Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Precise Measurement of Differential Cross Sections of the Σ

The differential cross sections of the Σ^{-}p→Λn reaction were measured accurately for the Σ^{-} momentum (p_{Σ}) ranging from 470 to 650 MeV/c at the J-PARC Hadron Experimental Facility. Precise angular information about the Σ^{-}p→Λn reaction was obtained for the first time by detecting approximately 100 reaction events at each angular step of Δcosθ=0.1. The obtained differential cross sections show a slightly forward-peaking structure in the measured momentum regions. The cross sections integrated for -0.7≤cosθ≤1.0 were obtained as 22.5±0.68 [statistical error(stat.)] ±0.65 [systematic error(syst.)] mb and 15.8±0.83(stat)±0.52(syst) mb for 470

Isolated posterior inferior cerebellar artery dissection with ischaemic stroke: evaluating the radiological features and diagnostic feasibility of high-resolution vessel wall imaging.

AIM: To evaluate the radiological features of isolated posterior inferior cerebellar artery dissection (PICAD) and the feasibility of using high-resolution vessel-wall imaging (HR-VWI) for diagnosing PICAD. MATERIALS AND METHODS: Three hundred and nine patients with arterial dissection involving the posterior cerebral circulation, who underwent HR-VWI between March 2012 and July 2019 were reviewed retrospectively. Among them, 44 patients (14.2%) were diagnosed with isolated PICAD in consensus among a neuroradiologist, a neurointerventionist, and a neurologist. Two neuroradiologists reviewed the vessel wall images independently for evidence of dissection (dissection flap, outer diameter enlargement on T2-weighted imaging [WI], mural haematoma). Diagnostic confidence was also scored on a five-point scale. Intra- and interobserver agreement for diagnosing PICAD and detecting evidence of dissection were evaluated. RESULTS: Dissection flaps were seen on T2WI in all cases (100%) and on contrast-enhanced T1WI in 34 patients (79.1%). Outer diameter enlargement of the steno-occlusive lesions on angiography was detected in most cases (97.7%). A mural haematoma was detected on three-dimensional (3D) contrast-enhanced motion-sensitised driven-equilibrium T1WI in 97.1% of the cases. The mean diagnostic confidence score derived by two neuroradiologists was 4.72. The two reviewers showed substantial to almost perfect agreement (weighted kappa coefficient: 0.62-0.97). CONCLUSION: Use of HR-VWI as a diagnostic tool for PICAD is feasible, and a dissection flap with outer wall enlargement on HR-T2WI allows confident dissection diagnosis. The present data suggest that PICAD might be considered as a stroke aetiology in patients with unexplained ischaemic stroke in the PICA territory, and that PICA evaluation with HR-VWI is both necessary and feasible.

Observation of Coulomb-Assisted Nuclear Bound State of Ξ

In an emulsion-counter hybrid experiment performed at J-PARC, a Ξ^{-} absorption event was observed which decayed into twin single-Λ hypernuclei. Kinematic calculations enabled a unique identification of the reaction process as Ξ^{-}+^{14}N→_{Λ}^{10}Be+_{Λ}^{5}He. For the binding energy of the Ξ^{-} hyperon in the Ξ^{-}-^{14}N system a value of 1.27±0.21 MeV was deduced. The energy level of Ξ^{-} is likely a nuclear 1p state which indicates a weak ΞN-ΛΛ coupling.

Potential anti-ageing effect of chondroitin sulphate through skin regeneration.

OBJECTIVE: Skin ageing is inevitably exposed through its typical features such as wrinkles and sagging. Therefore, skin anti-ageing is a major issue in cosmetic research to prevent and improve ageing symptoms using effective ingredients. Chondroitin sulphate (CS), a type of glycosaminoglycan, is an important structural component of the extracellular matrix (ECM) and is involved in various biological processes, such as cell proliferation, differentiation and migration. Here, we aimed to investigate the effects of CS on skin regeneration and examine its efficacy as a potential safe and effective skin anti-ageing ingredient. METHODS: We investigated the effects of CS on cell proliferation in normal human keratinocytes and fibroblasts. Then, cell migration, ECM synthesis and related signalling pathways were examined in fibroblasts through gene and protein expression analysis. Finally, the effect on skin wound healing and regeneration was validated using a full-thickness skin wound model and an aged skin model. RESULTS: Chondroitin sulphate treatment increased the proliferation of keratinocytes and fibroblasts. It also stimulated the migration and synthesis of ECM components of fibroblasts. Further analysis revealed that CS induced the expression of type I procollagen by activating the extracellular signal-regulated kinase pathway. Using a full-thickness skin wound model and an aged skin model, we confirmed that CS treatment promoted skin wound healing and regeneration. CONCLUSION: Together, our results indicated that CS has the potential to facilitate skin regeneration, implying that CS could be clinically applied to improve skin ageing.

OBJECTIF: Le vieillissement cutané est inévitable, dans ses caractéristiques intrinsèques nous trouvons l'apparition des rides et l'affaissement de la peau. Sachant cela, l'anti-âge cutané est un enjeu majeur de la recherche cosmétique où sa prévention ou son amélioration sont faites à l'aide d'ingrédients efficaces. Le sulfate de chondroïtine (CS), un type de glycosaminoglycane, est un composant structurel important de la matrice extracellulaire (ECM) et il est aussi impliqué dans les divers processus biologiques, tels que la prolifération, la différenciation et la migration cellulaire. Dans le travail présenté ici, nous avons étudié les effets du CS sur la régénération de la peau et son efficacité en tant qu'ingrédient anti-âge cutané sûr. MÉTHODES: Nous avons étudié les effets du CS sur la prolifération cellulaire des kératinocytes et fibroblastes humains normaux. Ensuite, la migration cellulaire, la synthèse de la ECM et les voies de signalisation associées ont été examinées dans les fibroblastes par l'analyse de l'expression des gènes et des protéines. Finalement, l'effet sur la cicatrisation et la régénération cutanées a été validé à l'aide d'un modèle de plaie cutanée « full thickness ¼ et d'un modèle de peau âgée. RÉSULTATS: Le traitement au sulfate de chondroïtine a augmenté la prolifération des kératinocytes et des fibroblastes. Il a également stimulé la migration et la synthèse des composants de la MEC des fibroblastes. Une analyse plus approfondie a démontré que CS induisait l'expression du procollagène du type I en activant la voie de la kinase régulée par le signal extracellulaire. En utilisant un modèle de plaie cutanée « full thickness ¼ et un modèle de peau âgée, nous avons confirmé que le traitement CS favorisait la cicatrisation et la régénération des blessures cutanées. CONCLUSION: Dans l'ensemble, nos résultats ont indiqué que le CS a le potentiel de faciliter la régénération de la peau, ce qui implique que le CS pourrait être appliqué cliniquement pour améliorer le vieillissement cutané.

Validation of a nomogram to predict the risk of cancer in patients with intraductal papillary mucinous neoplasm and main duct dilatation of 10 mm or less.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is premalignant pancreatic lesion. International guidelines offer limited predictors of individual risk. A nomogram to predict individual IPMN malignancy risk was released, with good diagnostic performance based on a large cohort of Asian patients with IPMN. The present study validated a nomogram to predict malignancy risk and invasiveness of IPMN using both Eastern and Western cohorts. METHODS: Clinicopathological and radiological data from patients who underwent pancreatic resection for IPMN at four centres each in Eastern and Western countries were collected. After excluding patients with missing data for at least one malignancy predictor in the nomogram (main pancreatic duct diameter, cyst size, presence of mural nodule, serum carcinoembryonic antigen and carbohydrate antigen (CA) 19-9 levels, and age). RESULTS: In total, data from 393 patients who fit the criteria were analysed, of whom 265 were from Eastern and 128 from Western institutions. Although mean age, sex, log value of serum CA19-9 level, tumour location, main duct diameter, cyst size and presence of mural nodule differed between the Korean/Japanese, Eastern and Western cohorts, rates of malignancy and invasive cancer did not differ significantly. Areas under the receiver operating characteristic (ROC) curve values for the nomogram predicting malignancy were 0·745 for Eastern, 0·856 for Western and 0·776 for combined cohorts; respective values for the nomogram predicting invasiveness were 0·736, 0·891 and 0·788. CONCLUSIONS: External validation of the nomogram showed good performance in predicting cancer in both Eastern and Western patients with IPMN lesions.

ANTECEDENTES: La neoplasia mucinosa papilar intraductal (intraductal papillary mucinous neoplasm, IPMN) es una lesión pancreática premaligna. Las guías internacionales incluyen un número limitado de factores predictivos de riesgo individual. Para predecir el riesgo individual de malignidad del IPMN se ha propuesto un nomograma con un buen rendimiento diagnóstico, basado en una gran cohorte de pacientes asiáticos con IPMN. Este estudio validó el nomograma para predecir el riesgo de cáncer y de invasión de la IPMN utilizando cohortes tanto orientales como occidentales. MÉTODOS: Se recogieron datos clínico-patológicos y radiológicos de pacientes en los que se realizó una resección de páncreas por IPMN en 4 centros en países orientales y en 4 centros de países occidentales. Se excluyeron los pacientes en los que en el nomograma faltaba ≥ 1 factor(es) predictivo(s) de malignidad (diámetro del conducto pancreático principal, tamaño del quiste, presencia de nódulo mural, niveles séricos de CEA y CA19-9, y edad). RESULTADOS: En total, se analizaron datos de 393 pacientes que cumplían con los criterios de inclusión, de los cuales 265 eran de centros orientales y 128 de centros occidentales. Aunque la edad media, el sexo, el valor logarítmico del nivel sérico de CA19-9, la localización del tumor, el diámetro del conducto principal, el tamaño del quiste y la presencia de un nódulo mural difirieron entre las cohortes de Corea/Japón y las cohortes oriental y occidental, las tasas de malignidad y de cáncer invasivo no fueron significativamente diferentes. Las áreas bajo la curva operativa del receptor (area under the receiver operating curve, AUC) que mostró el nomograma para predecir la malignidad fueron: cohorte oriental: 0,745; cohorte occidental: 0,856 y cohortes combinadas: 0,776; y para predecir la invasión tumoral fueron: cohorte oriental: 0,736; cohorte occidental: 0,891, y cohortes combinadas: 0,788. CONCLUSIÓN: La validación externa del nomograma mostró un buen rendimiento en la predicción de cáncer, tanto en pacientes orientales como occidentales con lesiones IPMN.

Favorable outcomes of culture-based Helicobacter pylori eradication therapy in a region with high antimicrobial resistance.

BACKGROUND: The eradication rate of Helicobacter pylori has declined, mainly due to antimicrobial resistance. To overcome resistance-associated treatment failure, the efficacy of culture-based, susceptibility-guided therapy was demonstrated as the first-line eradication therapy for H pylori infection. AIMS: To evaluate the efficacy of culture-based therapy as the first-line eradication therapy in regions with high levels of antimicrobial resistance. METHODS: Helicobacter pylori-positive patients without previous eradication treatment history were recommended to undergo culture to determine the minimal inhibitory concentration (MIC). If they consented, 7-day clarithromycin-containing PPI triple; 7-day esomeprazole, moxifloxacin, and amoxicillin (MEA) therapy; or 7- or 14-day esomeprazole, bismuth, metronidazole, and tetracycline (quadruple) therapy were administered based on the agar dilution-determined MIC. Eradication, treatment compliance, and adverse events were examined. RESULTS: In total, 74 patients were enrolled, and 69 patients completed the protocols. The overall resistance rates to amoxicillin, clarithromycin, metronidazole, and moxifloxacin were 6.7%, 31.0%, 41.8%, and 39.2%, respectively. The patients were allocated to the PPI triple (n = 50), MEA (n = 8) or quadruple (n = 16) therapy. The eradication rate in the intention-to-treat analysis was 93.1% (69 of 74 patients). The eradication rates in the per-protocol analysis were 100.0% (69 of 69 patients). Epigastric pain, nausea, and vomiting were less common than those of other empirical therapies. CONCLUSIONS: Culture-based, susceptibility-guided therapy is effective first-line eradication therapy, especially in regions with high levels of antimicrobial resistance.

Accuracy of the Childhood Autism Rating Scale: a systematic review and meta-analysis.

AIM: To assess the accuracy of the Childhood Autism Rating Scale (CARS) through systematic review and meta-analysis. METHOD: Studies that provided quantitative values for the reliability and validity for all versions of CARS were searched through MEDLINE, CINAHL, PsycINFO, Embase, and OpenDissertations. RESULTS: A total of 24 studies with 4433 participants were included in our analysis. Meta-analysis showed that the summary Cronbach's alpha regarding a team of physicians and psychologists or others subgroup, derived from six studies (952 participants), was considered to be acceptable at 0.90 (95% confidence interval, 0.87-0.92) with moderate heterogeneity. Analysis of two 'low risk of bias' studies on the criterion validity for CARS with a cut-off of 30 and DSM-IV resulted in sensitivity of 0.86 and 0.71 and specificity of 0.79 and 0.75. INTERPRETATION: Through the results of the current systematic review and meta-analysis, the internal consistency can be considered to be acceptable for a team of physicians and psychologists or others subgroup. In terms of the criterion validity, the sensitivity was thought to be acceptable although the specificity was not, suggesting that CARS should be used along with other confirmatory tools. WHAT THIS PAPER ADDS: The Childhood Autism Rating Scale can be considered as a supplementary diagnostic tool for autism spectrum disorder.

EXACTITUD DE LA ESCALA DE CALIFICACIÓN DE AUTISMO INFANTIL (CARS): UNA REVISIÓN SISTEMÁTICA Y METAANÁLISIS: OBJETIVO: Se evalúa la exactitud de la Escala de Calificación de Autismo Infantil (CARS) a través de revisión sistemática y metaanálisis. MÉTODO: Los estudios que proporcionaron valores cuantitativos para la confiabilidad y validez de todas las versiones de CARS fueron buscados a través de MEDLINE, CINAHL, PsycINFO, Embase y Open Dissertations. RESULTADOS: En nuestro análisis se incluyeron un total de 24 estudios con 4433 participantes. El metaanálisis mostró el resumen del alfa de Cronbach basado en datos de equipos de médicos y psicólogos u otros subgrupos, derivado de seis estudios (952 participantes), fue considerado aceptable en 0,90 (intervalo de confianza del 95%, 0,87 - 0,92) con moderada heterogeneidad. El análisis de dos estudios de «bajo riesgo de sesgo¼ sobre los criterios de validez para CARS con un corte de 30 y criterios de DSM-IV, mostró una sensibilidad de 0,86 y 0,71 y especificidad de 0,79 y 0,75. INTERPRETACIÓN: Los resultados de la revisión sistemática actual y el metaanálisis demostró que la consistencia interna de CARS puede considerarse aceptable cuando es utilizado por equipos de médicos y psicólogos u otros subgrupos. En cuanto a la validez de criterio, se considero que la sensibilidad era aceptable, aunque la especificidad no lo es, sugiriendo que CARS debería utilizarse junto con otras herramientas confirmatorias.

ACURÁCIA DA ESCALA DE PONTUAÇÃO DO AUTISMO NA INFÂNCIA (CHILDHOOD AUTISM RATING SCALE -CARS): UMA REVISÃO SISTEMÁTICA E METANÁLISE: OBJETIVO: Avaliar a acurácia da Escala de Pontuação do Autismo na Infância (Childhood Autism Rating Scale -CARS) por meio de revisão sistemática e metanálise. MÉTODO: Estudos que forneceram valores de confiabilidade e validade de todas as versões da CARS foram pesquisados por meio das bases MEDLINE, CINAHL, PsycINFO, Embase, e OpenDissertations. RESULTADOS: Um total de 24 estudos com 4433 participantes foram incluídos em nossa análise. A metanálise mostrou que o resumo do alfa de Cronbach para uma equipe de médicos e psicólogos ou outros subgrupos, derivado de seis estudos (952 participantes), foi considerado aceitável a 0,90 (intervalo de confiança a 95%, 0,87-0,92) com heterogeneidade moderada. Análise de dois estudos com "baixo risco de viés" sobre a validade de critério da CARS com valor de corte de 30 e DSM-IV resultou em sensibilidade de 0,86 e 0,71 e especificidade de 0,79 and 0,75. INTERPRETAÇÃO: Por meio dos resultados da presente revisão sistemática e metanálise, a consistência interna pode ser considerada aceitável para uma equipe de médicos e psicólogos ou outros subgrupos. Em termos de validade de critério, a sensibilidade foi considerada aceitável, embora a especificidade não tenha sido, sugerindo que a CARS deva ser usada juntamente com outros instrumentos confirmatórios.

Clinical Predictors for KRAS Codon 13 Mutations in Patients With Colorectal Cancer.

GOALS: This study sought to clarify sex differences in KRAS mutations and clinical predictors of KRAS 13 codon mutations. BACKGROUND: Sex differences in KRAS mutations and predictors for KRAS codon 13 mutations in colorectal cancer (CRC) are unclear. STUDY: Between October 2007 and May 2016, 328 patients underwent surgery for CRCs that were analyzed for KRAS mutations at a referral university hospital. Sex differences in the rates and distributions of KRAS mutations, and factors predictive of overall KRAS and KRAS codon 13 mutations were analyzed. RESULTS: KRAS mutations were significantly more common in women than men patients (46.0% vs. 34.4%, P<0.033). However, no sex differences were detected for KRAS mutations by codon subtypes (P=0.592). The Gly13Asp (GGC>GAC) point mutation was identified only within codon 13 in both sexes. For right-sided CRC, KRAS mutations were twice as frequent in men as in women (univariate analysis; P=0.016, multivariate analysis; P=0.019). High-plasma cholesterol level was an independent predictive factor of KRAS codon 13 mutations by univariate (odds ratio, 1.013; 95% confidence interval, 1.003-1.023) and multivariate analysis (odds ratio, 1.011; 95% confidence interval, 1.001-1.021). CONCLUSIONS: Sex differences may affect the presentation of KRAS mutations, as they were more frequently detected in women and in right-sided CRC in men. KRAS codon 13 mutations were significantly associated with high-plasma cholesterol. Further studies are needed on the clinical implications of this finding.

A comparison between McGrath MAC videolaryngoscopy and Macintosh laryngoscopy in children.

BACKGROUND: This prospective, randomised, controlled study was performed to evaluate the usefulness of the McGrath VL compared with Macintosh laryngoscopy in children with expected normal airway during endotracheal intubation, by comparing the time to intubation and difficulty of intubation. METHODS: Eighty-four patients aged 1-10 years who underwent endotracheal intubation for elective surgery were randomly assigned to the McGrath group (n = 42) or the Macintosh group (n = 42). Anaesthesia was induced with 2.5-3.0 mg/kg of propofol and sevoflurane 5-8 vol%. Orotracheal intubation was performed 2 min after injection of rocuronium 0.6 mg/kg with McGrath VL or Macintosh laryngoscope; the primary outcome was the time to intubation. The Cormack and Lehane glottic grade, intubation difficulty score (IDS), and success rate on intubation were assessed. Haemodynamic changes were also recorded. RESULTS: As the primary outcome, median time to intubation [interquartile range] did not differ between the McGrath group and the Macintosh group (25.0 [22.8-28.3] s vs. 26.0 [24.0-29.0] s, P = 0.301). The incidence of grade I glottic view was significantly higher in the McGrath group than in the Macintosh group (95% vs. 74%, P = 0.013). Median IDS was lower in the McGrath group than in the Macintosh group (0 [0-0] vs. 0 [0-1], P = 0.018). There were no significant differences in success rate on intubation or haemodynamics between the two groups. CONCLUSIONS: McGrath VL provides better laryngeal views and lower IDS but similar intubation times and success rates compared with the Macintosh laryngoscope in children with normal airway.

[Fitness to drive with cardiovascular diseases : Current guidelines of the German Federal Highway Research Institute]. / Kraftfahreignung bei Herzerkrankungen : Aktuelle Begutachtungsleitlinien der Bundesanstalt für Straßenwesen.

The general rules for participation in road traffic are specified in the German Driving License Regulations (FeV). The assessment of fitness to drive motor vehicles is, in addition to Annex 4 of the FeV, governed by the guidelines of the German Federal Highway Research Institute, which implements the requirements of the European Union in Germany. By anchoring the assessment guidelines on fitness to drive in the FeV (Annex 4) and the publication in the Traffic Journal, the guidelines have a normative character. On 28 December 2016 the 11th amendment of the FeV came into force with the newly revised Chapter 3.4 on "Cardiovascular diseases". For a physician there is a duty to inform the patient about the lack or loss of driving ability. This information must be documented. Taking into account the current state of knowledge, this article describes the preconditions as to when a person has limited or is permanently unfit to drive because of cardiac arrhythmia, for patients with implantable defibrillators, syncope, coronary heart disease, heart failure, cardiomyopathy, heart valve diseases and arterial hypertension.

Expression of DNA methylation-related proteins in metastatic breast cancer.

We aimed to investigate the expression of methylation-related proteins (5-meC and DNMT1) in the metastatic breast cancers of variable sites and its association with clinicopathologic factors. A total of 126 metastatic breast cancers (31 bone metastases, 36 brain metastases, 11 liver metastases, 48 lung metastases) were made into tissue microarray and immunohistochemical staining of ER, PR, HER-2, Ki-67, 5-meC, and DNMT1 were performed. Molecular classification was made on the basis of immunohistochemical staining result of ER, PR, HER-2, Ki-67; luminal A, luminal B, HER-2, triple negative breast cancer (TNBC). Methylation-related proteins were differentially expressed based on the metastatic sites. Tumoral and stromal 5-meC showed the lowest expression in the bone metastasis (P < 0.001), tumoral DNMT1 showed the least expression in bone metastasis and the highest expression in the brain metastasis (P < 0.001). Expression of DNMT1 was correlated with ER negativity (P = 0.004), PR negativity (P = 0.011), HER-2 positivity (P = 0.016), higher Ki-67 labeling indices (P = 0.016), and non-luminal A type (P = 0.017). DNMT1 positivity was associated with shorter overall survival in bone metastasis (P = 0.017) and lung metastasis (P = 0.028) by univariate analysis. In conclusion, methylation-related proteins differentially expressed according to the metastatic sites in metastatic breast cancer. Tumoral and stromal 5-meC showed the lowest expression in the bone metastasis. Tumoral DNMT1 expression was low in bone metastasis and highest in brain metastasis.

Genome-wide linkage disequilibrium and past effective population size in three Korean cattle breeds.

The routine collection and use of genomic data are useful for effectively managing breeding programs for endangered populations. Linkage disequilibrium (LD) using high-density DNA markers has been widely used to determine population structures and predict the genomic regions that are associated with economic traits in beef cattle. The extent of LD also provides information about historical events, including past effective population size (Ne ), and it allows inferences on the genetic diversity of breeds. The objective of this study was to estimate the LD and Ne in three Korean cattle breeds that are genetically similar but have different coat colors (Brown, Brindle and Jeju Black Hanwoo). Brindle and Jeju Black are endangered breeds with small populations, whereas Brown Hanwoo is the main breeding population in Korea. DNA samples from these cattle breeds were genotyped using the Illumina BovineSNP50 Bead Chip. We examined 13 cattle breeds, including European taurines, African taurines and indicines, and hybrids to compare their LD values. Brown Hanwoo consistently had the lowest mean LD compared to Jeju Black, Brindle and the other 13 cattle breeds (0.13, 0.19, 0.21 and 0.15-0.22 respectively). The high LD values of Brindle and Jeju Black contributed to small Ne values (53 and 60 respectively), which were distinct from that of Brown Hanwoo (531) for 11 generations ago. The differences in LD and Ne for each breed reflect the breeding strategy applied. The Ne for these endangered cattle breeds remain low; thus, effort is needed to bring them back to a sustainable tract.

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

Detection of Prostate Cancer: Quantitative Multiparametric MR Imaging Models Developed Using Registered Correlative Histopathology.

Purpose To develop multiparametric magnetic resonance (MR) imaging models to generate a quantitative, user-independent, voxel-wise composite biomarker score (CBS) for detection of prostate cancer by using coregistered correlative histopathologic results, and to compare performance of CBS-based detection with that of single quantitative MR imaging parameters. Materials and Methods Institutional review board approval and informed consent were obtained. Patients with a diagnosis of prostate cancer underwent multiparametric MR imaging before surgery for treatment. All MR imaging voxels in the prostate were classified as cancer or noncancer on the basis of coregistered histopathologic data. Predictive models were developed by using more than one quantitative MR imaging parameter to generate CBS maps. Model development and evaluation of quantitative MR imaging parameters and CBS were performed separately for the peripheral zone and the whole gland. Model accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC), and confidence intervals were calculated with the bootstrap procedure. The improvement in classification accuracy was evaluated by comparing the AUC for the multiparametric model and the single best-performing quantitative MR imaging parameter at the individual level and in aggregate. Results Quantitative T2, apparent diffusion coefficient (ADC), volume transfer constant (K(trans)), reflux rate constant (kep), and area under the gadolinium concentration curve at 90 seconds (AUGC90) were significantly different between cancer and noncancer voxels (P < .001), with ADC showing the best accuracy (peripheral zone AUC, 0.82; whole gland AUC, 0.74). Four-parameter models demonstrated the best performance in both the peripheral zone (AUC, 0.85; P = .010 vs ADC alone) and whole gland (AUC, 0.77; P = .043 vs ADC alone). Individual-level analysis showed statistically significant improvement in AUC in 82% (23 of 28) and 71% (24 of 34) of patients with peripheral-zone and whole-gland models, respectively, compared with ADC alone. Model-based CBS maps for cancer detection showed improved visualization of cancer location and extent. Conclusion Quantitative multiparametric MR imaging models developed by using coregistered correlative histopathologic data yielded a voxel-wise CBS that outperformed single quantitative MR imaging parameters for detection of prostate cancer, especially when the models were assessed at the individual level. (©) RSNA, 2016 Online supplemental material is available for this article.

Disruption of effective connectivity from the dorsolateral prefrontal cortex to the orbitofrontal cortex by negative emotional distraction in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) has been associated with abnormal cognitive and emotional functions and these dysfunctions may be dependent on the disruption of dynamic interactions within neuronal circuits associated with emotion regulation. Although several studies have shown the aberrant cognitive-affective processing in OCD patients, little is known about how to characterize effective connectivity of the disrupted neural interactions. In the present study, we applied effective connectivity analysis using dynamic causal modeling to explore the disturbed neural interactions in OCD patients. METHOD: A total of 20 patients and 21 matched healthy controls performed a delayed-response working memory task under emotional or non-emotional distraction while undergoing functional magnetic resonance imaging. RESULTS: During the delay interval under negative emotional distraction, both groups showed similar patterns of activations in the amygdala. However, under negative emotional distraction, the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) exhibited significant differences between groups. Bayesian model averaging indicated that the connection from the DLPFC to the OFC was negatively modulated by negative emotional distraction in patients, when compared with healthy controls (p < 0.05, Bonferroni-corrected). CONCLUSIONS: Exaggerated recruitment of the DLPFC may induce the reduction of top-down prefrontal control input over the OFC, leading to abnormal cortico-cortical interaction. This disrupted cortico-cortical interaction under negative emotional distraction may be responsible for dysfunctions of cognitive and emotional processing in OCD patients and may be a component of the pathophysiology associated with OCD.

The impacts of larval density and protease inhibition on feeding in medicinal larvae of the greenbottle fly Lucilia sericata.

Larval therapy, the therapeutic use of blowfly larvae to treat chronic wounds, is primarily used in debridement. There are, however, gaps in current knowledge of the optimal clinical application of the therapy and mechanisms of action in the debridement process. Using an artificial assay, two studies were undertaken to investigate these aspects of larval debridement by Lucilia sericata Meigen (Diptera: Calliphoridae); the first studied the effects of the density of larvae on tissue digestion and larval mass, and the second considered the effects on the same parameters of incorporating protease inhibitors into the feeding substrate. The total mass of tissue digested increased with larval density until saturation was observed at 5.0-7.5 larvae/cm(2) . This range was considered optimal as lower doses resulted in the removal of less tissue and higher doses offered no additional tissue removal and appeared to exacerbate competition for feeding. In the second study, increased protease inhibitor concentration led to significant decreases in tissue digestion and larval mass, suggesting that serine proteases, particularly trypsin, may play major roles in larval digestion. Such information is important in elucidating the main constituents that make up larval digestive products and may be significant in the development of new therapies.

Epigenetic regulation of miR-302 by JMJD1C inhibits neural differentiation of human embryonic stem cells.

It has been recently reported that the regulatory circuitry formed by OCT4, miR-302, and NR2F2 controls both pluripotency and neural differentiation of human embryonic stem cells (hESCs). We show here that JMJD1C, a histone 3 lysine 9 (H3K9) demethylase expressed in hESCs, directly interacts with this circuitry. hESCs with stable knockdown of JMJD1C remain pluripotent while having reduced miR-302 expression, decreased BMP signaling, and enhanced TGFß signaling. JMJD1C binds to the miR-302 promoter and reduces H3K9 methylation. Withdrawal of basic fibroblast growth factor (bFGF) from the culture induces neural differentiation of the knockdown, but not the control, cells within 3 days, accompanied by elevated NR2F2 expression. This can be attenuated with miR-302 mimics or an H3K9 methytransferase inhibitor. Together, our findings suggest that JMJD1C represses neural differentiation of hESCs at least partially by epigenetically sustaining miR-302 expression and that JMJD1C knockdown is sufficient to trigger neural differentiation upon withdrawal of exogenous bFGF.

Portal vein patency after pancreatoduodenectomy for periampullary cancer.

BACKGROUND: The fate of the portal vein (PV) after pancreatoduodenectomy, especially its long-term patency and associated complications, has received little attention. The aim of this study was to explore the long-term patency rate of the PV after pancreatoduodenectomy, focusing on risk factors for PV stenosis/occlusion and associated complications. METHODS: Serial CT images of patients who underwent pancreatoduodenectomy for periampullary cancer between January 2000 and June 2012 in a single institution were evaluated for PV stenosis or occlusion. RESULTS: A total of 826 patients were enrolled. The PV stenosis/occlusion rate after pancreatoduodenectomy was 19.6 per cent and the 5-year patency rate 69.9 per cent. The most frequent cause of PV stenosis/occlusion was local recurrence followed by postoperative change and PV thrombosis. Patients who underwent PV resection had a higher PV stenosis/occlusion rate than those who did not (51 versus 17.4 per cent; P < 0.001). The 3-year patency rate was highest in patients with cancer of the ampulla of Vater and lowest in patients with pancreatic cancer (91.9 versus 55.5 per cent respectively; P < 0.001). Multivariable analysis showed that risk factors for PV stenosis/occlusion included primary tumour location, chemoradiotherapy and PV resection. PV stenosis or occlusion without disease recurrence was observed in 17.3 per cent of the patients. PV resection and grade B or C pancreatic fistula were independent risk factors for PV stenosis/occlusion. Among 162 patients with PV stenosis or occlusion, five (3.1 per cent) had fatal recurrent gastrointestinal bleeding. CONCLUSION: PV stenosis or occlusion is common after pancreatoduodenectomy, particularly if the PV has been resected and/or chemoradiotherapy was given after surgery. Although recurrence is the most frequent cause of PV stenosis/occlusion, this complication is found in a significant proportion of patients without disease recurrence.

Conservation of an RNA regulatory map between Drosophila and mammals.

Alternative splicing is generally controlled by proteins that bind directly to regulatory sequence elements and either activate or repress splicing of adjacent splice sites in a target pre-mRNA. Here, we have combined RNAi and mRNA-seq to identify exons that are regulated by Pasilla (PS), the Drosophila melanogaster ortholog of mammalian NOVA1 and NOVA2. We identified 405 splicing events in 323 genes that are significantly affected upon depletion of ps, many of which were annotated as being constitutively spliced. The sequence regions upstream and within PS-repressed exons and downstream from PS-activated exons are enriched for YCAY repeats, and these are consistent with the location of these motifs near NOVA-regulated exons in mammals. Thus, the RNA regulatory map of PS and NOVA1/2 is highly conserved between insects and mammals despite the fact that the target gene orthologs regulated by PS and NOVA1/2 are almost entirely nonoverlapping. This observation suggests that the regulatory codes of individual RNA binding proteins may be nearly immutable, yet the regulatory modules controlled by these proteins are highly evolvable.