Decisional Conflict Regarding Disease-Modifying Treatment Choices Among Patients with Mid-Stage Relapsing-Remitting Multiple Sclerosis.

Purpose: Shared decision-making is critical in multiple sclerosis (MS) due to the uncertainty of the disease trajectory over time and the large number of treatment options with differing efficacy, safety and administration characteristics. The aim of this study was to assess patients' decisional conflict regarding the choice of a disease-modifying therapy and its associated factors in patients with mid-stage relapsing-remitting multiple sclerosis (RRMS). Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS (2017 revised McDonald criteria) and disease duration of 3 to 8 years were included. The level of uncertainty experienced by a patient when faced with making a treatment choice was assessed using the 4-item Decisional Conflict Scale. A battery of patient-reported and clinician-rated measures was administered to obtain information on symptom severity, illness perception, illness-related uncertainty, regret, MS knowledge, risk taking behavior, preferred role in the decision-making process, cognition, and self-management. Patients were recruited during routine follow-up visits and completed all questionnaires online using electronic tablets at the hospital. A multivariate logistic regression analysis was conducted. Results: A total of 201 patients were studied. Mean age (Standard deviation) was 38.7 (8.4) years and 74.1% were female. Median disease duration (Interquartile range) was 6.0 (4.0-7.0) years. Median EDSS score was 1.0 (0-2.0). Sixty-seven (33.3%) patients reported a decisional conflict. These patients had lower MS knowledge and more illness uncertainty, anxiety, depressive symptoms, fatigue, subjective symptom severity, a threatening illness perception, and poorer quality of life than their counterparts. Lack of decisional conflict was associated with MS knowledge (Odds ratio [OR]=1.195, 95% CI 1.045, 1.383, p=0.013), self-management (OR=1.049, 95% CI 1.013, 1.093, p=0.018), and regret after a healthcare decision (OR=0.860, 95% CI 0.756, 0.973, p=0.018) in the multivariate analysis. Conclusion: Decisional conflict regarding the selection of a disease-modifying therapy was a common phenomenon in patients with mid-stage RRMS. Identifying factors associated with decisional conflict may be useful to implement preventive strategies that help patients better understand their condition and strengthen their self-management resources.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Sarcoidosis with esophageal involvement: an uncommon clinical enigma.

We present the case of a 46-year-old male, a former smoker, with a medical history significant for morbid obesity grade III, hypothyroidism, hyperuricemia, and dyslipidemia. Four months ago, he was diagnosed with sarcoidosis involving mediastinal lymph nodes and is currently undergoing treatment with corticosteroids. The patient presented to the emergency department with persistent epigastric and thoracic pain lasting one week, accompanied by dysphagia and odynophagia intermittently. Laboratory tests showed elevated acute-phase reactants, with no other notable abnormalities. Chest X-ray revealed pre-existing mediastinal adenopathy. Despite an abdominal CT scan with contrast showing no significant findings, esophagogastroduodenoscopy revealed marked extrinsic compression of the esophagus between 25 and 32 cm from the dental arch, with less intensity distally. Although passage of the endoscope through this area caused significant pain, it did not hinder its advancement. A chest CT scan with oral contrast demonstrated filamentous narrowing of the esophagus in the middle third, along with concentric thickening of its walls and multiple paratracheal, parahilar, and periesophageal lymphadenopathies. Following a tapering regimen of corticosteroids, the patient was discharged with a clinical diagnosis of sarcoidosis with mediastinal and esophageal involvement secondary to extrinsic compression. Due to clinical improvement with the prescribed treatment, endoscopic ultrasound and biopsies to assess esophageal wall involvement were deemed unnecessary.

Assessing illness-related uncertainty in relapsing-remitting multiple sclerosis: A psychometric analysis of the Mishel Uncertainty of Illness Scale.

A multicenter study involving 204 adults with relapsing-remitting multiple sclerosis (RRMS) assessed the dimensionality and item characteristics of the Mishel-Uncertainty of Illness Scale (MUIS), a generic self-assessment tool. Mokken analysis identified two dimensions in the MUIS with an appropriate item and overall scale scalability after excluding nonclassifiable items. A refined 12-item MUIS, employing a grade response model, effectively discriminated uncertainty levels among RRMS patients (likelihood ratio test p-value = .03). These findings suggest the potential value of the 12-item MUIS as a reliable measure for assessing uncertainty associated with the course of illness in RRMS.

What was missed in child protection responses during COVID-19? Perceptions of professionals from various countries.

BACKGROUND: The COVID-19 pandemic increased the likelihood of child maltreatment and made already difficult circumstances for children and their families much worse. This increased the significance of the child protection system's role in responding to child maltreatment and ensuring children's rights, including their right to a safe life without violence. Unfortunately, accumulating evidence has indicated that the rates of child maltreatment increased during the pandemic. OBJECTIVE: The current study sought to identify the gaps within child protection responses in various countries during the COVID-19 pandemic and to discover how we can respond to crises in the future while preserving children's rights, including their right to protection from maltreatment. METHOD: Five focus groups with a total of 47 professionals working with children from various countries were conducted via Zoom and analyzed using a thematic approach. RESULTS: Three main themes were identified: 1) gaps in policies, 2) gaps in practice, and 3) professionals' messages to improve policy and practice. CONCLUSIONS: This study emphasizes what was missed in child protection policy and practice, highlighting the continuous neglect of children's needs and voices within policies, practices and guidelines worldwide during the pandemic. Professionals' recommendations for policy and practice are also discussed.

Hospital-based screening outperforms primary care screening as a means of achieving hepatitis C virus micro-elimination.

AIM: To assess the respective performances of a HCV screening program in a hospital setting and a HCV screening model applied concomitantly in a primary care centre. METHODS: Adult patients consecutively admitted to hospital for ambulatory surgery were screened for anti-HCV antibodies (hospital screening cohort, HPSC), as were patients receiving blood tests for medical reasons in a primary care centre (primary care screening cohort, PCSC). Serum anti-HCV and HCV RNA levels were tested by ELISA and real-time PCR, respectively. RESULTS: Seroprevalence of HCV infection was 2.2 % in the HPSC and 1.4 % in the PCSC (p = 0.044). All viraemic patients (0.2 % in HPSC and 0.1 % in PCSC) were treated with direct-acting antivirals and 85.7 % experienced a sustained virological response. CONCLUSIONS: Hospital-based HCV screening outperformed primary care-centered screening, significantly increasing HCV case findings.

Experiences and responses of child protection professionals during COVID-19: Lessons learned from professionals around the globe.

BACKGROUND: COVID-19 significantly worsened already challenging circumstances for children and their families and globally increased the likelihood of child maltreatment. This risk heightened the urgency of child protection professionals in preventing child maltreatment and defending children's rights. The vast and growing body of research on protecting children from child maltreatment during COVID-19 has emphasized practitioners' tremendous difficulty in this arena. OBJECTIVE: The current international study sought to identify the experiences and responses of child protection professionals to child maltreatment during COVID-19. PARTICIPANTS AND SETTING: Five real-time, virtual focus groups were conducted among professionals who work with children from countries around the globe. METHOD: Reflexive thematic analysis was employed to analyze the focus group transcripts. RESULTS: The participants identified their experiences and challenges in performing their role of protecting children. Additionally, they shared context-adapted and innovative responses to child maltreatment, while emphasizing self-care and their mental health. CONCLUSIONS: The results highlighted that child protection was significantly more challenging during the COVID-19 pandemic. Furthermore, they underlined the importance of establishing practices and policies for child protection in crisis times as well as ensuring both children's and professionals' well-being and mental health.

Effects of peppermint oil inhalation on vertical jump performance in elite young professional soccer players: A double-blinded randomized crossover study.

Aims: To evaluate peppermint essential oil (PEO) inhalation's effect on young soccer athletes' motor performance. Methods: A randomized crossover design was used to test the effect of the PEO. Eleven U-17 soccer players were evaluated into two conditions (PEO and Placebo - PLA). The players were tested in squat jump and countermovement jump and inhaled PEO or PLA and 10 min later performed the physical tests again. A mixed ANOVA was performed to test the hypotheses. Results: Main effects were found for the time in jumping height in the CMJ (p = 0.037). No main and interaction effects were found in the SJ variables. Conclusion: From the results, decrease CMJ performance acutely, both conditions presented decrease in JH, but based in effect size, PLA decrease is higher (more sample size for corroborate this) possibly due to improvements in the eccentric yielding sub-phase, where mentioned phase could be reflecting neural changes (required experimental verification). The PEO could be the interest in trainers for use before of match or in the half-time for minimize the decreased of physical performance by the rest.

Prior drug allergies are associated with worse outcome in patients with idiosyncratic drug-induced liver injury: A machine learning approach for risk stratification.

The impact of prior drug allergies (PDA) on the clinical features and outcomes of patients who develop idiosyncratic drug-induced liver injury (DILI) is largely unknown. We aimed to assess the clinical presentation and outcomes of DILI patients based on the presence or absence of PDA and explore the association between culprit drugs responsible for DILI and allergy. We analysed a well-vetted cohort of DILI cases enrolled from the Spanish DILI Registry. Bootstrap-enhanced least absolute shrinkage operator procedure was used in variable selection, and a multivariable logistic model was fitted to predict poor outcomes in DILI. Of 912 cases with a first episode of DILI, 61 (6.7%) had documented PDA. Patients with PDA were older (p = 0.009), had higher aspartate aminotransferase (AST) levels (p = 0.047), lower platelet count (p = 0.011) and higher liver-related mortality than those without a history of drug allergies (11% vs. 1.6%, p < 0.001). Penicillin was the most common drug associated with PDA in DILI patients (32%). A model including PDA, nR-based type of liver injury, female sex, AST, total bilirubin, and platelet count showed an excellent performance in predicting poor outcome in patients from the Spanish DILI Registry (area under the ROC curve [AUC] 0.887; 95% confidence interval [CI] 0.794 - 0.981) and the LATINDILI Network (AUC 0.932; 95% CI 0.884 - 0.981). Patients with suspected DILI should be screened for PDA as they would require a close monitoring for early detection of worsening clinical course.

Proposing new path-planning metrics for operating rovers on Mars.

The on-ground operation of Mars rovers is a complex task that requires comprehensive planning in which path planning plays a fundamental role. The selection of paths has to be carefully chosen considering the scientific objectives, terrain, energy, and safety. In this regard, operators are assisted by path-planning algorithms that generate candidate paths based on cost functions. Distance traveled has always been considered one of the primary criteria when comparing paths. Other metrics such as the run-time to generate the solution or the number of expanded nodes are common measures considered in the literature. However, we want to analyze if those metrics provide useful information in challenging and partially known terrain. In this paper, we will review those metrics using two-path planning algorithms on real Mars maps. Based on our experience operating Mars rovers, we propose new metrics for assessing paths in real-world applications.

Changing perspectives: unveiling the risks of ashwagandha-induced hepatotoxicity.

Ashwagandha, an herb popular in Ayurvedic medicine, is renowned for its health-enhancing properties. However, its association with liver damage in recent years has raised significant concerns, necessitating careful assessment and management. This case underscores the dangers of Ashwagandha, particularly for individuals with preexisting liver conditions, where it can lead to life-threatening acute-on-chronic liver failure. The lack of solid clinical evidence supporting Ashwagandha's health claims emphasizes the need for an evidence-based approach. Public education is essential to raise awareness of the risks associated with herbal supplements and prevent liver diseases.

Early exploration of the economic impact of transradial access (TRA) versus transfemoral access (TFA) for neurovascular procedures in Spain.

INTRODUCTION: Transfemoral access (TFA) is the primary access approach for neurointerventional procedures. Transradial access (TRA) is established in cardiology due to its lower complications, yet, it is at its early stages in neuroprocedures. This study performs an early exploration of the economic impact associated with the introduction of TRA in diagnostic and therapeutic neuroprocedures from the Spanish NHS perspective. METHODS: An economic model was developed to estimate the cost and clinical implications of using TRA compared to TFA. Costs considered access-related, complications and recovery time costs obtained from local databases and experts' inputs. Clinical inputs were sourced from the literature. A panel of eight experts from different Spanish hospitals, validated or adjusted the values based on local experience. Hypothetical cohorts of 10,000 and 1000 patients were considered for diagnostic and therapeutic neuroprocedures respectively. Deterministic sensitivity analysis was performed. RESULTS: TRA in diagnostic procedures was associated with lower costs with savings ranging between €486 and €157 depending on the TFA recovery time considered. TRA is estimated to lead to 158 fewer access-site complications. In therapeutic procedures, TRA resulted in 76.4 fewer complications and was estimated to be cost-neutral with an incremental cost of €21.56 per patient despite recovery times were not included for this group. Variation of the parameters in the sensitivity analysis did not change the direction of the results. LIMITATIONS: Clinical data was obtained from literature validated by experts therefore results generalizability is limited. In therapeutic neuroprocedures, there is an experience imbalance between approaches and recovery times were not included hence the total impact is not fully captured. CONCLUSIONS: The early economic model suggests that implementing TRA is associated with reduced costs and complications in diagnostic procedures. In therapeutic procedures, TRA lead to fewer complications and it is estimated to be cost-neutral, however its full potential still needs to be quantified.

One-Week Suicide Risk Prediction Using Real-Time Smartphone Monitoring: Prospective Cohort Study.

BACKGROUND: Suicide is a major global public health issue that is becoming increasingly common despite preventive efforts. Though current methods for predicting suicide risk are not sufficiently accurate, technological advances provide invaluable tools with which we may evolve toward a personalized, predictive approach. OBJECTIVE: We aim to predict the short-term (1-week) risk of suicide by identifying changes in behavioral patterns characterized through real-time smartphone monitoring in a cohort of patients with suicidal ideation. METHODS: We recruited 225 patients between February 2018 and March 2020 with a history of suicidal thoughts and behavior as part of the multicenter SmartCrisis study. Throughout 6 months of follow-up, we collected information on the risk of suicide or mental health crises. All participants underwent voluntary passive monitoring using data generated by their own smartphones, including distance walked and steps taken, time spent at home, and app usage. The algorithm constructs daily activity profiles for each patient according to these data and detects changes in the distribution of these profiles over time. Such changes are considered critical periods, and their relationship with suicide-risk events was tested. RESULTS: During follow-up, 18 (8%) participants attempted suicide, and 14 (6.2%) presented to the emergency department for psychiatric care. The behavioral changes identified by the algorithm predicted suicide risk in a time frame of 1 week with an area under the curve of 0.78, indicating good accuracy. CONCLUSIONS: We describe an innovative method to identify mental health crises based on passively collected information from patients' smartphones. This technology could be applied to homogeneous groups of patients to identify different types of crises.

The secretome atlas of two mouse models of progeria.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (LmnaG609G/G609G and Zmpste24-/- mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging.

RFcaller: a machine learning approach combined with read-level features to detect somatic mutations.

The cost reduction in sequencing and the extensive genomic characterization of a wide variety of cancers are expanding tumor sequencing to a wide number of research groups and the clinical practice. Although specific pipelines have been generated for the identification of somatic mutations, their results usually differ considerably, and a common approach is to use several callers to achieve a more reliable set of mutations. This procedure is computationally expensive and time-consuming, and it suffers from the same limitations in sensitivity and specificity as other approaches. Expert revision of mutant calls is therefore required to verify calls that might be used for clinical diagnosis. This step could take advantage of machine learning techniques, as they provide a useful approach to incorporate expert-reviewed information for the identification of somatic mutations. Here we present RFcaller, a pipeline based on machine learning algorithms, for the detection of somatic mutations in tumor-normal paired samples that does not require large computing resources. RFcaller shows high accuracy for the detection of substitutions and insertions/deletions from whole genome or exome data. It allows the detection of mutations in driver genes missed by other approaches, and has been validated by comparison to deep and Sanger sequencing.

Long-term potentiation and spatial memory training stimulate the hippocampal expression of RyR2 calcium release channels.

Introduction: Neuronal Ca2+ signals generated through the activation of Ca2+-induced Ca2+ release in response to activity-generated Ca2+ influx play a significant role in hippocampal synaptic plasticity, spatial learning, and memory. We and others have previously reported that diverse stimulation protocols, or different memory-inducing procedures, enhance the expression of endoplasmic reticulum-resident Ca2+ release channels in rat primary hippocampal neuronal cells or hippocampal tissue. Methods and Results: Here, we report that induction of long-term potentiation (LTP) by Theta burst stimulation protocols of the CA3-CA1 hippocampal synapse increased the mRNA and protein levels of type-2 Ryanodine Receptor (RyR2) Ca2+ release channels in rat hippocampal slices. Suppression of RyR channel activity (1 h preincubation with 20 µM ryanodine) abolished both LTP induction and the enhanced expression of these channels; it also promoted an increase in the surface expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR1 and GluR2 and caused a moderate but significant reduction of dendritic spine density. In addition, training rats in the Morris water maze induced memory consolidation, which lasted for several days after the end of the training period, accompanied by an increase in the mRNA levels and the protein content of the RyR2 channel isoform. Discussion: We confirm in this work that LTP induction by TBS protocols requires functional RyR channels. We propose that the increments in the protein content of RyR2 Ca2+ release channels, induced by LTP or spatial memory training, play a significant role in hippocampal synaptic plasticity and spatial memory consolidation.