Functional MRI correlates of cognitive performance in patients with a clinically isolated syndrome suggestive of MS at presentation: an activation and connectivity study

Background/Objective: To assess whether abnormalities on functional magnetic resonance imaging (fMRI) are related to cognitive function in patients at presentation with clinically isolated syndrome (CIS) suggestive of multiple sclerosis. Methods: Eighteen patients with CIS and 15 healthy controls (HCs) performed an adapted fMRI version of the Paced Auditory Serial Addition Test (PASAT). According to their PASAT performance, CIS patients were divided into two groups: 10 with a low PASAT performance (<1 SD from the mean value of HCs) were considered ‘cognitive impairment’ (CI); eight patients were defined as ‘cognitively preserved’ (CP). Between-group differences in the patterns of brain activations and effective connectivity were assessed. Results: During PASAT, compared to HCs, CIS patients showed increased activations of the bilateral inferior parietal lobe (IPL), bilateral precuneus, bilateral middle frontal gyrus (MFG), left anterior cingulate cortex (ACC), left claustrum, right thalamus and right caudate nucleus. When CIS patients were analyzed, the CI group had a more significant activation of the bilateral IPL than HCs and CP patients. Compared to CP patients, they also had more significant recruitment of the right superior parietal lobe, right cerebellum, left MFG and left ACC. The analysis of effective connectivity showed stronger connections between several regions of the right hemisphere involved in working memory function in CI patients versus CP and HC. Conclusions: During performance of the PASAT, CIS patients show abnormalities in the patterns of cortical recruitment and connectivity related to the level of their cognitive impairment.This research has been supported by the following grants: Alicia Koplowitz Foundation; CSD2007-00012 (Consolider-Ingenio 2010 Programme), SEJ2007-65929/PSIC and PSI2010-20168 from the Spanish Ministry of Science and Education; the Dávalos Foundation Grant and P1·1A2010-07 from Bancaixa

Lo que el prurito esconde

Pruritus is a frequent but inespecific symptom that can occur in a multitude of pathologies. Thorugh this clinical case we will see how this symptom allows us to reach the diagnosis of a rare hematological entity with poor prognosis.El prurito es un síntoma frecuente pero inespecífico que puede presentarse en multitud de patologías. A través de este caso clínico veremos como este síntoma nos permite llegar al diagnóstico de una entidad hematológica rara y de mal pronóstico

Saturated fatty acid-enriched small extracellular vesicles mediate a crosstalk inducing liver inflammation and hepatocyte insulin resistance

[Background & Aims]: Lipotoxicity triggers non-alcoholic fatty liver disease (NAFLD) progression owing to the accumulation of toxic lipids in hepatocytes including saturated fatty acids (SFAs), which activate pro-inflammatory pathways. We investigated the impact of hepatocyte- or circulating-derived small extracellular vesicles (sEV) secreted under NAFLD conditions on liver inflammation and hepatocyte insulin signalling. [Methods]: sEV released by primary mouse hepatocytes, characterised and analysed by lipidomics, were added to mouse macrophages/Kupffer cells (KC) to monitor internalisation and inflammatory responses. Insulin signalling was analysed in hepatocytes exposed to conditioned media from sEV-loaded macrophages/KC. Mice were i.v. injected sEV to study liver inflammation and insulin signalling. Circulating sEV from mice and humans with NAFLD were used to evaluate macrophage–hepatocyte crosstalk. [Results]: Numbers of sEV released by hepatocytes increased under NAFLD conditions. Lipotoxic sEV were internalised by macrophages through the endosomal pathway and induced pro-inflammatory responses that were ameliorated by pharmacological inhibition or deletion of Toll-like receptor-4 (TLR4). Hepatocyte insulin signalling was impaired upon treatment with conditioned media from macrophages/KC loaded with lipotoxic sEV. Both hepatocyte-released lipotoxic sEV and the recipient macrophages/KC were enriched in palmitic (C16:0) and stearic (C18:0) SFAs, well-known TLR4 activators. Upon injection, lipotoxic sEV rapidly reached KC, triggering a pro-inflammatory response in the liver monitored by Jun N-terminal kinase (JNK) phosphorylation, NF-κB nuclear translocation, pro-inflammatory cytokine expression, and infiltration of immune cells into the liver parenchyma. sEV-mediated liver inflammation was attenuated by pharmacological inhibition or deletion of TLR4 in myeloid cells. Macrophage inflammation and subsequent hepatocyte insulin resistance were also induced by circulating sEV from mice and humans with NAFLD. [Conclusions]: We identified hepatocyte-derived sEV as SFA transporters targeting macrophages/KC and activating a TLR4-mediated pro-inflammatory response enough to induce hepatocyte insulin resistance.This work was supported by grants PID2021-122766OB-I00 (AMV), PID2019-105989RB-I00 (JB), PID2020-113238RB-I00 (LB), PID2019-106581RB-I00 (MAM), PID2020-114148RB-I00 (MI), PID2019-107036RB-I00 (RF), and RD21/0006/0001 (ISCIII) (IL) funded by Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación/10.13039/501100011033 and ERDF ‘A way of making Europe’ by the European Union (MICINN/AEI/FEDER, EU), grant EFSD/Boehringer Ingelheim European Research Programme on ‘Multi-System Challenges in Diabetes’ from the European Foundation for the Study of Diabetes (AMV), P2022/BMD-7227 (Comunidad de Madrid, Spain) (AMV), Fundación Ramón Areces (Spain) (AMV), CIBERdem (AMV and JB), CIBERhed (RF), and CIBERcv (LB) (ISCIII, Spain). LB and AMV belong to the Spanish National Research Council’s (CSIC’s) Cancer Hub. We also acknowledge the Spanish Ministry of Economy and Competitiveness (MINECO) postdoctoral contract IJCI-2015-24758 to IGM and the Spanish Ministry of Education, Culture and Sport (MECD) FPU17/02786 grant to RA

Factors related with symptom duration until diagnosis and treatment of symptomatic colorectal cancer

BACKGROUND: Colorectal cancer (CRC) survival depends mostly on stage at the time of diagnosis. However, symptom duration at diagnosis or treatment have also been considered as predictors of stage and survival. This study was designed to: 1) establish the distinct time-symptom duration intervals; 2) identify factors associated with symptom duration until diagnosis and treatment. METHODS: This is a cross-sectional study of all incident cases of symptomatic CRC during 2006–2009 (795 incident cases) in 5 Spanish regions. Data were obtained from patients’ interviews and reviews of primary care and hospital clinical records. Measurements: CRC symptoms, symptom perception, trust in the general practitioner (GP), primary care and hospital examinations/visits before diagnosis, type of referral and tumor characteristics at diagnosis. Symptom Diagnosis Interval (SDI) was calculated as time from first CRC symptoms to date of diagnosis. Symptom Treatment Interval (STI) was defined as time from first CRC symptoms until start of treatment. Nonparametric tests were used to compare SDI and STI according to different variables. RESULTS: Symptom to diagnosis interval for CRC was 128 days and symptom treatment interval was 155. No statistically significant differences were observed between colon and rectum cancers. Women experienced longer intervals than men. Symptom presentation such as vomiting or abdominal pain and the presence of obstruction led to shorter diagnostic or treatment intervals. Time elapsed was also shorter in those patients that perceived their first symptom/s as serious, disclosed it to their acquaintances, contacted emergencies services or had trust in their GPs. Primary care and hospital doctor examinations and investigations appeared to be related to time elapsed to diagnosis or treatment. CONCLUSIONS: Results show that gender, symptom perception and help-seeking behaviour are the main patient factors related to interval duration. Health service performance also has a very important role in symptom to diagnosis and treatment interval. If time to diagnosis is to be reduced, interventions and guidelines must be developed to ensure appropriate examination and diagnosis during both primary and hospital care

Factors related with symptom duration until diagnosis and treatment of symptomatic colorectal cancer

[Abstract] Background: Colorectal cancer (CRC) survival depends mostly on stage at the time of diagnosis. However, symptom duration at diagnosis or treatment have also been considered as predictors of stage and survival. This study was designed to: 1) establish the distinct time-symptom duration intervals; 2) identify factors associated with symptom duration until diagnosis and treatment. Methods: This is a cross-sectional study of all incident cases of symptomatic CRC during 2006-2009 (795 incident cases) in 5 Spanish regions. Data were obtained from patients' interviews and reviews of primary care and hospital clinical records. Measurements: CRC symptoms, symptom perception, trust in the general practitioner (GP), primary care and hospital examinations/visits before diagnosis, type of referral and tumor characteristics at diagnosis. Symptom Diagnosis Interval (SDI) was calculated as time from first CRC symptoms to date of diagnosis. Symptom Treatment Interval (STI) was defined as time from first CRC symptoms until start of treatment. Nonparametric tests were used to compare SDI and STI according to different variables. Results: Symptom to diagnosis interval for CRC was 128 days and symptom treatment interval was 155. No statistically significant differences were observed between colon and rectum cancers. Women experienced longer intervals than men. Symptom presentation such as vomiting or abdominal pain and the presence of obstruction led to shorter diagnostic or treatment intervals. Time elapsed was also shorter in those patients that perceived their first symptom/s as serious, disclosed it to their acquaintances, contacted emergencies services or had trust in their GPs. Primary care and hospital doctor examinations and investigations appeared to be related to time elapsed to diagnosis or treatment. Conclusions: Results show that gender, symptom perception and help-seeking behaviour are the main patient factors related to interval duration. Health service performance also has a very important role in symptom to diagnosis and treatment interval. If time to diagnosis is to be reduced, interventions and guidelines must be developed to ensure appropriate examination and diagnosis during both primary and hospital care.Instituto de Salud Carlos III; PI:052273Instituto de Salud Carlos III; PI050787Instituto de Salud Carlos III; PI050700Instituto de Salud Carlos III; PI052692Instituto de Salud Carlos III; PI05214

Diagnosis delay and follow-up strategies in colorectal cancer. Prognosis implications: a study protocol

<p>Abstract</p> <p>Background</p> <p>Controversy exists with regard to the impact that the different components of diagnosis delay may have on the degree of invasion and prognosis in patients with colorectal cancer. The follow-up strategies after treatment also vary considerably. The aims of this study are: a) to determine if the symptoms-to-diagnosis interval and the treatment delay modify the survival of patients with colorectal cancer, and b) to determine if different follow-up strategies are associated with a higher survival rate.</p> <p>Methods/Design</p> <p>Multi-centre study with prospective follow-up in five regions in Spain (Galicia, Balearic Islands, Catalonia, Aragón and Valencia) during the period 2010-2012. Incident cases are included with anatomopathological confirmation of colorectal cancer (International Classification of Diseases 9th revision codes 153-154) that formed a part of a previous study (n = 953).</p> <p>At the time of diagnosis, each patient was given a structured interview. Their clinical records will be reviewed during the follow-up period in order to obtain information on the explorations and tests carried out after treatment, and the progress of these patients.</p> <p>Symptoms-to-diagnosis interval is defined as the time calculated from the diagnosis of cancer and the first symptoms attributed to cancer. Treatment delay is defined as the time elapsed between diagnosis and treatment. In non-metastatic patients treated with curative intention, information will be obtained during the follow-up period on consultations performed in the digestive, surgery and oncology departments, as well as the endoscopies, tumour markers and imaging procedures carried out.</p> <p>Local recurrence, development of metastases in the follow-up, appearance of a new tumour and mortality will be included as outcome variables.</p> <p>Actuarial survival analysis with Kaplan-Meier curves, Cox regression and competitive risk survival analysis will be performed.</p> <p>Discussion</p> <p>This study will make it possible to verify if the different components of delay have an impact on survival rate in colon cancer and rectal cancer. In consequence, this multi-centre study will be able to detect the variability present in the follow-up of patients with colorectal cancer, and if this variability modifies the prognosis. Ideally, this study could determine which follow-up strategies are associated with a better prognosis in colorectal cancer.</p

Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab

Ustekinumab has shown efficacy in Crohn's Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients' data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index <= 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission

Analysis of “task-positive” and “task-negative” functional networks during the performance of the Symbol Digit Modalities Test in patients at presentation with clinically isolated syndrome suggestive of multiple sclerosis

An abnormal pattern of brain activations has been shown in patients with multiple sclerosis during the performance of several cognitive tasks. The aim of this study is to investigate abnormalities of the patterns of activation/deactivation in the functional networks related to “task-positive” and “task-negative” events during the execution of the Symbol Digit Modalities Test (SDMT) in patients with clinically isolated syndromes (CIS) and preserved cognitive abilities. Eighteen CIS patients within 3 months from their first clinical attack and 15 healthy controls (HC) underwent neuropsychological assessment and performed an adapted functional magnetic resonance imaging (fMRI) version of the SDMT. “Task-positive” responses to task execution and “task-negative” activity of the default mode network were compared between groups. A regression analysis was performed to investigate the correlation between fMRI results and T2 lesion load (T2 LL) and brain atrophy. Neuropsychological performance did not differ between groups. Compared to HC, CIS patients exhibited an enhanced deactivation of the “task-negative” network at the level of the posterior cingulate cortex, whereas no differences between groups were found when the patterns of “task-positive” events were compared. A regression analysis detected a correlation (p < 0.001,r ranging from 0.62 to 0.73) between T2 LL and “task-positive” activations of areas that are part of the attention network, comprising the anterior cingulate gyrus, left prefrontal gyrus and inferior parietal lobe. No correlation was found between patterns of functional modifications and brain atrophy. CIS patients experience an enhanced pattern of brain deactivations during cognitive performances, which might contribute to their normal neuropsychological status