Extreme γ' fibrinogen levels in COVID-19 patients.

COVID-19 disease progression can be accompanied by a "cytokine storm" that leads to secondary sequelae such as acute respiratory distress syndrome. Several inflammatory cytokines have been associated with COVID-19 disease progression, but have high daily intra-individual variability. In contrast, we have shown that the inflammatory biomarker γ' fibrinogen (GPF) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP. The aims of the study were to measure GPF in serial blood samples from COVID-19 patients at a tertiary care medical center in order to investigate its association with clinical measures of disease progression. COVID-19 patients were retrospectively enrolled between 3/16/2020 and 8/1/2020. GPF was measured using a commercial ELISA. We found that COVID-19 patients can develop extraordinarily high levels of GPF. Our results showed that ten out of the eighteen patients with COVID-19 had the highest levels of GPF ever recorded. The previous highest GPF level of 80.3 mg/dL was found in a study of 10,601 participants in the ARIC study. GPF levels were significantly associated with the need for ECMO and mortality. These findings have potential implications regarding prophylactic anticoagulation of COVID-19 patients.

The Pediatric Data Science and Analytics Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators Network: Use of Supervised Machine Learning Applications in Pediatric Critical Care Medicine Research.

OBJECTIVE: Perform a scoping review of supervised machine learning in pediatric critical care to identify published applications, methodologies, and implementation frequency to inform best practices for the development, validation, and reporting of predictive models in pediatric critical care. DESIGN: Scoping review and expert opinion. SETTING: We queried CINAHL Plus with Full Text (EBSCO), Cochrane Library (Wiley), Embase (Elsevier), Ovid Medline, and PubMed for articles published between 2000 and 2022 related to machine learning concepts and pediatric critical illness. Articles were excluded if the majority of patients were adults or neonates, if unsupervised machine learning was the primary methodology, or if information related to the development, validation, and/or implementation of the model was not reported. Article selection and data extraction were performed using dual review in the Covidence tool, with discrepancies resolved by consensus. SUBJECTS: Articles reporting on the development, validation, or implementation of supervised machine learning models in the field of pediatric critical care medicine. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 5075 identified studies, 141 articles were included. Studies were primarily (57%) performed at a single site. The majority took place in the United States (70%). Most were retrospective observational cohort studies. More than three-quarters of the articles were published between 2018 and 2022. The most common algorithms included logistic regression and random forest. Predicted events were most commonly death, transfer to ICU, and sepsis. Only 14% of articles reported external validation, and only a single model was implemented at publication. Reporting of validation methods, performance assessments, and implementation varied widely. Follow-up with authors suggests that implementation remains uncommon after model publication. CONCLUSIONS: Publication of supervised machine learning models to address clinical challenges in pediatric critical care medicine has increased dramatically in the last 5 years. While these approaches have the potential to benefit children with critical illness, the literature demonstrates incomplete reporting, absence of external validation, and infrequent clinical implementation.

Nonresuscitation Fluid Accumulation and Outcomes After Pediatric Cardiac Surgery: Single-Center Retrospective Cohort Study.

OBJECTIVES: Postoperative patients after congenital cardiac surgery are at high risk of fluid overload (FO), which is known to be associated with poor outcomes. "Fluid creep," or nonresuscitation IV fluid in excess of maintenance requirement, is recognized as a modifiable factor associated with FO in the general PICU population, but has not been studied in congenital cardiac surgery patients. Our objective was to characterize fluid administration after congenital cardiac surgery, quantify fluid creep, and the association between fluid creep, FO, and outcome. DESIGN: Retrospective, observational cohort study. SETTING: Single-center urban mixed-medical and cardiac PICU. PATIENTS: Patients admitted to the PICU after cardiac surgery between January 2010 and December 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1,459 postoperative encounters with 1,224 unique patients. Total fluid intake was greater than maintenance requirements on 3,103 of 4,661 patient days (67%), with fluid creep present on 2,624 patient days (56%). Total nonresuscitation intake was higher in patients with FO (defined as cumulative fluid balance 10% above body weight) versus those without. Fluid creep was higher among patients with FO than those without for each of the first 5 days postoperatively. Each 10 mL/kg of fluid creep in the first 24 hours postoperatively was associated with 26% greater odds of developing FO (odds ratio [OR] 1.26; 95% CI, 1.17-1.35) and 17% greater odds of mortality (OR 1.17; 95% CI, 1.05-1.30) after adjusting for risk of mortality based on surgical procedure, age, and day 1 resuscitation volume. Increasing fluid creep in the first 24 hours postoperatively was associated with increased postoperative duration of mechanical ventilation and PICU length of stay. CONCLUSIONS: Fluid creep is present on most postoperative days for pediatric congenital cardiac surgery patients, and fluid creep is associated with higher-risk procedures. Fluid creep early in the postoperative PICU stay is associated with greater odds of FO, mortality, length of mechanical ventilation, and PICU length of stay. Fluid creep may be under-recognized in this population and thus present a modifiable target for intervention.

Glutamatergic neurometabolites during early abstinence from chronic methamphetamine abuse.

BACKGROUND: The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon. METHODS: We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment. RESULTS: In the methamphetamine group, small but significant (5-15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex. CONCLUSIONS: Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery.

Recognizing Pediatric ARDS: Provider Use of the PALICC Recommendations in a Tertiary Pediatric ICU.

BACKGROUND: For almost 50 years, pediatricians used adult guidelines to diagnose ARDS. In 2015, specific criteria for pediatric ARDS were defined. However, it remains unclear how frequently providers recognize pediatric ARDS and whether recognition affects adherence to consensus recommendations. METHODS: This was a mixed-method, retrospective study of mechanically ventilated pediatric subjects after the release of the pediatric ARDS recommendation statement. Pediatric ARDS cases were identified according to the new criteria. Provider recognition was defined by documentation in the medical record. Pediatric ARDS subjects with and without provider recognition were compared quantitatively according to clinical characteristics, adherence to lung-protective ventilation (LPV), adjunctive therapies, and outcomes. A qualitative document analysis (QDA) was performed to evaluate knowledge and beliefs surrounding the Pediatric Acute Lung Injury Consensus Conference recommendations. RESULTS: Of 1,983 subject encounters, pediatric ARDS was identified in 321 (16%). Provider recognition was present in 97 (30%) cases and occurred more often in subjects who were older, had worse oxygenation deficits, or were bone marrow transplant recipients. Recognition rates increased each studied year. LPV practices did not differ based on provider recognition; however, subjects who received it were more likely to experience permissive hypoxemia and adherence to extrapulmonary recommendations. Ultimately, there was no differences in outcomes between the provider recognition and non-provider recognition groups. Three themes emerged from the QDA: (1) pediatric ARDS presents within a complex, multidimensional context, with potentially competing organ system failures; (2) similar to historical conceptualizations, pediatric ARDS was often considered a visual diagnosis, with measures of oxygenation unreferenced; and (3) emphasis was placed on non-evidence-based interventions, such as pulmonary clearance techniques, rather than on consensus recommendations. CONCLUSIONS: Among mechanically ventilated children, pediatric ARDS was common but recognized in a minority of cases. Potential opportunities, such as an opt-out approach to LPV, may exist for improved dissemination and implementation of recommended best practices.

1H MRSI and social communication deficits in pediatric complex partial seizures.

PURPOSE: To investigate relationships between regional brain metabolites, social communication deficits, and seizure frequency in children and adolescents with cryptogenic epilepsy with complex partial seizures (CPS). METHODS: In 12 children and adolescents with CPS and 23 age- and gender-matched healthy controls, we acquired proton magnetic resonance spectroscopic imaging (MRSI) at 1.5 T and 30 ms echo-time from bilateral inferior frontal and superior temporal gyri, regions associated with social communication deficits. Videotaped speech samples of all the subjects were coded for social communication deficits and parents provided information on seizure frequency. KEY FINDINGS: Four MRSI findings emerged in right inferior frontal gyrus. N-acetyl-aspartate (NAA) plus N-acetyl-aspartyl-glutamate (NAAG)--together called "tNAA"--was 11.4% lower in patients with CPS than in controls. Choline-compounds (Cho) were 15.4% lower in CPS than in controls. Within CPS, higher tNAA was associated with more frequent seizures and abnormal social communication. SIGNIFICANCE: Localization of findings to right inferior frontal cortex supports the involvement of this area in social communication deficits and may be related to atypical lateralization of expressive language in pediatric epilepsy. Lower levels of tNAA and Cho may indicate local neuronal or glial damage or underpopulation due to excitotoxicity or other causes. The sensitivity of tNAA to seizure frequency suggests effects of ongoing CPS on neuronal and glial function in this brain region.

Terbinafine-induced subacute cutaneous lupus erythematosus.

Terbinafine is a synthetic oral allylamine that is used for systemic treatment of microscopy- or culture-proven dermatophyte infections of skin and nails. It is normally well-tolerated and side effects include transient gastrointestinal symptoms and skin reactions that can occur in up to 2.3% of treated patients. Subacute cutaneous lupus erythematosus (SCLE) is a skin reaction that has been reported secondary to use of a variety of drugs. The number of reports of SCLE with terbinafine is limited. We demonstrate 2 patients in one dermatology clinic who presented with a predisposing autoimmune diathesis within 3 months of each other.

Thalamic glutamate decreases with cigarette smoking.

RATIONALE: Findings from animal studies and human PET imaging indicate that nicotine and cigarette smoking affect glutamate (Glu) and related neurochemical markers in the brain and imply that smoking reduces extracellular Glu. As Glu release is mediated by nicotinic acetylcholine receptors (nAChRs), which are present at high concentrations in the thalamus, we examined the effects of smoking on thalamic Glu. OBJECTIVE: To determine the effects of tobacco smoking on thalamic glutamate levels. METHODS: Thalamic Glu levels were measured in vivo in 18 smokers and 16 nonsmokers using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T. RESULTS: Mean Glu levels did not differ significantly between the subject groups. However, within smokers, Glu levels were negatively correlated with self-reports of both cigarettes/day over the last 30 days (r = -0.64, p = 0.006) and pack-years of smoking (r = -0.66, p = 0.005). CONCLUSIONS: Consistent with expectations based on preclinical studies, within smokers, cigarettes/day and pack-years are associated with reduced Glu in thalamus, a brain region rich in nAchRs. These results encourage work on candidate glutamatergic therapies for smoking cessation and suggest a noninvasive metric for their action in the brain.

Cigarette smoking and white matter microstructure.

RATIONALE: Diffusion tensor imaging has been used before in testing associations between cigarette smoking and white matter integrity, with inconsistent results. Published reports indicate higher fractional anisotropy (FA, a measure of linear water diffusion) in some brain regions and lower FA in others in adult smokers compared to nonsmokers. Adolescent smokers exhibited elevated FA at several brain regions and a positive correlation of FA in the genu corpus callosum with exposure to smoking (pack-years). OBJECTIVE: To help resolve prior discrepancies, we studied adults, sampling multiple brain regions, and testing for relationships to clinical features of nicotine dependence and exposure to smoking. METHODS: Brain MRI scans (1.5 T) were acquired, and FA and apparent diffusion coefficient (ADC, a measure of random diffusion) were assayed in corpus callosum and prefrontal white matter, corona radiata, internal capsule, cingulum bundle, and hippocampal perforant fibers in 18 smokers (33.7 ± 7.9 years of age) and 18 age- and gender-matched nonsmokers. RESULTS: ADC showed no group difference, but smokers had higher (4.3-21.1%) FA than nonsmokers. The differences were significant in right prefrontal white matter, cingulum, and genu corpus callosum. FA in several regions was negatively correlated with nicotine dependence or cigarettes/day. CONCLUSIONS: Combined with earlier findings, these results suggest a model of changing trajectories whereby FA is higher with tobacco exposure during adolescence and declines with continued smoking in adulthood. This notion is supported by the observation that, at multiple sampling sites, participants who had started smoking earlier in life had higher FA than those who had started later.

Proton magnetic resonance spectroscopy and thought disorder in childhood schizophrenia.

OBJECTIVE: Although magnetic resonance spectroscopy has identified metabolic abnormalities in adult and childhood schizophrenia, no prior studies have investigated the relationship between neurometabolites and thought disorder. This study examined this association in language-related brain regions using proton magnetic resonance spectroscopic imaging ((1)H MRSI). METHOD: MRSI was acquired bilaterally from 28 youth with childhood-onset schizophrenia and 34 healthy control subjects in inferior frontal, middle frontal, and superior temporal gyri at 1.5T and short echo time (TR/TE = 1500/30 ms). CSF-corrected "total NAA" (tNAA; N-acetyl-aspartate + N-acetyl-aspartyl-glutamate), glutamate + glutamine (Glx), creatine + phosphocreatine (Cr + PCr), choline compounds (Cho), and myo-inositol (mI) were assayed in manually drawn regions-of-interest partitioned into gray matter, white matter, and CSF and then coregistered with MRSI. Speech samples of all subjects were coded for thought disorder. RESULTS: In the schizophrenia group, the severity of formal thought disorder correlated significantly with tNAA in the left inferior frontal and superior temporal gyri and with Cr + PCr in left superior temporal gyrus. CONCLUSIONS: Neurometabolite concentrations in language-related brain regions are associated with thought disorder in childhood-onset schizophrenia.

White-matter abnormalities in brain during early abstinence from methamphetamine abuse.

BACKGROUND: Previous studies revealed microstructural abnormalities in prefrontal white matter and corpus callosum of long-term abstinent chronic methamphetamine abusers. In view of the importance of the early abstinence period in treatment retention, we compared 23 methamphetamine-dependent subjects abstinent from methamphetamine for 7-13 days with 18 healthy comparison subjects. As certain metabolic changes in the brain first manifest after early abstinence from methamphetamine, it is also possible that microstructural white-matter abnormalities are not yet present during early abstinence. METHODS: Using diffusion tensor imaging at 1.5 T, fractional anisotropy (FA) was measured in prefrontal white matter at four inferior-superior levels parallel to the anterior commissure-posterior commissure (AC-PC) plane. We also sampled FA in the corpus callosum at the midline and at eight bilateral, fiber-tract sites in other regions implicated in effects of methamphetamine. RESULTS: The methamphetamine group exhibited lower FA in right prefrontal white matter above the AC-PC plane (11.9% lower; p = 0.007), in midline genu corpus callosum (3.9%; p = 0.019), in left and right midcaudal superior corona radiata (11.0% in both hemispheres, p's = 0.020 and 0.016, respectively), and in right perforant fibers (7.3%; p = 0.025). FA in left midcaudal superior corona radiata was correlated with depressive and generalized psychiatric symptoms within the methamphetamine group. CONCLUSIONS: The findings support the idea that methamphetamine abuse produces microstructural abnormalities in white matter underlying and interconnecting prefrontal cortices and hippocampal formation. These effects are already present during the first weeks of abstinence from methamphetamine and are linked to psychiatric symptoms assessed during this period.