Impact of preoperative haemoglobin A1c levels on postoperative outcomes in adults undergoing major noncardiac surgery: A systematic review.

AIMS: Diabetes is known to increase morbidity and mortality after major surgery. However, literature is conflicting on whether elevated preoperative haemoglobin A1c (HbA1c) levels are associated with worse outcomes following major noncardiac surgery. We aimed to investigate the effect of incremental preoperative HbA1c levels on postoperative outcomes in adults who had undergone major noncardiac surgery. METHODS: We systematically searched PubMed, EMBASE and the Cochrane Library databases for eligible studies published between January 2012 and July 2023. Randomised controlled trials and observational studies (cohort and case-control studies) which measured HbA1c within 6 months before surgery and compared outcomes between at least three incremental subgroups or analysed HbA1c as a continuous variable were included. The systematic review protocol was registered with PROSPERO (CRD42023391946). RESULTS: Twenty observational studies investigating outcomes across multiple surgical types were included. Higher preoperative HbA1c levels were associated with increased odds of overall postoperative complications, postoperative acute kidney injury, anastomotic leak, surgical site infections and increased length of stay. Each 1% increase in preoperative HbA1c was associated with increased odds of these complications. No association with reoperations and 30-day mortality was identified. The literature was highly variable with respect to composite major complications, perioperative cardiovascular events, hospital readmissions, postoperative pneumonia and systemic thromboembolism. CONCLUSIONS: Current evidence suggested that higher preoperative HbA1c levels were associated with increased odds of postoperative complications and extended length of stay in adults undergoing major noncardiac surgery. Further high-quality studies would be needed to quantify the risks posed and determine whether early intervention improves outcomes.

Neurosurgical management of Myelomeningocele in premature infants: a case series.

INTRODUCTION: Myelomeningocele (MMC) is the most common neural tube defect, but rarely seen in premature infants. Most centers advocate for closure of MMC within 24 h of birth. However, this is not always possible in severely premature infants. Given the rarity of this patient population, we aimed to share our institutional experience and outcomes of severely premature infants with MMC. METHODS: We performed a retrospective, observational review of premature infants (≤ 32 weeks gestational age) identified through our multidisciplinary spina bifida clinic (1995-2021) and surgical logs. Descriptive statistics were compiled about this sample including timing of MMC closure and incidence of adverse events such as sepsis, CSF diversion, meningitis, and death. RESULTS: Eight patients were identified (50% male) with MMC who were born ≤ 32 weeks gestational age. Mean gestational age of the population was 27.3 weeks (SD 3.5). Median time to MMC closure was 1.5 days (IQR = 1-80.8). Five patients were taken for surgery within the recommended 48 h of birth; 2 patients underwent significantly delayed closure (107 and 139 days); and one patient's defect epithelized without surgical intervention. Six of eight patients required permanent cerebrospinal fluid (CSF) diversion (2 patients were treated with ventriculoperitoneal shunting (VPS), three were treated with endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) and 1 patient treated with ETV; mean of 3 years after birth, ranging from 1 day to 16 years). Two patients required more than one permanent CSF diversion procedure. Two patients developed sepsis (defined as meeting at least 2/4 SIRS criteria). In both cases of sepsis, patients developed signs and symptoms more than 72 h after birth. Notably, both instances of sepsis occurred unrelated to operative intervention as they occurred before permanent MMC closure. Two patients had intraventricular hemorrhage (both grade III). No patients developed meningitis (defined as positive CSF cultures) prior to MMC closure. Median follow up duration was 9.7 years. During this time epoch, 3 patients died: Two before 2 years of age of causes unrelated to surgical intervention. One of the two patients with grade III IVH died within 24 h of MMC closure. CONCLUSIONS: In our institutional experience with premature infants with MMC, some patients underwent delayed MMC closure. The overall rate of meningitis, sepsis, and mortality for preterm children with MMC was similar to MMC patients born at term.

Pediatric non-galenic pial arteriovenous fistula's characteristics and outcomes: a systematic review.

INTRODUCTION: Pediatric non-galenic pial arteriovenous fistulas (pAVFs) are rare vascular malformations that are characterized by a pial arterial-venous connection without an intervening capillary bed. Outcomes and treatment strategies for pAVFs are highly individualized, owing to the rarity of the disease and lack of large-scale data guiding optimal treatment approaches. METHODS: We performed a systematic review of pediatric patients (< 18 years at diagnosis) diagnosed with a pAVF by digital subtraction angiogram (DSA). The demographics, treatment modalities, and outcomes were documented for each patient and clinical outcome data was collected. Descriptive information stratified by outcome scores were classified as follows: 1 = excellent (no deficit and full premorbid activity), 2 = good (mild deficit and full premorbid activity), 3 = fair (moderate deficit and impaired activity), 4 = poor (severe deficit and dependent on others), 5 = death. RESULTS: A total of 87 studies involving 231 patients were identified. Median age at diagnosis was 3 years (neonates to 18 years). There was slight male preponderance (55.4%), and 150 subjects (81.1%*) experienced excellent outcomes after treatment. Of the 189 patients treated using endovascular approaches, 80.3% experienced excellent outcomes and of the 15 patients surgically treated subjects 75% had an excellent outcome. The highest rate of excellent outcomes was achieved in patients treated with Onyx (95.2%) and other forms of EvOH (100%). High output heart failure and comorbid vascular lesions tended to result in worse outcomes, with only 54.2% and 68% of subjects experiencing an excellent outcome, respectively. *Outcomes were reported in only 185 patients. CONCLUSION: pAVFs are rare lesions, necessitating aggregation of patient data to inform natural history and optimal treatment strategies. This review summarizes the current literature on pAVF in children, where children presenting with heart failure as a result of high flow through the lesion were less likely to experience an excellent outcome. Prospective, large-scale studies would further characterize pediatric pAVFs and enable quantitative analysis of outcomes to inform best treatment practices.

Coordinated inositide lipid-phosphatase activities of synaptojanin modulates actin cytoskeleton organization.

Synaptojanin proteins are evolutionarily conserved regulators of vesicle transport and membrane homeostasis. Disruption of synaptojanin function has been implicated in a wide range of neurological disorders. Synaptojanins act as dual-functional lipid phosphatases capable of hydrolyzing a variety of phosphoinositides (PIPs) through autonomous SAC1-like PIP 4-phosphatase and PIP2 5-phosphatase domains. The rarity of an evolutionary configuration of tethering two distinct enzyme activities in a single protein prompted us to investigate their individual and combined roles in budding yeast. Both PIP and PIP2 phosphatase activities are encoded by multiple gene products and are independently essential for cell viability. In contrast, we observed that the synaptojanin proteins utilized both lipid-phosphatase activities to properly coordinate polarized distribution of actin during the cell cycle. Expression of each activity untethered (in trans) failed to properly reconstitute the basal actin regulatory activity; whereas tethering (in cis), even through synthetic linkers, was sufficient to complement these defects. Studies of chimeric proteins harboring PIP and PIP2 phosphatase domains from a variety of gene products indicate synaptojanin proteins have highly specialized activities and that the length of the linker between the lipid-phosphatase domains is critical for actin regulatory activity. Our data are consistent with synaptojanin possessing a strict requirement for both two-domain configuration for some but not all functions and provide mechanistic insights into a coordinated role of tethering distinct lipid-phosphatase activities.

A Predictive Algorithm for Discriminating Myeloid Malignancies and Leukemoid Reactions.

BACKGROUND: Adults presenting with a neutrophil-predominant leukocytosis (white cell count >50,000/µL) often necessitate urgent medical management. These patients are diagnosed with either acute presentations of chronic myeloid malignancies or leukemoid reactions, yet accurate models to distinguish between these entities do not exist. We used demographic and lab data to build a machine learning model capable of discriminating between these diagnoses. METHODS: The medical record at a tertiary care medical center was queried to identify adults with instances of white counts greater than 50,000/µL and >50% neutrophils from 2000 to 2021. For each patient, a full set of demographic and lab values were extracted at the time of their first presentation with a white count >50,000/µL. We generated a series of models in which the parameters most predictive of myeloid malignancies were identified, and a supervised machine learning approach was applied to the dataset. RESULTS: Our best model-using a support vector machine algorithm-produced a sensitivity of 96% and a specificity of 95.9% (area under the curve = 0.982) for identifying myeloid malignancies. We also identified a clinically meaningful and significant disparity in outcomes based on diagnosis-a 6-fold increase in 12-month mortality in those diagnosed with leukemoid reactions. CONCLUSIONS: These findings need to be validated but fill an unmet need for timely and accurate diagnosis in the setting of profound, neutrophil-predominant leukocytosis and support the use of predictive models as a means to improve patient outcomes.

Specific RNA structures in the 5' untranslated region of the human cytomegalovirus major immediate early transcript are critical for efficient virus replication.

Human cytomegalovirus (HCMV) requires the robust expression of two immediate early proteins, IE1 and IE2, immediately upon infection to suppress the antiviral response and promote viral gene expression. While transcriptional control of IE1 and IE2 has been extensively studied, the role of post-transcriptional regulation of IE1 and IE2 expression is relatively unexplored. We previously found that the shared major immediate early 5' untranslated region (MIE 5' UTR) of the mature IE1 and IE2 transcripts plays a critical role in facilitating the translation of the IE1 and IE2 mRNAs. As RNA secondary structure in 5' UTRs can regulate mRNA translation efficiency, we used selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) to identify RNA structures in the shared MIE 5' UTR. We found that the MIE 5' UTR contains three stable stem loop structures. Using a series of recombinant viruses to investigate the role of each stem loop in IE1 and IE2 protein synthesis, we found that the stem loop closest to the 5' end of the MIE 5' UTR (SL1) is both necessary and sufficient for efficient IE1 and IE2 mRNA translation and HCMV replication. The positive effect of SL1 on mRNA translation and virus replication was dependent on its location within the 5' UTR. Surprisingly, a synthetic stem loop with the same free energy as SL1 in its native location also supported wild type levels of IE1 and IE2 mRNA translation and virus replication, suggesting that the presence of RNA structure at a specific location in the 5' UTR, rather than the primary sequence of the RNA, is critical for efficient IE1 and IE2 protein synthesis. These data reveal a novel post-transcriptional regulatory mechanism controlling IE1 and IE2 expression and reinforce the critical role of RNA structure in regulating HCMV protein synthesis and replication.IMPORTANCEThese results reveal a new aspect of immediate early gene regulation controlled by non-coding RNA structures in viral mRNAs. Previous studies have largely focused on understanding viral gene expression at the level of transcriptional control. Our results show that a complete understanding of the control of viral gene expression must include an understanding of viral mRNA translation, which is driven in part by RNA structure(s) in the 5' UTR of viral mRNAs. Our results illustrate the importance of these additional layers of regulation by defining specific 5' UTR RNA structures regulating immediate early gene expression in the context of infection and identify important features of RNA structure that govern viral mRNA translation efficiency. These results may therefore broadly impact current thinking on how viral gene expression is regulated for human cytomegalovirus and other DNA viruses.

Clinical guidance for unfractionated heparin dosing and monitoring in critically ill patients.

INTRODUCTION: Unfractionated heparin is a widely used anticoagulant in critically ill patients. It has a well-established safety profile and remains an attractive option for clinicians due to its short half-life and reversibility. Heparin has a unique pharmacokinetic profile, which contributes to significant inter-patient and intra-patient variability in effect. The variability in anticoagulant effect combined with heparin's short half-life mean close monitoring is required for clinical efficacy and preventing adverse effects. To optimize heparin use in critically ill patients, effective monitoring assays and dose adjustment strategies are needed. AREAS COVERED: This paper explores the use of heparin as an anticoagulant and optimal approaches to monitoring in critically ill patients. EXPERT OPINION: Conventional monitoring assays for heparin dosing have significant limitations. Emerging data appear to favor using anti-Xa assay monitoring for heparin anticoagulation, which many centers have successfully adopted as the standard. The anti-Xa assay appears have important benefits relative to the aPTT for heparin monitoring in critically ill patients, and should be considered for broader use.

IPMK regulates HDAC3 activity and histone H4 acetylation in human cells.

Histone deacetylases (HDACs) repress transcription by catalyzing the removal of acetyl groups from histones. Class 1 HDACs are activated by inositol phosphate signaling molecules in vitro , but it is unclear if this regulation occurs in human cells. Inositol Polyphosphate Multikinase (IPMK) is required for production of inositol hexakisphosphate (IP6), pentakisphosphate (IP5) and certain tetrakisphosphate (IP4) species, all known activators of Class 1 HDACs in vitro . Here, we generated IPMK knockout (IKO) human U251 glioblastoma cells, which decreased cellular inositol phosphate levels and increased histone H4-acetylation by mass spectrometry. ChIP-seq showed IKO increased H4-acetylation at IKO-upregulated genes, but H4-acetylation was unchanged at IKO-downregulated genes, suggesting gene-specific responses to IPMK knockout. HDAC deacetylase enzyme activity was decreased in HDAC3 immunoprecipitates from IKO vs . wild-type cells, while deacetylase activity of other Class 1 HDACs had no detectable changes in activity. Wild-type IPMK expression in IKO cells fully rescued HDAC3 deacetylase activity, while kinase-dead IPMK expression had no effect. Further, the deficiency in HDAC3 activity in immunoprecipitates from IKO cells could be fully rescued by addition of synthesized IP4 (Ins(1,4,5,6)P4) to the enzyme assay, while control inositol had no effect. These data suggest that cellular IPMK-dependent inositol phosphates are required for full HDAC3 enzyme activity and proper histone H4-acetylation. Implications for targeting IPMK in HDAC3-dependent diseases are discussed.

The Montreal Cognitive Assessment: Norms and Reliable Change Indices for Standard and MoCA-22 Administrations.

OBJECTIVE: The Montreal Cognitive Assessment (MoCA) is among the most frequently administered cognitive screening tests, yet demographically diverse normative data are needed for repeated administrations. METHOD: Data were obtained from 18,410 participants using the National Alzheimer's Coordinating Center Uniform Data Set. We developed regression-based norms using Tobit regression to account for ceiling effects, explored test-retest reliability of total scores and by domain stratified by age and diagnosis with Cronbach's alpha, and reported the cumulative change frequencies for individuals with serial MoCA administrations to gage expected change. RESULTS: Strong ceiling effects and negative skew were observed at the total score, domain, and item levels for the cognitively normal group, and performances became more normally distributed as the degree of cognitive impairment increased. In regression models, years of education was associated with higher MoCA scores, whereas older age, male sex, Black and American Indian or Alaska Native race, and Hispanic ethnicity were associated with lower predicted scores. Temporal stability was adequate and good at the total score level for the cognitively normal and cognitive disorders groups, respectively, but fell short of reliability standards at the domain level. CONCLUSIONS: MoCA total scores are adequately reproducible among those with cognitive diagnoses, but domain scores are unstable. Robust regression-based norms should be used to adjust for demographic performance differences, and the limited reliability, along with the ceiling effects and negative skew, should be considered when interpreting MoCA scores.

Neurosurgical Management of Myelomeningocele in Premature Infants: A Case Series.

Introduction: Myelomeningocele (MMC) is the most common neural tube defect, but rarely seen in premature infants. Most centers advocate for closure of MMC within 24 hours of birth. However, this is not always possible in severely premature infants. Given the rarity of this patient population, we aimed to share our institutional experience and outcomes of severely premature infants with MMC. Methods: We performed a retrospective, observational review of premature infants (≤ 32 weeks gestational age) identified through our multidisciplinary spina bifida clinic (1995-2021) and surgical logs. Descriptive statistics were compiled about this sample including timing of MMC closure and incidence of adverse events such as sepsis, CSF diversion, meningitis, and death. Results: Eight patients were identified (50% male) with MMC who were born ≤ 32 weeks gestational age. Mean gestational age of the population was 27.3 weeks (SD 3.5). Median time to MMC closure was 1.5 days (IQR = 1 -80.8). Five patients were taken for surgery within the recommended 48 hours of birth; 2 patients underwent significantly delayed closure (107 and 139 days); and one patient's defect epithelized without surgical intervention. Six of eight patients required permanent cerebrospinal fluid (CSF) diversion (2 patients were treated with ventriculoperitoneal shunting (VPS), three were treated with endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) and 1 patient treated with ETV; mean of 3 years after birth, ranging from 1 day to 16 years). Two patients required more than one permanent CSF diversion procedure. Two patients developed sepsis (defined as meeting at least 2/4 SIRS criteria), and 2 patients had intraventricular hemorrhage (both grade III). No patients developed meningitis (defined as positive CSF cultures) prior to MMC closure. Median follow up duration was 9.7 years. During this time epoch, 3 patients died: Two before 2 years of age of causes unrelated to surgical intervention. One of the two patients with grade III IVH died within 24 hours of MMC closure. Conclusions: In our institutional experience with premature infants with MMC, some patients underwent delayed MMC closure. The overall rate of meningitis, sepsis, and mortality for preterm children with MMC was similar to MMC patients born at term.

Rethinking the consultation paradigm: Validity evidence for a new framework, a multimethods study.

BACKGROUND: In-hospital consultation is essential for patient care. We previously proposed a framework of seven specific consultation types to classify consult requests to improve communication, workflow, and provider satisfaction. METHODS: This multimethods study's aim was to evaluate the applicability of the consult classification framework to real internal medicine (IM) consults. We sought validity evidence using Kane's validity model with focus groups and classifying consult requests from five IM specialties. Participants attended five 1 h semi-structured focus groups that were recorded, transcribed, and coded for thematic saturation. For each specialty, three specialists and three hospitalists categorized 100 (total 500) random anonymized consult requests. The primary outcome was concordance in the classification of consult requests, defined as the sum of partial concordance and perfect concordance, where respectively 4-5/6 and 6/6 participants classified a consult in the same category. We used χ2 tests to compare concordance rates across specialties and between specialists and hospitalists. RESULTS: Five major themes were identified in the qualitative analysis of the focus groups: (1) consult question, (2) interpersonal interactions, (3) value, (4) miscommunication, (5) consult framework application, barriers, and iterative development. In the quantitative analysis, the overall concordance rate was 88.8% (95% confidence interval [CI]: 85.7-91.4), and perfect concordance was 46.6% (95% CI: 42.2-51.1). Concordance differed significantly between hospitalists and specialists overall (p = .01), with a higher proportion of hospitalists having perfect concordance compared to specialists (67.2% vs. 57.8%, p = .002). CONCLUSIONS: The consult classification framework was found to be applicable to consults from five different IM specialties, and could improve communication and education.

Endoluminal Biopsy for Vein of Galen Malformation.

BACKGROUND AND OBJECTIVES: Vein of Galen malformation (VOGM), the result of arteriovenous shunting between choroidal and/or subependymal arteries and the embryologic prosencephalic vein, is among the most severe cerebrovascular disorders of childhood. We hypothesized that in situ analysis of the VOGM lesion using endoluminal tissue sampling (ETS) is feasible and may advance our understanding of VOGM genetics, pathogenesis, and maintenance. METHODS: We collected germline DNA (cheek swab) from patients and their families for genetic analysis. In situ VOGM "endothelial" cells (ECs), defined as CD31+ and CD45-, were obtained from coils through ETS during routine endovascular treatment. Autologous peripheral femoral ECs were also collected from the access sheath. Single-cell RNA sequencing of both VOGM and peripheral ECs was performed to demonstrate feasibility to define the transcriptional architecture. Comparison was also made with a published normative cerebrovascular transcriptome atlas. A subset of VOGM ECs was reserved for future DNA sequencing to assess for somatic and second-hit mutations. RESULTS: Our cohort contains 6 patients who underwent 10 ETS procedures from arterial and/or venous access during routine VOGM treatment (aged 12 days to ∼6 years). No periprocedural complications attributable to ETS occurred. Six unique coil types were used. ETS captured 98 ± 88 (mean ± SD; range 17-256) experimental ECs (CD31+ and CD45-). There was no discernible correlation between cell yield and coil type or route of access. Single-cell RNA sequencing demonstrated hierarchical clustering and unique cell populations within the VOGM EC compartment compared with peripheral EC controls when annotated using a publicly available cerebrovascular cell atlas. CONCLUSION: ETS may supplement investigations aimed at development of a molecular-genetic taxonomic classification scheme for VOGM. Moreover, results may eventually inform the selection of personalized pharmacologic or genetic therapies for VOGM and cerebrovascular disorders more broadly.

The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact.

Hydrocephalus (HC) is a heterogenous disease characterized by alterations in cerebrospinal fluid (CSF) dynamics that may cause increased intracranial pressure. HC is a component of a wide array of genetic syndromes as well as a secondary consequence of brain injury (intraventricular hemorrhage (IVH), infection, etc.) that can present across the age spectrum, highlighting the phenotypic heterogeneity of the disease. Surgical treatments include ventricular shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, both of which are prone to failure, and no effective pharmacologic treatments for HC have been developed. Thus, there is an urgent need to understand the genetic architecture and molecular pathogenesis of HC. Without this knowledge, the development of preventive, diagnostic, and therapeutic measures is impeded. However, the genetics of HC is extraordinarily complex, based on studies of varying size, scope, and rigor. This review serves to provide a comprehensive overview of genes, pathways, mechanisms, and global impact of genetics contributing to all etiologies of HC in humans.

National HIV and HCV Screening Rates for Hospitalized People who Use Drugs Are Suboptimal and Heterogeneous Across 11 US Hospitals.

Background: To end the HIV and hepatitis C virus (HCV) epidemics, people who use drugs (PWUD) need more opportunities for testing. While inpatient hospitalizations are an essential opportunity to test people who use drugs (PWUD) for HIV and HCV, there is limited research on rates of inpatient testing for HIV and HCV among PWUD. Methods: Eleven hospital sites were included in the study. Each site created a cohort of inpatient encounters associated with injection drug use. From these cohorts, we collected data on HCV and HIV testing rates and HIV testing consent policies from 65 276 PWUD hospitalizations. Results: Hospitals had average screening rates of 40% for HIV and 32% for HCV, with widespread heterogeneity in screening rates across facilities. State consent laws and opt-out testing policies were not associated with statistically significant differences in HIV screening rates. On average, hospitals that reflexed HCV viral load testing on HCV antibody testing did not have statistically significant differences in HCV viral load testing rates. We found suboptimal testing rates during inpatient encounters for PWUD. As treatment (HIV) and cure (HCV) are necessary to end these epidemics, we need to prioritize understanding and overcoming barriers to testing.

Iron homeostasis and post-hemorrhagic hydrocephalus: a review.

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.