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Abstract Efficiency of evidence accumulation (EEA), an individual’s ability to selectively gather goal-relevant information to make adaptive choices, is thought to be a key neurocomputational mechanism associated with cognitive functioning and transdiagnostic risk for psychopathology. However, the neural basis of individual differences in EEA is poorly understood, especially regarding the role of largescale brain network dynamics. We leverage data from 5198 participants from the Human Connectome Project and Adolescent Brain Cognitive Development Study to demonstrate a strong association between EEA and flexible adaptation to cognitive demand in the “task-positive” frontoparietal and dorsal attention networks. Notably, individuals with higher EEA displayed divergent task-positive network activation across n-back task conditions: higher activation under high cognitive demand (2-back) and lower activation under low demand (0-back). These findings suggest that brain networks’ flexible adaptation to cognitive demands is a key neural underpinning of EEA.

Abstract Childhood attention-deficit/hyperactivity disorder (ADHD) symptoms are believed to result from disrupted neurocognitive development. However, evidence for the clinical and predictive value of neurocognitive assessments in this context has been mixed, and there have been no large-scale efforts to quantify their potential for use in generalizable models that predict individuals’ ADHD symptoms in new data. Using data drawn from the Adolescent Brain Cognitive Development Study (ABCD), a consortium that recruited a diverse sample of over 10,000 youth (ages 9–10 at baseline) across 21 U.S. sites, we develop and test cross-validated machine learning models for predicting youths’ ADHD symptoms using neurocognitive abilities, demographics, and child and family characteristics. Models used baseline demographic and biometric measures, geocoded neighborhood data, youth reports of child and family characteristics, and neurocognitive tests to predict parent- and teacher-reported ADHD symptoms at the 1-year and 2-year follow-up time points. Predictive models explained 15–20% of the variance in 1-year ADHD symptoms for ABCD Study sites that were left out of the model-fitting process and 12–13% of the variance in 2-year ADHD symptoms. Models displayed high generalizability across study sites and trivial loss of predictive power when transferred from training data to left-out data. Features from multiple domains contributed meaningfully to prediction, including neurocognition, sex, self-reported impulsivity, parental monitoring, and screen time. This work quantifies the information value of neurocognitive abilities and other child characteristics for predicting ADHD symptoms and provides a foundational method for predicting individual youths’ symptoms in new data across contexts.

In this work, we expand the normative model repository introduced in Rutherford et al., 2022a to include normative models charting lifespan trajectories of structural surface area and brain functional connectivity, measured using two unique resting-state network atlases (Yeo-17 and Smith-10), and an updated online platform for transferring these models to new data sources. We showcase the value of these models with a head-to-head comparison between the features output by normative modeling and raw data features in several benchmarking tasks: mass univariate group difference testing (schizophrenia versus control), classification (schizophrenia versus control), and regression (predicting general cognitive ability). Across all benchmarks, we show the advantage of using normative modeling features, with the strongest statistically significant results demonstrated in the group difference testing and classification tasks. We intend for these accessible resources to facilitate the wider adoption of normative modeling across the neuroimaging community.

Little is known about how exposure to limited socioeconomic resources (SER) in childhood gets “under the skin” to shape brain development, especially using rigorous whole-brain multivariate methods in large, adequately powered samples. The present study examined resting state functional connectivity patterns from 5821 youth in the Adolescent Brain Cognitive Development (ABCD) study, employing multivariate methods across three levels: whole-brain, network-wise, and connection-wise. Across all three levels, SER was associated with widespread alterations across the connectome. However, critically, we found that parental education was the primary driver of neural associations with SER. These parental education associations with the developing connectome exhibited notable concentrations in somatosensory and subcortical regions, and they were partially accounted for by home enrichment activities, child’s cognitive abilities, and child’s grades, indicating interwoven links between parental education, child stimulation, and child cognitive performance. These results add a new data-driven, multivariate perspective on links between household SER and the child’s developing functional connectome.

Abstract General cognitive ability (GCA) is an individual difference dimension linked to important academic, occupational, and health-related outcomes and its development is strongly linked to differences in socioeconomic status (SES). Complex abilities of the human brain are realized through interconnections among distributed brain regions, but brain-wide connectivity patterns associated with GCA in youth, and the influence of SES on these connectivity patterns, are poorly understood. The present study examined functional connectomes from 5937 9- and 10-year-olds in the Adolescent Brain Cognitive Development (ABCD) multi-site study. Using multivariate predictive modeling methods, we identified whole-brain functional connectivity patterns linked to GCA. In leave-one-site-out cross-validation, we found these connectivity patterns exhibited strong and statistically reliable generalization at 19 out of 19 held-out sites accounting for 18.0% of the variance in GCA scores (cross-validated partial η 2). GCA-related connections were remarkably dispersed across brain networks: across 120 sets of connections linking pairs of large-scale networks, significantly elevated GCA-related connectivity was found in 110 of them, and differences in levels of GCA-related connectivity across brain networks were notably modest. Consistent with prior work, socioeconomic status was a strong predictor of GCA in this sample, and we found that distributed GCA-related brain connectivity patterns significantly statistically mediated this relationship (mean proportion mediated: 15.6%, p

Abstract Convergent research identifies a general factor (“P factor”) that confers transdiagnostic risk for psychopathology. Large-scale networks are key organizational units of the human brain. However, studies of altered network connectivity patterns associated with the P factor are limited, especially in early adolescence when most mental disorders are first emerging. We studied 11,875 9- and 10-year olds from the Adolescent Brain and Cognitive Development (ABCD) study, of whom 6593 had high-quality resting-state scans. Network contingency analysis was used to identify altered interconnections associated with the P factor among 16 large-scale networks. These connectivity changes were then further characterized with quadrant analysis that quantified the directionality of P factor effects in relation to neurotypical patterns of positive versus negative connectivity across connections. The results showed that the P factor was associated with altered connectivity across 28 network cells (i.e., sets of connections linking pairs of networks); p PERMUTATION values

Quantifying individual differences in higher-order cognitive functions is a foundational area of cognitive science that also has profound implications for research on psychopathology. For the past 2 decades, the dominant approach in these fields has been to attempt to fractionate higher-order functions into hypothesized components (e.g., inhibition, updating) through a combination of experimental manipulation and factor analysis. However, the putative constructs obtained through this paradigm have recently been met with substantial criticism on both theoretical and empirical grounds. Concurrently, an alternative approach has emerged focusing on parameters of formal computational models of cognition that have been developed in mathematical psychology. These models posit biologically plausible and experimentally validated explanations of the data-generating process for cognitive tasks, allowing them to be used to measure the latent mechanisms that underlie performance. One of the primary insights provided by recent applications of this approach is that individual and clinical differences in performance on a wide variety of cognitive tasks, ranging from simple choice tasks to complex executive paradigms, are largely driven by efficiency of evidence accumulation, a computational mechanism defined by sequential sampling models. This review assembles evidence for the hypothesis that efficiency of evidence accumulation is a central individual difference dimension that explains neurocognitive deficits in multiple clinical disorders and identifies ways in which this insight can advance clinical neuroscience research. We propose that recognition of efficiency of evidence accumulation as a major driver of neurocognitive differences will allow the field to make clearer inferences about cognitive abnormalities in psychopathology and their links to neurobiology.

ABSTRACT Denham Harman’s oxidative damage theory identifies superoxide (O2•−) radicals as central agents of aging and radiation injury, with Mn2+-dependent superoxide dismutase (MnSOD) as the principal O2•−-scavenger. However, in the radiation-resistant nematode Caenorhabditis elegans, the mitochondrial antioxidant enzyme MnSOD is dispensable for longevity, and in the model bacterium Deinococcus radiodurans, it is dispensable for radiation resistance. Many radiation-resistant organisms accumulate small-molecule Mn2+-antioxidant complexes well-known for their catalytic ability to scavenge O2•−, along with MnSOD, as exemplified by D. radiodurans. Here, we report experiments that relate the MnSOD and Mn-antioxidant content to aging and oxidative stress resistances and which indicate that C. elegans, like D. radiodurans, may rely on Mn-antioxidant complexes as the primary defense against reactive oxygen species (ROS). Wild-type and ΔMnSOD D. radiodurans and C. elegans were monitored for gamma radiation sensitivities over their life spans while gauging Mn2+-antioxidant content by electron paramagnetic resonance (EPR) spectroscopy, a powerful new approach to determining the in vivo Mn-antioxidant content of cells as they age. As with D. radiodurans, MnSOD is dispensable for radiation survivability in C. elegans, which hyperaccumulates Mn-antioxidants exceptionally protective of proteins. Unexpectedly, ΔMnSOD mutants of both the nematodes and bacteria exhibited increased gamma radiation survival compared to the wild-type. In contrast, the loss of MnSOD renders radiation-resistant bacteria sensitive to atmospheric oxygen during desiccation. Our results support the concept that the disparate responses to oxidative stress are explained by the accumulation of Mn-antioxidant complexes which protect, complement, and can even supplant MnSOD. IMPORTANCE The current theory of cellular defense against oxidative damage identifies antioxidant enzymes as primary defenders against ROS, with MnSOD being the preeminent superoxide (O2•−) scavenger. However, MnSOD is shown to be dispensable both for radiation resistance and longevity in model organisms, the bacterium Deinococcus radiodurans and the nematode Caenorhabditis elegans. Measured by electron paramagnetic resonance (EPR) spectroscopy, small-molecule Mn-antioxidant content was shown to decline in unison with age-related decreases in cell proliferation and radioresistance, which again are independent of MnSOD presence. Most notably, the Mn-antioxidant content of C. elegans drops precipitously in the last third of its life span, which links with reports that the steady-state level of oxidized proteins increases exponentially during the last third of the life span in animals. This leads us to propose that global responses to oxidative stress must be understood through an extended theory that includes small-molecule Mn-antioxidants as potent O2•−-scavengers that complement, and can even supplant, MnSOD.

Defining reference models for population variation, and the ability to study individual deviations is essential for understanding inter-individual variability and its relation to the onset and progression of medical conditions. In this work, we assembled a reference cohort of neuroimaging data from 82 sites (N=58,836; ages 2–100) and used normative modeling to characterize lifespan trajectories of cortical thickness and subcortical volume. Models are validated against a manually quality checked subset (N=24,354) and we provide an interface for transferring to new data sources. We showcase the clinical value by applying the models to a transdiagnostic psychiatric sample (N=1985), showing they can be used to quantify variability underlying multiple disorders whilst also refining case-control inferences. These models will be augmented with additional samples and imaging modalities as they become available. This provides a common reference platform to bind results from different studies and ultimately paves the way for personalized clinical decision-making.

Supraventricular tachycardia (SVT) is one of the most common conditions requiring emergency cardiac care in neonates. Atrioventricular reentrant tachycardia utilizing an atrioventricular bypass tract is the most common form of SVT presenting in the neonatal period. There is high likelihood for spontaneous resolution for most of the common arrhythmia substrates in infancy. Pharmacological agents remain as the primary therapy for neonates. Keywords: Supraventricular tachycardia, Neonate

There is substantial interest in identifying biobehavioral dimensions of individual variation that cut across heterogenous disorder categories, and computational models can play a major role in advancing this goal. In this report, we focused on efficiency of evidence accumulation (EEA), a computationally characterized variable derived from sequential sampling models of choice tasks. We created an EEA factor from three behavioral tasks in the UCLA Phenomics dataset (n = 272), which includes healthy participants (n = 130) as well-participants with schizophrenia (n = 50), bipolar disorder (n = 49), and attention-deficit/hyperactivity disorder (n = 43). We found that the EEA factor was significantly reduced in all three disorders, and that it correlated with an overall severity score for psychopathology as well as self-report measures of impulsivity. Although EEA was significantly correlated with general intelligence, it remained associated with psychopathology and symptom scales even after controlling for intelligence scores. Taken together, these findings suggest EEA is a promising computationally-characterized dimension of neurocognitive variation, with diminished EEA conferring transdiagnostic vulnerability to psychopathology.

Voltage-gated sodium (NaV) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. NaV channel β subunits have been widely studied due to their modulatory role. Mice null for Scn1b, which encodes NaV β1 and β1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality. A mutation in exon 3 of SCN1B, c.308A>T leading to β1_p.D103V and β1b_p.D103V, was previously found in a patient with a history of proarrhythmic conditions with progressive atrial standstill as well as cognitive and motor deficits accompanying structural brain abnormalities. We investigated whether β1 or β1b subunits carrying this mutation affect NaV1.5 and/or NaV1.1 currents using a whole cell patch-clamp technique in tsA201 cells. We observed a decrease in sodium current density in cells co-expressing NaV1.5 or NaV1.1 and β1D103V compared to β1WT. Interestingly, β1bD103V did not affect NaV1.1 sodium current density but induced a positive shift in the voltage dependence of inactivation and a faster recovery from inactivation compared to β1bWT. The β1bD103V isoform did not affect NaV1.5 current properties. Although the SCN1B_c.308A>T mutation may not be the sole cause of the patient’s symptoms, we observed a clear loss of function in both cardiac and brain sodium channels. Our results suggest that the mutant β1 and β1b subunits play a fundamental role in the observed electrical dysfunction.

Exposure to high concentration of oxygen (hyperoxia) leads to lung injury in experimental animal models and plays a role in the pathogenesis of diseases such as Acute Respiratory Distress Syndrome (ARDS) and Bronchopulmonary dysplasia (BPD) in humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. The major goal of this study was to characterize the changes in the pulmonary transcriptome following hyperoxia exposure and further elucidate the sex-specific changes. Male and female (8-10 wk) wild type (WT) (C57BL/6J) mice were exposed to hyperoxia (FiO2>0.95) and gene expression in lung tissues was studied at 48 h. A combination of fold change ≥1.4 and false discovery rate (FDR)

Objective: Assess the long-term plate complications with patient-specific plates (PSPs) created with computer-aided design (CAD) and computer-aided manufacturing (CAM) for fibula free flap reconstructions for mandibular defects., Methods: Retrospective chart review from January 2010 to July 2022 of patients who underwent mandibular reconstruction with a fibula free flap and PSP. Primary outcome was plating-related complications, defined as plate exposure, fracture, loose screws, and plate removal., Results: A total of 221 patients underwent PSP fibula reconstruction. Average age was 59.8 + 14.3 years old with male to female ratio of 2:1. Squamous cell carcinoma of the mandible was the most common reason for resection, 47.5%, n = 105. Plate removal occurred in 11% of patients (n = 25) about 17.4 months after the initial surgery. Plates were removed due to exposure (76%, n = 19) or screw loosening (24%, n = 6). Malignancy was associated with an increased risk of plate complications when compared to benign tumor (odds ratio [OR] 9.04, confidence interval [CI] 1.36-3.85), osteonecrosis (OR 1.38, CI 0.59-3.48), and trauma (OR 1.26, CI 0.23-12.8). Postoperative radiation therapy (OR 2.27, CI 1.07-4.82, p = 0.026) and surgical site infection (OR 9.22, CI 4.11-21.88, p = 0.001) were associated with more plate complications., Conclusions: CAD creates PSPs that remain stable in the majority of patients over the long term. Plate removal is less compared to non-PSP reconstruction. Consideration of the soft tissue envelope over the plate and management of perioperative infection at the time of surgery should be entertained., Level of Evidence: 4 Laryngoscope, 134:4929-4934, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: The purpose of the following study was to explore the patient feedback on academic oral and maxillofacial surgeons (OMSs) practicing in the United States (US) using the physician rating website (PRW) Healthgrades.com., Methods: We conducted a retrospective cohort study on academic OMSs in the US using data from Healthgrades.com. Predictor variables included OMS characteristics or rating characteristics. The primary outcome variable was overall rating. Linear regression was used to determine independent predictors of overall rating., Results: The final study sample consisted of 309 academic OMSs (mean age, 56.4 years; males, 86.4%). Age group was significantly associated with overall rating (p = 0.034). Dual-degree OMSs had a higher mean overall rating than single-degree OMSs (4.26 vs. 3.98, p = 0.012). The number of ratings was also significantly associated with overall rating (p = 0.019). Upon controlling for all other variables, merely age group was independently associated with overall rating. Specifically, OMSs aged 41-55 years were associated with a higher overall rating (+0.96, p = 0.022) relative to OMSs aged >70 years., Conclusions: The OPRs on Healthgrades.com for academic OMSs within the US are generally positive. Age was the only independent predictor for overall rating - younger OMSs (aged 41-55 years) were independently associated with a higher overall rating relative to older OMSs (aged >70 years). The new generation of younger OMSs is likely to be aware of PRWs and their implications in the growing world of online exposure., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The majority of the vascular anomalies are seen in the head and neck region. Even though the incidence of this anomaly could be construed as a rare disease entity, with only 5% of overall affliction, the lack of knowledgeable management has disfigured many. A comprehensive understanding of this benign yet complex life-changing entity is essential. A historical perspective, pathophysiology-logical evolution, and the current knowledge of management modalities are essential for rendering clinical care in this subspecialty care. We propose a very succint Head and Neck Surgical classification for vascular anamolies, which has been a good guide for surgical approaches., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Discovery of inherited and somatic genetic mutations, along with advancements in clinical and scientific research, has improved understanding of vascular anomalies and changed the treatment paradigm. With aim of minimizing need for invasive procedures and improving disease outcomes, molecularly targeted medications and anti-angiogenesis agents have become important as both adjuncts to surgery, and increasingly, as the primary treatment of vascular anomalies. This article highlights the commonly used and emerging therapeutic medications for non-malignant vascular tumors and vascular malformations in addition to medical management of associated hematologic abnormalities., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Osseous vascular anomalies can be characterized as vascular tumors or malformations. Classification is vital for prognosis and treatment. Much remains unknown about conditions such as Gorham-Stout disease. Treatments target the proposed genetic pathways such as PI3KCA/AKT/mTOR pathway., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The treatment of hemangiomas and vascular malformations should be individualized, based upon the size of the lesion(s), morphology, location, presence or possibility of complications, the potential for scarring or disfigurement, the age of the patient, and the rate of growth or involution at the time of evaluation. The major challenge is the location in a head and neck can lead to unsightly scars if approached improperly, or with inadequate approaches can lead to intraoperative and postoperative morbidity with neurovascular damage and inadequate lesion excision. Facial, trigeminal, and other cranial nerve branches are of key importance in the functional outcome while accessing and approaching head and neck vascular lesions., Competing Interests: Disclosure No disclosures are reported for any of the authors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Airway injury, Ocular injury and neurovascular tissue damage, burns is all a spectrum of pediatric soft tissue injury complex. Soft tissue injuries to the head and neck area in children are challenging to manage, because these injuries significantly affect the child's overall health and development. Management of such injuries requires a multidisciplinary approach involving surgical and nonsurgical interventions and close collaboration among health care professionals, parents, and caregivers. This article reviews the various causes of injuries, specific considerations for each region of the head and neck, and approaches to the surgical management of soft tissue injuries in pediatric patients, including surgical and adjuvant therapies. Specific anatomic regions reviewed include the scalp/forehead, periorbital region, nose, cheeks, lips, ears, and neck/airway.Laceration repair in the growing pediatric populations may require revisions in the future. Facial soft tissue injuries are prone to poor cosmesis as in many occasions as may be constrained by available surgical specialists, thus proper multispecialty team approach along with surgical alignment and symmetry should be considered comprehensively., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Vascular anomalies and tumors are common in the head, neck, and craniofacial areas and are associated with abnormalities in the angiomatous architecture. However, the etiology and molecular basis for the pathogenesis of most vascular lesions are still unknown. Pericytes are mural cells that surround endothelial cells. Besides angiogenesis and other physiological functions, pericytes play an important role in vascularized tissue repair and as resident mesenchymal stem/progenitor cells. Perivascular cells demonstrate a distinct immunohistochemical profile, including expression of alpha-smooth muscle actin (α-SMA), CD146, CD105, and PDGFRβ, without endothelial differentiation (absence of CD31 and CD34 immunoreactivity). These pericyte markers have been shown to be expressed in soft tissue hemangiomas. However, they have not been fully examined in intraosseous hemangiomas., Methods: In this study, we compared mesenchymal stem cell (MSC) expression of CD146 and α-SMA markers in pericytes from hemangiomas from different tissues and malignant vascular tumors., Results: The results demonstrated an increased expression of pericyte markers in perivascular cells of benign hemangiomas, especially intraosseous hemangiomas and a significantly reduced expression of pericyte markers in malignant angiosarcomas., Conclusion: The evidence provides insight into the function of pericytes in vascular tumors and suggests their role in vascular tumor disease types., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: This study aimed to determine the association of the NF-κB inflammatory signaling pathway with vitamin D status in older cerebral small vessel disease (SVD) patients., Methods: We measured serum 25(OH)D, pro-and anti-inflammatory cytokines, and mRNA levels of the vitamin D-activating enzyme, CYP27B1, as well as NF-kB, COX-2, the chemokine-CCL2, IL-1β, IL-6, TNF-α, TGF-β, and IL-10, in cerebral SVD patients aged ≥60 years presenting with vascular dementia and age and gender-matched healthy controls., Results: Low vitamin D status (insufficiency: serum 25(OH)D 12-20 ng/ml; deficiency: ≤12 ng/ml) was more prevalent among patients compared to controls. The mRNA levels of NF-kB, COX-2, CCL2, IL-1β, and IL-6, and serum levels of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, and TNF-α) were significantly higher in cases compared to controls. There was a significant correlation between CYP27B1 and NF-kB, COX-2, CCL2, and IL-1β gene expression. Serum IL-1α, IL-1β, and IL-6 concentrations and the expression of CCL-2, NF-kB2, and NF-kB3 genes were higher in vitamin D-deficient subjects compared to vitamin D-sufficient subjects. There was a significant negative correlation between serum 25(OH)D and IL-1α, IL-6, and TNF-α, and a positive correlation between 25(OH)D and IL-10., Conclusion: Low vitamin D is associated with an inflammatory response via NF-kB signaling, which could play a role in the etio-pathogenesis of SVD. Further large-scale studies are required to validate our findings., (Copyright © 2023. Published by Elsevier B.V.)

Objective: The purpose of the following study was to determine whether health insurance impacts the risk of suicidal ideation among patients with head and neck cancer (HNC)., Study Design: A retrospective cohort study was completed using the 2016 to 2018 National Inpatient Sample on adult patients (≥18 years) with HNC. The primary predictor was health insurance. The primary outcome was suicidal ideation. Multivariate logistic regression was employed to identify risk factors for the primary outcome variable., Results: The final study sample consisted of 29 231 patients with HNC. Not controlling for confounders, being a Medicaid patient was a risk factor for suicidal ideation (odds ratio [OR] 2.44; P < .01). However, after controlling for confounders, Medicaid was no longer a risk factor or suicidal ideation (OR 1.52; P = .190). Patients with alcohol dependence/abuse (OR 2.94; P < .01) and depression (OR 8.30; P < .01) were each more likely to experience suicidal ideation., Conclusions: Medicaid insurance was not a risk factor for suicidal ideation in our study. Depression and alcohol dependence/abuse were each risk factors for suicidal ideation. Oral cancer and oropharyngeal cancer each decreased the risk for suicidal ideations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Free tissue transfer has become the reconstructive modality of choice for replacing composite tissue defects. While the success rate in high-volume centers is reported to be greater than 95%, up to 10% of patients will require revision of their vascular anastomosis secondary to thrombosis or compromise to flow. In the intraoperative setting, immediate revision is successful in the majority of cases. Rarely, the flap cannot be revascularized and a secondary option must be used. In the perioperative setting revision is successful if the patient can be brought back to the operating room in a timely fashion. Revision rates up to 70% are reported. A small number of these patients may then suffer a second episode of compromise where revision is less successful at 30%. In these cases, consideration should be given to secondary reconstruction rather than attempting salvage. Finally, there are a small number of patients whose flaps will fail following discharge from the hospital. These patients can rarely be salvaged and secondary reconstructive options should be explored., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Background and Objectives: X-linked adrenoleukodystrophy (X-ALD) occurs due to the mutation in the ABCD1-gene. Our study was to correlate the clinical, radiological, and biochemical features in a cohort of X-ALD patients., Methods: We retrospectively analyzed 48 (M: F: 47:1) biochemically confirmed cases of X-ALD, classified them as cerebral ALD (childhood, adolescent, and adult), adrenomyeloneuropathy, Addisonian only. The Magnetic Resonance Imaging (MRI) of the radiological patterns was classified based on Loes classification., Results: The various clinical phenotypes were childhood cerebral X-ALD (58.3%), adolescent cerebral X-ALD (14.6%), adult-cerebral X-ALD (20.8%), Addisonian variant (4.2%), and adrenomyeloneuropathy (AMN) (2.1%). The imaging features were posterior white matter (Pattern-1) observed in 33 (68.75%) patients, cerebellar white matter (Pattern-4) noted in 5 subjects, anterior white matter (Pattern-2) observed in 3 patients, combined parieto-occipital and frontal white matter (Pattern-5) observed in 3 patients, isolated projection fiber (Pattern-3) observed in 1 patient. Rare features of the involvement of optic tract, anterior and lateral columns of cervicodorsal cord, bilateral central tegmental tracts, basal ganglia, and tigroid appearance were observed., Interpretation: This is a comprehensive clinical, biochemical, and imaging analysis with follow-up information of one of the largest series of X-ALD patients. The knowledge regarding the clinical features, typical and atypical imaging patterns is of vital importance for early diagnosis and treatment., Competing Interests: None

Surgical management of head and neck melanoma starts from the primary biopsy of the cutaneous site by a narrow excision with a 1 to 3 mm margins. The margin should include the whole breadth and sufficient depth of the lesion. The key is not to transect the lesion. With the advent of molecular testing, gene expression profiling, and immunotherapies, the surgical management of advanced melanoma has changed. Sentinel lymph node biopsy is an essential armamentarium for T2a and higher staging/greater than 1 mm thick and advance stage disease. Molecular pathogenesis and cancer immunology are recognized in the recent treatment protocols along with surgery in advanced stages of melanoma., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Accurate diagnosis and staging of malignant melanoma remain crucial components in the overall treatment and prognosis of the patient. Advanced imaging modalities as well as laboratory testing continue to constitute an important part of the workup in melanoma and have seen several developments in recent years. The authors discuss imaging techniques and serum biomarkers used in the assessment of the melanoma patient., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Background: Disorders of tetrahydrobiopterin metabolism represent a rare group of inherited neurotransmitter disorders that manifests mainly in infancy or childhood with developmental delay, neuroregression, epilepsy, movement disorders, and autonomic symptoms., Methodology: A retrospective review of genetically confirmed cases of disorders of tetrahydrobiopterin metabolism over a period of three years (Jan 2018 to Jan 2021) was performed across two paediatric neurology centres from South India., Results: A total of nine patients(M:F=4:5) fulfilled the eligibility criteria. The genetic variants detected include homozygous mutations in the QDPR(n=6), GCH1(n=2), and PTS(n=1) genes. The median age at onset of symptoms was 6-months(range 3-78 months), while that at diagnosis was 15-months (8-120 months), resulting in a median delay in diagnosis of 9-months. The main clinical manifestations included neuroregression (89%), developmental delay(78%), dystonia(78%) and seizures(55%). Management strategies included a phenylalanine restricted diet, levodopa/carbidopa, 5-Hydroxytryphtophan, and folinic acid. Only, Patient-2 afforded and received BH4 supplementation at a sub-optimal dose later in the disease course. We had a median duration of follow up of 15 months (range 2-48 months). Though the biochemical response has been marked; except for patients with GTPCH deficiency, only mild clinical improvement was noted with regards to developmental milestones, seizures, or dystonia in others., Conclusion: Tetrahydrobiopterin deficiencies represent a rare yet potentially treatable cause for non-phenylketonuria hyperphenylalaninemia with better outcomes when treated early in life. Screening for disorders of biopterin metabolism in patients with hyperphenylalaninemia prevents delayed diagnosis. This study expands the genotype-phenotype spectrum of patients with disorders of tetrahydrobiopterin metabolism from South India., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Aspirin non-response due to persistent platelet reactivity has been associated with adverse vascular events. Light transmission aggregometry (LTA), the 'gold standard' for measuring the platelet response to aspirin therapy, is a cumbersome procedure and a simple and reliable alternative is required. Our aim was to explore whether serum thromboxane B2 (sTXB2) and soluble P-selectin can be used to identify patients who are at risk of increased platelet reactivity while on aspirin., Methods and Results: We recruited 293 ischemic stroke patients, taking aspirin for more than seven days, and performed LTA to classify them. Based on therapeutic serum salicylate levels, 63 patients were excluded due to suspected non-compliance, followed by ELISA measurement of TXB2 and P-selectin in serum. Accordingly, patients were classified into 'Responders' (n = 122, 53%), 'Semi-responders' (n = 76, 33%) and 'Non-responders' (n=32, 14%) by LTA. Patients who had platelet aggregation of ≥70% with 10μM ADP and ≥20% with 0.5mM AA were defined as 'Non-responders'. In comparison with 'Responders', 'Non-responders' had 8.63-fold increased risk of secondary vascular events (p = 0.008). ROC curve analysis revealed that sTXB2, at a cut-off level of >4.15 ng/mL, could distinguish the patient group with elevated platelet reactivity with a sensitivity of 84.3% (AUC = 0.84), and was in fair agreement with the LTA-based classification of patients. Soluble P-selectin levels, on the other hand, had no discriminatory ability., Conclusion: We suggest sTXB2 measurement as an alternative to the LTA approach for identifying aspirin-treated ischemic stroke patients who are at risk of enhanced platelet reactivity and subsequent vascular events., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: The objective of this study is to describe the clinical, biochemical, radiological, and genetic profile of patients presenting with progressive spastic paraparesis due to homocysteine remethylation pathway defect., Methods: This was a retrospective study conducted by reviewing the medical records of patients with serum homocysteine levels >50 μmol/L between January 2015 and January 2019 at our hospital. We included patients presenting with progressive spastic paraparesis, having serum homocysteine >50 μmol/L with low or normal blood methionine suggesting disorders of homocysteine remethylation. Demographic details, clinical manifestations, biochemical abnormalities, neuroimaging findings, and genetic profile were analyzed., Results: A total of seven patients (M: F = 5:2) fulfilled the study eligibility criteria. The mean age at onset of the disease was 13.4 ± 2.4 years (range: 9-17 years). Spastic paraparesis was the presenting manifestation in 4/7 (57.1%) patients. Other manifestations included cognitive decline, poor scholastic performance, behavioral disturbances, seizures, and spastic bladder. Severe hyperhomocysteinemia (>100 μmol/L) was noted in 6/7 (85.7%) patients with median levels of serum homocysteine being 185.7 μmol/L (range: 85.78-338.5 μmol/L). Neuroimaging showed parieto-occipital predominant leukoencephalopathy in 5/7 (71.4%) and diffuse cerebral atrophy in 1/7 (14.2%). Genetic analysis in three patients revealed pathogenic missense variants c.459C >G (p.Ile153Met), c.973C >T (p.Arg325Cys), and c.1031G >T (p.Arg344Met) in MTHFR gene. All the patients received vitamin B12 (injection and oral), folic acid, and pyridoxine and two patients received betaine. At the last follow-up of a median duration of 12 months, there was a good clinical and biochemical response with reduction in the median value of serum homocysteine by 77.5 μmol/L., Conclusion: Evaluation of serum homocysteine and blood methionine in adolescents presenting with progressive spastic paraparesis gives clue to a treatable homocysteine remethylation disorders., Competing Interests: There are no conflicts of interest., (Copyright: © 2006 - 2021 Annals of Indian Academy of Neurology.)

Protein kinase C (PKC) isozymes play essential roles in biological processes, and activation of PKC is proposed to alleviate the symptoms of a variety of diseases. It would be of great significance to find effective pharmacological modulators of PKC isozymes that can be translated for clinical use. Here, using in vitro activity assay, we demonstrated that green tea extract (-)-epigallocatechin-3-gallate (EGCG) dose-dependently activated PKCα with a half effective concentration (EC50) of 0.49 μM. We also performed surface plasmon resonance analysis and found that EGCG binds PKCα with an equilibrium dissociation constant ( K D ) value of 4.11 × 10 -6 mol/L. Further computational flexible docking analysis revealed that EGCG interacted with the catalytic C3-C4 domain of PKCα (PDB: 4RA4) through establishing polar hydrogen bonds with V420, T401, E387, and K368 of PKCα, and the benzene ring group of EGCG hydrophobically interacted with the hydrophobic pocket formed by L345, M470, I479, and V353 of PKCα. Interestingly, the PKCα-selective blocker Ro-32-0432 could compete with EGCG for the same substrate-binding pocket of PKCα. Moreover, we found that EGCG dose-dependently improved the spatial memory, object recognition ability, and hippocampal long-term potentiation of ovariectomized mice, which was offset by Ro-32-0432. Collectively, our findings reveal a novel PKCα agonist and open the way to a new perspective on PKCα pharmacology and the treatment of PKCα-related diseases, including cognitive impairment.

Objective: To delineate a distinct clinical, pathological, cytoimmunohistochemical distinguishing features of extracranial parotid neurogenic tumors. Pleomorphic adenoma, the most common parotid neoplasm by itself can mimic a neurogenic tumor, i.e., schwannoma. We have reported such rare entity in earlier publications. This is a systematic review with a case discussion of the third only documented malignant peripheral nerve sheath tumor (MPNST) arising in the parotid in a noncontiguous fashion. We review the management, diagnostic immunohistochemistry of this low-grade sarcoma, which has not been documented thus far., Purpose: Significant diagnostic and management pitfalls may occur even with fine-needle aspiration or biopsy, as they will not be ideal in diagnosis of parotid neurogenic neoplasms preoperatively. Ultrasound as well as magnetic resonance imaging may not offer a specific facial nerve course in association to the neoplastic lesion. Majority of the neurogenic tumors can be misdiagnosed and hence, improperly managed leading to facial nerve injury and tumor morbidity. Due to the lack of ideal diagnostic modality and morbidity of facial nerve injury, a thorough review of differential diagnosis inclusive of neurogenic tumors of the parotid is to be considered in indications of surgical approaches. We retrospectively review successful resection with preservation of facial nerve function in our parotid neurogenic tumors., Conclusion: The objective of this paper is to review the guidelines and treatment planning of parotid neurogenic tumors., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest associated with this publication., (© The Association of Oral and Maxillofacial Surgeons of India 2021.)

Background: Reflected image processing is a unique brain function and its abnormalities result in problems of localizing, recognizing the images, and utilizing this information in everyday life., Objectives: The aim of this study was to characterize clinical and neuropsychological profiles and to identify the probable neural substrate for this phenomenon in major cognitive disorder., Materials and Methods: We conducted a prospective study from February 2015 to May 2017 in patients with Major Cognitive Disorder (MCD, DSM-5 criteria). All patients were tested for problems in reflected image processing using the detailed protocol after ethical approval of the institute and consent. They also underwent a detailed neuropsychological evaluation, biochemical tests and neuroimaging (structural, diffusion, and resting-state functional MRI) as per established protocol., Results: Of the 18 patients, 11 had mirror agnosia (MA), 5 had mirror image agnosia (MIA) and 2 had both. MRI of MA patients showed parietal atrophy and whereas diffuse pattern of atrophy was seen with MIA. In the MA group, the left superior longitudinal fasciculus showed significantly greater fractional anisotropy and the left angular gyrus showed increased functional connectivity with left anterior cingulate, left dorsolateral prefrontal and bilateral posterior cingulate regions., Conclusion: Mirror image processing defects were not related to the type of MCD, severity or pattern of neuropsychological dysfunction. There are structural and functional alterations in localized regions as well as both hemispheres. Therefore, it is more likely to be a network disorder, irrespective of the MCD type or severity., Competing Interests: None

Although lots of new drugs are developed to treat Alzheimer's disease (AD), many clinical trials of monotherapy have failed to affect disease progression or symptoms compared with placebo. Recently, scientists believe that combination treatment is more promising than monotherapy. Previous studies found that microRNA-195 ( miR-195 ) was down-regulated in the hippocampi and cortices of chronic brain hypoperfusion (CBH) rats and ApoE4 (+/+) mice, and up-regulation of miR-195 can improve the declined cognitive function of ApoE4 (+/+) mice and CBH rats by targeting multi-genes that are related to AD pathology, including amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) genes. However, whether the gain-of-function of miR-195 could improve the impaired learning and memory ability of APP/PS1 transgenic mouse has not been reported. In this study, we stereotaxically injected lentiviral-carried miR-195 into the bilateral hippocampus of 4-month-old (4M) APP/PS1 mice. Morris water maze (MWM) was performed to detect the effect of miR-195 on the cognitive function of APP/PS1 mice after 1M, 2M, and 3M treatment. Western blot was used to detect the expression of APP, BACE1, and AT8. Aβ plagues were quantitatively assessed by immunofluorescence technique. We found that the declined cognitive phenotype of APP/PS1 mice occurred at the age of 6M, not at the age of 5M. And treatment of Lv-pre- miR-195 to APP/PS1 mice for 1M did not achieve any changes. Although Lv-pre- miR-195 treatment for 2M improved the declined learning ability of APP/PS1 mice, it did not affect the memory functions. However, Lv-pre- miR-195 treatment in APP/PS1 mice for 3M can effectively improve both the learning and memory ability of APP/PS1 mice at the age of 7M. Further studies demonstrated that gain-of-function of miR-195 by Lv-pre- miR-195 injection could inhibit the increased APP and AT8 expression of APP/PS1 mice but did not affect BACE1 level that was not changed in both hippocampus and cortex. By counting the number of Aβ plaques of different sizes, we found that Lv-pre- miR-195 treatment mainly reduced the number of Aβ plaques of less than 20 μm, but did not affect the number of Aβ plaques of greater than 50 μm. Taken together, the gain-of -function of miR-195 in the hippocampus can improve the cognition of APP/PS1 mice, probably by blocking the formation of Aβ plagues rather than clearing those that have already formed Aβ plagues., 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., (Copyright © 2021 Su, Chai, Yang, Wang, Liu, Ma, Tang, Mishra, Chandra, Yue and Ai.)

Background: Surgical management of mega-goiters in endemic areas with extreme iodine deficiency presents unique challenges. Based on our initial 5-year experience (2007 to 2011) operating on mega-goiters in Gitwe, Rwanda, Africa, we modified our technique to a lateral approach which affords better exposure of the superior pole vessels and other vital neurovascular structures, thereby improving safety. We describe this lateral approach technique and review outcomes compared to the standard technique., Methods: From 2007 to 2019, we have conducted 13 annual surgical missions to low resource setting in Gitwe, Rwanda. Retrospective chart review of surgeries between 2012 and 2019 was performed to study outcomes using standard approach and lateral technique during the same time period., Results: Over a period of 8 years (2012 to 2019), out of 192 total cases, lateral approach was used in 35 patients. No patient experienced significant intra-operative blood loss requiring transfusion. One patient had a post-operative hematoma requiring surgical intervention. Vocal cord mobility testing by transcutaneous laryngeal ultrasound was implemented in 2016. Of all patients, incidence of vocal cord weakness was 8.0% (11/137 patients tested) with less than 1/3 of these symptomatic. There was no statistically significant difference in vocal cord weakness noted in the two approaches (3/23 in lateral approach and 8/114 in standard approach) by Fisher's exact test (P=0.34)., Conclusions: Lateral approach, by affording optimal exposure of the great vessels and the laryngeal nerves, reduces the risk of bleeding and nerve injury. Furthermore, inferiorly based strap muscle flap provides excellent coverage and cosmetic outcome., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-725). The authors have no conflicts of interest to declare, (2021 Gland Surgery. All rights reserved.)

We measured C24:0 and C26:0-carnitines in dried blood spots by flow injection analysis-tandem mass spectrometry method to evaluate whether they can be used as markers for newborn screening of X-linked Adrenoleukodystrophy (X-ALD). We found that C26:0-carnitine was 95.1% and 44.7% sensitive for identifying male X-ALD cases and heterozygous females, respectively. False negatives were found for C24:0-carnitine (11/82) and C26:0-carnitine (4/82). We conclude that C24:0 and C26:0-carnitines may not be reliable markers for X-ALD screening., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 The Authors. Published by Elsevier Inc.)

X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation, is caused by defects in the ATP Binding Cassette Subfamily D Member 1 ( ABCD1 ) gene. X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild, severe cerebral adrenoleuko-dystrophy to mild adrenomyeloneuropathy (AMN). Although most female heterozygotes present with AMN-like symptoms after 60 years of age, occasional cases of females with the cerebral form have been reported. Phenotypic variability has been described within the same kindreds and even among monozygotic twins. There is no association between the nature of ABCD 1 mutation and the clinical phenotypes, and the molecular basis of phenotypic variability in X-ALD is yet to be resolved. Various genetic, epigenetic, and environmental influences are speculated to modify the disease onset and severity. In this review, we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD, which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest for this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Chronic cerebral hypoperfusion (CCH) is considered a preclinical condition of mild cognitive impairment and thought to precede dementia. However, as the principal cholinergic source of hippocampus, whether the septo-hippocampal neurocircuit was impaired after CCH is still unknown. In this study, we established the CCH rat model by bilateral common carotid artery occlusion (2VO). Under anesthesia, the medial septum (MS) of rats was stimulated to evoke the field excitatory post-synaptic potential (fEPSP) in the pyramidal cell layer of dCA1. Consequently, we observed decreased amplitude of fEPSP and increased paired-pulse ratio (PPR) after 8-week CCH. After tail pinch, we also found decreased peak frequency and shortened duration of hippocampal theta rhythm in 2VO rats, indicating the dysfunction of septo-hippocampal neurocircuit. Besides, by intracerebroventricularly injecting GABAergic inhibitor (bicuculline) and cholinergic inhibitors (scopolamine and mecamylamine), we found that CCH impaired both the pre-synaptic cholinergic release and the post-synaptic nAChR function in MS-dCA1 circuits. These results gave an insight into the role of CCH in the impairment of cholinergic MS-dCA1 neurocircuits. These findings may provide a new idea about the CCH-induced neurodegenerative changes., (Copyright © 2020 Xu, Zhang, Sun, Wang, Chai, Mishra, Chandra and Ai.)

Competing Interests: Conflicts of interest None declared.

Competing Interests: Disclosure The authors have nothing to disclose.