Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to low-voltage-fast onset seizures in Dravet syndrome.

Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials, and hippocampal single-unit neuronal activities in Scn1a+/- and Scn1aRH/+ DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single-unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients' EEG, which are consistent with the dysfunctions that we observed in single neurons and that allowed seizure prediction. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Preictal spectral features may be used as predictive seizure biomarkers.

Community-based mental health interventions in low- and middle-income countries: a qualitative study with international experts.

BACKGROUND: Mental health services are scarce in low- and middle-income countries (LMICs), and designing and implementing effective interventions can be difficult. The aim of this international study was to explore the key lessons for developing, implementing, and evaluating community-based mental health and well-being interventions in LMICs, with an additional focus on older adults. METHODS: Research and clinical experts in developing and implementing psychosocial community-based interventions in LMICs were interviewed remotely between October 2021 and January 2022. Participants were recruited via existing global health networks and via published literature searches. Participants were asked about their experiences of developing and implementing interventions, and about key barriers and facilitators during the process. Interviews lasted up to 45 min, and data were analysed using combined inductive and deductive thematic analysis. RESULTS: Sixteen global mental health experts participated. Five themes with different sub-themes were generated: Mechanisms and contexts; Barriers; Facilitators; Public and stakeholder involvement; Looking through an ageing lens. The development and delivery of mental health interventions in LMICs are facilitated through integration into existing health infrastructures and working with existing job roles as delivery agents. Public and stakeholder involvement are crucial at all stages of development through to implementation to focus on meeting local needs and sustaining participant motivation. Logistical barriers of transport, resources, and location need to be addressed, emphasising local sustainability. CONCLUSIONS: This study provides important insights for how the development, implementation, and evaluation of community-based mental health and well-being interventions in LMICs can be optimised, and can complement general guidance into complex interventions developments.

Fear response of rat pups to a non-aversive social stimulus: Evidence for the involvement of memory processes.

Learning processes in rats during early development are importantly mediated by the mother, which represents the primary source of environmental information. This study aimed to determine whether aversive early experiences can induce the expression of pups' fear responses toward a non-aversive stimulus as a consequence of a memory process. First, we determined pups' fear responses toward an anesthetized female after being exposed to this stimulus or an empty cage together with their mothers from Postnatal Day (PNDs) 1 to 4. Second, we evaluated if the administration of the protein synthesis inhibitor cycloheximide (CHX; 0.2 mg/kg, subcutaneously (sc).) disrupted the reconsolidation processes and abolished the fear response on PND 9. Only female pups previously exposed to the female intruder expressed fear responses toward an anesthetized female on PND 8. CHX administration to female pups immediately after exposure to an anesthetized female on PND 8 suppressed fear responses on PND 9, indicating that the fear expression was the result of a memory process, probably mediated by the mother. These findings demonstrated that early experiences can shape responses to social stimuli in a sex-dependent manner and emphasize the critical role of the mother in influencing fear learning in a social context.

Oral contraceptives do not modify the risk of a second attack and disability accrual in a prospective cohort of women with a clinically isolated syndrome and early multiple sclerosis.

OBJECTIVE: To evaluate whether oral contraceptive (OC) use is associated with the risk of a second attack and disability accrual in women with a clinically isolated syndrome (CIS) and early multiple sclerosis (MS). METHODS: Reproductive information from women included in the Barcelona CIS prospective cohort was collected through a self-reported cross-sectional survey. We examined the relationship of OC exposure with the risk of a second attack and confirmed Expanded Disability Status Scale of 3.0 using multivariate Cox regression models, adjusted by age, topography of CIS, oligoclonal bands, baseline brain T2 lesions, body size at menarche, smoking, and disease-modifying treatment (DMT). OC and DMT exposures were considered as time-varying variables. Findings were confirmed with sensitivity analyses using propensity score models. RESULTS: A total of 495 women were included, 389 (78.6%) referred to ever use OC and 341 (68.9%) started OC before the CIS. Exposure to OC was not associated with a second attack (adjusted hazard ratio (aHR) = 0.73, 95% confidence interval (CI) = 0.33-1.61) or disability accrual (aHR = 0.81, 95% CI = 0.17-3.76). Sensitivity analyses confirmed these results. CONCLUSION: OC use does not modify the risk of second attack or disability accrual in patients with CIS and early MS, once considered as a time-dependent exposure and adjusted by other potential confounders.

Menopause does not modify disability trajectories in a longitudinal cohort of women with clinically isolated syndrome and multiple sclerosis followed from disease onset.

BACKGROUND AND PURPOSE: To evaluate the effect of menopause on disability accumulation in women followed from their clinically isolated syndrome (CIS). METHODS: We examined the longitudinal changes in Expanded Disability Status Scale (EDSS) scores from CIS until the last follow-up in women belonging to the Barcelona CIS prospective cohort, followed through their menopausal transition. The analysis is based on 13,718 EDSS measurements, with an average of 28 EDSS measurements per patient. Differences in EDSS trajectories between menopausal and nonmenopausal women, controlling for age and disease duration, were evaluated. We performed two sensitivity analyses in women with confirmed MS and in those experiencing early menopause. RESULTS: From 764 eligible women, 496 (65%) responded to the questionnaire, and 74 (14.9%) reached menopause over the follow-up. We did not find a significant inflection point in EDSS trajectories around menopause (slope change -0.009; 95% CI -0.066; 0.046). The annual increase in EDSS over the complete course of the disease was significantly higher in menopausal women (0.049; 95% CI, 0.026-0.074) versus nonmenopausal (0.019; 95% CI, 0.008-0.031; interaction p value 0.025). This difference was lost when controlling for age and disease duration (EDSS annual increase of 0.059; 95% CI, 0.025-0.094 vs. 0.038; 95% CI, 0.021-0.057, respectively; interaction p value 0.321). No inflection point was detected when the analysis was restricted to women with confirmed MS or with earlier menopause. CONCLUSIONS: Menopause is not associated with an increased risk of disability in a CIS population, considering EDSS trajectories throughout the course of the disease together with age and disease duration.

Community-based mental health and well-being interventions for older adults in low- and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Mental health support is often scarce in low- and middle-income countries (LMIC), with mental health stigmatised. Older adults are some of the most vulnerable members of society and may require specific types of mental health support. The aim of this mixed-methods systematic review and meta-analysis was to explore the types, components, and efficacy of psychosocial community-based mental health interventions for older adults (aged 60 + years) residing in LMIC. METHODS: Six databases were searched in August 2021. Studies published since 2000 were included if they collected primary quantitative or qualitative data on community-based interventions for improving mental health for older adults residing in LMICs, focusing on improving mental health and well-being outcomes. Full texts were screened by two researchers. RESULTS: From 24,378 citations identified, 40 studies met eligibility criteria. Across 12 countries, interventions were categorised into those focusing on (1) Established forms of psychological therapy; (2) Exercise; (3) Education; (4) Social engagement; (5) Multi-component. Most interventions were effective in reducing levels of depression, anxiety, and improving well-being, including reminiscence therapy, different types of socialising, and breathing and laughter exercises. Some interventions reported no benefits and those that did at times failed to report continued benefits at follow-up. Given the variations in intervention type and delivery, cultures, and outcome measures used, underpinning factors of intervention success or failure were difficult to establish. CONCLUSIONS: Psychosocial interventions for older adults in LMIC need to be adapted to local contexts depending on culture and population needs. Existing interventions and their components can be used as a foundation to produce adapted and multi-component interventions, to tackle growing and inadequate mental health care provision in LMIC. TRIAL REGISTRATION: The review protocol was registered on PROSPERO [CRD42021271404].

Understanding post-conflict mental health needs and co-producing a community-based mental health intervention for older adults in Colombia: a research protocol.

BACKGROUND: Older adults in Colombia have seen a number of stressful life events - including the Colombian armed conflict, forced misplacement and recently COVID-19. These events likely have had and are having a substantial impact on people's mental health and well-being, whilst mental health care provision in Colombia is not sufficient and often access is limited and unaffordable. Therefore, the aim of this study is to understand the impact of stressful life events on the mental health of older adults living in Colombia, and co-produce, pilot, and evaluate a community-based mental health intervention in Turbo. METHODS: This 3-year international mixed-methods study comprises of three phases: Phase I will explore the impact of stressful life events on the mental health of older adults living in Colombia, and their mental health needs, via quantitative needs assessments and qualitative interviews and focus groups; Phase II will involve synthesising the findings from Phase I as well as conducting a systematic review and qualitative interviews with experts into implementing mental health interventions in LMICs to co-produce a community-based mental health intervention with older adults and local community group leaders and care providers; Phase III will involve the piloting and evaluation of the mental health intervention via quantitative and qualitative assessments. Co-production and public involvement underpin each element of this project. DISCUSSION: Appropriate mental health care is as important as physical health care, but this study also looks at how we might integrate these findings into community-level public health initiatives for application both within Colombia and more widely in both LMICs and more developed countries. This study protocol will act as a guide for the development and adaptation of psychosocial mental health interventions in different cultures and contexts.

Substantially thinner internal granular layer and reduced molecular layer surface in the cerebellar cortex of the Tc1 mouse model of down syndrome - a comprehensive morphometric analysis with active staining contrast-enhanced MRI.

Down Syndrome is a chromosomal disorder that affects the development of cerebellar cortical lobules. Impaired neurogenesis in the cerebellum varies among different types of neuronal cells and neuronal layers. In this study, we developed an imaging analysis framework that utilizes gadolinium-enhanced ex vivo mouse brain MRI. We extracted the middle Purkinje layer of the mouse cerebellar cortex, enabling the estimation of the volume, thickness, and surface area of the entire cerebellar cortex, the internal granular layer, and the molecular layer in the Tc1 mouse model of Down Syndrome. The morphometric analysis of our method revealed that a larger proportion of the cerebellar thinning in this model of Down Syndrome resided in the inner granule cell layer, while a larger proportion of the surface area shrinkage was in the molecular layer.

Sexual behaviour of the female rat during late adolescence: effect of chronic cocaine treatment.

Sexual behaviour is highly motivated and female rats begin to express it during adolescence. The circuitries implicated in the control of motivated behaviours continue to mature during adolescence and seem more sensitive to the effects of psychostimulants such as cocaine. However, a putative differential effect of this drug on the sexual behaviour of females according to age has not yet been studied. Therefore, we compared the motivational value of a male and the expression of sexual behaviour of late-adolescent and adult female rats after chronic treatment with a vehicle or 15.0 mg/kg cocaine. The strong incentive value of a male rat, in a male versus female preference test, for adolescent and adult female rats, was not affected by cocaine. During sexual interaction, adolescents were as sexually receptive as were adults; however, they expressed more runaways and social investigation. Cocaine treatment did not modify the expression of sexual behaviour in either group, but increased social investigation in adolescent rats. These results indicate that late-adolescent pro-oestrus females are highly sexually motivated and might express behaviours typical of this life period during sexual interaction. Moreover, although chronic cocaine treatment seemed to affect more adolescents, it did not alter the sexual motivation or behaviour of females.

Multispectroscopic methodology to study Libyan desert glass and its formation conditions.

Libyan desert glass (LDG) is a melt product whose origin is still a matter of controversy. With the purpose of adding new information about this enigma, the present paper analyzes the inner part of LDG specimens and compares them with the results of LDG surfaces. An integrated analytical methodology was used combining different techniques such as Raman spectroscopy, in point-by-point and imaging modes, scanning electron microscopy with X-ray microanalysis (SEM-EDS), energy-dispersive micro X-ray fluorescence spectrometry (µ-EDXRF), electron probe micro analyzer (EPMA), and optical cathodoluminescence (Optical-CL). According to our results, flow structures of the melt and the amorphous nature of the matrix could be discerned. Moreover, the observed displacement of Raman bands, such as in the cases of quartz and zircon, and the identification of certain compounds such as coesite (the most clarifying phase of high pressures), α-cristobalite, gypsum, anhydrite, corundum, rutile, amorphous calcite, aragonite, and calcite allowed us to know that LDGs could be subjected to shock pressures between 6 and more than 30 GPa, and temperatures between 300 and 1470 °C. The differences of temperature and pressure would be provoked by different cooling processes during the impact. Besides, in most cases the minerals corresponding to high pressure and temperatures were located in the inner part of the LDGs, with some exceptions that could be explained because they were trapped subsequently to the impact; there was more than one impact or heterogeneous cooling.Furthermore, nitrogen and oxygen gases were identified inside bubbles, which could have been introduced from the terrestrial atmosphere during the meteorite impact.These data helped us to clarify some clues about the origin of these enigmatic samples.

Differential hippocampal shapes in posterior cortical atrophy patients: A comparison with control and typical AD subjects.

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by predominant visual deficits and parieto-occipital atrophy, and is typically associated with Alzheimer's disease (AD) pathology. In AD, assessment of hippocampal atrophy is widely used in diagnosis, research, and clinical trials; its utility in PCA remains unclear. Given the posterior emphasis of PCA, we hypothesized that hippocampal shape measures may give additional group differentiation information compared with whole-hippocampal volume assessments. We investigated hippocampal volume and shape in subjects with PCA (n = 47), typical AD (n = 29), and controls (n = 48). Hippocampi were outlined on MRI scans and their 3D meshes were generated. We compared hippocampal volume and shape between disease groups. Mean adjusted hippocampal volumes were ∼ 8% smaller in PCA subjects (P < 0.001) and ∼ 22% smaller in tAD subject (P < 0.001) compared with controls. Significant inward deformations in the superior hippocampal tail were observed in PCA compared with controls even after adjustment for hippocampal volume. Inward deformations in large areas of the hippocampus were seen in tAD subjects compared with controls and PCA subjects, but only localized shape differences remained after adjusting for hippocampal volume. The shape differences observed, even allowing for volume differences, suggest that PCA and tAD are each associated with different patterns of hippocampal tissue loss that may contribute to the differential range and extent of episodic memory dysfunction in the two groups.

Social aversive stimuli presented to the mother produce the precocious expression of fear in rat pups.

During the stress hypo-responsive period, rat pups do not display fear responses toward adult males, yet they exhibit distress behavior in isolation. Since the mother modulates her offspring's affective development, we hypothesized that by altering the mother's behavior, a prolonged stressful situation would modify the ontogeny of the fear responses and distress behaviors in pups. Therefore, we repeatedly exposed the mother-litter dyad to different socially stressful stimuli and subsequently evaluated in 8-day-old pups their fear responses toward an anesthetized male, as well as their distress behavior in isolation. Our results show that repeated exposure to unfamiliar males and females, which altered maternal behavior by eliciting aggression in the mother, was associated with the precocious fear responses in pups, though without altering their distress behavior in isolation. We propose that the mother, as the principal mediator of environmental influences, provokes the precocious expression of fear in pups through alterations in her maternal behavior.

Fairness and bias correction in machine learning for depression prediction across four study populations.

A significant level of stigma and inequality exists in mental healthcare, especially in under-served populations. Inequalities are reflected in the data collected for scientific purposes. When not properly accounted for, machine learning (ML) models learned from data can reinforce these structural inequalities or biases. Here, we present a systematic study of bias in ML models designed to predict depression in four different case studies covering different countries and populations. We find that standard ML approaches regularly present biased behaviors. We also show that mitigation techniques, both standard and our own post-hoc method, can be effective in reducing the level of unfair bias. There is no one best ML model for depression prediction that provides equality of outcomes. This emphasizes the importance of analyzing fairness during model selection and transparent reporting about the impact of debiasing interventions. Finally, we also identify positive habits and open challenges that practitioners could follow to enhance fairness in their models.

Benchmarking the CoW with the TopCoW Challenge: Topology-Aware Anatomical Segmentation of the Circle of Willis for CTA and MRA.

The Circle of Willis (CoW) is an important network of arteries connecting major circulations of the brain. Its vascular architecture is believed to affect the risk, severity, and clinical outcome of serious neuro-vascular diseases. However, characterizing the highly variable CoW anatomy is still a manual and time-consuming expert task. The CoW is usually imaged by two angiographic imaging modalities, magnetic resonance angiography (MRA) and computed tomography angiography (CTA), but there exist limited public datasets with annotations on CoW anatomy, especially for CTA. Therefore we organized the TopCoW Challenge in 2023 with the release of an annotated CoW dataset. The TopCoW dataset was the first public dataset with voxel-level annotations for thirteen possible CoW vessel components, enabled by virtual-reality (VR) technology. It was also the first large dataset with paired MRA and CTA from the same patients. TopCoW challenge formalized the CoW characterization problem as a multiclass anatomical segmentation task with an emphasis on topological metrics. We invited submissions worldwide for the CoW segmentation task, which attracted over 140 registered participants from four continents. The top performing teams managed to segment many CoW components to Dice scores around 90%, but with lower scores for communicating arteries and rare variants. There were also topological mistakes for predictions with high Dice scores. Additional topological analysis revealed further areas for improvement in detecting certain CoW components and matching CoW variant topology accurately. TopCoW represented a first attempt at benchmarking the CoW anatomical segmentation task for MRA and CTA, both morphologically and topologically.

Prevalence of Neuropathic Pain in Patients with Osteoarthritis.

Objective The aim of this study was to determine the prevalence of neuropathic pain and characterize the quality of life of patients with osteoarthritis who consulted a pain clinic in Southwestern Colombia. Methods A cross-sectional study was conducted via telephone survey. Participants ≥18 years of age with a diagnosis of osteoarthritis were included. The LANSS questionnaire was used to evaluate symptoms and signs of neuropathic pain, and the Short Form-8 was used to evaluate quality of life. Results Response rate was 54.1% (46/85). The male-to-female ratio was 5:1, with an average age of 72 ± 10 years. Most participants (91.3%) had severe pain. The prevalence of neuropathic pain was 28.3% (95%CI = 15.99-43.46), and the prevalence of neuropathic pain amongst women was 84.6% (95%CI = 54.55-98.01). Dysesthesias and paroxysmal pain were present in 92.3% of individuals with neuropathic pain. Regarding quality of life, limitations in physical activity were the most significant, as 63% of individuals reported such limitations. Conclusion Neuropathic pain was found to be prevalent and had a negative impact on physical function, highlighting the need for therapeutic strategies targeted to specific neuropathic pain pathways in patients with osteoarthritis.

Treatment of older patients with multiple sclerosis: Results of an International Delphi Survey.

Background: People over age 50-55 have historically been excluded from randomized clinical trials for multiple sclerosis (MS). However, more than half of those living with an MS diagnosis are over 55. Objective: Explore the unique considerations of treating older people with MS (PwMS) using an iterative and structured Delphi-based assessment to gather expert opinions. Methods: Eight MS neurologists with an interest in older PwMS developed a 2-round survey. Survey respondents were qualified neurologists with ≥3 years' experience, personally responsible for treatment decisions, and treating ≥20 patients per month, of whom ≥10% were ≥50 years old. Consensus was defined as ≥75% agreement on questions with categorical responses or as a mean score ≥4 on questions with numerical responses. Results: In Survey 1, 224 neurologists responded; 180 of these completed Survey 2. Limited consensus was reached with varying levels of agreement on several topics including identification and assessment of older patients; factors relating to treatment decisions including immunosenescence and comorbidities; considerations for high-efficacy treatments; de-escalation or discontinuation of treatment; effects of COVID-19; and unmet needs for treating this population. Conclusion: The results of this Delphi process highlight the need for targeted studies to create guidance for the care of older PwMS.

Deep Learning Segmentation of the Right Ventricle in Cardiac MRI: The M&Ms Challenge.

In recent years, several deep learning models have been proposed to accurately quantify and diagnose cardiac pathologies. These automated tools heavily rely on the accurate segmentation of cardiac structures in MRI images. However, segmentation of the right ventricle is challenging due to its highly complex shape and ill-defined borders. Hence, there is a need for new methods to handle such structure's geometrical and textural complexities, notably in the presence of pathologies such as Dilated Right Ventricle, Tricuspid Regurgitation, Arrhythmogenesis, Tetralogy of Fallot, and Inter-atrial Communication. The last MICCAI challenge on right ventricle segmentation was held in 2012 and included only 48 cases from a single clinical center. As part of the 12th Workshop on Statistical Atlases and Computational Models of the Heart (STACOM 2021), the M&Ms-2 challenge was organized to promote the interest of the research community around right ventricle segmentation in multi-disease, multi-view, and multi-center cardiac MRI. Three hundred sixty CMR cases, including short-axis and long-axis 4-chamber views, were collected from three Spanish hospitals using nine different scanners from three different vendors, and included a diverse set of right and left ventricle pathologies. The solutions provided by the participants show that nnU-Net achieved the best results overall. However, multi-view approaches were able to capture additional information, highlighting the need to integrate multiple cardiac diseases, views, scanners, and acquisition protocols to produce reliable automatic cardiac segmentation algorithms.

Enhanced prostate cancer targeting by modified protease sensitive photosensitizer prodrugs.

Prodrugs combining macromolecular delivery systems with site-selective drug release represent a powerful strategy to increase selectivity of anticancer agents. We have adapted this strategy to develop new polymeric photosensitizer prodrugs (PPP) sensitive to urokinase-like plasminogen activator (uPA). In these compounds (to be referred to as uPA-PPPs) multiple copies of pheophorbide a are attached to a polymeric carrier via peptide linkers that can be cleaved by uPA, a protease overexpressed in prostate cancer (PCa). uPA-PPPs are non-phototoxic in their native state but become fluorescent and produce singlet oxygen after uPA-mediated activation. In the present work, we studied the influence of side-chain modifications, molecular weight, and overall charge on the photoactivity and pharmacokinetics of uPA-PPPs. An in vitro promising candidate with convertible phototoxicity was then further investigated in vivo. Systemic administration resulted in a selective accumulation and activation of the prodrug in luciferase transfected PC-3 xenografts, resulting in a 4-fold increase in fluorescence emission over time. Irradiation of fluorescent tumors induced immediate tumor cell eradication as shown by whole animal bioluminescence imaging. PDT with uPA-PPP could therefore provide a more selective treatment of localized PCa and reduce side effects associated with current radical treatments.

Chylothorax after surgery for congenital heart disease.

PURPOSE OF REVIEW: Postoperative chylothorax is a frequently encountered pathology in the cardiac intensive care unit. The continuous loss of chyle is a challenging problem to treat and is associated with increased morbidity and mortality. The purpose of this article is to review the pathophysiology of chylothorax in patients after surgery for congenital heart disease, its implications and the current therapies available. RECENT FINDINGS: The incidence of chylothorax has been increasing over the last two decades. Multiple uncontrolled case series describe octreotide as an effective treatment, and octreotide usage is increasing around the world for patients nonresponsive to dietary modifications. Most centers reserve surgical treatment for patients nonresponsive after 4 weeks of medical treatment. Less-invasive surgical procedures such as thoracic duct ligation by video-assisted thoracoscopy are gaining popularity. SUMMARY: Chylothorax is commonly seen in children after surgery for congenital heart disease. The multiple and serious complications associated with chylous effusions are well known. Conservative therapy with diet modification and octreotide remain the standard initial approach. Thoracic duct ligation has been reported as a highly successful treatment but has considerable risk. Thus, this procedure should be reserved for patients nonresponsive to conservative therapy.