Comprehensive evaluation of genetic and acquired thrombophilia markers for an individualized prediction of clinical thrombosis in patients with lymphoma and multiple myeloma.

Patients diagnosed with lymphoma or multiple myeloma are at elevated risk of venous thromboembolism (VTE). Optimum risk stratification and effective thromboprophylaxis can only be achieved through the development of a multiple-specific risk score that successfully captures all aspects of the heterogeneous prothrombotic environment existing in these patients. Our aim was to identify risk factors for thrombosis and suggest an improved tool combining clinical data, thrombo-inflammatory biomarkers and genetic (Thrombo inCode® test) variables for predicting thrombotic risk in patients with lymphoma and multiple myeloma. A prospective longitudinal study was conducted on newly-diagnosed lymphoma and multiple myeloma patients who presented at our institution between February 2020 and January 2021. The study included 47 patients with lymphoma and 16 patients with multiple myeloma. We performed a follow-up of 1 year or until September 2021. The incidence of venous thrombosis and associated risk factors were analysed, including the genetic Thrombo inCode® test. Khorana and ThroLy scores for lymphoma patients and IMPEDE VTE score for myeloma patients were calculated. At a median follow-up of 9.1 months, VTE incidence was 9.5% (6/63), with 4 and 2 patients with lymphoma and myeloma who developed the events, respectively. Univariate analysis showed that the incidence of thrombosis was significantly higher in patients with ECOG ≥ 2 and prior immobility. Median factor VIII levels were significantly higher in patients with thrombosis (with increased values in all of them). Moreover, there was a trend in genetic variant rs5985 (factor XIII) as a protective factor, and a trend to higher thrombotic risk in patients with factor V Leiden, rs2232698 variant (serpinA10), low total protein S activity, elevated D-dimer, aggressive lymphoma and treatment with dexamethasone. The results of our study demonstrate promise for the potential use of widely accessible markers to increase precision in risk prediction for VTE in patients with lymphoma and multiple myeloma, particularly ECOG ≥ 2, immobility and higher factor VIII levels, as well as lymphoma aggressiveness, treatment with dexamethasone and the haemostatic biomarkers D-dimer and total protein S activity. Additionally, genetic variants factor V Leiden, serpinA10 rs2232698 and factor XIII-A Val34Leu warrant further investigation for use in the research setting.

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.

Allelic Interference in Prion Replication Is Modulated by the Convertibility of the Interfering PrPC and Other Host-Specific Factors.

Early studies in transgenic mouse lines have shown that the coexpression of endogenous murine prion protein (PrPC) and transgenic PrPC from another species either inhibits or allows the propagation of prions, depending on the infecting prion strain and interacting protein species. The way whereby this phenomenon, so-called "interference," is modulated remains to be determined. In this study, different transgenic mouse lines were crossbred to produce mice coexpressing bovine and porcine PrPC, bovine and murine PrPC, or murine and porcine PrPC These animals and their respective hemizygous controls were inoculated with several prion strains from different sources (cattle, mice, and pigs) to examine the effects of the simultaneous presence of PrPC from two different species. Our results indicate interference with the infection process, manifested as extended survival times and reduced attack rates. The interference with the infectious process was reduced or absent when the potentiality interfering PrPC species was efficiently converted by the inoculated agent. However, the propagation of the endogenous murine PrPSc was favored, allowing us to speculate that host-specific factors may disturb the interference caused by the coexpression of an exogenous second PrPCIMPORTANCE Prion propagation can be interfered with by the expression of a second prion protein in the host. In the present study, we investigated prion propagation in a host expressing two different prion protein genes. Our findings indicate that the ability of the second prion protein to interfere with prion propagation is related to the transmissibility of the prion in the host expressing only the interfering prion protein. The interference detected occurs in a prion strain-dependent manner. Interestingly, a bias favoring the propagation of the murine PrP allele has been observed. These results open the door to future studies in order to determine the role of host factors other than the PrP amino acid sequence in the interference in prion propagation.

[Carbapenamase OXA-23 like-producing Acinetobacter baumanii epidemic outbreak in a hospitalization unit.] / Brote epidémico por Acinetobacter baumanii productor de carbapenamasa OXA-23 like en una unidad de hospitalización.

OBJECTIVE: Despite its great ubiquity and morbidity and mortality, the scientific evidence on the hospital control of multiresistant Acinetobacter baumanii (ABMR) outside the Intensive Care Units in Spain is scarce. The objective was to describe an epidemic outbreak by MRAB and analyze the effectiveness of the actions carried out. METHODS: Prospective observational study of admitted-rotated patients in a multipathological control at the University Hospital of Guadalajara, Spain, during the outbreak (September 20-November 3, 2017); using Mambrino Electronic Health Record. A genetic study of the resistance mechanism and molecular characterization of the strains were carried out. Frequency measurements were estimated, with subsequent comparative analysis of cases vs controls. RESULTS: The median age of the study population (N=138) was 83.2 years (Interquartile Range [IR]=69.7-90.1). There were 3 cases of ABMR infection among them. Thirteen percent required issolation, 17% because of MRAB. The MRAB incidence was 2.2 cases/100 admitted-rotated (mortality rate=33%). The excess stay for cases was 17±4.3 (95%CI=8.5-25.6), with an incidence density of 3 cases/103 days. The responsible strain was carbapenemase OXA-23. We found a single case in the colonization study of contacts. No MRAB was isolated from environmental samples. CONCLUSIONS: Along with epidemiological research, coordination and compliance with precautions; prompt identification and management of an outbreak are crucial to minimize the colonization pressure and to stop dissemination.

OBJETIVO: Pese a su gran ubicuidad y morbimortalidad, la evidencia científica sobre el control hospitalario de Acinetobacter baumanii multirresistente (ABMR) fuera de las Unidades de Cuidados Intensivos en España es escasa. El objetivo fue describir un brote epidémico por ABMR y analizar la efectividad del manejo. METODOS: Se realizó un estudio observacional retrospectivo de los ingresados-rotados (N=138) en un control de pluripatológicos del Hospital Universitario de Guadalajara (España), durante el brote (20 septiembre-3 noviembre de 2017), utilizando la Historia Clínica Electrónica Mambrino. Se realizó un estudio genético del mecanismo de resistencia y caracterización molecular de cepas. Se estimaron medidas de frecuencia y análisis comparativo de casos respecto a controles. RESULTADOS: La mediana de edad de la población expuesta fue de 83,2 años (Rango Intercuartílico [RI]=69,7-90,1). Hubo entre ellos tres casos de infección por ABMR. Requirieron aislamiento un 13% de los ingresados-rotados, el 17% por ABMR. La incidencia de ABMR fue de 2,2 por cada 100 ingresados-rotados (tasa de mortalidad=33%). El exceso de estancia de los casos fue de 17±4,3 días (IC95%=8,5-25,6), con una densidad de incidencia de 3/103 días. La cepa responsable fue carbapenemasa OXA-23. En el estudio de colonización de contactos se evidenció un caso. El estudio ambiental resultó negativo. CONCLUSIONES: Junto a la investigación epidemiológica, la coordinación y el cumplimiento de precauciones, la prontitud en la identificación y gestión del brote son determinantes para minimizar la presión de colonización y frenar la cadena de diseminación.

Jumping Translocation in a Patient with Acute Leukemia and Fatal Evolution.

Jumping translocations are uncommon cytogenetic abnormalities in which a segment of a donor chromosome, often 1q, is transferred to two or more receptor chromosomes. We describe the case of a 64-year-old man with a history of acute myeloid leukemia associated with myelodysplastic syndrome, who presented with a relapse of the leukemia and, concomitantly, with the appearance of a jumping translocation involving chromosome 1q. The patient had a poor clinical course without the possibility of performing targeted treatment, and he died 5 months after relapse. Jumping translocations are a reflection of chromosomal instability, and they could be related to epigenetic alterations such as pericentromeric chromatin hypomethylation, telomere shortening, or pathogenic variants of the TP53 gene. The existing data suggests a poor clinical outcome, a high risk of disease progression, and an unfavorable prognosis. More molecular studies are required to gain an in-depth understanding of the genetic mechanism underlying these alterations and their clinical significance and to be able to apply an optimal treatment to patients.

Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly.

Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and ß4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of ß4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of ß4-spectrin, and normally occurs early in development of the AIS. We further found that the neurospecific domain is highly phosphorylated in mouse brain, and that phosphorylation at 2 sites (S1982 and S2619) is required for the conformational change and for recruitment of ß4-spectrin. Together, these findings resolve a discrete intermediate stage in formation of the AIS that is regulated through phosphorylation of the neurospecific domain of gAnkG.

Plasmon-Based Biofilm Inhibition on Surgical Implants.

The insertion of an implant in the body of a patient raises the risk of a posterior infection and formation of a biofilm, which can have critical consequences on the patient's health and be associated with a high sanitary cost. While antibacterial agents can be used to prevent the infection, such a strategy is time-limited and causes bacteria resistance. As an alternative to biochemical approaches, we propose here to use light-induced local hyperthermia with plasmonic nanoparticles. This strategy is implemented on surgical meshes, extensively used in the context of hernia repairing, one of the most common general surgeries. Surgical meshes were homogeneously coated with gold nanorods designed to efficiently convert near-infrared light into heat. The modified mesh was exposed to a biofilm of Staphylococcus aureus ( S. aureus) bacteria before being treated with a train of light pulses. We systematically study how the illumination parameters, namely fluence, peak intensity and pulse length, influence the elimination of attached bacteria. Additionally, fluorescence confocal microscopy provides us some insight on the mechanism involved in the degradation of the biofilm. This proof-of-principle study opens a new set of opportunities for the development of novel disinfection approaches combining light and nanotechnology.

Role of the goat K222-PrP(C) polymorphic variant in prion infection resistance.

UNLABELLED: The prion protein-encoding gene (prnp) strongly influences the susceptibility of small ruminants to transmissible spongiform encephalopathies (TSEs). Hence, selective breeding programs have been implemented to increase sheep resistance to scrapie. For goats, epidemiological and experimental studies have provided some association between certain polymorphisms of the cellular prion protein (PrP(C)) and resistance to TSEs. Among them, the Q/K polymorphism at PrP(C) codon 222 (Q/K222) yielded the most promising results. In this work, we investigated the individual effects of the K222-PrP(C) variant on the resistance/susceptibility of goats to TSEs. For that purpose, we generated two transgenic mouse lines, expressing either the Q222 (wild type) or K222 variant of goat PrP(C). Both mouse lines were challenged intracerebrally with a panel of TSE isolates. Transgenic mice expressing the wild-type (Q222) allele were fully susceptible to infection with all tested isolates, whereas transgenic mice expressing similar levels of the K222 allele were resistant to all goat scrapie and cattle BSE isolates but not to goat BSE isolates. Finally, heterozygous K/Q222 mice displayed a reduced susceptibility to the tested panel of scrapie isolates. These results demonstrate a highly protective effect of the K222 variant against a broad panel of different prion isolates and further reinforce the argument supporting the use of this variant in breeding programs to control TSEs in goat herds. IMPORTANCE: The objective of this study was to determine the role of the K222 variant of the prion protein (PrP) in the susceptibility/resistance of goats to transmissible spongiform encephalopathies (TSEs). Results showed that transgenic mice expressing the goat K222-PrP polymorphic variant are resistant to scrapie and bovine spongiform encephalopathy (BSE) agents. This protective effect was also observed in heterozygous Q/K222 animals. Therefore, the single amino acid exchange from Q to K at codon 222 of the cellular prion protein provides resistance against TSEs. All the results presented here support the view that the K222 polymorphic variant is a good candidate for selective breeding programs to control and eradicate scrapie in goat herds.

Classical bovine spongiform encephalopathy by transmission of H-type prion in homologous prion protein context.

Bovine spongiform encephalopathy (BSE) and BSE-related disorders have been associated with a single major prion strain. Recently, 2 atypical, presumably sporadic forms of BSE have been associated with 2 distinct prion strains that are characterized mainly by distinct Western blot profiles of abnormal protease-resistant prion protein (PrPres), named high-type (BSE-H) and low-type (BSE-L), that also differed from classical BSE. We characterized 5 atypical BSE-H isolates by analyzing their molecular and neuropathologic properties during transmission in transgenic mice expressing homologous bovine prion protein. Unexpectedly, in several inoculated animals, strain features emerged that were highly similar to those of classical BSE agent. These findings demonstrate the capability of an atypical bovine prion to acquire classical BSE-like properties during propagation in a homologous bovine prion protein context and support the view that the epidemic BSE agent could have originated from such a cattle prion.

Análisis de fiabilidad y estructura factorial de la versión española del TPQ - Cuestionario de Percepción del Tratamiento en Drogodependencias / No disponible

El “Treatment Perceptions Questionnaire (TPQ)” es una escala breve y autoadministrada cuyo propósito es la valoración de la satisfacción de usuarios de drogas respecto al programa de tratamiento en el que son asistidos. El objetivo del estudio es analizar la consistencia interna y la fiabilidad de la versión española de esta escala, así como su validez de constructo. Para ello se ha aplicado el TPQ a 100 usuarios de un Centro de Tratamiento de Drogodependencias. Los resultados, registrados y codificados según los algoritmos originales, fueron sometidos a un análisis factorial de componentes principales resultando tres factores que en conjunto expresaban el 58,6% de la varianza explicada (VE). El primer factor, denominado “disponibilidad y confianza en el equipo”, asumía el 33,4% de VE y presentaba un alpha de Cronbach (α) de 0,62 y un Coeficiente de Correlación Intraclase (CCI) de 0,80. El segundo factor, con el 13,9% de VE, hace alusión a la “confianza y satisfacción con el equipo y programa”, y presenta un α = 0,71 y un CCI= 0,85. Por último, el tercer factor, con un una VE del 11,2%, un α = 0,56 y un CCI de 0,81, agrupa ítems que hacen referencia a la “recepción de información y motivación para el tratamiento”. Estos resultados no confirman las dimensiones halladas por los autores del TPQ, planteándose que la satisfacción con el tratamiento ha de ser contemplada y valorada desde un mayor número de áreas implicadas en dicho proceso (AU)

The Treatment Perception Questionnaire’ (TPQ) is a brief, self-administered scale designed to measure drug user satisfaction with the treatment programme they are following. The aim of this work is to analyse the internal consistency and reliability of the Spanish version of the TPQ, as well as the construct validity. A sample group of one hundred heroin users, diagnosed as opium dependents, treated in a Drugs Treatment Centre, was evaluated with TPQ. The results, registered and coded according to the original algorithms, were subjected to a principal components factor analysis (PCFA) with varimax rotation. The PCFA revealed a three factors solution stating 58.6% of the Explained Variance (EV). The first factor, named “readiness and trust in the treatment team”, assumed 33.4% EV and presented a Cronbach coefficient (α) of 0.62 and an Intraclass Correlation Coefficient (ICC) of 0.80. The second factor, with 13.9% of EV, referring to “trust and satisfaction with the treatment team and programme”, presents a α= 0.71 and an ICC= 0.85. Lastly, the third factor, with an 11.2% of EV (α= 0.56 and ICC= 0.81) groups together items which relate to “information reception and motivation for the treatment”. These results do not confirm the scope found by the TPQ authors, indicating that satisfaction with treatment must be addressed and assessed from a wider number of areas involved in such a process (AU)