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Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18 F-deoxyglucose positron emission tomography ( 18 F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18 F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18 F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.

Background: Bleeding is an intraoperative and postoperative complication of liver surgery of concern, and yet evidence to support utility and reproducibility of bleeding scales for liver surgery is limited. We determined the reproducibility of the clinician-reported validated intraoperative bleeding severity scale and its clinical value of implementation in liver surgery., Methods: In this descriptive and observational multicenter study, we assessed the performance of liver surgeons instructed on the clinician-reported intraoperative bleeding severity scale using training videos that covered all 5 grades of bleeding severity. Surgeons were stratified according to years of surgical experience and number of surgeries performed per year based on a median split in low and high values. Intraobserver and interobserver agreement was assessed using Kendall's coefficient of concordance (Kendall's W)., Results: Forty-seven surgeons from 10 hospitals in Spain participated in the study. The overall intraobserver concordance was 0.985, and the overall interobserver concordance was 0.929. For "high experience" surgeons, the intraobserver and interobserver agreement values were 0.990 and 0.941, respectively. For "low experience" surgeons, the intraobserver and interobserver agreement was 0.981 and 0.922, respectively. Regarding the annual number of surgeries, intraobserver and interobserver agreement values were 0.995 and 0.940, respectively, for surgeons performing >35 surgeries per year, with 0.979 and 0.923, respectively, for surgeons who perform ≤35 surgeries year., Conclusion: The clinician-reported intraoperative bleeding severity scale shows high interobserver and intraobserver concordance, suggesting it is a useful tool for assessing severity of bleeding during liver surgery; years of surgical experience and number of annual procedures performed did not affect the applicability of the clinician-reported intraoperative bleeding severity scale., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study describes and characterizes a narrow, hollow tubular structure, termed as duct-like diverticulum (DV), found specifically at the basal midline of papillary craniopharyngiomas (PCPs) located within the third ventricle (3V). The presence of this structure was systematically investigated on autopsy studies and magnetic resonance imaging (MRI) scans of 3536 craniopharyngioma (CP) cases published in the medical literature from 1911 to 2021, as well as in other twelve 3V tumor categories (n = 1470 cases). A basal DV was observed in a total of 50 PCPs, including two of our own cases. This DV corresponds to a tubular-shaped recess invaginated at the midline bottom of the tumor, following the same angled trajectory as the pituitary stalk. It can be easily seen as a hypointense linear structure on T1- and T2-weighted MRI scans, with two main length types: long DVs (74%), which reach the tumor center, and short DVs (26%), which penetrate the tumor only a few millimeters. The DV sign identifies the papillary CP type with a specificity of 100% and a sensitivity of 33% in the overall CP population. This finding also serves to establish the strictly intra-3V location of the lesion with a 95% specificity and 42% sensitivity among papillary CPs. No similar basal DV was found in adamantinomatous CPs nor among other categories of strictly 3V tumors. Consequently, the presence of a diverticulum in a 3V tumor represents a morphological signature pathognomonic of the papillary type and a valuable sign to reliably define the strictly 3V topography., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Gyriform mammals display neurophysiological and neural network activity that other species exhibit only in rudimentary or dissimilar form. However, neural recordings from large mammals such as the pig can be anatomically hindered and pharmacologically suppressed by anesthetics. This curtails comparative inferences. To mitigate these limitations, we set out to modify electrocorticography, intracerebral depth and intracortical recording methods to study the anesthetized pig. In the process, we found that common forms of infused anesthesia such as pentobarbital or midazolam can be neurophysiologic suppressants acting in dose-independent fashion relative to anesthetic dose or brain concentration. Further, we corroborated that standard laboratory conditions may impose electrical interference with specific neural signals. We thus aimed to safeguard neural network integrity and recording fidelity by developing surgical, anesthesia and noise reduction methods and by working inside a newly designed Faraday cage, and evaluated this from the point of view of neurophysiological power spectral density and coherence analyses. We also utilized novel silicon carbide electrodes to minimize mechanical disruption of single-neuron activity. These methods allowed for the preservation of native neurophysiological activity for several hours. Pig electrocorticography recordings were essentially indistinguishable from awake human recordings except for the small segment of electrical activity associated with vision in conscious persons. In addition, single-neuron and paired-pulse stimulation recordings were feasible simultaneously with electrocorticography and depth electrode recordings. The spontaneous and stimulus-elicited neuronal activities thus surveyed can be recorded with a degree of precision similar to that achievable in rodent or any other animal studies and prove as informative as unperturbed human electrocorticography., (© 2022. The Author(s).)

Background and Purpose: Papillary craniopharyngiomas (PCPs) are particularly challenging lesions requiring accurate diagnosis to plan the best therapy. Our aim was to define a narrow duct-like recess identified on MR imaging at the base of papillary craniopharyngiomas with a strict third ventricle location., Materials and Methods: A duct-like recess at the infundibular portion of craniopharyngiomas was observed on conventional T1WI and T2WI in 3 strict third ventricle papillary craniopharyngiomas in our craniopharyngioma series ( n = 125). We systematically investigated this finding on the MR imaging of 2582 craniopharyngiomas and 10 other categories of third ventricle tumors ( n = 690) published in the modern era (1986-2020). The diagnostic value and significance of this finding are addressed., Results: The duct-like recess was recognized in 52 papillary craniopharyngiomas, including 3 of our own cases, as a narrow canal-shaped cavity invaginated at the tumor undersurface, just behind the optic chiasm. This structure largely involves papillary craniopharyngiomas with a strict third ventricle topography (96%), follows the same diagonal trajectory as the pituitary stalk, and finishes at a closed end. The duct-like recess sign identifies the papillary craniopharyngioma type with a specificity of 100% and a sensitivity of 38% in the overall craniopharyngioma population. This finding can also establish the strictly intra-third ventricle location of the lesion with a 90% specificity and 33% sensitivity. These recesses appear as hypointense circular spots on axial/coronal T1WI and T2WI. Their content apparently corresponds to CSF freely flowing within the suprasellar cistern., Conclusions: The presence of a duct-like recess at the infundibular portion of a third ventricle tumor represents a distinctive hallmark of papillary craniopharyngiomas that can be used as a simple MR imaging sign to reliably diagnose these lesions., (© 2022 by American Journal of Neuroradiology.)

MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I  2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I  2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results., (Published by Oxford University Press 2022.)

Targeted therapies for epilepsies associated with the mTORC1 signaling negative regulator GATOR1 are lacking. NPRL2 is a subunit of the GATOR1 complex and mutations in GATOR1 subunits, including NPRL2 , are associated with epilepsy. To delineate the mechanisms underlying NPRL2-related epilepsies, we created a mouse ( Mus musculus ) model with neocortical loss of Nprl2 . Mutant mice have increased mTORC1 signaling and exhibit spontaneous seizures. They also display abnormal synaptic function characterized by increased evoked and spontaneous EPSC and decreased evoked and spontaneous IPSC frequencies, respectively. Proteomic and metabolomics studies of Nprl2 mutants revealed alterations in known epilepsy-implicated proteins and metabolic pathways, including increases in the neurotransmitter, glycine. Furthermore, glycine actions on the NMDA receptor contribute to the electrophysiological and survival phenotypes of these mice. Taken together, in this neuronal Nprl2 model, we delineate underlying molecular, metabolic, and electrophysiological mechanisms contributing to mTORC1-related epilepsy, providing potential therapeutic targets for epilepsy., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

This study investigates the presence of a hollow recess at the midline undersurface of tumors primarily localized within the third ventricle (3V). This structure was originally identified by magnetic resonance imaging (MRI) of 6 3V craniopharyngiomas (CPs) from our series and was then methodically scrutinized in autopsy studies (n = 1091) and MRI scans (n = 5558) of CPs and in 1251 3V tumors reported in the medical literature from 1839 to 2021. A recess at the tumor base was identified in 110 CPs, 95 with a verified papillary histology (papillary craniopharyngioma [PCP]) and 15 with typical gross appearance of PCP. Topographically, 90 tumors were strictly within the 3V (82%); 20 developed at the infundibulo-tuberal region of the 3V floor (18%). Morphologically, 2 main types of recess were identified: (i) a long, narrow recess with either a duct-like or a tubular shape that reached the central region of the CP (n = 47, 42.5%); and (ii) a short recess extending only a few millimeters into the lesion, either with a duct-like or a shallow cleft-like morphology (n = 63, 57.5%). Thus, the presence of a basal recess represents a pathological hallmark of a subpopulation of 3V PCPs. The presumed nature and diagnostic significance of this novel finding is comprehensively addressed., (© 2022 American Association of Neuropathologists, Inc. All rights reserved.)

This study aimed to analyze the psychological affectation of health professionals (HPs) of Spanish Emergency Medical Services (EMSs) according to the cumulative incidence (CI) of COVID-19 cases in the regions in which they worked. A cross-sectional descriptive study was designed, including all HPs working in any EMS of the Spanish geography between 1 February 2021 and 30 April 2021. Their level of stress, anxiety and depression (DASS-21) and the perception of self-efficacy (G-SES) were the study's main results. A 2-factor analysis of covariance was used to determine if the CI regions of COVID-19 cases determined the psychological impact on each of the studied variables. A total of 1710 HPs were included. A third presented psychological impairment classified as severe. The interaction of CI regions with the studied variables did not influence their levels of stress, anxiety, depression or self-efficacy. Women, younger HPs or those with less EMS work experience, emergency medical technicians (EMT), workers who had to modify their working conditions or those who lived with minors or dependents suffered a greater impact from the COVID-19 pandemic in certain regions. These HPs have shown high levels of stress, anxiety, depression and medium levels of self-efficacy, with similar data in the different geographical areas. Psychological support is essential to mitigate their suffering and teach them to react to adverse events.

Purpose: The aim of this prospective study was to evaluate the clinical-radiological outcomes of the Alteon Neck Preserving Stem (ANPS) (Exactech, Gainesville, FL, USA) implanted in four different centres by five senior hip surgeons with a minimum of 5 years of follow-up., Material and Method: We conducted a multicentre prospective study that analysed 155 consecutive total hip replacements during 2014. We performed clinical-radiological analysis measuring Harris Hip Score (HHS), subjective satisfaction evaluation, radiolucencies, position of components, limb length discrepancy, heterotopic ossification, medical and surgical complications and a survival analysis at 5 years follow-up., Results: Thigh pain was reported in 5 cases (3.2%), 2 of which reported mild pain, 2 moderate, and 1 severe. In 2 cases, subsidences of 3 mm were detected in the first scheduled X-ray, both related to intraoperative fractures with no progression after 3 months. The overall complication rate was 5.8% and 6 of the 9 complications were in the first 30 cases. Mean HHS improved from 42.9 points (range 37.2-55.7 points) preoperatively to 94.9 on average (range 87-98) at the end of the follow-up (p <0.01). Subjective evaluation was excellent in 130 (83.87%) cases and good in 25 patients (16.13%)., Conclusions: The clinical-radiographic results of ANPS THR are satisfactory. The mid-term results are promising. However, long-term follow-up studies are necessary to confirm the validity of the concept., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Biological principles sustain the inference that synaptic function is coupled to neural metabolism, but the precise relationship between these two activities is not known. For example, it is unclear whether all synaptic transmission events are uniformly dependent on metabolic flux. Most synapses use glutamate, and the principal metabolic function of the brain is glucose oxidation, which starts with glycolysis. Thus, we asked how glutamatergic synaptic currents are modified by partial deficiency of the main glycolytic enzyme pyruvate dehydrogenase (PDH), which generates the intermediary metabolism product acetyl coenzyme A (acetyl-CoA). Using brain slices obtained from mice that were genetically modified to harbor a behaviorally relevant degree of PDH suppression, we also asked whether such impact is indeed metabolic via the bypassing of PDH with a glycolysis-independent acetyl-CoA substrate. We analyzed spontaneous synaptic currents under recording conditions that minimize artificial metabolic augmentation. Principal component analysis identified synaptic charge transfer as the major difference between a subset of wild-type and PDH-deficiency (PDHD) postsynaptic currents. This was due to reduced charge transfer as well as diminished current rise and decay times. The alternate acetyl-CoA source acetate rapidly restored these features but only for events of large amplitude as revealed by correlational and kernel density analyses. Application of tetrodotoxin to block large-amplitude events evoked by action potentials removed synaptic event charge transfer and decay-time differences between wild-type and PDHD neurons. These results suggest that glucose metabolic flux and excitatory transmission are intimately coupled for synaptic events characterized by large current amplitude. NEW & NOTEWORTHY In all tissues, metabolism and excitation are coupled but the details of this relationship remain elusive. Using a brain-targeted genetic approach in mice, reduction of pyruvate dehydrogenase, a major gateway in glucose metabolism, leads to changes that affect the synaptic event charge associated primarily with large excitatory (i.e., glutamate mediated) synaptic potentials. This can be modified in the direction of normal using the alternative fuel acetate, indicating that this phenomenon depends on rapid metabolic flux.

The strictly third ventricle craniopharyngioma topography (strictly 3V CP) defines the subgroup of lesions developed above an anatomically intact third ventricle floor (3VF). The true existence of this exceedingly rare topographical category is highly controversial owing to the presumed embryological CP origin from Rathke's pouch, a structure developmentally situated outside the neural tube. This study thoroughly analyzes the largest series of strictly 3V CPs ever collected. From 5346 CP reports published between 1887 and 2021, we selected 245 cases with reliable pathological, surgical, and/or neuroradiological verification of an intact 3VF beneath the tumor. This specific topography occurs predominantly in adult (92.6%), male (64.4%) patients presenting with headache (69.2%), and psychiatric disturbances (59.2%). Neuroradiological features defining strictly 3V CPs are a tumor-free chiasmatic cistern (95.9%), an entirely visible pituitary stalk (86.4%), and the hypothalamus positioned around the tumor's lower pole (92.6%). Most are squamous papillary (82%), showing low-risk severity adhesions to the hypothalamus (74.2%). The adamantinomatous variant, however, associates a higher risk of severe hypothalamic adhesion (p < .001). High-risk attachments are also associated with psychiatric symptoms (p = .013), which represented the major predictor for unfavorable prognoses (83.3% correctly predicted) among cases operated from 2006 onwards. CP recurrence is associated with infundibulo-tuberal symptoms (p = .036) and incomplete surgical removal (p = .02). The exclusive demographic, clinico-pathological and neuroradiological characteristics of strictly 3V CPs make them a separate, unique topographical category. Accurately distinguishing strictly 3V CPs preoperatively from those tumors replacing the infundibulum and/or tuber cinereum (infundibulo-tuberal or not strictly 3V CPs) is critical for proper, judicious surgical planning., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Localization within the nervous system provides context for neurological disease manifestations and treatment, with numerous disease mechanisms exhibiting predilect locations. In contrast, the molecular function of most disease-causing genes is generally considered dissociated from such brain regional correlations because most genes are expressed throughout the brain. We tested the factual basis for this dissociation by discerning between two distinct genetic disease mechanism possibilities: One, gene-specific, in which genetic disorders are poorly localizable because they are multiform at the molecular level, with each mutant gene acting more widely or complexly than via mere loss or gain of one function. The other, more general, where aspects shared by groups of genes such as membership in a gene set that sustains a concerted biological process accounts for a common or localizable phenotype. We analyzed mitochondrial substrate disorders as a paradigm of apparently heterogeneous diseases when considered from the point of view of their manifestations and individual function of their causal genes. We used publicly available transcriptomes, disease phenotypes published in peer-reviewed journals and Human Ontology classifications for 27 mitochondrial substrate metabolism diseases and analyzed if these disorders manifest common phenotypes and if this relates to common brain regions or cells as demarcated by their transcriptome. The most frequent phenotypic manifestations and brain structures involved were almost stereotypic regardless of the individual gene affected, correlating with the regional abundance of the transcriptome that served mitochondrial substrate metabolism. This also applied to the transcriptome of inhibitory neurons, which are dysfunctional in some mitochondrial diseases. This stands in contrast with resistance to dementia atrophy from other causes, which is known to also associate with greater expression of a similar fraction of the transcriptome. The results suggest that brain region or cell type dysfunction stemming from a broad process such as mitochondrial substrate metabolism is more relevant for disease manifestations than individual gene participation in specific molecular function., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interests: The authors declare that they have no competing interests.

Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small intestine (30%). The advances in its knowledge and management succeeded in the last years have being spectacular. This review aims to summarize the most important of them for surgeons. We identified four areas of interest: molecular oncology, laparoscopic approach, management of GIST located at unusual locations, and management of advanced GIST. Advances in the field of molecular oncology lead to the discovery of new oncogenic mutations making the term Wil Type GIST obsolete. Moreover, these advances allow for the development of 2 new drugs: Avapritinib and Ripretinib, that added to the previous 3 commercially available drugs (imatinib, sunitinib and regorafenib) make possible the management of GIST with resistant mutations. The principles of the surgical management of primary GIST are well stablished which laparoscopic approach must accomplish. This approach is limited by 2 main factors: location and size. The diagnosis of GIST in unusual locations as esophagus, duodenum, rectum of out of the gastrointestinal tract (EGIST), implies an extraordinary therapeutic challenge, being imperative to manage them by surgeons and oncologist among others in the setting of a multidisciplinary team. The management of advanced/metastatic GIST has changed in a revolutionary fashion because surgery is now part of its treatment as adjuvant to tyrosine kinase inhibitors., (Copyright: © 2022 Permanyer.)

Background: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a safe and minimally invasive procedure for evaluating hilar and mediastinal lymph nodes. The reported sensitivity and specificity of EBUS-TBNA are 95% and 97%, respectively. A comparison of diagnostic sensitivity for lymph nodes suspected of lung cancer according to needle size in EBUS-TBNA is needed., Objectives: To compare the diagnostic sensitivity of the 19-G, 21-G, 22-G and 25-G needles for lymph nodes suspected of non-small cell lung cancer (NSCLC) using EBUS-TBNA., Methods: A literature search from PubMed, EMBASE, LILACS, DOAJ and CENTRAL through October 2020 was performed by two reviewers. The extracted data were evaluated using STATA® and Open Meta Analyst software for meta-analysis with a binary method model to compare sensitivity, specificity and summary receiver operating characteristic curve for each needle size., Results: Fourteen studies including 1296 participants were considered for the analysis. The overall sensitivity of EBUS-TBNA was 88.2% (95% CI 84%, 91%) and 93% (95% CI 88%, 95%) for the 19-G needle, 87.6% (95% CI 79.6%, 92.8%) for the 21-G needle and 85% (95% CI 80%, 88%) for the 22-G needle. The overall sensitivity of EBUS-TBNA for diagnosing NSCLC was 88.3% (95% CI, 81%, 93%) and 92.9% (95% CI, 85%, 97%) for the 19-G needle, 89.4% (95% CI 79.4%, 94.8%) for the 21-G needle and 82.1% (95% CI 66%, 91%) for the 22-G needle., Conclusion: The 19-G, 21-G and 22-G needles present a similarly high diagnostic sensitivity in EBUS-TBNA. The 19-G needle provided better sample adequacy for molecular and immunohistochemical testing, improving diagnostic yield in this subgroup., (© 2021 John Wiley & Sons Ltd.)

Enhanced understanding of the molecular features of glioma has led to an expansion of murine glioma models and successful preclinical studies. However, clinical trials continue to have a high cost, extended production time, and low proportion of success. Studies in large-animal models of various cancer types have emerged to bridge the translational gap between in vitro and in vivo animal studies and human clinical trials. The anatomy and physiology of large animals are of more direct relevance to human disease, allowing for more rigorous testing of treatments such as surgical resection and adjuvant therapy in glioma. The recent generation of multiple porcine glioma models supports their use in high-throughput preclinical studies. The demonstration of spontaneous glioblastoma formation in canines further provides a unique avenue for the study of de novo glioma. The aim of this review was to outline the current status of large animal models of glioma and their value as a transitional step between rodent models and human clinical trials., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Interest in human and experimental animal metabolism of substrates containing an odd number of carbons capable of fueling the tricarboxylic acid cycle such as heptanoic acid has motivated us to develop and validate a selective and specific liquid chromatographytandem mass spectrometric method for the simultaneous, quantitative determination of the ketone body byproducts 3-hydroxypentanoic acid and 3-oxopentanoic acid in plasma. Human plasma samples were protein-precipitated with methanol containing 0.2% formic acid. Chromatographic resolution was achieved on a Phenomenex Luna C18 column using gradient elution with mobile phases of water containing 0.1% formic acid and methanol containing 0.1% formic acid at 0.3 mL/min flow rate. The retention times of 3-hydroxypentanoic acid, 3-oxopentanoic acid and sulbactam (internal standard) were 3.85, 4.23, and 5.11 min, respectively. Validation was conducted in accordance with United States Food and Drug Administration guidance. The validated range of 3-hydroxypentanoic acid was 0.078-5 µg/mL and 0.156-10 µg/mL for 3-oxopentanoic acid. The method was accurate and precise over this range and exhibited 10-fold dilution integrity in human plasma. Recovery> 88% was achieved for analytes and internal standard. There was no matrix effect observed in human plasma. Both 3-hydroxypentanoic acid and 3-oxopentanoic acid were stable across conditions including autosampler, benchtop and freeze-thaw, as well as demonstrated long-term stability at -80 °C. The method was applied to the measurement of 3-hydroxypentanoic acid and 3-oxopentanoic acid concentrations in plasma from subjects receiving the triglyceride triheptanoin (as a source of heptanoate) for the experimental treatment of glucose transporter type I deficiency (G1D) syndrome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Thousands of years after dietary therapy was proposed to treat seizures, how alterations in metabolism relates to epilepsy remains unclear, and metabolism-based therapies are not always effective., Methods: We consider the state of the science in metabolism-based therapies for epilepsy across the research lifecycle from basic to translational to clinical studies., Results: This analysis creates a conceptual framework for creative, rigorous, and transparent research to benefit people with epilepsy through the understanding and modification of metabolism., Interpretation: Despite intensive past efforts to evaluate metabolism-based therapies for epilepsy, distinct ways of framing a problem offer the chance to engage different mindsets and new (or newly applied) technologies. A comprehensive, creative, and inclusive problem-directed research agenda is needed, with a renewed and stringent adherence to rigor and transparency across all levels of investigation., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: To evaluate physician perceptions and attitudes toward telemedicine use at a tertiary care academic institution in northeast Florida during the coronavirus disease 2019 pandemic., Patients and Methods: An anonymous 38-question cross-sectional survey was developed using Qualtrics survey software (Qualtrics) and e-mailed to all staff physicians from all specialty disciplines at Mayo Clinic in Florida. The survey was open from August 17, 2020, through September 1, 2020. Collected data included general demographic characteristics and employment information, attitude and experience with telemedicine use before and during the coronavirus disease 2019 pandemic, perception of patients' experience, and the effect of telemedicine on burnout., Results: The survey was distributed to 529 eligible physicians at our institution, with 103 physicians responding (20%). The distribution of specialties was 22% primary care specialties, 41% other internal medicine subspecialties, and 18% surgical specialties. Collectively, 63% found comparable quality of care when provided virtually (vs in-person) whereas 80% perceived telemedicine as cost-effective. A total of 76% of physicians felt that telemedicine increased flexibility and control over patient care activities, with 36% reporting improved work-life balance and 30% reporting improved burnout symptoms. Overall, 42% preferred using telemedicine over in-person visits when possible., Conclusion: Physicians generally had positive attitudes regarding the adoption of telemedicine and perceived that the quality of health care delivery as generally comparable to in-person care. Future studies are needed to explore attitudes regarding telemedicine after the pandemic and how this virtual technology may be further used to improve physicians' professional and personal well-being., (© 2021 [Author/Employing Institution].)

Time-to-fall off an accelerating rotating rod (rotarod) is widely utilized to evaluate rodent motor performance. We reasoned that this simple outcome could be refined with additional measures explicit in the task (however inconspicuously) to examine what we call movement sub-structure. Our goal was to characterize normal variation or motor impairment more robustly than by using time-to-fall. We also hypothesized that measures (or features) early in the sub-structure could anticipate the learning expected of a mouse undergoing serial trials. Using normal untreated and baclofen-treated movement-impaired mice, we defined these features and automated their analysis using paw video-tracking in three consecutive trials, including paw location, speed, acceleration, variance and approximate entropy. Spectral arc length yielded speed and acceleration uniformity. We found that, in normal mice, paw movement smoothness inversely correlated with rotarod time-to-fall for the three trials. Greater approximate entropy in vertical movements, and opposite changes in horizontal movements, correlated with greater first-trial time-to-fall. First-trial horizontal approximate entropy in the first few seconds predicted subsequent time-to-fall. This allowed for the separation, after only one rotarod trial, of different-weight, untreated mouse groups, and for the detection of mice otherwise unimpaired after baclofen, which displayed a time-to-fall similar to control. A machine-learning support vector machine classifier corroborated these findings. In conclusion, time-to-fall off a rotarod correlated well with several measures, including some obtained during the first few seconds of a trial, and some responsive to learning over the first two trials, allowing for predictions or preemptive experimental manipulations before learning completion., (© 2021. The Author(s).)

Background: The integration of 3D printing technology in hospitals is evolving toward production models such as point-of-care manufacturing. This study aims to present the results of the integration of 3D printing technology in a manufacturing university hospital., Methods: Observational, descriptive, retrospective, and monocentric study of 907 instances of 3D printing from November 2015 to March 2020. Variables such as product type, utility, time, or manufacturing materials were analyzed., Results: Orthopedic Surgery and Traumatology, Oral and Maxillofacial Surgery, and Gynecology and Obstetrics are the medical specialties that have manufactured the largest number of processes. Working and printing time, as well as the amount of printing material, is different for different types of products and input data. The most common printing material was polylactic acid, although biocompatible resin was introduced to produce surgical guides. In addition, the hospital has worked on the co-design of custom-made implants with manufacturing companies and has also participated in tissue bio-printing projects., Conclusions: The integration of 3D printing in a university hospital allows identifying the conceptual evolution to "point-of-care manufacturing."

The coronavirus disease 2019 (COVID-19) pandemic created an extremely disruptive challenge for health care leaders that required a rapid, dynamic, and innovative response. The purpose of this manuscript is to share the leadership actions and decisions at Mayo Clinic in Florida during the first 6 months of the pandemic (February to July 2020). We note 4 strategies that contributed to an effective response: (1) leverage experience with disaster preparedness and mobilize regional and national networks; (2) use surge models to anticipate and to address supply chain issues as well as practical and financial effects of the pandemic; (3) adapt creatively to establish new safety and procedural protocols in various areas for various populations; and (4) communicate timely information effectively and be the common source of truth. Mayo Clinic in Florida was able to address the surges of patients with COVID-19, to provide ongoing tertiary care, and to restore function within the first 6 months with new, strengthened practices and protocols., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

The concept of craniopharyngiomas (CPs) primarily affecting the hypothalamus, or "hypothalamic CPs" (Hy-CPs), refers, in a restrictive sense, to the subgroup of CPs originally developing within the neural tissue of the infundibulum and tuber cinereum, the components of the third ventricle floor. This subgroup, also known as infundibulo-tuberal CPs, largely occupies the third ventricle and comprises up to 40% of this pathological entity. The small subgroup of strictly intraventricular CPs (5%), lesions wholly developed within the third ventricle above an anatomically intact third ventricle floor, can also be included within the Hy-CP category. The remaining types of sellar and/or suprasellar CPs may compress or invade the hypothalamic region during their growth but will not be considered in this review. Hy-CPs predominantly affect adults, causing a wide range of symptoms derived from hypothalamic dysfunction, such as adiposogenital dystrophy (Babinski-Fröhlich's syndrome), diabetes insipidus (DI), abnormal diurnal somnolence, and a complex set of cognitive (dementia-like, Korsakoff-like), emotional (rage, apathy, depression), and behavioral (autism-like, psychotic-like) disturbances. Accordingly, Hy-CPs represent a neurobiological model of psychiatric disorders caused by a lesion restricted to the hypothalamus. The vast majority (90%) of squamous-papillary CPs belong to the Hy-CP category. Pathologically, most Hy-CPs present extensive and strong adhesions to the surrounding hypothalamus, usually formed of a thick band of gliotic tissue encircling the central portion of the tumor ("ring-like" attachment) or its entire boundary ("circumferential" attachment). CPs with these severe adhesion types associate high surgical risk, with morbidity and mortality rates three times higher than those for sellar/suprasellar CPs. Consequently, radical surgical removal of Hy-CPs cannot be generally recommended. Rather, Hy-CPs should be accurately classified according to an individualized surgery-risk stratification scheme considering patient age, CP topography, presence of hypothalamic symptoms, tumor size, and, most importantly, the CP-hypothalamus adhesion pattern., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To describe the effect of the coronavirus disease 2019 (COVID-19) pandemic on the initiation of cardiopulmonary resuscitation (CPR) in patients with out-of-hospital cardiopulmonary arrest. To compare the cardiopulmonary arrest caseload during the pandemic to the caseloads in other periods., Material and Methods: Observational, prospective study based on the registry of out-of-hospital cardiopulmonary arrest emergencies the SUMMA112 ambulance service responded to between March 1 and April 30, 2020, in the Spanish autonomous community of Madrid. The registry is a Utstein-style database. The period of March-April 2019 was the control period for direct comparison with the 2020 study period and with the January-February periods of 2019 and 2020., Results: The responders undertook advanced CPR in 146 of the 313 cardiopulmonary arrest cases registered during March-April, 2020. Of the 87 patients with COVID-19-positive tests, 33 reached the hospital alive. Advanced CPR was not applied in 167 cases; the most frequent reason was prolonged circulatory collapse. Most cases (92.7%) occurred in the home. The emergency dispatchers received more calls in March and April of 2020, but they sent out a similar number of ambulances., Conclusion: Mortality was higher in cases of cardiopulmonary arrest during the COVID-19 pandemic. The percentage of cases with no application of advanced CPR rose; the main reason was the amount of time between collapse and first response. Even though the number of emergency calls increased significantly, the SUMMA112 service did not dispatch more ambulances.

Aims: The influence of the COVID-19 pandemic on attendance to out-of-hospital cardiac arrest (OHCA) has only been described in city or regional settings. The impact of COVID-19 across an entire country with a high infection rate is yet to be explored., Methods: The study uses data from 8629 cases recorded in two time-series (2017/2018 and 2020) of the Spanish national registry. Data from a non-COVID-19 period and the COVID-19 period (February 1st-April 30th 2020) were compared. During the COVID-19 period, data a further analysis comparing non-pandemic and pandemic weeks (defined according to the WHO declaration on March 11th, 2020) was conducted. The chi-squared analysis examined differences in OHCA attendance and other patient and resuscitation characteristics. Multivariate logistic regression examined survival likelihood to hospital admission and discharge. The multilevel analysis examined the differential effects of regional COVID-19 incidence on these same outcomes., Results: During the COVID-19 period, the incidence of resuscitation attempts declined and survival to hospital admission (OR = 1.72; 95%CI = 1.46-2.04; p < 0.001) and discharge (OR = 1.38; 95%CI = 1.07-1.78; p = 0.013) fell compared to the non-COVID period. This pattern was also observed when comparing non-pandemic weeks and pandemic weeks. COVID-19 incidence impinged significantly upon outcomes regardless of regional variation, with low, medium, and high incidence regions equally affected., Conclusions: The pandemic, irrespective of its incidence, seems to have particularly impeded the pre-hospital phase of OHCA care. Present findings call for the need to adapt out-of-hospital care for periods of serious infection risk., Study Registration Number: ISRCTN10437835., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Severe cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO 2 /FiO 2 ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. C linical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle., (© 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Craniopharyngiomas (CPs) are benign histological tumors that may develop at different positions along the hypothalamic-pituitary axis. Their close, heterogenous relationship to the hypothalamus makes surgical removal challenging even though this remains the primary treatment strategy., Areas Covered: This article presents a critical overview of the pathological and clinical concepts regarding CPs that should be considered when planning treatment. Thus, we have performed a comprehensive review of detailed CP reports published between 1839 and 2020., Expert Opinion: CP surgery should pursue maximal tumor resection while minimizing the risk of injuring the hypothalamus. Therefore, surgical strategies should be individualized for each patient. Accurate assessment of presenting symptoms and preoperative MRI has proven useful to predict the type of CP-hypothalamus relationship that will be found during surgery. CPs with dense and extensive adhesions to the hypothalamus should be highly suspected when MRI shows the hypothalamus positioned around the mid-third of the tumor and an amputated upper portion of the pituitary stalk. Symptoms related to functional impairment of the infundibulo-tuberal area of the third ventricle floor, such as obesity/hyperphagia, Fröhlich's syndrome, diabetes insipidus, and/or somnolence, also indicate risky CP-hypothalamic adhesions. In these cases, limited tumor removal is strongly advocated followed by radiation therapy.

Joseph Engel (1816-1899) was a Viennese anatomist and pathologist trained under the mentorship of Carl von Rokitansky (1804-1878), the man who laid the foundations of gross anatomical pathology. In 1839, Engel completed his first scientific project: the dissertation entitled "Über den Hirnanhang und den Trichter" (About the pituitary gland and the infundibulum). This work analyzed the pathological and clinical characteristics of the pituitary and infundibulum tumor specimens collected at the Vienna Pathologic-Anatomical Museum. This little-known work represents one of the earliest attempts to determine the function of the pituitary gland-infundibulum complex. Among the 12 pituitary/infundibulum tumors examined in Engel's dissertation, one of the cases (no. 10) was instrumental for the definition of hypophyseal duct tumors, or craniopharyngiomas (CPs). This huge cyst, approximately the size of a goose egg (6 × 6 × 4.5 cm), was found in 1828 during the autopsy of a 33-year-old patient who suffered from severe headache, blindness, apathy, and finally somnolence. The cyst had replaced the hypophysis and extended upwards into the hypothalamic region and downwards into the sphenoid sinus, its inferior pole protruding through the soft palate. In 1904, the Viennese pathologist Jakob Erdheim (1874-1937) re-examined this lesion and conclusively categorized it as a hypophyseal duct tumor after a detailed histological study. The original tumor specimen corresponding to this CP case is still preserved at the Narrenturm, the circular building within the old Allgemeines Krankenhaus (Vienna General Hospital) that today holds the pathological collections of Vienna's Federal Pathologic-Anatomical Museum. To the best of our knowledge, this tumor is very probably the oldest preserved whole CP specimen in the world. This paper presents a comprehensive review of Engel's dissertation, the pioneering pathological work on pituitary and infundibulum tumors which laid the groundwork for the proper clinical, topographic, and pathological categorization of craniopharyngiomas.

Craniopharyngioma (CP) adherence represents a most baffling problem for the neurosurgeon. The highest priority of current surgical treatment is to maximize tumor removal without compromising the patients' long-term functional outcome. Surgical damage to the hypothalamus may be avoided or at least ameliorated with a precise knowledge regarding the type of adherence for each case. This article presents a comprehensive review of the pathological, surgical, and radiological sources of evidence supporting that CP adherence, despite being heterogenous, is characterized by repeating patterns. The key underlying factors of CP adherence are also discussed. Three components define the type of adherence for each case: (i) the intracranial structures attached to the tumor, (ii) the adherence morphology, and (iii) the adhesion strength. Combination of these three components gives rise to five hierarchical levels of increased risk of hypothalamic injury during tumor removal. Tumor topography has been identified as the major predictor of the type of CP adherence. The most extensive and strongest adhesions to the hypothalamus occur in CPs originated in the suprasellar cistern that secondarily invade the third ventricle (secondary intraventricular CPs) and in those originated within the third ventricle floor itself (not-strictly intraventricular CPs). Three findings observed on preoperative conventional MRI scans have proven to be reliable predictors of adherence severity. A position of the hypothalamus around the middle portion of the tumor, an amputated pituitary stalk, and an elliptical tumor shape points to the severe and critical risk levels, and in those cases, a safer limited removal is strongly recommended.

Importance: Discordance in the interpretations of genetic test results has occurred with the increased number of laboratories that are performing testing. Differences in diagnostic interpretations may have implications for the treatment of patients., Objective: To assess the interlaboratory variation in the interpretations of genetic test results with potential therapeutic implications., Design, Setting, and Participants: In this cross-sectional study, 70 genes that are commonly tested in patients with epilepsy were examined to identify 22 676 genetic variants from an unknown number of patients using the ClinVar public database of clinically annotated variants. Variant annotations submitted to ClinVar (data set version 2019-05) between November 16, 2012, and May 3, 2019, were included in the analysis. Conflicting interpretations of the genetic variants associated with epilepsy were analyzed for clinically substantial discrepancies between May 7 and June 29, 2019. Variants were examined only if they had been interpreted by 2 or more clinical laboratories. A variant with a clinically substantial difference in interpretation was defined as a variant that crossed the threshold between a likely pathogenic variant and a variant of uncertain significance., Main Outcomes and Measures: The frequency and types of variant interpretation conflicts were analyzed when a conflict was identified., Results: A total of 6292 of 22 676 variants related to epilepsy (27.7%) were interpreted by 2 or more clinical laboratories. Many variants (3307 of 6292 [52.6%]) had interpretations that were fully concordant. However, 2985 variants (47.4%) had conflicting interpretations. A clinically substantial conflict was identified in 201 of 6292 variants (3.2%). Furthermore, 117 of 201 variants (58.2%) with differences in interpretation occurred in genes with therapeutic implications., Conclusions and Relevance: In this cross-sectional study, most interpretations of genetic variants associated with epilepsy were concordant among laboratories, but more than half of the variants with conflicting interpretations occurred in genes that have therapeutic implications. It would be helpful for genetic laboratories to report known diagnostic discordance with other clinical laboratories.

Competing Interests: There are no conflicts of interest.

The decisive role Dr. Harvey Cushing (1869-1939) played in medicine goes far beyond the development of neurosurgery. His scientific devotion and commitment to patient care made him an ethical model of strict professionalism. This paper seeks to analyze the decisions Cushing made with the challenging case of HW, an adolescent boy with a craniopharyngioma (CP) involving the third ventricle. Cushing's earlier failure to successfully remove two similar lesions alerted him to the proximity of HW's tumor and the hypothalamus. Consequently, he decided to use the chiasm-splitting technique for the first time, with the aim of dissecting the CP-hypothalamus boundaries under direct view. Unexpectedly, HW suffered cardiac arrest during the surgery, but Cushing did not give up. He continued with the operation while his assistants performed resuscitation maneuvers. Such determined and courageous action allowed Cushing to succeed in an apparently hopeless case. Cushing's unwavering willingness to save patients' lives, even under extreme circumstances, was a fundamental trait defining his identity as a neurosurgeon. Analyzing the way Cushing dealt with HW's case provides valuable lessons for neurosurgeons today, particularly the importance of assuming proactive attitudes and, in certain cases, making painstaking efforts to overcome daunting situations to save a life.

Background: Brain energy failure is an early pathological event associated with synaptic dysfunction in Alzheimer's disease (AD). Thus, mitigation or enhancement of brain energy metabolism may offer a therapeutic avenue. However, there is uncertainty as to what metabolic process(es) may be more appropriate to support or augment since metabolism is a multiform process such that each of the various metabolic precursors available is utilized via a specific metabolic pathway. In the brain, these pathways sustain not only a robust rate of energy production but also of carbon replenishment., Objective: Triheptanoin, an edible odd-chain fatty acid triglyceride, is uncommon in that it replenishes metabolites in the tricarboxylic acid cycle (TCA) cycle via anaplerosis in addition to fueling the cycle via oxidation, thus potentially leading to both carbon replenishment and enhanced mitochondrial ATP production., Methods: To test the hypothesis that triheptanoin is protective in AD, we supplied mice with severe brain amyloidosis (5×FAD mice) with dietary triheptanoin for four and a half months, followed by biological and biochemical experiments to examine mice metabolic as well as synaptic function., Results: Triheptanoin treatment had minimal impact on systemic metabolism and brain amyloidosis as well as tauopathy while attenuating brain ATP deficiency and mitochondrial dysfunction including respiration and redox balance in 5×FAD mice. Synaptic density, a disease hallmark, was also preserved in hippocampus and neocortex despite profound amyloid deposition. None of these effects took place in treated control mice., Conclusion: These findings support the energy failure hypothesis of AD and justify investigating the mechanisms in greater depth with ultimate therapeutic intent.

Charles H. Frazier (1870-1936), one of the pioneers of neurosurgery in the US, is known worldwide for devising surgical procedures to relieve trigeminal neuralgia and intractable pain. Less well-known are his substantial contributions to understanding and treating pituitary and parahypophyseal lesions. Along with Bernard Alpers, he defined Rathke's cleft tumors as a different pathological entity from adenomas and hypophyseal stalk tumors (craniopharyngiomas [CPs]). The surgical challenge posed by CPs piqued Frazier's interest in these lesions, although he never published a complete account of his CP series. An examination of the Charles Frazier papers at the College of Physicians of Philadelphia allowed the authors to identify 54 CPs that he had treated during his career. In the early 1910s, Frazier developed the subfrontal approach, which would become the primary surgical route to access these lesions, providing better control of the adjacent vital neurovascular structures than the transsphenoidal route hitherto used. Nevertheless, strong adhesions between CPs and the third ventricle floor, the major reason underlying Frazier's disappointing results, moved him to advocate incomplete tumor removal followed by radiotherapy to reduce both the risk of hypothalamic injury and CP recurrence. This conservative strategy remains a judicious treatment for CPs to this day.