Elevated APE1 Dysregulates Homologous Recombination and Cell Cycle Driving Genomic Evolution, Tumorigenesis, and Chemoresistance in Esophageal Adenocarcinoma.

BACKGROUND & AIMS: The purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors. METHODS: An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in 6 cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as the top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells and the impact on genome stability and growth was monitored in vitro and in vivo. The impact on DNA and chromosomal instability was monitored using multiple approaches, including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing, and/or multicolor fluorescence in situ hybridization. RESULTS: Expression of 4 deoxyribonucleases correlated with genomic instability in 6 human cancers. Functional screens of these genes identified APE1 as the top candidate for further evaluation. APE1 suppression in EAC, breast, lung, and prostate cancer cell lines caused cell cycle arrest; impaired growth and increased cytotoxicity of cisplatin in all cell lines and types and in a mouse model of EAC; and inhibition of homologous recombination and spontaneous and chemotherapy-induced genomic instability. APE1 overexpression in normal cells caused a massive chromosomal instability, leading to their oncogenic transformation. Evaluation of these cells by means of whole genome sequencing demonstrated the acquisition of changes throughout the genome and identified homologous recombination as the top mutational process. CONCLUSIONS: Elevated APE1 dysregulates homologous recombination and cell cycle, contributing to genomic instability, tumorigenesis, and chemoresistance, and its inhibitors have the potential to target these processes in EAC and possibly other cancers.

Exploration of Vitamin B6-Based Redox-Active Pyridinium Salts Towards the Application in Aqueous Organic Flow Batteries.

Pyridoxal hydrochloride, a vitamin B6 vitamer, was synthetically converted to a series of diverse redox-active benzoyl pyridinium salts. Cyclic voltammetry studies demonstrated redox reversibility under basic conditions, and two of the most promising salts were subjected to laboratory-scale flow battery tests involving galvanostatic cycling at 10 mM in 0.1 M NaOH. In these tests, the battery was charged completely, corresponding to the transfer of two electrons to the electrolyte, but no discharge was observed. Both CV analysis and electrochemical simulations confirmed that the redox wave observed in the experimental voltammograms corresponds to a two-electron process. To explain the irreversibility in the battery tests, we conducted bulk electrolysis with the benzoyl pyridinium salts, affording the corresponding benzylic secondary alcohols. Computational studies suggest that the reduction proceeds in three consecutive steps: first electron transfer (ET), then proton-coupled electron transfer (PCET) and finally proton transfer (PT) to give the secondary alcohol. 1H NMR deuterium exchange studies indicated that the last PT step is not reversible in 0.1 M NaOH, rendering the entire redox process irreversible. The apparent reversibility observed in CV at the basic media likely arises from the slow rate of the PT step at the timescale of the measurement.

Nissen Fundoplication in Infants With Severe Bronchopulmonary Dysplasia: A Propensity-Matched Analysis.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is a common respiratory morbidity among premature infants. Nissen fundoplication may be performed on infants with BPD to protect the lungs from gastroesophageal reflux-related aspiration, but the indications and benefits associated with fundoplication are not well-defined. This study evaluated associations of Nissen with clinical outcomes in infants with severe BPD (sBPD), using propensity score matching to minimize bias and confounding. METHODS: Infants ≤31 wk gestational age with sBPD (grade 2-3) admitted to a single neonatal intensive care unit (NICU) between January 2016 and October 2021 were included. Patients with sBPD who underwent Nissen fundoplication during initial NICU admission were propensity score-matched at a 1:2 ratio with control patients who did not undergo Nissen (no-Nissen). Outcomes were compared, including time to freedom from respiratory support (defined as ≤2 L nasal cannula), time to initial NICU discharge, and incidence of hospital readmission or death within 1 y postdischarge. RESULTS: After propensity score matching, 18 Nissen infants were compared with 30 no-Nissen infants. The Nissen group trended toward longer time to freedom from respiratory support (median 105 versus 70 d, P = 0.09), and had longer initial hospital stays (188 versus 111 d, P = 0.002), more 1-y hospital readmissions (83% versus 50%, P = 0.04), and more tracheostomies (28% versus 0%, P = 0.005). Mortality during first-year postdischarge was similar (6% versus 10%, P = 1.0). CONCLUSIONS: Despite adjustment for confounding variables, Nissen fundoplication was associated with prolonged support and greater resource utilization among infants with sBPD. Prospective studies are needed to clarify indications for fundoplication in this population.

Combined open maxillectomy and endoscopic endonasal resection of a giant V2 trigeminal schwannoma.

BACKGROUND: Trigeminal schwannoma is a rare type of tumor that arises from the Schwann cells of the trigeminal nerve. METHOD: We present a case of a patient with a giant V2 trigeminal schwannoma with painful swelling in the left maxilla. A complete resection using a combined open maxillectomy and endoscopic endonasal approach was performed. CONCLUSION: This case highlights the importance of a multidisciplinary approach to perform a combined open and endoscopic approach for safe resection while preserving adequate speech and swallowing.

Multiple introductions of monkeypox virus to Ireland during the international mpox outbreak, May 2022 to October 2023.

BackgroundMpox, caused by monkeypox virus (MPXV), was considered a rare zoonotic disease before May 2022, when a global epidemic of cases in non-endemic countries led to the declaration of a Public Health Emergency of International Concern. Cases of mpox in Ireland, a country without previous mpox reports, could reflect extended local transmission or multiple epidemiological introductions.AimTo elucidate the origins and molecular characteristics of MPXV circulating in Ireland between May 2022 and October 2023.MethodsWhole genome sequencing of MPXV from 75% of all Irish mpox cases (182/242) was performed and compared to sequences retrieved from public databases (n = 3,362). Bayesian approaches were used to infer divergence time between sequences from different subclades and evaluate putative importation events from other countries.ResultsOf 242 detected mpox cases, 99% were males (median age: 35 years; range: 15-60). All 182 analysed genomes were assigned to Clade IIb and, presence of 12 distinguishable subclades suggests multiple introductions into Ireland. Estimation of time to divergence of subclades further supports the hypothesis for multiple importation events from numerous countries, indicative of extended and sustained international spread of mpox. Further analysis of sequences revealed that 92% of nucleotide mutations were from cytosine to thymine (or from guanine to adenine), leading to a high number of non-synonymous mutations across subclades; mutations associated with tecovirimat resistance were not observed.ConclusionWe provide insights into the international transmission dynamics supporting multiple introductions of MPXV into Ireland. Such information supported the implementation of evidence-informed public health control measures.

Isolation and Bioactivity Evaluation of Sesquiterpenes from an Alcyonarian of the Genus Lemnalia from the Saudi Arabian Red Sea.

Over the last decades, soft corals have been proven a rich source of biologically active compounds, featuring a wide range of chemical structures. Herein, we investigated the chemistry of an alcyonarian of the genus Lemnalia (Neptheidae), specimens of which were collected from the coral reefs near Al Lith, on the south-west coast of Saudi Arabia. A series of chromatographic separations led to the isolation of 31 sesquiterpenes, featuring mainly the nardosinane and neolemnane carbon skeletons, among which three (13, 14 and 28) are new natural products. The metabolites isolated in sufficient amounts were evaluated in vitro in human tumor and non-cancerous cell lines for a number of biological activities, including their cytotoxic, anti-inflammatory, anti-angiogenic, and neuroprotective activities, as well as for their effect on androgen receptor (AR)-regulated transcription. Among the tested metabolites, compound 12 showed comparable neuroprotective activity to the positive control N-acetylcysteine, albeit at a 10-fold lower concentration.

(F)utility of preoperative pulmonary function testing in pectus excavatum to assess severity.

PURPOSE: The utility of pulmonary function testing (PFT) in pectus excavatum (PE) has been subject to debate. Although some evidence shows improvement from preoperative to postoperative values, the clinical significance is uncertain. A high failure-to-completion rate for operative PFT (48%) was identified in our large institutional cohort. With such a high non-completion rate, we questioned the overall utility of PFT in the preoperative assessment of PE and sought to evaluate if other measures of PE severity or cardiopulmonary function could explain this finding. METHODS: Demographics, clinical findings, and results from cardiac MRI, PFT (spirometry and plethysmography), and cardiopulmonary exercise tests (CPET) were reviewed in 270 patients with PE evaluated preoperatively between 2015 and 2018. Regression modeling was used to measure associations between PFT completion and cardiopulmonary function. RESULTS: There were no differences in demographics, symptoms, connective tissue disorders, or multiple indices of pectus severity and cardiac deformation in PFT completers versus non-completers. While regression analysis revealed higher RVEF, LVEF, and LVEF-Z scores, lower RV-ESV/BSA, LV-ESV/BSA, and LV-ESV/BSA-Z scores, and abnormal breathing reserve in PFT completers vs. non-completers, these findings were not consistent across continuous and binary analyses. CONCLUSIONS: We found that PFT completers were not significantly different from non-completers in most structural and functional measures of pectus deformity and cardiopulmonary function. Inability to complete PFT is not an indicator of pectus severity.

A Review of Automation and Sensors: Parameter Control of Thermal Treatments for Electrical Power Generation.

This review delves into the critical role of automation and sensor technologies in optimizing parameters for thermal treatments within electrical power generation. The demand for efficient and sustainable power generation has led to a significant reliance on thermal treatments in power plants. However, ensuring precise control over these treatments remains challenging, necessitating the integration of advanced automation and sensor systems. This paper evaluates the pivotal aspects of automation, emphasizing its capacity to streamline operations, enhance safety, and optimize energy efficiency in thermal treatment processes. Additionally, it highlights the indispensable role of sensors in monitoring and regulating crucial parameters, such as temperature, pressure, and flow rates. These sensors enable real-time data acquisition, facilitating immediate adjustments to maintain optimal operating conditions and prevent system failures. It explores the recent technological advancements, including machine learning algorithms and IoT integration, which have revolutionized automation and sensor capabilities in thermal treatment control. Incorporating these innovations has significantly improved the precision and adaptability of control systems, resulting in heightened performance and reduced environmental impact. This review underscores the imperative nature of automation and sensor technologies in thermal treatments for electrical power generation, emphasizing their pivotal role in enhancing operational efficiency, ensuring reliability, and advancing sustainability in power generation processes.

Molecular Pharmacology of Gelsemium Alkaloids on Inhibitory Receptors.

Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABAA receptors (GABAARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between Gelsemium alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC50 of 31.5 ± 1.7 and 40.6 ± 8.2 µM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABAARs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major Gelsemium indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.

Adeno-Associated Virus 2 and Human Adenovirus F41 in Wastewater during Outbreak of Severe Acute Hepatitis in Children, Ireland.

During April-July 2022, outbreaks of severe acute hepatitis of unknown etiology (SAHUE) were reported in 35 countries. Five percent of cases required liver transplantation, and 22 patients died. Viral metagenomic studies of clinical samples from SAHUE cases showed a correlation with human adenovirus F type 41 (HAdV-F41) and adeno-associated virus type 2 (AAV2). To explore the association between those DNA viruses and SAHUE in children in Ireland, we quantified HAdV-F41 and AAV2 in samples collected from a wastewater treatment plant serving 40% of Ireland's population. We noted a high correlation between HAdV-F41 and AAV2 circulation in the community and SAHUE clinical cases. Next-generation sequencing of the adenovirus hexon in wastewater demonstrated HAdV-F41 was the predominant HAdV type circulating. Our environmental analysis showed increased HAdV-F41 and AAV2 prevalence in the community during the SAHUE outbreak. Our findings highlight how wastewater sampling could aid in surveillance for respiratory adenovirus species.

Human Adenovirus Type 4 Comprises Two Major Phylogroups with Distinct Replicative Fitness and Virulence Phenotypes.

Human adenovirus type 4 (HAdV-E4) is the only type (and serotype) classified at present within species Human mastadenovirus E that has been isolated from a human host. Recent phylogenetic analysis of whole-genome sequences of strains representing the spectrum of intratypic genetic diversity described to date identified two major evolutionary lineages designated phylogroups (PGs) I and II and validated the early clustering of HAdV-E4 genomic variants into two major groups by low-resolution restriction fragment length polymorphism analysis. In this study, we expanded our original analysis of intra- and inter-PG genetic variability and used a panel of viruses representative of the spectrum of genetic diversity described for HAdV-E4 to examine the magnitude of inter- and intra-PG phenotypic diversity using an array of cell-based assays and a cotton rat model of HAdV respiratory infection. Our proteotyping of HAdV-E strains using concatenated protein sequences in selected coding regions including E1A, E1B-19K and -55K, DNA polymerase, L4-100K, various E3 proteins, and E4-34K confirmed that the two clades encode distinct variants/proteotypes at most of these loci. Our in vitro and in vivo studies demonstrated that PG I and PG II differ in their growth, spread, and cell-killing phenotypes in cell culture and in their pulmonary pathogenic phenotypes. Surprisingly, the differences in replicative fitness documented in vitro between PGs did not correlate with the differences in virulence observed in the cotton rat model. This body of work is the first reporting phenotypic correlates of naturally occurring intratypic genetic variability for HAdV-E4. IMPORTANCE Human adenovirus type 4 (HAdV-E4) is a prevalent causative agent of acute respiratory illness of variable severity and of conjunctivitis and comprises two major phylogroups that carry distinct coding variations in proteins involved in viral replication and modulation of host responses to infection. Our data show that phylogroup (PG) I and PG II are intrinsically different regarding their ability to grow and spread in culture and to cause pulmonary disease in cotton rats. This is the first report of phenotypic divergence among naturally occurring known genetic variants of an HAdV type of medical importance. This research reveals readily detectable phenotypic differences between strains representing phylogroups I and II, and it introduces a unique experimental system for the elucidation of the genetic basis of adenovirus fitness and virulence and thus for increasing our understanding of the implications of intratypic genetic diversity in the presentation and course of HAdV-E4-associated disease.

Two novel recombinant human mastadenovirus D genotypes associated with acute respiratory illness.

Two novel genotypes of species human mastadenovirus D designated 109 and 110 were isolated from three epidemiologically unrelated cases of acute respiratory disease detected in January 2018 by surveillance efforts at the California/Mexico border. Both genotypes represent examples of intertypic recombination. Genotype D109 is most closely related to genotype D56 (97.68% genomic similarity) and features a type D22-like penton base, a type D19-like hexon gene, and a type D9-like fiber [P22/H19/F9]. On the other hand, genotype D110 is most closely related to type D22 (96.94% genomic similarity) and features a type D67-like penton base, a novel hexon gene, and a type D9-like fiber [P67/H110/F9]. Importantly, the fibers of both novel genotypes are highly similar to those of genotypes D56 and D59, which have also been isolated from a few cases of respiratory infections. The present report shows data contributing to the understanding of the molecular determinants of the expanded tissue tropism of certain members of species HAdV-D.

Programmed cell death ligand 1 expression associated with subtypes of post-transplant lymphoproliferative disorder among pediatric kidney transplant recipients.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression on tumor cells engages the PD-1 receptor on T cells, inhibiting anti-tumor responses. PD-L1 has been detected in cases of post-transplant lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD-L1 expression and evaluate for clinical correlations. METHODS: Twenty-one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin-embedded tissue biopsies, we examined 21 primary tumors for expression using PD-L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD-L1 on lesional B-cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review. RESULTS: Applying revised 2017 WHO PTLD classification showed five non-destructive, nine polymorphic, and seven monomorphic cases. Average PD-L1 expression based upon PTLD subtype was: non-destructive 11%, polymorphic 43%, and monomorphic 73% (p = .01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B-cells expressed PD-L1. CONCLUSION: In this case series, significant differences in PD-L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD-L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis.

Transplantation of organs from SARS-CoV-2-positive donors: Preliminary experience from Spain.

BACKGROUND: The utilization of non-lung organs from deceased donors with a positive polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the time of donation can be lifesaving, although the safety of this policy must be assessed. METHODS: This is a nationwide, prospective study, reporting the experience on the utilization of non-lung organs from SARS-CoV-2-positive donors between December 15, 2020 and May 31, 2022 in Spain. RESULTS: A total of 69 patients received a solid organ transplant (41 kidney, 18 liver, 8 heart, and 2 combined liver-kidney) obtained from 32 donors with a positive SARS-CoV-2 PCR at the time of donation (four of them with a cycle threshold value <30). All recipients tested negative for SARS-CoV-2 and were free of coronavirus disease 2019 (COVID-19) symptoms prior to transplantation. Nasopharyngeal swab turned positive for SARS-CoV-2 PCR in 4 (5.8%) recipients at 3, 8, 11, and 20 days after transplantation, though evidence did not support a donor-derived COVID-19. Four kidney recipients lost their grafts and two patients died: one heart recipient due to cardiogenic shock and one combined liver-kidney recipient due to lung hypertension and right heart failure. Graft losses and patient deaths were deemed unrelated to the donor SARS-CoV-2 status by the treating teams. No other adverse reactions were reported. CONCLUSIONS: This preliminary experience supports the safety of the use of organs other than lungs from SARS-CoV-2 PCR-positive donors, in alignment with previous series. However, the impact of SARS-CoV-2 infection upon organ quality should be established in future research.

Synthesis and neuroprotective activity of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives.

A library of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives was prepared from N-Boc-3-azetidinone employing the Horner-Wadsworth-Emmons reaction, rhodium(I)-catalyzed conjugate addition of arylboronic acids, and subsequent elaborations to obtain N-unprotected hydrochlorides, N-alkylated and N-acylated azetidine derivatives. The compounds were evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, revealing several derivatives to possess AChE inhibition comparable to that of the AChE inhibitor rivastigmine. The binding mode of the AChE inhibitor donepezil and selected active compounds 26 and 27 within the active site of AChE was studied using molecular docking. Furthermore, the neuroprotective activity of the prepared compounds was evaluated in models associated with Parkinson's disease (salsolinol-induced) and aspects of Alzheimer's disease (glutamate-induced oxidative damage). Compound 28 showed the highest neuroprotective effect in both salsolinol- and glutamate-induced neurodegeneration models, and its protective effect in the glutamate model was revealed to be driven by a reduction in oxidative stress and caspase-3/7 activity.

Effects of subconjunctival ropivacaine, liposomal bupivacaine, and mepivacaine on corneal sensitivity in healthy horses.

OBJECTIVE: To evaluate corneal sensitivity and adverse events following subconjunctival administration of three local anesthetics in horses. STUDY DESIGN: Randomized, masked, crossover study. ANIMALS: Twelve healthy adult mares. METHODS: The subconjunctival space of the treated eye was injected with 0.2 mL of liposomal bupivacaine (1.3%), ropivacaine (0.5%), or mepivacaine (2%). All horses received each medication once and the contralateral eye received saline (control). Corneal touch threshold (CTT) was measured using a Cochet-Bonnet esthesiometer before sedation, after sedation, and at specified intervals until it returned to baseline. Ocular examinations were performed at 24-, 72, and 168 h post-injection to monitor for adverse effects. RESULTS: The mean total time of anesthesia (TTA) was 168.3 min for ropivacaine, 169.2 min for liposomal bupivacaine, 103.3 min for mepivacaine and 30.7 min for the control. TTA for liposomal bupivacaine (p < .001) and ropivacaine (p = .001) was longer than the control. TTA for mepivacaine was not different from the control (p = .138), liposomal bupivacaine (p = .075) or ropivacaine (p = .150). Injection site hemorrhage reduced TTA regardless of treatments (p = .047). No adverse effects attributed to injections were noted. CONCLUSION: All three medications were well tolerated. Subconjunctival administration of ropivacaine and liposomal bupivacaine resulted in longer TTAs compared to the control; however, their TTAs were not different from that of mepivacaine. CLINICAL SIGNIFICANCE: Subconjunctivally administered liposomal bupivacaine and ropivacaine are viable options to provide prolonged corneal analgesia in horses. Future studies are needed to assess the efficacy in diseased eyes.

Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease.

BACKGROUND: Rare diseases are pathologies that affect less than 1 in 2000 people. They are difficult to diagnose due to their low frequency and their often highly heterogeneous symptoms. Rare diseases have in general a high impact on the quality of life and life expectancy of patients, which are in general children or young people. The advent of high-throughput sequencing techniques has improved diagnosis in several different areas, from pediatrics, achieving a diagnostic rate of 41% with whole genome sequencing (WGS) and 36% with whole exome sequencing, to neurology, achieving a diagnostic rate between 47 and 48.5% with WGS. This evidence has encouraged our group to pursue a molecular diagnosis using WGS for this and several other patients with rare diseases. RESULTS: We used whole genome sequencing to achieve a molecular diagnosis of a 7-year-old girl with a severe panvascular artery disease that remained for several years undiagnosed. We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. Bioinformatic analyses propose these mutations as the most likely cause of the disease, according to its frequency, in silico predictors, conservation analyses, and effect on the protein product. Additionally, we confirmed one mutation in each parent, supporting a compound heterozygous status in the child. CONCLUSIONS: In general, we think that this finding can contribute to the use of whole genome sequencing as a diagnosis tool of rare diseases, and in particular, it can enhance the set of known mutations associated with different diseases.

Presentation and outcomes of post-transplant lymphoproliferative disorder at a single institution pediatric transplant center.

BACKGROUND: This study aimed to characterize features present at the time of diagnosis and describe outcomes in patients with post-transplant lymphoproliferative disorder (PTLD) following pediatric solid organ transplantation. METHODS: We performed a retrospective review of solid organ transplant patients who developed pathologically confirmed PTLD at our center from 2006 to 2016. RESULTS: Of 594 patients included in this study, 41(6.9%) were diagnosed with PTLD. Median age at transplant was 5.6(IQR 1.7-16.1) years. Proportion of PTLD cases by organ transplanted and median time (IQR) to disease onset were: heart 11/144(7.6%) at 13.6(8.5-55.6) months, lung 7/52(13.5%) at 9.1(4.9-35) months, kidney 8/255(3.1%) at 39.5(13.9-57.1) months, liver 12/125(9.6%) at 7.7(5.5-22) months, intestine 0/4(0%), and multi-visceral 3/14(21.4%) at 5.4(5.4-5.6) months. No significant correlation was seen between recipient EBV status at transplant and timing of development of PTLD. There were six early lesions, 15 polymorphic, 19 monomorphic, and one uncharacterizable PTLD. Following immunosuppression reduction, 30 patients received rituximab, and 14 required chemotherapy. At median 25(IQR 12-53) months follow-up from the onset of PTLD, eight patients died secondary to transplant related complications, three are alive with active disease, and 30 have no evidence of disease. CONCLUSION: PTLD is a significant complication following pediatric solid organ transplantation. EBV levels in conjunction with symptomatic presentation following transplant may assist in detection of PTLD. Most patients can achieve long-term disease-free survival through immunosuppression reduction, anti-CD20 treatment, and chemotherapy in refractory cases.

Does age matter? Cardiopulmonary profiles of adolescents versus adults with pectus excavatum presenting for surgical evaluation.

PURPOSE: We sought to analyze differences in presentation and cardiopulmonary function between those referred for surgical consultation as adolescents (11-17 years) versus adults (18 + years). METHODS: Presenting symptoms, past medical history, and results from cardiac MRI (CMR), pulmonary function testing (PFT), and cardiopulmonary exercise testing (CPET) were reviewed in 329 patients evaluated preoperatively between 2015 and 2018. Adjusted regression modeling was used to measure associations between pectus indices and clinical endpoints of cardiopulmonary function. RESULTS: Our sample included 276 adolescents and 53 adults. Adults presented more frequently with chest pain (57% vs. 38%, p = 0.01), shortness of breath (76% vs. 59%, p = 0.02), palpitations (21% vs. 11%, p = 0.04), and exercise intolerance (76% vs. 59%, p = 0.02). Their Haller indices (5.2 [4.2, 7.0] vs. 4.7 [4.0, 5.7], p = 0.05) and cardiac asymmetry (1.8 [0.5] vs. 1.6 [0.5], p = 0.02) were also higher. In continuous outcome analysis, adolescents had higher FEV1/FVC on PFT and higher work on CPET (p < 0.01). CONCLUSIONS: Adults with pectus excavatum were more symptomatic than adolescents with deeper, more asymmetric deformities, decreased FEV1/FVC and exercise capacity. These findings may support earlier versus later repair to prevent age-related decline. Further studies are warranted.

Overview of the Role of Pharmacological Management of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) remains a prominent disease state characterized by the recurrent collapse of the upper airway while sleeping. To date, current treatment may include continuous positive airway pressure (CPAP), lifestyle changes, behavioral modification, mandibular advancement devices, and surgical treatment. However, due to the desire for a more convenient mode of management, pharmacological treatment has been thoroughly investigated as a means for a potential alternative in OSA treatment. OSA can be distinguished into various endotypic or phenotypic classes, allowing pharmacological treatment to better target the root cause or symptoms of OSA. Some medications available for use include antidepressants, CNS stimulants, nasal decongestants, carbonic anhydrase inhibitors, and potassium channel blockers. This review will cover the findings of currently available and future study medications that could potentially play a role in OSA therapy.