The still under-investigated role of cognitive deficits in PML diagnosis

Background: Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods: Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result: After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion: Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment

Explainable Artificial Intelligence (XAI) 2.0: A Manifesto of Open Challenges and Interdisciplinary Research Directions

As systems based on opaque Artificial Intelligence (AI) continue to flourish in diverse real-world applications, understanding these black box models has become paramount. In response, Explainable AI (XAI) has emerged as a field of research with practical and ethical benefits across various domains. This paper not only highlights the advancements in XAI and its application in real-world scenarios but also addresses the ongoing challenges within XAI, emphasizing the need for broader perspectives and collaborative efforts. We bring together experts from diverse fields to identify open problems, striving to synchronize research agendas and accelerate XAI in practical applications. By fostering collaborative discussion and interdisciplinary cooperation, we aim to propel XAI forward, contributing to its continued success. Our goal is to put forward a comprehensive proposal for advancing XAI. To achieve this goal, we present a manifesto of 27 open problems categorized into nine categories. These challenges encapsulate the complexities and nuances of XAI and offer a road map for future research. For each problem, we provide promising research directions in the hope of harnessing the collective intelligence of interested stakeholders

Unbalanced metalloproteinase-9 and tissue inhibitors of metalloproteinases ratios predict hemorrhagic transformation of lesion in ischemic stroke patients treated with thrombolysis: Results from the MAGIC study

Background Experimentally, metalloproteinases (MMPs) play a detrimental role related to severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA treated stroke patients Methods Blood was taken before and 24-hours after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as hemorrhagic infarction type 2 or any parenchimal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes Results Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17 – 2.38], p = 0.005; 1.74 [1.21 – 2.49], p=0.003 respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17 – 2.57], p=0.006) with a trend towards significance for MMP9/TIMP2 ratio (p=0.007).Discussion Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect

Pathways to connection: Mapping the impact of social connection interventions on depression outcomes – an umbrella review

Introduction Social connection (SC) encompasses multiple dimensions, including structural and functional aspects of social relationships. While substantial evidence highlights the relationship between different SC metrics and depression, the effectiveness of interventions aimed at enhancing SC to alleviate depressive symptoms remains inadequately understood. Objectives This umbrella review combines evidence from systematic reviews to evaluate the effectiveness of SC interventions in alleviating depression. It specifically examines interventions that strengthen natural social networks, while excluding formal health-based interventions - such as psychosocial or psychotherapeutic treatments - designed to enhance social skills or deliver formal or semi-formal support within healthcare settings. Methods This review synthesizes the consistency and the extent of the impact of SC interventions on depression. PubMed, Cochrane Library, EMBASE, and PsycINFO were searched, resulting in the inclusion of 12 systematic reviews/meta-analyses. AMSTAR-2 and GRADE instruments were used to assess the quality and certainty of the evidence reviewed. Results Interventions were grouped into three categories: i) Social network and support interventions; ii) Social engagement interventions; iii) Social inclusion interventions. Findings were mixed, with some interventions demonstrating minimal/no effect compared to usual care. Interventions addressing social disengagement and promoting social integration for older individuals and psychiatric patients showed substantial improvements in outcomes. Social inclusion interventions aimed at strengthening group identification in adolescents and young adults also showed positive outcomes. Conclusions SC is a key determinant of depression. Further examination of targeted interventions is needed to determine which are most effective in influencing the evolving psychopathology of depressive trajectories. This may help identify targeted interventions for those at risk, thereby informing and guiding public health policies

Classifications for Cesarean Section: A Systematic Review

Background: Rising cesarean section (CS) rates are a major public health concern and cause worldwide debates. To propose and implement effective measures to reduce or increase CS rates where necessary requires an appropriate classification. Despite several existing CS classifications, there has not yet been a systematic review of these. This study aimed to 1) identify the main CS classifications used worldwide, 2) analyze advantages and deficiencies of each system.Methods and Findings: Three electronic databases were searched for classifications published 1968-2008. Two reviewers independently assessed classifications using a form created based on items rated as important by international experts. Seven domains (ease, clarity, mutually exclusive categories, totally inclusive classification, prospective identification of categories, reproducibility, implementability) were assessed and graded. Classifications were tested in 12 hypothetical clinical case-scenarios. From a total of 2948 citations, 60 were selected for full-text evaluation and 27 classifications identified. Indications classifications present important limitations and their overall score ranged from 2-9 (maximum grade = 14). Degree of urgency classifications also had several drawbacks (overall scores 6-9). Woman-based classifications performed best (scores 5-14). Other types of classifications require data not routinely collected and may not be relevant in all settings (scores 3-8).Conclusions: This review and critical appraisal of CS classifications is a methodologically sound contribution to establish the basis for the appropriate monitoring and rational use of CS. Results suggest that women-based classifications in general, and Robson's classification, in particular, would be in the best position to fulfill current international and local needs and that efforts to develop an internationally applicable CS classification would be most appropriately placed in building upon this classification. the use of a single CS classification will facilitate auditing, analyzing and comparing CS rates across different settings and help to create and implement effective strategies specifically targeted to optimize CS rates where necessary.Universidade Federal de São Paulo, Dept Obstet, São Paulo, BrazilBrazilian Cochrane Ctr, São Paulo, BrazilWorld Hlth Org, Dept Reprod Hlth & Res, Geneva, SwitzerlandWorld Hlth Org, Dept Knowledge Management & Sharing, Geneva, SwitzerlandUniversidade Federal de São Paulo, Dept Obstet, São Paulo, BrazilWeb of Scienc

Genomic analysis reveals the molecular basis for capsule loss in the group B Streptococcus population

The human and bovine bacterial pathogen Streptococcus agalactiae (Group B Streptococcus, GBS) expresses a thick polysaccharide capsule that constitutes a major virulence factor and vaccine target. GBS can be classified into ten distinct serotypes differing in the chemical composition of their capsular polysaccharide. However, non-typeable strains that do not react with anti-capsular sera are frequently isolated from colonized and infected humans and cattle. To gain a comprehensive insight into the molecular basis for the loss of capsule expression in GBS, a collection of well-characterized non-typeable strains was investigated by genome sequencing. Genome based phylogenetic analysis extended to a wide population of sequenced strains confirmed the recently observed high clonality among GBS lineages mainly containing human strains, and revealed a much higher degree of diversity in the bovine population. Remarkably, non-typeable strains were equally distributed in all lineages. A number of distinct mutations in the cps operon were identified that were apparently responsible for inactivation of capsule synthesis. The most frequent genetic alterations were point mutations leading to stop codons in the cps genes, and the main target was found to be cpsE encoding the portal glycosyl trasferase of capsule biosynthesis. Complementation of strains carrying missense mutations in cpsE with a wild-type gene restored capsule expression allowing the identification of amino acid residues essential for enzyme activity

Explainable Artificial Intelligence (XAI) 2.0: a manifesto of open challenges and interdisciplinary research directions

Understanding black box models has become paramount as systems based on opaque Artificial Intelligence (AI) continue to flourish in diverse real-world applications. In response, Explainable AI (XAI) has emerged as a field of research with practical and ethical benefits across various domains. This paper highlights the advancements in XAI and its application in real-world scenarios and addresses the ongoing challenges within XAI, emphasizing the need for broader perspectives and collaborative efforts. We bring together experts from diverse fields to identify open problems, striving to synchronize research agendas and accelerate XAI in practical applications. By fostering collaborative discussion and interdisciplinary cooperation, we aim to propel XAI forward, contributing to its continued success. We aim to develop a comprehensive proposal for advancing XAI. To achieve this goal, we present a manifesto of 28 open problems categorized into nine categories. These challenges encapsulate the complexities and nuances of XAI and offer a road map for future research. For each problem, we provide promising research directions in the hope of harnessing the collective intelligence of interested stakeholders