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Abstract Background Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

To address the shortcomings of traditional prestressed concrete girders, a new hybrid beam element, the Hybrid Deck Bulb Tee (HDBT) is proposed. The HDBT utilizes staged fabrication. First, the bottom flange is cast with Ultra-high Performance Concrete (UHPC) and prestressed prior to casting the web and top flange with High-Performance Concrete (HPC). The purpose of this study is to analytically evaluate the structural performance of HDBT beams for bridge structures. Multiple HDBT bridges were designed following the state-of-the-art criteria in regard to UHPC bridge design. The performance was evaluated using the following criteria: 1) the deflections under live load and dead load, 2) design checks for temporary stresses before losses, 3) stresses at serviceability limit states after losses, and 4) demand-to-capacity ratios under the American Association of State Highway and Transportation Officials (AASHTO) Strength I load combination. To obtain more refined results for the serviceability limit state, the bridges were modeled using a commercial finite element software. The model captured the time dependent material properties such as strength gain, creep, and shrinkage, as well as the stages of fabrication. The analysis demonstrates that the innovative design and fabrication processes of HDBTs are capable of resolving the current limitations of prestressed concrete elements.

This paper addresses the critical knowledge gap in the structural performance of porcelain insulators in overhead railway power systems through experimental evaluations. The focus is on porcelain insulators as part of a contact wire registration assembly (CWRA) in the railway power system. While porcelain insulators are the most widely used high-voltage insulator material, no previous studies have investigated the impact of age on their ultimate load capacity in overhead rail systems. The paper presents the experimental design for tension and a novel 45-degree test setup that replicates field conditions, as well as an overview of the test specimens, which were both new and retired from the field. The results indicate that aging has no impact on the strength of insulators in direct tension tests, but retired insulators in the CWRA show a reduced capacity. Additionally, the location of the drop bracket has a notable influence on the failure mode and stiffness of the assembly. The findings contribute to future improvements in system design and performance. Future research should include material testing, finite element studies, and dynamic testing of the full CWRA setup to further understand insulator performance and support resilient power transmission and distribution systems. Additionally, similar tests should be conducted on polymeric insulators, due to their prevalence.

ADAM10 is the main α-secretase acting in the non-amyloidogenic processing of APP. We hypothesized that certain rare ADAM10 variants could increase the risk for AD by conferring the age-related downregulation of α-secretase. The ADAM10 gene was sequenced in 103 AD cases (82% familial) and 96 cognitively preserved nonagenarians. We examined rare variants (MAF < 0.01) and determined their potential association in the AD group with lower CSF protein levels, as analyzed by means of ELISA, and Western blot (species of 50 kDa, 55 kDa, and 80 kDa). Rare variants were found in 15.5% of AD cases (23% early-onset, 8% late-onset) and in 12.5% of nonagenarians, and some were group-specific. All were intronic variants except Q170H, found in three AD cases and one nonagenarian. The 3′UTR rs74016945 (MAF = 0.01) was found in 6% of the nonagenarians (OR 0.146, p = 0.057). Altogether, ADAM10 total levels or specific species were not significantly different when comparing AD with controls or carriers of rare variants versus non-carriers (except a Q170H carrier exhibiting low levels of all species), and did not differ according to the age at onset or APOE genotype. We conclude that ADAM10 exonic variants are uncommon in AD cases, and the presence of rare intronic variants (more frequent in early-onset cases) is not associated with decreased protein levels in CSF.

Abstract Background The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive. Methods Clinical-genetic and biomarker study of a first family with early- and late-onset AD associated with a nonsense ADAM10 mutation (p.Tyr167*). CSF analysis included AD core biomarkers, as well as Western blot of ADAM10 species and sAPPα and sAPPβ peptides. We evaluate variant’s pathogenicity, pattern of segregation, and further screened for the p.Tyr167* mutation in 197 familial AD cases from the same cohort, 200 controls from the same background, and 274 AD cases from an independent Spanish cohort. Results The mutation was absent from public databases and segregated with the disease. CSF Aβ42, total tau, and phosphorylated tau of affected siblings were consistent with AD. The predicted haploinsufficiency effect of the nonsense mutation was supported by (a) ADAM10 isoforms in CSF decreased around 50% and (b) 70% reduction of CSF sAPPα peptide, both compared to controls, while sAPPβ levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα and sAPPβ levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings. The p.Tyr167* mutation was not found in any of the other AD cases or controls screened. Conclusions This family illustrates the role of ADAM10 in the amyloidogenic process and the clinical development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model for sporadic late-onset AD due to age-related downregulation of α-secretase. This report encourages future research on ADAM10 enhancers.

En las economías emergentes, la implementación de la Gestión de Infraestructura del Transporte es una necesidad imperante. Con el propósito de utilizar de la forma más eficiente posible los limitados recursos disponibles, la tecnología surge como un aliado estratégico en dicho objetivo. Con el fin de preservar los pavimentos y puentes, diferentes metodologías han sido desarrolladas para la detección de vehículos con sobrepeso. En el presente artículo se presenta la implementación y validación del pesaje de vehículos en movimiento mediante la instrumentación de un puente en servicio ubicado en Costa Rica, con una cantidad reducida de sensores. Se utilizó el enfoque basado en áreas de influencia de ondas de respuesta de deformaciones unitarias. Dada la distribución de los sensores, minimizando los requisitos de instrumentación, se utilizaron dos tipos de deformación unitaria: horizontal y cortante. Dos camiones de calibración fueron utilizados como referencia y luego se procedió a estimar el peso del tráfico aleatorio, para confrontar dichos resultados con los datos de la estación de pesaje estática más cercana.

Introduction. Patients treated with vitamin K antagonists (VKA) are at increased risk of intracranial haemorrhage (ICH). The purpose of our study was to determine the quality of previous anticoagulation control in patients with VKA-associated ICH. Materials and Methods. We prospectively assessed every consecutive patient admitted to our stroke unit with VKA-associated ICH between 2013 and 2016. Demographic, clinical, and radiological variables, as well as consecutive international normalized ratios (INR) during 7 previous months, were extracted. Time in therapeutic range (TTR), time over range (TOR), time below range (TBR), and percentage of INR within range (PINRR) were calculated. Results and Discussion. The study population comprised 53 patients. Mean age was 79 years; 42% were women. Forty-eight patients had atrial fibrillation (AF) and 5 mechanical prosthetic valves. Therapeutic or infratherapeutic INR on arrival was detected in 64.4% of patients (95% CI 2.7 to 3.2). TTR was 67.8% (95% CI: 60.2 to 75.6 %) and PINRR was 75% (95% CI: 49.9-100). TOR was 17.2% (95% CI: 10.4 to 23.9% ) and TBR was 17% (95% CI: 10.6 to 23.9%). Conclusion. VKA-associated ICH happens usually in the context of good chronic anticoagulation control. Newer risk assessment methods are required.

Introducción: son escasos los estudios donde se valora la anemia en pacientes cirróticos internados. Objetivo: evaluar la prevalencia, los factores predictivos y el pronóstico para mortalidad de la anemia en cirróticos internados. Pacientes y métodos: estudio descriptivo de casos y controles. Se revisaron 178 internaciones de 114 pacientes (edad media 52.4 años; 106 alcohólicos) entre mayo de 2004 y junio de 2007. Se excluyeron aquellas con pérdidas agudas de sangre. La anemia se clasificó como leve, moderada y severa a partir de una hemoglobina < 12 g/dl. Fueron considerados casos las internaciones con hemoglobina < 10 g/dl (anemias moderadas y severas). Resultados: se diagnosticó anemia en 155 internaciones, 47% fueron moderadas y 19% severas. La tasa de mortalidad hospitalaria en los casos fue 19.6% y en los controles 5.3%, [OR 4.39 (p=0.004)]. Fueron identificados como predictores independientes de mortalidad: el score de Child-Pügh [OR 1.99 (p=0.0005)], la creatininemia > 1.5 mg/dl [OR 11.34 (p= 0.0006)] y las infecciones [OR 5.78 (p= 0.018)]. Los casos tuvieron un mayor riesgo de insuficiencia renal [27.5% vs 3.9%, OR 9.2 (p=0.0001)]. La clasificación de Child- Pügh, la bilirrubinemia total, la albuminemia, las infecciones, la encefalopatía hepática y la hepatitis alcohólica también fueron factores predictivos de anemia moderada- severa. Los factores predictivos independientes fueron el score de Child-Pügh y la insuficiencia renal. Conclusiones: la anemia tiene una elevada prevalencia con un aumento de la mortalidad hospitalaria, aunque no fue un predictor independiente para riesgo de muerte. La insuficiencia renal y la severidad de la enfermedad hepática se asociaron en forma independiente con anemia moderada-severa en pacientes hospitalizados con cirrosis.

Se realizó un estudio descriptivo, retrosprospectivo para analizar la prevalencia de la peritonitis bacteriana espontánea, manifestaciones clínicas, características microbiológicas y factores pronósticos para mortalidad en 218 internaciones de 125 pacientes con cirrosis y ascitis, entre abril 2004 a mayo 2008. Se hizo análisis univariado mediante la prueba de la t de Student y la prueba exacta de Fisher. Se usó el método de regresión logística para determinar factores asociados a mortalidad. Se incluyeron 39 episodios de peritonitis bacteriana espontánea en 31 pacientes, 83,8 % hombres, edad media 49,1 años, 93,6 % alcohólicos, con una prevalencia de 39/218 (17,9 %). Fallecieron 10 pacientes (32,2 %). Fue adquirida en la comunidad en 59 %; sintomática en 82 %. Tuvieron cultivo positivo de líquido ascítico 41%. Fueron por gérmenes gram-positivos 13/24 (54 %) cultivos positivos de líquido ascítico y/o hemocultivos. En el análisis univariado se identificaron como factores predictores de mortalidad, el score de Child-Pügh, el score de hepatitis alcohólica de Glasgow, sitio de adquisición, encefalopatía hepática, control por paracentesis a las 48 h del inicio antibiótico sin respuesta, presencia de shock séptico, insuficiencia renal, hiponatremia y bilirrubinemia total > 250 µmol/L (> 14,6 mg/dL). La presencia de shock séptico, bilirrubinemia total > 250 µmol/L y la creatininemia > 114,4 µmol/L (> 1,5 mg/dL) fueron los factores pronósticos independientes para mortalidad, Los que aumentaron más de 20 veces el riesgo de muerte las 2 primeras, y de 14 veces la insuficiencia renal.A descriptive and retrospective study was conducted to analyze the prevelence or spontaneous bacterial peritonitis, clinical manifestations, microbiological characteristics and prognostic factors for mortality in 218 admissions of 125 patients with cirrhosis and ascites between April 2004 and May 2008. A univariate analysis was made by the Student's t test and Fisher's exact test. The logistical regression method was used to determine factors associated with mortality. 39 episodes of spontaneous bacterial peritonitis in 39 patients were included, 83.8 % were males, average age was 49.1 and 93.6 % were alcoholic, with a prevalence of 39/218 (17.9 %). 10 patients died (32.2 %). It was community acquired in 59 % and symptomatic in 82 %. 41 % had a positive culture of ascitic fluid. 13/24 (54 %) positive cultures of ascitic fluid and/or hemocultures were by gram-posistive germs. Child-Pügh's score, Glasgow's score of alcoholic hepatitis, site of acquisition, hepatic encephalopathy, control by paracentesis at 48 h of the beginning of antibiotics without response, presence of septic shock, renal failure, hyponatremia and total bilirubinemia > 250 µmol/L (> 14,6 mg/dL) were identified as the predictor factors in the univariate analysis. The presence of septic shock, total bilirubinemia > 250 µmol/L and creatininemia > 114.4 µmol/L (> 1.5 mg/dL) were the independent prognostic factors for mortality, the first two increased more than 20 times the risk of death and 14 times the renal failure.