Human exposure to arsenicals is associated with devastating diseases such as cancer and neurodegeneration. At the same time, arsenic-based drugs are used as therapeutic agents. The ability of arsenic to directly bind to proteins is correlated with its toxic and therapeutic effects highlighting the importance of elucidating arsenic-protein interactions. In this study, we took a proteomic approach and identified 174 proteins that bind to arsenic in Saccharomyces cerevisiae. Proteins involved in nucleocytoplasmic transport were markedly enriched among the arsenic-binding proteins, and we demonstrate that arsenic-binding to nuclear import factors results in their relocation from the nuclear envelope and subsequent aggregation in the cytosol. Similarly, nuclear pore proteins that make up the nuclear pore complex mislocalized and aggregated in arsenic-exposed cells. Consequently, arsenic was shown to inhibit nuclear protein import and export. We propose a model in which arsenic-binding to nuclear transport factors leads to their mislocalization and aggregation, which disrupts nucleocytoplasmic transport and causes arsenic sensitivity.

Stress-activated protein kinases (SAPKs) respond to a wide variety of stressors. In most cases, the pathways through which specific stress signals are transmitted to the SAPK are not known. We show that the yeast SAPK Hog1 is activated by acetic acid through an intracellular mechanism that does not involve stimulation of the high osmolarity glycerol (HOG) signaling pathway beyond its basal level. Rather, acetic acid treatment drives the formation of stress granules, which function as a scaffold to bring Hog1 together with Pbs2, its immediately upstream activating kinase, in a stable assembly that leverages the basal activity of Pbs2 to phosphorylate Hog1. Deletion analysis of stress granule components revealed that the assembly is critical for both the acetic acid-induced activation of Hog1 and its association with Pbs2. Activated Hog1 remains associated with stress granules, which may have implications for its targeting.

Human exposure to arsenicals is associated with devastating diseases such as cancer and neurodegeneration. At the same time, arsenic-based drugs are used as therapeutic agents. The ability of arsenic to directly bind to proteins is correlated with its toxic and therapeutic effects highlighting the importance of elucidating arsenic-protein interactions. In this study, we took a proteomic approach and identified 174 proteins that bind to arsenic in Saccharomyces cerevisiae. Proteins involved in nucleocytoplasmic transport were markedly enriched among the arsenic-binding proteins, and we demonstrate that arsenic-binding to nuclear import factors results in their relocation from the nuclear envelope and subsequent aggregation in the cytosol. Similarly, nuclear pore proteins that make up the nuclear pore complex mislocalized and aggregated in arsenic-exposed cells. Consequently, arsenic was shown to inhibit nuclear protein import and export. We propose a model in which arsenic-binding to nuclear transport factors leads to their mislocalization and aggregation, which disrupts nucleocytoplasmic transport and causes arsenic sensitivity.

Importance Neonates requiring surgery are often cared for in neonatal intensive care units (NICUs). Despite a breadth of surgical pathology, neonates share many perioperative priorities that allow for the development of unit-wide evidence-based Enhanced Recovery After Surgery (ERAS) recommendations. Observations The guideline development committee included pediatric surgeons, anesthesiologists, neonatal nurses, and neonatologists in addition to ERAS content and methodology experts. The patient population was defined as neonates (first 28 days of life) undergoing a major noncardiac surgical intervention while admitted to a NICU. After the first round of a modified Delphi technique, 42 topics for potential inclusion were developed. There was consensus to develop a search strategy and working group for 21 topic areas. A total of 5763 abstracts were screened, of which 98 full-text articles, ranging from low to high quality, were included. A total of 16 recommendations in 11 topic areas were developed with a separate working group commissioned for analgesia-related recommendations. Topics included team communication, preoperative fasting, temperature regulation, antibiotic prophylaxis, surgical site skin preparation, perioperative ventilation, fluid management, perioperative glucose control, transfusion thresholds, enteral feeds, and parental care encouragement. Although clinically relevant, there were insufficient data to develop recommendations concerning the use of nasogastric tubes, Foley catheters, and central lines. Conclusions and Relevance Despite varied pathology, neonatal perioperative care within NICUs allows for unit-based ERAS recommendations independent of the planned surgical procedure. The 16 recommendations within this ERAS guideline are intended to be implemented within NICUs to benefit all surgical neonates.

Background: Moyamoya is a progressive arteriopathy condition characterized by steno-occlusion of the arteries of the circle of Willis. MRI performed with hypercapnic challenge can image blood-oxygen-level-dependent cerebrovascular reactivity (BOLD-CVR) thereby assessing cerebrovascular reserve. MRI studies of children <7 years of age, or with significant behavioural challenges require anesthesia. The purpose of this study was to validate the use of ventilator-induced hypercapnic challenge under general anaesthesia (GA). Methods: Children with moyamoya underwent two BOLD-CVR imaging in the same session under GA (GA-CVR). Differences in CVR estimates and intraclass correlation coefficient (ICC) between repeated scans were examined to determine repeatability across grey and white matter tissue and vascular territories. Bland-Altman plots were used to visulaize the overall variation between the scans. The associations with age, moyamoya types, and stroke presentation were also examined. Qualitative scoring by visual inspection was also conducted by trained neurologists. Results: Thirty-two paired GA-CVR studies (sixty-four scans in total) were analyzed (mean age: 7.07 (2.74 -17.95) years, 13 females). Forty-one percent (41%) were under 7 and 77%, under 10. No significant differences between repeated scans were found for any of the CVR estimates, when summarized by tissue and vascular territory. Of the paired studies, repeatability (ICC) for the whole-brain CVR estimates was excellent (≥0.74) in 14 (43.8%), good (≤0.59, >0.74) in 7 (21.9%), fair (≤0.41, >0.59) in 6 (18.8%) and poor (<0.41) in 5 (15.6%). Bland-Altman plots illustrated the overall variation of whole-brain CVR within 95% confidence interval level. Repeatability indices were not affected by children’s age and other clinical factors. On qualitative scoring, the Cohen weighted kappa showed substantial agreement in both right (0.75) and left (0.81) hemispheres. Conclusion: Our study support the clinical use of GA-CVR across all ages and disease conditions. The GA-CVR provides a feasible, repeatable, and reliably interpretable tool for the assessment of cerebrovascular reserve of very young and behaviourally challenged children with moyamoya.

Purpose Enhanced recovery after surgery [ERAS] is an approach for standardization of perioperative care aimed at improving patient outcomes. The primary aim of this study was to determine if length of stay (LOS) differed by protocol type (ERAS vs. non-ERAS [N-ERAS]) in patients undergoing surgery for adolescent idiopathic scoliosis (AIS). Methods A retrospective cohort study was conducted. Patient characteristics were collected and compared between groups. Differences in LOS were assessed using regression adjusting for age, sex, BMI, pre-surgical Cobb angle, levels fused and year of surgery. Results Fifty nine ERAS patients were compared to 81 N-ERAS patients. Patients were comparable in their baseline characteristics. Median LOS was 3 days (IQR = 3–4) for the ERAS group, compared to 5 days (IQR = 4–5) for the N-ERAS group ( p < 0.001). The ERAS group had a significantly lower adjusted rate of stay (RR = 0.75; 95% CI = 0.62–0.92). The ERAS group had significantly lower average pain on post-operative days 0 (least-squares-mean [LSM] 2.66 vs. 4.41, p < 0.001), POD1 (LSM 3.12 vs. 4.48, p < 0.001) and POD5 (LSM 2.84 vs. 4.42, p = 0.035). The ERAS group had lower opioid consumption ( p < 0.001). LOS was predicted by the number of protocol elements received; those receiving two (RR = 1.54 95% CI = 1.05–2.24), one (RR = 1.49; 95% CI = 1.09–2.03) or none (RR = 1.60, 95% CI = 1.21–2.13) had significantly longer rates of stay than those receiving all four. Conclusion Adoption of modified ERAS-based protocol for patients undergoing PSF for AIS led to significant reduction in LOS, average pain scores, and opioid consumption.

BACKGROUND:Liver transplantation is the life-saving treatment for many end-stage pediatric liver diseases. The perioperative course, including surgical and anesthetic factors, have an important influence on the trajectory of this high-risk population. Given the complexity and variability of the immediate postoperative course, there would be utility in identifying risk factors that allow prediction of adverse outcomes and intensive care unit trajectories. AIMS:The aim of this study was to develop and validate a risk prediction model of prolonged intensive care unit length of stay in the pediatric liver transplant population. METHODS:This is a retrospective analysis of consecutive pediatric isolated liver transplant recipients at a single institution between April 1, 2013 and April 30, 2020. All patients under the age of 18 years receiving a liver transplant were included in the study (n = 186). The primary outcome was intensive care unit length of stay greater than 7 days. RESULTS:Recipient and donor characteristics were used to develop a multivariable logistic regression model. A total of 186 patients were included in the study. Using multivariable logistic regression, we found that age < 12 months (odds ratio 4.02, 95% confidence interval 1.20-13.51, p = .024), metabolic or cholestatic disease (odds ratio 2.66, 95% confidence interval 1.01-7.07, p = .049), 30-day pretransplant hospital admission (odds ratio 8.59, 95% confidence interval 2.27-32.54, p = .002), intraoperative red blood cells transfusion >40 mL/kg (odds ratio 3.32, 95% confidence interval 1.12-9.81, p = .030), posttransplant return to the operating room (odds ratio 11.45, 95% confidence interval 3.04-43.16, p = .004), and major postoperative respiratory event (odds ratio 32.14, 95% confidence interval 3.00-343.90, p < .001) were associated with prolonged intensive care unit length of stay. The model demonstrates a good discriminative ability with an area under the receiver operative curve of 0.888 (95% confidence interval, 0.824-0.951). CONCLUSIONS:We develop and validate a model to predict prolonged intensive care unit length of stay in pediatric liver transplant patients using risk factors from all phases of the perioperative period.

TransfusionVolume 63, Issue S5 p. 187A-188A SUPPLEMENT ARTICLE P-IG-28 | JK Exon 4 Mutation Results in a Lack of Antigen Expression on Red Blood Cells V. Drinnon, V. Drinnon Blood Assurance, IncSearch for more papers by this authorG. Denomme, G. Denomme Grifols Laboratory Solutions, IncSearch for more papers by this authorM. Stef, M. Stef Grifols Laboratory Solutions, IncSearch for more papers by this authorM. Smith, M. Smith Blood Assurance, IncSearch for more papers by this authorD. Levin, D. Levin Blood Assurance, IncSearch for more papers by this authorA. Graves, A. Graves Blood Assurance, IncSearch for more papers by this author V. Drinnon, V. Drinnon Blood Assurance, IncSearch for more papers by this authorG. Denomme, G. Denomme Grifols Laboratory Solutions, IncSearch for more papers by this authorM. Stef, M. Stef Grifols Laboratory Solutions, IncSearch for more papers by this authorM. Smith, M. Smith Blood Assurance, IncSearch for more papers by this authorD. Levin, D. Levin Blood Assurance, IncSearch for more papers by this authorA. Graves, A. Graves Blood Assurance, IncSearch for more papers by this author First published: 12 October 2023 https://doi.org/10.1111/trf.246_17554Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume63, IssueS5October 2023Pages 187A-188A RelatedInformation

Background: Neonates who require surgery are often cared for in neonatal intensive care units (NICUs). Despite a breadth of surgical pathology and required procedures, infants share many perioperative priorities that can be harnessed to develop evidence-based Enhanced Recovery After Surgery (ERAS®) recommendations that apply to all surgical neonates within a NICU.

Arsenic is an environmental toxin that exists mainly as pentavalent arsenate and trivalent arsenite. Both forms activate the yeast SAPK Hog1 but with different consequences. We describe a mechanism by which cells distinguish between these arsenicals through one-step metabolism to differentially regulate the bidirectional glycerol channel Fps1, an adventitious port for arsenite. Cells exposed to arsenate reduce it to thiol-reactive arsenite, which modifies a set of cysteine residues in target proteins, whereas cells exposed to arsenite metabolize it to methylarsenite, which modifies an additional set of cysteine residues. Hog1 becomes arsenylated, which prevents it from closing Fps1. However, this block is overcome in cells exposed to arsenite through methylarsenylation of Acr3, an arsenite efflux pump that we found also regulates Fps1 directly. This adaptation allows cells to restrict arsenite entry through Fps1 and also allows its exit when produced from arsenate exposure. These results have broad implications for understanding how SAPKs activated by diverse stressors can drive stress-specific outputs.

OBJECTIVE To assess caregiver satisfaction, procedural outcomes and practitioner opinion regarding a novel program designed for patients to undergo a deferred Jewish ritual circumcision (Brit Milah) in the operating room (OR), combined with other indicated surgical procedures. METHODS All patients undergoing Brit Milah in the OR at our institution between 2013 and 2019 were included. Surveys were administered to assess caregiver satisfaction and Society for Pediatric Urology member practice patterns. A retrospective case-control series was completed to compare complication rates and operative times for procedures with and without Brit Milah. RESULTS Forty-four intraoperative Brit Milah patients were identified. The mean procedure time for a distal hypospadias repair with Brit Milah was 66.0 minutes, compared to 62.4 minutes without (P = .57). No complications were attributable to the addition of Brit Milah. The caregiver survey had a 100% response rate. The modal response for satisfaction with the perioperative experience was 5 of 5 (ie, highly satisfied), with 100% of respondents very likely to recommend the program. 132 active Society for Pediatric Urology members responded to the survey (34.1% response rate) with 44% regularly allowing Brit Milah in the OR at their institution. 90.5% received positive caregiver feedback and 64% believe it is important to offer. CONCLUSION This novel program incorporating Brit Milah into the OR yields high caregiver satisfaction, no additional OR time or postoperative complications, and provides an opportunity to combine family-centered care with cultural competence. (C) 2021 Elsevier Inc.

Editor—Large-scale international conflicts during the 20th century acted as important catalysts for innovation and the development of new technologies. This inevitably had lasting effects on medicine, including paving the way for improved approaches to monitoring human physiology. Here we discuss how modern-day capnography, pulse oximetry, and temperature measurements were all born in part through technological inventions necessitated by evolving approaches to warfare during World War I (WWI) and World War II (WWII).

We performed phosphorylation site mapping on of budding yeast Pkc1 applying a quantitative mass spectrometry (MS)-based proteomics approach based on stable isotope labeling with amino acids in cell culture (SILAC). We determined changes in the Pkc1 phosphorylation pattern in response to genotoxic stress induced by Hydroxyurea treatment. This dataset includes all MS RAW files.

We present a 9-year-old patient with end-stage renal disease, on peritoneal dialysis, who underwent a staged prone retroperitoneoscopic bilateral nephrectomy. Bilateral nephrectomy was indicated in preparation for renal transplant in the context of genetic predisposition malignancy when immunosuppressed. The two mirror-image surgeries enable the comparison of the anesthetic management and outcomes in a single patient. Features of interest to anesthesiologists include approach to a child with chronic kidney disease, different requirements for intraoperative antihypertensives; pain management strategies, including a comparison of erector spinae plane block with and without adjunct dexmedetomidine; anesthetic management of retroperitoneoscopic pediatric surgery and the first description of using a Foley bag attached to a peritoneal dialysis catheter to aid in diagnosis and repair of posterior peritoneal cavity entry.

Arsenic is an environmental toxin that exists mainly as pentavalent arsenate and trivalent arsenite. Both forms activate the yeast SAPK Hog1, but with different consequences. We describe a mechanism by which cells distinguish between these arsenicals through one-step metabolism to differentially regulate the bidirectional glycerol channel Fps1, an adventitious port for arsenite. Cells exposed to arsenate reduce it to thiol-reactive arsenite, which modifies a set of cysteine residues in target proteins; whereas cells exposed to arsenite metabolize it to methylarsenite, which modifies an additional set cysteine residues. Thus, the presence of methylarsenite signals an arsenite challenge, rather than arsenate challenge. Hog1 becomes arsenylated, which prevents it from closing Fps1. However, this block is overcome in cells exposed to arsenite through methylarsenylation of Acr3, an arsenite efflux pump that we found also regulates Fps1 directly. This adaptation allows cells to restrict arsenite entry through Fps1, but also allows its exit when produced from arsenate exposure. These results have broad implications for understanding how SAPKs activated by diverse stressors can drive stress-specific outputs.

Supplemental Digital Content is available in the text BACKGROUND Emergence delirium is a common complication in paediatric anaesthesia associated with significant morbidity. Total intravenous anaesthesia (TIVA) and intra-operative dexmedetomidine as an adjuvant to sevoflurane anaesthesia can both reduce the incidence of emergence delirium compared with sevoflurane alone, but no studies have directly compared their relative efficacy. OBJECTIVE The study objective was to compare the effects of TIVA and dexmedetomidine on the incidence of paediatric emergence delirium. STUDY DESIGN The current study is a systematic review and network meta-analysis (NMA) of randomised controlled trials. DATA SOURCES We conducted a systematic search of 12 databases including Medline (Ovid) and Web of Science (Clarivate Analytics) from their respective inception to December 2020. ELIGIBILITY Inclusion criteria were randomised controlled trials of paediatric patients undergoing general anaesthesia using sevoflurane, sevoflurane with dexmedetomidine or TIVA. Data were extracted by two reviewers according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and analysed using NMA methodology. Risk ratios and 95% credible intervals (CrI) were calculated for all outcomes [emergence delirium, postoperative nausea and vomiting (PONV), and time to emergence and extubation]. The protocol was registered with PROSPERO (CRD42018091237). RESULTS The systematic review returned 66 eligible studies comprising 5257 patients with crude median emergence delirium incidences of 12.8, 9.1 and 40% in the dexmedetomidine with sevoflurane, TIVA and sevoflurane alone groups, respectively. NMA indicated that compared with TIVA, sevoflurane with adjuvant dexmedetomidine decreased the incidence of emergence delirium without statistical difference (risk ratio 0.88, 95% CrI 0.61 to 1.20, low quality of evidence), but resulted in a higher incidence of PONV (risk ratio: 2.3, 95% CrI 1.1 to 5.6, low quality of evidence). CONCLUSION Clinical judgement, considering the patient's risk factors for the development of clinically significant outcomes such as emergence delirium and PONV, should be used when choosing between TIVA and sevoflurane with adjuvant dexmedetomidine. These findings are limited by the low quality of evidence (conditional recommendation).

The cell wall integrity (CWI) signaling pathway is best known for its roles in cell wall biogenesis. However, it is also thought to participate in the response to genotoxic stress. The stress-activated protein kinase Mpk1 (Slt2, is activated by DNA damaging agents through an intracellular mechanism that does not involve the activation of upstream components of the CWI pathway. Additional observations suggest that protein kinase C (Pkc1), the top kinase in the CWI signaling cascade, also has a role in the response to genotoxic stress that is independent of its recognized function in the activation of Mpk1. Pkc1 undergoes hyper-phosphorylation specifically in response to genotoxic stress; we have found that this requires the DNA damage checkpoint kinases Mec1 (Mitosis Entry Checkpoint) and Tel1 (TELomere maintenance), but not their effector kinases. We demonstrate that the casein kinase 1 (CK1) ortholog, Hrr25 (HO and Radiation Repair), previously implicated in the DNA damage transcriptional response, associates with Pkc1 under conditions of genotoxic stress. We also found that the induced association of Hrr25 with Pkc1 requires Mec1 and Tel1, and that Hrr25 catalytic activity is required for Pkc1-hyperphosphorylation, thereby delineating a pathway from the checkpoint kinases to Pkc1. We used SILAC mass spectrometry to identify three residues within Pkc1 the phosphorylation of which was stimulated by genotoxic stress. We mutated these residues as well as a collection of 13 phosphorylation sites within the regulatory domain of Pkc1 that fit the consensus for CK1 sites. Mutation of the 13 Pkc1 phosphorylation sites blocked hyper-phosphorylation and diminished RNR3 (RiboNucleotide Reductase) basal expression and induction by genotoxic stress, suggesting that Pkc1 plays a role in the DNA damage transcriptional response.