Translatable plasma and CSF biomarkers for use in mouse models of Huntington's disease.

Huntington's disease is an inherited neurodegenerative disorder for which a wide range of disease-modifying therapies are in development and the availability of biomarkers to monitor treatment response is essential for the success of clinical trials. Baseline levels of neurofilament light chain in CSF and plasma have been shown to be effective in predicting clinical disease status, subsequent clinical progression and brain atrophy. The identification of further sensitive prognostic fluid biomarkers is an active research area, and total-Tau and YKL-40 levels have been shown to be increased in CSF from Huntington's disease mutation carriers. The use of readouts with clinical utility in the preclinical assessment of potential therapeutics should aid in the translation of new treatments. Here, we set out to determine how the concentrations of these three proteins change in plasma and CSF with disease progression in representative, well-established mouse models of Huntington's disease. Plasma and CSF were collected throughout disease progression from R6/2 transgenic mice with CAG repeats of 200 or 90 codons (R6/2:Q200 and R6/2:Q90), zQ175 knock-in mice and YAC128 transgenic mice, along with their respective wild-type littermates. Neurofilament light chain and total-Tau concentrations were quantified in CSF and plasma using ultrasensitive single-molecule array (Quanterix) assays, and a novel Quanterix assay was developed for breast regression protein 39 (mouse homologue of YKL-40) and used to quantify breast regression protein 39 levels in plasma. CSF levels of neurofilament light chain and plasma levels of neurofilament light chain and breast regression protein 39 increased in wild-type biofluids with age, whereas total-Tau remained constant. Neurofilament light chain and breast regression protein 39 were elevated in the plasma and CSF from Huntington's disease mouse models, as compared with wild-type littermates, at presymptomatic stages, whereas total-Tau was only increased at the latest disease stages analysed. Levels of biomarkers that had been measured in the same CSF or plasma samples taken at the latest stages of disease were correlated. The demonstration that breast regression protein 39 constitutes a robust plasma biomarker in Huntington's disease mouse models supports the further investigation of YKL-40 as a CSF biomarker for Huntington's disease mutation carriers. Neurofilament light chain and Tau are considered markers of neuronal damage, and breast regression protein 39 is a marker of inflammation; the similarities and differences in the levels of these proteins between mouse models may provide future insights into their underlying pathology. These data will facilitate the use of fluid biomarkers in the preclinical assessment of therapeutic agents for Huntington's disease, providing readouts with direct relevance to clinical trials.

A CAG repeat threshold for therapeutics targeting somatic instability in Huntington's disease.

The Huntington's disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable and expansions of hundreds of CAGs have been detected in Huntington's disease post-mortem brains. The age of disease onset can be predicted partially from the length of the CAG repeat as measured in blood. Onset age is also determined by genetic modifiers, which in six cases involve variation in DNA mismatch repair pathways genes. Knocking-out specific mismatch repair genes in mouse models of Huntington's disease prevents somatic CAG repeat expansion. Taken together, these results have led to the hypothesis that somatic CAG repeat expansion in Huntington's disease brains is required for pathogenesis. Therefore, the pathogenic repeat threshold in brain is longer than (CAG)40, as measured in blood, and is currently unknown. The mismatch repair gene MSH3 has become a major focus for therapeutic development, as unlike other mismatch repair genes, nullizygosity for MSH3 does not cause malignancies associated with mismatch repair deficiency. Potential treatments targeting MSH3 currently under development include gene therapy, biologics and small molecules, which will be assessed for efficacy in mouse models of Huntington's disease. The zQ175 knock-in model carries a mutation of approximately (CAG)185 and develops early molecular and pathological phenotypes that have been extensively characterized. Therefore, we crossed the mutant huntingtin allele onto heterozygous and homozygous Msh3 knockout backgrounds to determine the maximum benefit of targeting Msh3 in this model. Ablation of Msh3 prevented somatic expansion throughout the brain and periphery, and reduction of Msh3 by 50% decreased the rate of expansion. This had no effect on the deposition of huntingtin aggregation in the nuclei of striatal neurons, nor on the dysregulated striatal transcriptional profile. This contrasts with ablating Msh3 in knock-in models with shorter CAG repeat expansions. Therefore, further expansion of a (CAG)185 repeat in striatal neurons does not accelerate the onset of molecular and neuropathological phenotypes. It is striking that highly expanded CAG repeats of a similar size in humans cause disease onset before 2 years of age, indicating that somatic CAG repeat expansion in the brain is not required for pathogenesis. Given that the trajectory for somatic CAG expansion in the brains of Huntington's disease mutation carriers is unknown, our study underlines the importance of administering treatments targeting somatic instability as early as possible.

Incidence, characteristics, and predictive factors of post-colonoscopy colorectal cancer.

BACKGROUND: Post-colonoscopy colorectal cancer (PCCRC) is colorectal cancer (CRC) diagnosed after a colonoscopy in which no cancer is found. OBJECTIVE: As PCCRC has become an important quality indicator, we determined its rates, characteristics, and index colonoscopy-related predictive factors. METHODS: We carried out a multicenter, observational, retrospective study between 2015 and 2018. Rates were calculated for PCCRC developing up to 10 years after colonoscopy. PCCRC was categorized according to the most plausible explanation using World Endoscopy Organization methodology. Our PCCRC population was compared to a control cohort without CRC matched 1:4 by sex, age, index colonoscopy date, indication, endoscopist, and hospital. RESULTS: One hundred seven PCCRC and 2508 detected CRC were diagnosed among 101,524 colonoscopy (0.1%), leading to rates of 0.4%, 2.2%, 3.1%, and 4.1% at 1, 3, 5, and 10 years, respectively. PCCRC was in right (42.4%), left (41.4%), and transverse (16.4%) colon with 31.5% at stage I, 24.7% stage II, 32.6% stage III, and 11.2% stage IV. Twenty point three percent were classified as incomplete resection, 5.4% as unresected lesions, 48.6% as missed lesions with adequate colonoscopy, and 25.7% as missed lesions with inadequate colonoscopy. The median time from colonoscopy to PCCRC was 42 months. Previous inadequate preparation (OR 3.05, 95%CI 1.73-5.36) and piecemeal polypectomy (OR 19.89, 95%CI 8.67-45.61) were independently associated with PCCRC. CONCLUSIONS: In our population, 4.1% of CRC cases were PCCRC. Most of these lesions were in right colon and attributable to lesions not visualized despite adequate bowel cleansing. Previous inadequate cleansing and piecemeal polypectomy were associated with PCCRC.

Communication of medical errors in a simulated clinical scenario. Experience with a pediatric residency group.

OBJECTIVE: To determine the performance of groups of pediatric residents from a Buenos Aires hospital, in terms of correct recognition and communication of a medical error (ME), in a high-fidelity simulation scenario. To describe the reactions and communication attempts following the ME and the self-perception by the trainees before and after a debriefing. METHODS: Quasi-experimental uncontrolled study conducted in a simulation center. First- and third-year pediatric residents participated. We designed a simulation case in which an ME occurred and the patient deteriorated. During the simulation, participants had to provide information on communicating the ME to the patient's father. We assessed communication performance and, additionally, participants completed a self-perception survey about ME management before and after a debriefing. RESULTS: Eleven groups of residents participated. Ten (90.9%) identified the ME correctly, but only 27.3% (n=3) of them reported that a ME had occurred. None of the groups told the father they were going to give him important news concerning his son's health. All 18 residents who actively participated in this communication completed the self-perception survey, with an average score before and after debriefing of 5.00 and 5.05 (out of 10) (p=0.88). CONCLUSIONS: We observed a high number of groups that recognized the presence of a ME, but the communication action was substantially low. Communication skills were insufficient and residents' self-perception of error management was regular and not modified by the debriefing.

Communication of medical errors in a simulated clinical scenario. Experience with a pediatric residency group / Comunicação de erros médicos em cenário clínico simulado. Experiência com residentes em Pediatria

ABSTRACT Objective: To determine the performance of groups of pediatric residents from a Buenos Aires hospital, in terms of correct recognition and communication of a medical error (ME), in a high-fidelity simulation scenario. To describe the reactions and communication attempts following the ME and the self-perception by the trainees before and after a debriefing. Methods: Quasi-experimental uncontrolled study conducted in a simulation center. First- and third-year pediatric residents participated. We designed a simulation case in which an ME occurred and the patient deteriorated. During the simulation, participants had to provide information on communicating the ME to the patient's father. We assessed communication performance and, additionally, participants completed a self-perception survey about ME management before and after a debriefing. Results: Eleven groups of residents participated. Ten (90.9%) identified the ME correctly, but only 27.3% (n=3) of them reported that a ME had occurred. None of the groups told the father they were going to give him important news concerning his son's health. All 18 residents who actively participated in this communication completed the self-perception survey, with an average score before and after debriefing of 5.00 and 5.05 (out of 10) (p=0.88). Conclusions: We observed a high number of groups that recognized the presence of a ME, but the communication action was substantially low. Communication skills were insufficient and residents' self-perception of error management was regular and not modified by the debriefing.

RESUMO Objetivo: Determinar o desempenho de grupos de residentes pediátricos de um hospital de Buenos Aires, em termos de reconhecimento e comunicação correta de um erro médico (EM),em cenário de simulação. Descrever as reações e tentativas de comunicação após o EM e a autopercepção pelos estagiários antes e depois de um questionário. Métodos: Estudo quase experimental não controlado realizado em centro de simulação. Participaram residentes pediátricos do primeiro e terceiro anos. Concebeu-se um caso de simulação em que ocorreu um EM com deterioração de um paciente. Durante a simulação, os participantes tiveram que fornecer informações relacionadas à comunicação do EM ao pai do paciente. Avaliou-se o desempenho da comunicação e, adicionalmente, os participantes completaram um inquérito de autopercepção sobre a gestão da EM, antes e depois de um questionário. Resultados: Onze grupos de residentes participaram. Dez (90,9%) identificaram corretamente o EM, mas apenas 27,3% (n=3) deles comunicaram que havia ocorrido o EM. Nenhum dos grupos disse ao pai que iria dar notícias importantes sobre a saúde do seu filho. Todos os 18 residentes que participaram ativamente da comunicação completaram o questionário de autopercepção com uma pontuação média antes e depois do questionário de 5,00 e 5,05 (máximo: 10 pontos) (p=0,88). Conclusões: Observamos elevado número de grupos que reconheceram a presença de um EM, mas a ação de comunicação foi rara. A capacidade de comunicação foi insuficiente e a autopercepção da gestão de erros por parte dos residentes foi regular, não sendo modificada pelo debriefing.

Limpieza de úlceras de etiología venosa. Una revisión sistemática / Cleansing venous leg ulcers. A systematic review

Objetivo: Evaluar los efectos de la limpieza, así como las soluciones y técnicas utilizadas, para el tratamiento de las úlceras de etiología venosa. Metodología: Se realizó una revisión sistemática siguiendo las últimas recomendaciones de la declaración PRISMA. La búsqueda se realizó en 3 bases de datos (PubMed, CINAHL, Cochrane), limitándose por idioma (inglés/español) y por año (de enero de 2011 a diciembre de 2021). Siguiendo el diagrama PRISMA, se realizó la depuración y evaluación de calidad de los estudios por pares, utilizando las normas de la Red EQUATOR, y seleccionando únicamente ensayos clínicos aleatorizados y revisiones sistemáticas de calidad media o alta. Resultados: Se identificaron un total de 790 artículos, de los cuales se eliminaron 58 por estar duplicados, 700 tras la revisión por título y resumen, y 25 en el cribado por texto completo. De los 7 artículos restantes, se incluyeron 5 al presentar alta calidad metodológica (cumplieron > 70% de los ítems), 3 con diseño de estudio clínico aleatorizado y 2 revisiones sistemáticas. Conclusiones: Actualmente, no se dispone de evidencias científicas sólidas que den valor a la limpieza dentro del tratamiento integral de las heridas. Se necesitan más estudios que permitan orientar a los profesionales en la toma de decisiones para realizar una práctica segura y una optimización de los recursos existentes, considerando a la persona, sus necesidades y su satisfacción en el proceso del cuidado de las lesiones (AU)

Objectives: To evaluate the effects of cleansing venous ulcers on the healing, as well as wound cleansing solutions available and wound cleansing techniques used. Methodology: A systematic review has been made following the PRISMA statement recommendations. This research used 3 databases (PubMed, CINAHL, Cochrane), filtering by language (English/Spanish) and by date (from January 2011 to December 2021). Diagram PRISMA was the base for filtering and evaluating the peer review quality, using the EQUATOR Network and selecting only the randomised clinical trial (RCT) and high or medium quality systematic reviews (SR). Results: A total of 790 articles were identified, of which 58 were eliminated as duplicates, 700 after reviewing by title and abstract, and 25 after screening by full text. Of the 7 remaining articles, 5 of them were included as they were of high methodological quality (more than 70% of the items were accomplished), 3 with an RCT design and 2 SR. Conclusions: Currently, there is no solid scientific evidence that gives credence that cleansing injuries, adds value, within the comprehensive treatment of wounds. More studies are needed, to give professionals decision-making guidelines for providing safe practices and optimising existing resources, considering the state of the patient, their needs and their comfort during the process of injury care (AU)

Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential.

BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.

Quality of Colonoscopy Is Associated With Adenoma Detection and Postcolonoscopy Colorectal Cancer Prevention in Lynch Syndrome.

BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and pan-chromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

Complicaciones y cuidado local de la piel tras la realización de un tatuaje: revisión sistemática / Complications and local skin care after getting a tattoo: a systematic review

Objetivos: Identificar las complicaciones dermatológicas y los cuidados locales de los tatuajes temporales y permanentes a través de una revisión sistemática. Metodología: Se realizó una revisión sistemática aplicando la Declaración PRISMA. La búsqueda se llevó a cabo en 6 bases de datos (PubMed, Cochrane Library, CUIDEN, CINHAL, DARE y LILACS) y dos bases no indexadas (Dermatología Elsevier y Dermatology Online Journal). Se delimitó la búsqueda por idioma (inglés/español) y por año (últimos 10 años). Una vez depurada la base de datos se procedió a la evaluación de la calidad por pares. Resultados: Se obtuvieron un total de 583 artículos, de los cuales se eliminaron 86 por duplicado y 379 tras la revisión por título y resumen. Se seleccionaron 118 artículos a texto completo, y una vez evaluada la calidad a través de los criterios propuestos por la Red EQUATOR, 30 artículos presentaron una calidad mediaalta. Finalmente, para su análisis cualitativo se incluyeron un total 22 casos clínicos (informe CARE), 5 estudios observacionales (informe STROBE), 2 ensayos clínicos (informe CONSORT) y una revisión sistemática (informe PRISMA). Conclusiones: Se ha evidenciado la necesidad de actualizar conocimientos orientados al abordaje de los tratamientos y la identificación de las complicaciones relacionadas con los tatuajes basados en evidencias sólidas. El desarrollo de guías de práctica clínica que aborden la detección y la aplicación de tratamientos adecuados a este problema de salud puede ser el primer paso para integrar el manejo de los tatuajes en la cartera de servicios del sistema sanitario, permitiendo conocer la dimensión epidemiológica y los recursos necesarios en atención primaria (AU)

Objectives: To identify dermatological complications and local care of temporary and permanent tattoos through a systematic review. Methods: A systematic review was carried out applying the PRISMA Declaration. The search was carried out in 6 databases (PubMed, Cochrane Library, CUIDEN, CINHAL, DARE and LILACS) and two non-indexed databases (Elsevier Dermatology and Dermatology Online Journal). The search was limited by language (English / Spanish) and by year (last 10 years). Once the database was refined, the quality evaluation was carried out in pairs. Results. A total of 583 articles were obtained, of which 86 were removed in duplicate and 379 after review by title and abstract. 118 full-text articles were selected, which, once the quality was evaluated through the criteria proposed by the EQUATOR Network, 30 articles presented a high average quality. Finally, 22 clinical cases (CARE report), 5 observational studies (STROBE report), 2 clinical trials (CONSORT report) and a systematic review (PRISMA report) were included for analysis. Conclusions: There is a need to update knowledge oriented to the treatment approach and the identification of complications related to tattoos based on solid evidence. The development of clinical practice guidelines that address the detection and application of appropriate treatments for this health problem, may be the first step in integrating the management of tattoos into the portfolio of services of the Health System, allowing to know the epidemiological dimension and the necessary resources in Primary Care (AU)

Psychiatric disorders, depression and quality of life in patients with psychogenic non-epileptic seizures and drug resistant epilepsy living in Argentina.

OBJECTIVES: Psychiatric disorders are frequently found in both patients with PNES and DRE, making the differential diagnosis even more complex. The aim of this study was to analyze and compare psychiatric aspects and the quality of life in patients with psychogenic non-epileptic seizures (PNES) and drug resistant epilepsy (DRE). METHODS: Patients admitted to video-electroencephalograpy (VEEG) unit with confirmed PNES and DRE were included. Demographical characteristics, psychiatric diagnosis according to SCID I and II of DSM IV, pharmacological treatment, general functioning measured with GAF (Global assessment of functionality), quality of life (QoL) using QlesQSF (Quality of Life Enjoyment and Satisfaction Questionnaire Short Form) and depression severity using BDI II (Beck depression inventory), were compared between the groups. Non-parametric tests, chi square test, and logistic regression were used for statistical analysis. RESULTS: 148 patients consecutively admitted to VEEG were included (DRE n = 97; PNES n = 51). Somatization disorder (RR: 13.02, 95% CI: 1.23-137.39, p = 0.03) and a history of trauma (RR: 8.66, 95% CI: 3.21-23.31, p = 0.001) were associated with PNES. The QlesQ score and the GAF score were lower with a higher prevalence of suicide attempts in the PNES group (p < 0.01). A negative correlation was observed between the severity of depression and the quality of life (DRE r = - 0.28, p = 0.013; PNES r = - 0.59, p = 0.001). CONCLUSIONS: Higher psychiatric comorbidity with poorer QoL were found in PNES patients compared to DRE. However, depression comorbidity negatively affected the QoL in both groups. Future studies based on illness perception will be orientated to complete this analysis.

Large-scale gene gains and losses molded the NLR defense arsenal during the Cucurbita evolution.

MAIN CONCLUSION: Genome-wide annotation reveals that the gene birth-death process of the Cucurbita R family is associated with a species-specific diversification of TNL and CNL protein classes. The Cucurbitaceae family includes nearly 1000 plant species known universally as cucurbits. Cucurbita genus includes many economically important worldwide crops vulnerable to more than 200 pathogens. Therefore, the identification of pathogen-recognition genes is of utmost importance for this genus. The major class of plant-resistance (R) genes encodes nucleotide-binding site and leucine-rich repeat (NLR) proteins, and is divided into three sub-classes namely, TIR-NB-LRR (TNL), CC-NB-LRR (CNL) and RPW8-NB-LRR (RNL). Although the characterization of the NLR gene family has been carried out in important Cucurbita species, this information is still linked to the availability of sequenced genomes. In this study, we analyzed 40 de novo transcriptomes and 5 genome assemblies, which were explored to investigate the Cucurbita expressed-NLR (eNLR) and NLR repertoires using an ad hoc gene annotation approach. Over 1850 NLR-encoding genes were identified, finely characterized and compared to 96 well-characterized plant R-genes. The maximum likelihood analyses revealed an unusual diversification of CNL/TNL genes and a strong RNL conservation. Indeed, several gene gain and loss events have shaped the Cucurbita NLR family. Finally, to provide a first validation step Cucurbita, eNLRs were explored by real-time PCR analysis. The NLR repertories of the 12 Cucurbita species presented in this paper will be useful to discover novel R-genes.

Transcriptomic analysis of a near-isogenic line of melon with high fruit flesh firmness during ripening.

BACKGROUND: A near-isogenic line (NIL) of melon (SC10-2) with introgression in linkage group X was studied from harvest (at firm-ripe stage of maturity) until day 18 of postharvest storage at 20.5 °C together with its parental control ('Piel de Sapo', PS). RESULTS: SC10-2 showed higher flesh firmness and whole fruit hardness but lower juiciness than its parental. SC10-2 showed a decrease in respiration rate accompanied by a decrease in ethylene production during ripening, both of which fell to a greater extent than in PS. The introgression affected 11 volatile organic compounds (VOCs), the levels of which during ripening were generally higher in SC10-2 than in PS. Transcriptomic analysis from RNA-Seq revealed differentially expressed genes (DEGs) associated with the effects studied. For example, 909 DEGs were exclusive to the introgression, and only 23 DEGs were exclusive to postharvest ripening time. Major functions of the DEGs associated with introgression or ripening time were identified by cluster analysis. About 37 genes directly and/or indirectly affected the delay in ripening of SC10-2 compared with PS in general and, more particularly, the physiological and quality traits measured and, probably, the differential non-climacteric response. Of the former genes, we studied in more detail at least five that mapped in the introgression in linkage group (LG) X, and 32 outside it. CONCLUSION: There is an apparent control of textural changes, VOCs and fruit ripening by an expression quantitative trait locus located in LG X together with a direct control on them due to genes presented in the introgression (CmTrpD, CmNADH1, CmTCP15, CmGDSL esterase/lipase, and CmHK4-like) and CmNAC18. © 2020 Society of Chemical Industry.

[Evaluation and perspective of 20 years of neonatal screening in Galicia. Program results.] / Evaluación y perspectiva de 20 años de cribado neonatal en Galicia. Resultados del programa.

Galician newborn screening program for early detection of endocrine and metabolic diseases began in 1978 and was a pioneer in expanded newborn screening in Spain with the incorporation of mass spectrometry in July 2000. As a primary objective, 28 diseases are screened, including those recommended SNS except sickle cell anemia which is in the inclusion phase. In its 20-year history, 404,616 newborns (nb) have been analyzed, identifying 547 cases affected by the diseases included, with a global incidence of 1: 739 newborns and 1: 1.237 of the screened inborn errors of metabolism (IEM) (1:1.580 nb if excluding benign hyperphenylalaninemia-HPA), with an average participation of 99.35%, progressively higher during the analyzed period. Among the pathologies screened, congenital hypothyroidism (1:2.211 nb), cystinuria (1:4.129 nb) and HPA (1:5.699 nb), followed by phenylketonuria and cystic fibrosis (1:10,936 nb) stand out for their incidence. Sixty-six cases of false positives were identified (seventeen of them in relation to maternal pathology) and five false negatives, being the overall PPV and NPV of the program respectively of 89.2% and 99.99%, with a sensitivity of 99.09% and a specificity of 99.98%. The mortality rate of diagnosed CME patients is 1.52%, with eleven cases presenting symptoms prior to the screening result (2%). The intelligence quotient of IEM patients at risk of neurological involvement is normal in more than 95% of cases.

El Programa Gallego para la Detección Precoz de Enfermedades Endocrinas y Metabólicas se inició en 1978 y fue pionero en España en el cribado neonatal ampliado con la incorporación de la espectrometría de masas en julio de 2000. Como objetivo primario se criban veintiocho enfermedades, incluyendo las de la cartera básica del Servicio Nacional de Salud excepto la anemia de células falciformes, que está en fase de inclusión. En sus veinte años de trayectoria se analizaron 404.616 recién nacidos (RN), identificando 547 casos afectos de las enfermedades incluidas, con una incidencia global de 1:739 RN vivos y de 1:1.237 RN de las enfermedades metabólicas congénitas (EMC) cribadas (1:1.580 RN excluyendo la hiperfenilalaninemia benigna-HPA), con una participación media del 99,35%, progresivamente creciente durante el período analizado. Entre las patologías cribadas destacan por su incidencia el hipotirodismo congénito (1:2.211 RN), la cistinuria (1:4.129 RN) y la HPA (1:5.699 RN), seguida de fenilcetonuria y fibrosis quística (1:10.936 RN). Se identificaron sesenta y seis casos de falsos positivos (diecisiete de los mismos en relación con patología materna) y cinco falsos negativos, siendo el VPP (valor predictivo positivo) y el VPN (valor predictivo negativo) global del programa del 89,2% y 99,99%, respectivamente, con una sensibilidad de 99,09% y una especificidad del 99,98%. La tasa de mortalidad de los pacientes con EMC diagnosticados fue del 1,52%, presentando once casos sintomatología previa al resultado del cribado (2%). El cociente intelectual de los pacientes con EMC y riesgo de afectación neurológica es normal en más del 95% de los casos.

Melon Genome Regions Associated with TGR-1551-Derived Resistance to Cucurbit yellow stunting disorder virus.

Cucurbit yellow stunting disorder virus (CYSDV) is one of the main limiting factors of melon cultivation worldwide. To date, no commercial melon cultivars resistant to CYSDV are available. The African accession TGR-1551 is resistant to CYSDV. Two major quantitative trait loci (QTLs) have been previously reported, both located near each other in chromosome 5. With the objective of further mapping the gene or genes responsible of the resistance, a recombinant inbred line (RIL) population derived from the cross between TGR-1551 and the susceptible cultivar 'Bola de Oro' was evaluated for resistance to CYSDV in five different assays and genotyped in a genotyping by sequencing (GBS) analysis. The major effect of one of the two QTLs located on chromosome 5 was confirmed in the multienvironment RIL assay and additionally verified through the analysis of three segregating BC1S1 populations derived from three resistant RILs. Furthermore, progeny test using the offspring of selected BC3 plants allowed the narrowing of the candidate interval to a 700 kb region. The SNP markers identified in this work will be useful in marker-assisted selection in the context of introgression of CYSDV resistance in elite cultivars.

Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome.

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56-2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67-4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44-2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26-5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.

Report on a psychoeducational intervention for psychogenic non-epileptic seizures in Argentina.

PURPOSE: To examine the effects of a three-session psychoeducational intervention on patients diagnosed with psychogenic non-epileptic seizures (PNES) in an Argentinian public hospital. It was hypothesized that patients would experience improvements in their understanding of PNES, illness perception and affective scores, but might not necessarily experience a significant change in post-traumatic and dissociative symptoms and in seizure frequency. METHODS: This study included 12 patients (10 women, 2 men) who were invited to participate in a psychoeducational group after receiving a V-EEG confirmed diagnosis of PNES. The group consisted of 3 sessions lasting 2 h each. Pre and post measures included Psychoeducational Intervention Questionnaire, State-Trait Anxiety Inventory, Beck Depression Inventory-II, Brief Illness Perception Questionnaire, Posttraumatic Stress Disorder Diagnostic Scale 5, Dissociative Experiences Scale (DES-M). RESULTS: This psychoeducational intervention produced results that were similar to interventions reported in US and European studies with regard to changes on psychological measures. Moreover, many patients also reported (on the final day of the intervention) a decrease in seizure frequency. All patients reported that participating in the intervention was a positive experience. Also, all but one patient referred that the participation in the group would have a positive impact on their quality of life. CONCLUSIONS: Psychoeducational interventions appear to have had positive results in Argentinian patients with PNES. This is initial step in the design of empirically based psychoeducational/supportive initiatives for patients in South America.

Low temperature conversion of levulinic acid into γ-valerolactone using Zn to generate hydrogen from water and nickel catalysts supported on sepiolite.

In the present article, γ-valerolactone has been obtained from levulinic acid with a yield exceeding 25% using very mild conditions without feeding hydrogen (30 °C, atmospheric pressure, water as the hydrogen source). The overall reaction conducted is a two-step process: first, a redox reaction involving the oxidation of metallic Zn to ZnO for in situ hydrogen production through the water splitting reaction and, second, a catalytic reaction involving Ni-supported catalysts for the production of γ-valerolactone from levulinic acid. Ni active sites have been supported on sepiolite, an abundant and cheap material. The nickel particle size has been demonstrated to be a parameter of paramount importance determining the catalytic activity, since the best catalytic performance is obtained with the smallest Ni nanoparticles. This combination of Zn and Ni supported on sepiolite shows a good catalytic stability after three catalytic runs.

Clinical and Pathological Characterization of Lynch-Like Syndrome.

BACKGROUND & AIMS: Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. METHODS: We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. RESULTS: We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. CONCLUSIONS: Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC.

La experiencia de pacientes con crisis no epilépticas psicógenas: marcos interpretativos y de acción / A experiência de pacientes com crises não epiléticas psicogênicas: marcos interpretativos e de ação / The experience of patients with psychogenic non epileptic seizures: interpretative and action framework / L´expérience des patients atteints de crise psychogène non épileptique: cadres dinterprétation et daction

Resumen La perspectiva del paciente se presenta como algo importante a tener en cuenta para la comprensión del padecimiento y para lograr un tratamiento efectivo. El objetivo de la presente investigación es indagar las trayectorias terapéuticas y las experiencias durante el recorrido terapéutico de pacientes con Crisis No Epilépticas Psicógenas (CNEP) pertenecientes a un Hospital General de la Ciudad Autónoma de Buenos Aires. Se realizaron entrevistas semiestructuradas a diez pacientes diagnosticados con CNEP. Para el análisis de los datos se utilizó una metodología cualitativa basada en los principios del análisis temático. Se ha identificado una categoría central: Itinerarios terapéuticos dentro del sistema etnomédico y tres subcategorías: (1) Diagnósticos Recibidos; (2) Recursos del sistema etnomédico y (3) Evaluaciones de los recursos utilizados. La dificultad de arribar a un diagnóstico y un tratamiento que permitiera mejorar las CNEP, así como el uso de distintas medicinas, fue destacada por la totalidad de los pacientes.

Resumo A perspectiva do paciente se apresenta como algo importante a levar em conta para a compreensão do sofrimento e para se alcançar um tratamento eficaz. O objetivo desta pesquisa é investigar as trajetórias terapêuticas e as experiências durante a jornada terapêutica de pacientes com crise não epilética psicogênica (CNEP) de um Hospital Geral da Cidade Autônoma de Buenos Aires. Entrevistas semiestruturadas foram realizadas com dez pacientes com diagnóstico de CNEP. Para a análise dos dados, utilizou-se metodologia qualitativa baseada nos princípios da análise temática. Uma categoria central foi identificada: Itinerários terapêuticos dentro do sistema etnomédico; e três subcategorias: (1) Diagnósticos recebidos; (2) Recursos do sistema etnomédico; e (3) Avaliações dos recursos utilizados. A dificuldade de se chegar a um diagnóstico e a um tratamento que permitisse melhorar a CNEP, bem como o uso de diferentes medicamentos, foi destacada por todos os pacientes.

Abstract The patient's perspective is essential to understand their condition and to achieve an effective treatment. The objective of this paper is to investigate the therapeutic trajectories and experiences of patients with Psychogenic Non-Epileptic Crisis (PNES) under treatment in a General Hospital of the Autonomous City of Buenos Aires. Semi-structured interviews were conducted with ten patients diagnosed with PNES. For data analysis, a qualitative methodology based on thematic analysis was adopted. A central category has been identified: Therapeutic Itineraries within the Ethnomedical System, and three subcategories: (1) Diagnoses received; (2) Resources of the ethnomedical system; and (3) Evaluation of the resources used. The difficulty of finding a diagnosis, a treatment to improve PNES, and proper medicine were highlighted by all the patients.

Résumé Le point de vue du patient est présenté comme quelque chose d'important à prendre en compte afin de comprendre la maladie et d'obtenir un traitement efficace. L'objectif de cette recherche est d'analyser les trajectoires thérapeutiques et les expériences au cours du parcours thérapeutique des patients atteints de Crise Psychogénique Non Épileptique (CPNE) dans un hôpital général de la ville de Buenos Aires. Des entretiens semi-structurés ont été menés auprès de 10 patients diagnostiqués avec une CPNE. Pour l'analyse des données, une méthodologie qualitative basée sur les principes de l'analyse thématique a été utilisée. Une catégorie centrale a été identifiée : Les itinéraires thérapeutiques au sein du système ethno-médical et trois sous-catégories : (1) Diagnostics reçus ; (2) Ressources du système ethno-médical ; et (3) Évaluations des ressources utilisées. La difficulté d'arriver à un diagnostic et à un traitement permettant d'améliorer la CPNE, ainsi que l'utilisation de médicaments différents, a été soulignée par l'ensemble des patients.

Evaluación y perspectiva de 20 años de cribado neonatal en Galicia. Resultados del programa / Evaluation and perspective of 20 years of neonatal screening in Galicia. Program results

El Programa Gallego para la Detección Precoz de Enfermedades Endocrinas y Metabólicas se inició en 1978 y fue pionero en España en el cribado neonatal ampliado con la incorporación de la espectrometría de masas en julio de 2000. Como objetivo primario se criban veintiocho enfermedades, incluyendo las de la cartera básica del Servicio Nacional de Salud excepto la anemia de células falciformes, que está en fase de inclusión. En sus veinte años de trayectoria se analizaron 404.616 recién nacidos (RN), identificando 547 casos afectos de las enfermedades incluidas, con una incidencia global de 1:739 RN vivos y de 1:1.237 RN de las enfermedades metabólicas congénitas (EMC) cribadas (1:1.580 RN excluyendo la hiperfenilalaninemia benigna-HPA), con una participación media del 99,35%, progresivamente creciente durante el período analizado. Entre las patologías cribadas destacan por su incidencia el hipotirodismo congénito (1:2.211 RN), la cistinuria (1:4.129 RN) y la HPA (1:5.699 RN), seguida de fenilcetonuria y fibrosis quística (1:10.936 RN). Se identificaron sesenta y seis casos de falsos positivos (diecisiete de los mismos en relación con patología materna) y cinco falsos negativos, siendo el VPP (valor predictivo positivo) y el VPN (valor predictivo negativo) global del programa del 89,2% y 99,99%, respectivamente, con una sensibilidad de 99,09% y una especificidad del 99,98%. La tasa de mortalidad de los pacientes con EMC diagnosticados fue del 1,52%, presentando once casos sintomatología previa al resultado del cribado (2%). El cociente intelectual de los pacientes con EMC y riesgo de afectación neurológica es normal en más del 95% de los casos

Galician newborn screening program for early detection of endocrine and metabolic diseases began in 1978 and was a pioneer in expanded newborn screening in Spain with the incorporation of mass spectrometry in July 2000. As a primary objective, 28 diseases are screened, including those recommended SNS except sickle cell anemia which is in the inclusion phase. In its 20-year history, 404,616 newborns (nb) have been analyzed, identifying 547 cases affected by the diseases included, with a global incidence of 1: 739 newborns and 1: 1.237 of the screened inborn errors of metabolism (IEM) (1:1.580 nb if excluding benign hyperphenylalaninemia-HPA), with an average participation of 99.35%, progressively higher during the analyzed period. Among the pathologies screened, congenital hypothyroidism (1:2.211 nb), cystinuria (1:4.129 nb) and HPA (1:5.699 nb), followed by phenylketonuria and cystic fibrosis (1:10,936 nb) stand out for their incidence. Sixty-six cases of false positives were identified (seventeen of them in relation to maternal pathology) and five false negatives, being the overall PPV and NPV of the program respectively of 89.2% and 99.99%, with a sensitivity of 99.09% and a specificity of 99.98%. The mortality rate of diagnosed CME patients is 1.52%, with eleven cases presenting symptoms prior to the screening result (2%). The intelligence quotient of IEM patients at risk of neurological involvement is normal in more than 95% of cases