Understanding social cognition in children with cerebral palsy: exploring the relationship with executive functions and the intervention outcomes in a randomized controlled trial.

Children with Cerebral Palsy (CP) experience Social Cognition (SC) difficulties, which could be related to executive functioning. While motor interventions are common, there is limited knowledge about the impact of cognitive interventions on SC in this population. This study examined the relationship between SC and Executive Function (EF) skills and the effectiveness of an EF intervention that included some SC tasks for improving SC in children with CP. SC and EF domains were assessed in 60 participants with CP (30 females; 8-12 years). The relationship between SC and EF baseline scores was analyzed by bivariate correlations and contingency tables. Participants were matched by age, sex, motor ability, and intelligence quotient and randomized into intervention or control groups. The intervention group underwent a 12-week home-based computerized EF intervention. Analysis of covariance was used to examine differences in SC components between groups at post-intervention and 9 months after. Significant positive correlations were found between the SC and EF scores. The frequencies of impaired and average scores in SC were distributed similarly to the impaired and average scores in EFs. The intervention group showed significant improvements in Affect Recognition performance post-intervention, which were maintained at the follow-up assessment, with a moderate effect size. Long-term improvements in Theory of Mind were observed 9 months after. CONCLUSIONS: This study highlights the association between SC and EFs. A home-based computerized cognitive intervention program improves SC in children with CP. Including SC tasks in EF interventions may lead to positive short- and long-term effects for children with CP. CLINICAL TRIAL REGISTRATION: NCT04025749 retrospectively registered on 19 July 2019. WHAT IS KNOWN: • Executive functions and social cognition are associated with social and community participation in people with cerebral palsy. • A home-based computerized cognitive intervention can improve the executive functioning of children with cerebral palsy. WHAT IS NEW: • Social cognition performance is related to core and higher-order executive functions. • A home-based computerized executive function intervention, including social cognition tasks, has positive short- and long-term effects on social cognition skills in children with cerebral palsy.

Factores de mal pronóstico en 113 pacientes sometidos a duodenopancreatectomía cefálica por colangiocarcinoma distal / Prognostic risk factors in 113 patients undergoing cephalic duodenopancreatectomy for distal cholangiocarcinoma

Introducción El colangiocarcinoma distal es una neoplasia epitelial maligna que afecta a los conductos biliares extrahepáticos, per debajo del conducto cístico. Existe poca evidencia sobre la relación entre factores perioperatorios y peor evolución a largo plazo tras la resección quirúrgica. Objetivo Analizar los factores de riesgo de mortalidad y recidiva a largo plazo del colangiocarcinoma distal de los pacientes resecados. Material y métodos Se ha analizado una base de datos prospectiva unicéntrica de pacientes intervenidos por colangiocarcinoma distal entre los años 1990 y 2021 con la finalidad de investigar los factores de mortalidad y recidiva. Resultados Se han intervenido 113 pacientes, con una supervivencia actuarial media de 100,2 (76-124) meses tras la resección. El estudio bivariante no evidenció diferencias entre los pacientes dependiendo de la edad o variables preoperatorias estudiadas. La presencia de adenopatías afectadas fue un factor de riesgo de mortalidad a largo plazo en el estudio multivariante. La presencia de adenopatías afectadas, la recidiva tumoral y la fístula biliar durante el postoperatorio implicaron peor supervivencia actuarial al comparar las curvas de Kaplan-Meier. Conclusiones La presencia de adenopatías afectadas influyen en el pronóstico de la enfermedad. La aparición de fístula biliar durante el postoperatorio del colangiocarcinoma distal podría agravar los resultados a largo plazo, hallazgo que debe ser reafirmado en futuros estudios. (AU)

Introduction Distal cholangiocarcinoma is a malignant epithelial neoplasia that affects the extrahepatic bile ducts, below the cystic duct. No relevant relationship between perioperative factors and worse long-term outcome has been proved. Objective To analyze the risk factors for mortality and long-term recurrence of distal cholangiocarcinoma in resected patients. Materials and methods A single-center prospective database of patients operated on for distal cholangiocarcinoma between 1990 and 2021 was analyzed in order to investigate mortality and recurrence factors. Results One hundred and thirteen patients have undergone surgery, with mean actuarial survival of 100.2 (76–124) months after resection. The bivariate study did not show differences between patients depending on age or preoperative variables studied. When multivariate analysis was performed, the presence of affected adenopathy was a risk factor for long-term mortality. The presence of affected lymph nodes, tumor recurrence, and biliary fistula during the postoperative period implied worse actuarial survival when comparing the Kaplan–Meier curves. Conclusions The presence of affected lymph nodes influence the prognosis of the disease. The occurrence of biliary fistula during postoperative cholangiocarcinoma distal could aggravate long-term outcomes, a finding that should be reaffirmed in future studies. (AU)

Inter-laboratory comparison of routine autoantibody detection methods for autoimmune neuropathies and myasthenia gravis.

Serological tests are important to detect autoantibodies (autoAbs) in patients with autoimmune neuropathies (AN) and myasthenia gravis (MG) as they are biomarkers for diagnosis, stratification, treatment selection, and monitoring. However, tests to detect autoAbs frequently lack proper standardization and results differ across diagnostic laboratories. We compared results for tests routinely performed in Spanish diagnostic laboratories to detect AN and MG autoAbs. In the Spanish Society of Immunology Autoimmunity Group national workshop, serum samples from 13 patients with AN or MG were tested for anti-ganglioside, anti-myelin-associated glycoprotein (MAG), anti-nicotinic acetylcholine receptor (AChR), and anti-muscle-specific kinase (MuSK) autoAbs using reference methods and were distributed for analysis to 27 participating laboratories using their routine methods. Overserved were inter-laboratory variability and worryingly low sensitivity, especially for anti-ganglioside immunoglobulin G and anti-MAG autoAb detection. This pilot study reflects autoAbs detection state of the art in AN and MG testing in leading diagnostic laboratories in Spain, highlighting the need for standardization prior to clinical use.

Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.

Have we improved postoperative and long-term outcomes of liver surgery for colorectal cancer metastasis? Analysis of 1736 hepatectomies performed over 3 decades in a single center.

INTRODUCTION: Surgery is the only potentially curative treatment for colorectal cancer liver metastases (CRLM) and its indication and results have varied in the last 30 years. METHODS: All patients operated on for CRLM in our centre from 1990 to 2021 were prospectively collected, establishing 3 subgroups based on the year of the first surgery: group A 1990-1999, group B 2000-2010, group C 2011-2021. Clinical characteristics and the results of survival, recurrence and prognostic factors were compared. RESULTS: 1736 hepatectomies were included (Group A n = 208; Group B n = 770; Group C n = 758). Patients in group C had better survival at 5 and 10 years (A 40.5%/28.2%; B 45.9%/32.2%; C 51.6%/33.1%, p = 0.013), although there were no differences between groups in overall recurrence at 5 and 10 years (A 73%/75.7%; B 67.6%/69.2%, and C 63.9%/66%, p = 0.524), nor in liver recurrence (A 46.4%/48.2%; B 45.8%/48.2%; and C 44.4%/48.4%, p = 0.899). An improvement was observed in median survival after recurrence, being 19 months, 23 months, and 31 months (groups A, B and C respectively). Prognostic factors of long-term survival changed over the 3 study periods. The only ones that remained relevant in the last decade were the presence of >4 liver metastasis, extrahepatic disease at the time of hepatectomy, and intraoperative blood transfusion. CONCLUSIONS: Survival after surgery for CRLM has improved significantly, although this cannot be explained by a reduction in overall and hepatic recurrence, but rather by an improvement in post-recurrence survival. Involvement of the resection margin has lost prognostic value in the last decade.

Diagnóstico y tratamiento de los quistes hepáticos. Utilidad de los marcadores tumorales intraquísticos (CEA y CA 19.9.) / Diagnosis and treatment of hepatic cysts: Usefulness of intracystic tumor markers (CEA and CA 19.9)

Introducción: El tratamiento de los quistes hepáticos requiere del diagnóstico diferencial de quiste simple hepático (QSH) de la neoplasia mucinosa quística (NMQ) hepática. Las características radiológicas no son patognomónicas. Algunos estudios han sugerido la utilidad de los marcadores tumorales (MKT) intraquísticos. Métodos: Análisis retrospectivo de base de datos prospectiva incluyendo pacientes diagnosticados de QSH sintomático desde el 2003 hasta el 2021. El objetivo del estudio es evaluar los resultados del tratamiento de los QSH sintomáticos y analizar la utilidad de la determinación de «carcinoembryonic antigen» (CEA) y «carbohydrate antigen» CA 19.9 intraquísticos. Resultados: Se incluyeron 50 pacientes tratados por quiste sintomático. En 15 pacientes el primer tratamiento fue el drenaje percutáneo. En 35 pacientes se realizó fenestración laparoscópica. Cuatro pacientes se diagnosticaron de lesiones premalignas/malignas (NMQ, NPIB, linfoma B); tres de ellos requirieron una segunda cirugía tras la fenestración y el diagnóstico anatomopatológico. La mediana de los valores de CEA y CA- 19.9 fue de 196μg/L y 227.321U/mL respectivamente. Los pacientes con lesiones premalignas no tuvieron valores elevados de MKT. El valor predictivo positivo fue del 0% en ambos MKT, y el valor predictivo negativo fue de 89% y 91% respectivamente. Conclusiones: Los valores de CEA y CA 19.9 intraquísticos no permiten distinguir los QSH de las NMH. El tratamiento más resolutivo de los QSH sintomáticos es la fenestración quirúrgica. El análisis anatomopatológico de la pared del quiste posibilita su correcto diagnóstico, permitiendo indicar una reintervención quirúrgica en los casos de NMQ.(AU)

Introduction: To decide treatment of hepatic cysts diagnosis between simple hepatic cyst (SHC) and cystic mucinous neoplasm (CMN). Radiological features are not pathognomonic. Some studies have suggested the utility of intracystic tumor markers. Methods: Retrospective analysis of our prospective database including patients treated due to symptomatic SHC from 2003 to 2021. The aim of the study was to evaluate the results of treatment of symptomatic SHC and the usefulness of the determination of intracystic “carcinoembryonic antigen” (CEA) and “carbohydrate antigen” CA 19.9. Results: Fifty patients diagnosed and treated for symptomatic SHC were included. In 15 patients the first treatment was percutaneous drainage. In 35 patients the first treatment was laparoscopic fenestration. Four patients were diagnosed of premalignant or malignant liver cystic lesions (MCN, IPMN, and lymphoma B); three of them required surgery after initial fenestration and pathological diagnosis. Median CEA and CA 19.9 were 196μg/L and 227.321U/mL, respectively. Patients with malignant or premalignant pathology did not have higher levels of intracystic tumor markers. Positive predictive value was 0% for both markers, and negative predictive value was 89% and 91%, respectively. Conclusion: Values of intracystic tumor markers CEA and CA 19.9 do not allow distinguishing simple cysts from cystic liver neoplasms. The most effective treatment for symptomatic simple liver cysts is surgical fenestration. The pathological analysis of the wall of the cysts enables the correct diagnosis, allowing to indicate a surgical reintervention in cases of hepatic cyst neoplasia.(AU)

Description of clinical and genetic features of 122 patients included in the Spanish Pompe registry.

Pompe disease is a rare genetic disorder with an estimated prevalence of 1:60.000. The two main phenotypes are Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). There is no published data from Spain regarding the existing number of cases, regional distribution, clinical features or, access and response to the treatment. We created a registry to collect all these data from patients with Pompe in Spain. Here, we report the data of the 122 patients registered including nine IOPD and 113 LOPD patients. There was a high variability in how the diagnosis was obtained and how the follow-up was performed among different centres. Seven IOPD patients were still alive being all treated with enzymatic replacement therapy (ERT) at last visit. Ninety four of the 113 LOPD patients had muscle weakness of which 81 were receiving ERT. We observed a progressive decline in the results of muscle function tests during follow-up. Overall, the Spanish Pompe Registry is a valuable resource for understanding the demographics, patient's journey and clinical characteristics of patients in Spain. Our data supports the development of agreed guidelines to ensure that the care provided to the patients is standardized across the country.

Diagnosis and treatment of hepatic cysts. Usefulness of intracystic tumor markers (CEA and CA 19.9.).

INTRODUCTION: To decide treatment of hepatic cysts diagnosis between simple hepatic cyst (SHC) and cystic mucinous neoplasm (CMN). Radiological features are not patognomonic. Some studies have suggested the utility of intracystic tumor markers. METHODS: Retrospective analysis of our prospective database including patients treated due to symptomatic SHC from 2003 to 2021. The aim of the study was to evaluate the results of treatment of symptomatic SHC and the usefulness of the determination of intracystic "carcinoembryonic antigen" (CEA) and "carbohydrate antigen" CA 19.9. RESULTS: 50 patients diagnosed and treated for symptomatic SHC were included. In 15 patients the first treatment was percutaneous drainage. In 35 patients the first treatment was laparoscopic fenestration. Four patients were diagnosed of premalignant or malignant liver cystic lesions (MCN, IPMN, lymphoma B); three of them required surgery after initial fenestration and pathological diagnosis. Median CEA and CA 19-9 were 196 µg/L and 227.321 U/mL respectively. Patients with malignant or premalignant pathology did not have higher levels of intracystic tumor markers. Positive predictive value was 0% for both markers, and negative predictive value was 89% and 91% respectively. CONCLUSION: Values of intracystic tumor markers CEA and CA 19-9 do not allow distinguishing simple cysts from cystic liver neoplasms. The most effective treatment for symptomatic simple liver cysts is surgical fenestration. The pathological analysis of the wall of the cysts enables the correct diagnosis, allowing to indicate a surgical reintervention in cases of hepatic cyst neoplasia.

Positive Parenting and Sociodemographic Factors Related to the Development of Chilean Children Born to Adolescent Mothers.

The lack of economic resources has a negative effect on the maternal role of younger mothers. In Chile, the majority of adolescent pregnancies occur in socially and economically vulnerable contexts. The current study aimed to examine the relationship between demographic variables within the family context and parenting behaviors among Chilean adolescent mothers (including affection, responsiveness, encouragement, and teaching). These factors were correlated with communication, problem-solving abilities, and personal-social development in typically developing infants. The study included a sample of 79 Chilean adolescent mother-child dyads with children aged 10 to 24 months. Communication, problem-solving, and personal-social development were assessed using the Ages and Stages Questionnaire-3, along with a demographic information questionnaire. The parenting behaviors mentioned above were observed using the Spanish version of Parenting Interactions with Children: Checklist of Observations Linked to Outcomes. The findings indicated that mothers in employment and those who had not dropped out of school had children with better problem-solving skills. Additionally, children residing with their fathers and female children performed better in communication, problem-solving, and personal-social development. Maternal responsiveness was associated with communication and problem-solving, while maternal encouragement was linked to improved problem-solving skills. Maternal teaching was connected to communication, problem-solving, and personal-social development. The study emphasized the significance of parenting and sociodemographic factors among adolescent mothers and their influence on their children's development.

Prognostic risk factors in 113 patients undergoing cephalic duodenopancreatectomy for distal cholangiocarcinoma. / Factores de mal pronóstico en 113 pacientes sometidos a duodenopancreatectomía cefálica por colangiocarcinoma distal.

INTRODUCTION: Distal cholangiocarcinoma is a malignant epithelial neoplasia that affects the extrahepatic bile ducts, below the cystic duct. No relevant relationship between perioperative factors and worse long-term outcome has been proved. OBJECTIVE: To analyze the risk factors for mortality and long-term recurrence of distal cholangiocarcinoma in resected patients. MATERIALS AND METHODS: A single-center prospective database of patients operated on for distal cholangiocarcinoma between 1990 and 2021 was analyzed in order to investigate mortality and recurrence factors. RESULTS: One hundred and thirteen patients have undergone surgery, with mean actuarial survival of 100.2 (76-124) months after resection. The bivariate study did not show differences between patients depending on age or preoperative variables studied. When multivariate analysis was performed, the presence of affected adenopathy was a risk factor for long-term mortality. The presence of affected lymph nodes, tumor recurrence, and biliary fistula during the postoperative period implied worse actuarial survival when comparing the Kaplan-Meier curves. CONCLUSIONS: The presence of affected lymph nodes influence the prognosis of the disease. The occurrence of biliary fistula during postoperative cholangiocarcinoma distal could aggravate long-term outcomes, a finding that should be reaffirmed in future studies.

A randomized controlled trial of a home-based computerized executive function intervention for children with cerebral palsy.

Children with cerebral palsy (CP) often show executive function (EF) impairments that are key to quality of life. The aim of this study was to assess whether a home-based computerized intervention program improves executive functions (EFs) compared to usual care. Sixty participants (30 females) with CP (8-12 years old) were paired by age, sex, motor ability, and intelligence quotient score and then randomized to intervention and waitlist control groups. The intervention group received a 12-week home-based computerized EF intervention (5 days/week, 30 min/day, total dose 30 h). Core and higher-order EFs were assessed before, immediately after, and 9 months after completing the intervention. The intervention group performed better than the waitlist control group in the three core EFs (immediately and 9 months after the intervention): inhibitory control (F = 7.58, p = 0.13 and F = 7.85, p = 0.12), working memory (F = 8.34, p = 0.14 and F = 7.55, p = 0.13), and cognitive flexibility (F = 4.87, p = 0.09 and F = 4.19, p = 0.08). No differences were found between the groups in higher-order EFs or EF manifestations in daily life. CONCLUSIONS: A home-based computerized EF intervention improved core EFs in children with CP, but further research is needed to identify strategies that allow the transfer of these improvements to everyday life. TRIAL REGISTRATION: NCT04025749 retrospectively registered on 19 July 2019. WHAT IS KNOWN: • One in two children with cerebral palsy has an intellectual impairment. Visual perception and executive functions are the most reported specific cognitive deficits. • The majority of interventions for cerebral palsy focus on motor impairments, but only a few randomized controlled trials have explored the effect of interventions on executive functions. WHAT IS NEW: • A home-based computerized cognitive intervention can improve the core executive functions of children with cerebral palsy. • Short- and long-term effects on core executive functions have been found.

Non-Intrusive Maternal Style as a Mediator between Playfulness and Children's Development for Low-Income Chilean Adolescent Mothers.

The aim of this study was to describe the relationship between low-income Chilean adolescent maternal playfulness and mothers' non-intrusiveness in their children's development and to analyze whether a mother's non-intrusiveness mediates the relationship between maternal playfulness and children's development. The Parental Playfulness Scale and the Subscale of Intrusiveness from the Early Head Start Research and Evaluation Project were used to assess maternal playfulness and mothers' non-intrusiveness respectively. Ages and Stages Questionnaire 3rd Edition (ASQ-3) was applied to measure the children's communication, gross and fine motor skills, problem-solving and personal-social development. The sample consisted of 79 mother-child dyads with children aged 10-24 months (M = 15.5, SD = 4.2) and their mothers aged 15-21 years old (M = 19.1, SD = 1.7). A bivariate analysis showed that maternal playfulness was significantly associated with communication, fine motor, problem-solving and personal-social development. Moreover, higher levels of communication, fine motor skills and problem-solving development were observed in the children of less intrusive mothers. Maternal playfulness had a significant effect on children's development of language, problem-solving and personal-social skills when their mothers showed less intrusiveness during interaction. These findings contribute to the understanding of the interaction between adolescent mothers and their children. Active play and less intrusiveness can enhance child development.

Differences in glucose metabolic activity in liver metastasis separates two groups of metastatic uveal melanoma patients with different prognosis.

BACKGROUND: Uveal melanoma metastasizes to the liver. We aimed to explore the metabolic activity of liver metastases (LM) as a biomarker for survival. METHODS: We analyzed newly diagnosed patients with metastatic UM (MUM) with LM detected by liver-directed imaging and had undergone a PET/CT at diagnosis. FINDINGS: 51 patients were identified between 2004 and 2019. Median age was 62 years, 41% male and 22% ECOG ≥1. LDH, ALP, and GGT were elevated in 49%, 37%, and 57% of patients. Median LM SUVmax was 8.5 (3-42.2). Same size lesions presented a wide range of metabolic activity. Median OS was 17.3 m (95% CI:10.6-23.9). Patients with SUVmax ≥8.5 had an OS of 9.4 m (95% CI:6.4-12.3), whereas patients with SUVmax <8.5 had an OS of 38.4 m (95% CI:21.4-55.5; p < 0.0001, HR = 2.9). We observed similar results when studying M1a disease separately. Multivariate analysis showed SUVmax as an independent prognostic factor for the whole population and those with M1a disease. INTERPRETATION: Increased metabolic activity of LM seems to be an independent predictor of survival. MUM is a heterogeneous disease and metabolic activity probably reflects a different intrinsic behavior.

Physical and mental health impact of the COVID-19 pandemic at first year in a Spanish adult cohort.

The COVID-19 pandemic and the political and health measures have profoundly affected the health of our populations. However, very few studies have been published assessing its impact using a prospective cohort. The aim of this study is to describe the impact on physical and mental health due to the COVID-19 pandemic in the general population in Spain, and according to COVID-19 clinical status, during the first year of the pandemic. A longitudinal cohort study with two online surveys were performed on a representative sample of the adult Spanish population before (N = 2005, October/November 2019) and during the pandemic (N = 1357, November/December 2020). We assessed disability using the World Health Organisation Disability Assessment Schedule (WHODAS), major depressive episode (MDE) and suicidal thoughts and behaviours (STB), using an adapted version of the Composite International Diagnostic Interview (CIDI 3.0); generalised anxiety disorder (GAD) using the GAD-7 scale; post-traumatic stress disorder (PTSD) symptoms using the PTSD checklist for DSM-5 (PCL-5). For physical health, there was a statistically significant loss of weight (mean/SD) (T0, 73.22/15.56 vs. T1, 71.21/11.94), less use of tobacco (T0, 11.4% vs. T1, 9.0%) and decreased disability (mean/SD) (T0, 21.52/9.22 vs. T1, 19.03/7.32). For mental health, there was a significant increase in MDE (T0, 6.5% vs. T1, 8.8%) and in the prevalence of GAD (T0, 13.7% vs. T1, 17.7%). The prevalence of STB (T0, 15.1% vs. T1, 7.1%) significantly decreased. Individuals who declared they had been diagnosed with COVID-19 (3.6%) showed a worsening in physical health and an increase in mental health problems and PTSD symptoms. Although suicide risk during the first year of the pandemic was significantly less, many suicide risk factors increased: such as the incidence and persistence of MDE and GAD, the presence of PTSD symptoms in those diagnosed with COVID-19, and a worsening in self-assessed health status. We expect an increase in STB in the population in the long-term. Future research should gather information about the long-term impact of the pandemic.

Relations between Positive Parenting Behavior during Play and Child Language Development at Early Ages.

Parental behavior in interactions with children has been related to child language development. Our study contributes to the literature about relations between the characteristics of parent-child interactions during play and a child's language development in typically developing children at early ages, with data from mothers and fathers from the same families in Spain. Our aim was to analyze the relation between positive parenting behaviors assessed with the Spanish version of the Parenting Interactions with Children: Checklist of Observations Linked to Outcomes (PICCOLO) and child language development assessed with the Bayley-III scales. We controlled for some sociodemographic variables. The participants were 90 children aged 15-31 months and their mothers and fathers. Bivariate analysis showed significant positive relations between mothers' responsive, encouraging and teaching behaviors and a child's language scores. Relations were found between fathers' encouraging and teaching behaviors and a child's language. Regression models indicate that maternal and paternal encouraging behaviors predicted 18% of the variability in the child's receptive language, and maternal responsive and teaching behaviors predicted 16% of the variability in the child's expressive language and total language scores. The study provides new data that support the relevance of positive parental behaviors to improve a child's linguistic development.

Reduced Number of Thymoma CTLA4-Positive Cells Is Associated With a Higher Probability of Developing Myasthenia Gravis.

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease associated with comorbid thymoma in 10%-15% of cases. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) expressed by T cells downregulates T-cell-mediated immune response. Polymorphisms in the CTLA4 gene have been associated with the development of MG. In this context, we aimed to determine whether CTLA4 expression in the thymoma differs between patients with and without MG and whether CTLA4 gene polymorphisms are associated with these differences. METHODS: This is a retrospective study of all patients, with and without MG, surgically treated at our institution for thymoma between January 2010 and December 2020. Ten samples were obtained from normal thymuses as controls. The number of CTLA4-positive cells in paraffin-embedded thymoma samples was determined by immunohistochemistry. The presence of follicular-center and regulatory T-cell lymphocytes was determined by immunohistochemistry (B-cell lymphoma [BCL]-6 expression) and double immunofluorescence-based staining of CD4-FOXP3, respectively. We evaluated the association between thymic expression of CTLA4 and the development of MG. We also determined the association between CTLA4 expression and various clinical and prognostic characteristics of MG. We sequenced the CTLA4 gene and evaluated possible associations between CTLA4 polymorphisms and thymic CTLA4 expression. Finally, we assessed the potential association between these polymorphisms and the risk of MG. RESULTS: Forty-one patients with thymoma were included. Of them, 23 had comorbid MG (56.1%). On average, patients with MG had fewer CTLA4-positive cells in the thymoma than non-MG patients: 69.3 cells/mm2 (95% CIs: 39.6-99.1) vs 674.4 (276.0-1,024.0) cells/mm2; p = 0.001 and vs controls (200.74 [57.9-343.6] cells/mm2; p = 0.02). No between-group differences (MG vs non-MG) were observed in the number of cells positive for BCL6 or CD4-FOXP3. CTLA4 expression was not associated with differences in MG outcome or treatment refractoriness. Two polymorphisms were detected in the CTLA4 gene, rs231770 (n = 30 patients) and rs231775 (n = 17). MG was present in a similar proportion of patients for all genotypes. However, a nonsignificant trend toward a lower CTLA4-positive cell count was observed among carriers of the rs231775 polymorphism vs noncarriers: 77.9 cells/mm2 (95% CI: -51.5 to 207.5) vs 343.3 cells/mm2 (95% CI: 126.2-560.4). DISCUSSION: Reduced CTLA4 expression in thymoma may predispose to a higher risk of developing MG.

Neuroinflammation-Related Proteins NOD2 and Spp1 Are Abnormally Upregulated in Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology and poorly understood pathophysiology. There is no specific biomarker either for diagnosis or prognosis. The aim of our study was to investigate differentially expressed proteins in the CSF and serum from patients with ALS to determine their role in the disease process and evaluate their utility as diagnostic or prognostic biomarkers. METHODS: We performed mass spectrometry in the CSF from 3 patients with ALS and 3 healthy controls (HCs). The results were compared with motor cortex dysregulated transcripts obtained from 11patients with sporadic ALS and 8 HCs. Candidate proteins were tested using ELISA in the serum of 123 patients with ALS, 30 patients with Alzheimer disease (AD), 28 patients with frontotemporal dementia (FTD), and 102 HCs. Patients with ALS, AD, and FTD were prospectively recruited from January 2003 to December 2020. A group of age-matched HCs was randomly selected from the Sant Pau Initiative on Neurodegeneration cohort of the Sant Pau Memory Unit. RESULTS: Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and osteopontin (Spp1) were differentially expressed in the CSF and the motor cortex transcriptome of patients with ALS compared with that in HCs (p < 0.05). NOD2 and Spp1 levels were significantly higher in sera from patients with ALS than in HCs (p < 0.001). Receiver operating characteristic analysis showed an area under the curve of 0.63 for NOD2 and 0.81 for Spp1. NOD2 levels were significantly lower in patients with AD and FTD than in patients with ALS (p < 0.0001), but we found no significant differences in Spp1 levels between patients with ALS, AD (p = 0.51), and FTD (p = 0.42). We found a negative correlation between Spp1 levels and ALS functional rating scale (r = -0.24, p = 0.009). DISCUSSION: Our discovery-based approach identified NOD2 as a novel biomarker in ALS and adds evidence to the contribution of Spp1 in the disease process. Both proteins are involved in innate immunity and autophagy and are increased in the serum from patients with ALS. Our data support a relevant role of neuroinflammation in the pathophysiology of the disease and may identify targets for disease-modifying treatments in ALS. Further longitudinal studies should investigate the diagnostic and prognostic value of NOD2 and Spp1 in clinical practice.

Phenotype and clinical outcomes of Glu89Lys hereditary transthyretin amyloidosis: a new endemic variant in Spain.

BACKGROUND: The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain. METHODS: Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals. RESULTS: Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7-9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis (p < 0.001). Haplotype analysis revealed a common origin from an ancestor who lived ∼500 years ago in southeast Spain. CONCLUSIONS: Glu89Lys ATTRv is a TTR variant with a founder effect in Spain. It is associated with near complete penetrance, early onset and mixed cardiac and neurologic phenotype. Patients have poor prognosis, particularly if not treated with disease-modifying therapies.

Azathioprine therapy induces selective NK cell depletion and IFN-γ deficiency predisposing to herpesvirus reactivation.

BACKGROUND: Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and reducing the numbers of circulating B and T lymphocytes. Case reports indicate increased risk for serious infections that can occur despite regular measurements of lymphocyte counts during azathioprine therapy. OBJECTIVE: We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use. METHODS: Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients. RESULTS: Azathioprine therapy selectively induced pronounced CD56dimCD16+ natural killer cell depletion and concomitant IFN-γ deficiency. Cytokine profiling revealed a specific contraction of classical TH1 cells during azathioprine treatment. We further observed an increased occurrence of reactivation of endogenous latent herpesviruses in the azathioprine-treated group versus in patients with myasthenia gravis who were not receiving immunomodulatory treatment; this increased occurrence was validated in an independent cohort. CONCLUSION: Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice.

Low Resilience Was a Risk Factor of Mental Health Problems during the COVID-19 Pandemic but Not in Individuals Exposed to COVID-19: A Cohort Study in Spanish Adult General Population.

BACKGROUND: The aim is to analyze whether people with low resilience are at higher risk of mental health problems during the COVID-19 pandemic in Spanish adults. METHODS: a longitudinal cohort study was carried out. Resilience was measured with the CD-RISC. Mental health problems that were assessed included: Major Depressive Episode (MDE), Generalized Anxiety Disorder (GAD), Suicidal Thoughts and Behaviors (STB), and Posttraumatic Stress Disorder (PTSD) symptoms. RESULTS: we found statistically significant differences between groups and resilience scores in MDE [F (3; 48.40) = 19.55], GAD [F (3; 19.63) = 6.45] and STB [F (3; 111.74) = 31.94]. Multivariable analyses showed individuals with very low resilience were at a 5-fold risk of Incidence of MDE and a 4-fold risk of STB. Persistent group presented a 21-fold risk of MDE and 54-fold risk of STB. No evidence of higher risk was found for GAD. Individuals with low resilience and exposed to COVID-19 were not at higher risk. Individuals with low resilience were at higher risk of PTSD in general population [ß(95% CI) = -3.25 (-3.969 to -2.54)], but not for individuals with COVID-19. CONCLUSIONS: in the general population, having low or very low resilience increases the risk of suffering MDE, STB, and PTSD, but not GAD during the COVID-19 pandemic, and not in the population with COVID-19.