Search

Introduction: Endoscopic detection of early neoplasia in Barrett's esophagus is difficult. Computer Aided Detection (CADe) systems may assist in neoplasia detection. The aim of this study was to report the first steps in the development of a CADe system for Barrett's neoplasia and to evaluate its performance when compared with endoscopists. Methods: This CADe system was developed by a consortium, consisting of the Amsterdam University Medical Center, Eindhoven University of Technology, and 15 international hospitals. After pretraining, the system was trained and validated using 1.713 neoplastic (564 patients) and 2.707 non-dysplastic Barrett's esophagus (NDBE; 665 patients) images. Neoplastic lesions were delineated by 14 experts. The performance of the CADe system was tested on three independent test sets. Test set 1 (50 neoplastic and 150 NDBE images) contained subtle neoplastic lesions representing challenging cases and was benchmarked by 52 general endoscopists. Test set 2 (50 neoplastic and 50 NDBE images) contained a heterogeneous case-mix of neoplastic lesions, representing distribution in clinical practice. Test set 3 (50 neoplastic and 150 NDBE images) contained prospectively collected imagery. The main outcome was correct classification of the images in terms of sensitivity. Results: The sensitivity of the CADe system on test set 1 was 84%. For general endoscopists, sensitivity was 63%, corresponding to a neoplasia miss-rate of one-third of neoplastic lesions and a potential relative increase in neoplasia detection of 33% for CADe-assisted detection. The sensitivity of the CADe system on test sets 2 and 3 was 100% and 88%, respectively. The specificity of the CADe system varied for the three test sets between 64% and 66%. Conclusion: This study describes the first steps towards the establishment of an unprecedented data infrastructure for using machine learning to improve the endoscopic detection of Barrett's neoplasia. The CADe system detected neoplasia reliably and outperformed a large group of endoscopists in terms of sensitivity.

The purpose of this study is to retrospectively evaluate the clinical and surgical outcomes of a large surgical series of vestibular schwannoma from North America over 20 years.After institutional review board approval a retrospective review of the senior author's personal case logs to identify patients who had operations for vestibular schwannoma was performed. The clinical notes, operative record, preoperative and postoperative imagings, and long-term clinical follow-up notes were evaluated.A total of 415 patients who underwent 420 surgeries were identified from the years 1998-2021. The average length of follow-up was 3 years and 9 months. Overall, at last follow-up the rate of "good" facial nerve outcomes (House-Brackmann [HB] score I and II) was 86% and "poor" facial nerve outcomes (HB III-VI) was 14%. The amount of cerebellopontine angle extension (P = 0.023), tumor volume (P = 0.015), facial nerve consistency (P0.001), preoperative HB score (P0.001), and FN stimulation threshold at the end of the procedure (P0.001) were correlated to facial nerve function at the last follow-up.This study represents one of the largest recently reported surgical series of vestibular schwannoma in North American literature with available long term follow-up. Facial nerve outcomes correlated with cerebellopontine angle extension, tumor volume, facial nerve stimulation threshold, facial nerve consistency, preoperative facial nerve function, and history of a prior resection. Tumor recurrence remains significantly higher after subtotal resection. We believe the data supports a continuation of a strategy of general intent of gross total resection, greatly modifiable by intraoperative findings and judgment.

Background: Moyamoya disease is a chronic, progressive cerebrovascular disease involving occlusion or stenosis of the terminal portion of the internal carotid artery. We conducted an updated systematic review and meta-analysis to investigate clinical and angiographic outcomes comparing direct, combined, and indirect bypass for the treatment of moyamoya disease in adults. Methods: Two independent authors performed Preferred Reporting Items for Systematic reviews and Meta-Analyses guided literature searches in December 2021 to identify articles reporting clinical/angiographic outcomes in adult moyamoya disease patients undergoing bypass. Primary end points used were ischemic and hemorrhagic strokes, clinical outcomes, and angiographic revascularization. Study quality was evaluated with Newcastle-Ottawa and the Oxford Center for Evidence-Based Medicine scales. Results: Four thousand four hundred fifty seven articles were identified in the initial search; 143 articles were analyzed. There were 3827 direct, 3826 indirect, and 3801 combined bypasses. Average length of follow-up was 3.59±2.93 years. Pooled analysis significantly favored direct (odds ratio [OR], 0.62 [0.48–0.79]; P P P P =0.0001) and combined (OR, 0.53 [0.41–0.69]; P P P P =0.0001) over indirect bypass for early stroke, late stroke, late intracerebral hemorrhage, and favorable outcomes, respectively. Indirect bypass was favored over combined (OR, 3.1 [1.7–5.6]; P P P P =0.002) and combined (OR, 0.23 [0.12–0.43]; P P P =0.01). Conclusions: Based on combined meta-analysis (43 articles) and pooled analysis (143 articles), the existing literature indicates that combined and direct bypasses have significant benefits for patients suffering from late stroke and hemorrhage versus indirect bypass. Combined bypass was favored over indirect bypass for favorable outcomes. This is a strong recommendation based on low-quality evidence when utilizing the Grades of Recommendation, Assessment, Development, and Evaluation system. These findings have important implications for bypass strategy selection.

This ESGE Position Statement defines the expected value of artificial intelligence (AI) for the diagnosis and management of gastrointestinal neoplasia within the framework of the performance measures already defined by ESGE. This is based on the clinical relevance of the expected task and the preliminary evidence regarding artificial intelligence in artificial or clinical settings. Main recommendations: (1) For acceptance of AI in assessment of completeness of upper GI endoscopy, the adequate level of mucosal inspection with AI should be comparable to that assessed by experienced endoscopists. (2) For acceptance of AI in assessment of completeness of upper GI endoscopy, automated recognition and photodocumentation of relevant anatomical landmarks should be obtained in ≥90% of the procedures. (3) For acceptance of AI in the detection of Barrett’s high grade intraepithelial neoplasia or cancer, the AI-assisted detection rate for suspicious lesions for targeted biopsies should be comparable to that of experienced endoscopists with or without advanced imaging techniques. (4) For acceptance of AI in the management of Barrett’s neoplasia, AI-assisted selection of lesions amenable to endoscopic resection should be comparable to that of experienced endoscopists. (5) For acceptance of AI in the diagnosis of gastric precancerous conditions, AI-assisted diagnosis of atrophy and intestinal metaplasia should be comparable to that provided by the established biopsy protocol, including the estimation of extent, and consequent allocation to the correct endoscopic surveillance interval. (6) For acceptance of artificial intelligence for automated lesion detection in small-bowel capsule endoscopy (SBCE), the performance of AI-assisted reading should be comparable to that of experienced endoscopists for lesion detection, without increasing but possibly reducing the reading time of the operator. (7) For acceptance of AI in the detection of colorectal polyps, the AI-assisted adenoma detection rate should be comparable to that of experienced endoscopists. (8) For acceptance of AI optical diagnosis (computer-aided diagnosis [CADx]) of diminutive polyps (≤5 mm), AI-assisted characterization should match performance standards for implementing resect-and-discard and diagnose-and-leave strategies. (9) For acceptance of AI in the management of polyps ≥ 6 mm, AI-assisted characterization should be comparable to that of experienced endoscopists in selecting lesions amenable to endoscopic resection.

OBJECTIVE Indication for surgery in brainstem cavernous malformations (BSCMs) is based on many case series, few comparative studies, and no randomized controlled trials. The objective of this study was to seek consensus about surgical management aspects of BSCM. METHODS A total of 29 experts were invited to participate in a multistep Delphi consensus process on the surgical treatment of BSCM. RESULTS Twenty-two (76%) of 29 experts participated in the consensus. Qualitative analysis (content analysis) of an initial open-ended question survey resulted in 99 statements regarding surgical treatment of BSCM. By using a multistep survey with 100% participation in each round, consensus was reached on 52 (53%) of 99 statements. These were grouped into 4 categories: 1) definitions and reporting standards (7/14, 50%); 2) general and patient-related aspects (11/16, 69%); 3) anatomical-, timing of surgery–, and BSCM-related aspects (22/37, 59%); and 4) clinical situation–based decision-making (12/32, 38%). Among other things, a consensus was reached for surgical timing, handling of associated developmental venous anomalies, handling of postoperative BSCM remnants, assessment of specific anatomical BSCM localizations, and treatment decisions in typical clinical BSCM scenarios. CONCLUSIONS A summary of typical clinical scenarios and a catalog of various BSCM- and patient-related aspects that influence the surgical treatment decision have been defined, rated, and interpreted.

The IMGT database profiles theTRgermline alleles for all fourTRloci (TRA,TRB,TRGandTRD), however, it does not comprise of the information regarding population specificity and allelic frequencies of these germline alleles. The specificity of allelic variants to different human populations can, however, be a rich source of information when studying the genetic basis of population-specific immune responses in disease and in vaccination. Therefore, we meticulously identified true germline alleles enriched with completeTRallele sequences and their frequencies across 26 different human populations, profiled by “1000 Genomes data”. We identified 205TRAV, 249TRBV, 16TRGVand 5TRDVgermline alleles supported by at least four haplotypes. The diversity of germline allelic variants in theTRloci is the highest in Africans, while the majority of the Non-African alleles are specific to the Asian populations, suggesting a diverse profile ofTRgermline alleles in different human populations. Interestingly, the alleles in the IMGT database are frequent and common across all five super-populations. We believe that this new set of germlineTRsequences represents a valuable new resource which we have made available through the new population-matchedTR(pmTR) database, accessible viahttps://pmtrig.lumc.nl/.

Background The rs72824905 single-nucleotide polymorphism in the PLCG2 gene, encoding the p.P522R residue change in Phospholipase C gamma 2 (PLCγ2), associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human circulating peripheral immune cells. Methods We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid cell assays, and in vivo SARS-CoV-2 vaccination. Results In line with expectations, p.P522R impacts immune cell function only slightly, but it does so across a wide array of immune cell types. Upon B-cell stimulation, we observed increased PLCγ2 phosphorylation and calcium release, suggesting increased B-cell sensitivity upon antigen recognition. Further, p.P522R-carriers had higher numbers of CD20++CD21-CD24+ naive B cells and IgG1+ memory B cells. In myeloid cells, normalized ROS production was higher upon PLCγ2-dependent stimulation. On classical monocytes, CD33 levels were elevated. Furthermore, carriers expressed lower levels of allergy-related FcεRI on several immune cell subsets. Nevertheless, carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination. Conclusion The immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.

Background: Intracranial dural arteriovenous fistulae (DAVF) are uncommon vascular anomalies with a reported incidence of 0.2 per 100,000 person years. An association between cerebral venous thrombosis (CVT) and DAVF has been reported; however, the direction of causality between the two remains uncertain. We aimed to identify the incidence and predictors of development of DAVF among patients with CVT. Methods: This is a post-hoc analysis of Anticoagulation in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT), a multicenter retrospective study comparing outcomes of CVT patients treated with warfarin versus direct oral anticoagulants (DOACs) from 2015 to 2020. Patients were included in this analysis if they did not have DAVF on initial imaging and had follow-up vascular imaging during the study. Clinical, imaging, and anticoagulation characteristics of patients who developed DAVF were compared to those who did not. Stepwise binary logistic regression including important variables (achieving p Results: A total of 751 patients (median age 43, 66% female) met inclusion criteria of whom 13 (1.7%) developed DAVF with an estimated rate of 2.40 per 100 patient years. Patients with DAVF were less likely to have headache at presentation (53.8% vs 79.3%, p=0.037), but more likely to have no venous recanalization on follow-up imaging (46.2% vs 14.8%, p=0.008), baseline cortical vein thrombosis (15.4% vs 2.7%, p=0.053), and received warfarin (vs. DOACs) as initial oral anticoagulant (84.6% vs 58.7%, p=0.085) but the latter two missed the statistical significance threshold. In stepwise binary logistic regression analysis, cortical vein thrombosis (OR 7.98, 95% CI 1.40-45.35, p=0.02) and lack of venous recanalization (OR 4.93, 95% CI 1.48-16.39, p=0.01) were associated with development of DAVF. Conclusion: In this large multicenter study of CVT, the incidence of DAVF development was higher than the previously reported rate in the general population. The presence of cortical vein thrombosis and lack of venous recanalization were associated with increased risk of development of DAVF.

The weapon systems created for the purpose of fighting the enemy in World War I caused terrible losses of human life on all sides of the conflict. However, World War I was also the event that gave birth to what became the field of Military Psychology. This position article, briefly tracing the development of the field, encourages the development of an expanded scope for this sub-discipline of Psychology. In its infancy, the role of Military Psychology was the selection and placement of soldiers based on a series of cognitive tests. After World War II, the scope of Military Psychology quickly expanded exponentially into areas such as leadership development, psychological warfare, and the enhancement of morale, motivation, resilience, and human factors, as military psychology with its sub-disciplines became integrated into national military forces to enhance the capabilities of the modern fighting soldier psychologically, physically and technologically. As the discipline matured, its present role can be described as to create soldiers whose skills sets greatly surpass those of their predecessors in meeting the ever-increasing complex demands of the modern battlefield. In recent years, Afghanistan and Iraq illustrated that conventional warfare tactics are rendered all but obsolete by small numbers of militia fighters with improvised devices and even outdated weapons in a demonstration of human ingenuity trumping advanced technology and well-equipped, superior military forces that inevitably failed dismally to subdue insurgent opposition forces. Even the destruction of the Islamic State in Libya (ISIL) and the Islamic State in Syria (ISIS) forces serves to emphasise that the world can no longer afford to continue armed conflict as a means to settle territorial and international disagreements because these eventually become the rationalisation for ongoing, unnecessary conflict. In its contribution to the defence role, alternatives to engagement in ill-advised military options must involve the strategic deployment of Military Psychology in a front-line capacity to research, comprehend and then, through diplomatic means, counter the psychological and ideological factors at play in creating the world's current conflict areas. If not, an even greater catastrophe will arise from ongoing ill-informed, ideology-driven international military interventions around the world.

Neurosurgical complications are unfortunately unavoidable events in our field. Notwithstanding the potentially devastating effect they can have on patients' lives, young neurosurgeons may equally feel devastated by their occurrence and find themselves poorly equipped emotionally to handle them. There is a significant literature discussing the psychological repercussions of these events. This special article, written in essay format, is simply a brief overview of the seasoned author's personal approach to complication avoidance and management, with an emphasis on the behavioral aspects and humane dimensions of our profession. The younger trainee may find value in the ideas and emotions expressed here, and the seasoned neurosurgeon may well identify with the author's thoughts.

T cell development in the mouse thymus has been studied extensively, but less is known regarding T cell development in the human thymus. We used a combination of single-cell techniques and functional assays to perform deep immune profiling of human T cell development, focusing on the initial stages of prelineage commitment. We identified three thymus-seeding progenitor populations that also have counterparts in the bone marrow. In addition, we found that the human thymus physiologically supports the development of monocytes, dendritic cells, and NK cells, as well as limited development of B cells. These results are an important step toward monitoring and guiding regenerative therapies in patients after hematopoietic stem cell transplantation.

The peptide hormone insulin-like 3 (INSL3) is produced almost exclusively by Leydig cells of the male gonad. INSL3 has several functions such as fetal testis descent and bone metabolism in adults.

In the testis, Leydig cells produce steroid hormones that are needed to masculinize typical genetic males during fetal development and to initiate and maintain spermatogenesis at puberty and adulthood, respectively. Steroidogenesis is initiated by the transfer of cholesterol from the outer to the inner mitochondrial membrane through the action of steroidogenic acute regulatory protein (STAR). Given its importance for the steroidogenic process, the regulation of

Cerebral extracranial-intracranial (EC-IC) direct bypass is a commonly used procedure for the treatment of cerebral hypoperfusion secondary to chronic steno-occlusive vasculopathy. We sought to determine clinical outcomes, intraoperative blood flow analysis, long term follow up, and long term patency rates from a single surgeon's series of direct cerebral bypass for moyamoya disease, moyamoya syndrome, and steno-occlusive disease.We reviewed clinical, demographic, operative and neuroimaging records for all patients who underwent a direct EC-IC bypass by the senior author between August 1999 and November 2020. Primary outcomes analyzed were functional long-term outcomes (by modified Rankin score [mRS]), surgical complications, and short-term and long-term bypass patency.A total of 162 revascularization procedures in 124 patients were performed. Mean clinical follow up time was 2 years 11 months. The combined immediate and long term postoperative stroke and/or intracerebral hemorrhage rate was 6.2%. There were 17 bypasses (10%) that were found to be occluded at long-term follow-up, all but one were asymptomatic. Long-term graft occlusion was correlated with presence of complete collateralization on preoperative angiography but not cut flow index (CFI). Overall, patients had a significant clinical improvement with a mean mRS score 1.8 preoperatively and 1.2 postoperatively.In our consecutive series of patients treated with direct EC-IC cerebral bypass, there was significant improvement in functional outcome as measured by the mRS. The long term patency rate was 90%. There was a statistically significant correlation between complete or incomplete angiographic collateralization patterns and long-term bypass occlusion. There was no correlation between bypass type, clinical syndrome, or CFI and long-term occlusions. The role of bypass surgery and the need for surgical expertise remain strong in the treatment of moyamoya variants and a select group of atherosclerotic steno-occlusive patients.

HYPOTHESIS: Vestibular Schwannoma (VS) can avoid cell death following radiation injury by entering cell cycle arrest and activating RAD51-related DNA repair. BACKGROUND: Although the radiobiology of various cancers is well-studied, the radiobiological effects in VS are poorly understood. In this study, we describe how VS cells enter cell cycle arrest (through p21 expression), activate DNA repair (through RAD51 upregulation), and avoid cell death after radiation-induced double-stranded breaks (DSB) in DNA (as measured by γ-H2AX). METHODS: Primary human VS cells were cultured on 96-well plates and 16-well culture slides at 10,000 cells/well and exposed to either 0 or 18 Gray of radiation. Viability assays were performed at 96 hours in vitro. Immunofluorescence for γ-H2AX, RAD51, and p21 was performed at 6 hours. RESULTS: Radiation (18 Gy) induced the expression of γ-H2AX, p21, and RAD51 in 6 cultured VS, suggesting that irradiated VS acquire DSBs, enter cell cycle arrest, and initiate RAD51 DNA repair to evade cell death. However, viability studies demonstrate variable responses in individual VS cells with 3 of 6 VS showing radiation resistance to 18 Gy. On further analyses, radiation-resistant VS cells expressed significantly more p21 than radiation-responsive tumors. CONCLUSIONS: In response to radiation-induced DNA damage, primary VS cells can enter cell cycle arrest and express RAD51 DNA repair mechanisms to avoid cell death. Radioresistant VS cells may mount a more robust p21 response to ensure sufficient time for DNA repair. Further investigation into DNA repair proteins and cell cycle checkpoints may provide important insight on the radiobiology of VS and mechanisms for resistance.

Background Cavernous malformations (CMs) of the optic nerve and chiasm are extremely rare, accounting for less than 1% of all intracranial CMs. Acute, subacute, or progressive visual loss from CM may occur with or without hemorrhage. Prompt surgical excision of the CM offers the best hope to improve or stabilize vision. Given its rarity, optic nerve and chiasm CMs may not be readily suspected. We provide 3 cases of optic nerve and chiasm CM, highlighting key neuroimaging features and the importance of expedited intervention. Methods Case records of the neuro-ophthalmology clinics of the Bascom Palmer Eye Institute and the University of Colorado, and literature review of reported cases of optic CM. Results A 49-year-old woman reported acute progressive painless vision loss in the right eye. MRI showed a suprasellar mass with heterogeneity in signal involving the right prechiasmatic optic nerve. Surgical excision of the CM 5 days after onset of visual loss improved vision from 20/300 to 20/30. A 29-year-old woman with acute painless blurred vision in the right eye had anterior chiasmal junctional visual field defects corresponding to a heterogeneously minimally enhancing mass with blood products enlarging the optic chiasm and proximal right optic nerve. Surgical excision of the CM 8 weeks after onset of visual loss improved vision from 20/40 to 20/15 with improved visual fields. A 33-year-old woman with a history of familial multiple CMs, diagnosed at age 18, reported new-onset severe headache followed by blurred vision. MRI showed a hemorrhagic lesion of the optic chiasm and right optic tract. She was 20/20 in each eye with a reported left superior homonymous hemianopia. No intervention was recommended. Vision of the right eye worsened to 20/400 2 months later. The patient was followed over 13 years, and the MRI and visual function remained unchanged. Literature review yielded 87 optic CM cases occurring across gender and nearly all ages with visual loss and headache as the most common presenting symptoms. Optic chiasm is the most common site of involvement (79%). Nearly 95% of reported CM cases were treated with surgery with 81% with improved vision and 1% with worsened vision. Conclusion MRI features are critical to the diagnosis of optic nerve and chiasm CM and may mimic other lesions. A high index of suspicion by the neuro-ophthalmologist and neuroradiologist leads to early recognition and intervention. Given optic CM displaces and does not infiltrate neural tissue, expedited surgical resection by a neurosurgeon after consideration of other diagnostic possibilities improves visual function in most cases.

Papaverine, a vasodilator approved for use by the U.S. Food and Drug Administration, has shown efficacy in treating vasospasm in cardiology, urology, and nephrology. The vasodilatory effect of papaverine is also hoped to protect the facial nerve from ischemic damage and nerve manipulation during vestibular schwannoma surgery. Our institution uses intracisternal papaverine irrigation during vestibular schwannoma resection to protect the facial nerve in patients with neuromonitoring changes. Our objective was to investigate the safety and facial nerve outcomes of intracisternal papaverine irrigation during vestibular schwannoma resection.We retrospectively reviewed patients who underwent resection of vestibular schwannoma at our institution between 2008 and 2021. Patients received papaverine if the intraoperative facial nerve stimulation threshold increased above 0.05 mA. Postoperative outcomes were compared with control patients who did not receive papaverine.A total of 283 cases were included in our analysis. Patients who received papaverine (n = 60) had lower immediate postoperative House-Brackmann (HB) grades than did control individuals (mean, 1.54 vs. 1.95; P = 0.029) and a lower likelihood of immediate postoperative HB grade1 (odds ratio, 0.514; P = 0.039). At long-term follow-up, there was no significant difference in HB grade. Papaverine use was not associated with increased rates of perioperative complications (P = 0.24).The off-label use of intracisternal papaverine irrigation during vestibular schwannoma resection can certainly be used safely for select cases. It is associated with improved immediate postoperative facial nerve outcomes, similar long-term facial nerve outcomes, and no significant increase in complications.

Leydig cells produce testosterone and insulin-like 3, two hormones essential for male sex differentiation and reproductive function. The orphan nuclear receptor, chicken ovalbumin upstream promoter transcription factor type II (COUP-TFII), and the zinc finger factor GATA4 are two transcription factors involved in Leydig cell differentiation, gene expression, and function.Several Leydig cell gene promoters contain binding motifs for both GATA factors and nuclear receptors. The goal of the present study is to determine whether GATA4 and COUP-TFII cooperate to regulate gene expression in Leydig cells.The transcriptomes from GATA4- and COUP-TFII-depleted MA-10 Leydig cells were analyzed using bioinformatic tools. Functional cooperation between GATA4 and COUP-TFII, and other related family members, was assessed by transient transfections in Leydig (MA-10 and MLTC-1) and fibroblast (CV-1) cell lines on several gene promoters. Recruitment of GATA4 and COUP-TFII to gene promoters was investigated by chromatin immunoprecipitation. Co-immunoprecipitation was used to determine whether GATA4 and COUP-TFII interact in MA-10 Leydig cells.Transcriptomic analyses of GATA4- and COUP-TFII-depleted MA-10 Leydig cells revealed 44 commonly regulated genes including the anti-Müllerian hormone receptor type (Amhr2) gene. GATA4 and COUP-TFII independently activated the Amhr2 promoter, and their combination led to a stronger activation. A GC-rich element, located in the proximal Amhr2 promoter was found to be essential for GATA4- and COUP-TFII-dependent activation as well as for the COUP-TFII/GATA4 cooperation. COUP-TFII and GATA4 directly interacted in MA-10 Leydig cell extracts. Chromatin immunoprecipitation revealed that GATA4 and COUP-TFII are recruited to the proximal Amhr2 promoter, which contains binding sites for both factors in addition to the GC-rich element. Cooperation between COUP-TFII and GATA6, but not GATA1 and GATA3, was also observed.Our results establish the importance of physical and functional cooperation between COUP-TFII/GATA4 in the regulation of gene expression in MA-10 Leydig cells, and more specifically the Amhr2 gene.

IntroductionThe gut microbiota influences and interacts with the host metabolism through effects on nutrient metabolism and digestion. Duodenal Mucosal Resurfacing (DMR) is a novel endoscopic procedure involving duodenal mucosal ablation by the use of hydrothermal energy. DMR, when combined with a glucagon-like peptide-1 receptor agonist (GLP-1RA), resulted in discontinuation of exogenous insulin treatment in 69% of patients with insulin dependent type 2 diabetes mellitus (T2DM) in the INSPIRE study. These patients also experienced improved glycaemic control and metabolic health. We thus investigated if these clinical effects were associated with a change in gut microbiota alpha and beta diversity.MethodsFaecal samples from the 16 patients were obtained for Illumina shotgun sequencing at baseline and 3 months after DMR. We assessed alpha and beta diversity of the gut microbiota in these samples and analysed its correlations with changes in HbA1c, body weight, and liver MRI proton density fat fraction (PDFF).ResultsHbA1c correlated negatively with alpha diversity (p=0.011, rho: -0.62) whereas changes in PDFF correlated significantly with beta diversity (p=0.036, rho: 0.55) 3 months after initiation of the combined intervention. These correlations with metabolic parameters were observed despite finding no change in gut microbiota diversity at 3 months post DMR.DiscussionThe correlation between gut microbiota richness (alpha diversity) and HbA1c as well as the change in PDFF and changed microbiota composition (beta diversity) suggests that changed gut microbiota diversity is associated with metabolic improvements after DMR in combination with glucagon-like-peptide-1 receptor agonist in type 2 diabetes. Larger controlled studies are however needed to find causal links between DMR with GLP-1RA, the gut microbiota, and improvements in metabolic health.

BACKGROUND AND AIMS: We previously identified a 5 methylated DNA marker (MDM) panel for nonendoscopic Barrett’s esophagus (BE) detection. In this study, we aimed to (1) recalibrate the performance of the 5 MDM marker panel using a simplified assay in a training cohort, (2) validate the panel in an independent test cohort, and (3) explore accuracy of an MDM panel with only 3 markers. METHODS: Participants were recruited from 3 medical centers. The SOS device (EsophaCap, CapNostics, Concord, NC, USA) was swallowed and withdrawn, followed by endoscopy, in BE cases and controls. A 5 MDM panel was blindly assayed using a simplified assay. Random forest modeling analysis was performed, in silico cross-validated in the training set, and then locked down, before test set analysis. RESULTS: The training set had 199 patients: 110 BE cases, 89 controls, and the test set had 89 patients: 60 BE cases and 29 controls. Sensitivity of the 5 marker panel for BE diagnosis was 93% at 90% specificity in the training set and 93% at 93% specificity in the test set. Areas under receiver operating characteristic curves were 0.96 and 0.97 in the training and test sets, respectively. Model accuracy was not influenced by age, sex, or smoking history. Multiple 3-MDM panels achieved similar accuracy. CONCLUSIONS: A 5-MDM panel for BE is highly accurate in training and test sets in a blinded multisite case-control analysis using a simplified assay. This panel may be reduced to only 3 MDMs in the future.

Because the current Barrett's esophagus (BE) surveillance protocol suffers from sampling error of random biopsies and a high miss-rate of early neoplastic lesions, many new endoscopic imaging and sampling techniques have been developed. None of these techniques, however, have significantly increased the diagnostic yield of BE neoplasia. In fact, these techniques have led to an increase in the amount of visible information, yet endoscopists and pathologists inevitably suffer from variations in intra- and interobserver agreement. Artificial intelligence systems have the potential to overcome these endoscopist-dependent limitations.

Background Lung carcinoma metastasizing to a skull base meningioma remains an extremely rare phenomenon, with only 3 studies reported. Furthermore, no documented cases have been reported in the petroclival region. Thus, we have presented the first 2 cases of tumor-to-tumor metastasis (TTM) in which a petroclival lesion, initially thought to be purely meningioma, was also found to contain metastatic lung adenocarcinoma. Case Description We present the cases of 2 patients with a known history of lung adenocarcinoma and stable petroclival meningioma who had presented with new-onset neurologic deficits. Repeat imaging studies for both patients found an increased lesion size and peritumoral enhancement; thus, both patients underwent emergent craniotomy for complete lesion resection. Intraoperatively, both lesions had zones of markedly different tumoral texture. On histologic analysis, both lesions showed metastatic lung adenocarcinoma contained within the primary petroclival meningioma. Conclusion Skull base TTM is a rare entity for which no specific management guidelines have been created. Therefore, even if the imaging characteristics suggest a more benign process, skull base TTM should remain high on the differential diagnosis for patients with a known primary cancer and new-onset, rapidly progressive, neurologic deficits. Close clinical follow-up with short-interval repeat imaging in this subset of patients might prevent misdiagnosis and facilitate prompt treatment.

BACKGROUND Moyamoya is a rare condition characterized by cerebral angiographic findings of intracranial carotid artery stenosis with abnormal net-like vessels in the brain, and often presents as transient ischemic attacks or intracranial hemorrhage. Revascularization in the form of extracranial-intracranial (EC-IC) artery bypass has demonstrated efficacy in preventing ischemic attacks and intracranial hemorrhage, although it is associated with a relatively high rate of perioperative ischemic and hemorrhagic stroke. This retrospective analysis aims to evaluate the possible association between postoperative hemoglobin (Hgb) concentration and early postoperative transient neurological events (TNEs) experienced at our center. METHODS Consecutive patients undergoing EC-IC bypass between January 1, 2017 and August 31, 2019 were identified, resulting in a study population of 24 patients with 34 individual cases for different cerebral hemispheres. Postoperative Hgb level was evaluated upon arrival to the intensive care unit (ICU) and the primary outcome was the occurrence of TNEs within 24-hours after surgery. RESULTS The incidence of TNEs within 24 hours postoperatively was 12% (n=4). Statistically significant differences were demonstrated between patients who did and did not experience TNEs in the postoperative period: total Hgb value (mean 9.4 vs. 11.3 g/dL, respectively; P=0.012) and percentage of patients with Hgb

Objectives This analysis of pooled individual patient data (IPD) aimed to evaluate the safety and efficacy of a bioresorbable polymer sirolimus eluting stent system (BP-SES; Orsiro) compared to a durable polymer everolimus eluting stent system (DP-EES; Xience) in the pooled population as well as in subgroups. Methods IPD with up to 12 months follow-up of the randomized controlled trials BIOFLOW-II (NCT01356888), -IV (NCT01939249), and -V (NCT02389946) as well as the all comers registry BIOFLOW-III (NCT01553526) were pooled. A total of 3,717 subjects (2,923 in BP-SES and 794 in DP-EES) with 5,328 lesions (4,225 lesions in BP-SES and 1,103 in DP-EES) were included in the IPD. The primary endpoint was target lesion failure (TLF) at 12 months follow-up. Subgroups analyzed included diabetes, age (≥65 years), gender, complex lesions (B2/C), small vessels (reference vessel diameter ≤2.75 mm), multivessel treatment, renal disease, and patients with acute coronary syndrome. Results Overall, TLF at 12 months was significantly lower with 5.2%in the BP-SES group versus 7.6% in the DP-EES group (p = .0098). Similarly, target vessel myocardial infarction (TV-MI) was 3.1 versus 5.7% (p = .0005). The rate of stent thrombosis was similar in both groups (0.004%). By regression analysis, an independent stent effect in favor of BP-SES was observed for TLF (p = .0043) and TV-MI (p = .0364) in small vessels. Conclusion Results of this IPD analysis suggest that the BP-SES with ultrathin struts is as safe as and more efficacious than DP-EES in the overall cohort and especially in small vessels.

Background Pituitary apoplexy is defined as a sudden neurologic deficit owing to infarction or hemorrhage within the pituitary gland. We report a rare case of apoplexy manifesting with cerebral infarction due to direct compression of the internal carotid artery (ICA) and review the literature. Case Description A 31-year-old man presented with sudden-onset headache, right hemiparesis, decreased left monocular visual acuity, and a nasal visual field deficit of the left eye. Computed tomography angiography revealed evidence of a hyperdense sellar/suprasellar mass with stenosis of the cavernous and supraclinoid segments of the ICAs bilaterally. Magnetic resonance angiography performed the following day showed complete occlusion of the left cervical ICA and cystic changes of the sellar and suprasellar mass suggestive of pituitary hemorrhage. The patient underwent urgent endoscopic endonasal decompression of the mass, and postoperative digital subtraction angiography demonstrated restored flow within the left cervical ICA. Conclusions Of 29 previously published cases of cerebral infarction due to pituitary apoplexy, the majority of cases were related to direct ICA compression. Vascular compression is associated with a high rate of mortality (24%) and should be treated urgently by surgical decompression in cases of severe or progressive neurologic symptoms.

Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare benign lesions that can arise anywhere within the central nervous system. The etiology of these lesions remains unknown and diagnosis is made on pathohistological analysis. We present the case of a 35-year-old male patient with a history of epilepsy since childhood who was evaluated for refractory seizures. MRI revealed a small lesion in the left-posterior temporal lobe suspected to be a cavernoma. A gross total resection of the lesion was achieved via a left temporal craniotomy and pathological analysis revealed CAPNON. At 6 months follow-up, the patient remained neurologically intact and his seizures had ceased.

Incretins, bile acids and the gut microbiome are involved in the pathophysiology of obesity and type 2 diabetes. The incretins glucagon-like peptide-1 and glucose-dependent-insulinetrophic polypeptide, both influence beta-cell function, insulin and glucose sensitivity, and food intake. Studies have shown that concentrations of both incretins change after bariatric surgery and nowadays glucagon-like peptide-1 agonists are administered as glucose and body weight regulating agents. Bile acids also play an important role in glycemic and metabolic regulation via multiple signaling pathways. After bariatric surgical interventions increase in bile acid concentrations have been observed combined with improvement of metabolic health. It is not clear though, whether this is a direct effect of the altered concentration of bile acids or an epiphenomenon. In addition, alterations in the microbiome are seen in patients with type 2 diabetes and people with obesity. The gut microbiome, probably together with incretins and bile acids, is essential in digestion and nutrient metabolism. After bariatric procedures several alterations in bacterial abundance have been demonstrated with specific bacterial species having different effects on glycemic and metabolic conditions

Objectives The aim of this study was to compare late-term clinical outcomes among patients treated with ultrathin-strut (60-μm) bioresorbable-polymer sirolimus-eluting stents (BP SES) and ...

Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.

BACKGROUND AND AIMS Belimumab (BEL), a recombinant human monoclonal antibody directed against B-cell activating factor (BAFF), is the first approved biological agent for patients with systemic lupus erythematosus (SLE) and a high level of disease activity or lupus nephritis (LN). BEL inhibits primary humoral immune responses by depleting naive B-cells that are dependent on BAFF for their survival while secondary humoral immune responses by memory B cells (MBCs) remain intact. Indeed, some studies reported an increase of circulating MBCs following neutralization of BAFF [1–3]. So far these effects of BEL on the MBC compartment in SLE patients have not been investigated. This study aimed to establish the dynamics of circulating MBCs in patients with SLE treated with BEL and to perform an in-depth analysis of the impact of BEL on the MBC compartment. METHOD First, extensive B cell subset phenotyping was performed prospectively by employing high-sensitivity flow cytometry (HSFC) based on EuroFlow protocols [4] in severe SLE/LN patients treated with BEL [5]. Additionally, in-depth characterisation of surging MBCs in circulation was performed by single-cell RNA sequencing (scRNA-seq). RESULTS HSFC established that the increase in MBCs was non-specific and observed in a broad range of MBC immunoglobulin subclasses peaking as early as 2 weeks after BEL initiation. Subsequent scRNA-seq analysis of the emerging MBCs revealed a non-proliferating phenotype with a prominent decrease in activation status. In these circulating MBCs, a large amount of migration and adhesion genes were downregulated suggesting that the accumulation of MBCs by BEL initiation was related to their impaired cell–cell adhesion disrupting cell-trafficking and preventing extravasation. CONCLUSION After initiation of BEL treatment, a substantial increase of circulating MBCs was firmly established in patients with SLE/LN. The surge of circulating MBCs appeared to be associated with disrupted lymphocyte trafficking of MBCs, thereby suggesting a new potential therapeutic mechanism of BEL on MBCs in SLE. These findings have important implications to our understanding and consequent improvement of B-cell targeted treatment strategies in patients with active SLE and LN as MBC accumulation in circulation might allow for more efficient targeting of the B-cell compartment.

The majority of the encouraging experimental results published on AI-based endoscopic Computer-Aided Detection (CAD) systems have not yet been reproduced in clinical settings, mainly due to highly curated datasets used throughout the experimental phase of the research. In a realistic clinical environment, these necessary high image-quality standards cannot be guaranteed, and the CAD system performance may degrade. While several studies have previously presented impressive outcomes with Frame Informativeness Assessment (FIA) algorithms, the current-state of the art implies sequential use of FIA and CAD systems, affecting the time performance of both algorithms. Since these algorithms are often trained on similar datasets, we hypothesise that part of the learned feature representations can be leveraged for both systems, enabling a more efficient implementation. This paper explores this case for early Barrett cancer detection by integrating the FIA algorithm within the CAD system. Sharing the weights between two tasks reduces the number of parameters from 16 to 11 million and the number of floating-point operations from 502 to 452 million. Due to the lower complexity of the architecture, the proposed model leads to inference time up to 2 times faster than the state-of-The-Art sequential implementation while retaining the classification performance.

The insulin-like 3 (INSL3) hormone produced by Leydig cells is essential for proper male sex differentiation, but the regulation of Insl3 expression remains poorly understood. This study describes a new physical and functional cooperation between the nuclear receptors SF1 and COUP-TFII in Insl3 expression.INSL3, a hormone abundantly produced by Leydig cells, is essential for testis descent during fetal life and bone metabolism in adults. The mechanisms regulating Insl3 expression in Leydig cells have been studied in several species but remain poorly understood. To date, only a handful of transcription factors are known to activate the Insl3 promoter and include the nuclear receptors AR, NUR77, COUP-TFII, and SF1, as well as the Krüppel-like factor KLF6. Some of these transcription factors are known to transcriptionally cooperate on the Insl3 promoter, but the mechanisms at play remain unknown. Here, we report that COUP-TFII and SF1 functionally cooperate on the Insl3 promoter from various species but not on the Inha, Akr1c14, Cyp17a1, Hsd3b1, Star, Gsta3, and Amhr2 promoters that are known to be regulated by COUP-TFII and/or SF1. The Insl3 promoter contains species-conserved binding sites for COUP-TFII (-91 bp) and SF1 (-134 bp). Mutation of either the COUP-TFII or the SF1 sequence had no impact on the COUP-TFII/SF1 cooperation, but the mutation of both binding sites abolished the cooperation. In agreement with this, we found that COUP-TFII and SF1 physically interact in Leydig cells. Finally, we report that the transcriptional cooperation is not limited to COUP-TFII and SF1 as it also occurred between all NR2F and NR5A family members. Our data provide new mechanistic insights into the cooperation between the orphan nuclear receptors COUP-TFII and SF1 in the regulation of Insl3 gene expression in Leydig cells.

Defining how genes get turned on and off in a correct spatiotemporal manner is integral to our understanding of the development, differentiation, and function of different cell types in both health and disease. Testis development and subsequent male sex differentiation of the XY fetus are well-orchestrated processes that require an intricate network of cell-cell communication and hormonal signals that must be properly interpreted at the genomic level. Transcription factors are at the forefront for translating these signals into a coordinated genomic response. The GATA family of transcriptional regulators were first described as essential regulators of hematopoietic cell differentiation and heart morphogenesis but are now known to impact the development and function of a multitude of tissues and cell types. The mammalian testis is no exception where GATA factors play essential roles in directing the expression of genes crucial not only for testis differentiation but also testis function in the developing male fetus and later in adulthood. This minireview provides an overview of the current state of knowledge of GATA factors in the male gonad with a particular emphasis on their mechanisms of action in the control of testis development, gene expression in the fetal testis, testicular disease, and XY sex differentiation in humans.

Cervical anastomotic strictures after esophagectomy cause significant disease burden. We aimed to study the technical feasibility and safety of intensive endoscopic therapy.In this pilot study, we included 15 patients with an untreated benign cervical anastomotic stricture after esophagectomy. Intensive endoscopic therapy comprised three endoscopic modalities: in- and excision using a needle-knife, intralesional steroid injections and bougie dilation. In two endoscopic procedures, the stricture was dilated up to a luminal diameter of 18 mm. Patients were followed up to 6 months.A luminal diameter of 18 mm was achieved in 13 of 15 patients (87%) after two endoscopic procedures. No major adverse events related to the investigational treatment occurred. Median dysphagia scores significantly improved from 2 (IQR, interquartile range, 2-3) at baseline to 0 (IQR 0-1) after 14 days (p 0.001). Eleven (73%) patients developed recurrent symptoms of dysphagia requiring a median of 1 (IQR 0-3) additional endoscopic dilation procedure.Achieving a luminal diameter of 18 mm in two procedures with intensive endoscopic therapy was technically feasible and effective in reducing dysphagia rapidly in patients with a cervical anastomotic stricture after esophagectomy. No major adverse events related to the investigational treatment were observed.

Cell differentiation and acquisition of specialized functions are inherent steps in events that lead to normal tissue development and function. These processes require accurate temporal, tissue, and cell-specific activation or repression of gene transcription. This is achieved by complex interactions between transcription factors that form a unique combinatorial code in each specialized cell type and in response to different physiological signals. Transcription factors typically act by binding to short, nucleotide-specific DNA sequences located in the promoter region of target genes. In males, Leydig cells play a crucial role in sex differentiation, health, and reproductive function from embryonic life to adulthood. To better understand the molecular mechanisms regulating Leydig cell differentiation and function, several transcription factors important to Leydig cells have been identified, including some previously unknown to this specialized cell type. This mini review summarizes the current knowledge on transcription factors in fetal and adult Leydig cells, describing their roles and mechanisms of action.

Human milk is a dynamic biofluid, and its detailed composition receives increasing attention. While most studies focus on changes over time or differences between maternal characteristics, interindividual variation receives little attention. Nevertheless, a comprehensive insight into this can help interpret human milk studies and help human milk banks provide targeted milk for recipients. This study aimed to map interindividual variation in the human milk proteome, peptidome, and metabolome and to investigate possible explanations for this variation. A set of 286 milk samples was collected from 29 mothers in the third month postpartum. Samples were pooled per mother, and proteins, peptides, and metabolites were analyzed. A substantial coefficient of variation (>100%) was observed for 4.6% and 36.2% of the proteins and peptides, respectively. In addition, using weighted correlation network analysis (WGCNA), 5 protein and 11 peptide clusters were obtained, showing distinct characteristics. With this, several associations were found between the different data sets and with specific sample characteristics. This study provides insight into the dynamics of human milk protein, peptide, and metabolite composition. In addition, it will support future studies that evaluate the effect size of a parameter of interest by enabling a comparison with natural variability.

Background: Extracranial-Intracranial (EC-IC) bypass is increasingly used for treatment of hemodynamic failure in Moya-Moya disease (MMD) or syndrome (MMS). No specific imaging parameter has been established to determine bypass patency in these patients. We sought to determine if vasomotor reactivity (VMR) testing could be correlated with pre-operative angiographic data and predict bypass patency. Methods: All available pre-operative VMRs and diagnostic angiograms (DSA) in patients with EC-IC direct bypass surgeries performed at our institution from 2007-2019 were reviewed to determine the degree of pre-procedural hemispheric failure (by VMR to the inhalation of carbon dioxide and hyperventilation, abnormal defined by less than 70%) and collateral compensation (categorized as complete vs. incomplete collaterals by DSA). Bypass patency was assessed on follow-up imaging (either immediate in post-op angiogram and delayed subsequent CTA or DSA). Results: Of the 113 bypass surgeries performed, 68 had pre-operative VMR and DSA. A total of 52 patients were included, in which 16 had both hemispheres operated on (median age 46 [IQR 25], 74% women, 60% with Moya-Moya disease, 51% presented with ischemic stroke, 37% TIA, 10% intracerebral hemorrhage and 1% headache). Pre-operatively, 97% had an abnormal VMR, 24% had incomplete collateralization. A total of 79% had bypass patency (87% immediate, 76% delayed, median time 1 year 8 months [IQR 1 year and 6 months)) on follow up. Patients with patent bypass had significantly lower VMR (27 [SD ± 18.8] vs. mean 36 [SD ± 14.5], p=0.005) and higher likelihood of incomplete collateralization pre-operatively (mean 25.1 [SD ± 16.4] vs. mean 39.2 [SD ± 18.8], p=0.013) as compared to non-patent bypass patients. In multivariate analysis low pre-operative VMR was a significant predictor for bypass patency adjusting for age, presenting stroke type and gender (p=0.01). Conclusion: Vasomotor reactivity is a non-invasive, low-cost test which predicted angiographic vessel collateralization and bypass patency. Bypass patency remains important predictor of outcomes in this population.