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BACKGROUND AND OBJECTIVES: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose). METHODS: Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment. RESULTS: In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone Cmax and AUC0-inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of Cmax and AUC0-inf values compared with healthy subjects were above 100% (138.22-176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), Cmax and AUC0-inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, Cmax and AUC0-inf were approximately 20-30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment. CONCLUSION: Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis.
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Metadona , Insuficiencia Renal Crónica , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Metadona/farmacocinética , Metadona/administración & dosificación , Metadona/efectos adversos , Insuficiencia Renal Crónica/terapia , Hepatopatías , Anciano , Área Bajo la Curva , Adulto Joven , Administración Oral , Tasa de Filtración Glomerular/efectos de los fármacosRESUMEN
BACKGROUND: The selection of patients who are going to be admitted to an emergency department observation unit (EDOU) is essential for the good management of these units, intended fundamentally to avoid unnecessary hospitalization of patients. This is especially important when dealing with older patients. It would be important to know what factors are associated with discharge home and to have a clinical predictive scale that appropriately selects older patients who are going to be admitted to an EDOU. METHODS: A retrospective cross-sectional study was conducted of all patients ≥65 years of age assisted in 48 Spanish Emergency Departments for 7 consecutive days and were admitted to the EDOU. Demographics-functional, vital signs data and initial laboratory results were analyzed to investigate its association with discharge home and develop and validate a prediction model for discharge home from EDOU. Multivariable logistic regression was performed to develop a prediction model, and a scoring system was created. RESULTS: Among 5457 patients admitted to the EDOU from the emergency room, 2508 (46%) patients were discharged home, and 2949 (54%) were admitted to the hospital. Five variables were strongly associated with discharge home: the absence of fever (adjusted OR: 3.61, 95% CI:1.53-8.54), Glasgow Coma Scale score of 15 points (2.80, 1.63-4.82), absence of tachypnea (2.51, 1.74-3.64) or leukocytosis (2.07, 1.70-2.52) and oxygen saturation >94% (2.00, 1.64-2.43). The final model achieved an area under the receiver operating characteristic curve of 0.648 (IC95% = 0.627-0.668) in the development cohort and 0.635 (0.614-0.656) in the validation cohort. CONCLUSIONS: There are factors associated with a greater probability of discharge home of older patients admitted to EDOUs. Prediction at the individual level remains elusive, as the best model obtained in this study did not have sufficient validity to be applied in the clinical setting.
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OBJECTIVE: To determine the changes in health-related quality of life (HRQoL) and sleep quality following a supervised combined exercise (EX) program compared to a Treatment-As-Usual (TAU) and to analyze the relationship between the differences in cardiorespiratory fitness (CRF) and HRQoL domains in people with schizophrenia (SZ). METHODS: The SZ (n = 112, 41.3 ± 10.4 year) was randomly assigned into a TAU control group (n = 53) or EX-group (n = 59, 3 days/week). The 36-item Short-Form Health Survey questionnaire assessed HRQoL and the sleep quality analysis (accelerometry). RESULTS: After the intervention (20 weeks), physical functioning (∆ = 12.9%), general health (∆ = 15.3%), mental health (∆ = 8.3%), physical component summary (PCS) (∆ = 5.1%), and sleep efficiency (∆ = 1.9%) increased (p < 0.05) in the EX, with no significant changes in the TAU for any domains studied. There were significant differences between groups whose EX showed improvements (p < 0.05) compared to TAU in physical functioning, general health, PCS, and sleep efficiency. A greater CRF was associated with better values in physical functioning, role-physical, bodily pain, general health, vitality, and PCS after the exercise program in SZ. CONCLUSIONS: A 20-week supervised combined exercise intervention program for SZ increased sleep efficiency and physical functioning, general and mental health, and PCS scores. This could lead to a critical HRQoL change from how they were to how they should be. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03509597.
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Capacidad Cardiovascular , Terapia por Ejercicio , Calidad de Vida , Esquizofrenia , Calidad del Sueño , Humanos , Esquizofrenia/terapia , Esquizofrenia/rehabilitación , Masculino , Femenino , Adulto , Terapia por Ejercicio/métodos , Persona de Mediana Edad , Encuestas y Cuestionarios , Salud MentalRESUMEN
The Spanish Society of Tropical Medicine and International Health (SEMTSI), the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Primary Care Physicians (SEMERGEN) and the Spanish Society of Family and Community Medicine (SEMFYC) have prepared a consensus statement on the diagnosis and management of patients with imported febrile illnesses. Twenty authors with different backgrounds and representing different healthcare perspectives (ambulatory primary care, travel and tropical medicine specialists, emergency medicine, hospital care, microbiology and parasitology and public health), identified 39 relevant questions, which were organised in 7 thematic blocks. After a systematic review of the literature and a thoughtful discussion, the authors prepared 125 recommendations, as well as several tables and figures to be used as a consulting tool. The present executive summary shows a selection of some of the most relevant questions and recommendations included in the guidelines.
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Enfermedades Transmisibles Importadas , Fiebre , Humanos , Fiebre/etiología , Fiebre/diagnóstico , Enfermedades Transmisibles Importadas/diagnóstico , Enfermedades Transmisibles Importadas/terapia , Enfermedad Relacionada con los Viajes , EspañaRESUMEN
Background: Older adults with bipolar disorder (OABD) are individuals aged 50 years and older with bipolar disorder (BD). People with BD may have fewer coping strategies or resilience. A long duration of the disease, as seen in this population, could affect the development of resilience strategies, but this remains under-researched. Therefore, this study aims to assess resilience levels within the OABD population and explore associated factors, hypothesizing that resilience could improve psychosocial functioning, wellbeing and quality of life of these patients. Methods: This study sampled 33 OABD patients from the cohort at the Bipolar and Depressive Disorders Unit of the Hospital Clinic of Barcelona. It was an observational, descriptive and cross-sectional study. Demographic and clinical variables as well as psychosocial functioning, resilience and cognitive reserve were analyzed. Resilience was measured using the CD-RISC-10. Non-parametric tests were used for statistical analysis. Results: The average CD-RISC-10 score was 25.67 points (SD 7.87). Resilience negatively correlated with the total number of episodes (p = 0.034), depressive episodes (p = 0.001), and the FAST (p < 0.001). Participants with normal resilience had a lower psychosocial functioning (p = 0.046), a higher cognitive reserve (p = 0.026), and earlier onset (p = 0.037) compared to those with low resilience. Conclusions: OABD individuals may have lower resilience levels which correlate with more psychiatric episodes, especially depressive episodes and worse psychosocial functioning and cognitive reserve. Better understanding and characterization of resilience could help in early identification of patients requiring additional support to foster resilience and enhance OABD management.
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OBJECTIVE: Analyse the association between the use of diagnostic tests and the characteristics of older patients 65 years of age or more who consult the emergency department (ED). METHODS: We performed an analysis of the EDEN cohort that includes patients who consulted 52 Spanish EDs. The association of age, sex, and ageing characteristics with the use of diagnostic tests (blood tests, electrocardiogram (ECG), microbiological cultures, X-ray, computed tomography, ultrasound, invasive techniques) was studied. The association was analysed by calculating the adjusted odds ratios (aOR) and their 95 % confidence intervals (CI) using a logistic regression model. RESULTS: A total of 25,557 patients were analysed. There was an increase in the use of diagnostic tests based on age, with an aOR for blood test of 1.805 (95 %CI 1.671 - 1.950), ECG 1.793 (95 %CI 1.664 - 1.932) and X-ray 1.707 (95 %CI 1.583 - 1.840) in the group of 85 years or more. The use of diagnostic tests is lower in the female population. Most ageing characteristics (cognitive impairment, previous falls, polypharmacy, dependence, and comorbidity) were independently associated with increased use of diagnostic tests. CONCLUSIONS: Age, and the characteristics of ageing itself are generally associated with a greater use of diagnostic tests in the ED.
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This study aimed to investigate the applicability of the Lactate Threshold (LT) to predict maximal oxygen uptake (ËVO2max) and demarcate the boundary between the moderate- to heavy-intensity domain (HRm-h) in old age in comparison to the most utilized methods. A cross-sectional validation study was conducted. Participants aged 61 to 77 performed a familiarization procedure, an incremental maximal exercise treadmill test (CPX) for ËVO2max determination, the Six-minute Walk Test (6MWT), and a discontinuous incremental field test for LT determination. Lower (P<0.01) internal effort was required for LT testing (76±8%HRmax) compared to 6MWT (92±9%HRmax). The application of the 6MWT reference equations overestimated ËVO2max by 10-23%. LTs better estimated the ËVO2max (r ≈0.90, SEE: ≈3.0] compared to the 6MWT (r=0.68, SEE=5.5). HRm-h determined by the CPX differed (20%; P=0.001) from that obtained by LT. HRm-h stratification indicated participants fall into the very light to the vigorous intensity domains. LT testing is more submaximal than the 6MWT, and is a valuable tool to estimate the ËVO2max in older male adults. Implementation of LT testing in physical activity programs might help improving the quality of aerobic exercise training in older men.
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Objective: To evaluate the moral distress (MD)in health professionals of pediatric and adult units to show how the complexity of care in the pediatric field causes the professionals who carry out their activity in these units to present a higher level of moral distress and a worse climate ethical. Design: Observational study with health professionals who currently work in Spanish Hospitals. Methods: A 58-item questionnaire was electronically distributed which included sociodemographic and employment characteristics, the Spanish version of the Measure of Moral Unrest for Healthcare Professionals (MMD-HP-SPA) and the Hospital Ethical Climate Survey (HECS). Results: A total of 169 health professionals completed the questionnaire. The moral distress was significantly higher among nurses than among physicians and nursing assistant care technicians. Focusing on the type of unit, moral distress it was only significantly higher for those physicians treating adult patients compared to those treating pediatric patients. Regarding the total score of the HECS survey, the medical group shows higher scores compared to the nursing group. Conclusion: Statistically significant differences have been found only in the medical group that treats adult patients, presenting a higher level of moral unrests than the pediatrician group. The MMD-HP-SPA questionnaire is a valid and useful instrument to detect MD in our hospital units in order to be able to implement strategies/interventions that improve the ethical climate and other factors that can mitigate and prevent this MD.
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INTRODUCTION: Surgical oncology patients have a high symptom burden and increased risk of morbidity. The aim of palliative care is to evaluate and treat the patient in a holistic manner focusing on the unique attributes of each patient. This goal-concordant approach could help surgical patients cope with the stress and uncertainty that often accompany serious illness and surgery, improving overall outcomes. This qualitative analysis sought to explore whether unmet specialist palliative care or end-of-life needs exist in this population. METHODS: Qualitative interviews were completed with a subset of participants in a randomized, controlled trial of a specialist palliative care intervention for patients undergoing abdominal oncologic surgery. The interview guide sought to elicit respondents' perceptions of palliative care and end-of-life needs perioperatively and postoperatively. Recurring themes were identified by two independent coders. RESULTS: Analysis of 47 interview transcripts revealed few serious concerns about end-of-life issues, however appreciation for the supportive presence offered by palliative care was present. Among participants who received specialist palliative care, many found the intervention helpful, but few were able to articulate issues that the intervention improved. CONCLUSION: These findings suggest low levels of unmet palliative care needs among this population, which is consistent with the results of the parent trial. Targeting patients with a higher symptom burden perioperatively may allow for improved symptom management and better adherence to the treatment plan postoperatively, as well as be a more focused use of specialist palliative care clinicians' efforts.
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RAS proteins regulate cell division, differentiation, and apoptosis through multiple downstream effector pathways. Oncogenic RAS variants are the commonest drivers in cancers; however, they also drive many benign lesions predisposing to malignancy, such as melanocytic nevi, thyroid nodules, and colonic polyps. Reversal of these benign lesions could reduce cancer incidence; however, the effects of oncogenic RAS have been notoriously difficult to target with downstream pathway inhibitors. In this study, we show effective suppression of oncogenic and currently undruggable NRASQ61K in primary cells from melanocytic nevi using small interfering RNA targeted to the recurrent causal variant. This results in striking reduction in expression of ARL6IP1, a known inhibitor of endoplasmic reticulum stress-induced apoptosis not previously linked to NRAS. We go on to show that a single dose of small interfering RNA in primary cells triggers an apoptotic cascade, in contrast to treatment with a MAPK/extracellular signal-regulated kinase kinase inhibitor. Protective packaging of the targeted small interfering RNA into lipid nanoparticles permits successful delivery into a humanized mouse model of melanocytic nevi and results in variant NRAS knockdown in vivo. These data show that RAS-induced protection from apoptosis is involved in persistence of NRAS-driven melanocytic nevi and anticipate that targeted small interfering RNA could form the basis of clinical trials for RAS-driven benign tumors.
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Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants.Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD (DSM-5) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35).Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant (P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% (P = .076), and response rates were 39.8% and 27.2% (P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 (P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups.Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies.Trial Registration: ClinicalTrials.gov identifier: NCT04688164.
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Antidepresivos , Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Masculino , Adulto , Femenino , Método Doble Ciego , Persona de Mediana Edad , Antidepresivos/efectos adversos , Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Resultado del Tratamiento , Quimioterapia CombinadaRESUMEN
Objective: The relationship between the duration of major depressive disorder (MDD) and therapeutic response to standard antidepressant treatment (SAT) is unknown. N-methyl-D-aspartate receptor uncompetitive antagonists are emerging drugs for MDD. We investigated whether the antidepressant effect of esmethadone (REL-1017) could be related to the duration of depression.Methods: We analyzed data from a Phase 2a study of adjunctive treatment with esmethadone in MDD patients (DSM-5) with inadequate response to ongoing SAT (May 2018-August 2019). Patients were randomized to treatment with esmethadone 25 mg, esmethadone 50 mg, or placebo for 7 days, followed by an observation period (Days 7-14). Duration of depression was derived from 2 measures: (1) time from onset (TFO), calculated as the difference in years between age at trial enrollment and age at the onset of the first major depressive episode (MDE), and (2) TFO index, calculated by computing the years of illness duration (number of years from the beginning of MDD), divided by age and multiplied by 100. First, bivariate correlations between TFO and change from baseline (CFB) were calculated by Spearman ρ. Linear mixed-model analyses were also conducted.Results: A total of 62 patients participated in the trial. The median values of time from MDD onset for the 62 patients were 11 years (absolute value) and 22% (percentage of life-years). Duration of depression was significantly correlated with Montgomery-Asberg Depression Rating Scale (MADRS) CFB on Day 14, even when controlling for the effect of current depression severity (MADRS baseline). In the linear mixed-model analyses, we found a significant effect of duration on reduction in MADRS score from T0 to subsequent assessments (P < .05). Number of previous MDEs and effect of esmethadone 50 mg when compared to 25 mg were not significant.Conclusion: Esmethadone 25 and 50 mg were more effective in reducing MADRS scores in patients with shorter time from first MDE onset.Trial Registration: ClinicalTrials.gov identifier: NCT03051256.
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Antidepresivos , Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Antidepresivos/uso terapéutico , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Método Doble CiegoRESUMEN
AIM: To examine the current literature on educational strategies and interventions developed with the objective of teaching or enhancing communication skills of student midwives during their pre-registration education programmes. DESIGN: A scoping review based on the Joanna Briggs Institute framework was conducted using predefined criteria and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. METHODS: A comprehensive search was conducted using various databases (Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, PsycINFO, Maternity and Infant Care Database (MIDIRS), Web of Science and Education Resources Information Centre (ERIC)) in October 2023. RESULTS: A total of 120 titles and abstracts were screened. A final number of eight articles were subjected to quality appraisal and included in the scoping review. Five themes were identified which describe educational strategies and interventions including: simulation-based training, the use of role-play, pedagogical approaches, theory-based information workshops and debrief and reflection. CONCLUSIONS: This review highlights a gap in research focusing on the importance of communication skills training for student midwives throughout midwifery education. Despite the limited numbers of studies, different interventions and educational strategies have been recognized for enhancing these skills. To equip midwives with strong communication skills, a combination of interventions is recommended, including communication-focused workshops tailored for midwifery education and debriefing and student reflection sessions specifically designed to enhanced communication skills. REGISTRATION NUMBER: to be included in abstract after acceptance.
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Comunicación , Partería , Estudiantes de Enfermería , Humanos , Partería/educación , Bachillerato en Enfermería , FemeninoRESUMEN
A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.
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Cricetulus , Canal de Sodio Activado por Voltaje NAV1.5 , Linaje , Penetrancia , Canal de Sodio Activado por Voltaje NAV1.5/genética , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Humanos , Animales , Células CHO , Femenino , Masculino , Adulto , Persona de Mediana Edad , España , Mutación con Pérdida de Función , Fenotipo , MutaciónRESUMEN
This study aims to determine the impact of 2 (low vs high volume) high-intensity interval training (HIIT) programs with Mediterranean diet (MedDiet) recommendations on health-related quality of life (HRQoL) and lifestyle modification, and to examine the relationships between the changes in anxiety and depression with HRQoL and lifestyle variables after myocardial infarction (MI). Participants (n = 80) were randomized to attention control or one of the two supervised HIIT groups (2 d/weeks). Surveys before and after intervention (16 weeks): HRQoL (SF-36), anxiety and depression (HADS), MedDiet adherence (MEDAS), and physical activity (PA) and sedentary behavior (SB) levels. After intervention, there were improvements (P < .05) in HRQoL, HADS scores, and MedDiet adherence, with higher PA level in both HIIT groups with no between-HIIT group differences. The HADS score decline correlated (P < .05) with both the increase in physical component of SF-36 (r = .42), the overall metabolic expenditure (r = .26), and adherence to the MedDiet (r = .24), and the reduction in the SB (r = .35). HIIT exercise intervention with MedDiet recommendations improved HRQoL, along with reduced anxiety and depression symptoms, and a healthier lifestyle after MI. Better mental health was related to higher values of PA and MedDiet adherence.
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Introduction: The pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression. Methods: Here, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity. Results: We found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (p < 0.01 vs. control untreated mice) and an extension of lifespan (p < 0.001 vs. control untreated mice) was observed in male G93A SOD1 mice. Female G93A SOD1 mice treated with REL-1017 showed an improvement of muscle strength (p < 0.01 vs. control untreated mice). Both males and females treated with REL-1017 showed a decrease in hind limb clasping. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles. Conclusion: In conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS.
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Resumen El trastorno por déficit de atención/hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo desde una perspectiva causal, clínica y pro nóstica. La investigación refleja su carácter multifactorial con un papel destacado de los factores genéticos. Los estudios poblacionales han señalado históricamente la implicación de numerosas variantes genéticas de escaso tamaño de efecto, las cuales por sí mismas apenas incre mentan el riesgo de TDAH y difícilmente justifican su ele vada heredabilidad. Muchas de ellas están presentes en más del 60% de la población general, lo que sugiere su pa pel modulador más que causal. No obstante, gracias a la irrupción de nuevas técnicas genéticas en los últimos 15 años, se están identificando un mayor número de casos con trastornos genéticos (muchos de ellos monogénicos), cuyas variantes genéticas explican por sí mismas la presencia del TDAH. El estudio detallado de los antecedentes personales y familiares, así como una exploración física completa, puede ayudar a identificar algunos de ellos. La identificación de la causa en este conjunto de casos tiene un valor crucial en el asesoramiento clínico, el consejo genético-familiar y la anticipación pronóstica, así como en la realización o evitación de estudios complementarios y en el diseño del plan terapéutico.
Abstract Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disor der from a causal, clinical and prognostic perspective. Research reflects its multifactorial nature with a promi nent role of genetic factors. Population studies have historically pointed to the involvement of numerous genetic variants of small effect size, which hardly by themselves increase the risk of presenting the disorder and hardly justify its high heritability. Many of them are present in more than 60% of the general population, suggesting their modulatory rather than causal role. However, after the irruption of new genetic techniques in the last 15 years, a greater number of cases are be ing identified with genetic disorders (many of them monogenic), whose genetic variants alone explain the presence of ADHD. A detailed study of the personal and family history, as well as a complete physical examination, can help to identify some of them. The identification of the cause in this group of cases has a crucial value in clinical counseling, genetic-familial counseling and prognostic anticipation, as well as in the performance or avoidance of complementary stud ies and in the design of the intervention plan.
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OBJECTIVES: To assess whether dementia is an independent predictor of death after a hospital emergency department (ED) visit by older adults with or without a COVID-19 diagnosis during the first pandemic wave. METHOD: We used data from the EDEN-Covid (Emergency Department and Elderly Needs during Covid) cohort formed by all patients ≥65 years seen in 52 Spanish EDs from March 30 to April 5, 2020. The association of prior history of dementia with mortality at 30, 180 and 365 d was evaluated in the overall sample and according to a COVID-19 or non COVID diagnosis. RESULTS: We included 9,770 patients aged 78.7 ± 8.3 years, 51.1% men, 1513 (15.5%) subjects with prior history of dementia and 3055 (31.3%) with COVID-19 diagnosis. 1399 patients (14.3%) died at 30 d, 2008 (20.6%) at 180 days and 2456 (25.1%) at 365 d. The adjusted Hazard Ratio (aHR) for age, sex, comorbidity, disability and diagnosis for death associated with dementia were 1.16 (95% CI 1.01-1.34) at 30 d; 1.15 at 180 d (95% CI 1.03-1.30) and 1.19 at 365 d (95% CI 1.07-1.32), p < .001. In patients with COVID-19, the aHR were 1.26 (95% CI: 1.04-1.52) at 30 days; 1.29 at 180 d (95% CI: 1.09-1.53) and 1.35 at 365 d (95% CI: 1.15-1.58). CONCLUSION: Dementia in older adults attending Spanish EDs during the first pandemic wave was independently associated with 30-, 180- and 365-day mortality. This impact was lower when adjusted for age, sex, comorbidity and disability, and was greater in patients diagnosed with COVID-19.