Tumour brain: pre‐treatment cognitive and affective disorders caused by peripheral cancers

People that develop extracranial cancers often display co-morbid neurological disorders, such as anxiety, depression and cognitive impairment, even before commencement of chemotherapy. This suggests bidirectional crosstalk between non-CNS tumours and the brain, which can regulate peripheral tumour growth. However, the reciprocal neurological effects of tumour progression on brain homeostasis are not well understood. Here, we review brain regions involved in regulating peripheral tumour development and how they, in turn, are adversely affected by advancing tumour burden. Tumour-induced activation of the immune system, blood–brain barrier breakdown and chronic neuroinflammation can lead to circadian rhythm dysfunction, sleep disturbances, aberrant glucocorticoid production, decreased hippocampal neurogenesis and dysregulation of neural network activity, resulting in depression and memory impairments. Given that cancer-related cognitive impairment diminishes patient quality of life, reduces adherence to chemotherapy and worsens cancer prognosis, it is essential that more research is focused at understanding how peripheral tumours affect brain homeostasis

Characterization of microsatellite markers in peach [Prunus persica (L.) Batsch]

Microsatellites have emerged as an important system of molecular markers. We evaluated the potential of microsatellites for use in genetic studies of peach [Prunus persica (L.) Batsch]. Microsatellite loci in peach were identified by screening a pUC8 genomic library, a λZAPII leaf cDNA library, as well as through database searches. Primer sequences for the microsatellite loci were tested from the related Rosaceae species apple (Malus×domestica) and sour cherry (Prunus cerasus L.). The genomic library was screened for CT, CA and AGG repeats, while the cDNA library was screened for (CT)n- and (CA)n-containing clones. Estimates of microsatellite frequencies were determined from the genomic library screening, and indicate that CT repeats occur every 100 kb, CA repeats every 420 kb, and AGG repeats every 700 kb in the peach genome. Microsatellite- containing clones were sequenced, and specific PCR primers were designed to amplify the microsatellite- containing regions from genomic DNA. The level of microsatellite polymorphism was evaluated among 28 scion peach cultivars which displayed one to four alleles per primer pair. Five microsatellites were found to segregate in intraspecific peach-mapping crosses. In addition, these microsatellite markers were tested for their utility in cross-species amplification for use in comparative mapping both within the Rosaceae, and with the un- related species Arabidopsis thaliana L

Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia

none40The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.noneYap Z.Y.; Efthymiou S.; Seiffert S.; Vargas Parra K.; Lee S.; Nasca A.; Maroofian R.; Schrauwen I.; Pendziwiat M.; Jung S.; Bhoj E.; Striano P.; Mankad K.; Vona B.; Cuddapah S.; Wagner A.; Alvi J.R.; Davoudi-Dehaghani E.; Fallah M.-S.; Gannavarapu S.; Lamperti C.; Legati A.; Murtaza B.N.; Nadeem M.S.; Rehman M.U.; Saeidi K.; Salpietro V.; von Spiczak S.; Sandoval A.; Zeinali S.; Zeviani M.; Reich A.; Jang C.; Helbig I.; Barakat T.S.; Ghezzi D.; Leal S.M.; Weber Y.; Houlden H.; Yoon W.H.Yap, Z. Y.; Efthymiou, S.; Seiffert, S.; Vargas Parra, K.; Lee, S.; Nasca, A.; Maroofian, R.; Schrauwen, I.; Pendziwiat, M.; Jung, S.; Bhoj, E.; Striano, P.; Mankad, K.; Vona, B.; Cuddapah, S.; Wagner, A.; Alvi, J. R.; Davoudi-Dehaghani, E.; Fallah, M. -S.; Gannavarapu, S.; Lamperti, C.; Legati, A.; Murtaza, B. N.; Nadeem, M. S.; Rehman, M. U.; Saeidi, K.; Salpietro, V.; von Spiczak, S.; Sandoval, A.; Zeinali, S.; Zeviani, M.; Reich, A.; Jang, C.; Helbig, I.; Barakat, T. S.; Ghezzi, D.; Leal, S. M.; Weber, Y.; Houlden, H.; Yoon, W. H

A prospective multicenter study evaluating EUS and ERCP competence during advanced endoscopy training and subsequent independent practice: The rapid assessment of trainee endoscopy skills (rates2) study.

Background: We have shown that AETs achieve EUS and ERCP competence at varying rates, validating the shift from defining competence based on an absolute number of procedures to well-defined metrics. However, there are no data to confirm that advanced endoscopy trainees (AETs) who achieve competence during training subsequently perform high quality EUS and ERCP in their 1st year of independent practice. Aims: To report the outcomes of AETs during their 1st year of independent practice using ASGE established quality indicator (QI) thresholds To measure the relationship between achieving competence benchmarks during training and reported outcomes during independent practice. Methods: ASGE recognized advanced endoscopy training programs (AETPs) were invited to participate. In Phase I, AETs were graded on every 5th EUS and ERCP exam after completion of 25 hands-on EUS and ERCPs using the validated EUS and ERCP Skills Assessment Tool (TEESAT). Grading for each skill was done using a 4-point scoring system. A comprehensive data collection and reporting system was used to create learning curves using cumulative sum (CUSUM) analysis. Learning curves were created using CUSUM for overall and technical and cognitive components of EUS and ERCP and shared with AETs and trainers quarterly. Acceptable and unacceptable (Table presented) failures rates were set a priori and AETs with \u3c20 evaluations were excluded. During Phase II, AETs provided QI performance data on all EUS and ERCP procedures during the 1st year of independent practice. Results: Of the 62 programs invited, 37 AETs from 32 AETPs participated in this study and 24 AETs were included in the final analysis (Phase I). At the end of training, median number of EUS and ERCPs performed/ AET was 400 (range 200-750) and 361 (250-650), respectively. Overall, 2616 exams were graded (EUS: 1277, ERCP-biliary 1143, pancreatic 196). Majority of graded EUS exams were performed for pancreatobiliary indications (70%) and ERCPs for ASGE biliary grade of difficulty 1 (72.1%). Majority of trainees achieved overall technical (EUS: 91.6%; ERCP: 73.9%) and cognitive (EUS: 91.6%, ERCP: 95.6%) competence at conclusion of training (Table 1). 22 of 24 AETs participated in (Phase II) and median EUS and ERCP procedures completed in independent practice/AET were 136 (IQR 102-204) and 116 (48-169), respectively. Table 2 highlights QI performance in EUS and ERCP during Phase II. Majority of AETs crossed the QI threshold for obtaining adequate samples (overall rate: 94.4%), diagnostic yield of malignancy (83.8%), and cannulation rates overall (94.9%) and native papilla cases (93.1%). Conclusions: Majority of AETs achieved EUS and ERCP competence by the end of training. Moreover, these AETs achieved QI thresholds for routine EUS and ERCP during their 1st year of independent practice, affirming the effectiveness of AETPs

Setting minimum standards for training in EUS and ERCP: Results from a prospective multicenter study evaluating learning curves and competence among advanced endoscopy trainees (AETS).

Background: Despite the dramatic increase in advanced endoscopy training programs (AETPs), there is no fixed mandatory curriculum and minimal standards as to what constitutes a “high quality” AETP has not been defined. Understanding the mean number of procedures required to achieve competence in all aspects of EUS and ERCP would help structure AETPs. Aims: To define the mean number of procedures required by an “average” AET to achieve competence in technical and cognitive EUS and ERCP tasks. Methods: ASGE recognized AETPs were invited and AETs were graded on every 5th EUS and ERCP exam after completion of 25 hands-on EUS and ERCP exams using the validated EUS and ERCP Skills Assessment Tool (TEESAT). Grading for each skill was done using a 4-point scoring system. A comprehensive data collection and reporting system was used to create learning curves (LCs) using cumulative sum (CUSUM) analysis for overall and technical and cognitive components of EUS and ERCP and shared with AETs and trainers quarterly. Acceptable and unacceptable failures rates were set a priori. In order to generate aggregate CUSUM LCs across AETs, we used generalized linear mixed effects models with a random intercept for each AET and an AR1 covariance structure. This allowed us to use data from all AETs to estimate the average learning experience for trainees with 95% CIs. We then fit a spline to the modeled estimates with knots at 40 and 80 evaluations to smooth the results and estimate the mean number of procedures needed to achieve competence. Results: Of the 62 AETPs invited, 37 AETs from 32 AETPs participated in this study; 24 AETs were included in the final analysis. Prior to AETP, 52% reported hands-on EUS (median 20 cases) and 68% hands-on ERCP (median 50 cases) experience prior to AETP. At the end of training, median number of EUS and ERCPs performed/AET was 400 (range 200-750) and 361 (250-650), respectively. Overall, 2616 exams were graded (EUS: 1277, ERCP-biliary 1143, pancreatic 196). Majority of graded EUS exams were performed for pancreatobiliary indications (69.9%) and ERCP exams for ASGE biliary grade of difficulty 1 (72.1%). Table 1 highlights the substantial variability in EUS and ERCP learning curves. The majority of trainees achieved overall technical (EUS: 91.7%; ERCP: 73.9%) and cognitive (EUS: 91.7%, ERCP: 95.7%) competence at the end of training. Table 1 and Figure highlight the number of procedures required by an average AET to achieve competence in all aspects of EUS and ERCP. Conclusions: The results of this study confirm the substantial variability in achieving competence in EUS and ERCP. The thresholds provided for an average AET to achieve competence in EUS (w225 cases) and ERCP (w250) may be used by ASGE and AETPs in establishing the minimal standards for case volume exposure for AETs during their training