Cladribine use trend in Latin America: the changes in patient profile impact in the drug effectiveness.

INTRODUCTION: Cladribine was approved for Multiple Sclerosis (MS) in our country in 2018. A previous study by our group showed that its use among high efficacy therapies options has been increasing along the years. OBJECTIVE: to analyze the cladribine use trend across time since its approval. METHOD: A retrospective cohort study was performed. People with MS (pwMS) treated with cladribine were included. Two periods were defined: P1 = 2018 - 2020 and P2 = 2021 - 2023. A comparative analysis was carry out between P1 and P2 to assess the trend of use, clinical/demographic characteristics, and effectiveness. RESULTS: One hundred ninety- seven people with MS (pwMS) were included, mean EDSS: 2.2 ± 3.08, 72.6% female, mean age: 35.2 ± 9 years, mean disease duration: 6.6 ± 5.6 years, mean time lapse under cladribine: 26.1 ± 12.4 months. Regarding patient profile, we found significant differences between P1 and P2 in the MS evolution (p = 0.001) and EDSS ( p = 0.018) prior to initiation of cladribine. In the individualized analysis by year, we found a decrease in relapse number in the year prior to starting cladribine (p = 0.02). A higher proportion of No Evidence of Disease Activity (NEDA) was found in patients treated at P2 compared to those treated at P1 (p < 0.001). CONCLUSION: An earlier use of cladribine achieved a significant increase in reaching NEDA. This learning curve in the use of cladribine allows a better identification of the candidate patient and influences the treatment effectiveness.

Do immunosuppressive treatments influence immune responses against adenovirus-based COVID-19 vaccines in patients with multiple sclerosis? An Argentine multicenter study.

Introduction: There are no reports in LATAM related to longitudinal humoral and cellular response to adenovirus based COVID-19 vaccines in people with Multiple Sclerosis (pwMS) under different disease modifying therapies (DMTs) and neutralization of the Omicron and Wuhan variants of SARS-COV-2. Methods: IgG anti- SARS-COV-2 spike titer were measured in a cohort of 101 pwMS under fingolimod, dimethyl fumarate, cladribine and antiCD20, as well as 28 healthy controls (HC) were measured 6 weeks after vaccination with 2nd dose (Sputnik V or AZD1222) and 3nd dose (homologous or heterologous schedule). Neutralizing capacity was against Omicron (BA.1) and Wuhan (D614G) variants and pseudotyped particles and Cellular response were analyzed. Results: Multivariate regression analysis showed anti-cd20 (ß= -,349, 95% CI: -3655.6 - -369.01, p=0.017) and fingolimod (ß=-,399, 95% CI: -3363.8 - -250.9, p=0.023) treatments as an independent factor associated with low antibody response (r2 adjusted=0.157). After the 2nd dose we found a correlation between total and neutralizing titers against D614G (rho=0.6; p<0.001; slope 0.8, 95%CI:0.4-1.3), with no differences between DMTs. Neutralization capacity was lower for BA.1 (slope 0.3, 95%CI:0.1-0.4). After the 3rd dose, neutralization of BA.1 improved (slope: 0.9 95%CI:0.6-1.2), without differences between DMTs. A fraction of pwMS generated anti-Spike CD4+ and CD8+ T cell response. In contrast, pwMS under antiCD20 generated CD8+TNF+IL2+ response without differences with HC, even in the absence of humoral response. The 3rd dose significantly increased the neutralization against the Omicron, as observed in the immunocompetent population. Discussion: Findings regarding humoral and cellular response are consistent with previous reports.

Application of the international criteria for optic neuritis in the Acute Optic Neuritis Network.

OBJECTIVE: The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON). METHODS: We included 160 patients with a first-ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present. RESULTS: According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody-associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%). INTERPRETATION: According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.

Strain fingerprinting of exciton valley character in 2D semiconductors.

Intervalley excitons with electron and hole wavefunctions residing in different valleys determine the long-range transport and dynamics observed in many semiconductors. However, these excitons with vanishing oscillator strength do not directly couple to light and, hence, remain largely unstudied. Here, we develop a simple nanomechanical technique to control the energy hierarchy of valleys via their contrasting response to mechanical strain. We use our technique to discover previously inaccessible intervalley excitons associated with K, Γ, or Q valleys in prototypical 2D semiconductors WSe2 and WS2. We also demonstrate a new brightening mechanism, rendering an otherwise "dark" intervalley exciton visible via strain-controlled hybridization with an intravalley exciton. Moreover, we classify various localized excitons from their distinct strain response and achieve large tuning of their energy. Overall, our valley engineering approach establishes a new way to identify intervalley excitons and control their interactions in a diverse class of 2D systems.

Endoscopic approaches to the posterior wall of the third ventricle: An anatomical comparison.

INTRODUCTION: Surgery of lesions in the posterior wall of the third ventricle requires great expertise due to its deep location and important surrounding structures. This region has been traditionally reached through a supracerebellar infratentorial approach, but new options have emerged, especially with the development of neuroendoscopy. METHODS: One formalin-fixed cadaver human head was dissected. Five different endoscopic approaches were performed: interhemispheric transcallosal transchoroidal, frontal transforaminal transchoroidal, supraorbital subfrontal translamina terminalis, expanded endonasal, and supracerebellar infratentorial. An anatomical description of the different approaches was conducted and quantitative measurements (craniocaudal and latero-lateral distances) were taken using the StealthStation ® workstation after performing a CT scan of the specimen. RESULTS: The interhemispheric transcallosal transchoroidal, frontal transforaminal transchoroidal, and supraorbital subfrontal translamina terminalis approaches provided great view of all the structures of the posterior wall of the third ventricle. Maximum craniocaudal distance was obtained through the supraorbital subfrontal translamina terminalis approach (10.6 mm), with great difference from the expanded endonasal approach (5.2 mm). The widest latero-lateral distance from inside the third ventricle was achieved through the interhemispheric transcallosal transchoroidal approach (4.6 mm), similar to the expanded endonasal (4.1 mm), and differing from the supraorbital subfrontal translamina terminalis (2.4 mm). CONCLUSIONS: The endoscopic approaches provided an adequate alternative to more traditional microsurgical approaches to the posterior wall of the third ventricle, with a great view of all its structures. The selection of the approach must be taken under consideration in each case.

HIV-1 Integrase T218I/S Polymorphisms Do Not Reduce HIV-1 Integrase Inhibitors' Phenotypic Susceptibility.

The recently Food and Drug Administration (FDA)-approved cabotegravir (CAB) has demonstrated efficacy as an antiretroviral agent for HIV treatment and prevention, becoming an important tool to stop the epidemic in the United States of America (USA). However, the effectiveness of CAB can be compromised by the presence of specific integrase natural polymorphisms, including T97A, L74M, M50I, S119P, and E157Q, particularly when coupled with the primary drug-resistance mutations G140S and Q148H. CAB's recent approval as a pre-exposure prophylaxis (PrEP) may increase the number of individuals taking CAB, which, at the same time, could increase the number of epidemiological implications. In this context, where resistance mutations, natural polymorphisms, and the lack of drug-susceptibility studies prevail, it becomes imperative to comprehensively investigate concerns related to the use of CAB. We used molecular and cell-based assays to assess the impact of T218I and T218S in the context of major resistance mutations G140S/Q148H on infectivity, integration, and resistance to CAB. Our findings revealed that T218I and T218S, either individually or in combination with G140S/Q148H, did not significantly affect infectivity, integration, or resistance to CAB. Notably, these polymorphisms also exhibited neutrality concerning other widely used integrase inhibitors, namely raltegravir, elvitegravir, and dolutegravir. Thus, our study suggests that the T218I and T218S natural polymorphisms are unlikely to undermine the effectiveness of CAB as a treatment and PrEP strategy.

Impact of Pulsatile Machine Perfusion on Posttransplant Recovery in Asystole Donation: Organ Optimization and the Future of Renal Transplantation.

OBJECTIVES: With the increase in life expectancy and the aging of the population, chronic kidney disease has become increasingly prevalent in our environment. Kidney transplantation remains the gold standard treatment for end-stage renal disease, but the supply of renal grafts has not been able to keep pace with growing demand. Because of this rationale, organ selection criteria have been extended (expanded criteria donation), and alternative donation types, such as donation after circulatory death, have been evaluated. These approaches aim to increase the pool of potential donors, albeit with organs of potentially lower quality. Various forms of donations, including donation after circulatory death, have also undergone assessment. This approach aims to augment the pool of potential donors, notwithstanding the compromised quality of organs associated with such methods. Diverse strategies have been explored to enhance graft function, with one of the most promising being the utilization of pulsatile machine perfusion. MATERIALS AND METHODS: We conducted a retrospective analysis on 28 transplant recipients who met the inclusion criterion of sharing the same donor, wherein one organ was preserved by cold storage and the other by pulsatile machine perfusion. We performed statistical analysis on posttransplant recovery parameters throughout the patients' hospitalization, including admission and discharge phases. RESULTS: Statistically significant differences were noted in delayed graft function (P = .04), blood transfusions requirements, and Clavien-Dindo complications. Furthermore, an overall trend of improvement in discharge parameters and hospital stay was in favor of the pulsatile machine perfusion group. CONCLUSIONS: The use of pulsatile machine perfusion as a method of renal preservation results in graft optimization, leading to earlier recovery and fewer complications compared with cold storage in the context of donation after circulatory death.

MAGinator enables accurate profiling of de novo MAGs with strain-level phylogenies.

Metagenomic sequencing has provided great advantages in the characterisation of microbiomes, but currently available analysis tools lack the ability to combine subspecies-level taxonomic resolution and accurate abundance estimation with functional profiling of assembled genomes. To define the microbiome and its associations with human health, improved tools are needed to enable comprehensive understanding of the microbial composition and elucidation of the phylogenetic and functional relationships between the microbes. Here, we present MAGinator, a freely available tool, tailored for profiling of shotgun metagenomics datasets. MAGinator provides de novo identification of subspecies-level microbes and accurate abundance estimates of metagenome-assembled genomes (MAGs). MAGinator utilises the information from both gene- and contig-based methods yielding insight into both taxonomic profiles and the origin of genes and genetic content, used for inference of functional content of each sample by host organism. Additionally, MAGinator facilitates the reconstruction of phylogenetic relationships between the MAGs, providing a framework to identify clade-level differences.

Psychometric properties of the arabic version of occupational value with pre-defined ítems.

BACKGROUND: Perceived occupational value is closely linked with well-being and there is need worldwide for assessment tools that target this phenomenon. The Occupational Value with pre-defined items (OVal-pd), measuring three dimensions of occupational value; concrete, socio-symbolic and self-rewarding, was designed for that purpose. AIM: To pilot an Arabic version of OVal-pd and evaluate its psychometric properties in terms of content validity, factor structure, homogeneity, construct validity, test-retest stability, floor and ceiling effects, and measurement error. METHODS: Snowball sampling was used to recruit Arabic-speaking persons living in Sweden (n = 55). They completed the OVal-pd and questionnaires addressing background factors, content validity and feasibility. Confirmatory factor analysis, Spearman's rank correlation, Cronbach's α, intraclass correlation coefficients, and minimum detectable change were calculated. RESULTS: A 22-item version of the Arabic OVal-pd was found to have acceptable content validity and feasibility and the proposed three occupational value dimensions were confirmed. Good properties in terms of construct validity, internal consistency and test-retest stability were also established. No floor or ceiling effects were observed. CONCLUSION: The Arabic OVal-pd showed good validity and reliability on various psychometric aspects. SIGNIFICANCE: In today's multicultural societies, the Arabic OVal-pd can be an important tool for occupational therapists working with Arabic-speaking clients.

Clinical effectiveness of dimethyl fumarate in multiple sclerosis patients from Argentina.

BACKGROUND: We assessed the effectiveness, safety and patient-reported outcomes (PROs) of dimethyl fumarate (DMF) in real-world clinical practice in patients with multiple sclerosis (PwMS) from Argentina. METHODS: We conducted a multicenter ambispective cohort study in Argentina between September 2020 and March 2023. Changes in annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, magnetic resonance imaging (MRI), no evidence of disease activity (NEDA), PROs (depression, anxiety, fatigue, burden of treatment and quality of life), and safety data were collected at clinical visits performed every 6 months for at least 24 months. RESULTS: We included 161 PwMS (64% female). DMF treatment was associated with a significant reduction in ARR from baseline after 24 months of treatment (from 0.87 to 0.23, p < 0.001). Disability progression was observed in 27.9% vs. 9.3% pre- and post-DMF, and disability improvement was found in 13% of patients from baseline to month 24. MRI activity was significantly reduced compared with baseline. Fatigue, depression, and quality of life scores were significantly improved from baseline to 24 months. Flushing was the most frequent adverse event reported in 19.2%. No significant reduction was observed in the hospitalization rate pre- and post-DMF (19.8% vs. 5.6%, p = 0.32). During follow-up, 135 (83%) patients were relapse-free, 110 (68.3%) were MRI free activity (Gad + lesion) and 108 (67%) reached NEDA. CONCLUSIONS: DMF significantly reduced disease activity in PwMS from Argentina with a good safety profile in real-world settings. A significant impact on the quality of life during follow-up was found.

Poorly Controlled New-Onset Diabetes Mellitus and Other Atypical Signs as an Early Sign of Pancreatic Adenocarcinoma.

A 50-year-old man presented with poorly controlled new-onset diabetes mellitus. Six months after diagnosis, episodes of intense abdominal pain with vomiting appeared. Abdominal CT revealed signs of acute pancreatitis with structural changes in the pseudocysts. In the absence of biliary lithiasis or a toxic etiology of acute pancreatitis, the patient progressed unfavorably with increased abdominal pain and fever. Control imaging tests (two and 10 months later) showed the evolution of phlegmonous/necrotic collections, together with portal vein thrombosis and splenomegaly. Given the suggestive signs of possible occult malignancy, such as portal thrombosis, histological analysis of the ascitic fluid revealed a pancreatic adenocarcinoma. Despite the initiation of chemotherapy, the patient died 12 months after diagnosis.

Traditional first-line treatment failure rates in neuromyelitis optica spectrum disorder patients included in the Argentinean registry (RelevarEM).

BACKGROUND: Immunosuppressive therapies as azathioprine (AZA), mycophenolate mofetil (MMF) and rituximab (RTX) are widely prescribed as first-line treatment to prevent relapses in NMOSD. However, the rate of response to these traditional therapies is unknown in Argentina. We aimed to describe and compare treatment failure rates in NMOSD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). METHODS: A retrospective cohort study was conducted in NMOSD patients included in RelevarEM (a nationwide, longitudinal, observational, non-mandatory registry of MS and NMOSD in Argentina). NMOSD patients were defined based on validate diagnostic criteria. Only NMOSD patients who received AZA or MMF for at least 6 months or RTX for at least 1 month were included. Patients who were receiving AZA, MMF, or RTX and then switched to another 1 of these 3 therapies were included if the above-mentioned criteria for each drug were fulfilled. Data on patient demographics, clinical, neuroradiological findings, and treatments administered were collected. Treatment failure was defined as any new attack/relapse that occurred despite immunosuppressive treatment. RESULTS: We included 139 NMOSD patients who were receiving AZA (n = 105), MMF (n = 5) or RTX (n = 29) with a mean follow-up time of 41.3 ± 11.4 months and median of EDSS at treatment initiation of 3. We observed a reduction in the annualized relapse rate from pre-treatment to post-treatment of 51.1 %, 48.4 %, and 79.1 % respectively with a Hazard Risk relative to RTX (95 % CI) of 1.67 (1.34-3.54, p = 0.01) for AZA and 2.01 (1.86-4.43, p = 0.008) for MMF. AZA, MMF and RTX failure was observed in 45/105 (42.8 %), 2/5 (40 %) and 3/29 (10.3 %) patients, respectively. CONCLUSIONS: Treatment failure rates were higher for AZA and MMF than RTX in Argentinean NMOSD patients in a real-world setting. High-efficacy treatment increases the opportunity to prevent attacks of NMOSD.

Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

OBJECTIVE: The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. METHODS: This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/µL; grade 2: ALC 500-799/µL; grade 3: ALC 200-499/µL and grade 4: ALC <200/µL. RESULTS: A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 ( P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). CONCLUSION: This information will help when choosing the best treatment option for Argentinean patients.

Smoking and Health-Related Quality of Life in Patients With Multiple Sclerosis From Latin America.

BACKGROUND: Tobacco smoking is an important, modifiable, environmental risk factor for multiple sclerosis (MS) with a relevant impact on health-related quality of life (HRQOL). We aimed to assess the use of tobacco in individuals with MS from Latin America (LATAM), and its impact on HRQOL. METHODS: We conducted a cross-sectional study based on a LATAM web-based survey. Demographics, social and clinical data, information on physical disability, and HRQOL scores were collected using the MS Impact Scale-29 (MSIS-29), the Fatigue Severity Scale (FSS), and the Hospital Anxiety and Depression Scale-Anxiety (HADS-A). Individuals with MS were classified at the time of the survey as follows: never-smokers (ie, patients who reported they had never smoked), past smokers (those who had smoked tobacco but not during the past year), or current smokers. For the analysis, groups were compared. RESULTS: 425 patients (74.6% female) from 17 LATAM countries were included, mean age 43.6 ± 11 years and median Expanded Disability Status Scale score 2. There were 122 (28.7%) current smokers, 178 (41.9%) past smokers, and 125 (30.4%) never-smokers. Current smokers had significantly higher MSIS-29 physical (physical worsening), FSS (fatigue), and HADS-A (anxiety) scores compared with past and never-smokers after being adjusted for covariables. No significant differences were observed in any of the other analyzed demographic, clinical, and therapeutic variables. Thirty percent of the current and past smokers groups had never had their neurologists discuss smoking cessation with them. CONCLUSIONS: Individuals with MS who were current smokers had higher fatigue and anxiety scores and worse HRQOL compared with past and never-smokers.

Phenotypic relationships between meat quality parameters and residual feed intake in Japanese black Wagyu cattle.

Japanese black Wagyu cattle are renowned for producing some of the world's most highly valued and recognized beef with exceptional marbling. Therefore, the primary focus of genetic selection for Wagyu cattle has historically been on meat quality, particularly achieving high marbling levels. However, even when the price of the final product is high, production costs also remain high, especially considering that most of the feed has to be imported. The objective of this study was to evaluate phenotypic relationships between feed efficiency, specifically residual feed intake (RFI), as the most utilized efficiency index in cattle, and various meat quality parameters in Japanese black cattle in order to determine if a common phenotypic selection for these parameters could be feasible. For this, a total of 39 Wagyu cattle were evaluated for feed efficiency over their entire fattening period (900 d), with a focus on RFI as a key indicator. Animals were fed high-starch diets with vitamin A deprivation to achieve the desired marbling. Results revealed positive correlations between feed efficiency and meat quality in Wagyu cattle. Specifically, animals with higher feed efficiency exhibited superior meat quality traits, including firmness, marbling, and overall meat rating. When comparing the 20 most extreme RFI individuals (10 most and 10 least efficient), we observed that efficient RFI animals showed increased marbling levels (+13.2%, P = 0.05) and ranking quality (+12%, P = 0.06) of the meat. In conclusion, this research contributes to understanding the interplay between feed efficiency and meat quality in Japanese black Wagyu cattle. Phenotypic correlations observed suggest the possibility of incorporating RFI criteria into genetic selection programs without compromising the prized meat quality traits of Wagyu beef.

The Japanese black cattle, or Wagyu, are known because of its exceptional meat quality and its high degree of marbling. However, to achieve this condition, animals are fed with high amount of concentrate and over long periods of time. In order to decrease both environmental impact and economic profitability of Wagyu producers, feed efficiency may be improved. Therefore, the present work evaluates the phenotypic relationship between meat quality variables of Japanese black cattle and their efficiency of feed utilization. Results showed how individuals with improved efficiency of feed utilization present higher degree of marbling than non-efficient, which may represent the footprint of a new genetic selection program which encompasses both meat quality criteria and feed efficiency values. These results have to be confirmed by genetic studies to verify heritability of these treatments.

Treatment strategies and responses for attacks of neuromyelitis optica spectrum disorder: A real-world retrospective cohort study.

We aimed to assess the treatment strategies utilized in patients with neuromyelitis optica spectrum disorder (NMOSD) experiencing relapses, including their frequency, types, and response after 6 months based on the Expanded Disability Status Scale (EDSS) score. METHODS: We conducted a retrospective study involving NMOSD patients from the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). Treatment response at 6 months was categorized as "good" if the EDSS score decreased by ≥1 point after a nadir EDSS score ≤ 3, or by ≥2 points after a nadir EDSS score > 3, "poor" if the EDSS score decrease was slighter, and as "absent" if the EDSS score remained unchanged or worsened. RESULTS: We included 120 NMOSD patients (seropositive N = 75), who experienced 250 NMOSD-related relapses and received 248 treatments. At 6 months, complete recovery was achieved in 70/98 (71.4%) and 15/19 (79%) patients, respectively. Predictors of a "good" response in our regression model were a younger age at disease onset (OR:3.54, CI95% 2.45-5.01, p < 0.0001) and a short delay from onset of relapse to treatment initiation (OR:1.56, CI95% 1.22-2.13, p = 0.004). CONCLUSIONS: Approximately two-thirds of patients experienced complete recovery, and younger age and a short delay to start treatment were independent predictors of a "good" response.

Placebo and nocebo effects of percutaneous needle electrolysis and dry-needling: an intra and inter-treatment sessions analysis of a three-arm randomized double-blinded controlled trial in patients with patellar tendinopathy.

Objective: This study aimed to investigate the influence of potential placebo and nocebo effects on pain perception of percutaneous needle electrolysis (PNE) in individuals with patellar tendinopathy. Methods: In this secondary analysis of a three-arm randomized double-blinded controlled trial, intra and inter-session pain perception data from 48 sporting participants with patellar tendinopathy between 18 and 45 years were investigated. Participants were divided into 3 parallel groups: "no-sham group" [PNE intervention], "single-sham group" [sham PNE by using dry needling], and "double-sham group" [sham PNE by using sham needles]. Every group received 4 sessions of the needling therapies targeting the patellar tendon over 8 weeks and was instructed to perform a unilateral eccentric exercise program of the quadriceps muscle on the affected side. Clinical and needle-related pain was assessed before, during, and after each treatment session using a visual analog scale. Results: No differences were found between groups intra- or inter-session in terms of pain reduction (P = 0.424) despite clinical pain decreased in all groups since the first treatment session (P < 0.001). Furthermore, although the double-sham group showed a lower percentage of participants reporting needle-related pain during needle intervention (P = 0.005), the needle-related pain intensity after needle intervention was similar between groups (P = 0.682). Moreover, there were no group differences for the duration of pain sensation after any needle intervention (P = 0.184), extending in many cases beyond 24 h. Conclusion: Needling therapies for individuals with patellar tendinopathy are prone to elicit placebo effects regarding clinical pain and nocebo effects regarding needling-related pain. Clinicians and physical therapists treating musculoskeletal pain conditions should consider the added value and potential mechanisms of action before routinely using needle techniques.

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.

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.

Multimodal sensorimotor assessment of hand and forearm asymmetries: a reliability and correlational study.

Background: Effective rehabilitation of upper limb musculoskeletal disorders requires multimodal assessment to guide clinicians' decision-making. Furthermore, a comprehensive assessment must include reliable tests. Nevertheless, the interrelationship among various upper limb tests remains unclear. This study aimed to evaluate the reliability of easily applicable upper extremity assessments, including absolute values and asymmetries of muscle mechanical properties, pressure pain threshold, active range of motion, maximal isometric strength, and manual dexterity. A secondary aim was to explore correlations between different assessment procedures to determine their interrelationship. Methods: Thirty healthy subjects participated in two experimental sessions with 1 week between sessions. Measurements involved using a digital myotonometer, algometer, inclinometer, dynamometer, and the Nine-Hole Peg test. Intraclass correlation coefficients, standard error of the mean, and minimum detectable change were calculated as reliability indicators. Pearson's correlation was used to assess the interrelationship between tests. Results: For the absolute values of the dominant and nondominant sides, reliability was 'good' to 'excellent' for muscle mechanical properties, pressure pain thresholds, active range of motion, maximal isometric strength, and manual dexterity. Similarly, the reliability for asymmetries ranged from 'moderate' to 'excellent' across the same parameters. Faster performance in the second session was consistently found for the Nine-Hole Peg test. No systematic inter-session errors were identified for the values of the asymmetries. No significant correlations were found between tests, indicating test independence. Conclusion: These findings indicate that the sensorimotor battery of tests is reliable, while monitoring asymmetry changes may offer a more conservative approach to effectively tracking recovery of upper extremity injuries.