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BACKGROUND : Attention-deficit/hyperactivity disorder (ADHD) in children affects every member of the family. Practical tools are needed to assess the effects of ADHD on families to better understand and address the level of stress, strain and burden that families experience. OBJECTIVE : To provide the preliminary reliability, validity and factor structure of the Family Strain Index (FSI), a 6-item parent-report questionnaire. METHODS : The FSI was completed by 1,477 parents of children with ADHD (aged 6-18 years) at the baseline visit of the ADORE study in 10 European countries (data missing for one patient). RESULTS : The FSI taps into an overall experience of worry and interruptions of activities in families of children with ADHD, as a single factor was identified with excellent internal consistency (alpha=0.87). Despite its brevity, almost no ceiling (worst score) or floor (best score) effects were observed for families of these highly symptomatic children. This score distribution and the 5-point response options suggest that the FSI will be responsive to changes in the experience of family strain associated with children's ADHD treatment. CONCLUSION : The ease of completion and coherence of the underlying construct indicates that the FSI may be a practical clinical tool for monitoring changes in family strain associated with children's ADHD treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVES : To examine the cross-sectional reliability and validity of the Parent Report Form of the Child Health and Illness Profile-Child Edition (CHIP-CE), a generic measure of health-related quality of life (HRQoL), in children with ADHD in the pan-European ADHD Observational Research in Europe (ADORE) study. METHODS : Parents of children with ADHD (aged 6-18 years) in 10 European countries completed the CHIP-CE at the baseline visit (n=1,477; data missing for one patient). Analyses included determination of internal consistency reliability, ceiling and floor effects, factor analysis, and Pearson's correlations between CHIP-CE and other scales used to measure ADHD severity, problems and family strain. RESULTS : Internal consistency reliability was good-to-excellent (Chronbach's alpha>0.70) for all CHIP-CE domains and subdomains, and almost no ceiling and floor effects were observed. Factor analysis of the subdomains yielded a 12-factor solution. The domainlevel factor analysis identified six factors, the four domains of Satisfaction, Comfort, Resilience and Risk Avoidance. The two subdomains of Achievement domain, Peer Relations and Academic Performance, were separate factors in this sample. There were moderate-to-high correlations between the CHIP-CE scales and measures of ADHD and family factors. The HRQoL of children in ADORE was dramatically lower than that of community youth,with mean CHIP-CE scores almost 2 standard deviations below community norms. CONCLUSIONS : The validity and reliability of CHIP-CE to measure HRQoL in children with ADHD across Europe was confirmed. [ABSTRACT FROM AUTHOR]

OBJECTIVE : To examine the psychometric properties of the Strengths and Difficulties Questionnaire (SDQ) parent version and to determine the effects of age, gender, country and investigator type (paediatrician, child psychiatrist, other physician) on the SDQ scores in the prospective, non-interventional ADORE study. METHODS : The SDQ was completed for 1,459 children with ADHD (aged 6-18 years) in 10 European countries. RESULTS : Factor analysis provided an exact replication of the original 5-factor SDQ subscale structure. All subscales were sufficiently homogeneous. The mean total difficulties and SDQ subscale scores of the ADORE sample clearly differed from UK normative data. Younger children were more impaired on different SDQ scales than older children, and girls were more emotionally affected than boys. Differences between countries were found for each SDQ scale, but the investigator type had no significant effect. Correlation coefficients between SDQ scales and other scales used in ADORE ranged from low (r<0.30) to high (r>0.50). CONCLUSIONS : The present study confirmed the validity and reliability of the parent-reported SDQ scale structure and showed that the scale scores are dependent on age and gender. In contrast to investigator type, different cultures had a significant effect on SDQ scores. Correlations with other scales used in the ADORE study underline both separate domains and meaningful associations. [ABSTRACT FROM AUTHOR]

OBJECTIVE : To describe the associations between a range of baseline factors (demographic, family and clinical) and parent-reported health-related quality of life (HRQoL) of children with ADHD taking part in the ADORE study. METHODS : HRQoL was rated using the Parent Report Form of the Child Health and Illness Profile-Child Edition (CHIP-CE). Forward-stepwise linear regression models were used to investigate associations with 26 independent variables. Separate models were fitted for each of the five CHIP-CE domains (Satisfaction, Comfort, Resilience, Risk Avoidance and Achievement) and two subdomains of Achievement (Academic Performance and Peer Relations). RESULTS : CHIP-CE domain mean scores were lower than community norms, especially for Risk Avoidance and Achievement, indicating a low level of HRQoL. Clinical factors significantly associated with a poorer HRQoL included ADHD symptoms (inattention, hyperactivity-impulsivity), conduct problems, peer relationship problems, having asthma, multiple other somatic symptoms and co-ordination problems. Family factors, such as having a parent with a health or mental health problem possibly caused by the child's illness, child not living with both parents and maternal smoking during pregnancy were also associated with a worse HRQoL in some CHIP-CE domains/subdomains. CONCLUSIONS : Numerous factors independently impact on the HRQoL of children with ADHD. [ABSTRACT FROM AUTHOR]

OBJECTIVE : To describe the methodology and to present the baseline findings of the Attention-deficit/hyperactivity Disorder Observational Research in Europe (ADORE) study, the primary objective of which is to describe the relationship between treatment regimen prescribed and quality of life of children with ADHD in actual practice. METHODS : In this 2-year prospective observational study, data on diagnosis, prescribed treatment and outcomes of ADHD were collected at seven time points by paediatricians and child psychiatrists on 1,573 children recruited in 10 European countries. The data presented here from the 1,478 patients included in the analyses describe the baseline condition, initial treatment regimen prescribed and quality of life of families with children with ADHD. RESULTS : Patients had a mean age of 9.0 years (SD 2.5) and 84% were male. Physicians diagnoses were made using DSM-IV (43%), ICD-10 (32%) and both DSM-IV and ICD-10 (12%). Mean age of awareness of a problem was 5.1 years, suggesting an average delay of approximately 4 years between awareness and diagnosis of ADHD. Baseline ADHD rating scale scores (physicianrated) indicated moderate to severe ADHD. Parent-rated SDQ scores were in agreement and suggested significant levels of co-existing problems. CGI-S, CGAS and CHIPCE scores also indicated significant impairment. Patients were offered the following treatments after the initial assessment: pharmacotherapy (25%), psychotherapy (19%), combination of pharmacotherapy and psychotherapy (25%), other therapy (10%) and no treatment (21%). CONCLUSION : The ADORE study shows that ADHD is similarly recognised across 10 European countries and that the children are significantly impaired across a wide range of domains. In this respect, they resemble children described in previous ADHD samples. [ABSTRACT FROM AUTHOR]

OBJECTIVE : To study the impact of co-existing psychiatric problems with ADHD on behavioural features, psychosocial functioning and quality of life in subjects of the ADORE cohort (N=1,478). METHODS : The following six groups of associated psychiatric problems with ADHD were compared: oppositional-defiant disorder or conduct disorder only (ODD/CD); anxiety or depressive disorder only (ANX/DEP); tic/Tourette's disorder only (TIC/ Tourette's); developmental co-ordination disorder only (DCD); two or more associated conditions; and none. Dependent variables included the ADHD Rating Scale-IV, the Strengths and Difficulties Questionnaire, the Clinical Global Impression-Severity scale, the Children's Global Assessment Scale and the Child Health Illness Profile-Child Edition. RESULTS : Having multiple co-existing psychiatric problems increased the severity of ADHD in all domains, be it behavioural features, psychosocial impairment or deterioration of quality of life. A similar though less consistent pattern applied to subjects with co-existing ODD/CD. CONCLUSIONS : The ADORE study provides impressive evidence for the far-reaching consequences of co-existing psychiatric problems in children with ADHD that warrant intensive consideration in clinical assessment and treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVES : To describe the associations between a range of demographic, family and clinical factors and clinician-rated measures of global impairment in children with ADHD symptoms obtained at the baseline assessment in the ADHD Observational Research in Europe (ADORE) study. METHODS : Global impairment was measured by clinicians using the Clinical Global Impression-Severity (CGIS) scale and the Children's Global Assessment Scale (CGAS).Associations with independent variables were investigated using forward-stepwise regression models. RESULTS : For the CGI-S and CGAS analyses, complete data sets were available for 1,265 and 985 children, respectively. The baseline mean CGI-S score in this population was 4.4 (SD 0.9) and the mean CGAS score was 55.0 (SD 10.6). Factors significantly associated with increased impairment on both outcome measures were: increased severity of ADHD symptoms, increased peer relationship problems and presence of oppositional defiant disorder and/or conduct disorder.Also, the presence of anxiety and/or depression and the presence of somatic symptoms were associated with increased impairment on CGI-S,while family health problems and premature birth were associated with increased impairment on CGAS. CONCLUSIONS : The severity of clinician-rated impairment in the ADORE sample is increased by the presence of disruptive behaviour problems and emotional problems, somatic symptoms, peer relationship difficulties, family health problems and premature birth. [ABSTRACT FROM AUTHOR]

BACKGROUND : Attention-deficit/hyperactivity disorder (ADHD) in girls in Europe is poorly understood; it is not known whether they exhibit similar symptom patterns or co-existing problems and receive the same type of treatment as boys. OBJECTIVE : To examine gender differences for referral patterns, social demographic factors, ADHD core symptomatology, co-existing health problems, psychosocial functioning and treatment. METHODS : Baseline data from the ADHD Observational Research in Europe (ADORE) study, a 24-month, naturalistic, longitudinal observational study in 10 European countries of children (aged 6-18 years) with hyperactive/inattentive/impulsive symptoms but no previous diagnosis of ADHD, were analysed by gender. RESULTS : Data from 1,478 children were analysed: 231 girls (15.7%) and 1,222 boys (84.3%) (gender data missing for 25 patients). Gender ratios (girl:boy) varied by country, ranging from 1:3 to 1:16. Comparisons showed few gender effects in core ADHD symptomatology and clinical correlates of ADHD. Compared with boys, girls had significantly more parent-rated emotional symptoms and prosocial behaviour and were more likely to be the victim of bullying and less likely to be the bully. Girls and boys had similar levels of co-existing psychiatric and physical health problems, and received the same type of treatment. CONCLUSIONS : Fewer girls than boys are referred for ADHD treatment, but they have a similar pattern of impairment and receive similar treatment. [ABSTRACT FROM AUTHOR]

Value of choromogranin A and neuron-specific enolase intracystic (EUS-FNB) in the preoperatory diagnosis of cystic pancreatic neuroendocrine tumors.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). However, its characterization after haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) is scarce. This study aimed to describe characteristics and outcomes of patients with SOS/VOD after haplo-HSCT with PT-Cy. We conducted a retrospective study of 797 patients undergoing a haplo-HSCT with PT-Cy between 2007 and 2019 in 9 centers in Spain. SOS/VOD was defined according to modified Seattle, Baltimore, or revised European Society for Blood and Marrow Transplantation (EBMT) criteria. Severity was graded retrospectively according to revised EBMT severity criteria into 4 categories: mild, moderate, severe, and very severe. From a total of 797 haplo-HSCTs performed, 46 patients (5.77%) were diagnosed with SOS/VOD at a median of 19 days (range, 4 to 84 days) after transplantation. Based on revised EBMT severity criteria, the SOS/VOD cases were classified as mild (n = 4; 8.7%), moderate (n = 10; 21.7%), severe (n = 12; 26.1%), and very severe (n = 20; 43.5%). Overall, 30 patients (65%) achieved SOS/VOD complete response, 25 (83%) of whom were treated with defibrotide. Twenty patients (43%) died before day +100 post-HSCT. Death was attributed to SOS/VOD in 11 patients, and 5 patients died of other causes without resolution of SOS/VOD. The incidence of SOS/VOD after haplo-HSCT with PT-Cy was comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe SOS/VOD according to revised EBMT severity criteria. Despite a promising SOS/VOD complete response (CR) rate (65%), 100-day mortality remained high (43%), indicating that further improvement in the management of this potentially fatal complication is needed., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Multicenter, retrospective database review and topical of 46 patients consecutives with subepithelial gastrointestinal tumors (SET). The diagnostic accuracy of deep biopsy miniprobe-guidded: 87%. Complications: seven minor bleeding (15%). The samples obtained of deep biopsy miniprobe-guidded, confirm abnormal submucosal arteries mimicking theappearance of SET, are sufficient for histophatological and immunohistochemical diagnosis.

Real-world data have revealed that a substantial portion of patients with myelodysplastic syndromes (MDS) does not respond to epigenetic therapy with hypomethylating agents (HMAs). The cellular and molecular reasons for this resistance to the demethylating agent and biomarkers that would be able to predict the treatment refractoriness are largely unknown. In this study, we shed light on this enigma by characterizing the epigenomic profiles of patients with MDS treated with azacitidine. Our approach provides a comprehensive view of the evolving DNA methylation architecture of the disease and holds great potential for advancing our understanding of MDS treatment responses to HMAs., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Case report of an advanced esophageal neuroendocrine carcinoma with hepatic metastasis.

Of 50 cases gastric neuroendocrine tumors, in 30 (60%) endoscopic treatment, with relapse rate of 25%, perforation 3,6% and bleeding 7,1%.

Stress urinary incontinence (SUI) is a condition that causes the involuntary loss of urine when making small efforts, which seriously affects daily life of people who suffer from it. Women are more affected by this form of incontinence than men, since parity is the main risk factor. Weakening of the pelvic floor tissues is the cause of SUI, although a complete understanding of the cellular and molecular mechanisms of the pathology is still lacking. Reconstructive surgery to strengthen tissue in SUI patients is often associated with complications and/or is ineffective. Mesenchymal stromal cells from the maternal side of the placenta, i.e. the decidua, are proposed here as a therapeutic alternative based on the regenerative potential of mesenchymal cells. The animal model of SUI due to vaginal distention simulating labor has been used, and decidual mesenchymal stromal cell (DMSC) transplantation was effective in preventing a drop in pressure at the leak point in treated animals. Histological analysis of the urethras from DMSC-treated animals after VD showed recovery of the muscle fiber integrity, low or no extracellular matrix (ECM) infiltration and larger elastic fibers near the external urethral sphincter, compared to control animals. Cells isolated from the suburethral connective tissue of SUI patients were characterized as myofibroblasts, based on the expression of several specific genes and proteins, and were shown to achieve premature replicative senescence. Co-culture of SUI myofibroblasts with DMSC via transwell revealed a paracrine interaction between the cells through signals that mediated DMSC migration, SUI myofibroblast proliferation, and modulation of the proinflammatory and ECM-degrading milieu that is characteristic of senescence. In conclusion, DMSC could be an alternative therapeutic option for SUI by counteracting the effects of senescence in damaged pelvic tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 De La Torre, Pérez-Lorenzo, Alcázar-Garrido, Collado, Martínez-López, Forcén, Masero-Casasola, García, Gutiérrez-Vélez, Medina-Polo, Muñoz and Flores.)

Background: The consequences of infectious toxicity of hypomethylating agents (HMAs) on overall survival (OS) of patients diagnosed with high-risk myeloid neoplasms have not been thoroughly investigated., Objectives: We aimed to evaluate whether infectious events (IEs) negatively influenced the results of HMA treatment in a real-world setting., Design: Observational study., Methods: We obtained data from 412 non-selected consecutive patients from 23 Spanish hospitals who were diagnosed with high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia and were treated with HMA. HMAs received after chemotherapy or stem cell transplant were excluded. All IEs were recorded. Outcomes included OS, modifications to the pre-planned treatment, incidence and characteristics of IEs, hospitalization, red blood cell transfusions, and factors associated with infection., Results: The rate of infection was 1.2 per patient/year. Next-cycle delay ( p  = 0.001) and hospitalizations ( p  = 0.001) were significantly influenced by IEs. Transfusion requirements during each cycle were significantly higher after infection compared with cycles without infection (coefficient = 1.55 [95% confidence interval (CI) = 1.26-1.84], p  < 0.001). The median number of cycles was lower in patients experiencing any infection during the first four cycles (5 [3-8] versu 8 [5-16], p  < 0.001). In the multivariable analysis, factors associated with lower OS were having any infection during the first four cycles (hazard ratio (HR) = 1.43 [95% CI = 1.09-1.88], p  = 0.01), bone marrow blasts ⩾30% (HR = 2.13 [95% CI = 1.14-3.96], p  = 0.01), adverse cytogenetics (HR = 1.70 [95% CI = 1.30-2.24], p  < 0.001), and platelet count <50 × 10 9 /l (HR = 1.69 [95% CI = 1.3-2.2], p  < 0.001). BM blasts >20% (HR = 1.57 [95% CI = 1.19-2.01], p  < 0.001) and adverse cytogenetics (HR = 1.7 [95% CI = 1.35-2.14], p  < 0.001) were associated with infection, whereas hemoglobin >9 g/dl (HR = 0.65 [95% CI = 0.51-0.82], p  < 0.001) and higher platelet count (HR = 0.997 [95% CI = 0.996-0.998], p  = 0.016) protected from it., Conclusion: HMA infectious toxicity worsens OS, hinders the adherence to antineoplastic treatment and results in significant morbidity. Preventive strategies are fundamental in vulnerable patients., (© The Author(s), 2022.)

The present work was performed to study the enterobacteria involved in the ripening of the artisanal raw ewe's milk PDO cheeses 'Torta del Casar' and 'Queso de la Serena' produced in Extremadura (Spain). These isolates were strain-typed, safety tested and characterized for some important technological properties. A total of 485 enterobacterial isolates were clustered by RAPD-PCR and subsequently identified by partial sequencing of the 16S rRNA gene. Among the 17 different species identified, Hafnia paralvei was the predominant species; H. alvei and Lelliottia amnigena were present to a lesser extent. Therefore, 55 Hafnia spp. strains, selected according to their genetic profile and dairy origin, were tested for the safe application. Overall, they were able to produce the biogenic amines putrescine and cadaverine under favourable conditions, presented α-haemolytic activity and did not produce cytolytic toxin active against HeLa cells or contain virulence genes. In addition, antibiotic susceptibility profiles showed that 17 Hafnia spp. strains were less resistant to the 33 antibiotics tested; subsequently, they were further technologically characterized. Although they showed differences, in general, they were well adapted to the stress conditions of cheese ripening. Among them, two strains, H. alvei 544 and 1142, are highlighted mainly due to their proteolytic activity at refrigeration temperatures and their low or null gas production. Although further studies are necessary before industrial application, these two strains are proposed for potential use as adjunct cultures to favour the homogeneity of these PDO cheeses, preserving their unique sensory characteristics., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The main causes of failure of allogeneic hematopoietic stem cell transplantation (allo-transplant) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are relapse and transplant-related mortality. Different scores have been designed to predict the prognosis of these patients. The objective of this study was to assess which score or combination has better outcome predictive capacity., Methods: Retrospective analysis of patients with AML and MDS who received a first peripheral blood allo-transplant in a single center, between December 2001 and October 2019. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), European Group for Blood and Marrow Transplantation (EBMT) and Disease Risk Index (DRI) scores were calculated. For each score and for the HCT-CI/DRI and HCT-CI/EBMT combinations, overall survival (OS), cumulative incidence of relapse (CIR), non-relapse-related mortality (NRM), and graft versus host disease-free relapse-free survival (GRFS) were analyzed., Results: 175 patients were evaluated. With a median (range) follow-up of 3.96 (0.32-17.22) years, the 5-year probabilities (95% CI) of OS, CIR, NRM, and GRFS were 36% (28%-44%), 28% (21%-35%), 38% (30%-46%) and 24% (17%-31%), respectively. For OS, only the DRI score selected two groups with statistically significant differences (DRI 0-1: 41% vs. DRI ≥2: 24%; p=0.011). The combination of DRI 0-1 and HCT-CI 0-2 showed OS probabilities of 45% vs. 26% for those with DRI 0-1 and HCT-CI ≥3; p=0.041., Conclusions: In patients with AML and MDS submitted to allo-transplant, the combination of HCT-CI and DRI scores provided the best stratification for OS., (Copyright © 2021 Elsevier España, S.L.U. All rights reserved.)

IL6 is an essential cytokine in metabolism regulation and for intercommunication among different organs and tissues. IL6 produced by different tissues has different functions and therefore it is very important to understand the mechanism of its expression in adipose tissue. In this work we demonstrated that IL6 expression in mouse preadipocytes, like in human, is partially dependent on Wnt5a and JNK. Using mouse preadipocytes lacking each one of the p38 SAPK family members, we have shown that IL6 expression is also p38γ and p38δ dependent. In fact, the lack of some of these two kinases increases IL6 expression without altering that of Wnt5a. Moreover, we show that the absence of p38δ promotes greater ERK1/2 phosphorylation in a MEK1/2 independent manner, and that this increased ERK1/2 phosphorylation state is contributing to the higher IL6 expression in p38δ -/- preadipocytes. These results suggest a new crosstalk between two MAPK signaling pathway, p38δ and ERK1/2, where p38δ modulates the phosphorylation state of ERK1/2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Díaz-Chamorro, Garrido-Jiménez, Barrera-López, Mateos-Quirós, Cumplido-Laso, Lorenzo, Román, Bernardo, Sabio, Carvajal-González and Centeno.)

Proper physiological function of mammalian airways requires the differentiation of basal stem cells into secretory or multiciliated cells, among others. In addition, the self-renewal ability of these basal stem cells is crucial for developing a quick response to toxic agents in order to re-establish the epithelial barrier function of the airways. Although these epithelial missions are vital, little is known about those mechanism controlling airway epithelial regeneration in health and disease. p53 has been recently proposed as the guardian of homeostasis, promoting differentiation programs, and antagonizing a de-differentiation program. Here, we exploit mouse and human tracheal epithelial cell culture models to study the role of MDM2-p53 signaling in self-renewal and differentiation in the airway epithelium. We show that p53 protein regulation by MDM2 is crucial for basal stem cell differentiation and to keep proper cell proliferation. Therefore, we suggest that MDM2/p53 interaction modulation is a potential target to control regeneration of the mammalian airway epithelia without massively affecting the epithelium integrity and differentiation potential., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Post-transplant cyclophosphamide (PTCY) effectively prevents graft-versus-host disease after unmanipulated HLA-haploidentical HSCT. The use of PTCY in the unrelated donor HSCT setting is less explored. We conducted a retrospective study of 132 consecutive patients undergoing a matched or 9/10 mismatched unrelated donor HSCT in 4 centers in Spain, 60 with anti-thymocyte globulin (ATG)-based prophylaxis combined with MTX-CsA, and 72 using a PTCY-based regimen. Peripheral blood stem cells were used as graft in most patients (111 patients, 84%); mMUD donors were balanced between groups. Cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days were lower in the PTCy group (46% vs. 67%, p = 0.008; 3% vs. 34%, p = 0.003), without statistically significant differences in the 2-year cumulative incidence of chronic moderate-severe GVHD. At 2 years, no significant differences were observed in overall survival, event-free survival, cumulative incidence of relapse, and non-relapse mortality. GVHD was the most frequent cause of NRM in the ATG group. No differences were observed between groups in the composite endpoint of GVHD-free and relapse-free survival. In this study, PTCy combined with additional immunosuppression after MUD/mMUD HSCT showed a reduction of aGVHD rate with safety results comparable to those obtained with the ATG-based prophylaxis.

Background: Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments., Methods: For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, ≥20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407)., Findings: 949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5-42·3) from diagnosis and 16·2 months (6·6-31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1-17·3) versus 20·7 months (17·9-23·4); hazard ratio (HR) 1·39 (1·17-1·65; p=0·0002) and 14·0 months (9·8-17·2) versus 20·7 months (17·9-23·4; HR 1·55 [1·16-2·05]; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7-15·0) versus 17·6 months (14·8-21·5; HR 1·38 [1·12-1·70]; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4-16·6) versus 17·6 months (14·8-21·5; HR 1·44 [1·02-2·03]; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with <10% blasts, CMML-0, or lower-risk CPSS)., Interpretation: These data suggest hypomethylating agents as the preferred therapy for patients with higher-risk chronic myelomonocytic leukaemia and those with myeloproliferative CMML. Our findings also suggest that CPSS is a valuable tool to identify patients who are most likely to benefit from hypomethylating agents. Further evidence from prospective cohorts would be desirable., Funding: The Austrian Group for Medical Tumor Therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The main strategy of cancer treatment has focused on attacking the tumor cells. Some cancers initially responsive to chemotherapy become treatment-resistant. Another strategy is to block the formation of tumor vessels. However, tumors also become resistant to anti-angiogenic treatments, mostly due to other cells and factors present in the tumor microenvironment, and hypoxia in the central part of the tumor. The need for new cancer therapies is significant. The use of nanoparticle-based therapy will improve therapeutic efficacy and targeting, while reducing toxicity. However, due to inefficient accumulation in tumor sites, clearance by reticuloendothelial organs and toxicity, internalization or conjugation of drug-loaded nanoparticles (NPs) into mesenchymal stem cells (MSCs) can increase efficacy by actively delivering them into the tumor microenvironment. Nanoengineering MSCs with drug-loaded NPs can increase the drug payload delivered to tumor sites due to the migratory and homing abilities of MSCs. However, MSCs have some disadvantages, and exosomes and membranes from different cell types can be used to transport drug-loaded NPs actively to tumors. This review gives an overview of different cancer approaches, with a focus on hypoxia and the emergence of NPs as drug-delivery systems and MSCs as cellular vehicles for targeted delivery due to their tumor-homing potential., Competing Interests: The authors declare no conflict of interest.

Traditionally, when antibody to the Hepatitis B core antigen (anti-HBc) and antibody to the Hepatitis B surface antigen (anti-HBs) are positive, the donor is considered suitable. However, the literature contains cases with this profile and circulating hepatitis B virus DNA. The aim of the study is to analyze the incidence of occult hepatitis B virus infection (OBI). Retrospective data were evaluated for deceased tissue donors in ten Tissue Establishments (Spain) during 2017. The data included demographic data and the serological markers for hepatitis B that each tissue establishment performed. A total number of 1933 tissue donors were evaluated. A total of 180 donors were excluded: 6 (0.3%) with Hepatitis B surface antigen (HBs positive), and 174 in which DNA testing was not performed. Anti-HBc was positive in 175 donors (10%), in which anti-HBs was negative in 30 (17.1%) and positive in 145 (82.9%). In total, 27 donors with DNA positive (1.5%) were found, of which 3 of 117 donors (1.7%) showed anti-HBc negative and anti-HBs positive (> 10 IU/ml), 4 of 30 donors (13.3%) showed anti-HBc positive and anti-HBs negative and 20 of 145 donors (13.8%) showed both anti-HBc and anti-HBs positive. The highest probability of finding DNA occurs when anti-HBc is positive, regardless of the presence of anti-HBs. In our study, the probability of OBI was 1.5%. The classic concept that when anti-HBc and anti-HBs are positive (even with a titer of over 100 IU/ml) the donor can be accepted should, therefore, be reconsidered, and DNA testing should be mandatory.

Introduction and Aims: Neuroendocrine tumors are of great scientific interest, given that they are difficult to diagnose and treat. Despite being relatively rare (< 1/100,000 individuals, 1-2% of the gastrointestinal neoplasias) and indolent, their potential malignancy must not be forgotten. An increase in the number of diagnosed tumors has been observed in recent years. The aim of the present study was to update a published case series of 19 patients suspected of presenting with pancreatic neuroendocrine tumor with 51 current cases, to study and compare the new results with those of the previous case series, as well as with other recent publications from Spain, the United States, China, and India., Materials and Methods: A retrospective, multicenter case series was conducted on 70 patients (19 cases published in 2011), whose data has been collected over a period of 23 years. The variables analyzed were: age, sex, symptomatology, tumor size, location, metastasis, final diagnosis, and surgery, among others., Results: Mean patient age was 55 years and 60% of the patients were men. Disease location was the pancreatic head in 28.5% of the patients and the tail in 27.1%, mean tumor size was 3.9cm (0.2-10cm), 71.4% of the patients had non-functioning tumors, 32.8% had metastases (100% to the liver), 74.2% of the patients were operated on, and actuarial survival was 75%., Conclusions: Differences were observed between the previously published case series and the current results. There was an increase in incidentalomas and non-functioning tumors, but no variation in the overall survival rate. The differences with other case series (age, sex, and tumor location) were dependent on the country where the cases were compiled. The increase in tumors could be related to a higher number of diagnoses made through imaging studies and to the greater sensitivity of the devices employed., (Copyright © 2018 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.)

It is widely agreed that the best source of nutrition for the newborn is the milk of their own mothers. In those cases where it is not available, especially in very premature and/or very low birth weight infants, as well as other sick newborns, the preferred choice before formula is the human milk provided by selected donors. This indication is supported by the highest international bodies dedicated to the health of the child population, including the World Health Organisation as well as the main national and international scientific societies in the field of Paediatrics. Milk banks are health institutions responsible for the collection, processing and distribution of donated human milk. Currently, there are 14 human milk banks operating in Spain, grouped in the Spanish Association of Human Milk Banks, created in September 2008. In order to homogenise the criteria and to unify the working methods of the different milk banks, the Spanish Association of Human Milk Banks has developed standards to harmonise the protocols, and to serve as a guide for the start-up of new milk banks in the Spanish territory. These standards, set out in the present article, range from the donor selection and the evaluation process to the collection, processing, storage, and distribution of donor human milk., (Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The need for high-cellular-content cord blood units (CBUs) for allogenic transplantation is evident to improve clinical outcomes. In our environment and with current donation programs, very few collected units meet suggested clinical thresholds, making collection programs highly inefficient. To increase the clinical conversion rate, we have assessed factors influencing the cellular content of the cord blood collection and established the estimated fetal weight percentile (EFWp) as a tool to predict which deliveries will obtain higher cellular counts., Study Design and Methods: We conducted a retrospective analysis of 11,349 collected CBUs. An analysis of diagnostic efficiency (receiver operating characteristic [ROC] curve) was performed to establish the cutoffs of several obstetric and perinatal variables from which we would obtain more than 1500 × 10 6 total nucleated cells and 4 × 10 6 CD34 cells. We then calculated the optimal EFWp cutoff to increase efficiency., Results: In the univariate analysis, factors positively and significantly associated were a greater neonatal and placental weight and longer weeks of gestation. In the multivariate analysis only neonatal and placental weight remain significant (p < 0.001). The ROC curve analysis showed that the optimal EFWp cutoff is 60, which has the maximum area under the curve. Applying this, donations meeting clinical cellular numbers will increase more than 30% with respect to not using any threshold., Conclusion: The EFWp predicts the quality of the collected CBUs and can be used to make a prenatal selection of the donors, therefore increasing the efficiency of umbilical cord blood collection programs., (© 2018 AABB.)

Background and Objectives: The most accurate technology to detect and diagnose subepithelial tumors (SETs) is the endoscopic ultrasonography (EUS) combined with puncture techniques, such as the endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) or the endoscopic ultrasonography-guided fine-needle biopsy. Going further in the improvement of the results of tumor samples obtained endoscopically to diagnose the SETs, the canalization technique guided by miniprobes (MPs) to obtain biopsies of SET could be an alternative to EUS-FNA. The objective of this study is to analyze the results of samples obtained by this procedure., Materials and Methods: A multicenter, retrospective study of a review of a database of 32 consecutive patients with a SET in the digestive tract, from 2000 to 2015 was conducted. All patients underwent EUS-performed by MP, to define the size, internal echostructure, and layer of origin of tumor. Once the echostructure was defined, it proceeded to the canalization technique to arrive to the tumor tissue., Results: The average diameter of SETs in this series (32 patients) was about 21.6±11 mm (range: 5-41 mm). The diagnostic accuracy was 28/32, 87.50% (Confidence interval 95%: 76.04%-98.99%), and there were no major complications. All procedures were performed on outpatients, none of which required additional hospitalization. The 50% of patients were operated or endoscopically resected and in all cases, the previous pathological diagnosis was confirmed., Conclusions: This is a feasible, safe, and effective procedure that allows to access to inside of SET to obtain deep biopsies. Tumor samples obtained by deep biopsy, with prior performing of the canalization technique guided by MP, were sufficient for histopathological and immunohistochemical diagnosis and similar to those obtained with other known methods (FNA Trucut, ProCore ® , etc.). However, more prospective comparative studies with a larger number of patients and different specialists carrying out the procedure to reach a higher statistical significance are necessary., Competing Interests: There are no conflicts of interest

Growing evidence suggests that Diabetes Mellitus increases the risk of developing Alzheimer's disease. It is well known that hyperglycemia, a key feature of Diabetes Mellitus, may induce plasma osmolarity disturbances. Both hyperglycemia and hyperosmolarity promote the altered post-translational regulation of microtubule-associated protein Tau. Interestingly, abnormal hyperphosphorylation and cleavage of Tau have been proven to lead to the genesis of filamentous structures referred to as neurofibrillary tangles, the main pathological hallmark of Alzheimer's disease. We have previously described that hyperosmotic stress induced by sorbitol promotes Tau proteolysis and apoptosis in SH-SY5Y cells via caspase-3 activation. In order to gain insights into the regulatory mechanisms of such processes, in this work we explored the intracellular signaling pathways that regulate these events. We found that sorbitol treatment significantly enhanced the activation of conventional families of MAPK in SH-SY5Y cells. Tau proteolysis was completely prevented by JNK inhibition but not affected by either ERK1/2 or p38 MAPK blockade. Moreover, inhibition of JNK, but not ERK1/2 or p38 MAPK, efficiently prevented sorbitol-induced apoptosis and caspase-3 activation. In summary, we provide evidence that JNK signaling pathway is an upstream regulator of hyperosmotic stress-induced Tau cleavage and apoptosis in SH-SY5Y through the control of caspase-3 activation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The emergency medical technician plays a fundamental role and is the most important figure quantitatively in pre-hospital emergencies. The aim was to asses the socio-demographic, work-related, health characteristics and technical skills of an Emergency Medical Technician in Spain., Methods: Cross-sectional descriptive study. An ad hoc questionnaire was managed using Google Docs® that was delivered between April-June 2014 via email and social networks. A total of 705 questionnaires were collected. Statistical analysis was performed with SPSS ® 20.0 Windows version. A significance level p≤0.05 was used for all analyzes., Results: The data analyzed show that the profile of the Emergency Medical Technician in Spain is an 39 year-old man, married or living as a couple and has a child. The average BMI is 27 kg/m2, does regular exercise, does not smoke. His seniority in the company is 10 years and has the Medium Cycle of Emergency Medical Technician. The analysis for gender shows that men have an average of 40, an average BMI of 27, 5 kg/m2 and work in an advanced life support unit; while women have an average of 36,5 years, an average BMI of 24,7 kg/m2, mainly work in Basic Life Support Unit and her seniority in the company is 6,76 years., Conclusions: Emergency Medical Technician profile is a overweight men, who refer to practise regular exercise, his seniority in the company is 10 years and is in possession of CMTES; differences were observed according to gender in BMI, resource where they perform their work, seniority and age.

The incidence of gastric and rectal carcinoids is increasing. This is probably due to endoscopic screening. The prognosis is primarily dependent upon tumor size, aggressiveness (pathology, Ki-67), metastatic disease and stage. However, neuroendocrine carcinoma usually behaves as an adenocarcinoma.

Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory cholangiopathy (disease of the bile ducts) of unknown pathogenesis. We reported that cholangiocyte senescence features prominently in PSC and that neuroblastoma RAS viral oncogene homolog (NRAS) is activated in PSC cholangiocytes. Additionally, persistent microbial insult ( e.g. LPSs) induces cyclin-dependent kinase inhibitor 2A (CDKN2A/p16 INK4a ) expression and senescence in cultured cholangiocytes in an NRAS-dependent manner. However, the molecular mechanisms involved in LPS-induced cholangiocyte senescence and NRAS-dependent regulation of CDKN2A remain unclear. Using our in vitro senescence model, we found that LPS-induced CDKN2A expression coincided with a 4.5-fold increase in ETS1 ( ETS proto-oncogene 1 ) mRNA, suggesting that ETS1 is involved in regulating CDKN2A This idea was confirmed by RNAi-mediated suppression or genetic deletion of ETS1, which blocked CDKN2A expression and reduced cholangiocyte senescence. Furthermore, site-directed mutagenesis of a predicted ETS-binding site within the CDKN2A promoter abolished luciferase reporter activity. Pharmacological inhibition of RAS/MAPK reduced ETS1 and CDKN2A protein expression and CDKN2A promoter-driven luciferase activity by ∼50%. In contrast, constitutively active NRAS expression induced ETS1 and CDKN2A protein expression, whereas ETS1 RNAi blocked this increase. Chromatin immunoprecipitation-PCR detected increased ETS1 and histone 3 lysine 4 trimethylation (H3K4Me3) at the CDKN2A promoter following LPS-induced senescence. Additionally, phospho-ETS1 expression was increased in cholangiocytes of human PSC livers and in the Abcb4 ( Mdr2 ) -/- mouse model of PSC. These data pinpoint ETS1 and H3K4Me3 as key transcriptional regulators in NRAS-induced expression of CDKN2A , and this regulatory axis may therefore represent a potential therapeutic target for PSC treatment., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objectives: The goal of this study was to determine the functional impact of paradoxical low-gradient aortic stenosis (PLGAS) and clarify whether the relevance of the valvular obstruction is related to baseline flow., Background: Establishing the significance of PLGAS is particularly challenging., Methods: Twenty symptomatic patients (77 ± 6 years of age; 17 female subjects) with PLGAS (mean gradient 28 ± 6 mm Hg; aortic valve area 0.8 ± 0.1 cm 2 ; ejection fraction 66 ± 7%) underwent cardiopulmonary exercise testing combined with right-heart catheterization and Doppler echocardiographic measurements., Results: Aortic valve area increased by 84 ± 23% (p < 0.001) and, in 70% of subjects, it reached values >1.0 cm 2 at peak exercise. Stroke volume index and blood pressure increased by 83 ± 56% and 26 ± 16%, respectively (both p < 0.0001). Peak oxygen consumption inversely correlated with the rate of increase in pulmonary capillary wedge pressure (PCWP) (PCWP slope: R = -0.61; p = 0.004). In turn, the PCWP slope was determined by changes in the valvular and vascular load but not by the rest of the indices of aortic stenosis. The functional impact of PLGAS was also not related to baseline flow. Agreement between Doppler echocardiography and the Fick technique was good up to intermediate workload., Conclusions: In symptomatic patients with PLGAS, the capacity to dynamically reduce vascular and valvular loads determines the effect of exercise on PCWP, which, in turn, conditions the functional status. A critically fixed valvular obstruction may not be the main mechanism of functional impairment in a large proportion of patients with PLGAS. Exercise echocardiography is suitable to study the dynamics of PLGAS., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Tau is a microtubule-associated protein implicated in the pathogenesis of Alzheimer's disease and other related tauopathies. In this subset of neurodegenerative disorders, Tau auto-assembles into insoluble fibrils that accumulate in neurons as paired helical filaments (PHFs), promoting cellular dysfunction and cytotoxic effects. Growing evidence suggests that abnormal post-translational regulation, mainly hyperphosphorylation and aberrant cleavage, drives Tau to this pathological state. In this work we show that sorbitol-induced hyperosmotic stress promotes Tau proteolysis in SH-SY5Y neuroblastoma cells. The appearance of cleaved Tau was preceded by the activation of μ-calpain, the proteasome system and caspase-3. Tau proteolysis was completely prevented by caspase-3 inhibition but unaffected by neither the proteasome system nor μ-calpain activity blockade. Concomitantly, hyperosmotic stress induced apoptosis in SH-SY5Y cells, which was efficiently avoided by the inhibition of caspase-3 activity. Altogether, our results provide the first evidence that Tau protein is susceptible to caspase-3 proteolysis under hyperosmotic stress and suggest a positive relationship between Tau proteolysis and apoptosis in SH-SY5Y cells. J. Cell. Biochem. 117: 2781-2790, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Treponema pallidum infections can have severe complications if not diagnosed and treated at an early stage. Screening and diagnosis of syphilis require assays with high specificity and sensitivity. The Elecsys Syphilis assay is an automated treponemal immunoassay for the detection of antibodies against T. pallidum The performance of this assay was investigated previously in a multicenter study. The current study expands on that evaluation in a variety of diagnostic settings and patient populations, at seven independent laboratories. The samples included routine diagnostic samples, blood donation samples, samples from patients with confirmed HIV infections, samples from living organ or bone marrow donors, and banked samples, including samples previously confirmed as syphilis positive. This study also investigated the seroconversion sensitivity of the assay. With a total of 1,965 syphilis-negative routine diagnostic samples and 5,792 syphilis-negative samples collected from blood donations, the Elecsys Syphilis assay had specificity values of 99.85% and 99.86%, respectively. With 333 samples previously identified as syphilis positive, the sensitivity was 100% regardless of disease stage. The assay also showed 100% sensitivity and specificity with samples from 69 patients coinfected with HIV. The Elecsys Syphilis assay detected infection in the same bleed or earlier, compared with comparator assays, in a set of sequential samples from a patient with primary syphilis. In archived serial blood samples collected from 14 patients with direct diagnoses of primary syphilis, the Elecsys Syphilis assay detected T. pallidum antibodies for 3 patients for whom antibodies were not detected with the Architect Syphilis TP assay, indicating a trend for earlier detection of infection, which may have the potential to shorten the time between infection and reactive screening test results., (Copyright © 2016 Kremastinou et al.)