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Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to a heritable mutation in ß-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate disease complications and has been intently pursued. However, safe and effective small-molecule inducers of HbF remain elusive. We report the discovery of dWIZ-1 and dWIZ-2, molecular glue degraders of the WIZ transcription factor that robustly induce HbF in erythroblasts. Phenotypic screening of a cereblon (CRBN)-biased chemical library revealed WIZ as a previously unknown repressor of HbF. WIZ degradation is mediated by recruitment of WIZ(ZF7) to CRBN by dWIZ-1, as resolved by crystallography of the ternary complex. Pharmacological degradation of WIZ was well tolerated and induced HbF in humanized mice and cynomolgus monkeys. These findings establish WIZ degradation as a globally accessible therapeutic strategy for SCD.
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Anemia Falciforme , Antidrepanocíticos , Hemoglobina Fetal , Fatores de Transcrição Kruppel-Like , Proteínas do Tecido Nervoso , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Antidrepanocíticos/química , Antidrepanocíticos/farmacologia , Antidrepanocíticos/uso terapêutico , Cristalografia por Raios X , Descoberta de Drogas , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Macaca fascicularis , Proteínas do Tecido Nervoso/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
The rise in antimicrobial resistance is a global health crisis and necessitates the development of novel strategies to treat infections. For example, in 2022 tuberculosis (TB) was the second leading infectious killer after COVID-19, with multi-drug-resistant strains of TB having an â¼40% fatality rate. Targeting essential biosynthetic pathways in pathogens has proven to be successful for the development of novel antimicrobial treatments. Fatty-acid synthesis (FAS) in bacteria proceeds via the type II pathway, which is substantially different from the type I pathway utilized in animals. This makes bacterial fatty-acid biosynthesis (Fab) enzymes appealing as drug targets. FabG is an essential FASII enzyme, and some bacteria, such as Mycobacterium tuberculosis, the causative agent of TB, harbor multiple homologs. FabG4 is a conserved, high-molecular-weight FabG (HMwFabG) that was first identified in M. tuberculosis and is distinct from the canonical low-molecular-weight FabG. Here, structural and functional analyses of Mycolicibacterium smegmatis FabG4, the third HMwFabG studied to date, are reported. Crystal structures of NAD+ and apo MsFabG4, along with kinetic analyses, show that MsFabG4 preferentially binds and uses NADH when reducing CoA substrates. As M. smegmatis is often used as a model organism for M. tuberculosis, these studies may aid the development of drugs to treat TB and add to the growing body of research that distinguish HMwFabGs from the archetypal low-molecular-weight FabG.
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Proteínas de Bactérias , Mycobacterium smegmatis , Mycobacterium smegmatis/metabolismo , Mycobacterium smegmatis/enzimologia , Mycobacterium smegmatis/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Cristalografia por Raios X , Modelos Moleculares , Sequência de Aminoácidos , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMO
Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.
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Inibidores de Proteínas Quinases , Proteínas Tirosina Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de SinaisRESUMO
The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4.
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Talidomida , Dedos de Zinco , Talidomida/farmacologia , Talidomida/química , Teratogênicos , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Concern over per- and polyfluoroalkyl substances (PFAS) has increased as more is learned about their environmental presence, persistence, and bioaccumulative potential. The limited monitoring, toxicokinetic (TK), and toxicologic data available are inadequate to inform risk across this diverse domain. Here, 73 PFAS were selected for in vitro TK evaluation to expand knowledge across lesser-studied PFAS alcohols, amides, and acrylates. Targeted methods developed using gas chromatography-tandem mass spectrometry (GC-MS/MS) were used to measure human plasma protein binding and hepatocyte clearance. Forty-three PFAS were successfully evaluated in plasma, with fraction unbound (fup) values ranging from 0.004 to 1. With a median fup of 0.09 (i.e., 91% bound), these PFAS are highly bound but exhibit 10-fold lower binding than legacy perfluoroalkyl acids recently evaluated. Thirty PFAS evaluated in the hepatocyte clearance assay showed abiotic loss, with many exceeding 60% loss within 60 min. Metabolic clearance was noted for 11 of the 13 that were successfully evaluated, with rates up to 49.9 µL/(min × million cells). The chemical transformation simulator revealed potential (bio)transformation products to consider. This effort provides critical information to evaluate PFAS for which volatility, metabolism, and other routes of transformation are likely to modulate their environmental fates.
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We present an adolescent male with a single intracardiac mass and pulmonary emboli, complicated by peripheral venous thrombosis and subsequent development of pulmonary pseudoaneurysms, leading to diagnosis of Hughes-Stovin syndrome. Remission was achieved with cyclophosphamide, corticosteroids, and pseudoaneurysm resection and maintained with infliximab and methotrexate.
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Falso Aneurisma , Aneurisma , Trombose , Vasculite , Masculino , Humanos , Adolescente , Falso Aneurisma/complicações , Falso Aneurisma/terapia , Síndrome , Artéria Pulmonar , Aneurisma/complicações , Aneurisma/diagnóstico , Vasculite/complicações , Trombose/tratamento farmacológico , Trombose/etiologiaRESUMO
Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy.
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Neoplasias , Fatores de Transcrição , Animais , Humanos , Camundongos , Fator de Transcrição Ikaros , Imunoterapia , Neoplasias/terapia , Neoplasias/metabolismo , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Per- and polyfluoroalkyl substances (PFAS) are a diverse set of commercial chemicals widely detected in humans and the environment. However, only a limited number of PFAS are associated with epidemiological or experimental data for hazard identification. To provide developmental neurotoxicity (DNT) hazard information, the work herein employed DNT new approach methods (NAMs) to generate in vitro screening data for a set of 160 PFAS. The DNT NAMs battery was comprised of the microelectrode array neuronal network formation assay (NFA) and high-content imaging (HCI) assays to evaluate proliferation, apoptosis, and neurite outgrowth. The majority of PFAS (118/160) were inactive or equivocal in the DNT NAMs, leaving 42 active PFAS that decreased measures of neural network connectivity and neurite length. Analytical quality control indicated 43/118 inactive PFAS samples and 10/42 active PFAS samples were degraded; as such, careful interpretation is required as some negatives may have been due to loss of the parent PFAS, and some actives may have resulted from a mixture of parent and/or degradants of PFAS. PFAS containing a perfluorinated carbon (C) chain length ≥8, a high C:fluorine ratio, or a carboxylic acid moiety were more likely to be bioactive in the DNT NAMs. Of the PFAS positives in DNT NAMs, 85% were also active in other EPA ToxCast assays, whereas 79% of PFAS inactives in the DNT NAMs were active in other assays. These data demonstrate that a subset of PFAS perturb neurodevelopmental processes in vitro and suggest focusing future studies of DNT on PFAS with certain structural feature descriptors.
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Fluorocarbonos , Síndromes Neurotóxicas , Humanos , Síndromes Neurotóxicas/metabolismo , Neurônios/metabolismo , Crescimento Neuronal , Apoptose , Fluorocarbonos/toxicidadeRESUMO
INTRODUCTION: The addition of cephalic drains (CDs) in extracorporeal membrane oxygenation (ECMO) to augment venous drainage may offer benefit, though their use is varied. Our objective was to describe our institution's experience with CDs including flow rates and patency. We also compared complication rates between patients with and without a CD. METHODS: This retrospective cohort study included infants <12 months of age cannulated for ECMO between January 1, 2010 and September 30, 2019 at a single institution. Flow data were obtained for those with a CD. Demographic and complication rates were obtained for all. RESULTS: Of 264 patients in the final cohort, 220 (83%) had a CD of which 93.2% remained patent to decannulation. CDs typically provided 30% or more of ECMO flow throughout the ECMO run. The median time to CD clot was 139 h (range 48-635 h). Patients with a clotted CD had longer ECMO runs than those whose CD remained patent (median 382 h [IQR 217-538] vs 139 h [IQR 91-246], p < 0.001). Survival to discharge was lower for those with clotted versus patent CD (14% vs 70%, p < 0.001). Mechanical complications were more common in patients with CD (p = 0.005). Seizures were more common in those without a CD (p = 0.021). CONCLUSIONS: In this cohort, the majority of CDs placed remained patent at decannulation and provided substantial additional venous drainage. Mechanical problems were common in patients with CDs, but without clinical sequelae. Further study is warranted to elucidate CD impact on short- and long-term outcomes.
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Oxigenação por Membrana Extracorpórea , Humanos , Lactente , Oxigenação por Membrana Extracorpórea/efeitos adversos , Estudos Retrospectivos , Fatores de Tempo , Drenagem , Alta do PacienteRESUMO
Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a noncovalent BTK-binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of ≤0.2 nM and DC90 of ≤0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR-mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at subnanomolar concentrations, and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).
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Leucemia Linfocítica Crônica de Células B , Humanos , Tirosina Quinase da Agamaglobulinemia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Xenoenxertos , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
Introduction: Choledocholithiasis is a disease process that can be managed by laparoscopic common bile duct exploration at the time of cholecystectomy. However, it can be negatively perceived by surgeons as lengthening procedure time and adding technical complexity. Materials and Methods: We have created a dual balloon biliary intervention catheter designed to make common duct exploration efficient, simple, and safe. The device consists of two balloons, one compliant and one noncompliant, to perform initial cholangiography, dilate the sphincter, and occlude the proximal duct for distal power flushing of stones. The catheter design facilitates a stepwise, over the wire progression of interventions with a singular device. Results: The catheter has been successfully deployed in a porcine feasibility model and the dual balloon concepts reduced to practice using currently available devices. Conclusion: Laparoscopic common bile duct exploration is a safe and effective way to treat choledocolithiasis. The Dual Balloon Catheter is a novel device that allows for duct occlusion for cholangiogram and power flushing in conjunction with duct and sphincter dilation.
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Colecistectomia Laparoscópica , Coledocolitíase , Suínos , Animais , Colecistectomia Laparoscópica/métodos , Coledocolitíase/cirurgia , Colangiografia/métodos , Dilatação , Ducto Colédoco/cirurgiaRESUMO
PURPOSE: Enhanced recovery protocols [ERPs] standardize care and have been demonstrated to improve surgical quality in adults. We retrospectively compared outcomes before and after implementation of ERPs in children undergoing elective laparoscopic cholecystectomy [ELC] surgery. METHODS: A pediatric-specific ERP was implemented for children undergoing ELC at one [C1] of the two Pediatric Surgical Centers in July 2016. We retrospectively reviewed 606 patients undergoing ELC between July 2014 and December 2019. Of these, 206 patients underwent ELC prior to ERP implementation [Pre-ERP] were compared to 400 patients undergoing ELC managed in the post-ERP implementation period (between January 2017 and December 2019), 21 of which were managed by enhanced recovery protocol. Primary Outcomes included immediate peri-operative and post-operative narcotic use in mean morphine equivalents [MME], narcotics at discharge, complications, nurse calls and returns to system [RTS]. RESULTS: There was a significant decrease in opioid use both post-operatively and at time of discharge in the ERP managed cohort. The MME use during the post-operative period was 0.85 in the in ERP-compliant patients compared to 6.40 in the non-compliant group (p < 0.027). Eighty-six percent of ERP-compliant patients in the study required no narcotics at discharge, which was statistically significant when compared to ERP non-compliant cohort (p < 0.0001). There was also no change in RTS, nurse calls or complications. In addition, in the post-ERP period (2017-2019), a dominant proportion of patients at C1 partially complied with the ERP, resulting in a statistically significantly decrease of opioid use between sites in the post-op period (6.54 vs 10.57 MME) post-ERP (p < 0.001). Similar effects were noted in discharge narcotics. CONCLUSION: The use of pediatric-specific ERP in children undergoing ELC is safe, effective, and provides compassionate pain control while leading to a reduction in opioid use peri-operatively and at discharge. This improvement occurred without changes in RTS, nursing calls or complications. LEVEL OF EVIDENCE: Level III; Retrospective study.
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Colecistectomia Laparoscópica , Adulto , Analgésicos Opioides/uso terapêutico , Criança , Endrin/análogos & derivados , Humanos , Tempo de Internação , Morfina , Dor Pós-Operatória/tratamento farmacológico , Estudos RetrospectivosRESUMO
INTRODUCTION: Functional lumen imaging probe (EndoFLIP) is a diagnostic technology that assesses esophageal cross-sectional area via impedance planimetry during controlled volumetric distention. The purpose of this study is to evaluate the utility of EndoFLIP intraoperatively during laparoscopic esophagomyotomy. METHODS: We performed a retrospective cohort study reviewing all patients undergoing EndoFLIP assisted laparoscopic esophagomyotomy for achalasia between January and December 2021 (nâ¯=â¯10). Twenty-two patients with achalasia that underwent traditional laparoscopic esophagomyotomy between July 2014 and September 2019 served as a comparison. Primary outcome evaluated was resolution of symptoms at discharge. Secondary outcomes included change in distensibility index (DI), operative time, length of stay, time to regular diet, and reinterventions. RESULTS: All patients managed with EndoFLIP assistance had resolution of dysphagia and postprandial vomiting following intervention. Mean change in DI was 5.32 mm2/mmHg with a myotomy length of 3.6â¯cm. Operative time was shorter in the EndoFLIP cohort (97 min versus 185 min, pâ¯=â¯<0.001). Study patients did not undergo an antireflux operation. There was no difference in length of stay or time to soft diet between groups. All patients were discharged on postoperative day 1 tolerating a mechanical soft diet. No acid suppressive medications were prescribed during the observation period. One patient required dilation for recurrent symptoms and one required reoperation for mucosal leak. CONCLUSION: EndoFLIP assisted laparoscopic esophagomyotomy results in similar short-term outcomes to traditional surgical technique. EndoFLIP allows for focused myotomy length and a shorter operative time. LEVEL OF EVIDENCE: III.
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Acalasia Esofágica , Laparoscopia , Miotomia , Humanos , Criança , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/cirurgia , Impedância Elétrica , Estudos Retrospectivos , Resultado do Tratamento , Laparoscopia/métodos , Fundoplicatura/métodosRESUMO
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder affecting respiratory control and autonomic nervous system function caused by variants in the paired-like homeobox 2B (PHOX2B) gene. Although most patients are diagnosed in the newborn period, an increasing number of patients are presenting later in childhood, adolescence, and adulthood. Despite hypoxemia and hypercapnia, patients do not manifest clinical features of respiratory distress during sleep and wakefulness. CCHS is a lifelong disorder. Patients require assisted ventilation throughout their life delivered by positive pressure ventilation via tracheostomy, noninvasive positive pressure ventilation, and/or diaphragm pacing. At different ages, patients may prefer to change their modality of assisted ventilation. This requires an individualized and coordinated multidisciplinary approach. Additional clinical features of CCHS that may present at different ages and require periodic evaluations or interventions include Hirschsprung's disease, gastrointestinal dysmotility, neural crest tumors, cardiac arrhythmias, and neurodevelopmental delays. Despite an established PHOX2B genotype and phenotype correlation, patients have variable and heterogeneous clinical manifestations requiring the formulation of an individualized plan of care based on collaboration between the pulmonologist, otolaryngologist, cardiologist, anesthesiologist, gastroenterologist, sleep medicine physician, geneticist, surgeon, oncologist, and respiratory therapist. A comprehensive multidisciplinary approach may optimize care and improve patient outcomes. With advances in CCHS management strategies, there is prolongation of survival necessitating high-quality multidisciplinary care for adults with CCHS.
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Early efforts to broaden the spectrum and potency of cyclic boronic acid ß-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important ß-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).
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Pró-Fármacos , Inibidores de beta-Lactamases , Antibacterianos/química , Antibacterianos/farmacologia , Disponibilidade Biológica , Pró-Fármacos/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismoRESUMO
BACKGROUND: Enhanced recovery protocols (ERPs) are effective means of standardizing and improving the quality of surgical care in adults. Our purpose was to retrospectively compare outcomes before and after implementation of ERPs in children undergoing laparoscopic Heller myotomy for achalasia. METHODS: A pediatric-specific ERP was used for children undergoing laparoscopic Heller myotomy starting July 2017 at two pediatric surgery centers within a single metropolitan healthcare system. A retrospective review of 8 patients undergoing Heller myotomies between July 2014 and July 2017 was performed as a control. This cohort was compared to 14 patients managed post-ERP implementation (2017-2020). Outcomes of interest investigated included opioid use during admission, narcotics at discharge, time to regular diet, length of stay (LOS), and readmissions. RESULTS: There was a significant decrease in opioid use both while in the hospital and at time of discharge. Mean morphine equivalent use was 4.50 mg in the pre-ERP cohort and 1.97 mg in the post-ERP cohort. Furthermore, 8 out of 14 (57%) patients in the post-ERP cohort received no opioids during the admission compared with only 2 out of 8 (25%) patients in the pre-ERP cohort. Only 1 out of 14 (7.14%) patients in the post-ERP cohort was discharged with a prescription for opioid medication while 6 out of 8 (75%) in the pre-ERP cohort were discharged with an opiate prescription. CONCLUSIONS: The use of ERP in children undergoing laparoscopic Heller myotomy surgery is safe and effective and leads to a reduction in opioid use during admission and at discharge. LEVELS OF EVIDENCE: Level III.
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Acalasia Esofágica , Miotomia de Heller , Laparoscopia , Adulto , Analgésicos Opioides/uso terapêutico , Criança , Acalasia Esofágica/cirurgia , Fundoplicatura/métodos , Humanos , Laparoscopia/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: The COVID-19 pandemic forced the cancelation of conventional in-person academic conferences due to the risk of virus transmission and limited ability to travel. Both the American Pediatric Surgical Association (APSA) and International Pediatric Endosurgery Group (IPEG) converted to a virtual format for their 2020 annual meetings. The purpose of this article is to review the successful implementation of the APSA and IPEG virtual meetings and reflect upon lessons learned for future virtual conferences. METHODS: Logistics, structure, and attendance statistics were reviewed. Informal interviews were conducted with key stakeholders and the number of presenters and participants were analyzed. Finally, post-meeting attendee surveys were conducted to elicit feedback after both virtual meetings. RESULTS: The meetings were organized in different ways, with APSA spreading a mix of scientific and clinical educational content over several months and IPEG keeping the meeting compressed, similar to previous in-person versions. Both meetings were free and therefore attracted a high proportion of participants (720 for APSA and 834 for IPEG). The meetings were felt to be educationally appropriate by most, although timing and lack of Continuing Medical Education (CME) opportunities were detractors. Most attendees said they would be willing to pay fees similar to in-person amounts. IPEG compressed presentations into four 2-hour sessions spread over 4 weeks, but also made material available on-line through a proprietary application. There was a broad range of international attendees. IPEG attracted a larger percentage of non-members than did APSA (3:1 nonmember to member ratio). Both societies reported net losses, largely due to lost registration revenue and non-refundable costs from having to switch from an in-person meeting. CONCLUSIONS: The main advantage of the virtual meeting was increased participation while disadvantages included the lack of networking. The key lessons learned from the meetings include methods to increase interactivity, adjustments of technical logistics, and creation of enduring material. In the future, hybrid conferences will likely become more prevalent with advantages of both platforms. LEVEL-OF-EVIDENCE: Level V - Expert Opinion.
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COVID-19 , Pandemias , Criança , Educação Médica Continuada , Humanos , Inquéritos e Questionários , Estados UnidosRESUMO
Minimally invasive surgery has moved from the fringe of pediatric surgery to the mainstream to address a variety of problems. Pancreatic pathology, though uncommon and complex, is frequently amenable to laparoscopic intervention. Indications for pediatric pancreatic operative intervention includes trauma, congenital hyperinsulinemia and neoplasm. Children may require distal pancreatectomy, subtotal pancreatectomy, enucleation, lateral pancreaticojejunostomy and pancreaticoduodenectomy. Of these operations, all but pancreaticoduodenectomy have been successfully described in children using a minimally invasive approach. Traumatic transection of the main pancreatic duct may require operative intervention if endoscopic techniques are unsuccessful. Distal pancreatectomy has been successfully utilized in this circumstance. Additionally, near total pancreatectomy may also be performed laparoscopically although successful reports are limited. Enucleation, especially with the use of intraoperative ultrasound may avoid a large laparotomy for isolated benign masses. Finally, chronic pancreatitis resulting in a dilated main pancreatic duct may benefit from a lateral pancreaticojejunostomy. This operation has also successfully been performed in children. Included is a review of pediatric pancreatic minimally invasive operations paired with corresponding pathology.