The role of tunneling in enzyme catalysis of C–H activation

AbstractRecent data from studies of enzyme catalyzed hydrogen transfer reactions implicate a new theoretical context in which to understand C–H activation. This is much closer to the Marcus theory of electron transfer, in that environmental factors influence the probability of effective wave function overlap from donor to acceptor atoms. The larger size of hydrogen and the availability of three isotopes (H, D and T) introduce a dimension to the kinetic analysis that is not available for electron transfer. This concerns the role of gating between donor and acceptor atoms, in particular whether the system in question is able to tune distance between reactants to achieve maximal tunneling efficiency. Analysis of enzyme systems is providing increasing evidence of a role for active site residues in optimizing the inter-nuclear distance for nuclear tunneling. The ease with which this optimization can be perturbed, through site-specific mutagenesis or an alteration in reaction conditions, is also readily apparent from an analysis of the changes in the temperature dependence of hydrogen isotope effects

Reproductive Complications in Childhood Cancer Survivors

Gonadal dysfunction and infertility after cancer treatment are major concerns for childhood cancer survivors and their parents. Uncertainty about fertility or being diagnosed with infertility has a negative impact on quality of survival. In this article, determinants of gonadal damage are reviewed and consequences for fertility and pregnancies are discussed. Recommendations for screening and treatment of gonadal function are provided. These should enable timely treatment of gonadal insufficiency aiming to improve linear growth, pubertal development, and sexual functioning. Options for fertility preservation are discussed

A systematic review on safety and surgical and anesthetic risks of elective abdominal laparoscopic surgery in infants to guide laparoscopic ovarian tissue harvest for fertility preservation for infants facing gonadotoxic treatment

Background: Infertility is an important late effect of childhood cancer treatment. Ovarian tissue cryopreservation (OTC) is established as a safe procedure to preserve gonadal tissue in (pre)pubertal girls with cancer at high risk for infertility. However, it is unclear whether elective laparoscopic OTC can also be performed safely in infants <1 year with cancer. This systematic review aims to evaluate the reported risks in infants undergoing elective laparoscopy regarding mortality, and/or critical events (including resuscitation, circulatory, respiratory, neurotoxic, other) during and shortly after surgery. Methods: This systematic review followed the Preferred reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline. A systematic literature search in the databases Pubmed and EMbase was performed and updated on February 15th, 2023. Search terms included ‘infants’, ‘intubation’, ‘laparoscopy’, ‘mortality’, ‘critical events’, ‘comorbidities’ and their synonyms. Papers published in English since 2000 and describing at least 50 patients under the age of 1 year undergoing laparoscopic surgery were included. Articles were excluded when the majority of patients had congenital abnormalities. Quality of the studies was assessed using the QUIPS risk of bias tool. Results: The Pubmed and Embase databases yielded a total of 12,401 unique articles, which after screening on title and abstract resulted in 471 articles to be selected for full text screening. Ten articles met the inclusion criteria for this systematic review, which included 1778 infants <1 years undergoing elective laparoscopic surgery. Mortality occurred once (death not surgery-related), resuscitation in none and critical events in 53/1778 of the procedures. Conclusion: The results from this review illustrate that morbidity and mortality in infants without extensive comorbidities during and just after elective laparoscopic procedures seem limited, indicating that the advantages of performing elective laparoscopic OTC for infants with cancer at high risk of gonadal damage may outweigh the anesthetic and surgical risks of laparoscopic surgery in this age group

The applicability of the central line-associated bloodstream infection (CLABSI) criteria for the evaluation of bacteremia episodes in pediatric oncology patients

Background: The aim of this study was to investigate the applicability of the central line-associated bloodstream infection (CLABSI) criteria of the Centers for Disease Control and Prevention in pediatric oncology patients. Methods: Bacteremia episodes from 2020 to 2022 from a prospective cohort of pediatric oncology patients with a central venous catheter were included. Episodes were classified by three medical experts following the CLABSI criteria as either a CLABSI or non-CLABSI (i.e., contamination, other infection source, or mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI)). Subsequently, they were asked if and why they (dis)agreed with this diagnosis following the criteria. The primary outcome was the percentage of episodes where the experts clinically disagreed with the diagnosis given following the CLABSI criteria. Results: Overall, 84 bacteremia episodes in 71 patients were evaluated. Following the CLABSI criteria, 34 (40%) episodes were classified as CLABSIs and 50 (60%) as non-CLABSIs. In 11 (13%) cases the experts clinically disagreed with the diagnosis following the CLABSI criteria. The discrepancy between the CLABSI criteria and clinical diagnosis was significant; McNemar's test p <.01. Disagreement by the experts with the CLABSI criteria mostly occurred when the experts found an MBI-LCBI a more plausible cause of the bacteremia than a CLABSI due to the presence of a gram negative bacteremia (Pseudomonas aeruginosa n = 3) and/or mucositis. Conclusions: A discrepancy between the CLABSI criteria and the evaluation of the experts was observed. Adding Pseudomonas aeruginosa as an MBI pathogen and incorporating the presence of mucositis in the MBI-LCBI criteria, might increase the applicability

A dynamic default revision mechanism for speculative computation

In this work a default revision mechanism is introduced into Speculative Computation to manage incomplete information. The default revision is supported by a method for the generation of default constraints based on Bayesian Networks. The method enables the generation of an initial set of defaults which is used to produce the most likely scenarios during the computation, represented by active processes. As facts arrive, the Bayesian Network is used to derive new defaults. The objective with such a new dynamic mechanism is to keep the active processes coherent with arrived facts. This is achieved by changing the initial set of default constraints during the reasoning process in Speculative Computation. A practical example in clinical decision support is described.info:eu-repo/semantics/publishedVersio

Memorial meshwork: the making of the commemorative space of the Hyde Park 7/7 memorial

How do memorials act to transmit memory through the organization of space? In this paper we contrast a ‘preservation’ model of the endurance of encoded memory with a ‘meshwork’ model which treats memory as emergent on the perdurance of the memorial site. Developing a theoretical framework from Tim Ingold’s (2011; 2013) work, we describe how memorialization receives its spatial form through a collective work of braiding together multiple threads of activities and material flows. To illustrate, we examine the spatial and temporal organization of the Hyde Park 7/7 memorial from its initial designs, through to installation and contemporary use. We draw on interview data featuring various stakeholders in the 7/7 memorial project to analyse the relationship between memorial space and material relations. We develop an approach to organizational space as an unfinished meshwork that folds together wanted and unwanted memory, making the historical a matter of ongoing live concern but with the absence of a permanent guiding narrative

Central Venous Catheter-related Bloodstream Infections Caused by Enterobacterales in Pediatric Oncology Patients: Catheter Salvage or Removal

Background: The aim was to determine whether salvage treatment with systemic antibiotics is a safe and effective strategy for Enterobacterales bloodstream infections (BSI) in pediatric oncology patients with a central venous catheter (CVC). Methods: A retrospective study was performed on oncology and stem cell recipient patients with a CVC and blood culture with Enterobacterales, at the Princess Máxima Centre for Pediatric Oncology, Utrecht, the Netherlands. Analyses were performed for all BSI and for episodes meeting central line-associated bloodstream infection (CLABSI) criteria. The cumulative incidence of an event (ie, removal, intensive care admission or death) was estimated after blood culture collection for episodes primarily treated with antibiotics. The effect of prognostic factors on the hazard of the event of interest was assessed by estimating a Cox proportional hazard regression model. Results: In total, 95 CVC-related Enterobacterales BSIs in 82 patients were included; 12 (13%) BSIs required immediate CVC removal and for 83 (87%) BSIs CVC salvage was attempted. The cumulative incidence of events at 60 days was 53.0% [95% confidence interval (CI): 41.7-63.1] for BSIs (n = 83), and 64.4% (95% CI: 48.3-76.7) for CLABSIs (n = 45). The events occurred after a median of 6 (Q1-Q3: 2-15) and 6 (Q1-Q3: 2-20) days for BSIs and CLABSIs, respectively. Intensive care admission after salvage treatment was required in 16% of the BSIs and CLABSIs, resulting in death in 5% and 2% of cases, respectively. No significant association between risk factors and events was found. Conclusions: The cumulative incidence of an event at 60 days after salvage treatment for Enterobacterales CLABSIs and BSIs in pediatric oncology patients is high. Immediate CVC removal appears recommendable for this patient group

Central venous catheter–associated complications in pediatric patients diagnosed with Hodgkin lymphoma: implications for catheter choice

Purpose: The purpose of this study was to determine the most optimal central venous catheter (CVC) for pediatric patients with Hodgkin lymphoma (HL) in terms of complications. Methods: A retrospective study including patients diagnosed with HL from 2015 to 2021 at the Princess Máxima Center was performed. Patients were followed from CVC insertion until removal or 06–2021, whichever came first. The primary outcome was the CVC-related complication incidence rate (IR) per 1000 CVC-days. Furthermore, the incidence rate ratio (IRR) was calculated by comparing complication IRs between peripherally inserted central catheters (PICC) and totally implantable venous access ports (TIVAP). Additionally, risk factors for central venous thrombosis (CVT) were identified. Results: A total of 98 patients were included. The most frequently observed complications were local irritation/infections (18%; IR 0.93), malfunctions (15%; IR 0.88), and CVC-related CVTs (10%; IR 0.52). Single lumen PICCs were associated with a higher risk of complications (49% vs. 26%; IRR 5.12, CI95% 2.76–9.50), severe complications (19% vs. 7%; IRR 11.96, CI95% 2.68–53.42), and early removal (18% vs. 7%; IRR 9.96, CI95% 2.18–45.47). A single lumen PICC was identified as a risk factor for CVC-related CVT when compared to TIVAPs (12% vs. 7%, IRR 6.98, CI95% 1.45–33.57). Conclusion: The insertion of a TIVAP rather than a PICC should be recommended for pediatric patients with HL, especially in the presence of CVT-related risk factors. Future trials should evaluate the efficacy and safety of direct oral anticoagulants for the primary prevention of CVT in pediatric patients with a PICC and other CVT-related risk factors

Do Biofilm Formation and Interactions with Human Cells Explain the Clinical Success of Acinetobacter baumannii?

BACKGROUND: The dramatic increase in antibiotic resistance and the recent manifestation in war trauma patients underscore the threat of Acinetobacter baumannii as a nosocomial pathogen. Despite numerous reports documenting its epidemicity, little is known about the pathogenicity of A. baumannii. The aim of this study was to obtain insight into the factors that might explain the clinical success of A. baumannii. METHODOLOGY/PRINCIPAL FINDINGS: We compared biofilm formation, adherence to and inflammatory cytokine induction by human cells for a large panel of well-described strains of A. baumannii and compared these features to that of other, clinically less relevant Acinetobacter species. Results revealed that biofilm formation and adherence to airway epithelial cells varied widely within the various species, but did not differ among the species. However, airway epithelial cells and cultured human macrophages produced significantly less inflammatory cytokines upon exposure to A. baumannii strains than to strains of A. junii, a species infrequently causing infection. CONCLUSION/SIGNIFICANCE: The induction of a weak inflammatory response may provide a clue to the persistence of A. baumannii in patients