Oxygen metabolism after cardiac arrest: Patterns and associations with survival.

Aim: Whether changes in oxygen metabolism, as measured by oxygen consumption (VO2), carbon dioxide production (VCO2) and the respiratory exchange ratio (RER), are associated with survival after cardiac arrest is poorly understood. In this prospective observational study, we investigated the association between VO2, VCO2, and RER in the initial 12 and 24 h after return of spontaneous circulation (ROSC) and survival to hospital discharge. Methods: Adults with ROSC after cardiac arrest, admitted to the intensive care unit, requiring mechanical ventilation and treated with targeted temperature management were included. VO2 and VCO2 were measured continuously for 24 h after ROSC, using a noninvasive anesthesia monitor. Area under the curve for VO2, VCO2 & RER was calculated using all available values over 12 and 24 h after ROSC. Using logistic regression, we evaluated the relationship between these metabolic variables and survival to hospital discharge. Analyses were adjusted for temperature, vasopressors, and neuromuscular blockade. Results: Sixty four patients were included. Mean age was 64 ± 16 years, and 59% were women. There was no significant association between the area under the curve of VO2 or VCO2 and survival. A higher RER in the initial 12 h was associated with better survival (aOR = 3.97, 95% CI [1.01,15.6], p = 0.048). Survival was lower in those with median RER < 0.7 in the initial 12 h compared with those with a median RER ≥ 0.7 (25% vs 67%, p = 0.011). Conclusion: Higher RER in the initial 12 h was associated with survival after cardiac arrest. The etiology of unusually low RERs in this patient population remains unclear.

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.

Refining the phenotypic spectrum of CCDC88A-related PEHO-like syndrome.

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO-like syndromes are very rare infantile disorders characterized by profound intellectual disability, hypotonia, convulsions, optic, and progressive brain atrophy. Many causative genes for PEHO and PEHO-like syndromes have been identified including CCDC88A. So far, only five patients from two unrelated families with biallelic CCDC88A variants have been reported in the literature. Herein, we describe a new family from Egypt with a lethal epileptic encephalopathy. Our patient was the youngest child born to a highly consanguineous couple and had a family history of five deceased sibs with the same condition. She presented with postnatal microcephaly, poor visual responsiveness, and epilepsy. Her brain MRI showed abnormal cortical gyration with failure of opercularization of the insula, hypogenesis of corpus callosum, colpocephaly, reduced white matter, hypoplastic vermis, and brain stem. Whole exome sequencing identified a new homozygous frameshift variant in CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4). Our study presents the third reported family with this extremely rare disorder. We also reviewed all described cases to better refine the phenotypic spectrum associated with biallelic loss of function variants in the CCDC88A gene.

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.

Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies.

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor ('ear-of-the-lynx' sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the 'ear-of-the-lynx' sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

Preoperative Dehydration Predicts Adverse Events Following Anterior Cervical Discectomy and Fusion.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a common procedure for neck arthritis, typically alleviating pain and improving function. Preoperative dehydration has been correlated with postoperative infection, acute renal failure, deep vein thrombosis, and increased hospital length of stay. However, some studies have suggested that preoperative dehydration has a minimal relationship with postoperative outcomes, specifically in arthroplasty and lumbar surgery candidates. METHODS: Patients who underwent ACDF from 2015 to 2020 as part of the American College of Surgeons National Surgical Quality Improvement Program database were identified. We excluded patients who presented with acute trauma. Dehydration was determined using the accepted definition of preoperative blood urea nitrogen to creatinine ratio greater than 20. Lengths of stay and 30-day postoperative adverse events were compared between dehydrated and nondehydrated cohorts, adjusting for baseline features using standard multivariate regression. RESULTS: We identified 14,932 patients, and 4206 (28.1%) of whom were preoperatively dehydrated. Dehydrated patients had significantly higher odds of wound, hematological, and pulmonary complications; Clavien-Dindo grade IV, delayed length of stay (>5 days); and a lower likelihood of being discharged home (P < 0.005), even after controlling for demographic features (eg, sex, age, body mass index, race, and ethnicity). Furthermore, linear regression suggested an overall half-day increased length of hospital stay for dehydrated patients (95% CI [0.36, 0.60], P < 0.001). CONCLUSION: Preoperative dehydration is common among ACDF surgery patients and appears to correlate with an increased risk of postoperative complications and prolonged length of hospital stay. Evaluation of a patient's hydration status from standard preoperative laboratory metrics can be employed for risk stratification, patient counseling, and timing of ACDF surgeries.

Kidney-specific biomarkers for predicting acute kidney injury following cardiac arrest.

AIM: To evaluate the performance of kidney-specific biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and cystatin-C) in early detection of acute kidney injury (AKI) following cardiac arrest (CA) when compared to serum creatinine. METHODS: Adult CA patients who had kidney-specific biomarkers of AKI collected within 12 h of return of spontaneous circulation (ROSC) were included. The association between renal biomarker levels post-ROSC and the development of KDIGO stage III AKI within 7 days of enrollment were assessed as well as their predictive value of future AKI development, neurological outcomes, and survival to discharge. RESULTS: Of 153 patients, 54 (35%) developed stage III AKI within 7 days, and 98 (64%) died prior to hospital discharge. Patients who developed stage III AKI, compared to those who did not, had higher median levels of creatinine, NGAL, and cystatin-C (p < 0.001 for all). There was no statistically significant difference in KIM-1 between groups. No biomarker outperformed creatinine in the ability to predict stage III AKI, neurological outcomes, or survival outcomes (p > 0.05 for all). However, NGAL, cystatin-C, and creatinine all performed better than KIM-1 in their ability to predict AKI development (p < 0.01 for all). CONCLUSION: In post-CA patients, creatinine, NGAL, and cystatin-C (but not KIM-1) measured shortly after ROSC were higher in patients who subsequently developed AKI. No biomarker was statistically superior to creatinine on its own for predicting the development of post-arrest AKI.

An atypical expression of core α-Dystroglycan and Laminin-α2 in skin fibroblasts of patients with congenital muscular dystrophies.

BACKGROUND: Congenital muscular dystrophies (CMDs) result from genetically inherited defects in the biosynthesis and/or the posttranslational modification (glycosylation) of laminin-α2 and α-dystroglycan (α-DG), respectively. The interaction between both proteins is responsible for the stability and integrity of the muscle cell. We aimed to study the expression profiles of both proteins in two classes of CMDs. SUBJECTS AND METHODS: Whole-exome sequencing (WES) was done for four patients with neuromuscular manifestations. The expression of core α-DG and laminin-α2 subunit in skin fibroblasts and MCF-7 cells was assessed by western blot. RESULTS: WES revealed two cases with nonsense mutations; c.2938G > T and c.4348 C > T, in LAMA2 encodes laminin-α2. It revealed also two cases with mutations in POMGNT1 encode protein O-mannose beta-1,2-N-acetylglucosaminyltransferase mutations. One patient had a missense mutation c.1325G > A, and the other had a synonymous variant c.636 C > T. Immunodetection of core α-DG in skin fibroblasts revealed the expression of truncated forms of core α-DG accompanied by reduced expression of laminin-α2 in POMGNT1-CMD patients and one patient with LAMA2-CMD. One patient with LAMA2-CMD had overexpression of laminin-α2 and expression of a low level of an abnormal form of increased molecular weight core α-DG. MCF-7 cells showed truncated forms of core α-CDG with an absent laminin-α2. CONCLUSION: A correlation between the expression pattern/level of core α-DG and laminin-α2 could be found in patients with different types of CMD.

Clinical and molecular spectrum of a large Egyptian cohort with ALS2-related disorders of infantile-onset of clinical continuum IAHSP/JPLS.

This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation.

AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model.

Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants in AMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families. Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment. The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications. Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins.

TMEM161B modulates radial glial scaffolding in neocortical development.

TMEM161B encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify TMEM161B homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying TMEM161B mutations exhibit striking neocortical PMG and intellectual disability. Tmem161b knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link TMEM161B with human PMG, likely regulating radial glia apical polarity during neocortical development.

Phenotypic continuum of NFU1-related disorders.

Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum.

Acute respiratory distress syndrome after in-hospital cardiac arrest.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) after out-of-hospital cardiac arrest is common and associated with worse outcomes. In the hospital setting, there are many potential risk factors for post-arrest ARDS, such as aspiration, sepsis, and shock. ARDS after in-hospital cardiac arrest (IHCA) has not been characterized. METHODS: We performed a single-center retrospective study of adult patients admitted to the hospital between 2014-2018 who suffered an IHCA, achieved return of spontaneous circulation (ROSC), and were either already intubated at the time of arrest or within 2 hours of ROSC. Post-IHCA ARDS was defined as meeting the Berlin criteria in the first 3 days following ROSC. Outcomes included alive-and-ventilator free days across 28 days, hospital length-of-stay, hospital mortality, and hospital disposition. RESULTS: Of 203 patients included, 146 (71.9%) developed ARDS. In unadjusted analysis, patients with ARDS had fewer alive-and-ventilator-free days over 28 days with a median of 1 (IQR: 0, 21) day, compared to 18 (IQR: 0, 25) days in patients without ARDS (p = 0.03). However, this association was not significant after multivariate adjustment. There was also a non-significant longer hospital length-of-stay (15 [IQR: 7, 26] vs 10 [IQR: 7, 22] days, p = 0.25; median adjusted increase in ARDS patients: 3 [95% CI: -2 to 8] days, p = 0.27) and higher hospital mortality (53% vs 44%, p = 0.26; aOR 1.6 [95% CI: 0.8-2.9], p = 0.17) in the ARDS group. CONCLUSION: Among IHCA patients, almost three-quarters developed ARDS within 3 days of ROSC. As in out of hospital cardiac arrest, post-IHCA ARDS is common.

Variable predicted pathogenic mechanisms for novel MECP2 variants in RTT patients.

BACKGROUND: Methyl CpG binding protein 2 (MeCP2) is essential for the normal function of mature neurons. Mutations in the MECP2 gene are the main cause of Rett syndrome (RTT). Gene mutations have been identified throughout the gene and the mutation effect is mainly correlated with its type and location. METHODS: In this study, a series of in silico algorithms were applied for analyzing the functional consequences of 3 novel gene missense mutations (D121A, S359Y, and P403S) and a rarely reported one with suspicious effect (R133H) on RettBASE. Besides, a ROC curve analysis was performed to investigate the critical factors affecting variant pathogenicity. RESULTS: (1) The ROC curve analysis for a retrieved set of MeCP2 variants showed that physicochemical characters do not significantly affect variant pathogenicity; (2) PREM PDI tool revealed that both D121A and R133H mainly contribute to disease progression via reducing MeCP2 affinity to DNA; (3) GPS v5.0 software indicated that P403S may correlate with altered protein phosphorylation; however, no defective protein interaction has been already documented. (4) The applied computational algorithms failed to explore any informative pathogenic mechanism for the S359Y variant. CONCLUSION: The conducted approach might provide an efficient prediction model for the effect of MECP2 variants that are located in MBD and CTD.

Diagnostic test accuracy of point-of-care ultrasound during cardiopulmonary resuscitation to indicate the etiology of cardiac arrest: A systematic review.

AIM: Point-of-care ultrasound (POCUS) is used in cardiac arrest patients to assess for reversible causes. We aimed to conduct a diagnostic test accuracy systematic review of intra-arrest POCUS to indicate the etiology of cardiac arrest in adults in any setting. METHODS: This review is registered with PROSPERO (CRD42020205207) and reported according to PRISMA guidelines. We searched Medline, EMBASE, Web of Science, CINAHL, and Cochrane Library on October 6, 2021. Two investigators screened titles and abstracts, extracted data, and assessed risks of bias using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) template. We estimated sensitivity and specificity when feasible and evaluated the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Of 8,621 search results, 12 observational studies reported 26 combinations of index tests and reference standards to indicate six different etiologies of cardiac arrest. All studies had high risks of bias from subject selection, lack of blinding, reference standards susceptible to confounding, and/or differential verification. One study reported sufficient data to complete contingency tables for sensitivity and specificity of POCUS to identify myocardial infarction, cardiac tamponade, and pulmonary embolism as the etiology of cardiac arrest. Heterogeneity and risk of bias precluded meta-analysis and the certainty of evidence was uniformly very low. CONCLUSIONS: It is feasible to identify reversible causes of cardiac arrest with POCUS, but the current literature is heterogenous with high risks of bias, wide confidence intervals, and very low certainty of evidence, which render these data difficult to interpret.

Performance of the APACHE II and SOFA Scores in Diabetic Ketoacidosis.

Accurate prediction of severity and mortality in diabetic ketoacidosis (DKA) is important for allocation of resources. The APACHE II and SOFA scores are used to predict mortality in critically ill patients, however neither has been tested exclusively in DKA. We sought to determine if these scoring systems can accurately predict mortality in patients with DKA. This was an observational study of patients presenting to an urban tertiary care center with a diagnosis of DKA. Adult patients (age ≥ 18 years) with glucose > 250 mg/dL, bicarbonate ≤ 20 mEg/L, an anion gap ≥ 16 mEg/L, pH ≤ 7.30, and urine ketones were included. Predicted mortality based upon APACHE II and SOFA scores were compared to observed mortality. A total of 50 patients were included. There was no observed mortality in our population. The median APACHE II score was 10 (IQR: 6, 15) which predicted a mortality of 15% and the median SOFA score was 1 (IQR: 0, 2) which predicted a mortality of 0%. In summary, we found the APACHE II illness severity score does not accurately predict mortality in a population of patients with DKA, while the SOFA score appears to predict mortality in the same population.

Viral load and disease severity in COVID-19.

The relationship between COVID-19 severity and viral load is unknown. Our objective was to assess the association between viral load and disease severity in COVID-19. In this single center observational study of adults with laboratory confirmed SARS-CoV-2, the first positive in-hospital nasopharyngeal swab was used to calculate the log10 copies/ml [log10 copy number (CN)] of SARS-CoV-2. Four categories based on level of care and modified sequential organ failure assessment score (mSOFA) at time of swab were determined. Median log10CN was compared between different levels of care and mSOFA quartiles. Median log10CN was compared in patients who did and did not receive influenza vaccine, and the correlation between log10CN and D-dimer was examined. We found that of 396 patients, 54.3% were male, and 25% had no major comorbidity. Hospital mortality was 15.7%. Median mSOFA was 2 (IQR 0-3). Median log10CN was 5.5 (IQR 3.3-8.0). Median log10CN was highest in non-intubated ICU patients [6.4 (IQR 4.4-8.1)] and lowest in intubated ICU patients [3.6 (IQR 2.6-6.9)] (p value < 0.01). In adjusted analyses, this difference remained significant [mean difference 1.16 (95% CI 0.18-2.14)]. There was no significant difference in log10CN between other groups in the remaining pairwise comparisons. There was no association between median log10CN and mSOFA in either unadjusted or adjusted analyses or between median log10CN in patients with and without influenza immunization. There was no correlation between log10CN and D-dimer. We conclude, in our cohort, we did not find a clear association between viral load and disease severity in COVID-19 patients. Though viral load was higher in non-intubated ICU patients than in intubated ICU patients there were no other significant differences in viral load by disease severity.

Thiamine Supplementation in Patients With Alcohol Use Disorder Presenting With Acute Critical Illness : A Nationwide Retrospective Observational Study.

BACKGROUND: Thiamine supplementation is recommended for patients with alcohol use disorder (AUD). The authors hypothesize that critically ill patients with AUD are commonly not given thiamine supplementation. OBJECTIVE: To describe thiamine supplementation incidence in patients with AUD and various critical illnesses (alcohol withdrawal, septic shock, traumatic brain injury [TBI], and diabetic ketoacidosis [DKA]) in the United States. DESIGN: Retrospective observational study. SETTING: Cerner Health Facts database. PATIENTS: Adult patients with a diagnosis of AUD who were admitted to the intensive care unit with alcohol withdrawal, septic shock, TBI, or DKA between 2010 and 2017. MEASUREMENTS: Incidence and predicted probability of thiamine supplementation in alcohol withdrawal and other critical illnesses. RESULTS: The study included 14 998 patients with AUD. Mean age was 52.2 years, 77% of participants were male, and in-hospital mortality was 9%. Overall, 7689 patients (51%) received thiamine supplementation. The incidence of thiamine supplementation was 59% for alcohol withdrawal, 26% for septic shock, 41% for TBI, and 24% for DKA. Most of those receiving thiamine (n = 3957 [52%]) received it within 12 hours of presentation in the emergency department. The predominant route of thiamine administration was enteral (n = 3119 [41%]). LIMITATION: Specific dosing and duration were not completely captured. CONCLUSION: Thiamine supplementation was not provided to almost half of all patients with AUD, raising a quality-of-care issue for this cohort. Supplementation was numerically less frequent in patients with septic shock, DKA, or TBI than in those with alcohol withdrawal. These data will be important for the design of quality improvement studies in critically ill patients with AUD. PRIMARY FUNDING SOURCE: National Institutes of Health.

A Trigger and Response System for Preventing Cardiac Arrest in the ICU.

Although patients in the ICU are closely monitored, some ICU cardiac arrest events may be preventable. In this study, we sought to reduce the rate of cardiac arrests occurring in the ICU through a quality improvement initiative. DESIGN: Prospective, observational study. SETTING: ICUs of a single tertiary care center. PATIENTS: Patients hospitalized in the ICUs between August 2017 and November 2019. INTERVENTIONS: A comprehensive trigger and response tool. MEASUREMENT AND MAIN RESULTS: Forty-three patients experienced an ICU cardiac arrest in the preintervention epoch (6.79 arrests per 1,000 discharges), and 59 patients experienced an ICU cardiac arrest in the intervention epoch (7.91 arrests per 1,000 discharges). In the intervention epoch, the clinical trigger and response tool was activated 106 times over a 1-year period, most commonly due to unexpected new/worsening hypotension. There was no step change in arrest rate (2.24 arrests/1,000 patients; 95% CI, -1.82 to 6.28; p = 0.28) or slope change (-0.02 slope of arrest rate; 95% CI, -0.14 to 0.11; p = 0.79) comparing the preintervention and intervention time epochs. Cardiac arrests in the preintervention epoch were more likely to be "potentially preventable" than that in the intervention epoch (25.6% vs 12.3%, respectively; odds ratio, 0.58; 95% CI, 0.20-0.88; p < 0.01). CONCLUSIONS: A novel trigger-and-response tool did not reduce the frequency of ICU cardiac arrest. Additional investigation is needed into the optimal approach for ICU cardiac arrest prevention.

Implication of folate deficiency in CYP2U1 loss of function.

Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.