[18F]Difluorocarbene for positron emission tomography.

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in fluorine-18 (18F) radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene-based reactions including O-H, S-H and N-H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.

Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity.

A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T-cell subset amongst exhausted CD8-positive T cells in chronic infection1-3, but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, TH17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4-7, although how such plasticity is regulated is poorly understood. Here we demonstrate that TH17 cells in a mouse model of autoimmune disease are functionally and metabolically heterogeneous; they contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports transdifferentiation into TH1-like cells. These two TH17-cell subsets are defined by selective expression of the transcription factors TCF-1 and T-bet, and by discrete levels of CD27 expression. We also identify signalling via the kinase complex mTORC1 as a central regulator of TH17-cell fate decisions by coordinating metabolic and transcriptional programmes. TH17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into TH1-like cells, but instead upregulate TCF-1 expression and acquire stemness-associated features. Single-cell RNA sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells.

Photoredox Nucleophilic (Radio)fluorination of Alkoxyamines.

Herein, we report a photoredox nucleophilic (radio)fluorination using TEMPO-derived alkoxyamines, a class of substrates accessible in a single step from a diversity of readily available carboxylic acids, halides, alkenes, alcohols, aldehydes, boron reagents, and C-H bonds. This mild and versatile one-electron pathway affords radiolabeled aliphatic fluorides that are typically inaccessible applying conventional nucleophilic substitution technologies due to insufficient reactivity and competitive elimination. Automation of this photoredox process is also demonstrated with a user-friendly and commercially available photoredox flow reactor and radiosynthetic platform, therefore expediting access to labeled aliphatic fluorides in high molar activity (Am) for (pre)clinical evaluation.

Robotic Enucleation of Pancreatic Head Insulinomas in Close Proximity to the Pancreatic Duct.

BACKGROUND: Insulinomas are rare pancreatic neuroendocrine tumors for which the main curative treatment is surgical resection. Enucleation is preferred over pancreatoduodenectomy to minimize morbidity and function loss.1 Robotic-assisted surgery offers improved versatility and less blood loss than laparoscopic surgery for pancreatic enucleation.2-4 Our video describes the technique for robotic enucleation of pancreatic head insulinomas in close proximity to the pancreatic duct. PATIENTS AND METHODS: The video describes the presentation, diagnostic imaging, and technical aspects of the surgical approach in two patients with pancreatic head insulinomas that underwent robotic enucleation. RESULTS: Case one was a 76-year-old woman who experienced syncope for 2 months. Case two was a 61-year-old man, previously treated for renal cancer, who had documented hypoglycemic symptoms. Computed tomography (CT) scan and magnetic resonance imaging (MRI) identified a 1.5 cm and 1.2 cm pancreatic head mass, respectively. Both patients presented with low glucose levels, and elevated C-peptide and proinsulin. In both cases, endoscopic retrograde cholangiopancreatography (ERCP) and pancreatic duct stent placement were performed the same day of surgery for intraoperative identification and preservation of the duct. Robotic enucleation of the masses was performed, and an ultrasound was used to identify the masses and relation with main pancreatic duct. Pathology revealed a well-differentiated neuroendocrine tumor in both cases. The patient's postoperative course was uneventful, and they were discharged on day 5. Successful resolution of hypoglycemic events occurred in both patients. CONCLUSION: Robotic enucleation is a safe and feasible option for treating pancreatic head tumors in challenging locations. Intraoperative ultrasound is an essential tool for the successful robotic enucleation of pancreatic head tumors.

Cost Analysis and Financial Implications of a Peritoneal Surface Malignancy Program in the USA.

BACKGROUND: We aimed to describe the financial implications of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in the USA. MATERIALS AND METHODS: We conducted a retrospective cost analysis of 100 CRS/HIPEC procedures to examine the impact of patient and procedural factors on hospital costs and reimbursement. A comparison of surgeons' work relative value units (wRVUs) between CRS/HIPEC and a representative sample of complex surgical oncology procedures was made to assess the physicians' compensation rate. Univariable and multivariable backward logistic regression was used to analyze the association between perioperative variables and high direct cost (HDCs). RESULTS: The median direct cost per CRS/HIPEC procedure was US $44,770. The median hospital reimbursement was US $43,066, while professional reimbursement was US $8608, resulting in a positive contribution margin of US $7493/procedure. However, the contribution margin significantly varied with the payer mix. Privately insured patients had a positive median contribution margin of US $23,033, whereas Medicare-insured patients had a negative contribution margin of US $13,034. Length of stay (LOS) had the most significant association with HDC, and major complications had the most significant association with LOS. Finally, CRS/HIPEC procedures generated a median of 13 wRVU/h, which is significantly lower than the wRVU/h generated by open pancreatoduodenectomies, open gastrectomies, and hepatectomies. However, higher operation complexity and multiple visceral resections help compensate for the relatively low wRVU/h. CONCLUSIONS: CRS/HIPEC is an expensive operation, and prolonged LOS has the most significant impact on the total cost of the procedure. High-quality care is essential to improve patient outcomes and maintain the economic sustainability of the procedure.

Detection of metabolic adaptation in a triple-negative breast cancer animal model with [18F]choline-PET imaging as a surrogate for drug resistance.

PURPOSE: Test the feasibility of an image-based method to identify taxane resistance in mouse bearing triple-negative breast cancer (TNBC) tumor xenografts. METHODS: Xenograft tumor-bearing mice from paclitaxel-sensitive and paclitaxel-resistant TNBC cells (MDA-MD-346) were generated by orthotopic injection into female NOD-SCID mice. When tumors reached 100-150 mm3, mice were scanned using [18F]choline PET/CT. Tumors were collected and sliced for autoradiography and immunofluorescence analysis. Quantitative data was analyzed accordingly. RESULTS: From fifteen mice scanned, five had taxane-sensitive cell line tumors of which two underwent taxol-based treatment. From the remaining 10 mice with taxane-resistant cell line tumors, four underwent taxol-based treatment. Only 13 mice had the tumor sample analyzed histologically. When normalized to the blood pool, both cell lines showed differences in metabolic uptake before and after treatment. CONCLUSIONS: Treated and untreated taxane-sensitive and taxane-resistant cell lines have different metabolic properties that could be leveraged before the start of chemotherapy.

Enhancing Readability of Online Patient-Facing Content: The Role of AI Chatbots in Improving Cancer Information Accessibility.

BACKGROUND: Internet-based health education is increasingly vital in patient care. However, the readability of online information often exceeds the average reading level of the US population, limiting accessibility and comprehension. This study investigates the use of chatbot artificial intelligence to improve the readability of cancer-related patient-facing content. METHODS: We used ChatGPT 4.0 to rewrite content about breast, colon, lung, prostate, and pancreas cancer across 34 websites associated with NCCN Member Institutions. Readability was analyzed using Fry Readability Score, Flesch-Kincaid Grade Level, Gunning Fog Index, and Simple Measure of Gobbledygook. The primary outcome was the mean readability score for the original and artificial intelligence (AI)-generated content. As secondary outcomes, we assessed the accuracy, similarity, and quality using F1 scores, cosine similarity scores, and section 2 of the DISCERN instrument, respectively. RESULTS: The mean readability level across the 34 websites was equivalent to a university freshman level (grade 13±1.5). However, after ChatGPT's intervention, the AI-generated outputs had a mean readability score equivalent to a high school freshman education level (grade 9±0.8). The overall F1 score for the rewritten content was 0.87, the precision score was 0.934, and the recall score was 0.814. Compared with their original counterparts, the AI-rewritten content had a cosine similarity score of 0.915 (95% CI, 0.908-0.922). The improved readability was attributed to simpler words and shorter sentences. The mean DISCERN score of the random sample of AI-generated content was equivalent to "good" (28.5±5), with no significant differences compared with their original counterparts. CONCLUSIONS: Our study demonstrates the potential of AI chatbots to improve the readability of patient-facing content while maintaining content quality. The decrease in requisite literacy after AI revision emphasizes the potential of this technology to reduce health care disparities caused by a mismatch between educational resources available to a patient and their health literacy.

Intensifying supportive care is associated with improved survival in gastric cancer patients with malignant ascites.

BACKGROUND: Gastric cancer patients with malignant ascites often have poor functional status and malnutrition that preclude receipt of systemic therapies. Thus, these patients have a very poor prognosis. Beginning in 2019, our multidisciplinary gastric cancer disease-oriented team implemented a more aggressive supportive care plan for gastric cancer patients with malignant ascites. The initiative included measures such as supplemental enteral nutrition, ascites drainage, and initiation of chemotherapy on an inpatient basis. We compared outcomes for gastric cancer patients who presented with synchronous malignant ascites treated before and after the implementation of the care plan. METHODS: We performed a retrospective review of our institutional database to identify patients diagnosed with gastric adenocarcinoma and synchronous malignant ascites between 2010 and 2022. We compared overall survival (OS) between patients diagnosed from 2010 to 2018, which will be referred to as the historical control era and patients diagnosed from 2019 to 2022, which will be called the aggressive supportive care era. RESULTS: Fifty-four patients were included in our analysis; 31 patients were treated in the historical control time frame, and 23 patients were treated during the aggressive supportive care era. Demographic, clinical, and pathologic characteristics were similar between groups. 3% of historical controls received supplemental tube feeds at diagnosis as compared to 30% of the aggressive supportive care cohort (p < 0.01). 3% of historical controls received their first cycle of chemotherapy in the inpatient setting versus 39% of patients treated during the aggressive supportive care era (p < 0.01). The median number of chemotherapy cycles received was 5 among historical controls and 9.5 among aggressive supportive care era patients (p = 0.02). There was no difference in the number of days spent as an inpatient between the two groups. The median OS for historical control patients was 5.4 months as compared with 10.4 months for patients treated during aggressive supportive care era (p = 0.04). CONCLUSIONS: Gastric cancer patients with synchronous malignant ascites treated during a timeframe when our multidisciplinary team implemented more aggressive supportive care measures had improved OS as compared with historic controls. Our results suggest that aggressive supportive measures for these patients with highly challenging clinical issues and poor prognosis can prolong survival. Specifically, initiation of chemotherapy in the inpatient setting and supplemental nutrition should be considered for patients at high risk for treatment intolerance.

The development of a deep learning model for automated segmentation of the robotic pancreaticojejunostomy.

BACKGROUND: Minimally invasive surgery provides an unprecedented opportunity to review video for assessing surgical performance. Surgical video analysis is time-consuming and expensive. Deep learning provides an alternative for analysis. Robotic pancreaticoduodenectomy (RPD) is a complex and morbid operation. Surgeon technical performance of pancreaticojejunostomy (PJ) has been associated with postoperative pancreatic fistula. In this work, we aimed to utilize deep learning to automatically segment PJ RPD videos. METHODS: This was a retrospective review of prospectively collected videos from 2011 to 2022 that were in libraries at tertiary referral centers, including 111 PJ videos. Each frame of a robotic PJ video was categorized based on 6 tasks. A 3D convolutional neural network was trained for frame-level visual feature extraction and classification. All the videos were manually annotated for the start and end of each task. RESULTS: Of the 100 videos assessed, 60 videos were used for the training the model, 10 for hyperparameter optimization, and 30 for the testing of performance. All the frames were extracted (6 frames/second) and annotated. The accuracy and mean per-class F1 scores were 88.01% and 85.34% for tasks. CONCLUSION: The deep learning model performed well for automated segmentation of PJ videos. Future work will focus on skills assessment and outcome prediction.

Optimizing donor fascicle selection in Oberlin's procedure: A retrospective review of anatomical variability using intraoperative neuromonitoring.

BACKGROUND: Transfer of the fascicle carrying the flexor carpi ulnaris (FCU) branch of the ulnar nerve (UN) to the biceps/brachialis muscle branch of the musculocutaneous nerve (Oberlin's procedure), is a mainstay technique for elbow flexion restoration in patients with upper brachial plexus injury. Despite its widespread use, there are few studies regarding the anatomic location of the donor fascicle for Oberlin's procedure. Our report aims to analyze the anatomical variability of this fascicle within the UN, while obtaining quantifiable, objective data with intraoperative neuromonitoring (IONM) for donor fascicle selection. METHODS: We performed a retrospective review of patients at our institution who underwent an Oberlin's procedure from September 2019 to July 2023. We used IONM for donor fascicle selection (greatest FCU muscle and least intrinsic hand muscle activation). We prospectively obtained demographic and electrophysiological data, as well as anatomical location of donor fascicles and post-surgical morbidities. Surgeon's perception of FCU/intrinsic muscle contraction was compared to objective muscle amplitude during IONM. RESULTS: Eight patients were included, with a mean age of 30.5 years and an injury-to-surgery interval of 4 months. Donor fascicle was located anterior in two cases, posterior in two, radial in two and ulnar in two patients. Correlation between surgeon's perception and IONM findings were consistent in six (75%) cases. No long term motor or sensory deficits were registered. CONCLUSIONS: Fascicle anatomy within the UN at the proximal arm is highly variable. The use of IONM can aid in optimizing donor fascicle selection for Oberlin's procedure.

Regenerative Peripheral Nerve Interfaces (RPNIs) in Animal Models and Their Applications: A Systematic Review.

Regenerative Peripheral Nerve Interfaces (RPNIs) encompass neurotized muscle grafts employed for the purpose of amplifying peripheral nerve electrical signaling. The aim of this investigation was to undertake an analysis of the extant literature concerning animal models utilized in the context of RPNIs. A systematic review of the literature of RPNI techniques in animal models was performed in line with the PRISMA statement using the MEDLINE/PubMed and Embase databases from January 1970 to September 2023. Within the compilation of one hundred and four articles employing the RPNI technique, a subset of thirty-five were conducted using animal models across six distinct institutions. The majority (91%) of these studies were performed on murine models, while the remaining (9%) were conducted employing macaque models. The most frequently employed anatomical components in the construction of the RPNIs were the common peroneal nerve and the extensor digitorum longus (EDL) muscle. Through various histological techniques, robust neoangiogenesis and axonal regeneration were evidenced. Functionally, the RPNIs demonstrated the capability to discern, record, and amplify action potentials, a competence that exhibited commendable long-term stability. Different RPNI animal models have been replicated across different studies. Histological, neurophysiological, and functional analyses are summarized to be used in future studies.

Association of race, demographic and socioeconomic factors with failure to rescue after hepato-pancreato-biliary surgery in the United States.

BACKGROUND: We aimed to describe the association of patient-related factors such as race, socioeconomic status, and insurance on failure to rescue (FTR) after hepato-pancreato-biliary (HPB) surgeries. METHODS: Using the National Inpatient Sample, we analyzed 98,788 elective HPB surgeries between 2004 and 2017. Major and minor complications were identified using ICD9/10 codes. We evaluated mortality rates and FTR (inpatient mortality after major complications). We used multivariate logistic regression analysis to assess racial, socioeconomic, and demographic factors on FTR, adjusting for covariates. RESULTS: Overall, 43 % of patients (n = 42,256) had pancreatic operations, 36% (n = 35,526) had liver surgery, and 21% (n = 21,006) had biliary interventions. The overall major complication rate was 21% (n = 20,640), of which 8% (n = 1655) suffered FTR. Factors independently associated with increased risk for FTR were male sex, older age, higher Charlson Comorbidity Index, Hispanic ethnicity, Asian or other race, lower income quartile, Medicare insurance, and southern region hospitals. CONCLUSIONS: Medicare insurance, male gender, Hispanic ethnicity, and lower income quartile were associated with increased risk for FTR. Efforts should be made to improve the identification and subsequent treatment of complications for those at high risk of FTR.

The Estimated Lifetime Quality-Adjusted Life-Years Lost Due to Chlamydia, Gonorrhea, and Trichomoniasis in the United States in 2018.

BACKGROUND: Comprehensive evaluation of the quality-adjusted life-years (QALYs) lost attributable to chlamydia, gonorrhea, andtrichomoniasis in the United States is lacking. METHODS: We adapted a previous probability-tree model to estimate the average number of lifetime QALYs lost due to genital chlamydia, gonorrhea, and trichomoniasis, per incident infection and at the population level, by sex and age group. We conducted multivariate sensitivity analyses to address uncertainty around key parameter values. RESULTS: The estimated total discounted lifetime QALYs lost for men and women, respectively, due to infections acquired in 2018, were 1541 (95% uncertainty interval [UI], 186-6358) and 111 872 (95% UI, 29 777-267 404) for chlamydia, 989 (95% UI, 127-3720) and 12 112 (95% UI, 2 410-33 895) for gonorrhea, and 386 (95% UI, 30-1851) and 4576 (95% UI, 13-30 355) for trichomoniasis. Total QALYs lost were highest among women aged 15-24 years with chlamydia. QALYs lost estimates were highly sensitive to disutilities (health losses) of infections and sequelae, and to duration of infections and chronic sequelae for chlamydia and gonorrhea in women. CONCLUSIONS: The 3 sexually transmitted infections cause substantial health losses in the United States, particularly gonorrhea and chlamydia among women. The estimates of lifetime QALYs lost per infection help to prioritize prevention policies and inform cost-effectiveness analyses of sexually transmitted infection interventions.

Estimation of the Lifetime Quality-Adjusted Life Years (QALYs) Lost Due to Syphilis Acquired in the United States in 2018.

BACKGROUND: The purpose of this study was to estimate the health impact of syphilis in the United States in terms of the number of quality-adjusted life years (QALYs) lost attributable to infections in 2018. METHODS: We developed a Markov model that simulates the natural history and management of syphilis. The model was parameterized by sex and sexual orientation (women who have sex with men, men who have sex with women [MSW], and men who have sex with men [MSM]), and by age at primary infection. We developed a separate decision tree model to quantify health losses due to congenital syphilis. We estimated the average lifetime number of QALYs lost per infection, and the total expected lifetime number of QALYs lost due to syphilis acquired in 2018. RESULTS: We estimated the average number of discounted lifetime QALYs lost per infection as 0.09 (95% uncertainty interval [UI] .03-.19). The total expected number of QALYs lost due to syphilis acquired in 2018 was 13 349 (5071-31 360). Although per-case loss was the lowest among MSM (0.06), MSM accounted for 47.7% of the overall burden. For each case of congenital syphilis, we estimated 1.79 (1.43-2.16) and 0.06 (.01-.14) QALYs lost in the child and the mother, respectively. We projected 2332 (1871-28 250) and 79 (17-177) QALYs lost for children and mothers, respectively, due to congenital syphilis in 2018. CONCLUSIONS: Syphilis causes substantial health losses in adults and children. Quantifying these health losses in terms of QALYs can inform cost-effectiveness analyses and can facilitate comparisons of the burden of syphilis to that of other diseases.

Anti-GM-CSF Neutralizing Autoantibodies in Colombian Patients with Disseminated Cryptococcosis.

BACKGROUND: Cryptococcosis is a potentially life-threatening fungal disease caused by encapsulated yeasts of the genus Cryptococcus, mostly C. neoformans or C. gattii. Cryptococcal meningitis is the most frequent clinical manifestation in humans. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) have recently been discovered in otherwise healthy adult patients with cryptococcal meningitis, mostly caused by C. gattii. We hypothesized that three Colombian patients with cryptococcal meningitis caused by C. neoformans in two of them would carry high plasma levels of neutralizing auto-Abs against GM-CSF. METHODS: We reviewed medical and laboratory records, performed immunological evaluations, and tested for anti-cytokine auto-Abs three previously healthy HIV-negative adults with disseminated cryptococcosis. RESULTS: Peripheral blood leukocyte subset levels and serum immunoglobulin concentrations were within the normal ranges. We detected high levels of neutralizing auto-Abs against GM-CSF in the plasma of all three patients. CONCLUSIONS: We report three Colombian patients with disseminated cryptococcosis associated with neutralizing auto-Abs against GM-CSF. Further studies should evaluate the genetic contribution to anti-GM-CSF autoantibody production and the role of the GM-CSF signaling pathway in the immune response to Cryptococcus spp.

Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease.

Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.

Old and cold: Diverse phylogenomic datasets support an ancient transantarctic dispersive route on the scorpion family Bothriuridae in temperate Gondwana.

In this contribution we try to unveil the diversification process of Bothriuridae in temperate Gondwana through dated phylogenomic analyses using UCE and transcriptomics, and including in the analyses species of genera Urophonius and Cercophonius, the most closely related genera of Bothriuridae from South America and Australia respectively. Additionally we explored the hypothesis that the winter activity period of some species of Urophonius, as well as the cold environmental preferences of this genus, could be related to the climatic conditions of the time frame and area in which it evolved. Genus Urophonius was recovered as sister group to Cercophonius using amino acids and UCE. The time frame obtained for the split between South American and Australian bothriurids is 94 Ma., which suggests a dispersal event through temperate Gondwana, before the final breakup of the land bridge of South America-Antarctica-Australia ca. 35 Ma. The split between summer and winter species of Urophonius, taking place at 64 Ma, is considered representative to the turnover time from the summer activity period to the winter activity period in some species of the genus. This time frame is compatible with a period of global warming of the late Cretaceous greenhouse episode that could have triggered this change.

The meningeal lymphatic vasculature in neuroinflammation.

The lymphatic vasculature is a unidirectional network of lymphatic endothelial cells, whose main role is to maintain fluid homeostasis along with the absorption of dietary fat in the gastrointestinal organs and management and coordination of immune cell trafficking into lymph nodes during homeostasis and under inflammatory conditions. In homeostatic conditions, immune cells, such as dendritic cells, macrophages, or T cells can enter into the lymphatic vasculature and move easily through the lymph reaching secondary lymph nodes where immune cell activation or peripheral tolerance can be modulated. However, under inflammatory conditions such as pathogen infection, increased permeabilization of lymphatic vessels allows faster immune cell migration into inflamed tissues following a chemokine gradient, facilitating pathogen clearance and the resolution of inflammation. Interestingly, since the re-discovery of lymphatic vasculature in the central nervous system, known as the meningeal lymphatic vasculature, the role of these lymphatics as a key player in several neurological disorders has been described, with emphasis on the neurodegenerative process. Alternatively, less has been discussed about meningeal lymphatics and its role in neuroinflammation. In this review, we discuss current knowledge about the anatomy and function of the meningeal lymphatic vasculature and specifically analyze its contribution to different neuroinflammatory processes, highlighting the potential therapeutic target of meningeal lymphatic vasculature in these pathological conditions.

Congruence between ultraconserved element-based matrices and phylotranscriptomic datasets in the scorpion Tree of Life.

Scorpions are ancient and historically renowned for their potent venom. Traditionally, the systematics of this group of arthropods was supported by morphological characters, until recent phylogenomic analyses (using RNAseq data) revealed most of the higher-level taxa to be non-monophyletic. While these phylogenomic hypotheses are stable for almost all lineages, some nodes have been hard to resolve due to minimal taxonomic sampling (e.g. family Chactidae). In the same line, it has been shown that some nodes in the Arachnid Tree of Life show disagreement between hypotheses generated using transcritptomes and other genomic sources such as the ultraconserved elements (UCEs). Here, we compared the phylogenetic signal of transcriptomes vs. UCEs by retrieving UCEs from new and previously published scorpion transcriptomes and genomes, and reconstructed phylogenies using both datasets independently. We reexamined the monophyly and phylogenetic placement of Chactidae, sampling an additional chactid species using both datasets. Our results showed that both sets of genome-scale datasets recovered highly similar topologies, with Chactidae rendered paraphyletic owing to the placement of Nullibrotheas allenii. As a first step toward redressing the systematics of Chactidae, we establish the family Anuroctonidae (new family) to accommodate the genus Anuroctonus.

The effect of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes in drug-resistant epilepsy.

OBJECTIVE: The impact of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes has not been extensively evaluated outside of the original clinical trials and post-approval studies. The goal of this study was to ascertain the potential real-world effects of RNS on cognitive, psychiatric, and quality of life (QOL) outcomes in relation to seizure outcomes by examining 50 patients undergoing RNS implantation for drug-resistant epilepsy (DRE). METHODS: We performed a retrospective review of all patients treated at our institution with RNS for DRE with at least 12 months of follow-up. In addition to baseline demographic and disease-related characteristics, we collected cognitive (Full-Scale Intelligence Quotient, Verbal Comprehension, and Perceptual Reasoning Index), psychiatric (Beck Depression and Anxiety Inventory Scores), and QOL (QOLIE-31) outcomes at 6 and 12 months after RNS implantation and correlated them with seizure outcomes. RESULTS: Fifty patients (median age 39.5 years, 64% female) were treated with RNS for DRE in our institution from 2005 to 2020. Of the 37 of them who had well-documented pre and post-implantation seizure diaries, the 6-month median seizure frequency reduction was 88%, the response rate (50% or greater seizure frequency reduction) was 78%, and 32% of patients were free of disabling seizures in this timeframe. There was no statistically significant difference at a group level in any of the evaluated cognitive, psychiatric, and QOL outcomes at 6 and 12 months post-implantation compared to the pre-implantation baseline, irrespective of seizure outcomes, although a subset of patients experienced a decline in mood or cognitive variables. SIGNIFICANCE: Responsive neurostimulation does not appear to have a statistically significant negative or positive impact on neuropsychiatric and psychosocial status at the group level. We observed significant variability in outcome, with a minority of patients experiencing worse behavioral outcomes, which seemed related to RNS implantation. Careful outcome monitoring is required to identify the subset of patients experiencing a poor response and to make appropriate adjustments in care.