Tumor necrosis factor α receptor 1A transduces the inhibitory effect on axon regeneration triggered by IgG anti-ganglioside GD1a antibodies.

Anti-ganglioside antibodies (anti-Gg Abs) have been linked to delayed/poor clinical recovery in both axonal and demyelinating forms of Guillain-Barrè Syndrome (GBS). In many instances, the incomplete recovery is attributed to the peripheral nervous system's failure to regenerate. The cross-linking of cell surface gangliosides by anti-Gg Abs triggers inhibition of nerve repair in both in vitro and in vivo axon regeneration paradigms. This mechanism involves the activation of the small GTPase RhoA, which negatively modulates the growth cone cytoskeleton. At present, the identity/es of the receptor/s responsible for transducing the signal that ultimately leads to RhoA activation remains poorly understood. The aim of this work was to identify the transducer molecule responsible for the inhibitory effect of anti-Gg Abs on nerve repair. Putative candidate molecules were identified through proteomic mass spectrometry of ganglioside affinity-captured proteins from rat cerebellar granule neurons (Prendergast et al., 2014). These candidates were evaluated using an in vitro model of neurite outgrowth with primary cultured dorsal root ganglion neurons (DRGn) and an in vivo model of axon regeneration. Using an shRNA-strategy to silence putative candidates on DRGn, we identified tumor necrosis factor receptor 1A protein (TNFR1A) as a transducer molecule for the inhibitory effect on neurite outgrowth from rat/mouse DRGn cultures of a well characterized mAb targeting the related gangliosides GD1a and GT1b. Interestingly, lack of TNFr1A expression on DRGn abolished the inhibitory effect on neurite outgrowth caused by anti-GD1a but not anti-GT1b specific mAbs, suggesting specificity of GD1a/transducer signaling. Similar results were obtained using primary DRGn cultures from TNFR1a-null mice, which did not activate RhoA after exposure to anti-GD1a mAbs. Generation of single point mutants at the stalk region of TNFR1A identified a critical amino acid for transducing GD1a signaling, suggesting a direct interaction. Finally, passive immunization with an anti-GD1a/GT1b mAb in an in vivo model of axon regeneration exhibited reduced inhibitory activity in TNFR1a-null mice compared to wild type mice. In conclusion, these findings identify TNFR1A as a novel transducer receptor for the inhibitory effect exerted by anti-GD1a Abs on nerve repair, representing a significant step forward toward understanding the factors contributing to poor clinical recovery in GBS associated with anti-Gg Abs.

Machine Learning and External Validation of the IDENTIFY Risk Calculator for Patients with Haematuria Referred to Secondary Care for Suspected Urinary Tract Cancer.

BACKGROUND: The IDENTIFY study developed a model to predict urinary tract cancer using patient characteristics from a large multicentre, international cohort of patients referred with haematuria. In addition to calculating an individual's cancer risk, it proposes thresholds to stratify them into very-low-risk (<1%), low-risk (1-<5%), intermediate-risk (5-<20%), and high-risk (≥20%) groups. OBJECTIVE: To externally validate the IDENTIFY haematuria risk calculator and compare traditional regression with machine learning algorithms. DESIGN, SETTING, AND PARTICIPANTS: Prospective data were collected on patients referred to secondary care with new haematuria. Data were collected for patient variables included in the IDENTIFY risk calculator, cancer outcome, and TNM staging. Machine learning methods were used to evaluate whether better models than those developed with traditional regression methods existed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The area under the receiver operating characteristic curve (AUC) for the detection of urinary tract cancer, calibration coefficient, calibration in the large (CITL), and Brier score were determined. RESULTS AND LIMITATIONS: There were 3582 patients in the validation cohort. The development and validation cohorts were well matched. The AUC of the IDENTIFY risk calculator on the validation cohort was 0.78. This improved to 0.80 on a subanalysis of urothelial cancer prevalent countries alone, with a calibration slope of 1.04, CITL of 0.24, and Brier score of 0.14. The best machine learning model was Random Forest, which achieved an AUC of 0.76 on the validation cohort. There were no cancers stratified to the very-low-risk group in the validation cohort. Most cancers were stratified to the intermediate- and high-risk groups, with more aggressive cancers in higher-risk groups. CONCLUSIONS: The IDENTIFY risk calculator performed well at predicting cancer in patients referred with haematuria on external validation. This tool can be used by urologists to better counsel patients on their cancer risks, to prioritise diagnostic resources on appropriate patients, and to avoid unnecessary invasive procedures in those with a very low risk of cancer. PATIENT SUMMARY: We previously developed a calculator that predicts patients' risk of cancer when they have blood in their urine, based on their personal characteristics. We have validated this risk calculator, by testing it on a separate group of patients to ensure that it works as expected. Most patients found to have cancer tended to be in the higher-risk groups and had more aggressive types of cancer with a higher risk. This tool can be used by clinicians to fast-track high-risk patients based on the calculator and investigate them more thoroughly.

European randomized controlled trial evaluating differential target multiplexed spinal cord stimulation and conventional medical management in subjects with persistent back pain ineligible for spine surgery: 24-month results.

BACKGROUND: Differential target multiplexed spinal cord stimulation (DTM SCS) was shown to be superior to conventional SCS for treating chronic low back pain (CLBP) in subjects with persistent spinal pain syndrome with previous spinal surgery (PSPS-T2) or ineligible for it (PSPS-T1). This study reports 24-month efficacy and safety of DTM SCS vs. conventional medical management (CMM) in PSPS-T1 subjects across four European countries. METHODS: This is a prospective, multicenter, open-label, randomized, controlled trial with optional crossover. Subjects randomized 1:1 to DTM SCS or CMM. Primary endpoint was responder rate (% subjects reporting ≥50% CLBP relief) at 6 months. A superiority test compared responder rates between treatments. CLBP and leg pain levels, functional disability, quality of life (QoL), patient satisfaction and global impression of change were evaluated for 24 months. A Composite Responder Index (CRI) was obtained using CLBP relief, disability and QoL. Incidence of study-related adverse events evaluated safety. RESULTS: A total of 55 and 57 subjects were randomized to DTM SCS and CMM respectively. DTM SCS was superior, with CLBP responder rates ≥80% and CLBP relief >5.6 cm (>70% reduction) through the 24-month follow-up. Improvements with DTM SCS in other outcomes were sustained. The CRI was >80% for DTM SCS through 24 months. Opioid medication intake decreased in subjects treated with DTM SCS. Most patients treated with DTM SCS felt satisfied and improved at the end of the study. Safety was congruent with other studies. CONCLUSION: DTM SCS is efficacious and safe during 24 months for the treatment of CLBP and leg pain in PSPS-T1 patients ineligible for spine surgery. SIGNIFICANCE STATEMENT: This randomized controlled trial shows that Differential Target Multiplexed SCS (DTM SCS) is an effective and safe long-term treatment for PSPS type 1 patients suffering from axial low back pain with or without leg pain and who are ineligible for spinal surgery. Currently, CMM treatments are their only option and provide limited benefits. Besides superior pain relief, DTM SCS provides significant improvements in functional disability, quality of life, high levels of satisfaction and perceived impression of change.

Impact of Genotype-Phenotype Interactions on Cardiovascular Function in Paediatric Loeys-Dietz Syndrome.

Background: The relationship between genotype and phenotypical vascular and cardiac properties in paediatric Loeys-Dietz syndrome (LDS) patients are not well characterized. This study explores the phenotypical differences in aortic properties and cardiac structural and functional parameters between paediatric LDS patients with TGFBR1 and TGFBR2 mutations. Methods: We included 32 LDS patients with either TGFBR1 (n = 17) or TGFBR2 (n = 15) mutations. Echocardiographic data included aortic dimensions, distensibility, strain, and stiffness at the level of the annulus, sinuses of Valsalva, sinotubular junction, ascending aorta, and descending aorta. Parameters for left ventricular size and function were also recorded. Results: Demographics were similar between the groups. Patients with TGFBR2 were more likely to have undergone aortic surgery (47% vs 12%, P = 0.057) and use angiotensin receptor blockers (93% vs 47%, P = 0.015). Aortic z scores were significantly larger in the TGFBR2 group at the level of the aortic valve annulus (P = 0.007), sinuses of Valsalva (P = 0.001), sinotubular junction (P = 0.001), and ascending aorta (P = 0.054). Patients with TGFBR2 also had significantly lower aortic distensibility and strain coupled with higher stiffness index at the level of the annulus, sinotubular junction, and ascending aorta. Parameters for the descending aorta, cardiac morphology, and cardiac function were similar between the groups. Conclusions: Paediatric LDS patients with TGFBR2 present with more severe cardiovascular phenotypes than patients with TGFBR1 with larger aortic dimensions and increased aortic stiffness. Our findings suggest that genotypes should be taken into consideration in the clinical management of paediatric LDS patients.

Contexte: Les liens entre le génotype des enfants atteints du syndrome de Loeys-Dietz (SLD) et les particularités phénotypiques vasculaires et cardiaques n'ont pas encore été bien caractérisés. La présente étude vise à explorer les différences phénotypiques entre les propriétés de l'aorte et les paramètres cardiaques structuraux et fonctionnels des enfants atteints du SLD qui présentent une mutation du gène TGFBR1 et ceux qui présentent une mutation du gène TGFBR2. Méthodologie: Nous avons inclus dans notre analyse 32 patients atteints du SLD présentant une mutation de TGFBR1 (n = 17) ou de TGFBR2 (n = 15). Les données échocardiographiques colligées incluaient les dimensions de l'aorte, sa distensibilité, sa déformation (strain) et sa rigidité au niveau de l'anneau aortique, des sinus de Valsalva, de la jonction sinotubulaire, de l'aorte ascendante et de l'aorte descendante. Les paramètres ayant trait à la taille et à la fonction du ventricule gauche ont également été consignés. Résultats: Les caractéristiques démographiques étaient comparables dans les deux groupes. Les patients présentant une mutation du gène TGFBR2 étaient plus susceptibles d'avoir subi une intervention chirurgicale de l'aorte (47 % vs 12 %, p = 0,057) et de prendre un antagoniste des récepteurs de l'angiotensine (93 % vs 47 %, p = 0,015). Les scores z aortiques étaient significativement plus élevés chez les patients présentant une mutation de TGFBR2 pour les dimensions de l'anneau de la valve aortique (p = 0,007), des sinus of Valsalva (p = 0,001), de la jonction sinotubulaire (p = 0,001) et de l'aorte ascendante (p = 0,054). Les patients avec une mutation de TGFBR2 présentaient aussi une élasticité et une déformation aortiques significativement plus faibles ainsi qu'une rigidité accrue au niveau de l'anneau aortique, de la jonction sinotubulaire et de l'aorte ascendante. Les paramètres de l'aorte descendante, les caractéristiques morphologiques cardiaques et la fonction cardiaque étaient comparables pour les deux groupes. Conclusions: Chez les enfants atteints du SLD, une mutation du gène TGFBR2 se traduisait par des phénotypes plus défavorables que dans le cas d'une mutation du gène TGFBR1 et se caractérisait par des dimensions et une rigidité aortiques accrues. Nos observations indiquent qu'il convient de prendre le génotype des patients en considération lors de la prise en charge clinique des enfants atteints du SLD.

Enhancing AI Research for Breast Cancer: A Comprehensive Review of Tumor-Infiltrating Lymphocyte Datasets.

The field of immunology is fundamental to our understanding of the intricate dynamics of the tumor microenvironment. In particular, tumor-infiltrating lymphocyte (TIL) assessment emerges as essential aspect in breast cancer cases. To gain comprehensive insights, the quantification of TILs through computer-assisted pathology (CAP) tools has become a prominent approach, employing advanced artificial intelligence models based on deep learning techniques. The successful recognition of TILs requires the models to be trained, a process that demands access to annotated datasets. Unfortunately, this task is hampered not only by the scarcity of such datasets, but also by the time-consuming nature of the annotation phase required to create them. Our review endeavors to examine publicly accessible datasets pertaining to the TIL domain and thereby become a valuable resource for the TIL community. The overall aim of the present review is thus to make it easier to train and validate current and upcoming CAP tools for TIL assessment by inspecting and evaluating existing publicly available online datasets.

The Positive Side Effect of Anterior Cervical Decompression and Fusion on Axial Neck Pain.

STUDY DESIGN: Observational Cohort Study. OBJECTIVES: This study aims to comprehensively assess the outcomes of anterior cervical spine surgery in patients who have undergone surgical intervention for radiculopathy or myelopathy, with a specific focus on the surgery's impact on axial neck pain. METHODS: Data from an institutional spine surgery registry were analyzed for patients who underwent anterior cervical spine surgery between January 2016 and March 2022. Patient demographics, clinical variables, and outcome measures, including the Neck Disability Index (NDI), numeric rating scales for neck and arm pain (NRS-Neck and NRS-Arm), and 36-Item Short Form Health Survey (SF-36) scores, were collected. Statistical analysis included paired t-tests, chi-squared tests, and multivariate linear regression. RESULTS: Of 257 patients, 156 met the inclusion criteria. Patients showed significant improvement in NDI, NRS-Neck, NRS-Arm, SF-36 (Physical and Mental components), and all changes exceeded the minimum clinically important difference. Multivariate regression revealed that lower preoperative physical and mental component scores and higher preoperative NRS-Neck predicted worse NDI scores at follow-up. CONCLUSIONS: This study underscores that anterior cervical fusion not only effectively alleviates arm pain and disability but also has a positive impact on axial neck pain, which may not be the primary target of surgery. Our findings emphasize the potential benefits of surgical intervention when neck pain coexists with neurologic compression. This contribution adds to the growing body of evidence emphasizing the importance of precise diagnosis and patient selection. Future research, ideally focusing on patients with isolated neck pain, should further explore alternative surgical approaches to enhance treatment options.

Dual role of signaling pathways in myeloma requires cell type-specific targeting of ligand-receptor interactions.

ABSTRACT: Although most patients with multiple myeloma respond to treatment initially, therapy resistance develops almost invariably, and only a subset of patients show durable responses to immunomodulatory therapies. Although the immune microenvironment has been extensively studied in patients with myeloma, its composition is currently not used as prognostic markers in clinical routine. We hypothesized that the outcome of immune signaling pathway engagement can be highly variable, depending on which 2 cellular populations participate in this interaction. This would have important prognostic and therapeutic implications, suggesting that it is crucial for immune pathways to be targeted in a specific cellular context. To test this hypothesis, we investigated a cohort of 25 patients with newly diagnosed multiple myeloma. We examined the complex regulatory networks within the immune compartment and their impact on disease progression. Analysis of immune cell composition and expression profiles revealed significant differences in the B-cell compartment associated with treatment response. Transcriptional states in patients with short time to progression demonstrated an enrichment of pathways promoting B-cell differentiation and inflammatory responses, which may indicate immune dysfunction. Importantly, the analysis of molecular interactions within the immune microenvironment highlights the dual role of signaling pathways, which can either be associated with good or poor prognosis depending on the cell types involved. Our findings therefore argue that therapeutic strategies targeting ligand-receptor interactions should take into consideration the composition of the microenvironment and the specific cell types involved in molecular interactions.

Predictive Models for Assessing Patients' Response to Treatment in Metastatic Prostate Cancer: A Systematic Review.

Background and objective: The treatment landscape of metastatic prostate cancer (mPCa) has evolved significantly over the past two decades. Despite this, the optimal therapy for patients with mPCa has not been determined. This systematic review identifies available predictive models that assess mPCa patients' response to treatment. Methods: We critically reviewed MEDLINE and CENTRAL in December 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Only quantitative studies in English were included with no time restrictions. The quality of the included studies was assessed using the PROBAST tool. Data were extracted following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews criteria. Key findings and limitations: The search identified 616 citations, of which 15 studies were included in our review. Nine of the included studies were validated internally or externally. Only one study had a low risk of bias and a low risk concerning applicability. Many studies failed to detail model performance adequately, resulting in a high risk of bias. Where reported, the models indicated good or excellent performance. Conclusions and clinical implications: Most of the identified predictive models require additional evaluation and validation in properly designed studies before these can be implemented in clinical practice to assist with treatment decision-making for men with mPCa. Patient summary: In this review, we evaluate studies that predict which treatments will work best for which metastatic prostate cancer patients. We found that existing studies need further improvement before these can be used by health care professionals.

The Integration of 3D Virtual Reality and 3D Printing Technology as Innovative Approaches to Preoperative Planning in Neuro-Oncology.

Our study explores the integration of three-dimensional (3D) virtual reality (VR) and 3D printing in neurosurgical preoperative planning. Traditionally, surgeons relied on two-dimensional (2D) imaging for complex neuroanatomy analyses, requiring significant mental visualization. Fortunately, nowadays advanced technology enables the creation of detailed 3D models from patient scans, utilizing different software. Afterwards, these models can be experienced through VR systems, offering comprehensive preoperative rehearsal opportunities. Additionally, 3D models can be 3D printed for hands-on training, therefore enhancing surgical preparedness. This technological integration transforms the paradigm of neurosurgical planning, ensuring safer procedures.

Does the distribution of musculoskeletal pain shape the fate of long-term sick leave? A prospective cohort study with register follow-up.

ABSTRACT: Although multisite pain can markedly reduce work ability, the relevance of the bodily pain distribution as a predictor of long-term sick leave is still unknown. This study aimed to investigate the association between musculoskeletal pain distributions and long-term sick leave in the general working population of Denmark and included 66,177 currently employed wage earners without long-term sick leave during the prior 52 weeks. Participants reported whether they had pain in the lower extremity (hips/knees), upper extremity (neck/shoulders), or the low back. The analysis controlled for age, sex, year of survey reply, educational level, occupational group, psychosocial work factors, body max index, smoking, leisure-time physical activity, and mental health confounders. The results demonstrated that the risk of long-term sick leave increased with the number of pain sites. Compared with no pain, localized pain in any body region increased the risk/hazard by 25% to 29% (HR [95% CI]: 1.29 [1.07-1.54] for pain only in the low back), whereas pain in 2 regions increased the risk by 39% to 44% (HR [95% CI]: 1.41 [1.18-1.69] for pain in the low back + hips/knees). Workers reporting pain in all 3 regions experienced a 72% increased risk (HR [95% CI]: 1.72 [1.55-1.91]). Thus, the number of pain regions seems to matter more than the exact pain location. The spatial extension of musculoskeletal pain in workers functions as a gradient system, where pain spread throughout the body is an independent indicator of the high risk of long-term sick leave.

Physical Therapist Interventions Versus or Combined With Surgical Treatment in Nontraumatic Degenerative Meniscal Pathology: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: This study aimed to synthesize the evidence from randomized clinical trials in people with nontraumatic degenerative meniscal pathology by comparing physical therapist interventions versus or combined with arthroscopic partial meniscectomy (APM). METHODS: Seven electronic databases were searched. Methodological quality was evaluated using the Physiotherapy Evidence Database scale. Data synthesis was performed with random-effects network meta-analysis, and results were summarized using the standardized mean differences. RESULTS: From 2103 studies, 10 randomized clinical trials comprising 1411 individuals were included. Ninety percent of the selected randomized clinical trials were classified as good quality according to the Physiotherapy Evidence Database scale. All interventions (physical therapist interventions, APM, and APM plus physical therapist interventions) showed reduced pain and physical impairments at 3-month follow-up. However, when a physical therapist intervention was included, greater reductions in pain at rest (APM vs physical therapist interventions: 0.73 [95% CI = 0.20 to 1.26]; APM vs APM plus physical therapist interventions: 0.59 [95% CI = 0.15 to 1.03]) and greater increases in the strength of knee extensor muscles (APM vs physical therapist interventions: 0.44 [95% CI = 0.07 to 0.80]; APM vs APM plus physical therapist interventions: 0.73 [95% CI = 0.29 to 1.16]) were observed at 3 months. By contrast, no differences were found between treatments beyond 3 months. CONCLUSION: Physical therapist interventions based on exercise programs demonstrate superior short-term outcomes in pain reduction and knee extensor strength compared to surgical treatment. IMPACT: For nontraumatic degenerative meniscal pathology, conservative treatment utilizing a physical therapist intervention approach should be prioritized as the first choice over surgical treatment. It offers comparable or superior short-term pain reduction and strength improvements, with a lower risk of side effects. In cases where surgery is deemed necessary, including postsurgical, physical therapist interventions are highly recommended to enhance muscle strength and alleviate pain.

Microneurosurgical training in the anatomical specimen: A structured plan for endoscopic and microsurgical skull base training during the residency.

BACKGROUND AND OBJECTIVE: The development of a high level of competence and technical proficiency is one of the main objectives of any neurosurgical training program. Due to many factors, this progressive skill development can be complex during the residency. Despite its high cost and infrastructure requirements, there is renewed interest regarding the role of anatomy labs. The study and dissection of the human cadaver has been the environment where many surgeons have developed the necessary skills for microneurosurgery. We propose a structured endoscopic and microsurgical training dissection program to enable residents to maximize the benefits of their training in the lab. MATERIAL AND METHODS: During the months of September, October and November 2021, a stay was done at the Microneurosurgery and Skull Base Laboratory of the Miguel Hernández University of Alicante. A total of 2 specimens were used. The first specimen underwent a first endoscopic endonasal dissection phase. After completing the endonasal part, a set of incisions were made to perform the transcranial part. In the second specimen, the transcranial part was performed first, leaving the endonasal endoscopic work for the last phase. RESULTS: The results of the dissection program are presented. During the endonasal endoscopic phase, the transsphenoidal approach to the sella was simulated while focusing on the extended approaches in the sagittal plane. During the transcranial phase, right and left anterolateral approaches, a left anterior transcallosal interhemispheric approach, a left transcondylar posterolateral approach and a combined right lateral approach were performed. CONCLUSIONS: The structured dissection of the specimen allowed both endonasal endoscopic and transcranial microsurgical training in the same specimen. This design facilitated the realization of the core skull base approaches in the same specimen. According to our initial experience, we believe that developing common dissection programs is a powerful tool to maximize the results of our residents' laboratory training.

Robot-assisted implantation of a microelectrode array in the occipital lobe as a visual prosthesis: technical note.

The prospect of direct interaction between the brain and computers has been investigated in recent decades, revealing several potential applications. One of these is sight restoration in profoundly blind people, which is based on the ability to elicit visual perceptions while directly stimulating the occipital cortex. Technological innovation has led to the development of microelectrodes implantable on the brain surface. The feasibility of implanting a microelectrode on the visual cortex has already been shown in animals, with promising results. Current research has focused on the implantation of microelectrodes into the occipital brain of blind volunteers. The technique raises several technical challenges. In this technical note, the authors suggest a safe and effective approach for robot-assisted implantation of microelectrodes in the occipital lobe for sight restoration.

The role of clinically relevant intra-abdominal collections after pancreaticoduodenectomy : Clinical impact and predictors. A retrospective analysis from a European tertiary centre.

BACKGROUND: There is controversial evidence regarding the impact of clinically relevant postoperative intra-abdominal collections (CR-IC) on the clinical course after pancreaticoduodenectomy. C-reactive Protein (CRP) has been validated as a predictor of postoperative pancreatic fistula (POPF). Still, its role in predicting CR-IC has not been studied. METHODS: A retrospective analysis was conducted on patients who underwent PD at a tertiary hospital between October 2012 and October 2017. The incidence of CR-IC, clinically relevant POPF and other complications, as well as mortality and length of hospitalisation, was retrieved. The impact of CR-IR on mortality and major complications was analysed. The serum CRP levels were retrieved on the third and fifth postoperative days (POD3 and POD5), followed by an analysis of sensitivity, specificity, and area under the curve to predict CR-IC using CRP. RESULTS: One hundred forty patients were enrolled following inclusion and exclusion criteria. The mean age was 66.5 years (15-83). The incidence of CR-IC was 33.7% (47), and CR-POPF was 24.3%. Pancreatic duct diameter ≤ 4 mm was identified as a risk factor related to CR-IC occurrence. The group of patients who developed CR-IC after PD exhibited a higher rate of complications Clavien-Dindo ≥ III compared to patients without CR-IC (40.4% vs 7.5%, p < 0.001), as well as other events such as admission to the intensive care unit (25.5% vs 4.3%, p < 0.001), the incidence of CR-POPF (66% vs 3.2%, p < 0.001), prolonged hospital stay (32 vs 13 days, p < 0.001), postoperative haemorrhage (23.4 vs 5.4%, p = 0.002), and delayed gastric empty (38.8% vs 11.8%, p < 0.001) respectively. Logistic regression analysis identified CR-IC related to POPF as a risk factor for Clavien-Dindo > III: OR = 10.6 (95% CI: 3.90-28.7). No differences in mortality were reported between the CR-IC group and non-CR-IC group. CRP at postoperative day 3 (POD3) > 17.55 mg/dl and CRP at postoperative day 5 (POD5) > 13.46 mg/dl were predictors of CR-IC (AUC: 0.731 and AUC:0.821, respectively). CONCLUSIONS: CR-IC has a significant impact after pancreaticoduodenectomy and is associated with a higher incidence of Clavien-Dindo ≥ III complications. Additionally, CRP levels at POD3 and POD5 play a role in predicting CR-IC. Prospective studies are essential to explore strategies for mitigating the occurrence of CR-IC after PD.

Epidemiology of human papillomavirus-associated anogenital cancers in Granada: a three-decade population-based study.

Introduction: HPV infection is a common risk factor for all anogenital cancers. However, there are important differences in the epidemiology of anogenital cancers and these have not been compared considering diverse epidemiological indicators over a long period of time. To fill this gap, we investigated incidence, mortality, and survival trends of anogenital cancers over a period of three decades. Methods: We conducted an observational registry-based study using data from the population-based cancer registry of Granada in southern Spain. We collected data on all incident cases of anogenital cancer (cervical, anal, penile, vulvar, and vaginal cancer) diagnosed between 1985 and 2017. We calculated crude and age-standardized incidence and mortality rates, and 1, 3, and 5-year overall and net survival. We further conducted time-trend analysis calculating annual percent changes (APC) for each cancer site. Results: The incidence of anogenital cancers decreased slightly during the past 30 years, with the exception of vulvar cancer, where a slight increase was observed. Mortality decreased significantly for cervical cancer over the study period but increased non-significantly for the remaining cancer sites. Survival rates were similar to those reported in comparable countries and increased for cervical and vulvar cancer. Discussion: Cervical cancer was the greatest contributor to the burden of anogenital cancers and showed a marked improvement in all indicators in comparison to the remaining cancer sites.

Clinical and anatomical analysis of the epileptogenic spread patterns in focal cortical dysplasia patients.

Background: Focal cortical dysplasia (FCD) is one of the main causes of intractable epilepsy, which is amendable by surgery. During the surgical management of FCD, the understanding of its epileptogenic foci, interconnections, and spreading pathways is crucial for attaining a good postoperative seizure free outcome. Methods: We retrospectively evaluated 54 FCD patients operated in Federal Center of Neurosurgery, Tyumen, Russia. The electroencephalogram findings were correlated to the involved brain anatomical areas. Subsequently, we analyzed the main white matter tracts implicated during the epileptogenic spreading in some representative cases. We prepared 10 human hemispheres using Klinger's method and dissected them through the fiber dissection technique. Results: The clinical results were displayed and the main white matter tracts implicated in the seizure spread were described in 10 patients. Respective FCD foci, interconnections, and ectopic epileptogenic areas in each patient were discussed. Conclusion: A strong understanding of the main implicated tracts in epileptogenic spread in FCD patient remains cardinal for neurosurgeons dealing with epilepsy. To achieve meaningful seizure freedom, despite the focal lesion resection, the interconnections and tracts should be understood and somehow disconnected to stop the spreading.

The influence of peri-operative depressive symptoms on medium-term spine surgery outcome: a prospective study.

PURPOSE: To investigate the role of depressive symptoms on clinical outcomes in patients undergoing spinal surgery up to 2-year follow-up. METHODS: The study used data from an institutional spine surgery registry (January 2016, through March 2022) to identify patients (> 18 years) undergoing spine surgery. Patients with Oswestry Disability Index (ODI) < 20/100 at baseline or undergoing surgery on the cervical spine or for idiopathic spinal deformity and trauma patients were excluded. The patients were divided into two groups based on the pre-operative Mental Component Summary (MCS) score of the SF-36: depression group (MCS ≤ 35) or non-depression group (MCS > 35). The ODI and MCS scores trajectory were wined over the 24-month post-surgery between groups. Additionally, a secondary subgroup analysis was conducted comparing outcomes between those with depressive symptoms (persistent-depression subgroup) and those without depressive symptoms (never-depression subgroup) at 3 months after surgery. RESULTS: A total of 2164 patients who underwent spine surgery were included. The pre-operative depression group reported higher ODI total scores and lower MCS than the pre-operative non-depression group at all time points (P < 0.001). The persistent-depression subgroup reported higher ODI total scores and lower MCS than the never-depression subgroup at all follow-ups (P < 0.001). CONCLUSION: Functional disability and mental health status improve in patients with depression symptoms undergoing spinal surgery. Despite this improvement, they do not reach the values of non-depressed subjects. Over the 2-year follow-up time, patients with depression show a different trajectory of ODI and MCS. Caregivers should be aware of these results to counsel patients with depression symptoms.

Serological response to SARS-COV-2 vaccines in patients with multiple sclerosis in Argentina / Respuesta serológica a vacunas contra SARS-CoV-2 en pacientes con esclerosis múltiple en Argentina

Abstract Introduction : The objective was to assess the im munogenicity and effectiveness of vaccines against SARSCoV-2 in multiple sclerosis (MS) patients included in the Argentinean MS registry. Methods : A prospective cohort study between May and December 2021. The primary outcome was im munogenicity and effectiveness of vaccines during a three-month follow-up. Immunogenicity was evalua ted based on detection of total antibodies (Ab) against spike protein and neutralizing Ab in serum 4 weeks after the second vaccine dose. A positive COVID-19 case was defined according to Argentinean Ministry of Health. Results : 94 patients were included, mean age: 41.7 ± 12.1 years. Eighty (85.1%) had relapsing remitting mul tiple sclerosis (RRMS); 30 (31.9%) were under fingolimod treatment. The Sputnik V vaccine was the first dose in 33 (35.1%), and AstraZeneca in 61 (64.9%). In 60 (63.8%), the vaccine elicited a specific humoral response. Immu nological response according to the vaccination schemes showed no qualitative differences (p = 0.45). Stratified analysis according to the MS treatment showed that a significantly smaller number of subjects developed anti bodies against spike antigen among those that were on ocrelizumab compared to other groups (p ≤ 0.001), while a reduced number of patients under ocrelizumab where evaluated (n = 7). This was also observed for neutralizing antibodies in the ocrelizumab group (p < 0.001). During the three-month follow-up, two individuals were diag nosed with COVID-19. Conclusion: We found that MS patients that recei ved Sputnik V or AstraZeneca vaccines for SARS-CoV-2 developed a serological response with no differences between the vaccines used.

Resumen Introducción : El objetivo fue evaluar la inmunogeni cidad y efectividad de las vacunas contra el SARS-CoV-2 en pacientes con esclerosis múltiple (EM) incluidos en el registro argentino de EM (RelevarEM, NCT 03375177). Métodos : Estudio de cohorte prospectivo entre mayo y diciembre 2021. Se evaluó la inmunogenicidad (detec ción de anticuerpos totales (Ab) contra proteína espiga y anticuerpos neutralizantes en suero) y eficacia (nueva infección por COVID-19) durante seguimiento de tres meses. El momento de detección de anticuerpos fue 4 semanas después de segunda dosis de vacuna. Un caso positivo de COVID-19 se definió de acuerdo con la defi nición del Ministerio de Salud. Resultados : Se incluyeron 94 pacientes, edad media de 41.7 ± 12.1 años. Ochenta (85.1%) tenían EM remiten te-recurrente; 30 (31.9%) en tratamiento con fingolimod. La vacuna Sputnik V fue usada en 33 (35.1%), mientras que AstraZeneca se administró en 61 (64.9%). En 60 pa cientes (63.8 %), la vacuna provocó respuesta humoral específica. La respuesta inmunológica según esquemas de vacunación (Sputnik V, Astra Zeneca o esquemas he terólogos) no mostró diferencias cualitativas (p = 0.45). El análisis estratificado según tratamiento recibido para la EM mostró que número significativamente menor de sujetos desarrolló anticuerpos contra el antígeno espiga en los pacientes que recibieron ocrelizumab (p ≤ 0.001), aunque con un número reducido de pacientes evaluados bajo este tratamiento (n = 7). Esto también se observó para anticuerpos neutralizantes en el grupo bajo ocrelizumab (p < 0.001). Durante el seguimiento de tres meses, dos personas fueron diagnosticadas con COVID-19. Conclusión : Encontramos que los pacientes con EM que recibieron vacunas Sputnik V o AstraZeneca para el SARS-CoV-2 desarrollaron respuesta serológica sin diferencias entre las vacunas utilizadas.

Ribosomal S6 kinase 4 (RSK4) tumor suppressor gene promoter methylation status in ovarian cancer.

BACKGROUND: Previously, we reported lower RSK4 mRNA and protein levels in malignant ovarian tumors compared to normal and benign ovarian tissues. Also, we observed a significant inverse correlation between the advanced ovarian cancer stages and RSK4 mRNA levels. We did not investigate the mechanisms involved in RSK4-reduced expression in ovarian cancer. Thus, this study investigates whether RSK4 promoter methylation in ovarian cancer tissues is responsible for its low expression. Additionally, the reactivation of RSK4 expression and its effect was studied in ovarian cancer cell lines. METHODS AND RESULTS: RSK4 promoter methylation percentage in malignant and benign ovarian tumors and normal ovary tissues was determined by combined bisulfite restriction analysis. The reactivation of RSK4 expression by decitabine treatment was studied in OVCAR3, SKOV3, TOV-112D, and TOV-21G cells by Western blotting. Cell proliferation was determined by XTT. A significantly high methylation percentage of the RSK4 promoter was observed among malignant and benign ovarian tumors but not in normal ovarian tissue. RSK4 promoter methylation was not associated with age, histological subtype, or stages of ovarian cancer. RSK4 promoter methylation correlates weakly but not significantly with RSK4 protein expression. No correlation was shown between RSK4 methylation and RSK4 mRNA expression. Decitabine induces RSK4 reactivation in all cell lines. However, cell proliferation was reduced only in TOV-112D cells. CONCLUSION: These data indicate that although RSK4 promoter methylation is increased in malignant ovarian tumors, this mechanism is unlikely to regulate its expression in ovarian cancer. RSK4 reactivation reduced cell proliferation only in the endometroid histological subtype.