patients. Understanding search content could inform more comprehensive approaches to family education and support initiatives.

Development and evaluation of a computable phenotype to identify pediatric patients with leukemia and lymphoma treated with chemotherapy using electronic health record data.

BACKGROUND: Widespread implementation of electronic health records (EHR) has created new opportunities for pediatric oncology observational research. Little attention has been given to using EHR data to identify patients with pediatric hematologic malignancies. METHODS: This study used EHR-derived data in a pediatric clinical data research network, PEDSnet, to develop and evaluate a computable phenotype algorithm to identify pediatric patients with leukemia and lymphoma who received treatment with chemotherapy. To guide early development, multiple computable phenotype-defined cohorts were compared to one institution's tumor registry. The most promising algorithm was chosen for formal evaluation and consisted of at least two leukemia/lymphoma diagnoses (Systematized Nomenclature of Medicine codes) within a 90-day period, two chemotherapy exposures, and three hematology-oncology provider encounters. During evaluation, the computable phenotype was executed against EHR data from 2011 to 2016 at three large institutions. Classification accuracy was assessed by masked medical record review with phenotype-identified patients compared to a control group with at least three hematology-oncology encounters. RESULTS: The computable phenotype had sensitivity of 100% (confidence interval [CI] 99%, 100%), specificity of 99% (CI 99%, 100%), positive predictive value (PPV) and negative predictive value (NPV) of 100%, and C-statistic of 1 at the development institution. The computable phenotype performance was similar at the two test institutions with sensitivity of 100% (CI 99%, 100%), specificity of 99% (CI 99%, 100%), PPV of 96%, NPV of 100%, and C-statistic of 0.99. CONCLUSION: The EHR-based computable phenotype is an accurate cohort identification tool for pediatric patients with leukemia and lymphoma who have been treated with chemotherapy and is ready for use in clinical studies.

Relationship Between State-Level Google Online Search Volume and Cancer Incidence in the United States: Retrospective Study.

BACKGROUND: In the United States, cancer is common, with high morbidity and mortality; cancer incidence varies between states. Online searches reflect public awareness, which could be driven by the underlying regional cancer epidemiology. OBJECTIVE: The objective of our study was to characterize the relationship between cancer incidence and online Google search volumes in the United States for 6 common cancers. A secondary objective was to evaluate the association of search activity with cancer-related public events and celebrity news coverage. METHODS: We performed a population-based, retrospective study of state-level cancer incidence from 2004 through 2013 reported by the Centers for Disease Control and Prevention for breast, prostate, colon, lung, and uterine cancers and leukemia compared to Google Trends (GT) relative search volume (RSV), a metric designed by Google to allow interest in search topics to be compared between regions. Participants included persons in the United States who searched for cancer terms on Google. The primary measures were the correlation between annual state-level cancer incidence and RSV as determined by Spearman correlation and linear regression with RSV and year as independent variables and cancer incidence as the dependent variable. Temporal associations between search activity and events raising public awareness such as cancer awareness months and cancer-related celebrity news were described. RESULTS: At the state level, RSV was significantly correlated to incidence for breast (r=.18, P=.001), prostate (r=-.27, P<.001), lung (r=.33, P<.001), and uterine cancers (r=.39, P<.001) and leukemia (r=.13, P=.003) but not colon cancer (r=-.02, P=.66). After adjusting for time, state-level RSV was positively correlated to cancer incidence for all cancers: breast (P<.001, 95% CI 0.06 to 0.19), prostate (P=.38, 95% CI -0.08 to 0.22), lung (P<.001, 95% CI 0.33 to 0.46), colon (P<.001, 95% CI 0.11 to 0.17), and uterine cancers (P<.001, 95% CI 0.07 to 0.12) and leukemia (P<.001, 95% CI 0.01 to 0.03). Temporal associations in GT were noted with breast cancer awareness month but not with other cancer awareness months and celebrity events. CONCLUSIONS: Cancer incidence is correlated with online search volume at the state level. Search patterns were temporally associated with cancer awareness months and celebrity announcements. Online searches reflect public awareness. Advancing understanding of online search patterns could augment traditional epidemiologic surveillance, provide opportunities for targeted patient engagement, and allow public information campaigns to be evaluated in ways previously unable to be measured.

RARα/RXR synergism potentiates retinoid responsiveness in cutaneous T-cell lymphoma cell lines.

Retinoids, natural and synthetic derivatives of vitamin A, induce cellular changes by activating nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). Although the ability of retinoids to govern gene expression is exploited clinically for cancer therapeutics, the full benefit of retinoid-based strategies is unrealized due to detrimental side effects. Delineating the receptors that prompt cellular outcomes is critical to advancing retinoid-based approaches. Here, we identify the receptors that evoke multiple responses in cutaneous T-cell lymphoma (CTCL). The data demonstrate that RARα drives integrin ß7-dependent adhesion and CCR9-mediated chemotaxis in CTCL cells. Of note, concomitant activation of RARα and RXR nuclear receptors yielded synergistic increases in adhesion and migration at concentrations where single agents were ineffective. As the established paradigm of retinoid action in CTCL is apoptosis and growth arrest, the role of RARα/RXR in these events was studied. As with adhesion and migration, RARα/RXR synergism prompted apoptosis and dampened CTCL cell proliferation. Strikingly, RARα/RXR synergism induced responses from CTCL cell lines previously reported to be unresponsive to retinoids. These data provide a novel framework that may further refine a proven CTCL therapy.

I Do Not Like Green Eggs.

Shells of pinworm ova contain chitin, which stains bright green when exposed to chlorazol black E. The objective was to determine whether chlorazol black E could assist in identification of pinworm ova from skin scrapings. Skin scrapings were stained using chlorazol black E and pinworm ova were more easily recognized, staining a blue-green color.

CbGRiTS: cerebellar gene regulation in time and space.

The mammalian CNS is one of the most complex biological systems to understand at the molecular level. The temporal information from time series transcriptome analysis can serve as a potent source of associative information between developmental processes and regulatory genes. Here, we introduce a new transcriptome database called, Cerebellar Gene Regulation in Time and Space (CbGRiTS). This dataset is populated with transcriptome data across embryonic and postnatal development from two standard mouse strains, C57BL/6J and DBA/2J, several recombinant inbred lines and cerebellar mutant strains. Users can evaluate expression profiles across cerebellar development in a deep time series with graphical interfaces for data exploration and link-out to anatomical expression databases. We present three analytical approaches that take advantage of specific aspects of the time series for transcriptome analysis. We demonstrate the use of CbGRiTS dataset as a community resource to explore patterns of gene expression and develop hypotheses concerning gene regulatory networks in brain development.

Electrical impedance tomography (EIT) for quantification of pulmonary edema in acute lung injury.

BACKGROUND: Assessment of pulmonary edema is a key factor in monitoring and guidance of therapy in critically ill patients. To date, methods available at the bedside for estimating the physiologic correlate of pulmonary edema, extravascular lung water, often are unreliable or require invasive measurements. The aim of the present study was to develop a novel approach to reliably assess extravascular lung water by making use of the functional imaging capabilities of electrical impedance tomography. METHODS: Thirty domestic pigs were anesthetized and randomized to three different groups. Group 1 was a sham group with no lung injury. Group 2 had acute lung injury induced by saline lavage. Group 3 had vascular lung injury induced by intravenous injection of oleic acid. A novel, noninvasive technique using changes in thoracic electrical impedance with lateral body rotation was used to measure a new metric, the lung water ratioEIT, which reflects total extravascular lung water. The lung water ratioEIT was compared with postmortem gravimetric lung water analysis and transcardiopulmonary thermodilution measurements. RESULTS: A significant correlation was found between extravascular lung water as measured by postmortem gravimetric analysis and electrical impedance tomography (r = 0.80; p < 0.05). Significant changes after lung injury were found in groups 2 and 3 in extravascular lung water derived from transcardiopulmonary thermodilution as well as in measurements derived by lung water ratioEIT. CONCLUSIONS: Extravascular lung water could be determined noninvasively by assessing characteristic changes observed on electrical impedance tomograms during lateral body rotation. The novel lung water ratioEIT holds promise to become a noninvasive bedside measure of pulmonary edema.

Impact of a decision-making aid for suspected urinary tract infections on antibiotic overuse in nursing homes.

BACKGROUND: Antibiotics are highly utilized in nursing homes. The aim of the study was to test the effectiveness of a decision-making aid for urinary tract infection management on reducing antibiotic prescriptions for suspected bacteriuria in the urine without symptoms, known as asymptomatic bacteriuria (ASB) in twelve nursing homes in Texas. METHOD: A pre- and post-test with comparison group design was used. The data was collected through retrospective chart review. The study sample included 669 antibiotic prescriptions for suspected urinary tract infections ordered for 547 nursing home residents. The main measurement for the outcome variable was whether an antibiotic was prescribed for suspected urinary tract infections with no symptoms present. RESULTS: Most of the prescriptions for antibiotics UTIs were written without documented symptoms - thus for asymptomatic bacteuria (ASB) (71 % during the pre-intervention period). Exposure to the decision-making aid decreased the number of prescriptions written for ASB (from 78 % to 65 % in the low-intensity homes and from 65 % to 57 % in the high-intensity homes), and decreased odds of a prescription being written for ASB (OR = 0.63, 95 % CI = 0.25 - 1.60 for low-intensity homes; OR = 0.79, 95 % CI = 0.33 - 1.88 for high-intensity homes). The odds of a prescription being written for ASB decreased significantly in homes that succeeded in implementing the decision-making aid (OR = 0.35, 95 % CI = 0.16-0.76), compared to homes with no fidelity. CONCLUSIONS: The decision-making aid improved antibiotic stewardship in nursing homes.

A 10-year review of outpatient skin biopsy results and skin cancer subtypes.

The results of skin biopsies over a 10 year period were reviewed from the outpatient dermatology clinic at the Brody School of Medicine in Greenville, North Carolina. This research was conducted because there are very few studies that characterize this information over a long-term horizon. The biopsy rate per patient encounter, the clinical reason for the biopsy, the biopsy outcomes, the distribution of cutaneous malignancies per encounter, and the distribution of the subtypes of basal cell carcinoma, squamous cell carcinoma, and melanoma were analyzed. Biopsy logs from January 1, 2001 to December 31, 2010 were reviewed. Our investigation found that 20% of patient encounters resulted in a biopsy. Of these biopsies, 87.9% were performed to rule out malignancy and 12.1% were completed on patients suspected of having inflammatory skin conditions. The basal cell carcinomas diagnosed in Greenville, NC have more aggressive histologic subtypes compared to other studies, whereas the squamous cell carcinomas and melanomas were less aggressive.