Identifying Patients with Polycythemia Vera at Risk of Thrombosis after Hydroxyurea Initiation: The Polycythemia Vera-Advanced Integrated Models (PV-AIM) Project.

Patients with polycythemia vera (PV) are at significant risk of thromboembolic events (TE). The PV-AIM study used the Optum® de-identified Electronic Health Record dataset and machine learning to identify markers of TE in a real-world population. Data for 82,960 patients with PV were extracted: 3852 patients were treated with hydroxyurea (HU) only, while 130 patients were treated with HU and then changed to ruxolitinib (HU-ruxolitinib). For HU-alone patients, the annualized incidence rates (IR; per 100 patients) decreased from 8.7 (before HU) to 5.6 (during HU) but increased markedly to 10.5 (continuing HU). Whereas for HU-ruxolitinib patients, the IR decreased from 10.8 (before HU) to 8.4 (during HU) and was maintained at 8.3 (after switching to ruxolitinib). To better understand markers associated with TE risk, we built a machine-learning model for HU-alone patients and validated it using an independent dataset. The model identified lymphocyte percentage (LYP), neutrophil percentage (NEP), and red cell distribution width (RDW) as key markers of TE risk, and optimal thresholds for these markers were established, from which a decision tree was derived. Using these widely used laboratory markers, the decision tree could be used to identify patients at high risk for TE, facilitate treatment decisions, and optimize patient management.

Safety and efficacy of tisagenlecleucel plus pembrolizumab in patients with r/r DLBCL: phase 1b PORTIA study results.

Tisagenlecleucel demonstrated high response rates and a manageable safety profile in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. However, lack of response and chimeric antigen receptor (CAR) T-cell exhaustion were observed in patients with programmed cell death protein 1 (PD-1) overexpression. Hence, pembrolizumab, a PD-1 inhibitor, was hypothesized to improve efficacy and cellular expansion of CAR T-cells in vivo. Here, we report the final analysis of the PORTIA trial in adult patients with r/r DLBCL who had ≥2 prior lines of therapy and had an Eastern Cooperative Oncology Group performance status of ≤1. Patients received 1 tisagenlecleucel infusion on day 1. Pembrolizumab (200 mg) was given every 21 days, for up to 6 doses. Three cohorts initiated pembrolizumab on days 15 (n = 4), 8 (n = 4), or -1 (n = 4). Safety, efficacy, cellular kinetics, and biomarker analyses were included. Tisagenlecleucel plus pembrolizumab was feasible and showed a manageable safety profile, without dose-limiting toxicities. Emerging efficacy with tisagenlecleucel was observed when pembrolizumab was given the day before tisagenlecleucel; however, the limited patient sample and short follow-up do not allow for definitive conclusions. Adding pembrolizumab to tisagenlecleucel did not augment the cellular expansion of tisagenlecleucel but delayed peak expansion if given the day before tisagenlecleucel (NCT03630159).

Treatment and Therapeutic Change of Individuals Imprisoned for Child Abuse in the Barcelona Study on Sex Offenders.

The sexual abuse of children is a serious social problem that must be prevented through distinct measures. Among them is the application of treatments to those who have already committed sex crimes in order to prevent them from committing a new one. To assess the efficacy of sexual offense treatment, the most common method has been to compare the recidivism rates of treated and untreated groups. Several meta-analyses in this regard-as well as some specific studies in Spain-have shown that the application of treatment is associated with lower recidivism rates. However, the analysis of the subjects' recidivism alone does not reveal the therapeutic changes that the treatment may elicit in them. Some international studies have evaluated the therapeutic improvements resulting from the application of treatments to men who had sexually abused children. In this context, this study explores the therapeutic changes experienced by a sample of subjects imprisoned for child abuse (N = 145), after participating in the treatment program applied in the Spanish prison system. Nine therapeutic variables were assessed (such as anxiety, cognitive distortions, impulsivity, and social self-esteem), before and after treatment, using an instrument named the Psychological Assessment Scale for Sex Offenders (PASSO). The obtained results show that most of the assessed therapeutic variables improved after treatment, with strong correlations between them. The implications of the results for treatment practice are discussed, as well as the main methodological limitations of this research.

Conjugation Inhibitors Effectively Prevent Plasmid Transmission in Natural Environments.

Plasmid conjugation is a major route for the spread of antibiotic resistance genes. Inhibiting conjugation has been proposed as a feasible strategy to stop or delay the propagation of antibiotic resistance genes. Several compounds have been shown to be conjugation inhibitors in vitro, specifically targeting the plasmid horizontal transfer machinery. However, the in vivo efficiency and the applicability of these compounds to clinical and environmental settings remained untested. Here we show that the synthetic fatty acid 2-hexadecynoic acid (2-HDA), when used as a fish food supplement, lowers the conjugation frequency of model plasmids up to 10-fold in controlled water microcosms. When added to the food for mice, 2-HDA diminished the conjugation efficiency 50-fold in controlled plasmid transfer assays carried out in the mouse gut. These results demonstrate the in vivo efficiency of conjugation inhibitors, paving the way for their potential application in clinical and environmental settings. IMPORTANCE The spread of antibiotic resistance is considered one of the major threats for global health in the immediate future. A key reason for the speed at which antibiotic resistance spread is the ability of bacteria to share genes with each other. Antibiotic resistance genes harbored in plasmids can be easily transferred to commensal and pathogenic bacteria through a process known as bacterial conjugation. Blocking conjugation is thus a potentially useful strategy to curtail the propagation of antibiotic resistance. Conjugation inhibitors (COINS) are a series of compounds that block conjugation in vitro. Here we show that COINS efficiently block plasmid transmission in two controlled natural environments, water microcosms and the mouse gut. These observations indicate that COIN therapy can be used to prevent the spread of antibiotic resistance.

Early narratives of desistance from crime in different prison regimes / Narración temprana del desistimiento delictivo en diferentes regímenes penitenciarios

Priority given to investigating the onset and maintenance of criminal behavior in the past is currently giving way to a new focus on the process of criminal desistance. Early narratives of future desistance are the first step in this process and, although they do not assure withdrawal from crime, they are the beginning of the personal change that precedes a progressive desistance from criminal activity. This study analyzes early desistance narratives of offenders still in prison and whether these narratives differed depending on their personal, criminal, and social characteristics. Participants were 44 imprisoned male offenders, aged between 20 and 50 years old at different stages of their sentence and in three different prison regimes. They were interviewed using Cid and Martí's protocol and their accounts were accordingly coded in three categories: early narratives towards a non-criminal identity, perceived self-efficacy to desist from crime, and will to desist. The results show that participants' early desistance narratives vary depending on their personal, criminal, and social variables. Results on the periods of sentence completion and prison regimes are discussed in terms of how prisons could contribute to enhancing the narratives of desistance from crime

La prioridad otorgada en el pasado a la investigación sobre el inicio y mantenimiento de la conducta delictiva está dando paso actualmente al análisis del proceso de desistimiento delictivo. Las narrativas tempranas del desistimiento futuro son el primer paso en este proceso y, aunque no aseguran dicho desistimiento, son el comienzo del cambio personal que precede al abandono progresivo de la actividad delictiva. Este estudio analiza las narrativas tempranas de desistimiento de delincuentes aún en prisión y si estas narrativas difieren según sus características personales, delictivas y sociales. Los participantes fueron 44 varones encarcelados, con edades comprendidas entre los 20 y los 50 años, en diferentes fases de su sentencia y en tres grados penitenciarios distintos. Fueron entrevistados utilizando el protocolo de Cid y Martí y sus relatos fueron codificados en tres categorías: narrativas tempranas sobre una identidad no delictiva, autoeficacia percibida para desistir del delito y voluntad para desistir. Los resultados muestran que las narrativas tempranas de desistimiento de los participantes difieren según sus características personales, delictivas y sociales. Los resultados relativos a la fase de la sentencia y a los grados penitenciarios se discuten en términos de cómo las prisiones pueden contribuir a potenciar las narrativas de desistimiento delictivo

Miositis osificante en el triángulo de Petit. Caso clínico / Myositis ossificans on Petit triangle. Case report

La miositis osificante es una osificación heterotópica, autolimitada, que afecta a cualquier grupo de edad y suele presentarse en la musculatura de las extremidades, en su variante más frecuente, en zonas de traumatismo por su relación íntima con la lesión mecánica. Es considerada benigna y si la identificación por imágenes es clara, su tratamiento consiste en seguimiento clínico. Sin embargo, cuando existen dudas diagnósticas, conviene realizar biopsia para definir el tratamiento quirúrgico. Presentamos una paciente con tumoración dolorosa en región lumbar, a nivel del triángulo de Petit, de 18 meses de evolución. La biopsia de partes blandas era sugerente de tumor fibromixoide osificante cuyo análisis postoperatorio reveló miositis osificante. Se realizó extirpación local amplia y reconstrucción con malla biológica sin tensión y cierre por planos, ya que se han descrito hernias espontáneas y también secundarias a través del triángulo de Petit. Estas últimas, en su mayoría, son hernias postincisionales

Myositis ossificans is a heterotopic self-limited ossification that affects every age. It usually appears in limb musculature, commonly in exposed areas due to its intimate relationship with mechanical trauma. It is considered a benign disease and, if clinical and radiological identification results obvious, suggested treatment is clinical follow-up. But if there is a diagnostic doubt, a biopsy must be performed in order to define surgical treatment. We present a case report of a patient with an 18 month-evolution painful tumour in the lumbar area, at the level of Petit triangle. The initial biopsy of the soft tissue mass suggested fibromyxoid ossificans tumour, but after postoperative analysis, diagnosis of myositis ossificans was stated. Surgical treatment consisted of a wide local resection and immediate reconstruction with a biological mesh, achieving a non-tension closure in order to avoid spontaneous and secondary hernias, which are described specifically in the triangle of Petit triangle. These hernias are usually post-incisional

Towards a taxonomy of conjugative plasmids.

Conjugative plasmids are the keystone of horizontal gene transfer. Metagenomic research and clinical understanding of plasmid transmission beg for a taxonomical approach to conjugative plasmid classification. Up to now, a meaningful classification was difficult to achieve for lack of appropriate analytical tools. The advent of the genomic era revolutionized the landscape, offering a plethora of plasmid sequences as well as bioinformatic analytical tools. Given the need and the opportunity, in view of the available evidence, a taxonomy of conjugative plasmids is proposed in the hope that it will leverage plasmid studies.

Psychological treatment and therapeutic change in incarcerated rapists / Tratamiento psicológico y cambio terapéutico en agresores sexuales encarcelados

Most Spanish prisons provide specialised treatment for incarcerated sex offenders, both rapists and child molesters. This treatment is a cognitive-behavioural intervention that has shown relative effectiveness in previous research. With regard to offenders’ rehabilitation, recidivism assessments are necessary as a final measure of treatment effectiveness. However, the evaluation of recidivism by itself does not provide sufficient information on the treatment process and the specific effects that treated subjects could undergo. This paper aims to analyse the therapeutic effectiveness of psychological treatment provided to rapists (in general, males sentenced for committing a sexual offence against women). To this aim, a group of treated rapists (N=153) serving a sentence in prison was analysed. Using a specially designed scale (PASSO), the global therapeutic change and ten specific variables (including assertiveness, readiness to change, cognitive distortions, impulsivity, etc.) were assessed. The within-subjects comparison showed that treated sex offenders improved, in therapeutic terms, globally as well as in most of the specific variables assessed (improvements not experimented by the control group). Also, different therapeutic subscales showed relevant associations between them. The findings regarding treatment effectiveness are discussed (AU)

La mayoría de los centros penitenciarios españoles ofrecen un programa de tratamiento psicológico especializado para agresores sexuales, tanto para violadores como para abusadores de menores. Se trata de un programa de orientación cognitivo-conductual, que en algunas evaluaciones ya realizadas ha evidenciado una eficacia terapéutica relativa en términos de reducción de las tasas de reincidencia. Aunque la evaluación de la reincidencia delictiva sea una medida necesaria para ponderar la eficacia final del tratamiento de los agresores sexuales, dicha medida no permite conocer con precisión las mejoras específicas que los sujetos pueden experimentar. Este artículo dirige su atención precisamente a evaluar con detalle la eficacia terapéutica del tratamiento de los agresores sexuales de mujeres adultas. Con esta finalidad, se analiza una muestra de agresores sexuales tratados (N=153) que cumplen condena en prisión por un delito contra una mujer adulta. Para ello se evalúa mediante una escala diseñada al efecto (EPAS) el cambio terapéutico global de los sujetos tras el tratamiento y también su evolución en diez variables terapéuticas específicas (como asertividad, disposición al cambio personal, distorsiones cognitivas, etc.). La comparación intra-sujetos indicó que los agresores tratados mejoran, en términos terapéuticos, tanto globalmente como en la mayoría de las variables específicas evaluadas (mejoras que no se produjeron en el grupo control). Así mismo, se encontraron asociaciones significativas relevantes entre diversas variables terapéuticas. Finalmente, se comentan críticamente los resultados obtenidos y algunos de los retos existentes en el campo de la evaluación del tratamiento psicológico de los agresores sexuales (AU)

A Dynamic Risk Factors-Based Typology of Sexual Offenders.

The purpose of this article was to develop an Spanish psychometric typology of sexual offenders taking into account dynamic risk factors. The sample comprised 94 sex offenders imprisoned in Spain (52 rapists and 42 child molesters). The analysis yielded two different offender categories based on the subjects' criminogenic needs level (high and low). The results also showed that social desirability has a strong influence on the developed typologies, whereas the offence type, sociodemographic characteristics, and criminal history do not. A dynamic risk factors typology, such as the one proposed here, could help criminal and correctional facilities to fulfill their remit. It could also be useful for linking treatment intensity to offenders' criminogenic needs, as well as providing a platform for recidivism risk assessments.

Clinical differences between cocaine-dependent patients with and without antisocial personality disorder.

The aim of this study is to compare the features of two groups of cocaine dependent patients in treatment, one of them with co-morbid diagnosis of antisocial personality disorder and the other not. Cross-sectional design, with 143 cocaine-dependent patients attending a drug unit, distributed in two groups: patients with and without Antisocial Personality Disorder. As results, we found that the 15.38% of the sample were diagnosed with an Antisocial Personality Disorder. In relation to socio-demographic variables, Antisocial Personality Disorder patients have less probability of being working or studying (9.1% vs. 47.9%). After multivariate analysis it was found that significantly Antisocial Personality Disorder patients have more opiates dependence (OR: 0.219; 95% IC 0.072-0.660), sedative dependence (OR: 0.203; 95% IC 0.062-0.644) and in more cases show Borderline Personality Disorder (OR: 0.239; 95% IC 0.077-0.746). This study highlights significant differences between cocaine addicts with or without an Antisocial Personality Disorder. All these differences are good indicators of the complexity of the patients with this personality disorder. Better knowledge of their profile will help us to improve the design of specific treatment programs.

Guía de procedimientos de esterilización a baja temperatura / No disponible

No disponible

Mielofibrosis idiopática en medicina interna / Idiopathic myelofibrosis in internal medicine

No disponible

Hemodynamic response in a geographical word naming verbal fluency test

Functional hemodynamic response was studied in a new Verbal Fluency Task (VFT) that demanded the production of geographical words while fMRI data was obtained. Participants completed 7 trials with a total duration of 2 min. 20 s. Four simple arithmetic subtraction trials were alternated with 3 geographical naming trials. Each trial had a duration of 20 s. Brain activity was contrasted between both conditions and significant differences (p < .05, Family Wise Error correction) were observed in the prefrontal medial gyrus, typically associated with word retrieval and phonological awareness, and in the parahippocampal gyrus, posterior cingulate cortex and lingual gyrus, areas related to spatial cognition. These results indicate that geographic VFT could be incorporated into a browser of cognitive processes using VFT considering its specific relationship with spatial cognition. Further investigations are proposed, taking special interest in the gender variable and eliminating phonological restrictions, because the evoked Argentinean cities and towns ended in a consonant letter (AU)

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Selected CD133⁺ progenitor cells to promote angiogenesis in patients with refractory angina: final results of the PROGENITOR randomized trial.

RATIONALE: Refractory angina constitutes a clinical problem. OBJECTIVE: The aim of this study was to assess the safety and the feasibility of transendocardial injection of CD133(+) cells to foster angiogenesis in patients with refractory angina. METHODS AND RESULTS: In this randomized, double-blinded, multicenter controlled trial, eligible patients were treated with granulocyte colony-stimulating factor, underwent an apheresis and electromechanical mapping, and were randomized to receive treatment with CD133(+) cells or no treatment. The primary end point was the safety of transendocardial injection of CD133(+) cells, as measured by the occurrence of major adverse cardiac and cerebrovascular event at 6 months. Secondary end points analyzed the efficacy. Twenty-eight patients were included (n=19 treatment; n=9 control). At 6 months, 1 patient in each group had ventricular fibrillation and 1 patient in each group died. One patient (treatment group) had a cardiac tamponade during mapping. There were no significant differences between groups with respect to efficacy parameters; however, the comparison within groups showed a significant improvement in the number of angina episodes per month (median absolute difference, -8.5 [95% confidence interval, -15.0 to -4.0]) and in angina functional class in the treatment arm but not in the control group. At 6 months, only 1 simple-photon emission computed tomography (SPECT) parameter: summed score improved significantly in the treatment group at rest and at stress (median absolute difference, -1.0 [95% confidence interval, -1.9 to -0.1]) but not in the control arm. CONCLUSIONS: Our findings support feasibility and safety of transendocardial injection of CD133(+) cells in patients with refractory angina. The promising clinical results and favorable data observed in SPECT summed score may set up the basis to test the efficacy of cell therapy in a larger randomized trial.

Hemodynamic response in a geographical word naming verbal fluency test.

Functional hemodynamic response was studied in a new Verbal Fluency Task (VFT) that demanded the production of geographical words while fMRI data was obtained. Participants completed 7 trials with a total duration of 2 min. 20 s. Four simple arithmetic subtraction trials were alternated with 3 geographical naming trials. Each trial had a duration of 20 s. Brain activity was contrasted between both conditions and significant differences (p < .05, Family Wise Error correction) were observed in the prefrontal medial gyrus, typically associated with word retrieval and phonological awareness, and in the parahippocampal gyrus, posterior cingulate cortex and lingual gyrus, areas related to spatial cognition. These results indicate that geographic VFT could be incorporated into a browser of cognitive processes using VFT considering its specific relationship with spatial cognition. Further investigations are proposed, taking special interest in the gender variable and eliminating phonological restrictions, because the evoked Argentinean cities and towns ended in a consonant letter.

Age-dependent defective TGF-beta1 signaling in patients undergoing coronary artery bypass grafting.

BACKGROUND: Transforming growth factor beta (TGF-ß1) is a pleiotropic cytokine, which is deregulated in atherosclerosis; however the role of age in this process is unknown. We aimed to assess whether TGF-ß1 signaling is affected by age. METHODS: Vascular smooth muscle cells (VSMC) were obtained from patients undergoing abdominal surgery. Levels of TGF-ß1 were measured by ELISA in sera from 169 patients undergoing coronary artery bypass grafting (CABG). The p27 expression was determined by Western blot from internal mammary arteries (IMA) obtained from CABG patients (n=13). In VSMC from these patients undergoing abdominal surgery, secretion of TGF-ß1 was determined by ELISA of cell-conditioned media. RESULTS: In VSMC from aged patients we observed a lower TGF-ß1 secretion, measured as TGF-ß1 concentration in cell conditioned medium (p<0.001). This effect was correlated to an age-dependent decrease of p27 expression in IMA from aged CABG patients. In a similar manner, there was an age-dependent decrease of serum TGF-ß1 levels in CABG patients (p=0.0195). CONCLUSIONS: VSMC from aged patients showed a higher degree of cellular senescence and it was associated to a lower TGF-ß1 secretion and signaling.

Proteomic analysis reveals heat shock protein 70 has a key role in polycythemia Vera.

JAK-STAT signaling through the JAK2V617F mutation is central to the pathogenesis of myeloproliferative neoplasms (MPN). However, other events could precede the JAK2 mutation. The aim of this study is to analyze the phenotypic divergence between polycytemia vera (PV) and essential thrombocytemia (ET) to find novel therapeutics targets by a proteomic and functional approach to identify alternative routes to JAK2 activation. Through 2D-DIGE and mass spectrometry of granulocyte protein from 20 MPN samples, showed differential expression of HSP70 in PV and ET besides other 60 proteins. Immunohistochemistry of 46 MPN bone marrow samples confirmed HSP70 expression. The median of positive granulocytes was 80% in PV (SD 35%) vs. 23% in ET (SD 34.25%). In an ex vivo model KNK437 was used as an inhibition model assay of HSP70, showed dose-dependent inhibition of cell growth and burst formation unit erythroid (BFU-E) in PV and ET, increased apoptosis in the erythroid lineage, and decreased pJAK2 signaling, as well as a specific siRNA for HSP70. These data suggest a key role for HSP70 in proliferation and survival of the erythroid lineage in PV, and may represent a potential therapeutic target in MPN, especially in PV.

Safety and efficacy of splenectomy in over 65-yrs-old patients with immune thrombocytopenia.

AIM: Few studies specifically focus on elderly splenectomized immune thrombocytopenia (ITP) patients. Older patients with ITP and excellent health are often excluded from surgery splenectomy. We aimed to compare the safety and efficacy of splenectomy in elderly and non-elderly ITP patients and to examine the effect of age on therapeutic response. MATERIAL AND METHODS: We carried out a retrospective analysis of a series of 218 patients who had undergone splenectomy for ITP. We compared the data from the elderly group (≥65 yrs, 57 patients) with the young group (<65 yrs, 162 patients). RESULTS: Surgical technique (laparoscopy or open laparotomy splenectomy) was comparable between the two age groups. The adjusted risk of major bleeding following splenectomy for elderly patients was three times that for young patients (OR 3.05, 95% CI: 1.44-6.52). The median duration of postoperative hospital stay was longer for elderly than for young patients (8 d vs. 4 d, P < 0.001). However, we identified a subgroup of elderly ITP patients, those aged between 65 and 70 yrs who had undergone laparoscopic splenectomy, with a low risk of postoperative complications. Of the 218 patients, 89% achieved a favorable response to splenectomy. A favorable response was significantly less common in elderly than in young people (79% vs. 92%, P = 0.005). However, we observed an acceptable long-term control of ITP in the elderly group, in which the probability of maintaining response for 14 yrs after splenectomy was 56%. CONCLUSIONS: Patients aged ≥65 yrs experienced negative effects on safety and efficacy outcomes of splenectomy for ITP, but further studies are needed to identify predictors of postsplenectomy outcomes in this group.

Relationship between serum levels of triglycerides and vascular inflammation, measured as COX-2, in arteries from diabetic patients: a translational study.

BACKGROUND: Inflammation is a common feature in the majority of cardiovascular disease, including Diabetes Mellitus (DM). Levels of pro-inflammatory markers have been found in increasing levels in serum from diabetic patients (DP). Moreover, levels of Cyclooxygenase-2 (COX-2) are increased in coronary arteries from DP. METHODS: Through a cross-sectional design, patients who underwent CABG were recruited. Vascular smooth muscle cells (VSMC) were cultured and COX-2 was measured by western blot. Biochemical and clinical data were collected from the medical record and by blood testing. COX-2 expression was analyzed in internal mammary artery cross-sections by confocal microscopy. Eventually, PGI2 and PGE2 were assessed from VSMC conditioned media by ELISA. RESULTS: Only a high glucose concentration, but a physiological concentration of triglycerides exposure of cultured human VSMC derived from non-diabetic patients increased COX-2 expression .Diabetic patients showed increasing serum levels of glucose, Hb1ac and triglycerides. The bivariate analysis of the variables showed that triglycerides was positively correlated with the expression of COX-2 in internal mammary arteries from patients (r(2) = 0.214, P < 0.04). CONCLUSIONS: We conclude that is not the glucose blood levels but the triglycerides levels what increases the expression of COX-2 in arteries from DP.