Early Visual Processing in Autism Spectrum Disorder as Assessed by Visual Evoked Potentials

Understanding early visual processing and the integrity of the visual pathways in Autism Spectrum Disorder (ASD) could help to develop a potential neuromarker. If these early stages of visual perception are compromised it could be impacting higher cognitive abilities that are necessary for social perception. For example, atypical visual behaviors such as poor eye gaze, difficulty with facial expression, and difficulty processing motion have been highly documented in social and nonsocial domains in ASD. These symptoms have been linked to abnormal sensory processing suggesting possible impairments in the magnocellular visual pathway (M-pathway). To assess early visual processing and the integrity of the visual pathways we used achromatic pattern-reversal along with a motion-onset and offset stimuli in children and adolescents with and without a diagnosis of ASD. Visual-evoked potentials (VEPs) were used to investigate early visual processing in adolescents with ASD compared to neurotypicals (NTs). For pattern-reversal, we used a black-and-white checkerboard with two different sizes (1° and 0.25°) and four different contrast levels (0.025 contrast, 0.05 contrast, 0.1 contrast, and 0.98 contrast). To study motion-onset and offset we used an expanding and contracting ‘dartboard.’ These stimuli were displayed to a total of seven male ASD and eight male NT subjects, ranging in age from 10-15 years old. VEPs were recorded on the scalp midline over the occipital (Oz) and parietal (Pz) cortices. For pattern-reversal, we examined the negative component N75, and the positive component P100. For motion-onset and motion-offset, we explored the positive component P100 and the negative component N135. VEPs responses were analyzed using measures of peak latency, peak amplitude, mean amplitude, and fractional area latency. Our results point to a disruption of the M-pathway where the ASD subjects often showed hyper-responsiveness to lower contrast stimuli presented at the largest check size. Individual waveforms in ASD subjects were variable, and may not be useful as a reliable early neuromarker. Some measures of the VEP seem to be related to symptom severity as assessed by the GARS-2, although these results never reached significance. For motion-onset, the ASD group presented larger amplitudes for the components P100 and N135 at electrode size Oz. Alterations to early visual processing in the ASD group suggest specific difficulties in the magnocellular system which could be causing a cascade of symptoms that impairs social communication. Although individual waveform variability limits the use of VEPs as a neuromarker, there is some potential relationship to symptom severity that deserves further study

Appendiceal Adenocarcinoma PDX Models Have Improved Tumor Growth in an Orthotopic Tumor Environment

https://openworks.mdanderson.org/sumexp23/1085/thumbnail.jp

Intraperitoneal Paclitaxel Is a Safe and Effective Therapeutic Strategy for Treating Mucinous Appendiceal Adenocarcinoma

Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given the localization of AA to the peritoneal space, intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here, we tested the efficacy of paclitaxel given by IP administration using three orthotopic patient-derived xenograft (PDX) models of AA established in immunodeficient NSG mice. Weekly IP paclitaxel treatment dramatically reduced AA tumor growth in all three PDX models. Comparing the safety and efficacy of intravenous (IV) to IP administration, IP delivery of paclitaxel was more effective with reduced systemic side effects in mice. Given the established safety record of IP paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of IP paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of IP paclitaxel in a prospective clinical trial

Systematic Association Mapping Identifies NELL1 as a Novel IBD Disease Gene

Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p<10−6; OR = 1.66, 95% CI: 1.30–2.11). The novel 5p13.1 locus was also replicated in the French/Canadian sample and in an independent UK CD patient panel (453 cases, 521 controls, combined p<10−6 for SNP rs1992660). Several associations were replicated in at least one independent sample, point to an involvement of ITGB6 (upstream), GRM8 (downstream), OR5V1 (downstream), PPP3R2 (downstream), NM_152575 (upstream) and HNF4G (intron)

Analysis of applying a patient safety taxonomy to patient and clinician-reported incident reports during the COVID-19 pandemic: a mixed methods study

Background: The COVID-19 pandemic resulted in major disruption to healthcare delivery worldwide causing medical services to adapt their standard practices. Learning how these adaptations result in unintended patient harm is essential to mitigate against future incidents. Incident reporting and learning system data can be used to identify areas to improve patient safety. A classification system is required to make sense of such data to identify learning and priorities for further in-depth investigation. The Patient Safety (PISA) classification system was created for this purpose, but it is not known if classification systems are sufficient to capture novel safety concepts arising from crises like the pandemic. We aimed to review the application of the PISA classification system during the COVID-19 pandemic to appraise whether modifications were required to maintain its meaningful use for the pandemic context. Methods: We conducted a mixed-methods study integrating two phases in an exploratory, sequential design. This included a comparative secondary analysis of patient safety incident reports from two studies conducted during the first wave of the pandemic, where we coded patient-reported incidents from the UK and clinician-reported incidents from France. The findings were presented to a focus group of experts in classification systems and patient safety, and a thematic analysis was conducted on the resultant transcript. Results: We identified five key themes derived from the data analysis and expert group discussion. These included capitalising on the unique perspective of safety concerns from different groups, that existing frameworks do identify priority areas to investigate further, the objectives of a study shape the data interpretation, the pandemic spotlighted long-standing patient concerns, and the time period in which data are collected offers valuable context to aid explanation. The group consensus was that no COVID-19-specific codes were warranted, and the PISA classification system was fit for purpose. Conclusions: We have scrutinised the meaningful use of the PISA classification system’s application during a period of systemic healthcare constraint, the COVID-19 pandemic. Despite these constraints, we found the framework can be successfully applied to incident reports to enable deductive analysis, identify areas for further enquiry and thus support organisational learning. No new or amended codes were warranted. Organisations and investigators can use our findings when reviewing their own classification systems

The Dynamin Chemical Inhibitor Dynasore Impairs Cholesterol Trafficking and Sterol-Sensitive Genes Transcription in Human HeLa Cells and Macrophages

Intracellular transport of cholesterol contributes to the regulation of cellular cholesterol homeostasis by mechanisms that are yet poorly defined. In this study, we characterized the impact of dynasore, a recently described drug that specifically inhibits the enzymatic activity of dynamin, a GTPase regulating receptor endocytosis and cholesterol trafficking. Dynasore strongly inhibited the uptake of low-density lipoprotein (LDL) in HeLa cells, and to a lower extent in human macrophages. In both cell types, dynasore treatment led to the abnormal accumulation of LDL and free cholesterol (FC) within the endolysosomal network. The measure of cholesterol esters (CE) further showed that the delivery of regulatory cholesterol to the endoplasmic reticulum (ER) was deficient. This resulted in the inhibition of the transcriptional control of the three major sterol-sensitive genes, sterol-regulatory element binding protein 2 (SREBP-2), 3-hydroxy-3-methyl-coenzymeA reductase (HMGCoAR), and low-density lipoprotein receptor (LDLR). The sequestration of cholesterol in the endolysosomal compartment impaired both the active and passive cholesterol efflux in HMDM. Our data further illustrate the importance of membrane trafficking in cholesterol homeostasis and validate dynasore as a new pharmacological tool to study the intracellular transport of cholesterol