Search

Summary: Abdominal and thoracic aortic aneurysms (AAAs, TAAs) remain a major cause of deaths worldwide, in part due to the lack of reliable prognostic markers or early warning signs. Sox6 has been found to regulate renin controlling blood pressure. We hypothesized that Sox6 may serve as an important regulator of the mechanisms contributing to hypertension-induced aortic aneurysms. Phenotype and laboratory-wide association scans in a clinical cohort found that SOX6 gene expression is associated with aortic aneurysm in subjects of European ancestry. Sox6 and tumor necrosis factor alpha (TNF-α) expression were upregulated in aortic tissues from patients affected by either AAA or TAA. In Sox6 knockout mice with angiotensin-II-induced AAA, we found that Sox6 plays critical role in the development and progression of AAA. Our data support a regulatory role of SOX6 in the development of hypertension-induced AAA, suggesting that Sox6 may be a therapeutic target for the treatment of aortic aneurysms.

Tubular SOFC have the advantage over planar SOFC of the low temperature sealing and more resistance to thermal shock. On the other hand the volumetric power density of tubular Fuel Cells goes with the inverse of the tube diameter which added to the faster warm-up kinetics makes low diameter tubular SOFC favorable for low power applications. Anode supported tubular SOFC of 3mm diameter and 150 mm length with YSZ electrolyte were fabricated and tested by V-I measurements using H2-Ar (5, 10, 100 vol%) as fuel and air for the cathode. The NiO-YSZ tubes of about 400 μm thickness were produced by hydrostatic pressure and then coated with an YSZ film of 15-20 μm. The electrolyte was deposited using a manual aerograph. After sintering either Pt paste or LSF (with YSZ or SDC) coatings of about 20-50 μm thickness were deposited for the cathode. The OCV of the cells were excellent, very close to the expected Nernst law prediction indicating that there were not gas leaks. The maximun electrical power of the cell was near to 500mW/cm2 at 850ºC operation temperature. Complex impedance measurements of the cells were performed in order to determine the resistance of the different cell components.La principal ventaja de las SOFC tubulares frente a las planares es el sellado de la cámara anódica y catódica a bajas temperaturas. Además la densidad de energía volumétrica de las pilas tubulares es inversamente proporcional al diámetro del tubo, que añadido a los tiempos cortos de encendido y apagado hacen que las mini-tubulares sean interesantes para usos de baja potencia. Se han fabricado y caracterizado SOFC tubulares soportadas en ánodo de 3mm de diámetro y de 150 mm de longitud, 400μm de espesor, con electrolito de YSZ depositado por spray de 15-20 μm. Los tubos de NiO-YSZ son producidos por prensado isostático. La caracterización eléctrica se ha realizado empleando H2-Ar como combustible anódico (5, 10, 100%vol) y aire para el cátodo. Los cátodos empleados son pintura de Pt o capas de LSF (con YSZ o SDC) de entre 20-50μm. Los OCV medidos ajustan con la predicción prevista de la ley de Nernst lo que indica que las capas de YSZ son estancas al paso de gas. Las curvas I-V muestran una corriente eléctrica máxima próxima a 500mW/cm2 operando a 850ºC. También se han realizado medidas de impedancia compleja para determinar la resistencia de los diversos componentes de la pila.

Resumen: Objetivo: Descripción y análisis de la relación entre las fracturas de húmero proximal y la lesión traumática del nervio axilar circunflejo. Material y método: Estudio prospectivo, observacional, de una serie de casos consecutivos de fracturas de extremo proximal de húmero. Se realizó valoración radiográfica, clasificando las fracturas según el sistema AO (Arbeitsgemeinshaft für Osteosynsthesefragen, Asociación de Grupo de Trabajo para el Estudio de la Fijación Interna de las Fracturas), y electromiografía (EMG) para la evaluación de la lesión del nervio axilar. Resultados: De 105 casos consecutivos de fracturas de húmero proximal, 31 pacientes cumplían los criterios de inclusión. Muestra: 86% mujeres y 14% hombres con edad media de 71,8 años (30-96 años). De los pacientes incluidos en el estudio, 58% presentó una EMG normal o leve axonotmesis, 23% presentó neuropatía del nervio axilar sin denervación muscular y 19%, lesión con denervación del nervio axilar. Los pacientes que sufrieron fracturas complejas de húmero proximal (AO11B y AO11C) tuvieron más riesgo de presentar lesiones tipo neuropatía axilar con denervación muscular en la EMG, siendo esta relación estadísticamente significativa (p < 0,001). Conclusiones: Los pacientes que sufren fracturas complejas de húmero proximal (AO11B y AO11C) tienen más riesgo de presentar lesiones tipo neuropatía axilar con denervación muscular en la EMG (p < 0,001). Abstract: Objective: Description and analysis of the relation between the proximal humerus fracture patterns and the traumatic injury of the axillary nerve. Material and method: Prospective, observational study of a consecutive case series that analyzed proximal humerus fractures. Radiographic evaluation was performed, and AO (Arbeitsgemeinshaft für Osteosynsthesefragen) system was used to classify the fractures. Electromyography was used to diagnose the axillary nerve injury. Results: Thirty-one patients on 105 who had a proximal humerus fracture met inclusion criteria. Eighty-six percent of the patients included were women and 14% men. The mean age was 71.8 years (30–96 years). Of the patients included in the study, 58% had normal or mild axonotmesis EMG, 23% had axillary nerve neuropathy without muscle denervation and 19% had injury with axillary nerve denervation. Patients who suffered complex fractures of the proximal humerus (AO11B and AO11C) had a higher risk of presenting axillary neuropathy type lesions with muscle denervation in the EMG, this relationship being statistically significant (p

A procedure for surface densification and/or texturing of Al2O3-YSZ (yttria stabilised zirconia) ceramics with eutectic composition by means of laser surface melting is presented. By scanning a high-power laser beam on a ceramic surface, we achieve a textured and fully dense surface layer from 30 to 1000 microns thick. For example, using a thin diode laser line with fluence 1.23 kW/cm2 and 0.14 mm/s scan rate, the solidified layer has 560 μm depth. We get a low roughness and dense surface. The microstructure is fine (micron size) due to the eutectic composition. The orientation of the microstructure is determined by the shape of the solid-liquid interface in the solidification process. We study the shape of this interface in transverse and longitudinal cross-sections in single as well as overlapping scans, which are required to process large surfaces. From the macroscopic point of view, the transition between adjacent scans is smooth. However, the microstructure presents discontinuity in the interphase spacing due to microstructural evolution in the heat affected region as well as the nucleation of an Al2O3 layer at the beginning of the crystal growth. The thermal shock inherent to the procedure generates cracks longitudinal and transverse to the scanning direction, as well as delaminating cracks. We analyse different possibilities to reduce this thermal shock. The best results are obtained by preheating the substrate, allowing us to process surfaces of Al2O3-YSZ eutectic ceramics 99% dense.Se presenta un procedimiento para la densificación y/o texturado superficial de cerámicas de Al2O3-YSZ (circona estabilizada con itria) con composición eutéctica mediante fusión zonal asistida por láser. Haciendo un barrido con la radiación proveniente de un láser de potencia sobre piezas cerámicas conseguimos modificar la microestructura y densificar completatmente la capa superficial, con un espesor que va de 30 a 1000 μm. Por ejemplo, con línea estrecha de láser de diodo, fluencia de 1.23 kW/cm2 y velocidades de barrido de 0.14 mm/s, solidificamos capas de 560 μm. El resultado es una superficie de baja rugosidad y no porosa. La microestructura de la muestra es fina debido a su composición eutéctica. La interfase sólido-líquido en el proceso de crecimiento determina la orientación de la microestructura. Se estudia la forma de esta interfase tanto en cortes transversales como longitudinales, lo que permite analizar el efecto que sobre la microestructura tiene la superposición de barridos, que es una alternativa para tratar superficies extensas. Macroscópicamente la frontera entre barridos contiguos es suave. Sin embargo, su microestructura presenta discontinuidad en el espaciado entre las fases debido a la evolución microestructural en la región no fundida sometida a altas temperaturas y a la nucleación preferencial de Al2O3 al comenzar el crecimiento cristalino. Se analizan distintas posibilidades para disminuir el choque térmico inherente al proceso y que conduce a la formación de grietas paralelas a la dirección de procesado y de delaminación. Se observa una mejora importante cuando se precalienta la pieza a tratar, de modo que es posible procesar superficies de cerámicas eutécticas 99% densas.

Objectives: Adherence to healthy lifestyle recommendations has been reported to improve health-related quality of life (HRQL) in breast cancer (BC) patients, but the influence of long-term behavioral changes remains unknown. We evaluated the association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and HRQL both, at BC diagnosis and the change 7−12 years later. Design: Prospective cohort study. Settings and participants: A total of 406 breast cancer survivors, from the EpiGEICAM study, were recruited in 16 Spanish hospitals. Measurements: Epidemiological, clinical, dietary, physical activity and HRQL information was collected both at recruitment and 7−12 years later. A 7-item score to measure compliance with recommendations was assessed according to the 2018 WCRF/AICR scoring criteria. HRQL was evaluated using SF-36 questionnaire. Linear mixed models for longitudinal data were used to assess the cross-sectional and longitudinal association between adherence score and the physical and mental component summary scores. Results: At diagnosis, for each unit increase in WCRF/AICR score adherence, the HRQL physical domain increased 0.78 points (95%CI: −0.04 to 1.60; P trend:0.06). The mean change in physical HRQL from diagnosis to follow-up per unit increase in within-subject adherence score was 0.73 points (95%CI: −0.18 to 1.65; P trend: 0.12). For the mental domain, no association was observed with compliance with the recommendations at diagnosis, nor with changes in adherence over time. Conclusions: Our results suggest that Increased adherence to WCRF/AICR cancer prevention recommendations over time could contribute to slightly improved long-term physical HRQoL in BC survivors.

Summary: Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion and tethering with the ER. The role of MFN2 in mitochondrial transport has however remained elusive. Like MFN2, acetylated microtubules play key roles in mitochondria dynamics. Nevertheless, it is unknown if the α-tubulin acetylation cycle functionally interacts with MFN2. Here, we show that mitochondrial contacts with microtubules are sites of α-tubulin acetylation, which occurs through MFN2-mediated recruitment of α-tubulin acetyltransferase 1 (ATAT1). This activity is critical for MFN2-dependent regulation of mitochondria transport, and axonal degeneration caused by CMT2A MFN2 associated R94W and T105M mutations may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in α-tubulin acetylation and suggest that disruption of this activity plays a role in the onset of MFN2-dependent CMT2A.

Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, its clinical translation faces challenges due to issues with poor pharmacokinetics and side effects. Here, we developed engineered liposomes loaded with JQ1 with the aim of enhancing kidney drug delivery and reducing the required minimum effective dose by leveraging cargo protection. These liposomes efficiently encapsulated JQ1 in both the membrane and core, demonstrating superior therapeutic efficacy compared to freely delivered JQ1 in a mouse model of kidney ischemia-reperfusion injury. JQ1-loaded liposomes (JQ1-NPs) effectively targeted the kidneys and only one administration, one-hour after injury, was enough to decrease the immune cell (neutrophils and monocytes) infiltration to the kidney—an early and pivotal step to prevent damage progression. By inhibiting BRD4, JQ1-NPs suppress the transcription of pro-inflammatory genes, such as cytokines (il-6) and chemokines (ccl2, ccl5). This success not only improved early the kidney function, as evidenced by decreased serum levels of BUN and creatinine in JQ1-NPs-treated mice, along with reduced tissue expression of the damage marker, NGAL, but also halted the production of extracellular matrix proteins (Fsp-1, Fn-1, α-SMA and Col1a1) and the fibrosis development. In summary, this work presents a promising nanotherapeutic strategy for AKI treatment and its progression and provides new insights into renal drug delivery.

Objective: Description and analysis of the relation between the proximal humerus fracture patterns and the traumatic injury of the axillary nerve. Material and method: Prospective, observational study of a consecutive case series that analysed proximal humerus fractures. Radiographic evaluation was performed, and AO (Arbeitsgemeinshaft für Osteosynsthesefragen) system was used to classify the fractures. Electromyography was used to diagnose the axillary nerve injury. Results: Thirty-one patients on 105 who had a proximal humerus fracture met inclusion criteria. Eighty-six percent of the patients included were women and 14% men. The mean age was 71.8 years (30–96 years). Of the patients included in the study, 58% had normal or mild axonotmesis EMG, 23% had axillary nerve neuropathy without muscle denervation and 19% had injury with axillary nerve denervation. Patients who suffered complex fractures of the proximal humerus (AO11B and AO11C) had a higher risk of presenting axillary neuropathy type lesions with muscle denervation in the EMG, this relationship being statistically significant (p

A willingness to explore new ideas and to maintain reflective skepticism is necessary to exercise critical citizenship. Importantly, the disposition to think critically is a dynamic (rather than static) characteristic of a person that can be developed through different educational experiences. The aim of this study was to examine the influence of three applied learning experiences – namely, internships, service learning and participation in international mobility programmes – on higher education students' disposition toward critical thinking. Participants were 147 Spanish undergraduates aged between 17 and 24 years (M = 18.36, SD = 1.16; 69.39% women). They were enrolled in degree programmes in the fields of social and legal sciences (81.6% of students) and engineering and architecture (18.4%). Critical thinking disposition was assessed at two time points: at the beginning of their undergraduate studies and at the end of year 2, by which time some students had participated in applied learning experiences. No changes were found in the disposition toward critical thinking of students who did not participate in experiences of this kind. However, students who had engaged in service learning projects showed gains in their critical thinking disposition. Contrary to expectations, no significant improvement in critical thinking disposition was observed among students who carried out internships or participated in mobility programmes. These findings emphasize the importance of promoting service learning experiences in higher education so as to promote and develop students' disposition toward critical thinking.

Introduction/Objectives: To evaluate the efficacy and safety of elranatamab in a pooled analysis of patients (pts) enrolled in MagnetisMM trials with relapsed or refractory multiple myeloma (RRMM) who had prior exposure to B-cell maturation antigen (BCMA)-directed therapy. Materials and methods: Eligible pts received at least 1 proteasome inhibitor, 1 immunomodulatory drug, 1 anti-CD38 antibody, and 1 BCMA-directed therapy (antibody-drug conjugate [ADC] and/or chimeric antigen receptor [CAR]-T cells). The pooled analysis included pts in the MagnetisMM-1 trial (NCT03269136; n = 13) who received subcutaneous (SC) elranatamab 215-1000 μg/kg; MM-3 (NCT04649359; n = 64) and MM-9 (NCT05014412; n = 9) who received the recommended phase 2 dose of 76 mg SC once-weekly. Efficacy endpoints were evaluated by investigator per IMWG criteria. TEAEs were graded by CTCAE (MM-1, v4.03; MM-3 & MM-9, v5.0); CRS and ICANS were graded by ASTCT criteria. Results include data up through ≍10 months after last pt initial dose in all pooled studies. Results: In total, 86 pts were included. Median age was 66.0 y (range, 40-84); 47.7% male. At baseline, 69.8% had an ECOG PS ≥1; 24.4% had high risk cytogenetics; 54.7% had extramedullary disease. Pts received a median of 7.0 (3-19) prior lines of therapy, including BCMA-directed ADC (67.4%), CAR T-cells (41.9%); 9.3% received both. 96.5% and 54.7% of pts were triple-class and penta-drug refractory, respectively; among pts who received ADC and CAR-T cells respectively, 79.3% and 27.8% were refractory to ADC and CAR-T cells. After a median follow-up of 10.3 mo (0.3-32.3), median duration of treatment was 3.3 mo (0.03-30.4). At the cut-off date, 24.4% of pts remained on treatment; most common reason for permanent treatment discontinuation was progressive disease (44.2%). The overall response rate (ORR) was 45.3% (95% CI 34.6-56.5), with ≥CR achieved in 17.4% of pts. ORR for pts with prior BCMA-directed ADC and CAR-T cells was 41.4% (95% CI 28.6-55.1) and 52.8% (95% CI 35.5-69.6), respectively. Among responders, median time to objective response was 1.9 mo (0.3-9.3). Median duration of response (DOR) was not reached by 10 mo; the DOR rate at 9 mo was 72.4% (95% CI 54.7-84.2). DOR rate (95% CI) for pts with prior BCMA-directed ADC and CAR-T cells were 67.3% (43.1-83.0) and 78.9% (53.2-91.5) at 9 mo, respectively. Median progression-free survival was 4.8 mo (95% CI 1.9-7.7); median overall survival was not reached by 10 mo, with a rate of 60.1% (95% CI 48.9-69.6) at 9 mo. Most common (≥25% of pts) TEAEs were CRS (65.1% [G3 1.2%]), anemia (59.3% [G3/4, 46.5%]), neutropenia (44.2% [G3/4, 40.7%]), thrombocytopenia (40.7% [G3/4, 29.1%]), diarrhea (33.7% [G3/4, 0%], and lymphopenia (32.6% [G3/4, 30.2%]). 5.8% (G3, 2.3%) of pts. Discussion: In pts with RRMM and prior exposure to BCMA-directed therapies, elranatamab was efficacious and well tolerated; no new safety signals were observed vs the BCMA-naïve population. Conclusions: These results support treatment with elranatamab in pts with RRMM post BCMA-directed therapy.

Alluvial small-scale gold mining (ASGM) mining in the Amazon is expanding fiercely, generating severe environmental degradation, which includes the fast disappearance of primary forests in a highly biodiverse area of the world. Different factors motivate the growth of mining in the areas and understanding this expansion is important to safeguard protected areas or implement strategies to mitigate the related social and environmental impacts. Thus, the goal of this study is to apply machine learning techniques to explore gold mining expansion in Madre de Dios, in the Peruvian Amazon, and to identify possible future hotspots of these activities. Using an unsupervised learning algorithm and a random forest classification model, past expansion trends were analyzed and an explicit geo-spatial model was built. Results demonstrate that proximity to infrastructure is not always indicative of high mining probability. In fact, when analyzing the spatial distribution of model accuracy, it is observed that model performance decreases in clusters where accessibility and mining activity showed opposite trends. In contrast, the models yield accuracies greater than 0.9 when accessibility-related variables stand out as the most important. The model, which is flexible and reproducible, demonstrates to be useful to enhance decision making when implementing geo-spatial policies to address the problem of ASGM expansion in the Amazon.

Resumen: Objetivo: Determinar la relación del índice de privación de la población con la utilización del sistema sanitario, la mala evolución y la mortalidad durante la pandemia de COVID-19. Método: Estudio de cohorte retrospectivo de personas con infección por SARS-CoV-2 del 1 de marzo de 2020 al 9 de enero de 2022. Se recopilaron datos sociodemográficos, comorbilidad y tratamientos basales prescritos, otros datos basales y el índice de privación, estimado por sección censal. Se realizaron modelos multivariable de regresión logística multinivel para cada variable de resultado: fallecimiento, mala evolución (definida como fallecimiento o ingreso en la unidad de cuidados intensivos), ingreso y visitas a urgencias. Resultados: La cohorte se compone de 371.237 personas con infección por SARS-CoV-2. En los modelos multivariable se observó un mayor riesgo de fallecimiento, de mala evolución, de ingreso hospitalario o de visita a urgencias en los quintiles de mayor privación en comparación con el quintil de menor privación. Para el riesgo de ser hospitalizado o de acudir a urgencias, en términos generales hubo diferencias entre todos los quintiles. También se observó que estas diferencias se daban en el primer y el tercer periodos de la pandemia para la mortalidad y la mala evolución, y en todos para el riesgo de ser ingresado o de acudir a urgencias. Conclusiones: Los colectivos con mayor nivel de privación han tenido mayores tasas de mortalidad y de ingreso en comparación con los colectivos con unas tasas de privación más bajas. Es necesario realizar intervenciones que minimicen estas desigualdades. Abstract: Objective: To see the relationship between the population deprivation index and the use of the health services, adverse evolution and mortality during the COVID-19 pandemic. Method: Retrospective cohort study of patients with SARS-CoV-2 infection from March 1, 2020 to January 9, 2022. The data collected included sociodemographic data, comorbidities and prescribed baseline treatments, other baseline data and the deprivation index, estimated by census section. Multivariable multilevel logistic regression models were performed for each outcome variable: death, poor outcome (defined as death or intensive care unit), hospital admission, and emergency room visits. Results: The cohort consists of 371,237 people with SARS-CoV-2 infection. In the multivariable models, a higher risk of death or poor evolution or hospital admission or emergency room visit was observed within the quintiles with the greatest deprivation compared to the quintile with the least. For the risk of being hospitalized or going to the emergency room, there were differences between most quintiles. It has also been observed that these differences occurred in the first and third periods of the pandemic for mortality and poor outcome, and in all due for the risk of being admitted or going to the emergency room. Conclusions: The groups with the highest level of deprivation have had worse outcomes compared to the groups with lower deprivation rates. It is necessary to carry out interventions that minimize these inequalities.

Objective: To estimate the effectiveness of a Medication Discrepancy Detection Service (MDDS), a collaborative service between the community pharmacy and Primary Care. Design: Non-controlled before-and-after study. Setting: Bidasoa Integrated Healthcare Organisation, Gipuzkoa, Spain. Participants: The service was provided by a multidisciplinary group of community pharmacists (CPs), general practitioners (GPs), and primary care pharmacists, to patients with discrepancies between their active medical charts and medicines that they were actually taking. Outcomes: The primary outcomes were the number of medicines, the type of discrepancy, and GPs’ decisions. Secondary outcomes were time spent by CPs, emergency department (ED) visits, hospital admissions, and costs. Results: The MDDS was provided to 143 patients, and GPs resolved discrepancies for 126 patients. CPs identified 259 discrepancies, among which the main one was patients not taking medicines listed on their active medical charts (66.7%, n = 152). The main GPs’ decision was to withdraw the treatment (54.8%, n = 125), which meant that the number of medicines per patient was reduced by 0.92 (9.12 ± 3.82 vs. 8.20 ± 3.81; p

Summary: Background: Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal death in low- to middle-income countries (LMIC). The American College of Obstetricians and Gynecologists (ACOG) updated diagnostic guidelines to align signs and symptoms with those associated with maternal death. We performed an observational study to ask whether ACOG guidelines were employed and associated with adverse outcomes in La Paz-El Alto, Bolivia, an LMIC. Methods: Medical records for all HDP discharge diagnoses (n = 734) and twice as many controls (n = 1647) were reviewed for one year at the three largest delivery sites. For the 690 cases and 1548 controls meeting inclusion criteria (singleton, 18–45 maternal age, local residence), health history, blood pressures, symptoms, lab tests, HDP diagnoses (i.e., gestational hypertension [GH]; preeclampsia [PE]; haemolysis, low platelets, high liver enzymes [HELLP] syndrome, eclampsia), and adverse outcomes were recorded. Bolivian diagnoses were compared to ACOG guidelines using accuracy analysis and associated with adverse outcomes by logistic regression. Findings: Both systems agreed with respect to eclampsia, but only 27% of all Bolivian HDP diagnoses met ACOG criteria. HDP increased adverse maternal- or perinatal-outcome risks for both systems, but ACOG guidelines enabled more pre-delivery diagnoses, graded maternal-risk assessment, and targeting of HDP terminating in maternal death. Interpretation: Bolivia diagnoses agreed with ACOG guidelines concerning end-stage disease (eclampsia) but not the other HDP due mainly to ACOG's recognition of a broader range of severe features. ACOG guidelines can aid in identifying pregnancies at greatest risk in LMICs, where most maternal and perinatal deaths occur. Funding: NIH TW010797, HD088590, HL138181, UL1 TR002535.

Purpose: This study aims to describe the late retinal and optic nerve vascular complications due Coronavirus disease 2019 (COVID-19) in a Spanish young population. Methods: We describe 15 eyes of 15 young patients without any other systemic risk factors, except controlled arterial hypertension in 5 of them, with the diagnosis of Central retinal vein occlusion (CRVO), Branch retinal vein occlusion (BRVO), Central retinal artery occlusion (CRAO), Branch retinal artery occlusion (BRAO), Mixed occlusions (Artery and Vein) and Non-arteritic ischemic optic neuropathy (NAION) with a previous COVID-19 infection demonstrated with a positive COVID-19 IgG Test (COVID-19 IgG/IgM Rapid Test Cassette, Lambra Laboratories, Madrid, Spain. Results: 9 males and 6 females, with a mean age of presentation of 49.7 ± 9 years old were included. The mean time between infection and diagnosis of the disease was 3.5 ± 1.2 months. The most common retinal or optic nerve vascular complication was CRVO (6 cases), following by CRAO (4 cases), Mixed arterial and venous occlusions (2 cases), NAION (2 cases) and BRAO (1 case). Conclusions: The presence of a retinal or optic nerve vascular event in a young patient without any other hypercoagulable or genetic thrombophilic disorder, should make us rule out a previous COVID-19 infection. Ophthalmologists must be awared that retinal circulation could be another potential site for thromboembolic and optic nerve circulatory insufficiency complications of COVID-19. To our knowledge, this is the longest case series of retinal or optic nerve vascular events described after COVID-19 infection.

Objective: This investigation aimed to detect coincidences in the antimicrobial resistance genes (ARG) profiles between members of a group living in a household and to compare them between other groups in order to establish if an exchange of ARG occurs and if dental plaque microbiota can be considered as a source and reservoir of ARG that can be shared between humans and pets. Methods: One hundred sixty dental plaque samples were obtained from four groups: Shelter dogs group (n = 20), adult pet owners and dogs group (AD group, n = 40), adult pet owners, children and dogs group (ACD group, n = 60), and adult non-pet owners and children group (AC group, n = 40). DNA was obtained, and specific primers with polymerase chain reaction for ARG detection were used. Results: The AD group exhibited the most coincidences in their ARG profiles, 14 (70%) of the 20 profiles coincided in 100% followed by the ACD group with 9 (45%) coincidences. While the AC group was the less coincident group, only 7 (35%) of the 20 profiles coincided. tetM was the most prevalent with 53.1%, followed by tetQ with 52.5% and cfxA with 51.2%, while the less prevalent were tetW with 31.8%, blaTEM-1 with 27.5%, and ermC with 18.7%. Conclusion: Dental plaque microbiota can be considered as a source and reservoir of ARG that can be shared between humans and dogs living in a household. The dogs seem to play an important role in the transference of ARG, and the children appear to be the most affected by carrying the most significant number of ARG.

Objective: Diabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell's response to an adverse metabolic environment with impaired mitochondrial function remains unclear. Methods: Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and nicotinamide actin dysfunction (NAD)/reduced nicotinamide actin dysfunction (NADH) ratios. Results: The expression of Cyb5r3 is decreased in FoxO1-deficient β cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient β cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability. Conclusions: The findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate β-cell failure. Keywords: Beta cell dedifferentiation, Mitochondrial complex III failure, Type 2 diabetes, Diabetes genetics, Endocrine pancreas, Transcription factor in beta cell function, Hyperglycemia, Glucose clamp, Diabetes therapy

Objective: Vestibular afferents converge with nociceptive ones within the posterior insula, and can therefore modulate nociception. Consistent with this hypothesis, caloric vestibular stimulation (CVS) has been shown to reduce experimental and clinical pain. Since CVS can induce undesirable effects in a proportion of patients, here we explored an alternative means to activate non-invasively the vestibular pathways using innocuous bi-mastoid galvanic stimulation (GVS), and assessed its effects on experimental pain. Methods: Sixteen healthy volunteers participated in this study. Experimental pain was induced by noxious laser-heat stimuli to the left hand while recording pain ratings and related brain potentials (LEPs). We evaluated changes of these indices during left- or right-anodal GVS (cathode on contralateral mastoid), and contrasted them with those during sham GVS, optokinetic vestibular stimulation (OKS) using virtual reality, and attentional distraction to ascertain the vestibular-specific analgesic effects of GVS. Results: GVS elicited brief sensations of head/trunk deviation, inoffensive to all participants. Both active GVS conditions showed analgesic effects, greater for the right anodal stimulation. OKS was helpful to attain significant LEP reductions during the left-anodal stimulation. Neither sham-GVS nor the distraction task were able to modulate significantly pain ratings or LEPs. Conclusions: GVS appeared as a well-tolerated and powerful procedure for the relief of experimental pain, probably through physiological interaction within insular nociceptive networks. Either isolated or in combination with other types of vestibular activation (e.g., optokinetic stimuli), GVS deserves being tested in clinical settings.

Purpose: To assess the short and long-term changes in Visual Field (VF) Mean Deviation (MD), Visual Field Index (VFI), and intraocular pressure (IOP) after femtosecond laser-assisted cataract surgery (FLACS) in glaucomatous eyes. Materials and methods: Interventional, prospective case series. Patients with glaucoma, who required cataract surgery were included. All patients underwent a complete ophthalmologic assessment and Visual Fields. FLACS was performed in all patients by a single experienced surgeon. IOP was measured during surgery immediately before and after pretreatment suction docking. Changes from baseline in VF MD and VFI, IOP, visual acuity (VA), and number of glaucoma medications were evaluated up to one-year follow-up. Results: Fourteen eyes of 11 patients were included. Eighty-five percent were female, with a mean age of 74.2 ± 7.9 years. Nine (64.3%) and 5 (35.7%) were diagnosed with primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG), respectively. We found a slight IOP reduction after the docking phase during FLACS in both glaucoma subtype groups. No significant changes in visual field mean deviation (MD) and visual field index (VFI) were found from baseline to 12 months after surgery in both groups. A significant reduction in IOP values was found in all cases from baseline up to one year follow up. No significant changes were observed in BCVA and number of topical glaucoma medications after one year in both groups. Conclusion: In our patients, there was an IOP reduction immediately after suction docking FLACS pretreatment. Mean IOP at final follow-up showed a reduction from baseline. There was no change in VF MD and VFI from baseline to final one-year follow-up. FLACS appears to be well tolerated in early and moderate glaucoma and appears to be a safe tool for glaucoma patients undergoing cataract surgery. Similar results to traditional surgery can be obtained with the advantages of femtosecond laser precision.

Resumen: Objetivo: Analizar si la nota informativa de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), de 30 de octubre del 2018, sobre agranulocitosis y metamizol contiene la información precisa y necesaria para proteger a los pacientes de la aparición de esta reacción adversa (RA) y si la documentación oficial de los medicamentos con metamizol para médicos, farmacéuticos y población general está adaptada a las directrices de la AEMPS para disminuir el riesgo. Emplazamiento y participantes: Nota informativa, búsqueda bibliográfica, información sobre los medicamentos con metamizol comercializados en España en la Agencia Europea del Medicamento, fichas técnicas, prospectos, base de datos de información sanitaria Bot PLUS y Catálogo de Especialidades Farmacéuticas. Notificación de 4 casos de agranulocitosis por metamizol posteriores a la fecha de la nota informativa. Intervenciones y mediciones principales: Comparación de los puntos clave de la nota informativa y de los documentos oficiales sobre metamizol con la bibliografía. Descripción de 4 casos de agranulocitosis por metamizol y aplicación del algoritmo de causalidad y gravedad. Resultados: La nota informativa presenta ausencias y dudas respecto a la bibliografía y al uso de metamizol en la práctica asistencial. Los documentos oficiales presentan faltas de actualización, indicaciones no aprobadas y dosis superiores a las recomendadas. La nota informativa no ha frenado la presentación de casos de agranulocitosis por metamizol. Conclusiones: La nota informativa de la AEMPS es mejorable y es necesario actualizar los documentos oficiales de información sobre el metamizol para profesionales sanitarios y pacientes para disminuir el riesgo de agranulocitosis. Abstract: Objective: To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and metamizole contains accurate and necessary information to protect patients from the presentation of this adverse reaction (AR) and if the official documentation of medicines containing metamizole for doctors, pharmacists and the general population conforms to the guidelines of the AEMPS to reduce this risk. Setting and participants: Drug safety update, bibliographic search, information at the European Medicines Agency on metamizole drugs marketed in Spain, technical datasheets, leaflets, Bot PLUS Health Information Database and Catalog of Pharmaceutical Specialties. Notification of 4 cases of agranulocytosis due to metamizole after the drug safety update was issued. Main interventions and measurements: Comparison of the key points of the drug safety update and official documents on metamizole with the bibliography. Description of the 4 cases of agranulocytosis due to metamizole and application of the causality and severity algorithm. Results: The drug safety update contains omissions and contradiction in respect to the bibliography and the actual use of metamizole in healthcare practice. The official documents show a lack of updating, unapproved indications and doses higher than those recommended. The drug safety update has not stopped the presentation of cases of agranulocytosis due to metamizole. Conclusions: The AEMPS drug safety update can be improved and it is necessary to update the official information documents on metamizole for health professionals and patients in order to decrease the risk of agranulocytosis.

Introduction: Comprehensive national non-communicable disease (NCD) policy development and implementation are crucial for preventing and controlling the increasing NCD burden, particularly in the Africa region where the largest increase in NCD related mortality is expected by 2030. Yet, even where national NCD policies exist, effective implementation remains hindered for reasons not clearly elucidated. This study explored the experiences of key health stakeholders at national and sub-national levels with implementing a national NCD policy in Ghana. Methods: This was an explanatory, cross-sectional and grounded theory study using in-depth interview guides to collect primary data from 39 purposively sampled health policymakers and implementing officials at the national and sub-national levels in Ghana. A thematic approach was used in data analysis. Results: Several interwoven factors including poor policy awareness, poor coordination and intersectoral engagements and inadequate funding for NCD programs and activities are key challenges thwarting the effective implementation of the national NCD policy in Ghana. At the sub-national levels, inadequate clarity and structure for translating policy into action and inadequate integration further affect operationalizing of the national NCD policy. Conclusion: The findings call for policymakers to adopt a series of adaptive measures including sustainable NCD financing mechanisms, effective intersectoral coordination, policy sensitisation and capacity building for implementing health professionals, which should be coupled with governmental and global resource investment in effective implementation of national NCD policies to make sustained population level gains in NCD control in Ghana and in other resource constrained settings.

The discovery of contact sites was a breakthrough in cell biology. We have learned that an organelle cannot function in isolation, and that many cellular functions depend on communication between two or more organelles. One such contact site results from the close apposition of the endoplasmic reticulum (ER) and mitochondria, known as mitochondria-associated ER membranes (MAMs). These intracellular lipid rafts serve as hubs for the regulation of cellular lipid and calcium homeostasis, and a growing body of evidence indicates that MAM domains modulate cellular function in both health and disease. Indeed, MAM dysfunction has been described as a key event in Alzheimer disease (AD) pathogenesis. Our most recent work shows that, by means of its affinity for cholesterol, APP-C99 accumulates in MAM domains of the ER and induces the uptake of extracellular cholesterol as well as its trafficking from the plasma membrane to the ER. As a result, MAM functionality becomes chronically upregulated while undergoing continual turnover. The goal of this review is to discuss the consequences of C99 elevation in AD, specifically the upregulation of cholesterol trafficking and MAM activity, which abrogate cellular lipid homeostasis and disrupt the lipid composition of cellular membranes. Overall, we present a novel framework for AD pathogenesis that can be linked to the many complex alterations that occur during disease progression, and that may open a door to new therapeutic strategies.

Alpha-synuclein (aSyn) protein levels are sufficient to drive Parkinson's disease (PD) and other synucleinopathies. Despite the biomedical/therapeutic potential of aSyn protein regulation, little is known about mechanisms that limit/control aSyn levels. Here, we investigate the role of a post-translational modification, N-terminal acetylation, in aSyn neurotoxicity. N-terminal acetylation occurs in all aSyn molecules and has been proposed to determine its lipid binding and aggregation capacities; however, its effect in aSyn stability/neurotoxicity has not been evaluated. We generated N-terminal mutants that alter or block physiological aSyn N-terminal acetylation in wild-type or pathological mutant E46K aSyn versions and confirmed N-terminal acetylation status by mass spectrometry. By optical pulse-labeling in living primary neurons we documented a reduced half-life and accumulation of aSyn N-terminal mutants. To analyze the effect of N-terminal acetylation mutants in neuronal toxicity we took advantage of a neuronal model where aSyn toxicity was scored by longitudinal survival analysis. Salient features of aSyn neurotoxicity were previously investigated with this approach. aSyn-dependent neuronal death was recapitulated either by higher aSyn protein levels in the case of WT aSyn, or by the combined effect of protein levels and enhanced neurotoxicity conveyed by the E46K mutation. aSyn N-terminal mutations decreased E46K aSyn-dependent neuronal death both by reducing protein levels and, importantly, by reducing the intrinsic E46K aSyn toxicity, being the D2P mutant the least toxic. Together, our results illustrate that the N-terminus determines, most likely through its acetylation, aSyn protein levels and toxicity, identifying this modification as a potential therapeutic target.