UW Neurological Surgery Recent PubMed Publications

Variability in multimodality treatment influences survival in non-metastatic gastric cancer patients.

J Gastrointest Oncol. 2020 Oct;11(5):952-963

Authors: Hoang T, Dayyani F, Alfaro A, Huynh J, Ji J, Ko AH, Cho M, Hiyama D

Abstract
Background: While gastric cancer is a leading cause of cancer-related mortality in Eastern Europe and Asia, it is less common in the USA. Recommendations regarding optimal treatment of non-metastatic gastric cancer (nmGC) with regard to type and extent of surgery, choice and sequence of chemotherapeutic agents, and use of radiation therapy vary across geographic locations. To determine how variability in treatment practices affects patient outcomes, we conducted a retrospective study to evaluate clinical outcomes in nmGC patients treated at four high-volume academic institutions.
Methods: California Cancer Registry data were collected for nmGC patients who underwent gastrectomy with curative intent from 2010 to 2018. We conducted chart reviews of the patients' electronic health records to validate clinical factors and outcomes. We performed multivariable Cox regressions to determine prognostic factors for outcomes.
Results: Demographics of study cohort (n=326): mean age 66 years; 64% male; 44% Caucasian, 35% Asian, 16% Latino. Tumor stage: 48% loco-regional (pT4 or pN1+) vs. 52% localized (pT1-3, pN0). Histology: 47% intestinal, 30% diffuse, 8% mixed, 15% unknown. Surgery: 34% open gastrectomy, 48% laparoscopic, 18% unknown; number of recovered lymph nodes varied from 0 to 60 in any tumor stage. Chemotherapy: 20% neoadjuvant alone, 25% adjuvant alone, 16% perioperative, 39% none. Multimodality therapy: 44% surgery only, 31% chemotherapy, 25% chemotherapy and radiation. With a median post-surgical follow-up of 6 years, 24% of patients developed recurrence and 40% had died. Compared to open surgery, laparoscopic surgeries were associated with fewer recovered lymph nodes (mean =18 vs. 25, P=0.0042). Fewer recovered lymph nodes were associated with a significant decrease in 5-year overall survival [hazard ratio (HR) =1.9, 95% confidence interval (CI): 1.3-2.8]. Timing of chemotherapy and addition of radiation therapy to chemotherapy did not confer further improvements in survival; in contrast, greater lymph node recovery plus chemotherapy were associated with a significant increase in survival (HR =0.3, 95% CI: 0.1-0.6).
Conclusions: This study highlights major practice differences in the management of nmGC patients across providers and institutions. Further efforts should be made to standardize the use of chemotherapy and adequate recovery and assessment of lymph nodes in this patient population.

PMID: 33209490 [PubMed]

Ultrasonographic cystometry for neurogenic bladder using elastography.

Neurourol Urodyn. 2020 Nov 16;:

Authors: Do MT, Kim K, Kim L, Im YJ, Choi YH, Park K

Abstract
AIM: Ultrasound shear wave elastography (SWE) has been used to measure elasticity (Young's modulus: YM) in solid organs. It was reported to show a better correlation with intravesical pressure (Pves) than with compliance, supporting its potential use in noninvasive cystometry. Contrariwise, conceptually, YM should be more correlated with compliance than with Pves. To optimize the potential use of YM as a noninvasive urodynamic study, the relationship between YM, Pves, and compliance was reassessed in this study.
METHOD: YM was serially measured using SWE along with bladder filling. To overcome problems inherent to current compliance measurements, modified dynamic compliance was developed from cystometry by a locally weighted scatter plot smoothing algorithm. Then it was matched with YM from SWE. YM was also correlated with Pves. Furthermore, to understand the nature of YM, which was measured by ultrasound, the bladder wall's modulus, which was the mathematical assessment of YM derived from cystometric data, was also calculated and compared.
RESULTS: Thirty-two neurogenic bladder patients were included in this study. YM correlated with Pves (r = .72, p < .0001) better than with modified dynamic compliance (r = -0.43, p < .0001). The correlation of YM with Pves was even higher than that with the calculated bladder wall's modulus (r = .52, p < .0001).
CONCLUSION: YM measured by SWE associates with Pves better than with compliance, confirming the results of previous studies. SWE reflects the integration of both the holding capability of the bladder wall and urine rather than either of one, implying its potential utilization in noninvasive cystometry.

PMID: 33197068 [PubMed - as supplied by publisher]

The cost of opioid use disorder and the value of aversion.

Drug Alcohol Depend. 2020 Oct 26;:108382

Authors: Murphy SM

Abstract
BACKGROUND: The objective of this study was twofold. First, to update and estimate the economic burden of opioid use disorder (OUD) to the U.S. from the perspectives of the healthcare sector, taxpayer, and society, overall and by age. Second, to estimate the mean present value of averting an OUD, overall and by age, for use in economic evaluations of prevention-focused interventions.
METHODS: This was a retrospective secondary analysis using 2018 data from the National Survey on Drug Use and Health, and the CDC WONDER Database on all U.S. persons, at least 12 years old, with an OUD, or who died of opioid overdose. Total OUD-related costs were estimated according to age and stakeholder perspective. Mean costs weighted by insurance type and the probability of mortality were estimated for each age, then used to estimate the mean present value of OUD aversion according to age and stakeholder perspective.
RESULTS: The total annual OUD-related costs to the U.S. in 2018 were $786.8 billion to society, $93 billion to taxpayers, and $89.1 billion to the healthcare sector. The mean present value of averting an OUD, across all ages, was $2.2 million, $325,125, and $244,030 from the societal, taxpayer, and healthcare sector perspectives, respectively.
CONCLUSIONS AND RELEVANCE: The age-specific values of averting an OUD allow for more robust and targeted economic evaluations of competing interventions to reduce the burden of opioids on multiple stakeholders. The rise in the annual OUD-related cost largely reflects the increase in overdose deaths attributable to synthetic opioids (e.g., fentanyl).

PMID: 33183909 [PubMed - as supplied by publisher]

A phosphorylation-regulated eIF3d translation switch mediates cellular adaptation to metabolic stress.

Science. 2020 11 13;370(6518):853-856

Authors: Lamper AM, Fleming RH, Ladd KM, Lee ASY

Abstract
Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by the induction of distinct gene programs tailored to each stress. Although the mechanisms driving repression of general protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here, we found that the noncanonical 5' cap-binding protein eIF3d was activated in response to metabolic stress in human cells. Activation required reduced CK2-mediated phosphorylation near the eIF3d cap-binding pocket. eIF3d controls a gene program enriched in factors important for glucose homeostasis, including members of the mammalian target of rapamycin (mTOR) pathway. eIF3d-directed translation adaptation was essential for cell survival during chronic glucose deprivation. Thus, this mechanism of translation reprogramming regulates the cellular response to metabolic stress.

PMID: 33184215 [PubMed - indexed for MEDLINE]

Atrial Natriuretic Peptide and Treatment With Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction.

JACC Heart Fail. 2020 Nov 04;:

Authors: Murphy SP, Prescott MF, Camacho A, Iyer SR, Maisel AS, Felker GM, Butler J, Piña IL, Ibrahim NE, Abbas C, Burnett JC, Solomon SD, Januzzi JL

Abstract
OBJECTIVES: This study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).
BACKGROUND: Neprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP.
METHODS: In a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment.
RESULTS: Among 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p < 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p < 0.001 for both).
CONCLUSIONS: Concentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

PMID: 33189632 [PubMed - as supplied by publisher]

Liquid Presenting as Solid: A Rare Presentation of Acute Myeloid Leukaemia as a Solid Epidural Mass.

Eur J Case Rep Intern Med. 2020;7(11):001802

Authors: Gupta V, Ajam F, Conte G, Al Hillan A, Al-Banaa K, Singh V, Levitt M

Abstract
Myeloid sarcoma (MS) is a very rare malignant tumour composed of myeloblasts. It most commonly involves soft tissue, bone, periosteum and lymph nodes, but unusual presentation sites have also been reported. Typically, MS evolves concurrently with active leukaemia or following remission, when it is known as secondary MS. But rarely MS can occur de novo without evidence of concomitant haematological disease. Herein, we report an unusual case of central nervous system-MS in a patient without evidence of concomitant haematological disease. In this case, progressive thoracic and lumbar pain with paraplegia ultimately led to the diagnosis of acute myeloid leukaemia. We also conducted a PubMed search for case reports, case series and reviews of past literature regarding central nervous system-MS and report our findings.
LEARNING POINTS: Myeloid sarcoma (MS) can present de novo in the absence of antecedent leukaemia.Clinical manifestations of neural MS can be variable, including rare ones like spinal cord compression.Timely recognition of MS is paramount, as it is potentially curable.

PMID: 33194852 [PubMed]

Factors influencing precision medicine knowledge and attitudes.

PLoS One. 2020;15(11):e0234833

Authors: Chakravarthy R, Stallings SC, Williams M, Hollister M, Davidson M, Canedo J, Wilkins CH

Abstract
Precision medicine holds great promise for improving health and reducing health disparities that can be most fully realized by advancing diversity and inclusion in research participants. Without engaging underrepresented groups, precision medicine could not only fail to achieve its promise but also further exacerbate the health disparities already burdening the most vulnerable. Yet underrepresentation by people of non-European ancestry continues in precision medicine research and there are disparities across racial groups in the uptake of precision medicine applications and services. Studies have explored possible explanations for population differences in precision medicine participation, but full appreciation of the factors involved is still developing. To better inform the potential for addressing health disparities through PM, we assessed the relationship of precision medicine knowledge and trust in biomedical research with sociodemographic variables. Using a series of linear regression models applied to survey data collected in a diverse sample, we analyzed variation in both precision medicine knowledge and trust in biomedical research with socioeconomic factors as a way to understand the range of precision medicine knowledge (PMK) in a broadly representative group and its relationship to trust in research and demographic characteristics. Our results demonstrate that identifying as Black, while significantly PMK, explains only 1.5% of the PMK variance in unadjusted models and 7% of overall variance in models adjusted for meaningful covariates such as age, marital status, employment, and education. We also found a positive association between PMK and trust in biomedical research. These results indicate that race is a factor affecting PMK, even after accounting for differences in sociodemographic variables. Additional work is needed, however, to identify other factors contributing to variation in PMK as we work to increase diversity and inclusion in precision medicine applications.

PMID: 33175834 [PubMed - in process]

Comparison of Clinical Outcomes 1 and 5 Years Post-Injury Following Combat Concussion.

Neurology. 2021 01 19;96(3):e387-e398

Authors: Mac Donald CL, Barber J, Patterson J, Johnson AM, Parsey C, Scott B, Fann JR, Temkin NR

Abstract
OBJECTIVE: To compare 1-year and 5-year clinical outcomes in 2 groups of combat-deployed service members without brain injury to those of 2 groups with combat-related concussion to better understand long-term clinical outcome trajectories.
METHODS: This prospective, observational, longitudinal multicohort study examined 4 combat-deployed groups: controls without head injury with or without blast exposure and patients with combat concussion arising from blast or blunt trauma. One-year and 5-year clinical evaluations included identical batteries for neurobehavioral, psychiatric, and cognitive outcomes. A total of 347 participants completed both time points of evaluation. Cross-sectional and longitudinal comparisons were assessed. Overall group effect was modeled as a 4-category variable with rank regression adjusting for demographic factors using a 2-sided significance threshold of 0.05, with post hoc Tukey p values calculated for the pairwise comparisons.
RESULTS: Significant group differences in both combat concussion groups were identified cross-sectionally at 5-year follow-up compared to controls in neurobehavioral (Neurobehavioral Rating Scale-Revised [NRS]; Cohen d, -1.10 to -1.40, confidence intervals [CIs] [-0.82, -1.32] to [-0.97, -1.83] by group) and psychiatric domains (Clinician-Administered PTSD Scale for DSM-IV [CAPS]; Cohen d, -0.91 to -1.19, CIs [-0.63, -1.19] to [-0.76, -1.62] by group) symptoms with minimal differences in cognitive performance. Both combat concussion groups also showed clinically significant decline from 1- to 5-year evaluation (66%-76% neurobehavioral NRS; 41%-54% psychiatric CAPS by group). Both control groups fared better but a subset also had clinically significant decline (37%-50% neurobehavioral NRS; 9%-25% psychiatric CAPS by group).
CONCLUSIONS: There was an evolution, not resolution, of symptoms from 1- to 5-year evaluation, challenging the assumption that chronic stages of concussive injury are relatively stable. Even some of the combat-deployed controls worsened. The evidence supports new considerations for chronic trajectories of concussion outcome in combat-deployed service members.

PMID: 33177226 [PubMed - indexed for MEDLINE]

Aryl Amination Using Soluble Weak Base Enabled by a Water-Assisted Mechanism.

J Am Chem Soc. 2020 Nov 12;:

Authors: Lau SH, Yu P, Chen L, Madsen-Duggan CB, Williams MJ, Carrow BP

Abstract
The amination of aryl halides has become one of the most commonly practiced C-N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C-N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively unsaturated Pd-OH species that can bind amine substrate triggering intramolecular N-H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.

PMID: 33179489 [PubMed - as supplied by publisher]

Segmented quantitative diffusion tensor imaging evaluation of acute traumatic cervical spinal cord injury.

Br J Radiol. 2021 Feb 01;94(1118):20201000

Authors: Mossa-Basha M, Peterson DJ, Hippe DS, Vranic JE, Hofstetter C, Reyes M, Bombardier C, Jarvik JG

Abstract
OBJECTIVES: To evaluate segmented diffusion tensor imaging (DTI) white matter tract fractional anisotropy (FA) and mean diffusivity (MD) values in acute cervical spinal cord injury (CSCI).
METHODS: 15 patients with acute CSCI and 12 control subjects were prospectively recruited and underwent axial DTI as part of the spine trauma MRI. Datasets were put through a semi-automated probabilistic segmentation algorithm that analyzed white matter, motor and sensory tracts. FA and MD values were calculated for white matter, sensory (spinal lemniscal) and motor tracts (ventral/lateral corticospinal) at the level of clinical injury, levels remote from injury and in normal controls.
RESULTS: There were significant differences in FA between the level of injury and controls for total white matter (0.65 ± .09 vs 0.68 ± .07; p = .044), motor tracts (0.64 ± .07 vs 0.7 ± .09; p = .006), and combined motor/sensory tracts (0.63 ± .09 vs 0.69 ± .08; p = .022). In addition, there were significant FA differences between the level of injury and one level caudal to the injury for combined motor tracts (0.64 ± .07 vs 0.69 ± .05; p = .002) and combined motor/sensory tracts (0.63 ± .09 vs 0.7 ± .07; p = .011). There were no significant differences for MD between the level of injury and one level caudal to the injury or normal controls.
CONCLUSION: Abnormalities in DTI metrics of DTI-segmented white matter tracts were detected at the neurological level of injury relative to normal controls and levels remote from the injury site, confirming its value in CSCI assessment.
ADVANCES IN KNOWLEDGE: Segmented DTI analysis can help identify microstructural spinal cord abnormalities in the setting of traumatic cervical spinal cord injury.

PMID: 33180553 [PubMed - indexed for MEDLINE]

Cardiologist Evaluation of Patients with Type 2 Myocardial Infarction.

Circ Cardiovasc Qual Outcomes. 2020 Nov 09;:

Authors: McCarthy CP, Olshan DS, Rehman S, Jones-O'Connor M, Murphy S, Cohen JA, Singh A, Vaduganathan M, Januzzi JL, Wasfy JH

PMID: 33161772 [PubMed - as supplied by publisher]

High-sensitivity C-Reactive Protein is a Prognostic Biomarker of 6-month Disability After Traumatic Brain Injury: Results from the TRACK-TBI Study.

J Neurotrauma. 2020 Nov 09;:

Authors: Xu L, Yue JK, Korley FK, Puccio AM, Yuh EL, Sun X, Rabinowitz M, Vassar M, Taylor SR, Winkler EA, Puffer R, Deng H, McCrea M, Stein MB, Robertson CS, Levin H, Dikmen S, Temkin N, Giacino JT, Mukherjee P, Wang KKW, Okonkwo DO, Markowitz AJ, Jain S, Manley GT, Diaz-Arrastia R

Abstract
BACKGROUND: Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI.
METHODS: The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver Operating Characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE).
RESULTS: We included 1206 TBI subjects, 122 orthopedic trauma controls (OTC), and 209 healthy controls (HC). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1-5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HC (p<0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC=0.892). Combining hsCRP and GFAP at 2 weeks produced AUC=0.939 for prediction of disability.
CONCLUSIONS: Serum high-sensitivity CRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies.

PMID: 33161875 [PubMed - as supplied by publisher]

Complicated versus uncomplicated mild traumatic brain injuries: A comparison of psychological, cognitive, and post-concussion symptom outcomes.

J Clin Exp Neuropsychol. 2020 Nov 09;:1-10

Authors: Karr JE, Iverson GL, Williams MW, Huang SJ, Yang CC

Abstract
INTRODUCTION: A complicated mild traumatic brain injury (MTBI) is defined as mild by all clinical severity indicators but is complicated due to a traumatic intracranial abnormality visible on neuroimaging. Researchers have reported mixed findings regarding whether neuropsychological and functional outcomes following complicated MTBI are worse than, or similar to, outcomes following uncomplicated MTBI. This study examined patients referred from a Taiwanese emergency department to a neurosurgical outpatient clinic. Participants with complicated MTBI, uncomplicated MTBI, and those who did not undergo head computed tomography (CT) were compared on psychological, neuropsychological, and post-concussion symptom outcomes within 21 days of injury.
METHOD: Participants with complicated MTBI (n = 42), uncomplicated MTBI (n = 77), and no head CT (n = 172) completed the Paced Auditory Serial Attention Test, Taiwanese Word Sequence Learning Test, a semantic Verbal Fluency Test, the Checklist of Post-Concussion Symptoms, and the Beck Depression and Anxiety Inventories.
RESULTS: No significant differences were observed between groups on any measure. For individual post-concussion symptoms, dizziness, anxiety, and attention difficulty were endorsed more often after uncomplicated MTBIs, but these group differences were not significant after controlling for multiple comparisons.
CONCLUSIONS: Participants with complicated MTBIs did not have worse acute or subacute outcomes than participants with uncomplicated MTBIs or no head CT. These results are consistent with many studies finding comparable outcomes between those with complicated and uncomplicated MTBIs. This study is limited by small sample size and minimal information on intracranial abnormalities, broadly categorizing groups based on positive or negative neuroimaging as opposed to specific lesion types and locations.

PMID: 33161877 [PubMed - as supplied by publisher]

CG4928 Is Vital for Renal Function in Fruit Flies and Membrane Potential in Cells: A First In-Depth Characterization of the Putative Solute Carrier UNC93A.

Front Cell Dev Biol. 2020;8:580291

Authors: Ceder MM, Aggarwal T, Hosseini K, Maturi V, Patil S, Perland E, Williams MJ, Fredriksson R

Abstract
The number of transporter proteins that are not fully characterized is immense. Here, we used Drosophila melanogaster and human cell lines to perform a first in-depth characterization of CG4928, an ortholog to the human UNC93A, of which little is known. Solute carriers regulate and maintain biochemical pathways important for the body, and malfunctioning transport is associated with multiple diseases. Based on phylogenetic analysis, CG4928 is closely related to human UNC93A and has a secondary and a tertiary protein structure and folding similar to major facilitator superfamily transporters. Ubiquitous knockdown of CG4928 causes flies to have a reduced secretion rate from the Malpighian tubules; altering potassium content in the body and in the Malpighian tubules, homologous to the renal system; and results in the development of edema. The edema could be rescued by using amiloride, a common diuretic, and by maintaining the flies on ion-free diets. CG4928-overexpressing cells did not facilitate the transport of sugars and amino acids; however, proximity ligation assay revealed that CG4928 co-localized with TASK1 channels. Overexpression of CG4928 resulted in induced apoptosis and cytotoxicity, which could be restored when cells were kept in high-sodium media. Furthermore, the basal membrane potential was observed to be disrupted. Taken together, the results indicate that CG4928 is of importance for generating the cellular membrane potential by an unknown manner. However, we speculate that it most likely acts as a regulator or transporter of potassium flows over the membrane.

PMID: 33163493 [PubMed]

Quantitative Assessment of Blood Lactate in Shock: Measure of Hypoxia or Beneficial Energy Source.

Biomed Res Int. 2020;2020:2608318

Authors: Levitt DG, Levitt JE, Levitt MD

Abstract
Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer ("shuttle") of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05 mmol/min/70 kg and 1.5 L/min/70 kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.

PMID: 33150168 [PubMed - in process]

Health economic design for cost, cost-effectiveness and simulation analyses in the HEALing Communities Study.

Drug Alcohol Depend. 2020 Oct 03;217:108336

Authors: Aldridge AP, Barbosa C, Barocas JA, Bush JL, Chhatwal J, Harlow KJ, Hyder A, Linas BP, McCollister KE, Morgan JR, Murphy SM, Savitzky C, Schackman BR, Seiber EE, E Starbird L, Villani J, Zarkin GA

Abstract
BACKGROUND: The HEALing Communities Study (HCS) is designed to implement and evaluate the Communities That HEAL (CTH) intervention, a conceptually driven framework to assist communities in selecting and adopting evidence-based practices to reduce opioid overdose deaths. The goal of the HCS is to produce generalizable information for policy makers and community stakeholders seeking to implement CTH or a similar community intervention. To support this objective, one aim of the HCS is a health economics study (HES), the results of which will inform decisions around fiscal feasibility and sustainability relevant to other community settings.
METHODS: The HES is integrated into the HCS design: an unblinded, multisite, parallel arm, cluster randomized, wait list-controlled trial of the CTH intervention implemented in 67 communities in four U.S. states: Kentucky, Massachusetts, New York, and Ohio. The objectives of the HES are to estimate the economic costs to communities of implementing and sustaining CTH; estimate broader societal costs associated with CTH; estimate the cost-effectiveness of CTH for overdose deaths avoided; and use simulation modeling to evaluate the short- and long-term health and economic impact of CTH, including future overdose deaths avoided and quality-adjusted life years saved, and to develop a simulation policy tool for communities that seek to implement CTH or a similar community intervention.
DISCUSSION: The HCS offers an unprecedented opportunity to conduct health economics research on solutions to the opioid crisis and to increase understanding of the impact and value of complex, community-level interventions.

PMID: 33152672 [PubMed - as supplied by publisher]

Disordered autonomic function during exposure to moderate heat or exercise in a mouse model of Dravet syndrome.

Neurobiol Dis. 2020 Oct 31;:105154

Authors: Sahai N, Bard AM, Devinsky O, Kalume F

Abstract
OBJECTIVE: To examine autonomic regulation of core body temperature, heart rate (HR), and breathing rate (BR) in response to moderately elevated ambient temperature or moderate physical exercise in a mouse model of Dravet syndrome (DS).
METHODS: We studied video-EEG, ECG, respiration, and temperature in mice with global heterozygous Scn1a knockout (KO) (DS mice), interneuron specific Scn1a KO, and wildtype (WT) mice during exposure to increased environmental temperature and moderate treadmill exercise.
RESULTS: Core body temperatures of WT and DS mice were similar during baseline. After 15 mins of heat exposure, the peak value was lower in DS than WT mice. In the following mins of heat exposure, the temperature slowly returned close to baseline level in WT, whereas it remained elevated in DS mice. KO of Scn1a in GABAergic neurons caused similar thermoregulatory deficits in mice. During exercise, the HR increase was less prominent in DS than WT mice. After exercise, the HR was significantly more suppressed in DS. The heart rate variability (HRV) was lower in DS than WT mice during baseline and higher in DS during exercise-recovery periods.
SIGNIFICANCE: We found novel abnormalities that expand the spectrum of interictal, ictal, and postictal autonomic dysregulation in DS mice. During mild heat stress, there was a significantly blunted correction of body temperature, and a less suppression of both HR and respiration rate in DS than WT mice. These effects were seen in mice with selective KO of Scn1A in GABAergic neurons. During exercise stress, there was diminished increase in HR, followed by an exaggerated HR suppression and HRV elevation during recovery in DS mice compared to controls. These findings suggest that different environmental stressors can uncover distinct autonomic disturbances in DS mice. Interneurons play an important role in thermoregulation. Understanding the spectrum and mechanisms of autonomic disorders in DS may help develop more effective strategies to prevent seizures and SUDEP.

PMID: 33144172 [PubMed - as supplied by publisher]

A Genital Infection-Attenuated Chlamydia muridarum Mutant Infects the Gastrointestinal Tract and Protects against Genital Tract Challenge.

mBio. 2020 Nov 03;11(6):

Authors: Morrison SG, Giebel AM, Toh E, Banerjee A, Nelson DE, Morrison RP

Abstract
Chlamydia spp. productively infect mucosal epithelial cells of multiple anatomical sites, including the conjunctiva, lungs, gastrointestinal (GI) tract, and urogenital tract. We, and others, previously established that chlamydial GI tropism is mediated by distinct chromosomal and plasmid factors. In this study, we describe a genital infection-attenuated Chlamydia muridarum mutant (GIAM-1) that is profoundly and specifically attenuated in the murine genital tract. GIAM-1 infected the murine GI tract similarly to wild-type (WT) Chlamydia muridarum but did not productively infect the lower genital tract of female mice, ascend to infect the upper genital tract, or cause hydrosalpinx. However, GI infection of mice with GIAM-1 elicited a transmucosal immune response that protected against subsequent genital challenge with WT Chlamydia muridarum Collectively, our results demonstrate that chlamydia mutants that are profoundly attenuated for specific organ tissues can be derived and demonstrate that live-attenuated vaccine strains that infect the GI tract, but do not elicit genital tract disease, could be used to protect against chlamydia genital tract infection and disease.IMPORTANCE Chlamydia is the most common sexually transmitted bacterial infection in the United States. Most chlamydia genital infections resolve without serious consequences; however, untreated infection in women can cause pelvic inflammatory disease and infertility. Antibiotics are very effective in treating chlamydia, but most genital infections in both men and women are asymptomatic and go undiagnosed. Therefore, there is a critical need for an effective vaccine. In this work, we show that a mutant chlamydia strain, having substantially reduced virulence for genital infection, colonizes the gastrointestinal tract and produces robust immunity to genital challenge with fully virulent wild-type chlamydia. These results are an important advance in understanding chlamydial virulence and provide compelling evidence that safe and effective live-attenuated chlamydia vaccines may be feasible.

PMID: 33144378 [PubMed - in process]

Medicolegal issues in abusive head trauma for the pediatric neurosurgeon.

Neurosurg Focus. 2020 Nov;49(5):E23

Authors: Bass DI, Lee A, Browd SR, Ellenbogen RG, Hauptman JS

Abstract
The purpose of this article is to serve as a rational guide for the pediatric neurosurgeon in navigating common medicolegal issues that arise in the management of abusive head trauma (AHT). Many of these issues may be unfamiliar or unpleasant to surgeons focused on addressing disease. The authors begin with a brief history on the origins of the diagnosis of AHT and the controversy surrounding it, highlighting some of the facets of the diagnosis that make it particularly unique in pediatric neurosurgery. They then review some special medical considerations in these patients through the perspective of the neurosurgeon and provide several examples as illustration. The authors discuss how to appropriately document these cases in the medical record for expected legal review, and last, they provide an overview of the legal process through which the neurosurgeon may be called to provide testimony.

PMID: 33130608 [PubMed - in process]

The effect of durotomy versus myelotomy on tissue sparing and functional outcome after spinal cord injury.

J Neurotrauma. 2020 Oct 29;:

Authors: Khaing ZZ, Cates LN, Dewees DM, Hyde JE, Gaing A, Birjandian Z, Hofstetter CP

Abstract
Various surgical strategies have been developed to alleviate elevated intraspinal pressure (ISP) following acute traumatic spinal cord injury (tSCI). Surgical decompression of either the dural (durotomy) or the dural and pial (myelotomy) lining of the spinal cord has been proposed. However, a direct comparison of these two strategies is lacking. Here, we compare the histological and functional effects of durotomy alone and durotomy + myelotomy in a rodent model of acute thoracic tSCI. Our results indicate that tSCI causes local tissue edema and significantly elevates intraspinal pressure (ISP, 7.4 ± 0.3 mmHg) compared to physiological ISP (1.7 ± 0.4 mmHg; P < 0.001). Both durotomy alone and durotomy + myelotomy effectively mitigate elevated local ISP (P < 0.001). Histological examination at 10 weeks after tSCI revealed that durotomy + myelotomy promoted spinal tissue sparing by 13.7% compared to durotomy alone and by 25.9% compared to tSCI-only (P < 0.0001). Both types of decompression surgeries elicited a significant beneficial impact onto grey matter sparing (P < 0.01). Impressively, durotomy + myelotomy surgery increased preservation of motoneurons by 174.3% compared to tSCI-only (P < 0.05). Durotomy + myelotomy surgery also significantly promoted recovery of hindlimb locomotor function in an open-field test (P < 0.001). Interestingly, only durotomy alone resulted in favorable recovery of bladder and Ladder Walk performance. Combined, our data suggest that durotomy + myelotomy following acute tSCI facilitates tissue sparing and recovery of locomotor function. In the future, biomarkers identifying spinal cord injuries that can benefit from either durotomy alone or durotomy + myelotomy need to be developed.

PMID: 33121382 [PubMed - as supplied by publisher]