Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration.

Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinal in vivo calcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.

Feasibility, Reliability, and Effectiveness of Oral cancer screening in South Asia and Southeast Asian countries: A systematic review and Meta-analysis.

OBJECTIVES: The incidence of oral cancer is significantly high in South Asia and Southeast Asia. Organized screening is an effective approach to early detection. The aim of this systematic review and meta-analysis was to evaluate the reliability, diagnostic accuracy, and effectiveness of visual oral screening by community health workers (CHWs) in identifying oral cancer/oral potentially malignant disorders (OPMDs) in this region. MATERIALS AND METHODS: We conducted a bibliographic search in PubMed, Scopus, the gray literature of Google Scholar, ProQuest dissertations, and additional manual searches. Twelve articles were included for qualitative synthesis and six for meta-analysis. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), and forest plot analysis were performed. RESULTS: Meta-analysis showed CHWs identified 8% (n = 6365) as suspicious and 92% (n = 74,140) as normal. The diagnostic accuracy of visual oral screening by CHWs showed a sensitivity of 75% (CI: 74-76) and specificity of 97% (CI: 97-97) in the detection of OPMDs/oral cancer. Forest plots were obtained using a random effects model (DOR: 24.52 (CI: 22.65-26.55)) and SAUC: 0.96 (SE = 0.05). CONCLUSIONS: Oral visual examination by trained CHWs can be utilized for community screenings to detect oral cancer early. This approach can be used in primary healthcare to triage patients for further referral and management.

COVID-19 in patients with Down syndrome: A systematic review.

INTRODUCTION: Down syndrome (DS) is associated with multiple comorbid conditions and chronic immune dysfunction. Persons with DS who contract COVID-19 are at high risk for complications and have a poor prognosis. We aimed to study the clinical symptoms, laboratory and biochemical profiles, radiologic findings, treatment, and outcomes of patients with DS and COVID-19. METHOD: We systematically searched PubMed, MEDLINE, Web of Science, Scopus, and the Cochrane Library using the keywords COVID-19 or coronavirus or SARS-CoV-2 and DS or trisomy 21. Seventeen articles were identified: eight case reports and nine case series published from December 2019 through March 2022, with a total of 55 cases. RESULTS: Patients averaged 24.8 years (26 days to 60 years); 29 of the patients were male. The most common symptoms were fever, dyspnea, and cough. Gastrointestinal and upper respiratory tract symptoms were commonly reported for pediatric patients. The most common comorbidities present in patients with DS were obesity (49.0%), hypothyroidism (21.6%) and obstructive sleep apnea (15.6%). The patients were hospitalized for a mean of 14.8 days. When the patients were compared with the general COVID-19 population, the mean number of hospitalized days was higher. Most patients had leukopenia, lymphopenia, and elevated inflammatory markers (d-dimer and C-reactive protein). Bilateral infiltrations and bilateral ground-glass opacifications were frequently seen in chest radiographs and chest computed tomographic imaging. Most of the patients were treated with methylprednisolone, macrolides, and hydroxychloroquine. Of the 55 patients, 22 died. The mean age of the patients who died was 42.8 years. Mortality rate was higher in individuals with DS over 40 years of age. CONCLUSION: More studies are needed to better understand COVID-19 infections among persons with DS. In addition, the study was limited by a lack of statistical analyses and a specific comparison group.

Neuro-immune interactions in health and disease: Insights from FENS-Hertie 2022 Winter School.

In a great partnership, the Federation of European Neuroscience Societies (FENS) and the Hertie Foundation organized the FENS-Hertie 2022 Winter School on 'Neuro-immune interactions in health and disease'. The school selected 27 PhD students and 13 postdoctoral fellows from 20 countries and involved 14 faculty members experts in the field. The Winter School focused on a rising field of research, the interactions between the nervous and both innate and adaptive immune systems under pathological and physiological conditions. A fine-tuned neuro-immune crosstalk is fundamental for healthy development, while disrupted neuro-immune communication might play a role in neurodegeneration, neuroinflammation and aging. However, much is yet to be understood about the underlying mechanisms of these neuro-immune interactions in the healthy brain and under pathological scenarios. In addition to new findings in this emerging field, novel methodologies and animal models were presented to foment research on neuro-immunology. The FENS-Hertie 2022 Winter School provided an insightful knowledge exchange between students and faculty focusing on the latest discoveries in the biology of neuro-immune interactions while fostering great academic and professional opportunities for early-career neuroscientists from around the world.

Inflammatory myofibroblastic disease of right petrous apex: A rare case with review of literature.

ABSTRACT: Inflammatory myofibroblastic tumor (IMFT) is a rare tumor of unknown etiology. It can involve any part of the body. The IMFT involving the base of skull is rare with only 36 cases reported in the literature. We report a rare case of IMFT of temporal bone with review of literature. A 42 year old male presented with complaints of headache and double vision and MRI brain showed lesion in the right petrous apex region suggestive of a neurogenic mass. He had excision of lesion and histopathology was suggestive of IMFT with IgG4 and ALK positive. He had complete clinical response but a month later he presented with right eyelid ptosis and decreased rotation of eye medially with recurrent lesion on MRI. Patient received radiation by SRT technique and then started on Ceretinib with partial response. The IMFT is rare tumor of unknown etiology and tumors of temporal bone are more aggressive. It is benign but locally invasive tumor. Treatment of IMFT is controversial. Extensive surgery with complete excision has about 80% response rates and with intracranial extension, adjuvant radiation is need. In head and neck IMFT response rates are lower (30 to 40%). Monoclonal antibodies and steroids are used in IMFT at recurrence. In advanced or metastatic ALK positive tumors, Crizotinib is used with a response rate of 50%. Radiotherapy (25 to 30 Gy) induces remission and helps to taper the steroids. Temporal bone IMFT is a rare tumor with multimodality approach and variable response to treatment.

Corrigendum: Delphi: A Democratic and Cost-Effective Method of Consensus Generation in Transplantation.

[This corrects the article DOI: 10.3389/ti.2023.11589.].

Corrigendum: Thrombotic Microangiopathy in the Renal Allograft: Results of the TMA Banff Working Group Consensus on Pathologic Diagnostic Criteria.

[This corrects the article DOI: 10.3389/ti.2023.11590.].

Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous mechanisms (cells other than motor neurons) are believed to contribute to cortical hyperexcitability. Decoding the pathological relevance of these dynamic changes in motor neurons and glial cells has remained a major challenge. This review summarizes the evidence of cortical hyperexcitability from both clinical and preclinical research, as well as the underlying mechanisms. We discuss the potential role of glial cells, particularly microglia, in regulating abnormal neuronal activity during the disease progression. Identifying early changes such as neuronal hyperexcitability in the motor system may provide new insights for earlier diagnosis of ALS and reveal novel targets to halt the disease progression.

Delphi: A Democratic and Cost-Effective Method of Consensus Generation in Transplantation.

The Thrombotic Microangiopathy Banff Working Group (TMA-BWG) was formed in 2015 to survey current practices and develop minimum diagnostic criteria (MDC) for renal transplant TMA (Tx-TMA). To generate consensus among pathologists and nephrologists, the TMA BWG designed a 3-Phase study. Phase I of the study is presented here. Using the Delphi methodology, 23 panelists with >3 years of diagnostic experience with Tx-TMA pathology listed their MDC suggesting light, immunofluorescence, and electron microscopy lesions, clinical and laboratory information, and differential diagnoses. Nine rounds (R) of consensus resulted in MDC validated during two Rs using online evaluation of whole slide digital images of 37 biopsies (28 TMA, 9 non-TMA). Starting with 338 criteria the process resulted in 24 criteria and 8 differential diagnoses including 18 pathologic, 2 clinical, and 4 laboratory criteria. Results show that 3/4 of the panelists agreed on the diagnosis of 3/4 of cases. The process also allowed definition refinement for 4 light and 4 electron microscopy lesions. For the first time in Banff classification, the Delphi methodology was used to generate consensus. The study shows that Delphi is a democratic and cost-effective method allowing rapid consensus generation among numerous physicians dealing with large number of criteria in transplantation.

Thrombotic Microangiopathy in the Renal Allograft: Results of the TMA Banff Working Group Consensus on Pathologic Diagnostic Criteria.

The Banff community summoned the TMA Banff Working Group to develop minimum diagnostic criteria (MDC) and recommendations for renal transplant TMA (Tx-TMA) diagnosis, which currently lacks standardized criteria. Using the Delphi method for consensus generation, 23 nephropathologists (panelists) with >3 years of diagnostic experience with Tx-TMA were asked to list light, immunofluorescence, and electron microscopic, clinical and laboratory criteria and differential diagnoses for Tx-TMA. Delphi was modified to include 2 validations rounds with histological evaluation of whole slide images of 37 transplant biopsies (28 TMA and 9 non-TMA). Starting with 338 criteria in R1, MDC were narrowed down to 24 in R8 generating 18 pathological, 2 clinical, 4 laboratory criteria, and 8 differential diagnoses. The panelists reached a good level of agreement (70%) on 76% of the validated cases. For the first time in Banff classification, Delphi was used to reach consensus on MDC for Tx-TMA. Phase I of the study (pathology phase) will be used as a model for Phase II (nephrology phase) for consensus regarding clinical and laboratory criteria. Eventually in Phase III (consensus of the consensus groups) and the final MDC for Tx-TMA will be reported to the transplantation community.

Towards the design of self-sorting nanomaterials through kinetically directed chemoselective control over interfacial surface chemistry.

A gold nanoparticle platform is described in which post-synthesis surface modifications can be conducted using kinetically-tunable strain-promoted cycloaddition chemistry, which is dependent on the electronic properties of the complementary dipolar species. This permits chemoselective reactivity with one reactive dipole over another less reactive dipole, providing exciting opportinities for kinetically-directed self-sorting strategies.

Study of Non-Thyroidal Illness Syndrome and Its Recovery in Critically Ill Patients at a Tertiary Care Centre in South India.

Background and Objectives: Transient thyroid hormone alterations are common during critical illness and are termed non-thyroidal illness syndrome (NTIS). We studied the prevalence of NTIS in the ICU setting and its impact on predicting mortality and other outcomes and compared it to the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Materials and Methods: The study included 119 consecutive patients admitted with a critical illness. APACHE II score was calculated. Total T3, total T4, TSH, free T3, and free T4 were measured at admission and after six weeks of discharge. NTIS and euthyroid groups were studied for ICU, hospital stays, mortality, readmission, and recovery. Predictors of mortality were compared between survivors and non-survivors. Results: The mean age was 60.15 ± 14.50 years with M:F = 84 (71%):35 (29%). NTIS was observed in 84 (71%), low T3 being the most common abnormality in 53 (63%). The occurrence of NTIS was significantly higher among non-survivors (28/30, 93%) versus survivors (56/89, 63%) (P = 0.002). Non-survivors showed significantly lower T3, TSH, and FT3/FT4 ratios and higher readmissions. NTIS group showed significantly greater ICU stay (P = 0.02) and had higher readmission rates (P = 0.032). Baseline T3 had the greatest power to predict mortality. APACHE II score also correlated significantly with mortality (19.60 ± 10.58 vs 11.99 ± 6.80, P < 0.001). The area under the curve (0.677) for the T3 level was lower than the APACHE II score (0.760). After six weeks, 61% had recovered from NTIS. Conclusions: NTIS was common amongst critically ill patients (71.5%), which reversed in 61% at six weeks. Low T3 was the most common abnormality and independently predicted mortality. Free T3/free T4 also significantly predicted mortality. The correlation between thyroid dysfunction and the severity of primary illness makes it an additional attractive low-cost marker of mortality.

Parietal Epithelial Cell Behavior and Its Modulation by microRNA-193a.

Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, activated PECs are speculated to be pathogenic and comprise extracapillary proliferation in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CrescGN). The reparative and pathogenic roles of PECs seem to represent two sides of PEC behavior directed by the local milieu and mediators. Recent studies suggest microRNA-193a (miR193a) is involved in the pathogenesis of FSGS and CrescGN. In a mouse model of primary FSGS, the induction of miR193a caused the downregulation of Wilms' tumor protein, leading to the dedifferentiation of podocytes. On the other hand, the inhibition of miR193a resulted in reduced crescent lesions in a mouse model of CrescGN. Interestingly, in vitro studies report that the downregulation of miR193a induces trans-differentiation of PECs into a podocyte phenotype. This narrative review highlights the critical role of PEC behavior in health and during disease and its modulation by miR193a.

Urethral Injuries: Diagnostic and Management Strategies for Critical Care and Trauma Clinicians.

Urologic trauma is a well-known cause of urethral injury with a range of management recommendations. Retrograde urethrogram remains the preferred initial diagnostic modality to evaluate a suspected urethral injury. The management thereafter varies based on mechanism of injury. Iatrogenic urethral injury is often caused by traumatic catheterization and is best managed by an attempted catheterization performed by an experienced clinician or suprapubic catheter to maximize urinary drainage. Penetrating trauma, most commonly associated with gunshot wounds, can cause either an anterior and/or posterior urethral injury and is best treated with early operative repair. Blunt trauma, most commonly associated with straddle injuries and pelvic fractures, can be treated with either early primary endoscopic realignment or delayed urethroplasty after suprapubic cystostomy. With any of the above injury patterns and treatment options, a well thought out and regimented follow-up with a urologist is of utmost importance for accurate assessment of outcomes and appropriate management of complications.

Minimally Invasive Surgery (MIS) fellowship website content: are applicants receiving enough information?

BACKGROUND: Advanced GI/Minimally Invasive Surgery (MIS) fellowships are one of the largest non-ACGME post-residency training pathways. MIS programs are highly competitive, with only 68% of applicants in the 2021 cycle successfully matching into fellowship positions. An evaluation of MIS fellowship program websites is warranted to determine if applicants are receiving adequate information to meet their needs. METHODS: Using the Fellowship Council website, the authors identified 92 MIS fellowship programs that advertised open fellowships positions for general surgery residency graduates. These 92 fellowship websites were evaluated for 12 pre-identified variables based on published literature. RESULTS: 90% of websites included access to contact information for a program director/coordinator and 72% of websites displayed selection criteria; however, other recruitment information offered to applicants was limited. Only 25% of websites mentioned interview details, 34% of websites showcased current or past fellows, and 51% included a faculty directory. Regarding operative information, only 46% of MIS fellowship websites mentioned case volume, 23% mentioned locations of rotations, and 55% mentioned rotation schedule selection criteria. Didactic information was focused on research productivity with 80% of websites highlighting scholarly requirements; academic conferences were only mentioned in 40% of websites. Fellow wellness and career information was skipped on many websites, with 30% describing resident benefits and 16% dedicating a section to career development. Overall, the mean number of pre-identified variables present on a fellowship website was 6.57 ± 2.39 (54.75 ± 19.17%). CONCLUSIONS: General surgery residents turn to program websites when evaluating MIS fellowships. Although websites contain adequate information on several variables evaluated in the study, information on benefits and career development, fellow and faculty support, and case volume were limited. By including relevant information, MIS fellowship websites can align with ACGME requirements, strengthen existing frameworks, and help display data that are important to applicants.

Consensus guidelines on management of oral potentially malignant disorders.

Oral cancer is usually preceded by oral potentially malignant disorders (OPMDs) and early detection can downstage the disease. The majority of OPMDs are asymptomatic in early stages and can be detected on routine oral examination. Though only a proportion of OPMDs may transform to oral squamous cell carcinoma (OSCC), they may serve as a surrogate clinical lesion to identify individuals at risk of developing OSCC. Currently, there is a scarcity of scientific evidence on specific interventions and management of OPMDs and there is no consensus regarding their management. A consensus meeting with a panel of experts was convened to frame guidelines for clinical practices and recommendations for management strategies for OPMDs. A review of literature from medical databases was conducted to provide the best possible evidence and provide recommendations in management of OPMDs.

Controlling the Structure, Properties and Surface Reactivity of Clickable Azide-Functionalized Au25 (SR)18 Nanocluster Platforms Through Regioisomeric Ligand Modifications.

To fine-tune structure-property correlations of thiolate-protected gold nanoclusters through post-assembly surface modifications, we report the synthesis of the o, m, and p regioisomeric forms of the anionic azide-functionalized [Au25 (SCH2 CH2 -C6 H4 -N3 )18 ]1- platform. They can undergo cluster-surface strain-promoted alkyne-azide cycloaddition (CS-SPAAC) chemistry with complementary strained-alkynes. Although their optical properties are similar, the electrochemical properties appear to correlate with the position of the azido group. The ability to conduct CS-SPAAC chemistry without altering the parent nanocluster structure is different as the isomeric form of the surface ligand is changed, with the [Au25 (SCH2 CH2 -p-C6 H4 -N3 )18 ]1- isomer having the highest reaction rates, while the [Au25 (SCH2 CH2 -o-C6 H4 -N3 )18 ]1- isomer is not stable following CS-SPAAC. Single-crystal X-ray diffraction provide the molecular structure of the neutral forms of the three regioisomeric clusters, [Au25 (SCH2 CH2 -o/m/p-C6 H4 -N3 ]0 , which illustrates correlated structural features of the central core as the position of the azido moiety is changed.

Opiate Prescriptions Vary among Common Urologic Procedures: A Claims Dataset Analysis.

Objectives: This study aimed to better understand differences in the total days' supply and fills of common opiates following urologic procedures. Materials and Methods: The Truven Health MarketScan® database was used to extract CPT codes from adults 18 years or older who underwent a urologic procedure with 90-day follow-up from 2012−2015 within the Austin−Round Rock, Texas metropolitan service area. A multivariate analysis and first hurdle modeling with a logistic outcome for any opiates was used to (1) assess differences in opioid prescribing patterns, (2) investigate opioid prescription outcomes, and (3) explore variability among opiate prescription patterns across seven urologic procedure categories. Results: Among the 2312 patients who met the inclusion criteria, 23.7% received an opiate, with an average total day's supply of 6.20 (range 2.61−10.59). The proportion of patients receiving opiates varied significantly by procedure type (p = 0.028). Patients that had reconstructive procedures had the highest proportion of any opiates and the highest number of mean opiate prescriptions among the seven procedure categories (42% received opiates, p = 0.028, mean opiate prescriptions were 1.0 among all patients, p = 0.026). After adjustments, the multivariate analysis demonstrated that patients undergoing reconstructive procedures filled more opiate prescriptions (odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.00−3.50, p = 0.05) compared to other subcategories. Of those that received opiates, reconstructive patients had a shorter time to fills (mean −18.4 days, CI −8.40 to −28.50, p < 0.001). Conclusion: Patients undergoing reconstructive procedures are prescribed and fill more opiates compared to other common urological procedures. The standardization and implementation of postoperative pain regimens may help curtail this variability.

Widespread choroid plexus contamination in sampling and profiling of brain tissue.

The choroid plexus, a tissue responsible for producing cerebrospinal fluid, is found predominantly in the lateral and fourth ventricles of the brain. This highly vascularized and ciliated tissue is made up of specialized epithelial cells and capillary networks surrounded by connective tissue. Given the complex structure of the choroid plexus, this can potentially result in contamination during routine tissue dissection. Bulk and single-cell RNA sequencing studies, as well as genome-wide in situ hybridization experiments (Allen Brain Atlas), have identified several canonical markers of choroid plexus such as Ttr, Folr1, and Prlr. We used the Ttr gene as a marker to query the Gene Expression Omnibus database for transcriptome studies of brain tissue and identified at least some level of likely choroid contamination in numerous studies that could have potentially confounded data analysis and interpretation. We also analyzed transcriptomic datasets from human samples from Allen Brain Atlas and the Genotype-Tissue Expression (GTEx) database and found abundant choroid contamination, with regions in closer proximity to choroid more likely to be impacted such as hippocampus, cervical spinal cord, substantia nigra, hypothalamus, and amygdala. In addition, analysis of both the Allen Brain Atlas and GTEx datasets for differentially expressed genes between likely "high contamination" and "low contamination" groups revealed a clear enrichment of choroid plexus marker genes and gene ontology pathways characteristic of these ciliated choroid cells. Inclusion of these contaminated samples could result in biological misinterpretation or simply add to the statistical noise and mask true effects. We cannot assert that Ttr or other genes/proteins queried in targeted assays are artifacts from choroid contamination as some of these differentials may be due to true biological effects. However, for studies that have an unequal distribution of choroid contamination among groups, investigators may wish to remove contaminated samples from analyses or incorporate choroid marker gene expression into their statistical modeling. In addition, we suggest that a simple RT-qPCR or western blot for choroid markers would mitigate unintended choroid contamination for any experiment, but particularly for samples intended for more costly omic profiling. This study highlights an unexpected problem for neuroscientists, but it is also quite possible that unintended contamination of adjacent structures occurs during dissections for other tissues but has not been widely recognized.