Predictive potential of serum and cerebrospinal fluid biomarkers for disease activity in treated multiple sclerosis patients.

BACKGROUND: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS). METHODS: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile. RESULTS: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35-5.4) and 2.67 (CI: 1.32-5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5-6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51-6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models. DISCUSSION: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi.

Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients.

BACKGROUND: Calcitriol, the active form of vitamin D (also known as 1,25-dihydroxycholecalciferol), improves the phenotype and increases frataxin levels in cell models of Friedreich ataxia (FRDA). OBJECTIVES: Based on these results, we aimed measuring the effects of a calcitriol dose of 0.25 mcg/24h in the neurological function and frataxin levels when administered to FRDA patients for a year. METHODS: 20 FRDA patients where recluted and 15 patients completed the treatment for a year. Evaluations of neurological function changes (SARA scale, 9-HPT, 8-MWT, PATA test) and quality of life (Barthel Scale and Short Form (36) Health Survey [SF-36] quality of life questionnaire) were performed. Frataxin amounts were measured in isolated platelets obtained from these FRDA patients, from heterozygous FRDA carriers (relatives of the FA patients) and from non-heterozygous sex and age matched controls. RESULTS: Although the patients did not experience any observable neurological improvement, there was a statistically significant increase in frataxin levels from initial values, 5.5 to 7.0 pg/µg after 12 months. Differences in frataxin levels referred to total protein levels were observed among sex- and age-matched controls (18.1 pg/µg), relative controls (10.1 pg/µg), and FRDA patients (5.7 pg/µg). The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial. CONCLUSIONS: Calcitriol dosage used (0.25 mcg/24 h) is safe for FRDA patients, and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Bibliometric analysis of equity in transportation.

This paper aims to map the research landscape in equity and justice in transport and mobility, identifying key publications, authors, institutions, and interdisciplinary connections to inform future research and policy development. A systematic search of scientific articles on equity and justice in transport and mobility was conducted in the Web of Science, resulting in 759 selected articles that were analyzed using bibliometric and network analysis methods. The analysis reveals a growing trend in scientific production since 2013, with the Journal of Transport Geography, Transport Research Part A: Policy and Practice, and the Journal of Transport Policy being the most prominent journals. The most influential authors and institutions are identified, along with the most cited works. Keyword usage trends and thematic analysis show a shift in focus from environmental equity to urban transport, congestion, and accessibility. Cluster analyses highlight focal points and themes, such as accessibility, mobility, social aspects, transport and spatial equity, environmental justice, transport planning, active transport, and methodological evaluations. Co-citation networks reveal three major clusters with differing research focuses: Lukas K. & Martens K.; Litman T. and Currie, G., and Scwanen T. and Cresswell, T. The findings contribute to a better understanding of the existing knowledge in equity and justice in transport and mobility, enabling researchers and policymakers to identify areas requiring further exploration. Additionally, the paper fosters interdisciplinary connections and sets priorities for future research and policy development.

Improving the efficiency of free kappa light chains as diagnostic biomarker of Multiple Sclerosis by using a novel algorithm.

BACKGROUND: Intrathecal immunoglobulin synthesis (ITS) plays a crucial role in the diagnosis of multiple sclerosis (MS). Traditionally, the gold standard method for detecting ITS has been through the analysis of oligoclonal bands (OCB). However, the paradigm has shifted with the introduction of the free kappa light chains (FKLC) method. In fact, a recent consensus recommends evaluating FKLC index (FKLCi) as the primary approach and reserving oligoclonal bands with borderline results. The objective of our study is to investigate the diagnostic efficiency of combining FKLC with other methods to predict ITS while minimizing the reliance on OCB. METHODS: A total of 192 patients were included in the study, consisting of 145 individuals diagnosed with multiple sclerosis (pwMS) and 46 with other neurological diseases (controls). Among the MS cases, 100 patients were assigned to the Training Cohort (TC), while an external Validation Cohort (VC) comprised of 45 MS patients was established. Diagnostic efficiency was assessed for FKLCi, OCB, Link index, and the Reiber formula for IgG and FKLC. Optimal cutoff values for Link index and FKLCi were also determined. The last procedure was developed for diverse algorithms using the parameters mentioned above, which included the optimal cutoffs previously obtained. The calculations were conducted independently for both the TC and the VC, as well as for a composite cohort formed by combining data from all patients (OC) RESULTS: One algorithm, named KRO, was developed based on the determination of FKLCi and Reiber Formula as the primary diagnostic parameters. For cases where the FKLCi result was mildly increased, OCB was utilized as a supplementary test. The KRO algorithm demonstrated superior diagnostic accuracy in the OC (89%), resulting in a reduction of OCB consumption by 91%. DISCUSSION: The KRO algorithm demonstrated superior sensitivity and accuracy although lower specificity and NPV compared to the use of FKLCi and OCB alone. The present research aligns with the new consensus recommendations regarding the diagnostic approach. Our findings indicate that employing a combined marker approach via KRO could prove to be a proficient screening tool for multiple sclerosis. This approach also holds the potential to address inherent limitations associated with each individual marker. However, to further validate and solidify the efficacy of our algorithm, additional studies involving larger cohorts are warranted.

Geographical Distribution and Social Justice of the COVID-19 Pandemic: The Case of Palma (Balearic Islands).

The spatial distribution of the COVID-19 infection rate in the city of Palma (Balearic Islands) is analyzed from the geolocation of positive cases by census tract and its relationship with socioeconomic variables is evaluated. Data on infections have been provided by the Health Service of the Ministry of Health and Consumption of the Government of the Balearic Islands. The study combines several methods of analysis: spatial autocorrelation, calculation of the Gini index and least squares regression, and weighted geographical regression. The results show that the pandemic comprised five waves in the March 2020-March 2022 period, corresponding to the months of April 2020, August 2020, December 2020, July 2021, and January 2022. Each wave shows a particular geographical distribution pattern, however, the second and third waves show higher levels of spatial concentration. In this sense, the second wave, affecting the peripheral neighborhoods of the eastern part of the city. The Gini index confirms geographical imbalances in the distribution of infections in the first waves of the pandemic. In addition, the regression models indicate that the most significant socioeconomic variables in the prediction of COVID-19 infection are average income, percentage of children under 18 years of age, average size of the household, and percentage of single-person households. The study shows that economic imbalances in the city have had a clear influence on the spatial pattern of pandemic distribution. It shows the need to implement spatial justice policies in income distribution to balance the effects of the pandemic.

Testing eye temperature assessed with infrared thermography to evaluate stress in meat goats raised in a semi-intensive farming system: a pilot study.

The Blanca Serrana goat is selected for meat production and usually raised in an extensive farm system. The meat goat industry is getting bigger in Spain, evolving to more intensive farming systems. The negative influence of stress produced by daily management on animal welfare is even bigger in these animals as they are not used to getting so close to humans. Eye temperature has recently appeared as an appropriate and noninvasive tool for welfare assessment in cattle, but no previous studies have been developed in goats. Thus, the main aim of this pilot study was to test eye temperature as a noninvasive tool to explore stress levels associated with a semi-intensive farming system for meat goats in comparison with the standard measurements of stress. For that, 24 Blanca Serrana goats were used. Heart rate (HR), respiratory rate (RR) and eye temperature (ET), assessed with infrared thermography samples, were collected just before and just after a stressful situation created to check how the routine management of semi-intensive farming systems affected this species. A factorial ANOVA, least square means and Scheffé post hoc comparison analyses found statistically significant differences due to the stress test moment for RR ( p < 0.05 ) and ET ( p < 0.001 ) with higher values shown after the stress test than before it. Differences due to age were found just for HR ( p < 0.05 ) and RR ( p < 0.01 ) stress parameters, with kids showing higher results than adults. Pearson correlations between HR, RR and ET parameters showed a medium-high positive correlation of 0.56 between RR and ET. Thus, ET appears as an appropriate and noninvasive tool to explore stress levels associated with a semi-intensive farming system for meat goats.

Whole-exome sequencing analysis in twin sibling males with an anterior cruciate ligament rupture.

Familial predisposition is among the major genetic risk factors for non-contact musculoskeletal tissue injuries. Personal genome sequence shows that different polymorphism profiles may account for the number and the degree of injuries and the recovery time. Genotyping studies allow investigation into genome factors with potential impact on pathogenesis of non-contact ligament injuries. We have studied a family with twin sibling males surgically diagnosed of an anterior cruciate ligament non-contact rupture and non-affected progenitors (father and mother) were subjected to whole exome sequencing (WES) analysis. WES analysis previously carried out on 16 individuals, without ACL injury medical records, were also included in this study for single nucleotide variants (SNVs) and small insertions and deletions detection (indels), variant filtering and to prioritize variants relative to the disease. WES analysis to identify SNVs and indels was performed using open web-based bioinformatics tools. A set of 11 new variants shared by family members can be associated to ACL non-contact injury, including SerpinA11, ARSI, NOCHT4, EPB41, FDFT1, POMC, KIF26A, OLFML2B, ATG7, FAH and WDR6. All of them, except ATG7 and WDR6, have shown a damaging predictive pattern by combinatorial standard predictive scores. In combination to the identified SNVs of EPB41 and SerpinA11 genes, ACTL7A gene showed a predicted deleterious variant reinforcing the idea these variants impact on of fibroblast-like cells deformability and ECM misbalance, Differential gene expression and RNA sequencing analysis will help to understand the combined participation of these protein coding genes in ACL non-contact injuries.

Controversies on the management of clinical situations with low therapeutic effectiveness in oncology.

Clinical scenarios associated with low therapeutic effectiveness (LTE) are especially complex and highly relevant in oncology. The objective was to test a methodological framework for creating consensual clinical recommendations for routine practice. The study was in three phases from Mars 2006 to January 2008: 1) Definition of LTE situations; 2) Preparation by 10 experts of a panel of LTE situations in cancers of breast, lung, head and neck, colon and rectum and brain; and 3) Development of a consensus on each situation and its optimal treatment by gathering agreement and disagreements (two-round Delphi method) from 68 practicing oncologists in Andalusian Community. Three major and three minor criteria were established for an LTE situation, defined when at least one major or two minor criteria were met. The expert group proposed 48 possible LTE clinical scenarios for breast (n = 7), lung (10), brain (11), head and neck (11) and colorectal cancers (9). Sixty-eight oncologists agreed to participate in the study; the response rate was 79% (from 34 medical and 17 radiation oncologists) In the first round (definition), maximum agreement was obtained with the LTE definition of 10 of the 48 scenarios; in the second round (treatment options), maximum agreement was obtained on the treatment of 3 of these 10 scenarios. Oncologists reached low levels of agreement on the definition of an LTE situation and on its treatment recommendations. This study proposes an approach to the improvement of cancer management in situations of high uncertainty.

Correction of nonvertex presentation with moxibustion: a systematic review and metaanalysis.

We searched systematically for randomized controlled trials, comparing moxibustion with a nonmoxibustion control group or other methods such as external cephalic version, postural methods, and acupuncture in databases, both Western and Chinese, up to June 2007. Six studies, with 1087 subjects and a high degree of heterogeneity, compared moxibustion vs observation or postural methods and reported a rate of cephalic version among the moxibustion group of 72.5% vs 53.2% in the control group (relative risk, 1.36; 95% confidence interval, 1.17-1.58); the number needed to treat was 5 (95% confidence interval, 4-7). In terms of safety, no significant differences were found in the comparison of moxibustion with other techniques. Moxibustion at acupuncture point BL67 has been shown to produce a positive effect, whether used alone or in combination with acupuncture or postural measures, in comparison with observation or postural methods alone, for the correction of nonvertex presentation, although these results should be viewed with caution, given the considerable heterogeneity found among studies.