IBRAP: integrated benchmarking single-cell RNA-sequencing analytical pipeline.

Single-cell ribonucleic acid (RNA)-sequencing (scRNA-seq) is a powerful tool to study cellular heterogeneity. The high dimensional data generated from this technology are complex and require specialized expertise for analysis and interpretation. The core of scRNA-seq data analysis contains several key analytical steps, which include pre-processing, quality control, normalization, dimensionality reduction, integration and clustering. Each step often has many algorithms developed with varied underlying assumptions and implications. With such a diverse choice of tools available, benchmarking analyses have compared their performances and demonstrated that tools operate differentially according to the data types and complexity. Here, we present Integrated Benchmarking scRNA-seq Analytical Pipeline (IBRAP), which contains a suite of analytical components that can be interchanged throughout the pipeline alongside multiple benchmarking metrics that enable users to compare results and determine the optimal pipeline combinations for their data. We apply IBRAP to single- and multi-sample integration analysis using primary pancreatic tissue, cancer cell line and simulated data accompanied with ground truth cell labels, demonstrating the interchangeable and benchmarking functionality of IBRAP. Our results confirm that the optimal pipelines are dependent on individual samples and studies, further supporting the rationale and necessity of our tool. We then compare reference-based cell annotation with unsupervised analysis, both included in IBRAP, and demonstrate the superiority of the reference-based method in identifying robust major and minor cell types. Thus, IBRAP presents a valuable tool to integrate multiple samples and studies to create reference maps of normal and diseased tissues, facilitating novel biological discovery using the vast volume of scRNA-seq data available.

Pancreatic masses in children: a single-center experience over two decades.

Pancreatic masses are extremely rare in pediatric patients, with limited data available. This lack of data makes the diagnosis and management of these tumors in children extremely challenging. Therefore, we aimed to describe the presentations, clinical course, and outcomes of children with pancreatic tumors at our center. A retrospective analysis was performed of all pediatric patients diagnosed with pancreatic masses between 2003 and 2022 in an academic freestanding children's hospital. Data including demographics, clinical presentation, workup, management, and subsequent morbidity and mortality were collected and aggregated. Furthermore, we reviewed cases of pancreatic tumor resections in the National Surgical Quality Improvement Program - Pediatric (NSQIP-P) database to identify common adverse outcomes and measures for quality improvement. In total, 17 patients were identified at our institution. Diagnoses included solid pseudopapillary (n = 9), gastrinoma (n = 1), rhabdomyosarcoma (n = 2), pancreatoblastoma (n = 2), and insulinoma (n = 1). Two patients did not have a histopathologic diagnosis and were excluded from subsequent analysis. Overall, 12 patients underwent surgical intervention, with the most common procedures being pancreaticoduodenectomy and distal pancreatectomy, and all 12 were known to be alive at last contact. There were 3 deaths, all due to complications related to metastatic disease. Furthermore, 30-day postoperative outcomes in the NSQIP-P dataset for pancreatic surgeries in pediatric patients are excellent, with negligible morbidity and no mortalities after the index surgery. CONCLUSIONS: Children with pancreatic tumors amenable to surgical resection appear to have adequate long-term survival. Short-term outcomes at diagnosis are excellent and mainly appear to be influenced by the presence of metastatic disease at initial presentation. WHAT IS KNOWN: • Pancreatic masses are a rare entity in children with limited data on their presentation, management and surgical outcomes. • Solid Pseudopapillary tumors are one of the most common pancreatic tumors in children with a fair prognosis after surgical intervention. WHAT IS NEW: • Surgical management of pediatric patients with pancreatic tumors is safe and effective in patients who do not have aggressive tumor types or metastatic disease. • Our case series provides a notable cohort of these pancreatic tumors with insight into the presentation, management and outcomes of five of these tumor types.

Hepatic resections for pediatric hepatoblastoma: analysis of 30-day outcomes using the National Surgical Quality Improvement Program-Pediatric database.

BACKGROUND: Surgical resection remains the cornerstone of treatment for hepatoblastoma in children and offers the best chance of disease-free survival. We aimed to analyze the 30 day outcomes of hepatic resection for hepatoblastoma stratified by extent using the National Surgical Quality Improvement Program-Pediatric (NSQIP-P). METHODS: We queried NSQIP-P for children undergoing resection of Hepatoblastoma from 2012 to 2021. Relevant clinical characteristics and outcomes were extracted for multivariate logistic regression to identify predictors of common adverse outcomes. RESULTS: We included 458 children with a median age of 1.90 years. Overall complications were rare, and perioperative blood transfusion (64.2%) and postoperative ventilation > 48 h (10.0%) were the only adverse events prevalent in more than 5% of patients. Median transfusion volume was 15.7 ml/kg. On multivariate regression, only patients undergoing Trisectionectomy (aOR = 3.387, 95% C.I. = 1.348-8.510) had higher odds of receiving > 75th percentile blood transfusion. Furthermore, only perioperative transfusion and postoperative ventilation > 48 h were statistically more common in patients undergoing extended versus standard resections. CONCLUSIONS: Outcomes following resection of hepatoblastoma are excellent, with low rates of postoperative adverse events. Although children undergoing trisectionectomy likely require greater transfusion volume, extended hepatic resections do not appear to have worse 30 day outcomes despite greater operative complexity and duration.

Optimal Timing of Inguinal Hernia Repair in Premature Infants: A NSQIP-P Study.

INTRODUCTION: Among premature infants, the incidence of inguinal hernias is reported to be as high as 30%. Despite being one of the most commonly performed procedures, the optimal setting of inguinal hernia repair (IHR) that is inpatient versus outpatient remains debatable. We sought to compare the 30-day outcomes of each approach by querying the National Surgical Quality Improvement Program-Pediatric database. MATERIALS AND METHODS: A retrospective cohort study comparing inpatient versus outpatient IHR using the National Surgical Quality Improvement Program-Pediatric database from 2013 to 2019 was performed. Demographic and clinical data were initially compared using univariate analysis. Continuous variables are presented as median and interquartile range and categorical variables are presented as n (%). Subsequently, cohorts were propensity matched using clinically and statistically significant patient characteristics. RESULTS: 928 patients underwent IHR, 634 (68.3%) while inpatient, 294 (31.7%) following hospital discharge. Inpatient IHR was associated with lower age at the time of surgery (120 versus 147 d; P < 0.0001), younger gestational age (27 versus 33 wk; P < 0.0001), decreased probability of repair in elective setting (87.2% versus 97.3%; P < 0.0001), and increased preoperative supplemental oxygen need (42% versus 4.4%; P < 0.0001). Comparison of propensity matched cohorts revealed that inpatient IHR was associated with increased procedure time (82 versus 51 min; P < 0.0001) and anesthetic duration (146 versus 102 min; P < 0.0001), wound infection rates (3.8% versus 0%; P = 0.007), blood transfusions (4.2% versus 0.5%; P = 0.036), unplanned intubations (2.8% versus 0%; P = 0.03), ventilator days (0 versus 0; range [0,30 versus 0,2]; P = 0.002), reoperation rate (5.6% versus 0%; P < 0.001), postoperative hospital length of stay (4 versus 1 d; P < 0.0001), and unplanned readmissions (8.9% versus 0.9%; P = 0.002). CONCLUSIONS: Inpatient IHR in premature neonates were associated with different postoperative outcomes than outpatient IHR. At least in the elective setting among premature infants, outpatient IHR can be considered safe in select patients while we await higher quality prospective data.

Pulse arrival time variation as a non-invasive marker of acute response to cardiac resynchronization therapy.

AIMS: Successful cardiac resynchronization therapy (CRT) shortens the pre-ejection period (PEP) which is prolonged in the left bundle branch block (LBBB). In a combined animal and patient study, we investigated if changes in the pulse arrival time (PAT) could be used to measure acute changes in PEP during CRT implantation and hence be used to evaluate acute CRT response non-invasively and in real time. METHODS AND RESULTS: In six canines, a pulse transducer was attached to a lower limb and PAT was measured together with left ventricular (LV) pressure by micromanometer at baseline, after induction of LBBB and during biventricular pacing. Time-to-peak LV dP/dt (Td) was used as a surrogate for PEP. In twelve LBBB patients during implantation of CRT, LV and femoral pressures were measured at baseline and during five different pacing configurations. PAT increased from baseline (277 ± 9 ms) to LBBB (313 ± 16 ms, P < 0.05) and shortened with biventricular pacing (290 ± 16 ms, P < 0.05) in animals. There was a strong relationship between changes in PAT and Td in patients (r2 = 0.91). Two patients were classified as non-responders at 6 months follow-up. CRT decreased PAT from 320 ± 41 to 298 ± 39 ms (P < 0.05) in the responders, while PAT increased by 5 and 8 ms in the two non-responders. CONCLUSION: This proof-of-concept study indicates that PAT can be used as a simple, non-invasive method to assess the acute effects of CRT in real time with the potential to identify long-term response in patients.

Short-term outcomes of thoracoscopic versus open lobectomy for congenital lung malformations.

PURPOSE: Thoracoscopic and open approaches for the management of congenital lung malformations (CLM) has been debated. The aim of this study is to compare 30-day outcomes for non-emergent lobectomies in children. METHODS: The National Surgical Quality Improvement Program-Pediatric database was queried for patients undergoing CLM resection from 2013 to 2020. Outcomes were compared by operative technique in an intention-to-treat model and then propensity matched. RESULTS: 2157 patients met inclusion criteria and underwent non-emergent pulmonary lobectomy for CLM. The intended operative approach was thoracoscopic in 57.7% of patients. Patients in the open group compared to the thoracoscopic were more likely to be born premature, have chronic lung disease, require preoperative oxygen support, and be ventilator dependent. After propensity matching, there was no statistically significant difference in 30-day mortality, unplanned readmission, and other complications between the thoracoscopic and open groups. Thoracoscopic approach was associated with a shorter length of stay. The proportion of cases approached via thoracoscopy increased over time from 48.8% in 2013 to 69.9% in 2020. CONCLUSIONS: This large multicenter retrospective matched analysis demonstrates thoracoscopic lobectomy in children has similar favorable 30-day outcomes and shorter length of stay for the non-emergent management of CLM, compared to open thoracotomy. LEVEL OF EVIDENCE: Level III.

Single site versus conventional laparoscopic appendectomy: some pain for no gain?

INTRODUCTION: The optimal laparoscopic appendectomy approach is not clear, comparing single site laparoscopic appendectomy (SILA) to conventional 3-port appendectomy (CLA). We investigated outcomes in pediatric patients comparing SILA to CLA: length of operation, length of stay, time to resumption of regular diet, follow up, rehospitalization, and cost. METHODS: Data was collected from children 1 to 18 years with appendectomy at Loma Linda University from 2018 to 2020, operated by two surgeons. Analysis utilized two-sample T, chi-squared, and Fisher's exact tests. RESULTS: Of 173 patients, 77 underwent SILA and 96 had CLA. There was no gender, age, or race difference between groups. Mean WBC was 17.5 × 103/mL in SILA group, compared to 15.3 × 103/mL in CLA group (P = 0.004). Operative time was 47.0 SILA compared to 49.5 minutes CLA (P = 0.269). Of SILA cases, 55.8% were simple appendicitis, while 53.3% of the CLA cases were simple (P = 0.857). Regular diet was resumed after 1.7 days in the SILA group, 1.1 days in CLA (P = 0.018). Length of stay was 2.9 days for SILA, 2.4 days for CLA (P = 0.144). Seven children required hospital readmission, 5 SILA and 2 CLA (P = 0.244). Five of the children who returned had intra-abdominal abscesses, of whom 4 had SILA. There was no difference in cost. CONCLUSIONS: The operative techniques had similar outcomes and operative times. There was a trend toward more intra-abdominal abscesses in the SILA group. Further study and longer follow up is needed to determine if there is an advantage to one laparoscopic approach over another.

Safe Zone for Dissection in Frontotemporal Region to Avoid Injury to the Temporal Branch of Facial Nerve.

ABSTRACT: The objective of this study is to provide a reliable roadmap for temporal branch of the facial nerve, in order to minimize, the risk of injury to the nerve during surgical dissections. A literature search was conducted on temporal branch of facial nerve. The date search range was 1950 to 2017. Databases searched included Medline, Web of science, Biosis, SciELO, Data Citation, and Zoologic Records. Data were collected on, author specialty, date of publication, and the relationship of the temporal branch of facial nerve to various landmarks in the frontotemporal region reported in human anatomic studies. Among the 48 studies reviewed, a total of 3477 anatomic dissections were performed in the craniofacial region. Temporal branch of facial nerve was located between 2.5 and 3 cm from lateral orbital rim. In relation to the zygomatic arch, it was found anywhere from the midpoint of the arch to 1 finger breath posterior to the arch. For the plane, it was most commonly described as being under the superficial temporal fascia (STF) or within the loose areolar tissue. Most anatomic dissections found 2 to 4 twigs of the temporal branch of facial nerve. In relation to the lateral canthus, it was found to be 2.85 +/- 0.69 cm superior and 2.54 +/- 0.43 cm lateral to the lateral canthus. Our study suggests consolidated data on surgical landmarks in order to ensure safe dissection in temporal region and prevent injury to the temporal branch of facial nerve.

Study of Association of Metabolic Syndrome and Risk Factors of Nephrolithiasis.

BACKGROUND AND AIM: The increasing incidence of nephrolithiasis in recent decades is coinciding with rising epidemic of obesity, metabolic syndrome, and type 2 diabetes. This temporal concordance suggests that a link might exist between these metabolic abnormalities and urinary stone disease. Therefore, the present study was aimed to investigate the association between presence of risk factors of nephrolithiasis and metabolic syndrome. METHODS: In a hospital-based, case control study, hundred patients of metabolic syndrome diagnosed according to IDF criteria and hundred age and matched controls were studied for presence of risk factors of nephrolithiasis. RESULTS: Patients with metabolic syndrome had significantly higher uricosuri a,hypercalciuria,oxaluria and hypocitraturia. The prevalence of risk factors of nephrolithiasis was also higher in patients with metabolic syndrome. The most prevalent was low urinary pH in 40% patients with mean pH of 5.8±1.6. Amongst other factors, 33% had hyperuricemia, 29% had hypercalciuria, 15% had oxaluria 13% had hypocitraturia and 10% had hyperuricosuria. Significant correlation was observed between risk factors of nephrolithiasis and components of metabolic syndrome. CONCLUSION: The present study provides an evidence of association between risk factors of nephrolithiasis and metabolic syndrome and suggests that nephrolithiasis may be a systemic disorder representing the interaction of multiple metabolic derangements. Determining common modifiable risk factors for the development of kidney stones might uncover new preventive strategies.

A novel crosslinking protocol stabilizes amyloid ß oligomers capable of inducing Alzheimer's-associated pathologies.

Amyloid ß oligomers (AßOs) accumulate early in Alzheimer's disease (AD) and experimentally cause memory dysfunction and the major pathologies associated with AD, for example, tau abnormalities, synapse loss, oxidative damage, and cognitive dysfunction. In order to develop the most effective AßO-targeting diagnostics and therapeutics, the AßO structures contributing to AD-associated toxicity must be elucidated. Here, we investigate the structural properties and pathogenic relevance of AßOs stabilized by the bifunctional crosslinker 1,5-difluoro-2,4-dinitrobenzene (DFDNB). We find that DFDNB stabilizes synthetic Aß in a soluble oligomeric conformation. With DFDNB, solutions of Aß that would otherwise convert to large aggregates instead yield solutions of stable AßOs, predominantly in the 50-300 kDa range, that are maintained for at least 12 days at 37°C. Structures were determined by biochemical and native top-down mass spectrometry analyses. Assayed in neuronal cultures and i.c.v.-injected mice, the DFDNB-stabilized AßOs were found to induce tau hyperphosphorylation, inhibit choline acetyltransferase, and provoke neuroinflammation. Most interestingly, DFDNB crosslinking was found to stabilize an AßO conformation particularly potent in inducing memory dysfunction in mice. Taken together, these data support the utility of DFDNB crosslinking as a tool for stabilizing pathogenic AßOs in structure-function studies.

Inguinal hernias in premature neonates: exploring optimal timing for repair.

PURPOSE: Inguinal hernias have been reported in as many as 10-30% premature neonates, making inguinal herniorrhaphy (IHR) one of the most commonly performed surgical procedures. The timing of surgery remains controversial. The purpose of this report is to compare outcomes of IHR while in the NICU (inpatient) versus repair following discharge (outpatient) to determine optimal timing. METHODS: Premature neonates having undergone IHR over a 5-year period were identified and a retrospective case cohort analysis was performed. RESULTS: 263 patients underwent IHR during the 5-year study period with 115 (43.7%) having surgical repair inpatient (IP; prior to discharge) and 148 having outpatient herniorrhaphy (OP). Patients with IHR performed IP had significantly lower birth weight (p < 0.001), gestational age (p < 0.001), longer duration of surgery (p = 0.01) and were more likely to have post-operative ventilator dependence following repair; however, there were no differences in the rate of recurrence (p = 0.44) and incarceration (p = 0.45). CONCLUSION: Our study demonstrated no significant differences in the rates of incarceration or recurrence, following in- or out-patient IHR. These findings suggest that IHR can potentially be offered as an outpatient procedure following hospital discharge in appropriate patients. The optimal timing of IHR in premature infants remains elusive and will likely require additional multicenter investigation.

Esterified Trehalose Analogues Protect Mammalian Cells from Heat Shock.

Trehalose is a disaccharide produced by many organisms to better enable them to survive environmental stresses, including heat, cold, desiccation, and reactive oxygen species. Mammalian cells do not naturally biosynthesize trehalose; however, when introduced into mammalian cells, trehalose provides protection from damage associated with freezing and drying. One of the major difficulties in using trehalose as a cellular protectant for mammalian cells is the delivery of this disaccharide into the intracellular environment; mammalian cell membranes are impermeable to the hydrophilic sugar trehalose. A panel of cell-permeable trehalose analogues, in which the hydrophilic hydroxyl groups of trehalose are masked as esters, have been synthesized and the ability of these analogues to load trehalose into mammalian cells has been evaluated. Two of these analogues deliver millimolar concentrations of free trehalose into a variety of mammalian cells. Critically, Jurkat cells incubated with these analogues show improved survival after heat shock, relative to untreated Jurkat cells. The method reported herein thus paves the way for the use of esterified analogues of trehalose as a facile means to deliver high concentrations of trehalose into mammalian cells for use as a cellular protectant.

Publication Trends in Craniofacial Distraction: A Bibliometrical Analysis.

PURPOSE: The purpose of this study was to analyze the craniofacial distraction literature published over the last 50 years and to determine various trends in publications. METHODS: A literature search was conducted in November and December 2015. The date search range was 1965 to 2015. Databases searched included Medline, Web of Science, Biosis, SciELO, Data Citation, and Zoologic Records. Data were collected on distraction type, author specialty, date of publication, country, state (if United States), number of citations, journal name, journal type, and Le Fort type (for midfacial distractions). RESULTS: Total number of craniofacial distraction publications was 1729. Cranial distraction accounted for (11%), midfacial (11%), and mandibular (78%). Largest increase in publications was in the 1990s, with 48 publications from 1991 to 1995 rising to 261 publications from 1996 to 2000. Among the cranial distraction publications, Plastic and Reconstructive Surgery (PRS) (67%) were the most frequent authors but among the midfacial and mandibular distraction publications, Oral and Maxillofacial Surgery (OMFS) were the most frequent authors (68% and 64%, respectively). Total number of citations was 26,281 with OMFS (50.4%) and PRS (37%) being cited most frequently. Oral and Maxillofacial Surgery was cited most for mandibular and midfacial distraction, and PRS was cited most for cranial distraction. CONCLUSION: Research on craniofacial distraction has significantly increased since the 1970s, with mandibular distraction accounting for the majority of this rise. Among specialties, OMFS and PRS account for the majority of the literature. The United States leads the publication. Authors tend to publish distraction literature in their corresponding journal specialty, with the exception of PRS who publishes most frequently in OMFS journals.

Paget-Schroetter syndrome in 21 children: outcomes after multidisciplinary care.

OBJECTIVE: To review the presentation, management, and outcomes of Paget-Schroetter syndrome (PSS) in children and propose a multidisciplinary treatment algorithm involving pediatric and vascular surgery, interventional radiology, and hematology. STUDY DESIGN: Patients with PSS presenting between 2003 and 2013 were reviewed. Demographics, symptoms, therapies, and functional outcomes were noted. Data from early patients informed the development of a multidisciplinary treatment algorithm applied to later patients. RESULTS: Of 21 patients, mean ± SD age was 16 ± 1.6 years and 11 (52%) were male. Of patients with complete presentation data, common symptoms were edema (84%), discoloration (58%), and pain (58%). Thrombophilia workup revealed one heterozygote for factor V Leiden, 2 patients with factor VIII elevation and 1 patient with mildly low antithrombin. The most recent 8 patients were treated according to an algorithm developed by a multidisciplinary working group through experience with the first 13 cases. All patients underwent a venogram, endovascular intervention (including 15 receiving catheter-directed thrombolysis), and operative ipsilateral thoracic outlet decompression (first rib resection, anterior scalenectomy, and venolysis). Postoperative complications included hemothorax (2), pneumothorax (1), and recurrent thrombosis (2). Follow up duration was 12 ± 9.5 months. Symptoms recurred transiently in 1 patient. CONCLUSION: Pediatric patients with PSS can be treated successfully using a multidisciplinary treatment algorithm including anticoagulation, catheter-directed thrombolysis, and operative decompression of the thoracic outlet. Early outcomes are promising.

Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study.

OBJECTIVES: In a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy. STUDY DESIGN: A multicenter, retrospective cohort analysis from the Pediatric Intestinal Failure Consortium was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with dependence on parenteral nutrition (PN) >60 days. Enteral autonomy was defined as PN discontinuation >3 months. RESULTS: A total of 272 infants were followed for a median (IQR) of 33.5 (16.2-51.5) months. Enteral autonomy was achieved in 118 (43%); 36 (13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified necrotizing enterocolitis (NEC; OR 2.42, 95% CI 1.33-4.47), care at an IF site without an associated intestinal transplantation program (OR 2.73, 95% CI 1.56-4.78), and an intact ileocecal valve (OR 2.80, 95% CI 1.63-4.83) as independent risk factors for enteral autonomy. A second model (n = 144) that included only patients with intraoperatively measured residual small bowel length found NEC (OR 3.44, 95% CI 1.36-8.71), care at a nonintestinal transplantation center (OR 6.56, 95% CI 2.53-16.98), and residual small bowel length (OR 1.04 cm, 95% CI 1.02-1.06 cm) to be independently associated with enteral autonomy. CONCLUSIONS: A substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ileocecal valve, and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF.

Preservation of biochemical liver function with low-dose soy-based lipids in children with intestinal failure-associated liver disease.

OBJECTIVES: Intestinal failure-associated liver disease (IFALD) contributes to significant morbidity in pediatric patients with intestinal failure (IF); however, the use of parenteral nutrition (PN) with a fish oil-based intravenous (IV) emulsion (FO) has been associated with biochemical reversal of cholestasis and improved outcomes. Unfortunately, FO increases the complexity of care: because it can be administered only under Food and Drug Administration compassionate use protocols requiring special monitoring, it is not available as a 3-in-1 solution and is more expensive than comparable soy-based IV lipid emulsion (SO). Because of these pragmatic constraints, a series of patient families were switched to low-dose (1 g kg(-1) day(-1)) SO following biochemical resolution of cholestasis. The present study examines whether reversal of cholestasis and somatic growth are maintained following this transition. METHODS: The present study is a chart review of all children with IFALD who switched from FO to SO following resolution of cholestasis. Variables are presented as medians (interquartile ranges). Comparisons were performed using the Wilcoxon signed-rank test. RESULTS: Seven patients ages 25.9 (16.2-43.2) months were transitioned to SO following reversal of cholestasis using FO. At a median follow-up of 13.9 (4.3-50.1) months, there were no significant differences between pretransition and post-transition serum alanine and aspartate aminotransferases, direct bilirubin, and weight-for-age z scores. Because of recurrence of cholestasis, 1 patient was restarted on FO after 4 months on SO. CONCLUSIONS: Biochemical reversal of IFALD and growth were preserved after transition from FO to SO in 6 of 7 (86%) patients. Given the challenges associated with the use of FO, SO may be a viable alternative in select patients with home PN.

Tight Glycemic Control With Insulin Does Not Affect Skeletal Muscle Degradation During the Early Postoperative Period Following Pediatric Cardiac Surgery.

OBJECTIVE: Critical illness is associated with significant catabolism, and persistent protein loss correlates with increased morbidity and mortality. Insulin is a potent anticatabolic hormone; high-dose insulin decreases skeletal muscle protein breakdown in critically ill pediatric surgical patients. However, insulin's effect on protein catabolism when given at clinically utilized doses has not been studied. The objective was to evaluate the effect of postoperative tight glycemic control and clinically dosed insulin on skeletal muscle degradation in children after cardiac surgery with cardiopulmonary bypass. DESIGN: Secondary analysis of a two-center, prospective randomized trial comparing tight glycemic control with standard care. Randomization was stratified by study center. PATIENTS: Children 0-36 months who were admitted to the ICU after cardiac surgery requiring cardiopulmonary bypass. INTERVENTIONS: In the tight glycemic control arm, insulin was titrated to maintain blood glucose between 80 and 110 mg/dL. Patients in the control arm received standard care. Skeletal muscle breakdown was quantified by a ratio of urinary 3-methylhistidine to urinary creatinine. MEASUREMENTS AND MAIN RESULTS: A total of 561 patients were included: 281 in the tight glycemic control arm and 280 receiving standard care. There was no difference in 3-methylhistidine to creatinine between groups (tight glycemic control, 249 ± 127 vs standard care, 253 ± 112, mean ± SD in µmol/g; p = 0.72). In analyses restricted to the patients in tight glycemic control arm, higher 3-methylhistidine to creatinine correlated with younger age, as well as lower weight, weight-for-age z score, length, and body surface area (p < 0.005 for each) and lower postoperative day 3 serum creatinine (r = -0.17; p = 0.02). Sex, prealbumin, and albumin were not associated with 3-methylhistidine to creatinine. During urine collection, 245 patients (87%) received insulin. However, any insulin exposure did not impact 3-methylhistidine to creatinine (t test, p = 0.45), and there was no dose-dependent effect of insulin on 3-methylhistidine to creatinine (r = -0.03; p = 0.60). CONCLUSION: Although high-dose insulin has an anabolic effect in experimental conditions, at doses necessary to achieve normoglycemia, insulin appears to have no discernible impact on skeletal muscle degradation in critically ill pediatric cardiac surgical patients.

Structural analysis of dUTPase from Helicobacter pylori reveals unusual activity for dATP.

Helicobacter pylori deoxyuridine triphosphate nucleotidohydrolase (HpdUTPase) is a key enzyme in the synthesis of the thymidine nucleotide pathway. It catalyzes the hydrolysis of dUTP to dUMP and releases pyrophosphate. This enzyme has been shown to be essential in several pathogenic organisms. Here, we have determined the crystal structures of HpdUTPase in complex with α, ß-imido dUTP (non-hydrolyzable substrate analog) and apo-state at resolution of 2 Šand 2.5 Šrespectively. The flexible c terminal end of HpdUTPase which is not observed in apo-state structure and becomes ordered in the complex structure, suggesting its role in forming active site and substrate interaction. The Isothermal titration calorimetry (ITC) experiments reveal that hydrolysis of dUTP is an exothermic reaction with Km = 35.0 ±â€¯0.19 µM and the kcat = 1.20 ±â€¯0.19 s-1. The ITC studies combined with MD simulations for all other nucleotides (dATP.dGTP, dCTP and dTTP) show that the active site of HpdUTPase strangely can also accommodate dATP. The structural comparison with the host (human) dUTPases reveals critical differences in substrate binding affinity of the active site of HpdUTPase. The detailed study suggests that the dATP binds in the active site of HpdUTPase making the number of preferable hydrogen bonds and shows activity with KM of 47 ±â€¯2.4 µM.

Current Status and Management of Chronic Myeloid Leukemia in the Gulf Region: Survey Results and Expert Opinion.

Studies on chronic myeloid leukemia (CML) in the Gulf region are scarce, consisting of a survey and expert meeting that included 15 experts in 2023 which discussed CML diagnosis, testing, treatment objectives, toxicities, and discontinuation in the Gulf region. Most patients were reported to be in first-line therapy, and the most common treatments were imatinib/imatinib generic in first-line and dasatinib in second- and third-lines. Mutation analysis was not reported to be routinely performed at the time of diagnosis but rather in case of progression to accelerated/blast phase or any sign of loss of response. While all participants were aware that BCR-ABL should be monitored every three months during the first year of treatment, 10% reported monitoring BCR-ABL every six months in practice due to test cost and lab capability. The most important first-line therapy objective was "achievement of major molecular response" (MMR) in younger patients and "overall survival" in older ones. The most important treatment objectives were "MMR" and "early molecular response followed by prolongation of overall survival" in the short term and "treatment-free remission" in the long term. The current practices in CML in the Gulf region appear to be similar to global figures.

Consensus-Based Guidelines for Acute Myeloid Leukemia Management in Gulf Cooperation Council Countries: Addressing Unmet Regional Needs and the Changing AML Landscape.

PURPOSE: AML is a heterogeneous hematologic malignancy. Region-specific recommendations for AML management can enhance patient outcomes. This article aimed to develop recommendations for the Gulf Cooperation Council (GCC) countries. METHODS: Ten AML panel members from Kuwait, Oman, Qatar, and the United Arab Emirates (KOQU) participated in a modified two-round Delphi process. The panel first identified the unmet regional needs and finalized a list of core variables. Next, they voted on iterative statements drawn from international recommendations and provided feedback via a questionnaire. Consensus voting ≤70% was discussed, and additional clinical decision making statements were suggested. At round closure, a consensus vote took place on revised statements. RESULTS: The panel reached ≥97.8% consensus on AML management. The panel agreed to use international risk stratification categories for personalized treatment of AML. The presence of ≥10% blasts for recurrent genetic abnormalities was required for a diagnosis of AML. Key consensus was reached for different treatment stages. The panel noted that older patients pose a challenge because of poor cytogenetics and genetic anomalies and require different treatment approaches. The panel recommended venetoclax-hypomethylating agents; fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor; and targeted therapy for AML relapsed/refractory disease. Supportive care is considered on the basis of prevailing organisms and drug resistance. CONCLUSION: The GCC KOQU's consensus-based recommendations for managing AML include an evidence-based and region-specific framework.