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Abstract The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson’s disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n = 20) and DaT-positive L2NMC (n = 20), pheno-converted G2019S L2PD patients (n = 20), idiopathic PD (iPD) (n = 19), and controls (n = 40). We also screened a second cohort of L2PD patients (n = 19) and controls (n = 20) (Total n = 158). Compared to healthy controls, we identified eight deregulated miRNAs in DaT-negative L2NMC, six in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified four miRNAs with relatively high discriminative ability (AUC = 0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.

Introduction In recent years, multiple studies have aimed to develop and validate portable technological devices capable of monitoring the motor complications of Parkinson’s disease patients (Parkinson’s Holter). The effectiveness of these monitoring devices for improving clinical control is not known.Methods and analysis This is a single-blind, cluster-randomised controlled clinical trial. Neurologists from Spanish health centres will be randomly assigned to one of three study arms (1:1:1): (a) therapeutic adjustment using information from a Parkinson’s Holter that will be worn by their patients for 7 days, (b) therapeutic adjustment using information from a diary of motor fluctuations that will be completed by their patients for 7 days and (c) therapeutic adjustment using clinical information collected during consultation. It is expected that 162 consecutive patients will be included over a period of 6 months.The primary outcome is the efficiency of the Parkinson’s Holter compared with traditional clinical practice in terms of Off time reduction with respect to the baseline (recorded through a diary of motor fluctuations, which will be completed by all patients). As secondary outcomes, changes in variables related to other motor complications (dyskinesia and freezing of gait), quality of life, autonomy in activities of daily living, adherence to the monitoring system and number of doctor–patient contacts will be analysed. The noninferiority of the Parkinson’s Holter against the diary of motor fluctuations in terms of Off time reduction will be studied as the exploratory objective.Ethics and dissemination approval for this study has been obtained from the Hospital Universitari de Bellvitge Ethics Committee. The results of this study will inform the practical utility of the objective information provided by a Parkinson’s Holter and, therefore, the convenience of adopting this technology in clinical practice and in future clinical trials. We expect public dissemination of the results in 2022.Trial registration NCT04176302; https://clinicaltrials.gov/show/NCT04176302

The problem concerning facilities delocation in the retail sector is addressed in this paper by proposing a novel mixed 0-1 linear optimization model. For this purpose, the aim of the problem is to decide whether to close existing stores or consider an alternative type of store management policy aimed at optimizing the profit of the entire retail network. Each management policy has a different repercussion on the final profit of the stores due to the different margins obtained from the customers. Furthermore, closing stores can cause customers to leave the whole retail network according to their behavior. This behavior is brought about through their tendency to abandon this network. There are capacity constraints imposed depending on the number of stores that should stay open and cease operation costs, customer behavior and final prices. These constraints depend on the type of management policy implemented by the store. Due to the commercial requirements concerning customer behavior, a set of non-linear constraints appears in the definition of the model. Classical Fortet inequalities are used in order to linearize the constraints and, therefore, obtain a mixed 0-1 linear optimization model. As a result of the size of the network, border constraints have been imposed to obtain results in a reasonable computing time. The model implementation is done by introducing smart sets of indices to reduce the number of constraints and variables. Finally, the computational results are presented using data from a real-world case study and, additionally, a set of computational experiments using data randomly generated as shown.

Recent records of bird species in the Colombian Andes have shown that this region is not as well known as was previously believed. We compiled data from a major collection of Colombian birds and from our recent field observations to complement the bird species list of Quindío department. We report the addition of 14 species to Quindío’s checklist and data of museum vouchers for 12 species reported only from field observations. The majority of additions were from localities below 1,900 m above sea level, a zone that has been highly transformed by human activities. Our dataset, and other information, raised the number of bird species in Quindío to 560. This information must be considered in decisions about the land use in this region of the Colombian Andes.

INTRODUCTION: The emotional interaction between personal attributes and the environment is a key element to understand aggression. This study identified emotional responses of people with different aggressive traits to pictures with a specific affective content.METHODS:Three hundred fifteen individuals were divided into five groups according to their scores on the Buss-Perry Aggression Questionnaire, which consists of 24 pictures of the International Affective Picture System that depict aggression, the suffering of others, filial situations, and sexual content. Each picture was evaluated for valence, arousal, and dominance using the Self-Assessment Manikin scale.RESULTS:Sexual pictures were more appetitive and associated with more arousal in the groups of individuals with some aggression-related dimension than in the non-aggressive group.CONCLUSIONS: A strong interaction was found between aggressive traits (e.g., verbal aggression, physical aggression, anger, and hostility) and pictures with a sexual content. This interaction is decisive in understanding the later phases of aggressive behaviors and sexual aggression.

Objetivo: Establecer la frecuencia de la infección por Hepatitis B en los pacientes VIH positivos atendidos en la IPS VitalSalud de Barranquilla, Colombia. Métodos: Se realizó un perfil serológico para Hepatitis B en los pacientes VIH positivos, consistente en: HBs Ag, Anticore IgG. Estos exámenes se practicaron entre el mes de junio del 2007 hasta julio del 2009. Resultados: En 24 meses se realizaron exámenes para la detección de Hepatitis B en 103 pacientes VIH positivos. Hubo una prevalencia del 3,1% (tres pacientes) con Hepatitis B crónica. Cuatro pacientes fallecieron durante el período del estudio, ninguno positivo para infección por Hepatitis B. Se detectaron 6 pacientes con Ig G core para VHB positivo aislado, es decir con sospecha de Hepatitis B oculta, la cual se confirmó solo en un paciente con carga viral para ADN de VHB positiva (158 copias/ml). Este paciente no se hallaba usando lamivudina en el momento del examen. Conclusión: La prevalencia de Hepatitis B en nuestros pacientes corresponde a la reportada en todo el territorio nacional. La búsqueda de infección oculta por Virus de Hepatitis B en los pacientes VIH positivos asistentes a nuestra institución arrojó como resultado un solo paciente con esta patología y con una baja carga viral. La estrategia para el diagnóstico la infección oculta por VHB en los pacientes usando lamivudina debe ser más estudiada.Objective: The objective is to establish the frequency of Hepatitis B (VHB) co-infection in HIV outpatients at VitalSalud Health Center in Barranquilla, Colombia. Methods: Two serological tests to diagnose Hepatitis B in our HIV patients were performed: Hepatitis B surface antigen and Anticore type Ig G (anti HBC Ig G). These tests were run between July, 2007 and July, 2009. Results: The tests were applied to 103 HIV patients. There was a prevalence of 3.1% (3 patients) for chronic Hepatitis B. Four patients passed away during the study term, none of them was Hepatitis B positive. Six patients with isolated anti HBc Ig G were detected, and only one of them had a positive viral load for VHB DNA (158 copies/ml). This patient was not taking lamivudine at the time of the test. Conclusions: The prevalence of VHB in our patients is similar to the prevalence reported in our country as a whole. The search for occult hepatitis B was positive, with a low viral load, in one out of 103 of our patients. The strategies for diagnosis of occult hepatitis B in HIV patients under lamivudine treatment require further research.

Este artículo se sitúa en una encrucijada historiográfica en la que la historia de las emociones se combina con otros enfoques con el objeto de indagar en las claves culturales profundas de la acción política. No entiende la historia de las emociones tanto como un campo específico de estudio sino antes bien como una sensibilidad analítica que puede ser empleada transversalmente y potenciada con los aportes de otros enfoques. Desde estos planteamientos, se aproxima al Romanticismo como un “régimen emocional”, tomando pero a la vez discutiendo el concepto acuñado por William Reddy. En este marco, se considera la masculinidad como una cuestión fundamental en la configuración del orden político y sentimental liberal posrevolucionario, analizándose algunos espacios de creación de la virilidad burguesa. En la última parte del artículo, se confronta el conjunto de normativas que configuran este régimen con las líneas de fisura y fractura existentes en paralelo a su misma imposición. Para ello, se extraen de la historia biográfica algunas preguntas y posibles respuestas sobre los factores culturales que posibilitaron el desbordamiento y superación de este régimen emocional, apuntando finalmente una interpretación sobre el Romanticismo como estilo emocional.

[es] El crecimiento urbano se tradujo en una ciudad compuesta por piezas separadas; la ciudad amurallada y los barrios periféricos: Le Vernet al norte del Têt, Maulóles, Saint-Martin, Saint- Gauderique y Saint-Assiscle. Durante el siglo XX se realizó el reagrupamiento de las distintas partes y su organización en conjunto, mediante la recuperación de los terrenos militares y la implantación de la red de transportes. [fr] L'accroissement urbain s'est traduit en une ville composée d'éléments séparés, l'enceinte de murailles et les quartiers périphériques : Le Vernet au nord du Têt, Mailloles, Saint-Martin, Saint Gauderique et Saint-Assiscle. Tout au long du XXe. siècle se réalisa le regroupement des différentes parties et leur organisation dans l'ensemble, en regagnant les terrains militaires et aussi, grâce à l'implantation d'un réseau urbain des transports.

La Enfermedad Inflamatoria Intestinal (EII) raramente se asocia a obesidad, ya que la malabsorción es una característica frecuente de este grupo de patologías (1). Sin embargo, algunos pacientes pueden padecer obesidad mórbida asociada a complicaciones y refractaria a tratamiento dietético y beneficiarse de la cirugía bariátrica. Incluso se ha postulado que podría producirse una mejoría de la EII al disminuir los marcadores inflamatorios tras la cirugía (2). No obstante, los pacientes pueden experimentar mayor incidencia de complicaciones tras la cirugía en el contexto de terapias inmunosupresoras y agravamiento de la malabsorción previa. Por ello, si se realiza la cirugía, la cuidadosa selección de los pacientes y la individualización de la técnica a realizar son imprescindibles. Presentamos una paciente diagnosticada de Colitis Ulcerosa que presenta desnutrición proteica severa tras cirugía bariátrica tipo derivación bilio-pancreática y realizamos una revisión de la literatura disponible.

Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined.To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients.The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated.University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p

Esta comunicación resume parte del trabajo de investigación que estamos realizando como tesis doctoral, dedicado al estudio de la clase política conservadora sevillana de la Restauración. Podemos ofrecer ya un primer adelanto, que en forma de Tesina y con el mismo título que el que encabeza estas páginas, presentamos en la Universidad de Sevilla en julio de 1989. Este trabajo, cuyas conclusiones iniciales proporcionamos, está centrado en el estudio de unos miembros característicos de la clase dirigente provincial, los Ybarra, líderes durante veinticinco años del Partido Conservador sevillano.

Human induced pluripotent stem cells (iPSCs) provide a virtually inexhaustible source of starting material for next generation cell therapies, offering new opportunities for regenerative medicine. Among different cell sources for the generation of iPSCs, urine cells are clinically relevant since these cells can be repeatedly obtained by non-invasive methods from patients of any age and health condition. These attributes encourage patients to participate in preclinical and clinical research. In particular, the use of urine-derived iPSC products is a convenient strategy for children with brain tumors, which are medically fragile patients. Here, we investigate the feasibility of using urine samples as a source of somatic cells to generate iPSC lines from pediatric patients with brain tumors (BT-iPSC). Urinary epithelial cells were isolated and reprogrammed using non-integrative Sendai virus vectors harboring the Yamanaka factors KLF4, OCT3/4, SOX2 and C-MYC. After reprogramming, BT-iPSC lines were subject to quality assessment and were compared to iPSCs obtained from urine samples of non-tumor pediatric patients (nonT-iPSC). We demonstrated that iPSCs can be successfully derived from a small volume of urine obtained from pediatric patients. Importantly, we showed that BT-iPSCs are equivalent to nonT-iPSCs in terms of morphology, pluripotency, and differentiation capacity into the three germ layers. In addition, both BT-iPSCs and nonT-iPSCs efficiently differentiated into functional mesenchymal stem/stromal cells (iMSC) with immunomodulatory properties. Therefore, this study provides an attractive approach to non-invasively generate personalized iMSC products intended for the treatment of children with brain tumors. [ABSTRACT FROM AUTHOR]

Summary: Background: The clinical relevance of recurrent venous thromboembolism (VTE) after discontinuing anticoagulation in patients with COVID-19-associated VTE remains uncertain. We estimated the incidence rates and mortality of VTE recurrences developing after discontinuing anticoagulation in patients with COVID-19-associated VTE. Methods: A prospective, multicenter, non-interventional study was conducted between March 25, 2020, and July 26, 2023, including patients who had discontinued anticoagulation after at least 3 months of therapy. All patients from the registry were analyzed during the study period to verify inclusion criteria. Patients with superficial vein thrombosis, those who did not receive at least 3 months of anticoagulant therapy, and those who were followed for less than 15 days after discontinuing anticoagulation were excluded. Outcomes were: 1) Incidence rates of symptomatic VTE recurrences, and 2) fatal PE. The rate of VTE recurrences was defined as the number of patients with recurrent VTE divided by the patient-years at risk of recurrent VTE during the period when anticoagulation was discontinued. Findings: Among 1106 patients with COVID-19-associated VTE (age 62.3 ± 14.4 years; 62.9% male) followed-up for 12.5 months (p25-75, 6.3–20.1) after discontinuing anticoagulation, there were 38 VTE recurrences (3.5%, 95% confidence interval [CI]: 2.5–4.7%), with a rate of 3.1 per 100 patient-years (95% CI: 2.2–4.2). No patient died of recurrent PE (0%, 95% CI: 0–7.6%). Subgroup analyses showed that patients with diagnosis in 2021–2022 (vs. 2020) (Hazard ratio [HR] 2.86; 95% CI 1.45–5.68) or those with isolated deep vein thrombosis (vs. pulmonary embolism) (HR 2.31; 95% CI 1.19–4.49) had significantly higher rates of VTE recurrences. Interpretation: In patients with COVID-19-associated VTE who discontinued anticoagulation after at least 3 months of treatment, the incidence rate of recurrent VTE and the case-fatality rate was low. Therefore, it conceivable that long-term anticoagulation may not be required for many patients with COVID-19-associated VTE, although further research is needed to confirm these findings. Funding: Sanofi and Rovi, Sanofi Spain.