Cross-Modal Plasticity in Brains Deprived of Visual Input Before Vision.

Unimodal sensory loss leads to structural and functional changes in both deprived and nondeprived brain circuits. This process is broadly known as cross-modal plasticity. The evidence available indicates that cross-modal changes underlie the enhanced performances of the spared sensory modalities in deprived subjects. Sensory experience is a fundamental driver of cross-modal plasticity, yet there is evidence from early-visually deprived models supporting an additional role for experience-independent factors. These experience-independent factors are expected to act early in development and constrain neuronal plasticity at later stages. Here we review the cross-modal adaptations elicited by congenital or induced visual deprivation prior to vision. In most of these studies, cross-modal adaptations have been addressed at the structural and functional levels. Here, we also appraise recent data regarding behavioral performance in early-visually deprived models. However, further research is needed to explore how circuit reorganization affects their function and what brings about enhanced behavioral performance.

Cutaneous immune-related adverse events: incidence rates, risk factors and association with extracutaneous toxicity - a prospective study of 189 patients treated with checkpoint inhibitors at a Spanish tertiary care hospital.

BACKGROUND: Clinicians are increasingly prescribing immune checkpoint inhibitors (ICIs) to treat cancer, but the real-world incidence, characteristics and risk factors of cutaneous immune-related adverse events (cirAEs) are unclear. OBJECTIVES: To determine the incidence, features and risk factors of cirAEs and to measure their possible association with extracutaneous toxicity. METHODS: We conducted a prospective observational study in a Spanish tertiary care hospital, including people who started an ICI between March 2020 and May 2022. We used a survival analysis and a log-rank test to obtain and compare incidence rates, and a multivariate Cox model to detect risk factors for cirAEs. RESULTS: We included 189 patients, 82 (43.4%) of whom presented cutaneous toxicity. The incidence of cirAEs was 75.0 per 100 person-years, with a 50.0% probability of the appearance of a cirAE at 10 months of follow-up. The most frequent cirAE category was inflammatory dermatoses, and the most frequent types were pruritus, eczema and maculopapular eruptions. ICI combination therapy, a family history of psoriasis and rheumatological and pulmonary immune-related adverse events increased the risk of cirAEs. CONCLUSIONS: We found a high incidence of cirAEs, and they occurred early in the follow-up period. Dermatologists should be involved in the management of cirAEs, especially in people with risk factors.

Efficacy of omalizumab for the treatment of bullous pemphigoid: Spanish multicentre real-world experience.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. Most patients are older and have associated multiple comorbidities. Topical and systemic corticosteroids are considered the first-line treatment for BP, and immunosuppressants are used as steroid-sparing treatments. However, both have side-effects and contraindications, which are even more common in this older population. New treatments targeting interleukins and receptors related to BP pathogenesis have been proposed to decrease these side-effects while achieving equal or better effectiveness and response rates. Omalizumab is a monoclonal antibody that targets IgE and has been proposed for the treatment of BP due to the evidence that IgE autoantibodies play an essential role in BP pathogenesis. OBJECTIVES: To assess the efficacy and safety of omalizumab for the treatment of BP. METHODS: We carried out a multicentre, retrospective, observational study including patients diagnosed with BP who received omalizumab for ≥ 3 months from 15 tertiary hospitals in Spain. IgE levels prior to treatment were measured, and we evaluated the possible correlation with clinical response. We excluded patients treated with omalizumab for < 3 months, as we consider this duration to be insufficient for a comprehensive assessment of its efficacy. To evaluate the effectiveness of the treatment, we used the percentage of body surface area improvement. RESULTS: We included 36 patients. The vast majority had associated multiple comorbidities, and all patients had used other systemic therapies apart from corticosteroids before omalizumab. In total, 83% experienced some kind of treatment response and 42% of all patients treated achieved complete response. We did not find any correlation between higher IgE levels and a better response (P = 0.2). All patients tolerated omalizumab without reported side-effects. CONCLUSIONS: Omalizumab is a good therapeutic alternative for BP as it provided clinical response in most patients, and nearly one-half of the cases achieved complete response. It showed no side-effects, which is crucial in older patients with BP.

Atypical pediatric presentation of lymphocytic thrombophilic arteritis: Diagnostic difficulties and recent nosological clarification.

A 4-year-old girl presented with a 2-month history of round, hypopigmented, slightly scaly patches measuring 1-6 cm and encircled by an erythematous halo, first appearing on the lower limbs then spreading to the whole body. Three biopsies were taken as the condition progressed, each showing a lymphocytic infiltrate affecting a medium-sized artery at the dermal-subcutaneous junction, with a concentric fibrin ring. These findings are characteristic of lymphocytic thrombophilic arteritis (LTA). The young age of our patient and the type of skin lesions she developed make this an atypical presentation of LTA, which usually manifests as hyperpigmented macules on the lower extremities, predominantly in dark-skinned women.

High fructose-containing drinking water-induced steatohepatitis in rats is prevented by the nicotinamide-mediated modulation of redox homeostasis and NADPH-producing enzymes.

An imbalance in the redox state, increased levels of lipid precursors and overactivation of de novo lipogenesis determine the development of fibrosis during nonalcoholic steatohepatitis (NASH). We evaluated the modulation of NADPH-producing enzymes associated with the antifibrotic, antioxidant and antilipemic effects of nicotinamide (NAM) in a model of NASH induced by excess fructose consumption. Male rats were provided drinking water containing 40% fructose for 16 weeks. During the last 12 weeks of fructose administration, water containing NAM was provided to some of the rats for 5 h/day. The biochemical profiles and the ghrelin, leptin, lipoperoxidation and TNF-α levels in serum and the glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and NADP+-dependent isocitric dehydrogenase (IDP) levels, the reduced/oxidized glutathione (GSH/GSSG) and reduced/oxidized nicotinamide adenine dinucleotide (phosphate) (NAD(P)H/NAD(P)+) ratios, and the levels of various lipogenic and fibrotic markers in the liver were evaluated. The results showed that hepatic fibrosis induced by fructose consumption was associated with weight gain, hunger-satiety system dysregulation, hyperinsulinemia, dyslipidemia, lipoperoxidation and inflammation. Moreover, increased levels of hepatic G6PD and ME activity and expression, the NAD(P)H/NAD(P)+ ratios, and GSSG concentration and increased expression of lipogenic and fibrotic markers were detected, and these alterations were attenuated by NAM administration. Specifically, NAM diminished the activity and expression of G6PD and ME, and this effect was associated with a decrease in the NADPH/NADP+ ratios, increased GSH levels and decreased lipoperoxidation and inflammation, ameliorating fibrosis and NASH development. NAM reduces liver steatosis and fibrosis by regulating redox homeostasis through a G6PD- and ME-dependent mechanism.

No SARS-CoV-2 antibody response in 25 patients with pseudo-chilblains.

Chilblain-like acral lesions have been identified in some coronavirus disease 2019 (COVID-19) patients. It has been suggested that these pseudo-chilblains could be a specific marker of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Most patients with these lesions have had negative polymerase chain reactions (PCRs), but some authors believe serology tests are likely to give positive results. We designed a prospective study including all patients with pseudo-chilblains treated in outpatient department in April and May 2020 and then performed SARS-CoV-2 PCR and serology tests on all available patients. We evaluated 59 patients, of whom 17 had undergone PCR before the study period, all with negative results. For the present study, we performed 20 additional PCRs, serology tests in 25 patients, and a parvovirus B19 antibody test in 15 patients. All results were negative. Our findings counter the hypothesis that serology is likely to reveal SARS-CoV-2 infection in patients with pseudo-chilblains. One hypothesis for our negative results is that the time period between symptom onset and antibody production is longer in these patients; another is that the lesions are caused by behavioral changes during lockdown rather than SARS-CoV-2 infection. We nevertheless maintain that COVID-19 should be ruled out in people presenting with chilblain-like lesions.

Umbilical Cord Blood Cytomegalovirus Serostatus Does Not Have an Impact on Outcomes of Umbilical Cord Blood Transplantation for Acute Leukemia.

Several studies have reported an impact of adult hematopoietic stem cell donor cytomegalovirus (CMV) serostatus on allogeneic hematopoietic cell transplantation outcomes. Limited data, however, are available on the impact of cord blood unit (CBU) CMV serostatus on allogeneic umbilical cord blood transplantation (UCBT) outcomes. We analyzed, retrospectively, the impact of CBU CMV serostatus on relapse incidence (RI) and 2-year nonrelapse mortality (NRM) of single-unit CBU transplantation for acute leukemia. Data from 1177 de novo acute leukemia pediatric and adult patients transplanted within European Group for Blood and Marrow Transplantation centers between 2000 and 2012 were analyzed. CBUs were provided by the European Cord Blood Banks. The median follow-up time for live patients was 59.9 months. The recipients of CMV-seropositive and -seronegative CBUs showed a comparable RI (33% versus 35%, respectively, P = .6) and 2-year cumulative incidence of NRM (31% versus 32%, respectively, P = .5). We conclude that CBU CMV serostatus did not influence RI and NRM in de novo acute leukemia patients after allo-UCBT and should not be included as a criteria for cord blood choice.

Real-Time Electrical Bioimpedance Characterization of Neointimal Tissue for Stent Applications.

To follow up the restenosis in arteries stented during an angioplasty is an important current clinical problem. A new approach to monitor the growth of neointimal tissue inside the stent is proposed on the basis of electrical impedance spectroscopy (EIS) sensors and the oscillation-based test (OBT) circuit technique. A mathematical model was developed to analytically describe the histological composition of the neointima, employing its conductivity and permittivity data. The bioimpedance model was validated against a finite element analysis (FEA) using COMSOL Multiphysics software. A satisfactory correlation between the analytical model and FEA simulation was achieved in most cases, detecting some deviations introduced by the thin "double layer" that separates the neointima and the blood. It is hereby shown how to apply conformal transformations to obtain bioimpedance electrical models for stack-layered tissues over coplanar electrodes. Particularly, this can be applied to characterize the neointima in real-time. This technique is either suitable as a main mechanism for restenosis follow-up or it can be combined with proposed intelligent stents for blood pressure measurements to auto-calibrate the sensibility loss caused by the adherence of the tissue on the micro-electro-mechanical sensors (MEMSs).

Nrg1 intracellular signaling regulates the development of interhemispheric callosal axons in mice.

Schizophrenia is associated with altered cortical circuitry. Although the schizophrenia risk gene NRG1 is known to affect the wiring of inhibitory interneurons, its role in excitatory neurons and axonal development is unclear. Here, we investigated the role of Nrg1 in the development of the corpus callosum, the major interhemispheric connection formed by cortical excitatory neurons. We found that deletion of Nrg1 impaired callosal axon development in vivo. Experiments in vitro and in vivo demonstrated that Nrg1 is cell-autonomously required for axonal outgrowth and that intracellular signaling of Nrg1 is sufficient to promote axonal development in cortical neurons and specifically in callosal axons. Furthermore, our data suggest that Nrg1 signaling regulates the expression of Growth Associated Protein 43, a key regulator of axonal growth. In conclusion, our study demonstrates that NRG1 is involved in the formation of interhemispheric callosal connections and provides a novel perspective on the relevance of NRG1 in excitatory neurons and in the etiology of schizophrenia.

Development of an Automated Design Tool for FEM-Based Characterization of Solid and Hollow Microneedles.

Microneedle design for biomedical applications, such as transdermal drug delivery, vaccination and transdermal biosensing, has lately become a rapidly growing research field. In this sense, finite element analysis has been extendedly used by microneedle designers to determine the most suitable structural parameters for their prototypes, and also to predict their mechanical response and efficiency during the insertion process. Although many proposals include computer-aided tools to build geometrical models for mechanical analysis, there is a lack of software utilities intended to automate the design process encompassing geometrical modeling, simulation setup and postprocessing of results. This work proposes a novel MATLAB-based design tool for microneedle arrays that permits personalized selection of the basic characteristics of a mechanical model. The tool automatically exports the selected options to an ANSYS batch file, including instructions to run a static and a linear buckling analysis. Later, the subsequent simulation results can be retrieved for on-screen display and potential postprocessing. In addition, this work reviews recent proposals (2018-2022) about finite element model characterization of microneedles to establish the minimum set of features that any tool intended for automating a design process should provide.

Accompanying mental health problems at home: Preliminary data from a crisis resolution and home treatment team in Catalonia.

WHAT IS KNOWN ON THE SUBJECT?: Home treatment teams help people in a mental health crisis to recover. The staff goes to the person's home, avoiding the need to go to the hospital and providing care in the person's environment. The teams have been created in our country in recent years, becoming part of the mental health care network. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: The paper presents the functioning of a CRHTT, the type of care it provides, and the coordination with the rest of the care network. It also shows the clinical results obtained in the first two years since its creation, supporting the CRHTT's effectiveness in accompanying people with mental health crises and reducing the need for hospital care. The outstanding factors in the team operation were coordination fluidity with referral services (facilitating accessibility), a prolonged care time (about two months), and continuity of care during the CRHTT intervention (the same CRHTT professionals visited the user and the family at home) and upon discharge (CRHTT staff organized joint visits with the professionals who would care for the user and the family after home treatment). The CRHTT followed a person-centered orientation based on horizontality and dialogue. The CRHTT fostered the inclusion of the family and social network in the treatment and a deep understanding of the crisis considering social determinants. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Flexibility, approach to the person's environment, dialogue, shared decision-making, and the inclusion of the family and social network in the treatment are central factors in CRHTT functioning. It helps the person regain control over their life and enhance their resources to face possible future crises. Training in crisis management, community mental health and family care, and teamwork (which implies joint home visits and co-responsibility with the rest of the staff, user, and the family) are relevant for CRHTT professionals. ABSTRACT: INTRODUCTION: Crisis resolution and home treatment teams (CRHTTs) provide intensive home care to people in a mental health crisis, becoming an increasingly widespread alternative to hospital admissions. However, there are wide variations in service delivery, organization, and outcomes, and little literature on how these teams work in clinical practice and different settings. AIM: To share the organizational functioning, the therapeutic approach, and the outcomes obtained in a CRHTT in Catalonia, Spain. METHOD: A descriptive analysis of the functioning of a home treatment team, the characteristics of the people served, and the clinical results from November 2017 to December 2019 are presented. RESULTS: One hundred and five people were served, with an average stay of 57 days. And 55.24% were women, and the mean age was 41. Most people could overcome the crisis at home, and 5.71% required hospital admission during home care. A statistically significant improvement was observed in the results of the GAF and HoNOS scales at admission and discharge. DISCUSSION: Despite reduced staff, home care was an alternative to hospital admission for most people treated. IMPLICATIONS FOR PRACTICE: Flexibility, teamwork, and collaboration with the social network are relevant factors when accompanying the recovery process at home.

Frailty in hemodialysis patients: results of a screening program and multidisciplinary interventions.

Background: The number of frail patients of advanced age with end-stage kidney disease (ESKD) undergoing hemodialysis is increasing globally. Here we evaluated a frailty screening program of ESKD patients starting hemodialysis, and subsequent multidisciplinary interventions. Methods: This was a prospective observational study of ESKD patients in a hemodialysis program. Patients were evaluated for frailty (Fried frail phenotype) before and after a 12-month period. Patients followed standard clinical practice at our hospital, which included assessment and multidisciplinary interventions for nutritional (malnutrition-inflammation score, protein-energy wasting), physical [short physical performance battery (SPPB)] and psychological status. Results: A total of 167 patients (mean ± standard deviation age 67.8 ± 15.4 years) were screened for frailty, and 108 completed the program. At screening, 27.9% of the patients were frail, 40.0% pre-frail and 32.1% non-frail. Nutritional interventions (enrichment, oral nutritional supplements, intradialytic parenteral nutrition) resulted in stable nutritional status for most frail and pre-frail patients after 12 months. Patients following recommendations for intradialytic, home-based or combined physical exercise presented improved or stable in SPPB scores after 12 months, compared with those that did not follow recommendations, especially in the frail and pre-frail population (P = .025). A rate of 0.05 falls/patient/year was observed. More than 60% of frail patients presented high scores of sadness and anxiety. Conclusions: Frailty screening, together with coordinated interventions by nutritionists, physiotherapists, psychologists and nurses, preserved the health status of ESKD patients starting hemodialysis. Frailty assessment helped in advising patients on individual nutritional, physical or psychological needs.

Psychometric properties of the Spanish SABA Reliance Questionnaire (SRQ) among patients with asthma.

Background: Patient beliefs about their asthma and its treatment may contribute to overreliance on short-acting ß2-agonist (SABA) therapy, leading to increased risk for potentially life-threatening exacerbations. The SABA Reliance Questionnaire (SRQ) is a validated tool for evaluating patients beliefs about SABAs that may lead to overreliance and overuse. Objective: Our aim was to evaluate the psychometric properties of the Spanish version of the SRQ. Methods: This was an observational, cross-sectional, single-country questionnaire validation study in adults with asthma. Reliability (ordinal α) and validity (convergent and discriminant) of SRQ were evaluated. Concurrent validity was assessed with the Beliefs about Medication Questionnaire, the Treatment Satisfaction Questionnaire for Medication, and a visual analog scale item to assess patients' perceptions of the importance of their reliever inhaler. Discriminant validity was assessed through differences in mean SRQ sum score between patients with high adherence to inhaled corticosteroids and those with low adherence, as measured by the Medication Adherence Report Scale-9 and the Test of Adherence to Inhalers. Results: The Spanish-SRQ exhibited good psychometric properties among 131 patients with asthma. Internal consistency was confirmed with an ordinal α of 0.85. All 5 items were useful for measuring patients' beliefs about SABAs that may lead them to be overreliant on SABAs. Concurrent validity with the Beliefs about Medication Questionnaire, Treatment Satisfaction Questionnaire for Medication, and a visual analog scale item assessing patients' perceptions of the importance of their reliever inhaler was demonstrated. Conclusion: The Spanish version of the SRQ is a valid tool for evaluating potential overreliance on SABAs in Spanish-speaking patients to enable early intervention and support.

Spontaneous Thalamic Activity Modulates the Cortical Innervation of the Primary Visual Nucleus of the Thalamus.

Sensory processing relies on the correct development of thalamocortical loops. Visual corticothalamic axons (CTAs) invade the dorsolateral geniculate nucleus (dLGN) of the thalamus in early postnatal mice according to a regulated program that includes activity-dependent mechanisms. Spontaneous retinal activity influences the thalamic incursion of CTAs, yet the perinatal thalamus also generates intrinsic patterns of spontaneous activity whose role in modulating afferent connectivity remains unknown. Here, we found that patterned spontaneous activity in the dLGN contributes to proper spatial and temporal innervation of CTAs. Disrupting patterned spontaneous activity in the dLGN delays corticogeniculate innervation under normal conditions and upon eye enucleation. The delayed innervation was evident throughout the first two postnatal weeks but resumes after eye-opening, suggesting that visual experience is necessary for the homeostatic recovery of corticogeniculate innervation.

Input-dependent segregation of visual and somatosensory circuits in the mouse superior colliculus.

Whereas sensory perception relies on specialized sensory pathways, it is unclear whether these pathways originate as modality-specific circuits. We demonstrated that somatosensory and visual circuits are not by default segregated but require the earliest retinal activity to do so. In the embryo, somatosensory and visual circuits are intermingled in the superior colliculus, leading to cortical multimodal responses to whisker pad stimulation. At birth, these circuits segregate, and responses switch to unimodal. Blocking stage I retinal waves prolongs the multimodal configuration into postnatal life, with the superior colliculus retaining a mixed somato-visual molecular identity and defects arising in the spatial organization of the visual system. Hence, the superior colliculus mediates the timely segregation of sensory modalities in an input-dependent manner, channeling specific sensory cues to their appropriate sensory pathway.

Dynamic interplay between thalamic activity and Cajal-Retzius cells regulates the wiring of cortical layer 1.

Cortical wiring relies on guidepost cells and activity-dependent processes that are thought to act sequentially. Here, we show that the construction of layer 1 (L1), a main site of top-down integration, is regulated by crosstalk between transient Cajal-Retzius cells (CRc) and spontaneous activity of the thalamus, a main driver of bottom-up information. While activity was known to regulate CRc migration and elimination, we found that prenatal spontaneous thalamic activity and NMDA receptors selectively control CRc early density, without affecting their demise. CRc density, in turn, regulates the distribution of upper layer interneurons and excitatory synapses, thereby drastically impairing the apical dendrite activity of output pyramidal neurons. In contrast, postnatal sensory-evoked activity had a limited impact on L1 and selectively perturbed basal dendrites synaptogenesis. Collectively, our study highlights a remarkable interplay between thalamic activity and CRc in L1 functional wiring, with major implications for our understanding of cortical development.

Embryo quality, blastocyst and ongoing pregnancy rates in oocyte donation patients whose embryos were monitored by time-lapse imaging.

PURPOSE: In the current study, our aim was to demonstrate that EmbryoScope incubation conditions is comparable to standard laboratory incubation circumstances by comparing embryo quality, development and ongoing pregnancy rates between the EmbryoScope (ES) and a standard incubator (SI). We analyzed 478 embryos from 60 couples undergoing oocyte donation were included in the study. METHODS: All embryos retrieved from a patient were randomly distributed in the ES or SI. We calculated blastocyst development rate, blastocyst viability and ongoing pregnancy rate for embryo transfers from ES, SI and mixed (one embryo from the ES and one from the SI). Statistical analysis was conducted by Chi square tests, considering p < 0.05 significant. RESULTS: No significant differences were found between the ES and SI from all the parameters evaluated. CONCLUSIONS: Thus we concluded that time-lapse monitoring in the EmbryoScope does not impair embryo quality while allowing for morphological, spatial and temporal analysis of embryo development.

A New Methodology to Design Sustainable Archimedean Screw Turbines as Green Energy Generators.

Current energy demand and climate target plans are leading to green energy facilities which are efficient and sustainable. Archimedean screw turbines (ASTs) are used to generate hydroelectricity in low heads. They have been manufactured and installed worldwide. However, there is a lack of knowledge about how to design them efficiently. In this study, the performance of ASTs is analyzed using an analogy between ASTs and bucket elevators. Based on this analogy, a theoretical hypothesis on how to produce efficient ASTs is proposed. The new methodology for the design of ASTs is based on two considerations: the filling level of the AST buckets must be 85% and the increase of leakage losses must be minimized. This hypothesis is numerically and experimentally studied. Two experimental prototypes were developed and installed in the north of Spain. The numerical and experimental results are provided. A discussion comparing the results of this work and other results from the literature is presented. Finally, conclusions are drawn from this work that contribute to the improvement of AST technology as a sustainable facility to generate green energy.