Eosinophilic gastrointestinal diseases with esophageal involvement: Analysis of 212 patients / Enfermedades gastrointestinales eosinofilicas con afectación esofágica: Análisis de 212 pacientes

Background Primary eosinophilic gastrointestinal diseases (EGID) are chronic inflammatory disorders of the gastrointestinal tract with unknown etiology. Features, utility, and evolution are still unknown in screening for EGID in adult patients with eosinophilic esophagitis (EoE). Objectives To evaluate the prevalence, characteristics, comorbidities, and evolution of EGID in adults diagnosed with EoE and investigate differences between both groups. Methods Prospective unicenter observational and analytical study. Gastric and duodenal biopsies were obtained during upper baseline endoscopy in all consecutive EoE adult patients evaluated. A colonoscopy with colon biopsies was performed upon persistent diarrhea and normal duodenal biopsies. Results 212 EoE patients were included. Nine patients (4.3%) also showed significant eosinophilic infiltration in at least one organ within the digestive tract. The most common site affected was the small bowel (78%). Gastrointestinal symptoms (43% vs. 100%, p<0.002) and, more specifically, either abdominal pain or diarrhea (17% vs. 78%, p<0.001), some food sensitizations, and digestive comorbidities (p<0.05) were significantly more common in patients with EGID. Gastrointestinal symptoms were present in 94/212 (44%) patients, of whom 9 (10%) had EGID. Considering only abdominal pain or diarrhea, 20% suffered from it. Conclusions EGID rarely coexist with EoE, even when gastrointestinal symptoms are present. These findings advise against routine gastric, duodenal, or colon biopsies in adult EoE patients with gastrointestinal symptoms. Most of the characteristics of EoE do not change due to having EGID except gastrointestinal symptoms, digestive comorbidities, and sensitizations to some foods. The evolution was generally favorable despite intermittent adherence to treatment, especially maintenance (AU)

Antecedentes Las enfermedades gastrointestinales eosinofílicas primarias (EGIE) son trastornos inflamatorios crónicos del tracto gastrointestinal con etiología desconocida. Aún se desconocen las características, la utilidad y la evolución en el cribado de EGIE en pacientes adultos con esofagitis eosinofílica (EoE). Objetivos Evaluar la prevalencia, características, comorbilidades y evolución de las EGIE en adultos diagnosticados de EoE e investigar las diferencias entre ambos grupos. Métodos Estudio observacional y analítico prospectivo de un único centrro. Se obtuvieron biopsias gástricas y duodenales durante la endoscopia digestiva superior en todos los pacientes adultos con EoE consecutivos evaluados. Se realizó colonoscopia con biopsias de colon ante diarrea persistente y biopsias de duodeno normales. Resultados Se incluyeron 212 pacientes con EoE. Nueve pacientes (4,3%) también mostraron infiltración eosinofílica significativa en al menos un órgano dentro del tracto digestivo. El sitio más común afectado fue el intestino delgado (78%). Los síntomas gastrointestinales (43 vs. 100%, p < 0,002) y, más específicamente, dolor abdominal o diarrea (17 vs. 78%, p < 0,001), algunas sensibilizaciones alimentarias y comorbilidades digestivas (p < 0,05) fueron significativamente más comunes en pacientes con EGIE. Los síntomas gastrointestinales estuvieron presentes en 94/212 (44%) pacientes, de los cuales nueve (10%) tenían EGIE. Considerando solo dolor abdominal o diarrea, 20% la padecía. Conclusiones Las EGIE rara vez coexisten con EoE, incluso cuando hay síntomas gastrointestinales. Estos hallazgos desaconsejan las biopsias gástricas, duodenales o de colon de rutina en pacientes adultos con EoE con síntomas gastrointestinales. La mayoría de las características de la EoE no cambian por tener EGIE, excepto los síntomas gastrointestinales, las comorbilidades digestivas y las sensibilizaciones a algunos alimentos (AU)

Impact of environmental factors on the epidemiology of eosinophilic esophagitis in southwestern Europe (2007-2020).

Background: Eosinophilic esophagitis (EoE) is a disease characterized by symptoms of esophageal dysfunction and at least 15 eosinophils/hpf in the esophagus. Other systemic and local causes of esophageal eosinophilia should be excluded. Objectives: The study objectives were to examine the annual epidemiology of EoE for 14 consecutive years, investigate whether there is a relationship between the count of aeroallergens and the incidence of EoE for 12 years, evaluate whether there are family ties between the patients with EoE, and determine whether there are cases of EoE that are triggered or exacerbated by pollens. Methods: We conducted a prospective, descriptive, and analytic study in patients with EoE for 14 years (2007-2020). The study variables were age, sex, relatives with EoE, time of evolution of the symptoms until diagnosis of the disease, and symptoms. We examined incidence and prevalence, annual counts of aeroallergens for 12 years, and number of diagnoses per year (in 2007-2020). We studied patients with active EoE (in April-July) and EoE in remission (in August-March) for 2 consecutive years. Exacerbations were investigated by measuring symptoms using a visual analog scale of 1 to 10. Results: Of the 366 patients with EoE (studied from 2007 to 2020), 83.5% were atopic, with respiratory allergy and 28% had a food allergy. Their mean age was 35 years. The time of evolution of the symptoms was more than 6 years. Only 11% of the patients had a degree of kinship. Of the 366 patients, 87% had dysphagia, 27% had had impactions, and 12.5% had other symptoms of esophageal dysfunction. We found a positive correlation between the incidence of EoE and Platanaceae pollens. We did not detect any case of EoE triggered or exacerbated by pollens. Conclusions: The epidemiology of EoE in southwestern Europe continues to grow. We have corroborated the relevant impact of the environment on genetics. Future studies will clarify the possible relevance of Platanaceae pollens in the increased epidemiology of EoE. The role of grass and Oleaceae pollens in triggering EoE is limited by having a short pollination in time.

The importance of CXCR4 expression in tumor stroma as a potential biomarker in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the main causes of cancer mortality in the world. A characteristic feature of this cancer is that a large part of the tumor volume is composed of a stroma with different cells and factors. Among these, we can highlight the cytokines, which perform their function through binding to their receptors. Given the impact of the CXCR4 receptor in the interactions between tumor cells and their microenvironment and its involvement in important signaling pathways in cancer, it is proposed as a very promising prognostic biomarker and as a goal for new targeted therapies. Numerous studies analyze the expression of CXCR4 but we suggest focusing on the expression of CXCR4 in the stroma. METHODS: Expression of CXCR4 in specimens from 33 patients with PDAC was evaluated by immunohistochemistry techniques and matched with clinicopathological parameters, overall and disease-free survival rates. RESULTS: The percentage of stroma was lower in non-tumor tissue (32.4 ± 5.2) than in tumor pancreatic tissue (67.4 ± 4.8), P-value = 0.001. The level of CXCR4 expression in stromal cells was diminished in non-tumor tissue (8.7 ± 4.6) and higher in tumor pancreatic tissue (23.5 ± 6.1), P-value = 0.022. No significant differences were identified in total cell count and inflammatory cells between non-tumor tissue and pancreatic tumor tissue. No association was observed between CXCR4 expression and any of the clinical or pathological data, overall and disease-free survival rates. Analyzing exclusively the stroma of tumor samples, the CXCR4 expression was associated with tumor differentiation, P-value = 0.05. CONCLUSIONS: In this study, we reflect the importance of CXCR4 expression in the stroma of patients diagnosed with PDAC. Our results revealed a high CXCR4 expression in the tumor stroma, which is related to a poor tumor differentiation. On the contrary, we could not find an association between CXCR4 expression and survival and the rest of the clinicopathological variables. Focusing the study on the CXCR4 expression in the tumor stroma could generate more robust results. Therefore, we consider it key to develop more studies to enlighten the role of this receptor in PDAC and its implication as a possible biomarker.

Eosinophilic gastrointestinal diseases with esophageal involvement: Analysis of 212 patients.

BACKGROUND: Primary eosinophilic gastrointestinal diseases (EGID) are chronic inflammatory disorders of the gastrointestinal tract with unknown etiology. Features, utility, and evolution are still unknown in screening for EGID in adult patients with eosinophilic esophagitis (EoE). OBJECTIVES: To evaluate the prevalence, characteristics, comorbidities, and evolution of EGID in adults diagnosed with EoE and investigate differences between both groups. METHODS: Prospective unicenter observational and analytical study. Gastric and duodenal biopsies were obtained during upper baseline endoscopy in all consecutive EoE adult patients evaluated. A colonoscopy with colon biopsies was performed upon persistent diarrhea and normal duodenal biopsies. RESULTS: 212 EoE patients were included. Nine patients (4.3%) also showed significant eosinophilic infiltration in at least one organ within the digestive tract. The most common site affected was the small bowel (78%). Gastrointestinal symptoms (43% vs. 100%, p<0.002) and, more specifically, either abdominal pain or diarrhea (17% vs. 78%, p<0.001), some food sensitizations, and digestive comorbidities (p<0.05) were significantly more common in patients with EGID. Gastrointestinal symptoms were present in 94/212 (44%) patients, of whom 9 (10%) had EGID. Considering only abdominal pain or diarrhea, 20% suffered from it. CONCLUSIONS: EGID rarely coexist with EoE, even when gastrointestinal symptoms are present. These findings advise against routine gastric, duodenal, or colon biopsies in adult EoE patients with gastrointestinal symptoms. Most of the characteristics of EoE do not change due to having EGID except gastrointestinal symptoms, digestive comorbidities, and sensitizations to some foods. The evolution was generally favorable despite intermittent adherence to treatment, especially maintenance.

Faster-acting insulin aspart reduces glycaemic variability in sensor-augmented pump treated type 1 diabetes patients.

AIM: To evaluate the effect of faster aspart over glycaemic variability in type 1 diabetes (T1D) patients treated with sensor-augmented pump (SAP) in a real-world scenario. METHODS: Observational study with SAP-treated adult T1D patients treated with faster aspart for three months. The primary endpoint was the mean amplitude of glucose excursions (MAGE). RESULTS: Fifty patients were treated with faster aspart. Eleven patients (23%) withdrew during the follow-up mainly due to worsening of diabetes control (9 patients). Mean age was 41.2 yrs. (range 21-59) and T1D duration 22.4±10.0 yrs. Mean SAP treatment duration was 3.6±3.1 yrs. We detected a reduction of -7.0 (95% CI -1.1, -12.9; p=0.021) in MAGE at the end of the study. Other glycemic variability indices were also improved: standard deviation of mean interstitial glucose (-3mg/dl; 95% CI, -1, -5; p=0.01), CONGA4 (-2.2; 95% CI -0.3, -4.2; p=0.029), CONGA6 (-2.6; 95% CI -0.6, -4.6; p=0.011), GRADE (-0.5; 95% CI -0.1, -0.9; p=0.022), HBGI (-0.7; 95% CI -0.2, -1.3; p=0.013), J-index (-2.9; 95% CI -0.7, -5.0; p=0.011) and MODD (-5.7; 95% CI -1.7, -9.7; p=0.006). A slight reduction in mean glucose management indicator was also detected (-0.14%; 95% CI, -0.02, -0.27; -1.4mmol/mol; 95% CI -0.1, -3.3; p=0.03). CONCLUSIONS: In SAP-treated T1D patients, faster aspart insulin was associated with reduced glycaemic variability, but also a high percentage of dropouts due to worsened glycaemic control. NCT04233203.

Effect of the historic Spanish heatwave over glycemic control in adult patients with type 1 diabetes.

AIM: To evaluate the effect of the historic Spanish heatwave (9th-26th July 2022) over glycemic control in adults with type 1 diabetes (T1D). METHODS: Cross-sectional retrospective analysis of adult patients with T1D in Castilla-La Mancha (south-central Spanish region) using intermittently scanned continuous glucose monitoring (isCGM) during and after the heatwave. Primary outcome was change in time in range (TIR) 3.0-10 mmol/L (70-180 mg/dL) of interstitial glucose in the two weeks following the heatwave. RESULTS: A total of 2701 T1D patients were analyzed. We detected a TIR reduction of 4.0 % (95 % CI -3.4, -4.6; P < 0.001) in the two weeks following the heatwave. Patients in the highest daily scan frequency quartile (>13 scans/day) during the heatwave showed the greatest deterioration in TIR after it concluded (-5.4 % [95 % CI -6.5, -4.3; P < 0.001]). The percentage of patients meeting all the recommendations of the International Consensus of Time in Range was greater during the heatwave than after it ended (10.6 % vs. 8.4 %, P < 0.001). CONCLUSIONS: Adults with T1D had better glycemic control during the historic Spanish heatwave compared to the following period.

To evaluate the use and clinical effect of intermittently scanned continuous glucose monitoring in adults with type 1 diabetes: Results of a multicentre study.

AIM: To evaluate the use and clinical effect of intermittently scanned continuous glucose monitoring (isCGM) in adults with type 1 diabetes (T1D) in a public health service scenario. METHOD: Cross-sectional retrospective analysis of all patients with T1D and medical indication for isCGM use from a cohort followed since 2010 at Castilla-La Mancha Public Health Service (Spain). Primary outcome was HbA1c change during the first year of follow-up after isCGM initiation. Secondary outcomes included evaluation of self-monitoring of blood glucose (SMBG), isCGM and insulin use, along with glycometric indexes. RESULTS: A total of 945 T1D patients were analyzed. Median age was 49.5 years (IQ range 19.0 years) and T1D duration of 28.9 years (IQ range 14.0 years). The most frequent insulin therapy alternatives were multiple daily injections (85%) followed by insulin pump (11%). Eighty percent of the patients were active isCGM users with a 90% of adherence to the device. Patients showed a mean daily scan frequency of 10.1±6.4scans/day. Daily SMBG reduced by -3.5 test/day [95% CI -3.7, -3.2; P<0.001]. We detected an HbA1c reduction of -0.3% (-4mmol/mol) [95% CI -0.2, -0.4 (-3, -5); P<0.001] at the end of the follow-up. An inverse correlation between HbA1c levels at the end of the follow-up and daily frequency of isCGM scanning (R=-0.34, P<0.001) was observed. Dropout rate was 4%, and 4% of patients were not willing to use isCGM. CONCLUSIONS: Adult patients with T1D improved glycaemic control after isCGM initiation in a public health service scenario. Despite described clinical benefits, a higher than expected percentage of patients were not using isCGM technology. NCT05095610.

Índice de masa triponderal y marcadores de riesgo metabólico en niños y adolescentes con obesidad / Triponderal mass index and markers of metabolic risk in children and adolescents with obesity

Antecedentes y objetivo El índice de masa triponderal (IMT) estimaría mejor que el índice de masa corporal (IMC) el exceso de adiposidad, manteniendo valores estables durante la infancia. Este trabajo pretende determinar la correlación del IMT con marcadores de riesgo metabólico y establecer valores del IMT que se relacionen con un aumento del riesgo metabólico. Material y métodos Estudio multicéntrico, observacional, transversal y prospectivo en menores de 14 años con obesidad. Variables: edad, sexo, estadio puberal, peso, talla, perímetro abdominal, IMC, IMT, glucosa e insulina basales, índice HOMA, presión arterial, perfil lipoproteico, transaminasas y ácido úrico. El IMC y el IMT se expresaron según los valores del estudio longitudinal de Barcelona. Se realizó análisis estadístico con el programa SPSS*. Resultados Se incluyeron 199 pacientes (50,3% varones), con una edad media de 11,08 (2,48) años e IMT de 19,68 (2,36) kg/m3. Se observó correlación del IMT con el perímetro abdominal (r = 0,571; p = 0), la insulina (r = 0,198; p = 0,005), el índice HOMA (r = 0,189; p = 0,008) y el c-HDL (r = −0,188; p = 0,008). El IMT > 20,15 kg/m3 se asoció a insulina ≥ 15 mUI/ml (p = 0,029) y el IMT > 20,36 kg/m3 a c-HDL < 40 mg/dl (p = 0,023). Conclusiones El IMT se correlacionó con el incremento del perímetro abdominal, la insulina y el índice HOMA, y la disminución del c-HDL. El IMT > 20 kg/m3 puede asociarse a elevación de la insulina y a descenso del c-HDL. Por ello, el IMT parece ser un parámetro útil en la valoración de los pacientes pediátricos con obesidad (AU)Background and objective

Triponderal mass index (TMI) would estimate excess adiposity better than body mass index (BMI), maintaining stable values during childhood. This work aims to determine the correlation between TMI and markers of metabolic risk as well as set values of TMI that are related to an increase of metabolic risk. Material and methods Multicenter, observational, cross-sectional and prospective study in children under 14 years of age with obesity. Variables: age, sex, pubertal stage, weight, height, abdominal circumference, BMI, TMI, basal glucose and insulin, HOMA index, blood pressure, lipoprotein profile, transaminases and uric acid. BMI and TMI were expressed according to the values of the Barcelona longitudinal study. Statistical analysis was performed with the SPSS* program. Results One hundred and ninety-nine patients (50.3% male), age 11.08 (2.48) years, TMI 19.68 (2.36) kg/m3. Correlation between TMI and abdominal circumference (r = 0.571; p = 0), insulin (r = 0.198; p = 0.005), HOMA index (r = 0.189; p = 0.008) and HDL-c (r = −0.188; p = 0.008) was observed. IMT > 20.15 kg/m3 was associated with insulin ≥ 15 mIU/ml (p = 0.029) and IMT > 20.36 kg/m3 with HDL-c < 40 mg/dl (p = 0.023). Conclusions TMI was correlated with increase of abdominal circumference, insulin and HOMA index and decrease of HDL-c. IMT > 20 kg/m3 can be associated with increased insulin and decreased HDL-c. Therefore, the IMT seems to be a useful parameter in the assessment of pediatric patients with obesity (AU)

[Triponderal mass index and markers of metabolic risk in children and adolescents with obesity]. / Índice de masa triponderal y marcadores de riesgo metabólico en niños y adolescentes con obesidad.

BACKGROUND AND OBJECTIVE: Triponderal mass index (TMI) would estimate excess adiposity better than body mass index (BMI), maintaining stable values during childhood. This work aims to determine the correlation between TMI and markers of metabolic risk as well as set values of TMI that are related to an increase of metabolic risk. MATERIAL AND METHODS: Multicenter, observational, cross-sectional and prospective study in children under 14 years of age with obesity. VARIABLES: age, sex, pubertal stage, weight, height, abdominal circumference, BMI, TMI, basal glucose and insulin, HOMA index, blood pressure, lipoprotein profile, transaminases and uric acid. BMI and TMI were expressed according to the values of the Barcelona longitudinal study. Statistical analysis was performed with the SPSS* program. RESULTS: One hundred and ninety-nine patients (50.3% male), age 11.08 (2.48) years, TMI 19.68 (2.36)kg/m3. Correlation between TMI and abdominal circumference (r=0.571; p=0), insulin (r=0.198; p=0.005), HOMA index (r=0.189; p=0.008) and HDL-c (r=-0.188; p=0.008) was observed. IMT>20.15kg/m3 was associated with insulin≥15mIU/ml (p=0.029) and IMT>20.36kg/m3 with HDL-c<40mg/dl (p=0.023). CONCLUSIONS: TMI was correlated with increase of abdominal circumference, insulin and HOMA index and decrease of HDL-c. IMT>20kg/m3 can be associated with increased insulin and decreased HDL-c. Therefore, the IMT seems to be a useful parameter in the assessment of pediatric patients with obesity.

Black Garlic and Thiosulfinate-Enriched Extracts as Adjuvants to Ceftriaxone Treatment in a Rat Peritonitis Model of Sepsis.

To date, there have been no new drugs or adjuvants able to decrease both morbidity and mortality in the context of sepsis and septic shock. Our objective was to evaluate the use of thiosulfinate-enriched Allium sativum and black garlic extracts as adjuvants in the management of sepsis. An experimental in vivo study was carried out with male Sprague-Dawley® rats. Animals were randomized in four treatment groups: antibiotic (ceftriaxone) treatment (group I), ceftriaxone plus thiosulfinate-enriched extract (TASE, group II), ceftriaxone plus thiosulfinate-enriched extract and black garlic extracts (TASE + BGE, group III), and ceftriaxone plus black garlic extract (BGE, group IV). All animals were housed and inoculated with 1 × 1010 CFU/15 mL of intraperitoneal Escherichia coli ATCC 25922. Subsequently, they received a daily treatment according to each group for 7 days. Clinical, analytical, microbiological, and histopathological parameters were evaluated. Statistically significant clinical improvement was observed in rats receiving garlic extracts in weight (groups II and III), ocular secretions, and piloerection (group IV). Moreover, less liver edema, vacuolization, and inflammation were observed in groups receiving adjuvant support (groups II, III, and IV). When comparing interleukins 24 h after bacteria inoculum, we found statistically significant differences in TNF-alpha levels in groups receiving BGE (groups III and IV, p ≤ 0.05). Blood and peritoneal liquid cultures were also analyzed, and we detected a certain level of Enterococcus faecalis in peritoneal cultures from all treatment groups and less bacteria presence in blood cultures in rats receiving garlic extracts (groups II, III, and IV). In conclusion, TASE and BGE could be promising nutraceutical or medicinal agents as coadjuvants in the treatment of sepsis because of its effects in modulating the inflammatory response.

Continuous Subcutaneous Insulin Infusion in Type 1 Diabetes Mellitus Patients: Results from the Spanish National Registry.

Aim: To analyze the clinical effect of continuous subcutaneous insulin infusion (CSII) in type 1 diabetes mellitus (T1D) patients in the Spanish real-world scenario. Methods: All T1D patients on CSII registered in the SPAnish Insulin Pump (SPAIP) registry were included. The primary efficacy outcome was change in HbA1c during follow-up. Secondary efficacy outcomes included: insulin pump indications, diabetes complication rates, insulin and pump use, and continuous glucose monitoring (CGM) glycometrics. Patient data were typed through the web-based SPAIP registry. Results: Data from 2979 T1D patients treated with CSII were analyzed. The median age was 44 years (interquartile range [IQR] 34-52 years), and T1D duration was 27 years (IQR 18-35 years). The median duration of CSII therapy was 6 years (IQR 3-10 years). The main indications for treatment were suboptimal glycemic control (33.8%), hypoglycemia (22.1%), and increased glycemic variability (18.8%). Glycated hemoglobin decreased by 6 mmol/mol (95% CI, -5 to -6 mmol/mol, P < 0.001) [-0.5%, 95% CI, -0.4 to -0.5, P < 0.001] during the follow-up. The percentage of patients with severe hypoglycemia decreased from 14.9% to 0.9% (P < 0.001). We observed an inverse correlation between final HbA1c levels and CGM adherence (R = -0.24, P < 0.001) or percentage of time with active hybrid closed-loop functions (R = -0.25, P < 0.001). Conclusions: CSII treatment was associated with a sustained improvement in glycemic control in the Spanish population. This benefit was greater among patients with higher CGM or active hybrid closed-loop functions adherence. The protocol was publicly registered at ClinicalTrials.gov (NCT04761094).

Clinical features and mortality of COVID-19 patients admitted to ICU according to SOFA score.

The Sequential Organ Failure Assessment (SOFA) could function as an effective risk stratification tool in the admission of critically ill patients with COVID-19 and would allow stratification based on a risk assessment. We aimed to examine whether the SOFA score is useful to define 2 severity profiles in COVID-19 patients admitted to ICU: mild with SOFA < 5, and severe with SOFA ≥ 5. A retrospective cohort, multicenter study was conducted from February 11 to May 11, 2020. We analyzed patients admitted to all ICUs of the 14 public hospitals of the Castilla-La Mancha Health Service at the beginning of the pandemic and with SARS-CoV-2 infection. Patients were divided in 2 groups according to the level of severity by SOFA at admission to the ICU. Cox regression was used to evaluate factors associated with survival and Kaplan-Meier test to examine survival probability. In total, 405 patients with a complete SOFA panel were recruited in the 14 participating ICUs. SOFA <5 group showed that age above 60 years and D-dimer above 1000 ng/mL were risk factors associated with lower survival. In SOFA ≥ 5 it was found that high blood pressure was a risk factor associated with shorter survival. Kaplan-Meier showed lower survival in SOFA ≥ 5 in combination with high blood pressure, time since viral symptom onset to admission in ICU < 7 days, D-dimer ≥1000 ng/mL and respiratory pathology. However, SOFA < 5 showed only higher age (≥60 years) associated with lower survival. Age over 60 years and D-dimer over 1000 ng/mL were risk factors reflecting lower survival in patients with SOFA < 5. Moreover, SOFA ≥ 5 patients within a week after COVID-19 onset and comorbidities such as high blood pressure and previous respiratory pathology showed lower survival.

Sex differences on the relation among gross motor competence, cognition, and academic achievement in children.

An association between gross motor competence (GMC) and academic achievement (AA) has been described, but the potential mechanisms behind this association are still unknown. It is not known either whether these mechanisms are similar for boys and girls. The aim of this study was to analyse whether the association between GMC and AA is mediated by executive functions (EFs), and to investigate whether this mediation differs by sex. This cross-sectional study involved 451 children aged 8 to 10 (234 girls; mean age 9.95 ± 0.59). The Movement Assessment Battery for Children-Second Edition (MABC-2), NIH Toolbox, and grades in language and mathematics were used to test GMC, EFs, and AA, respectively. Multifactorial structural equation model (SEM) was used to evaluate a possible relation between variables, controlling for confounders. The differences by sex were examined using a multi-group SEM approach. The results showed that EFs acted as a full mediator of the relationship between GMC and AA in boys (ß = 0.14, p = 0.012) but not in girls (ß = 0.10, p = 0.326). These results show that the benefit of GMC on AA is mediated by EFs in boys but not in girls. Nevertheless, these conclusions should be carefully considered due to the cross-sectional nature of the study.

Aprotinin treatment against SARS-CoV-2: A randomized phase III study to evaluate the safety and efficacy of a pan-protease inhibitor for moderate COVID-19.

BACKGROUND: SARS-CoV-2 virus requires host proteases to cleave its spike protein to bind to its ACE2 target through a two-step furin-mediated entry mechanism. Aprotinin is a broad-spectrum protease inhibitor that has been employed as antiviral drug for other human respiratory viruses. Also, it has important anti-inflammatory properties for inhibiting the innate immunity contact system. METHODS: This was a multicentre, double-blind, randomized trial performed in four Spanish hospitals comparing standard treatment versus standard treatment + aprotinin for patients with COVID-19 between 20 May 2020 and 20 October 2021. The primary efficacy outcomes were length of hospital stay and ICU admission. The secondary endpoints were each of the primary efficacy outcomes and a composite of oxygen therapy, analytical parameters and death. Safety outcomes included adverse reactions to treatment during a 30-day follow-up period. Treatment was given for 11 days or till discharge. RESULTS: With almost identical analytical profiles, significant differences were observed in treatment time, which was 2 days lower in the aprotinin group (p = .002), and length of hospital admission, which was 5 days shorter in the aprotinin group (p = .003). The incidence of discharge was 2.19 times higher (HR: 2.188 [1.182-4.047]) in the aprotinin group than in the placebo group (p = .013). In addition, the aprotinin-treated group required less oxygen therapy and had no adverse reactions or side effects. CONCLUSION: Inhaled aprotinin may improve standard treatment and clinical outcomes in hospitalized patients with COVID-19, resulting in a shorter treatment time and hospitalization compared with the placebo group. The administration of aprotinin was safe.

"Clinical status and mortality in older adults with type 1 diabetes: Results from a public health system".

AIM: To evaluate clinical status and mortality in older adults with long-standing type 1 diabetes mellitus (T1D). METHODS: Cross-sectional analysis of all patients with T1D for 50 years or more from a cohort followed since 2010 at Castilla-La Mancha Public Health Service (Spain). Primary outcome was HbA1c change during the follow-up (2010-2020 period). Secondary outcomes included evaluation of insulin and continuous glucose monitoring (CGM) use, cardiovascular risk factors (CVRF), diabetes chronic complications and mortality. RESULTS: A total of fifty-five T1D patients were analysed. Mean age was 69.5 ± 8.3 yrs. and T1D duration of 54.7 ± 4.7 yrs. We detected a HbA1c reduction of -0.5% (-6 mmol/mol) [95% CI -0.1, -0.9 (-2, -10); P = 0.016]. CGM was used by 26% of the patients. More patients suffered from hypertension and obesity in 2020 (66% vs. 78%, P = 0.016; and 26% vs. 31%, P = 0.016; respectively). An increase of diabetic polyneuropathy was detected (45% vs. 67%, P = 0.008). Rate of mortality was higher among patients with long-standing T1D (26% vs. 3.5%, P < 0.001), due to cardiovascular disease (57%). CONCLUSIONS: Older adults with long-standing T1D patients improved glycemic control although a worsening of CVRF and higher mortality rateweredetected.

Análisis de los pacientes menores de edad con sospecha de COVID-19 en un servicio de urgencias y su impacto en el estudio de contactos / Pediatric patients with suspected COVID-19 in an emergency department: analysis of characteristics and transmission to contacts

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The interactions of alcohol and cocaine regulate the expression of genes involved in the GABAergic, glutamatergic and endocannabinoid systems of male and female rats.

Although the pharmacological and behavioural interactions between cocaine and alcohol are well established, less is known about how polyconsumption of these drugs affects the neurotransmitter systems involved in their psychoactive effects and in particular, in the process of addiction. Here, rats of both sexes at two stages of development were studied under a chronic regime of intravenous cocaine and/or alcohol administration. Brain samples from the medial prefrontal cortex, nucleus accumbens, hippocampus and amygdala were extracted to analyse the mRNA expression of genes encoding subunits of the GABA, NMDA and AMPA receptors, as well as the expression of the CB1 receptor, and that of enzymes related to the biosynthesis and degradation of endocannabinoids. Moreover, two synaptic scaffold proteins related to GABA and NMDA receptors, gephyrin and PSD-95, were quantified in Western blots. Significant interactions between cocaine and alcohol were common, affecting the GABAergic and endocannabinoid systems in the medial prefrontal cortex and amygdala of young adults, whereas such interactions were evident in the glutamatergic and endocannabinoid systems in adults, as well as a more pronounced sex effect. Significant interactions between these drugs affecting the scaffold proteins were evident in the medial prefrontal cortex and nucleus accumbens of young adults, and in the nucleus accumbens and amygdala of adults, but not in the hippocampus. These results highlight the importance of considering the interactions between cocaine and alcohol on neurotransmitter systems in the context of polyconsumption, specifically when treating problems of abuse of these two substances.

Characteristics and Risk Factors Associated With Mortality in a Multicenter Spanish Cohort of Patients With COVID-19 Pneumonia.

INTRODUCTION: Spain is one of the countries with the highest number of COVID-19 patients. Unfortunately, few data for regions are available. OBJECTIVES: This study aimed to describe the characteristics and independent risk factors associated with COVID-19 mortality in Castilla-La Mancha, Spain. METHODS: Cohort and multicenter study in all 14 public hospitals of the Castilla-La Mancha Health Service. Baseline characteristics, preexisting comorbidities, symptoms, clinical features and treatments were included. Multivariable logistic regression was used to evaluate factors associated with death and Kaplan-Meier test to examine survival probability. Statistical significance was considered with p < 0.05 (95% CI). SPSS (version 24.0 for Windows) and R 4.0.2 (R Statistics) software were used. RESULTS: The cohort comprised 12,126 patients sequentially attended between February 11 and May 11, 2020. The mean age of patients was 66.4 years; 5667 (46.7%) were women. Six protective factors against exitus were defined: female sex, anosmia, cough, chloroquine and azithromycin. The risk factors were: age over 50, obesity, cardiac pathology, fever, dyspnea, lung infiltrates, lymphopenia, D-dimer above 1000 ng/mL, and mechanical ventilation requirement. Survival analysis showed higher survival rate in women (75.7%) than men (72.1%). Cumulative survival was 87.5% for non-hospitalized patients, 70.2% for patients admitted to hospital and 61.2% in ICU patients. Additionally, survival probability decreased with increasing age range. CONCLUSION: Determination of protective or death-promoting factors could be useful to stratify patients by severity criteria and to improve COVID-19 care management.

INTRODUCCIÓN: España es uno de los países con mayor número de pacientes con COVID-19. Desafortunadamente, se dispone de pocos datos por regiones. OBJETIVOS: Describir las características y los factores de riesgo independientes asociados a mortalidad por COVID-19 en Castilla-La Mancha, España. MÉTODOS: Estudio de cohorte, multicéntrico de los 14 hospitales públicos de Castilla-La Mancha. Se evaluaron las características clínicas, comorbilidades preexistentes, síntomas y tratamientos. Se utilizó una regresión logística multivariable para evaluar los factores asociados a muerte y Kaplan-Meier para medir supervivencia. Se consideró significación estadística con p < 0,05 (IC 95%). Se utilizaron los programas SPSS (versión 24.0 para Windows) y R 4.0.2 (R Statistics). RESULTADOS: Se estudiaron 12.126 pacientes atendidos secuencialmente entre el 11 de febrero y el 11 de mayo de 2020. La edad media fue de 66,4 años; 5.667 (46,7%) fueron mujeres. Se definieron seis factores protectores contra el exitus: sexo femenino, anosmia, tos, cloroquina y azitromicina. Los factores de riesgo fueron: edad superior a 50, obesidad, patología cardíaca, fiebre, disnea, infiltrados pulmonares, linfopenia, dímero-D > 1.000 ng/mL y necesidad de ventilación mecánica. Se observó mayor tasa de supervivencia en mujeres (75,7%) que en hombres (72,1%). La supervivencia acumulada fue del 87,5% para pacientes no hospitalizados, 70,2% para admitidos en planta hospitalaria y 61,2% en la Unidad de Cuidados Intensivos (UCI). Además, la probabilidad de supervivencia disminuyó con el aumento del rango de edad. CONCLUSIÓN: La determinación de los factores protectores o favorecedores de muerte podría ser útil para estratificar pacientes por criterios de gravedad y mejorar la atención frente a la COVID-19.

Characterization of Permeability Barrier Dysfunction in a Murine Model of Cutaneous Field Cancerization Following Chronic UV-B Irradiation: Implications for the Pathogenesis of Skin Cancer.

Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting on the skin and poses a risk of developing photoaging, skin with cutaneous field cancerization (CFC), actinic keratosis (AKs), and squamous cell carcinomas (SCCs). Most of the UV-B light is absorbed in the epidermis, affecting the outermost cell layers, the stratum corneum, and the stratum granulosum, which protects against this radiation and tries to maintain the permeability barrier. In the present work, we show an impairment in the transepidermal water loss, stratum corneum hydration, and surface pH after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice) of skin with CFC. Macroscopic lesions of AKs and SCCs may develop synchronically or over time on the same cutaneous surface due to both the presence of subclinical AKs and in situ SCC, but also the accumulation of different mutations in keratinocytes. Focusing on skin with CFC, yet without the pathological criteria of AKs or SCC, the presence of p53 immunopositive patches (PIPs) within the epidermis is associated with these UV-B-induced mutations. Reactive epidermis to chronic UV-B exposure correlated with a marked hyperkeratotic hyperplasia, hypergranulosis, and induction of keratinocyte hyperproliferation, while expressing an upregulation of filaggrin, loricrin, and involucrin immunostaining. However, incidental AKs and in situ SCC might show neither hypergranulosis nor upregulation of differentiation markers in the upper epidermis. Despite the overexpression of filaggrin, loricrin, involucrin, lipid enzymes, and ATP-binding cassette subfamily A member 12 (ABCA12) after chronic UV-B irradiation, the permeability barrier, stratum corneum hydration, and surface pH were severely compromised in the skin with CFC. We interpret these results as an attempt to restore the permeability barrier homeostasis by the reactive epidermis, which fails due to ultrastructural losses in stratum corneum integrity, higher pH on skin surface, abundant mast cells in the dermis, and the common presence of incidental AKs and in situ SCC. As far as we know, this is the first time that the permeability barrier has been studied in the skin with CFC in a murine model of SCC induced after chronic UV-B irradiation at high doses. The impairment in the permeability barrier and the consequent keratinocyte hyperproliferation in the skin of CFC might play a role in the physiopathology of AKs and SCCs.