Mammalian CDC14 phosphatases control exit from stemness in pluripotent cells.

Maintenance of stemness is tightly linked to cell cycle regulation through protein phosphorylation by cyclin-dependent kinases (CDKs). However, how this process is reversed during differentiation is unknown. We report here that exit from stemness and differentiation of pluripotent cells along the neural lineage are controlled by CDC14, a CDK-counteracting phosphatase whose function in mammals remains obscure. Lack of the two CDC14 family members, CDC14A and CDC14B, results in deficient development of the neural system in the mouse and impairs neural differentiation from embryonic stem cells (ESCs). Mechanistically, CDC14 directly dephosphorylates specific proline-directed Ser/Thr residues of undifferentiated embryonic transcription Factor 1 (UTF1) during the exit from stemness, triggering its proteasome-dependent degradation. Multiomic single-cell analysis of transcription and chromatin accessibility in differentiating ESCs suggests that increased UTF1 levels in the absence of CDC14 prevent the proper firing of bivalent promoters required for differentiation. CDC14 phosphatases are dispensable for mitotic exit, suggesting that CDC14 phosphatases have evolved to control stemness rather than cell cycle exit and establish the CDK-CDC14 axis as a critical molecular switch for linking cell cycle regulation and self-renewal.

Fluctuating hydrodynamics and the Rayleigh-Plateau instability.

The Rayleigh-Plateau instability occurs when surface tension makes a fluid column become unstable to small perturbations. At nanometer scales, thermal fluctuations are comparable to interfacial energy densities. Consequently, at these scales, thermal fluctuations play a significant role in the dynamics of the instability. These microscopic effects have previously been investigated numerically using particle-based simulations, such as molecular dynamics (MD), and stochastic partial differential equation-based hydrodynamic models, such as stochastic lubrication theory. In this paper, we present an incompressible fluctuating hydrodynamics model with a diffuse-interface formulation for binary fluid mixtures designed for the study of stochastic interfacial phenomena. An efficient numerical algorithm is outlined and validated in numerical simulations of stable equilibrium interfaces. We present results from simulations of the Rayleigh-Plateau instability for long cylinders pinching into droplets for Ohnesorge numbers of Oh = 0.5 and 5.0. Both stochastic and perturbed deterministic simulations are analyzed and ensemble results show significant differences in the temporal evolution of the minimum radius near pinching. Short cylinders, with lengths less than their circumference, were also investigated. As previously observed in MD simulations, we find that thermal fluctuations cause these to pinch in cases where a perturbed cylinder would be stable deterministically. Finally, we show that the fluctuating hydrodynamics model can be applied to study a broader range of surface tension-driven phenomena.

The NADH recycling enzymes TsaC and TsaD regenerate reducing equivalents for Rieske oxygenase chemistry.

Many microorganisms use both biological and nonbiological molecules as sources of carbon and energy. This resourcefulness means that some microorganisms have mechanisms to assimilate pollutants found in the environment. One such organism is Comamonas testosteroni, which metabolizes 4-methylbenzenesulfonate and 4-methylbenzoate using the TsaMBCD pathway. TsaM is a Rieske oxygenase, which in concert with the reductase TsaB consumes a molar equivalent of NADH. Following this step, the annotated short-chain dehydrogenase/reductase and aldehyde dehydrogenase enzymes TsaC and TsaD each regenerate a molar equivalent of NADH. This co-occurrence ameliorates the need for stoichiometric addition of reducing equivalents and thus represents an attractive strategy for integration of Rieske oxygenase chemistry into biocatalytic applications. Therefore, in this work, to overcome the lack of information regarding NADH recycling enzymes that function in partnership with Rieske non-heme iron oxygenases (Rieske oxygenases), we solved the X-ray crystal structure of TsaC to a resolution of 2.18 Å. Using this structure, a series of substrate analog and protein variant combination reactions, and differential scanning fluorimetry experiments, we identified active site features involved in binding NAD+ and controlling substrate specificity. Further in vitro enzyme cascade experiments demonstrated the efficient TsaC- and TsaD-mediated regeneration of NADH to support Rieske oxygenase chemistry. Finally, through in-depth bioinformatic analyses, we illustrate the widespread co-occurrence of Rieske oxygenases with TsaC-like enzymes. This work thus demonstrates the utility of these NADH recycling enzymes and identifies a library of short-chain dehydrogenase/reductase enzyme prospects that can be used in Rieske oxygenase pathways for in situ regeneration of NADH.

ePlatypus: an ecosystem for computational analysis of immunogenomics data.

MOTIVATION: The maturation of systems immunology methodologies requires novel and transparent computational frameworks capable of integrating diverse data modalities in a reproducible manner. RESULTS: Here, we present the ePlatypus computational immunology ecosystem for immunogenomics data analysis, with a focus on adaptive immune repertoires and single-cell sequencing. ePlatypus is an open-source web-based platform and provides programming tutorials and an integrative database that helps elucidate signatures of B and T cell clonal selection. Furthermore, the ecosystem links novel and established bioinformatics pipelines relevant for single-cell immune repertoires and other aspects of computational immunology such as predicting ligand-receptor interactions, structural modeling, simulations, machine learning, graph theory, pseudotime, spatial transcriptomics, and phylogenetics. The ePlatypus ecosystem helps extract deeper insight in computational immunology and immunogenomics and promote open science. AVAILABILITY AND IMPLEMENTATION: Platypus code used in this manuscript can be found at github.com/alexyermanos/Platypus.

Ocular Mucous Membrane Pemphigoid: The Effect of Risk Factors at Presentation on Treatment Outcomes.

PURPOSE: Analyze the influence of risk factors at presentation in the long-term immunosuppressive therapy (IMT) outcomes of ocular mucous membrane pemphigoid (OMMP). DESIGN: Retrospective multicenter study. PARTICIPANTS: Patients with OMMP seen at the Duke Eye Center, Tecnologico de Monterrey, and Hospital Clinic of Barcelona from 1990 to 2022. METHODS: Data at presentation on demographics, direct immunofluorescence, ocular findings, sites of extraocular manifestations (EOMs), and previous treatments in patients with a clinical or laboratory diagnosis of OMMP, were analyzed with multivariable analysis and Kaplan-Meier plots to identify factors associated with adverse outcomes. MAIN OUTCOME MEASURES: (1) Inflammatory control (no conjunctival inflammation in both eyes at 3 months on IMT); (2) relapse (new-onset inflammation after absolute control in either eye); (3) progression (≥ 1 cicatrizing stage progression in either eye); and (4) vision loss (≥ 2 Snellen lines). RESULTS: A total of 117 patients (234 eyes), 61% (71/117) of whom were women, with a mean age of 66.6 (SD: 12.4) years (range: 37-97 years) and median follow-up of 34 months (interquartile range: 16-66 months; range: 3-265 months), were enrolled. Inflammatory control was achieved in 57% of patients (67/117), with high-risk EOM (HR-EOM), including esophageal, nasopharyngeal, and/or genital involvement (adjusted odds ratio [aOR]: 12.51; 95% confidence interval [CI]: 2.61-59.99; P = 0.002) and corneal scarring (aOR: 3.06; 95% CI, 1.15-8.14; P = 0.025), as significant risk factors for persistent inflammation. Disease relapse, progression, and vision loss occurred in 20% of patients (23/117), 12% of patients (14/117), and 27% of patients (32/117), respectively. Baseline corneal scarring was a risk factor for relapse (adjusted hazard ratio: 4.14; 95% CI: 1.61-10.62; P = 0.003), progression (aOR: 11.46; 95% CI: 1.78-73.75; P = 0.010), and vision loss (aOR: 3.51; 95% CI: 1.35-9.10; P = 0.010). HR-EOM was associated with stage progression (aOR, 34.57; 95% CI, 6.57-181.89; P<0.001) and vision loss (aOR, 8.42; 95% CI, 2.50-28.42; P = 0.001). No significant differences were found between IMT regimes and relapse (P = 0.169). CONCLUSIONS: Ocular mucous membrane pemphigoid presenting with HR-EOMs and corneal scarring has an increased risk of stage progression and vision loss. Corneal scarring and severe inflammation at baseline were associated with an increased risk of relapse. A disease progression staging system incorporating both the HR-EOMs and corneal involvement is required to predict the visual outcome of OMMP better. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Access to Laparoscopic Pediatric Surgery: Do Ethnic and Racial Disparities Exist?

INTRODUCTION: Disparate access to laparoscopic surgery may contribute to poorer health outcomes among racial and ethnic minorities, especially among children. We investigated whether racial and ethnic disparities in laparoscopic procedures existed among four common surgical operations in the pediatric population in the United States. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program-Pediatrics, we conducted a retrospective review of pediatric patients, aged less than 18 y old, undergoing appendectomy, fundoplication, cholecystectomy, and colectomy from 2012 to 2021. To compare the surgical approach (laparoscopy or open), a propensity score matching algorithm was used to compare laparoscopic and open procedures between non-Hispanic Black with non-Hispanic White children and Hispanic with non-Hispanic White children. RESULTS: 143,205, 9,907, 4,581, and 26,064 children underwent appendectomy, fundoplication, colectomy, and cholecystectomy, respectively. After propensity score matching, non-Hispanic Black children undergoing appendectomy were found to be treated laparoscopically less than non-Hispanic White children (93.5% versus 94.4%, P = 0.007). With fundoplication, Hispanic children were more likely to be treated laparoscopically than White ones (86.7% versus 80.9%, P < 0.0001). There were no statistically significant differences between Black or Hispanic children and White children in rates of laparoscopy for other procedures. CONCLUSIONS: Though some racial and ethnic disparities exist with appendectomies and fundoplications, there is limited evidence to indicate that widespread inequities among common laparoscopic procedures exist in the pediatric population.

Access to Laparoscopic Pediatric Surgery: Do Ethnic and Racial Disparities Exist?

INTRODUCTION: Disparate access to laparoscopic surgery may contribute to poorer health outcomes among racial and ethnic minorities, especially among children. We investigated whether racial and ethnic disparities in laparoscopic procedures existed among four common surgical operations in the pediatric population in the United States. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program-Pediatrics, we conducted a retrospective review of pediatric patients, aged less than 18 y old, undergoing appendectomy, fundoplication, cholecystectomy, and colectomy from 2012 to 2021. To compare the surgical approach (laparoscopy or open), a propensity score matching algorithm was used to compare laparoscopic and open procedures between non-Hispanic Black with non-Hispanic White children and Hispanic with non-Hispanic White children. RESULTS: 143,205, 9,907, 4,581, and 26,064 children underwent appendectomy, fundoplication, colectomy, and cholecystectomy, respectively. After propensity score matching, non-Hispanic Black children undergoing appendectomy were found to be treated laparoscopically less than non-Hispanic White children (93.5% versus 94.4%, P = 0.007). With fundoplication, Hispanic children were more likely to be treated laparoscopically than White ones (86.7% versus 80.9%, P < 0.0001). There were no statistically significant differences between Black or Hispanic children and White children in rates of laparoscopy for other procedures. CONCLUSIONS: Though some racial and ethnic disparities exist with appendectomies and fundoplications, there is limited evidence to indicate that widespread inequities among common laparoscopic procedures exist in the pediatric population.

Cryoablation Reduces Opioid Consumption and Length of Stay After Pulmonary Metastasectomy.

INTRODUCTION: Intraoperative cryoablation of intercostal thoracic nerves is gaining popularity as a technique that decreases postoperative pain in thoracic surgery. Our study evaluates the efficacy and safety of cryoablation in pain management of pediatric cancer patients undergoing thoracotomy. METHODS: We reviewed cancer patients undergoing thoracotomies for pulmonary metastasis resection at our children's hospital from 2017 to 2023. Patients who received cryoablation were compared to those who did not. Our primary outcomes were self-reported postoperative pain scores (from 0 to 10) and opioid consumption, measured as oral morphine equivalent per kilogram. RESULTS: Thirty eight procedures were performed in 17 patients, of which 11 (64.7%) were males. Cryoablation was used in 14 (32.4%) procedures, while it was not in 24 (67.6%). Median age (17 y in both groups, P = 0.84) and length of surgery (300 cryoablation versus 282 no cryoablation, P = 0.65) were similar between the groups. Patients treated with cryoablation had a shorter hospital stay compared to those who did not (3.0 versus 4.5 d, respectively, P = 0.04) and received a lower total dose of opioids (2.2 oral morphine equivalent per kilogram versus 14.4, P = 0.004). No significant difference was noted in daily pain scores between the two groups (3.8 cryoablation versus 3.9 no cryoablation, P = 0.93). There was no difference in rates of readmissions between the cryoablation and no-cryoablation groups (14.3% versus 8.3%, P = 0.55). CONCLUSIONS: Our study suggests that cryoablation of the thoracic nerves during a thoracotomy is associated with reduced opiate consumption and shorter hospital stay. Cryoablation appears to be a promising technique for pain management in this patient population.

Enhanced Recovery After Surgery 2.0: Optimizing Pain Management in Nuss Procedure: Cryoablation and Nerve Block Strategies for Reduced Opioid Use.

INTRODUCTION: Our study assesses the association between cryoablation, with and without nerve block supplementation, post-Nuss procedure pain, and opioid use in pectus excavatum (PE) patients. METHODS: We conducted a retrospective cohort study at a single center for PE patients who underwent the Nuss procedure from 2017 to 2022. Outcomes included postoperative opioid use (measured in oral morphine milligram equivalent per kilogram [OME/kg]), average pain score (scale 0-10), and length of stay (LOS). RESULTS: One hundred sixty-four patients (146 males and 18 females) were included, with 79 (48.2%) receiving neither cryoablation nor nerve block, 60 (36.6%) receiving intraoperative cryoablation alone, and 25 (15.2%) receiving both cryoablation and nerve block. The median age was 16 y. Nerve block recipients consumed fewer opioids during hospitalization than cryoablation alone and nonintervention groups (1.5 versus 2.3 versus 5.8 OME/kg, respectively, P < 0.0001). Average pain scores over the total LOS were lower in nerve block recipients (3.5 versus 3.8 versus 4.2, P = 0.03), particularly on postoperative day 0 (P = 0.002). Nerve block recipients had a shorter LOS than cryoablation alone and nonintervention groups (43.4 versus 54.7 versus 66.2 h, P < 0.0001). On multivariate analysis, cryoablation alone resulted in significantly less opioid use compared to no intervention (3.32 OME/kg reduction, 95% confidence interval -4.16 to -2.47, P < 0.0001). Addition of nerve block further reduced opioid use by 1.10 OME/kg (95% confidence interval -2.07 to -0.14, P = 0.04). CONCLUSIONS: Cryoablation with nerve block supplementation is associated with reduced pain, opioid use, and LOS post-Nuss for PE repair compared to cases without cryoablation or with cryoablation only. Cryoablation with regional nerve blocks should be considered for Nuss repair under the enhanced recovery after surgery pathway.

Evaluation of Limited English Proficiency in the Management and Outcomes of Appendicitis in Children.

INTRODUCTION: Appendectomies are one of the most common pediatric surgical procedures. Limited English proficiency (LEP) may lead to disparities in health outcomes between English-proficient and LEP patients. This study assesses the association between LEP and postoperative outcomes in pediatric appendectomy. METHODS: We analyzed records from the American College of Surgeons National Surgical Quality Improvement Program-Pediatric database from 2010 to 2023 under 18 y of age undergoing appendectomy at our institution. LEP was defined as the need for an interpreter. Primary outcomes were postoperative complications, length of stay (LOS), and postoperative emergency department (ED) visits within 30 d of discharge. Multivariable analyses were performed. RESULTS: One thousand one hundred forty three children with appendicitis were identified, with 208 (18.2%) LEP and 935 (81.8%) English-proficient patients. LEP children were more likely to present with complicated appendicitis (42.8% versus 25.5%, P < 0.0001) and sepsis (34.1% versus 21.6%, P = 0.0003). LEP patients experience more serious (8.6% versus 3.9%, P = 0.02), overall complications (10.1% versus 5.5%, P = 0.006), and organ/surgical space site infections (8.2% versus 3.3%, P = 0.003). On multivariable analysis controlling for ethnicity and factors associated with complicated presentation, LEP was associated with increased postoperative ED visits (adjusted odds ratio [aOR] 2.64, 95% confidence interval [CI] = 1.40-4.39), but not LOS (aOR 1.86, 95% CI = 0.87-3.97) or complications (aOR 1.76, 95% CI = 0.79-4.00). CONCLUSIONS: LEP is independently associated with increased postoperative ED visits. Higher rates of complications and longer LOS may be related to increased complicated appendicitis at presentation. The role of cultural preferences and other social determinants of health that contribute to these disparities needs more investigation.

A Scoping Review of Limited English Proficiency and Immigration in Pediatric Surgery.

INTRODUCTION: With increasing globalization and diversity, the intersection of immigration and language barriers can impact patient outcomes. This scope review aims to summarize current evidence on immigration and language barriers on pediatric surgical outcomes. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Four databases were searched with Medical Subject Heading terms describing pediatric surgery, immigration, limited English proficiency (LEP), and refugees between 2000-2023. Four independent reviewers screened and analyzed texts for final inclusion. RESULTS: Thirty-three studies were included. Ten studies described disease incidence and severity, finding that LEP, immigrant, and refugee patients were more likely to present with severe disease in appendicitis and traumatic injuries. five studies described pain management, finding patients with LEP received fewer pain assessments, waited longer for analgesia, and had more discrepancies in pain scores. Seventeen studies investigated treatment receipt and delay, finding that immigrants and patients with LEP had longer time to and reduced rates of treatment. Seventeen studies described surgical outcomes, finding that patients with LEP have longer length of stay and more postoperative emergency department visits but fewer follow-up appointments. In kidney transplants, patients with LEP and immigrants had worse outcomes, but these trends are not seen in immigrants from Europe. Overall, immigrants and refugees have higher rates of complications and mortality. CONCLUSIONS: Immigrants and patients with LEP and are more likely to present with advanced disease and severe injuries, receive inadequate pain management, experience delays in surgery, and suffer more complications. There is continued need to assess the impact of LEP and immigration on pediatric surgery outcomes.

Early-onset scoliosis.

PURPOSE OF REVIEW: The aim of this review is to provide the reader with the most updated available information so that it can be helpful in the approach of patients with early-onset scoliosis (EOS). RECENT FINDINGS: While confirming the efficacy and safety of classic techniques for the treatment of EOS such as traditional growing rods or Mehta casting, recent research suggests that there is room for improvement with less invasive techniques. SUMMARY: The most important goal when treating patients with EOS should be to promote rib cage expansion and lung development. Different techniques have been described and may be used depending on the specific patient's characteristics.

Spider mite infestation triggers coordinated hormonal trade-offs enabling plant survival with a fitness cost.

Tetranychus urticae is an important pest that causes severe damage to a wide variety of plants and crops, leading to a substantial productivity loss. Previous research has been focused on plant defence response to T. urticae to improve plant resistance. However, plant growth, development and reproduction throughout the infestation process have not been previously studied. Through physiological, biochemical, transcriptomic and hormonomic evaluation, we uncover the molecular mechanisms directing the defence-growth trade-off established in Arabidopsis upon T. urticae infestation. Upon mite attack, plants suffer an adaptation process characterized by a temporal separation between the defence and growth responses. Jasmonic and salicylic acids regulate the main defence responses in combination with auxin and abscisic acid. However, while the reduction of both auxin signalling and gibberellin, cytokinin and brassinosteroid biosynthesis lead to initial growth arrest, increasing levels of growth hormones at later stages enables growth restart. These alterations lead to a plant developmental delay that impacts both seed production and longevity. We demonstrate that coordinated trade-offs determine plant adaptation and survival, revealing mite infestation has a long-lasting effect negatively impacting seed viability. This study provides additional tools to design pest management strategies that improve resistance without penalty in plant fitness.

Immunization of recombinant NS3 protein (protease region) of dengue virus induces high levels of CTLA-4 and apoptosis in splenocytes of BALB/c mice.

DENV infection outcomes depend on the host's variable expression of immune receptors and mediators, leading to either resolution or exacerbation. While the NS3 protein is known to induce robust immune responses, the specific impact of its protease region epitopes remains unclear. This study investigated the effect of recombinant NS3 protease region proteins from all four DENV serotypes on splenocyte activation in BALB/c mice (n = 5/group). Mice were immunized with each protein, and their splenocytes were subsequently stimulated with homologous antigens. We measured the expression of costimulatory molecules (CD28, CD80, CD86, CD152) by flow cytometry, along with IL-2 production, CD25 expression, and examined the antigen-specific activation of CD4 + and CD8 + T cells. Additionally, the expression of IL-1, IL-10, and TGF-ß1 in splenocytes from immunized animals was assessed. Apoptosis was evaluated using Annexin V/PI staining and DNA fragmentation analysis. Stimulation of splenocytes from immunized mice triggered apoptosis (phosphatidylserine exposure and caspase 3/7 activation) and increased costimulatory molecule expression, particularly CD152. Low IL-2 production and low CD25 expression, as well as sustained expression of the IL-10 gene. These results suggest that these molecules might be involved in mechanisms by which the NS3 protein contributes to viral persistence and disease pathogenesis.

Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia.

Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100 000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2182 individuals presenting with ataxia and 6658 non-neurological probands recruited in the 100 000 Genomes Project. Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100 000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100 000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci.

Ethnic disparities in pediatric appendicitis: the impact of hispanic ethnicity on presentation, complications, and postoperative outcomes.

PURPOSE: Our study investigates ethnic disparities in pediatric appendicitis, focusing on the impact of Hispanic ethnicity on presentation, complications, and postoperative outcomes. METHODS: We conducted a retrospective analysis of pediatric patients undergoing appendectomy for acute appendicitis from 2015 to 2020 using the National Surgical Quality Improvement Program-Pediatric database. We compared 30-day postoperative complications, postoperative length of stay, and postoperative interventions between Hispanic and non-Hispanic White patients. RESULTS: 65,976 patients were included, of which 23,462 (35.56%) were Hispanic and 42,514 (64.44%) non-Hispanic White. Hispanic children were more likely to present to the hospital with complicated appendicitis (31.75% vs. 25.15%, P < 0.0001) and sepsis (25.22% vs. 19.02%, P < 0.0001) compared to non-Hispanic White. Hispanics had higher rates of serious complications (4.06% vs. 3.55%, P = 0.001) but not overall complications (5.37% vs. 5.09%, P = 0.12). However, after multivariate analysis, Hispanic ethnicity was not associated with an increased rate of serious postoperative complications (OR 0.93, CI 0.85-1.01, P = 0.088); it was associated with less overall complications (OR 0.88, CI 0.81-0.96, P = 0.003) but a longer postoperative length of stay (OR 1.09, CI 1.04-1.14, P < 0.0001). CONCLUSION: Hispanic children are more likely to present with complicated appendicitis, contributing to increased postoperative complications. Notably, upon adjustment for the impact of complicated appendicitis, our findings suggest potentially favorable outcomes for Hispanic ethnicity. This emphasizes the need to understand delays in presentation to improve outcomes in the Hispanic population.

Management of Extracorporeal Membrane Oxygenation Anticoagulation in the Perioperative Period: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic review-informed, modified Delphi consensus regarding the management of children on extracorporeal membrane oxygenation (ECMO) undergoing invasive procedures or interventions developed by the Pediatric Anticoagulation on ECMO CollaborativE (PEACE) Consensus Conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: ECMO anticoagulation and hemostasis management in the perioperative period and during procedures. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. Seventeen references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. Four good practice statements, 7 recommendations, and 18 consensus statements are presented. CONCLUSIONS: Although agreement among experts was strong, important future research is required in this population for evidence-informed recommendations.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

SCoV2-MD: a database for the dynamics of the SARS-CoV-2 proteome and variant impact predictions.

SCoV2-MD (www.scov2-md.org) is a new online resource that systematically organizes atomistic simulations of the SARS-CoV-2 proteome. The database includes simulations produced by leading groups using molecular dynamics (MD) methods to investigate the structure-dynamics-function relationships of viral proteins. SCoV2-MD cross-references the molecular data with the pandemic evolution by tracking all available variants sequenced during the pandemic and deposited in the GISAID resource. SCoV2-MD enables the interactive analysis of the deposited trajectories through a web interface, which enables users to search by viral protein, isolate, phylogenetic attributes, or specific point mutation. Each mutation can then be analyzed interactively combining static (e.g. a variety of amino acid substitution penalties) and dynamic (time-dependent data derived from the dynamics of the local geometry) scores. Dynamic scores can be computed on the basis of nine non-covalent interaction types, including steric properties, solvent accessibility, hydrogen bonding, and other types of chemical interactions. Where available, experimental data such as antibody escape and change in binding affinities from deep mutational scanning experiments are also made available. All metrics can be combined to build predefined or custom scores to interrogate the impact of evolving variants on protein structure and function.

Targeting bacterial growth in biofilm conditions: rational design of novel inhibitors to mitigate clinical and food contamination using QSAR.

Antimicrobial resistance (AMR) is a pressing global issue exacerbated by the abuse of antibiotics and the formation of bacterial biofilms, which cause up to 80% of human bacterial infections. This study presents a computational strategy to address AMR by developing three novel quantitative structure-activity relationship (QSAR) models based on molecular topology to identify potential anti-biofilm and antibacterial agents. The models aim to determine the chemo-topological pattern of Gram (+) antibacterial, Gram (-) antibacterial, and biofilm formation inhibition activity. The models were applied to the virtual screening of a commercial chemical database, resulting in the selection of 58 compounds. Subsequent in vitro assays showed that three of these compounds exhibited the most promising antibacterial activity, with potential applications in enhancing food and medical device safety.