Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders.

PURPOSE: Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs. METHODS: We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect changes in these HRQoL measures. RESULTS: Individuals with UCDs demonstrated worse physical and psychosocial HRQoL than their healthy peers and peers with PKU and diabetes. In children, HRQoL scores did not differ by diagnosis or severity. In adults, individuals with decreased severity had worse psychosocial HRQoL. Finally, we show that a large number of individuals would be required in clinical trials to detect differences in HRQoL in UCDs. CONCLUSION: Individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.

Networks Underlie Temporal Onset of Dysplasia-Related Epilepsy: A MELD Study.

OBJECTIVE: The purpose of this study was to evaluate if focal cortical dysplasia (FCD) co-localization to cortical functional networks is associated with the temporal distribution of epilepsy onset in FCD. METHODS: International (20 center), retrospective cohort from the Multi-Centre Epilepsy Lesion Detection (MELD) project. Patients included if >3 years old, had 3D pre-operative T1 magnetic resonance imaging (MRI; 1.5 or 3 T) with radiologic or histopathologic FCD after surgery. Images processed using the MELD protocol, masked with 3D regions-of-interest (ROI), and co-registered to fsaverage_sym (symmetric template). FCDs were then co-localized to 1 of 7 distributed functional cortical networks. Negative binomial regression evaluated effect of FCD size, network, histology, and sulcal depth on age of epilepsy onset. From this model, predictive age of epilepsy onset was calculated for each network. RESULTS: Three hundred eighty-eight patients had median age seizure onset 5 years (interquartile range [IQR] = 3-11 years), median age at pre-operative scan 18 years (IQR = 11-28 years). FCDs co-localized to the following networks: limbic (90), default mode (87), somatomotor (65), front parietal control (52), ventral attention (32), dorsal attention (31), and visual (31). Larger lesions were associated with younger age of onset (p = 0.01); age of epilepsy onset was associated with dominant network (p = 0.04) but not sulcal depth or histology. Sensorimotor networks had youngest onset; the limbic network had oldest age of onset (p values <0.05). INTERPRETATION: FCD co-localization to distributed functional cortical networks is associated with age of epilepsy onset: sensory neural networks (somatomotor and visual) with earlier onset, and limbic latest onset. These variations may reflect developmental differences in synaptic/white matter maturation or network activation and may provide a biological basis for age-dependent epilepsy onset expression. ANN NEUROL 2022;92:503-511.

Focal to bilateral tonic-clonic seizures predict pharmacoresistance in focal cortical dysplasia-related epilepsy.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common etiology of surgically-remediable epilepsy in children. Eighty-seven percent of patients with FCD develop epilepsy (75% is pharmacoresistant epilepsy [PRE]). Focal to bilateral tonic-clonic (FTBTC) seizures are associated with worse surgical outcomes. We hypothesized that children with FCD-related epilepsy with FTBTC seizures are more likely to develop PRE due to lesion interaction with restricted cortical neural networks. METHODS: Patients were selected retrospectively from radiology and surgical databases from Children's National Hospital. INCLUSION CRITERIA: 3T magnetic resonance imaging (MRI)-confirmed FCD from January 2011 to January 2020; ages 0 days to 22 years at MRI; and 18 months of documented follow-up. FCD dominant network (Yeo 7-network parcellation) was determined. Association of FTBTC seizures with epilepsy severity, surgical outcome, and dominant network was tested. Binomial regression was used to evaluate predictors (FTBTC seizures, age at seizure onset, pathology, hemisphere, lobe) of pharmacoresistance and Engel outcome. Regression was used to evaluate predictors (age at seizure onset, pathology, lobe, percentage default mode network [DMN] overlap) of FTBTC seizures. RESULTS: One hundred seventeen patients had a median age at seizure onset of 3.00 years (interquartile range [IQR] .42-5.59 years). Eighty-three patients had PRE (71%); 34 had pharmacosensitive epilepsy (PSE) (29%). Twenty patients (17%) had FTBTC seizures. Seventy-three patients underwent epilepsy surgery. Multivariate regression showed that FTBTC seizures are associated with an increased risk of PRE (odds ratio [OR] 6.41, 95% confidence interval [CI] 1.21-33.98, p = .02). FCD hemisphere/lobe was not associated with PRE. Percentage DMN overlap predicts FTBTC seizures. Seventy-two percent (n = 52) overall and 53% (n = 9) of patients with FTBTC seizures achieved Engel class I outcome. SIGNIFICANCE: In a heterogeneous population of surgical and non-operated patients with FCD-related epilepsy, the presence of FTBTC seizures is associated with a tremendous risk of PRE. This finding is a recognizable marker to help neurologists identify those children with FCD-related epilepsy at high risk of PRE and can flag patients for earlier consideration of potentially curative surgery. The FCD-dominant network also contributes to FTBTC seizure clinical expression.

Preschool neurodevelopment in Zika virus-exposed children without congenital Zika syndrome.

BACKGROUND: Children with in utero Zika virus (ZIKV) exposure without congenital Zika syndrome (CZS) are at risk for abnormal neurodevelopment. Preschool-age outcomes for children with antenatal ZIKV exposure have not yet been established. METHODS: Children with in utero ZIKV exposure and non-exposed controls had neurodevelopmental evaluations at age 3-5 years in Sabanalarga, Colombia. Cases did not have CZS and were previously evaluated prenatally through age 18 months. Controls were born before ZIKV arrival to Colombia. Neurodevelopmental assessments included Pediatric Evaluation of Disability Inventory (PEDI-CAT), Behavior Rating Inventory of Executive Function (BRIEF-P), Bracken School Readiness Assessment (BSRA), and Movement Assessment Battery for Children (MABC). Family demographics and child medical history were recorded. RESULTS: Fifty-five ZIKV-exposed children were evaluated at mean age 3.6 years and 70 controls were evaluated at 5.2 years. Family demographics were similar between groups. BRIEF-P t-scores were higher for cases than controls in shift and flexibility domains. Cases had lower PEDI-CAT mobility t-scores compared to controls. There was no difference in MABC between groups. In 11% of cases and 1% of controls, parents reported child mood problems. CONCLUSIONS: Children with in utero ZIKV exposure without CZS may demonstrate emerging differences in executive function, mood, and adaptive mobility that require continued evaluation. IMPACT: Preschool neurodevelopmental outcome in children with in utero Zika virus exposure is not yet known, since the Zika virus epidemic occurred in 2015-2017 and these children are only now entering school age. This study finds that Colombian children with in utero Zika virus exposure without congenital Zika syndrome are overall developing well but may have emerging differences in executive function, behavior and mood, and adaptive mobility compared to children without in utero Zika virus exposure. Children with in utero Zika virus exposure require continued multi-domain longitudinal neurodevelopmental evaluation through school age.

Telemedicine in sickle cell disease: Patient, parent, and provider perspectives.

INTRODUCTION: Patients with sickle cell disease (SCD) need frequent health maintenance visits and may face barriers accessing care. Telemedicine, during COVID pandemic, has provided a unique model of care to improve access; however, potential barriers and satisfaction with its use in SCD have not been fully evaluated. OBJECTIVE: To determine caregiver, patient, and healthcare provider (HCP) perspectives and satisfaction with telemedicine in healthcare delivery. METHODS: We surveyed patients with SCD, caregivers, and HCP, who participated in at least one telemedicine visit from March 2020 to June 2021, using the Telemedicine Usability Questionnaire (TUQ). We also accessed and compared the Press Ganey surveys completed by families who completed a telemedicine or in-person visit. Data were summarized using descriptive statistics. The internal reliability of TUQ was assessed using Cronbach's coefficient alpha. Press Ganey data comparing satisfaction with telemedicine versus in-person visits were analyzed by Mann-Whiney U test. RESULTS: Fifty-two patients/caregivers and 10 HCP completed the survey. Patients/caregivers rated satisfaction "excellent" in the five areas (Usefulness, Ease of use, Effectiveness, Reliability and Satisfaction). HCP rated Usefulness, Ease of use, Effectiveness, Satisfaction as "good," and Reliability as "excellent." Press Ganey scores for satisfaction with care for telemedicine and in-person visits were not statistically different (p > .05). DISCUSSION: We found high satisfaction for caregivers and patients as well as HCP in the delivery of clinical services via telemedicine for SCD. We suggest that telemedicine is a viable option for this population and may help overcome the barriers SCD families often face accessing care.

Positive and negative effects of the COVID-19 pandemic on families of young children in rural Colombia and implications for child outcome research.

BACKGROUND: The COVID-19 pandemic has impacted the lives of children and families worldwide. The objective of this study is to examine exposures and impact of the COVID-19 pandemic on preschool-aged children and caregivers in the Atlántico region of Colombia. METHODS: The COVID-19 Exposure and Family Impact Scales (CEFIS) questionnaire was administered in Fall 2021 to 63 caregivers of children in Sabanalarga, Colombia enrolled in a neurodevelopment study as healthy controls. The CEFIS assesses pandemic-related exposures/events and impact; higher scores indicate greater exposure and negative impact. Descriptive and correlation analyses among exposure and impact scores were conducted. RESULTS: Caregivers reported a mean (standard deviation[SD]) of 11.1 (3.2) among 25 COVID-19-related exposures/events; most common types included stay-at-home orders, school closures, disruptions to living conditions and income loss. Total number of events was correlated with higher caregiver (P < .001) and child distress (P = .002). However, the mean (SD) impact score of 2.0 (0.6) suggests a trend toward more positive impact than negative. Caregivers reported improvements to sleep, exercise and family interactions. Some caregivers (n = 21) qualitatively reported negative effects including unemployment, fear/anxiety and inability to visit family, and positive effects such as unification, family closeness and spending more time with children. CONCLUSIONS: This study highlights the importance of comprehensively exploring positive and negative impacts of COVID-19 and families' subsequent resilience and transformation. Using tools like the CEFIS, those seeking to mitigate negative impacts can contextualize data to better understand study outcomes and tailor services, resources and policy to families' unique needs. CEFIS data likely depend on timing, economic/public health resources and cultural values; future work should prioritize understanding the generalizability of CEFIS findings across samples.

Cerebral Sinus Venous Thrombosis in Infants after Surgery for Congenital Heart Disease.

OBJECTIVE: To determine the prevalence of and risk factors for cerebral sinus venous thrombosis (CSVT) in neonates undergoing congenital heart disease (CHD) repair. STUDY DESIGN: Neonates who had CHD repair with cardiopulmonary bypass and postoperative brain magnetic resonance imaging (MRI) between 2013 and 2019 at a single tertiary care center were identified from institutional databases. Demographic, clinical, and surgical data were abstracted from these databases and from the medical record; 278 neonates with CHD had cardiopulmonary bypass, 184 of whom had a postoperative brain MRI. RESULTS: Eight patients (4.3%) had a CSVT. Transposition of the great arteries with an intact ventricular septum (P < .01) and interrupted aortic arch (P = .02) were associated with an increased risk for CSVT. Other risk factors for CSVT included cross-clamp time (98 [IQR, 77.5-120] minutes vs 67 [IQR, 44-102] minutes; P = .03), units of platelets (3.63 [IQR, 3-4] vs 2.17 [IQR, 1-4]; P < .01) and packed red blood cells (0.81 [IQR, 0.25-1] vs 1.21 [IQR, 1-1]; P = .03) transfused intraoperatively, and time between surgery and MRI (10 [IQR, 7-12.5] days vs 20 [IQR, 12-35] days; P < .01). Five patients (62.5%) were treated with anticoagulation. All patients had complete or partial resolution of their CSVT, regardless of treatment. CONCLUSIONS: Brain MRI after cardiopulmonary bypass in neonates revealed a low prevalence of CSVT (4.3%). Further studies are needed to establish best practices for surveillance, prevention, and treatment of CSVT in this population.

National Characteristics of Non-Transported Children by Emergency Medical Services in the United States.

Study Objective: Most 911 calls result in ambulance transport to an emergency department. In some cases, transport is refused or deemed unnecessary. The frequency of pediatric non-transport is unknown. Our primary objective was to describe the proportion of pediatric EMS activations resulting in non-transport. Our secondary objective was to identify patient, community, and EMS agency factors associated with pediatric non-transport.Methods: We conducted a cross-sectional study using 2019 data from the National EMS Information System registry. We compared non-transport rates for children (<18 y/o), adults (18 - 60 y/o) and elderly (>60 y/o) patients. We then used generalized estimating equations to identify factors associated with pediatric non-transport while accounting for geographical clustering.Results: There were 21,931,490 EMS activations, including 1,403,454 pediatric 911 responses. 30% of pediatric 911 responses resulted in non-transport. Non-transport was less likely for adults (19%, OR 0.54 [0.54, 0.55]) and elderly patients (13%, OR 0.35 [0.35, 0.36]). The most common pediatric non-transport dispositions were: refused evaluation/care, and treated/released. Non-transport was associated with: pulmonary (aOR 3.84 [3.30, 4.48]) and musculoskeletal chief complaints (aOR 3.75 [3.22, 4.36]). Non-transport was more likely for: rural EMS calls (aOR 1.28 [1.24, 1.32]); calls classified by EMS as Lower Acuity (aOR 7.88 [5.98, 10.38]); and Tribal EMS agencies (aOR 3.49 [3.09, 3.94]).Conclusion: Almost one-third of pediatric 911 activations result in non-transport. Although very few children have been included in pilots of alternate transport processes to date, non-transport is actually more common in children than adults. More work is needed to understand better the patient safety and economic implications of this practice.

Incidence and predictors of epilepsy in children with congenital heart disease.

OBJECTIVE: Children with CHD may be at increased risk for epilepsy. While the incidence of perioperative seizures after surgical repair of CHD has been well-described, the incidence of epilepsy is less well-defined. We aim to determine the incidence and predictors of epilepsy in patients with CHD. METHODS: Retrospective cohort study of patients with CHD who underwent cardiopulmonary bypass at <2 years of age between January, 2012 and December, 2013 and had at least 2 years of follow-up. Clinical variables were extracted from a cardiac surgery database and hospital records. Seizures were defined as acute if they occurred within 7 days after an inciting event. Epilepsy was defined based on the International League Against Epilepsy criteria. RESULTS: Two-hundred and twenty-one patients were identified, 157 of whom were included in our analysis. Five patients (3.2%) developed epilepsy. Acute seizures occurred in 12 (7.7%) patients, only one of whom developed epilepsy. Predictors of epilepsy included an earlier gestational age, a lower birth weight, a greater number of cardiac surgeries, a need for extracorporeal membrane oxygenation or a left ventricular assist device, arterial ischaemic stroke, and a longer hospital length of stay. CONCLUSIONS: Epilepsy in children with CHD is rare. The mechanism of epileptogenesis in these patients may be the result of a complex interaction of patient-specific factors, some of which may be present even before surgery. Larger long-term follow-up studies are needed to identify risk factors associated with epilepsy in these patients.

TNK2 promoted esophageal cancer progression via activating egfr-akt signaling.

BACKGROUND: This study investigated the clinical implication of TNK2 expression in esophageal cancer patients' cancer tissue samples. METHODS: The expression of TNK2 in esophageal cancer tissues and para-carcinoma tissue was assessed with immunohistochemistry and Western blot analysis; besides, the proteins of CDC42, EGFR, and Akt were also analyzed. Then, Kaplan-Meier survival curves of TNK2 protein expression level were assayed with 184 esophageal cancer patients from TCGA database. Moreover, with multiple linear regression analysis, we detected the correlations of TNK2 expression associated with tumor differentiation degree and metastasis status. RESULTS: It revealed that TNK2 was highly expressed in the cytoplasm of esophageal cancer tissues compared with para-carcinoma tissue; besides, the proteins of CDC42, EGFR, and Akt were also up-regulated in different levels of esophageal cancer tissues. However, there was no significant difference of the overall survival time of TNK2 protein expression in 184 esophageal cancer patients from TCGA database (p = 0.37). But, in the included study samples of our study, there was positive coefficience between TNK2 protein expression and differentiation degree in esophageal cancer with multiple linear regression analysis [R = 0.928, 95% confidence interval (0.085-0.12)]. CONCLUSION: Our results indicated that TNK2 was a potential diagnostic marker and promoted esophageal cancer progression through activating EGFR-AKT signaling.

Association of temperature management strategy with fever in critically ill children after out-of-hospital cardiac arrest.

Objective: To determine whether ICU temperature management strategy is associated with fever in children with return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA). Methods: We conducted a single-center retrospective cohort study at a quaternary Children's hospital between 1/1/2016-31/12/2020. Mechanically ventilated children (<18 y/o) admitted to Pediatric or Cardiac ICU (PICU/CICU) with ROSC after OHCA who survived at least 72 h were included. Primary exposure was initial PICU/CICU temperature management strategy of: (1) passive management; or (2) warming with an air-warming blanket; or (3) targeted temperature management with a heating/cooling (homeothermic) blanket. Primary outcome was fever (≥38°C) within 72 h of admission. Results: Over the study period, 111 children with ROSC after OHCA were admitted to PICU/CICU, received mechanical ventilation and survived at least 72 h. Median age was 31 (IQR 6-135) months, 64% (71/111) were male, and 49% (54/111) were previously healthy. Fever within 72 h of admission occurred in 51% (57/111) of patients. The choice of initial temperature management strategy was associated with occurrence of fever (χ2 = 9.36, df = 2, p = 0.009). Fever occurred in 60% (43/72) of patients managed passively, 45% (13/29) of patients managed with the air-warming blanket and 10% (1/10) of patients managed with the homeothermic blanket. Compared to passive management, use of homeothermic, but not of air-warming, blanket reduced fever risk [homeothermic: Risk Ratio (RR) = 0.17, 95%CI 0.03-0.69; air-warming: RR = 0.75, 95%CI 0.46-1.12]. To prevent fever in one child using a homeothermic blanket, number needed to treat (NNT) = 2. Conclusion: In critically ill children with ROSC after OHCA, ICU temperature management strategy is associated with fever. Use of a heating/cooling blanket with homeothermic feedback reduces fever incidence during post-arrest care.

Use of Evidence-Based Vital Signs in Pediatric Early Warning Score to Predict Clinical Deterioration on Acute Care Units.

The pediatric early warning score (PEWS) is a tool used to predict clinical deterioration. Referenced vital sign parameters are based on expert opinion but heart rate and respiratory rate percentiles in hospitalized children have been published. This retrospective case-control study of unplanned intensive care unit (ICU) transfers compares evidence-based vital signs (EBVS) effect on PEWS sensitivity and specificity, determines the impact of age categories on PEWS deterioration prediction, and evaluates whether EBVS PEWS is associated with need for invasive ICU supports. EBVS PEWS improved sensitivity (43%-71% vs 30%-63%) for unplanned transfers with slightly decreased specificity (88%-98% vs 93%-99%). Logistic regression analysis and odds ratios (ORs) demonstrated EBVS PEWS was associated with increased risk for ICU-specific supports (OR = 1.16, 95% confidence interval [CI] = 1.0-1.34, P = .0498). Evidence-based vital signs can improve PEWS sensitivity to identify unplanned ICU transfers and identify patients requiring ICU-specific interventions.

Predictive Value of Methicillin-Resistant Staphylococcus aureus Nasal Swab PCR Assay for MRSA Infection in Critically Ill Pediatric Patients.

BACKGROUND: Critically ill pediatric patients are frequently initiated methicillin-resistant Staphylococcus aureus (MRSA) active antibiotics during infection evaluation even though MRSA infections are rare in many patient populations. The MRSA nasal swab polymerase chain reaction assay (MRSA-NS-PCR) is a test that has been shown to have a high negative predictive value (NPV) for MRSA infection in adults. This study evaluated the diagnostic test characteristics of the MRSA-NS-PCR in predicting the presence of MRSA infection in critically ill pediatric patients. STUDY DESIGN: A retrospective cohort study was performed in a 44-bed pediatric intensive care unit (PICU) between 2013 and 2017. 3860 pediatric patients (54% male, median age 4 years [IQR 1-11 years]) admitted to the PICU who met pediatric systemic inflammatory response syndrome (pSIRS) criteria, were screened with a MRSA-NS-PCR, and had cultures obtained within seven days of MRSA-NS-PCR collection were included. Predictive values and post-test probabilities of the MRSA-NS-PCR for MRSA infection were calculated. RESULTS: MRSA-NS-PCR was positive in 8.6% of patients. MRSA infection was identified in 40 patients, equaling an incidence rate of 2 per 1000 patient days. The MRSA-NS-PCR demonstrated a positive predictive value (PPV) of 9.7%, a NPV of 99.8%, and a post-test probability for a negative test of 0.2% for MRSA infection. CONCLUSIONS: The MRSA-NS-PCR has a poor PPV but a high NPV for MRSA infection in PICU patients when the incidence of MRSA infection is low. Creation of protocols to guide antimicrobial selection based on MRSA-NS-PCR results may lead to improved antimicrobial stewardship and significant risk reduction.

Vosoritide treatment for children with hypochondroplasia: a phase 2 trial.

Background: Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in FGFR3. It presents with disproportionate short stature with a wide range of clinical severity. There are currently no approved medications to treat short stature in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide analog that was recently approved for improving growth in children with achondroplasia. We aimed to evaluate the safety and efficacy of vosoritide in children with hypochondroplasia. Methods: We conducted a single-arm, phase 2, open-label trial at a single centre in the USA and enrolled 26 children with hypochondroplasia. The trial consists of a 6-month observation period to establish a baseline annualized growth velocity followed by a 12-month intervention period during which vosoritide is administered daily via subcutaneous injection at a dose of 15 µg/kg/day. The trial's co-primary endpoints included the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height standardized deviation score (SDS) after 12 months of treatment. This trial is registered with ClinicalTrials.gov (NCT04219007). Findings: Twenty-four participants with a mean age of 5.86 years received vosoritide therapy. The first participant was enrolled on August 4, 2020, and the final participant completed the 18-month trial on September 8, 2023. Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. Hypochondroplasia specific height SDS increased by 0.38 SD. There was a 1.81 cm/year increase in absolute annualized growth velocity. Interpretation: Vosoritide was safe and effective in increasing growth velocity in children with hypochondroplasia. Efficacy was similar to what has been reported in children with achondroplasia. Funding: This study was supported by an investigator-initiated grant from BioMarin Pharmaceutical.

Inhibition of ATM with KU-55933 Sensitizes Endometrial Cancer Cell Lines to Olaparib.

Background: Endometrial cancer (EC) is one of the most prevalent gynecologic cancers, which poses a serious threat to women's health worldwide. Olaparib, the first FDA-approved PARP inhibitor for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers, triggers apoptosis of cancer cells through synthetic lethality by inhibiting PARP1/2 enzymatic activity and BRCA1/2-dependent homologous recombination (HR) repair deficiency. However, the synergistic lethal effects between Olaparib and inhibitors of other DNA damage response proteins, such as ATM, PTEN and RAD51, are still unknown. Aim: Exploring the synergistic lethal effect between Olaparib and KU-55933 on EC. Methods: The GEPIA database was used to test EC patient survival rate. CCK8 was used for cell viability assays. Western blot was used for examining gene levels. The wound healing assay was used to detect cell migration ability. Flow cytometry was used for detecting the apoptosis rate. All experimental conditions were repeated independently in triplicate and analyzed in three separate experiments. Results: In this study, we discovered that the frequency of ATM alterations in endometrial cancer reaches nearly 20% and that there is a positive correlation between ATM alterations and prognosis. Furthermore, we discovered that endometrial cells with low expression levels of ATM are sensitive to Olaparib. Treatment with KU-55933, a specific inhibitor of ATM, significantly enhanced the sensitivity of endometrial cancer cells to Olaparib, as evidenced by colony formation, cell migration and apoptosis assay. Further analysis revealed that KU-55933 potentiates Olaparib-induced cell apoptosis by inhibiting ATM phosphorylation. Conclusion: Our study demonstrates that inhibiting ATM could enhance the sensitivity of endometrial cancer to Olaparib, thereby providing a potential alternative treatment for the clinical treatment of endometrial cancer.

Stability of trapped Bose-Einstein condensate under a density-dependent gauge field.

We study the ground-state stability of the trapped one-dimensional Bose-Einstein condensate under a density-dependent gauge field by variational and numerical methods. The competition of density-dependent gauge field and mean-field atomic interaction induces the instability of the ground state, which results in irregular dynamics. The threshold of the gauge field for exciting the instability is obtained analytically and confirmed numerically. When the gauge field is less than the threshold, the system is stable, and the gauge field induces chiral dynamics of the wave packet. When the gauge field is greater than the threshold, the system is unstable, and the ground-state wave packet will be deformed and fragmented. Interestingly, we find that as the gauge field approaches the threshold, strong dipolar and breathing dynamics take place, and strong modes mixing occurs, the instability of the system sets in. In addition, we show that the stability of the system can be well controlled by periodical modulation of the trapping potential. We provide theoretical evidence to understand and control the irregular dynamics associated with chiral superfluid induced by density-dependent gauge field.

Impact of bronchopulmonary dysplasia on brain GABA concentrations in preterm infants: Prospective cohort study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with cognitive-behavioral deficits in very preterm (VPT) infants, often in the absence of structural brain injury. Advanced GABA-editing techniques like Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) can quantify in-vivo gamma-aminobutyric acid (GABA+, with macromolecules) and glutamate (Glx, with glutamine) concentrations to investigate for neurophysiologic perturbations in the developing brain of VPT infants. OBJECTIVE: To investigate the relationship between the severity of BPD and basal-ganglia GABA+ and Glx concentrations in VPT infants. METHODS: MRI studies were performed on a 3 T scanner in a cohort of VPT infants [born ≤32 weeks gestational age (GA)] without major structural brain injury and healthy-term infants (>37 weeks GA) at term-equivalent age. MEGA-PRESS (TE68ms, TR2000ms, 256averages) sequence was acquired from the right basal-ganglia voxel (∼3cm3) and metabolite concentrations were quantified in institutional units (i.u.). We stratified VPT infants into no/mild (grade 0/1) and moderate-severe (grade 2/3) BPD. RESULTS: Reliable MEGA-PRESS data was available from 63 subjects: 29 healthy-term and 34 VPT infants without major structural brain injury. VPT infants with moderate-severe BPD (n = 20) had the lowest right basal-ganglia GABA+ (median 1.88 vs. 2.28 vs. 2.12 i.u., p = 0.025) and GABA+/choline (0.73 vs. 0.99 vs. 0.88, p = 0.004) in comparison to infants with no/mild BPD and healthy-term infants. The GABA+/Glx ratio was lower (0.34 vs. 0.44, p = 0.034) in VPT infants with moderate-severe BPD than in infants with no/mild BPD. CONCLUSIONS: Reduced GABA+ and GABA+/Glx in VPT infants with moderate-severe BPD indicate neurophysiologic perturbations which could serve as early biomarkers of future cognitive deficits.

Limbic network co-localization predicts pharmacoresistance in dysplasia-related epilepsy.

To evaluate the role of focal cortical dysplasia co-localization to cortical functional networks in the development of pharmacoresistance. One hundred thirty-six focal cortical dysplasia patients with 3.0 T or 1.5 T MRI were identified from clinical databases at Children's National Hospital. Clinico-radio-pathologic factors and network co-localization were determined. Using binomial logistic regression, limbic network co-localization (odds ratio 4.164 95% confidence interval 1.02-17.08, p = 0.048), and focal to bilateral tonic-clonic seizures (4.82, 1.30-18.03, p = 0.019) predicted pharmacoresistance. These findings provide clinicians with markers to identify patients with focal cortical dysplasia-related epilepsy at high risk of developing pharmacoresistance and should facilitate earlier epilepsy surgical evaluation.

Feasibility and Challenges with Measuring Adverse Childhood Experiences in the Pediatric Intensive Care Unit.

Purpose: The Adverse Childhood Experiences (ACEs) screening tool captures some experiences of childhood adversity, ranging from abuse to parental separation. Research has shown a correlation between ACEs and both adult and childhood disease. This study evaluated the feasibility of conducting ACE screening in the pediatric intensive care unit (PICU) and investigated associations with markers for severity of illness and utilization of resources. Methods: This was a cross sectional study screening for ACEs among children admitted to a single quaternary medical-surgical PICU. Children age 0-18 years old admitted to the PICU over a one-year period were considered for enrollment. A 10-question ACE screen was used to evaluate children for exposure to ACEs. Chart review was used to collect demographic and clinical data. Results: Of the 432 parents approached for enrollment, 400 (92.6%) agreed to participate. Most parents reported an ACE score of zero (68.9%) while 31% of participants experienced at least 1 ACE, of whom 14.8% experienced ≥ 2 ACEs. There was not a statistically significant association between ACE score and length of stay (p-value = 0.26) or level of respiratory support in patients with asthma (p-value = 0.15) or bronchiolitis (p-value = 0.83). The primary reasons for not approaching families were parent availability, non-English speaking parents, and social work concerns. Conclusions: This study demonstrates feasibility to collect sensitive psychosocial data in the PICU and highlights challenges to enrollment. Supplementary Information: The online version contains supplementary material available at 10.1007/s40653-023-00555-9.