Kismet/CHD7/CHD8 affects gut microbiota, mechanics, and the gut-brain axis in Drosophila melanogaster.

The gut microbiome affects brain and neuronal development and may contribute to the pathophysiology of neurodevelopmental disorders. However, it is unclear how risk genes associated with such disorders affect gut physiology in a manner that could impact microbial colonization and how the mechanical properties of the gut tissue might play a role in gut-brain bidirectional communication. To address this, we used Drosophila melanogaster with a null mutation in the gene kismet, an ortholog of chromodomain helicase DNA-binding protein (CHD) family members CHD7 and CHD8. In humans, these are risk genes for neurodevelopmental disorders with co-occurring gastrointestinal symptoms. We found that kismet mutant flies have a significant increase in gastrointestinal transit time, indicating the functional homology of kismet with CHD7/CHD8 in vertebrates. Rheological characterization of dissected gut tissue revealed significant changes in the mechanics of kismet mutant gut elasticity, strain stiffening behavior, and tensile strength. Using 16S rRNA metagenomic sequencing, we also found that kismet mutants have reduced diversity and abundance of gut microbiota at every taxonomic level. To investigate the connection between the gut microbiome and behavior, we depleted gut microbiota in kismet mutant and control flies and quantified the flies' courtship behavior. Depletion of gut microbiota rescued courtship defects of kismet mutant flies, indicating a connection between gut microbiota and behavior. In striking contrast, depletion of the gut microbiome in the control strain reduced courtship activity, demonstrating that antibiotic treatment can have differential impacts on behavior and may depend on the status of microbial dysbiosis in the gut prior to depletion. We propose that Kismet influences multiple gastrointestinal phenotypes that contribute to the gut-microbiome-brain axis to influence behavior. We also suggest that gut tissue mechanics should be considered as an element in the gut-brain communication loop, both influenced by and potentially influencing the gut microbiome and neurodevelopment.

The Severity of Reduced Esophageal Distensibility Parallels Eosinophilic Esophagitis Disease Duration.

BACKGROUND & AIMS: Chronic inflammation of eosinophilic esophagitis (EoE) results in progressive, fibrostenotic remodeling of the esophageal wall. This study aimed to demonstrate objective changes in esophageal distensibility relative to duration of EoE disease using a functional lumen imaging probe (FLIP). METHODS: Adult patients with EoE who completed a 16-cm FLIP protocol during endoscopy were evaluated in a cross-sectional study. FLIP analysis focused on distensibility plateau (DP) of the esophageal body. The time from onset of symptoms to time of endoscopy with FLIP was assessed, as was time from symptom onset to EoE diagnosis (ie, diagnostic delay). RESULTS: A total of 171 patients (mean age 38 ± 12 years; 31% female) were included; the median symptom duration was 8 (interquartile range, 3-15) years and diagnostic delay was 4 (interquartile range, 1-12) years. At the time of endoscopy with FLIP, there were 54 patients (39%) in histologic remission (<15 eosinophils per high-power field [eos/hpf]). Symptom duration and diagnostic delay were negatively correlated with DP (rho = -0.326 and -0.309; P values < .001). Abnormal esophageal distensibility (DP ≤17 mm) was more prevalent with increased duration of symptoms (P < .004): 23% at <5 years to 64% at ≥25 years. When stratifying the cohort based on mucosal eosinophil density, patients with ≥15 eos/hpf had significantly lower DP with greater symptom duration (P = .004), while there was not a significant difference among patients with <15 eos/hpf (P = .060). CONCLUSIONS: Esophageal distensibility objectively measured with FLIP was reduced in EoE patients with greater symptom duration and diagnostic delay. This supports that EoE is a progressive, fibrostenotic disease and that FLIP may be a useful tool to monitor disease progression in EoE.

Esophageal Dysmotility Is Associated With Disease Severity in Eosinophilic Esophagitis.

BACKGROUND & AIMS: An association of eosinophilic esophagitis (EoE) with esophageal dysmotility has been described, however, the related mechanism remains unclear. We aimed to evaluate clinical and physiologic characteristics, including esophageal distensibility, associated with secondary peristalsis in patients with EoE. METHODS: A total of 199 consecutive adult patients with EoE (age, 18-78 y; 32% female) who completed a 16-cm functional luminal imaging probe (FLIP) during endoscopy were evaluated in a cross-sectional study. FLIP panometry contractile response (CR) patterns were classified as normal CR or borderline CR if antegrade contractions were present, and abnormal CRs included impaired/disordered CR, absent CR, or spastic-reactive CR. The distensibility plateau of the esophageal body and esophagogastric junction distensibility was measured with FLIP. RESULTS: FLIP CR patterns included 68 (34%) normal CR, 65 (33%) borderline CR, 44 (22%) impaired/disordered CR, 16 (8%) absent CR, and 6 (3%) spastic-reactive CR. Compared with normal CRs, abnormal CRs more frequently had reduced esophageal distensibility (distensibility plateau <17 mm in 56% vs 32%), greater total EoE reference scores (median, 5; interquartile range [IQR], 3-6 vs median, 4; IQR, 3-5) with more severe ring scores, and a greater duration of symptoms (median, 10 y; IQR, 4-23 y vs median, 7 y; IQR, 3-15 y). Mucosal eosinophil density, however, was similar between abnormal CRs and normal CRs (median, 34 eosinophils/high-power field [hpf]; IQR, 14-60 eosinophils/hpf vs median, 25 eosinophils/hpf; IQR, 5-50 eosinophils/hpf). CONCLUSIONS: Although normal secondary peristalsis was observed frequently in this EoE cohort, abnormal esophageal CRs were related to EoE disease severity, especially features of fibrostenosis. This study evaluating secondary peristalsis in EoE suggests that esophageal wall remodeling, rather than eosinophilic inflammatory intensity, was associated with esophageal dysmotility in EoE.

Blending Active Student Responding with Online Instruction to Evaluate Response Accuracy and Student Engagement.

High rates of active student responding and opportunities to respond are considered best-practice instructional strategies for learning. Many educators in higher education have shifted from teaching primarily in-person to either a hybrid or an online format over the past decade. The global pandemic hastened further shifts from in-person to online learning for many institutions of higher education. Given this rapid shift to online instruction, it is critical to evaluate evidence-based teaching practices in online formats. Although there is a robust body of literature that supports the effectiveness of embedding opportunities to respond and active student responding during in-person instruction, to date, there is limited research that evaluates the effects of increased opportunities to respond during synchronous online courses in post-secondary settings. Using an alternating treatments design, this study evaluated the effects of two active student response modalities on response accuracy for seventeen students enrolled in a synchronous online graduate course. The results suggest that students performed more accurately on post-lecture queries following conditions that required written active student responses compared to responds cards. Moreover, the accuracy of correct responding maintained across the exams and the cumulative final exam. Limitations and future implications are discussed.

Which Readmissions May Be Preventable? Lessons Learned From a Posthospitalization Care Transitions Program for High-risk Elders.

BACKGROUND: Care transitions programs have been shown to reduce hospital readmissions. OBJECTIVES: The main objective of this study was to evaluate effects of the Mayo Clinic Care Transitions (MCCTs) Program on potentially preventable and nonpreventable 30-day unplanned readmissions among high-risk elders. RESEARCH DESIGN: This was a retrospective cohort study of patients enrolled in MCCT following hospitalization and propensity score-matched controls receiving usual primary care. SUBJECTS: The subjects were primary care patients, who were 60 years or older, at high-risk for readmission, and hospitalized for any cause between January 1, 2011 and June 30, 2013. MEASURES: Hospital readmission within 30 days. The 3M algorithm was used to identify potentially preventable readmissions. Readmissions for ambulatory care sensitive conditions, a subset of preventable readmissions identified by the 3M algorithm, were also assessed. RESULTS: The study cohort included 365 pairs of MCCT enrollees and propensity score-matched controls. Patients were similar in age (mean 83 y) and other baseline demographic and clinical characteristics, including reason for index hospitalization. MCCT enrollees had a significantly lower all-cause readmission rate [12.4% (95% confidence interval: CI, 8.9-15.7) vs. 20.1% (15.8-24.1); P=0.004] resulting from a decrease in potentially preventable readmissions [8.4% (95% CI, 5.5-11.3) vs. 14.3% (95% CI, 10.5-17.9); P=0.01]. Few potentially preventable readmissions were for ambulatory care sensitive conditions (6.7% vs. 12.0%). The rates of nonpotentially preventable readmissions were similar [4.3% (95% CI, 2.2-6.5) vs. 6.7% (95% CI, 4.0-9.4); P=0.16]. Potentially preventable readmissions were reduced by 44% (hazard ratio, 0.56; 95% CI, 0.36-0.88; P=0.01) with no change in other readmissions. CONCLUSIONS: The MCCT significantly reduces preventable readmissions, suggesting that access to multidisciplinary care can reduce readmissions and improve outcomes for high-risk elders.

Risk of brain metastases in patients with nonmetastatic lung cancer: Analysis of the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) data.

BACKGROUND: Brain metastases (BM) remain an important cause of morbidity and mortality in patients with lung cancer. The current study evaluated population-based incidence and outcomes of BM in patients with nonmetastatic lung cancer. METHODS: Patients diagnosed with nonmetastatic first primary lung cancer between 1973 and 2011 in the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) registry were used for the current analysis. Age-adjusted odds ratios of developing BM based on various demographic characteristics and histology were calculated with 95% confidence intervals. Adjusted Cox proportional hazard ratios and log-rank tests of Kaplan-Meier survival curves were calculated to evaluate survival differences for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). RESULTS: The incidence of BM in patients with nonmetastatic NSCLC and SCLC was 9% and 18%, respectively. There was variation in the incidence of BM according to NCSLC histology. The incidence of BM was higher in patients aged <60 years for both NSCLC and SCLC, but there were no differences noted by race for either histological group. Female patients with NSCLC were more likely to have BM than male patients. There was variation in the proportion of BM in both patients with NSCLC and SCLC over the three 13-year periods of diagnosis. The risk of death (hazard ratio) was found to be significantly higher for patients with NSCLC with BM, but was not significantly higher in patients with SCLC with BM. CONCLUSIONS: The incidence of BM in patients with nonmetastatic lung cancer varies according to histology, age, and sex. BM are associated with worse survival for patients with NSCLC but not those with SCLC. Cancer 2016;122:1921-7. © 2016 American Cancer Society.

The Tangle of Autonomy, Beneficence, Liberty, and Consent in the CESS Debate.

This commentary on the task force report addresses the complex issues involved in autonomy, beneficence, liberty, and consent, which are often in competition in this and many other treatment issues for individuals with intellectual and developmental disabilities, especially those with limited vocal/verbal repertoires. The issues at hand are multifaceted, and behavior analysts should be aware there is much we do not know enough about. As good scientists, it is important to maintain an attitude of philosophic doubt and endeavor to deepen understanding.

Report of the ABAI Task Force on Contingent Electric Skin Shock.

As a task force appointed by the Executive Council of the Association for Behavior Analysis International (ABAI), we investigated the clinical use of contingent electric skin shock (CESS) in behavior analytic treatments for severe problem behavior. We studied how CESS is used in contemporary behavior analysis, reinforcement-based alternatives to CESS, and current ethical and professional guidelines for applied behavior analysts. We recommended that ABAI uphold clients' right to receive CESS when it is restricted to extreme cases and used under rigorous professional and legal oversight. Our recommendation was rejected by a vote of the full members of ABAI, who instead endorsed an alternative recommendation, developed by members of the Executive Council, that opposed the use of CESS under any condition. Here we present for the record our report and initial recommendations, the formal statement that was rejected by the members of ABAI, and the statement that was endorsed.

Effect of a Fructose-Rich Diet on Gut Microbiota and Immunomodulation: Potential Factors for Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS that is linked with both genetic and environmental factors. A Western-style diet rich in fat and simple sugars is hypothesized as a potential factor contributing to the increased incidence of inflammatory autoimmune diseases, such as MS, in developed countries. Although the adverse effects of a high-fat diet in MS have been studied extensively, the effect of a fructose-rich diet (FRD) on MS etiology is unknown. We hypothesized that an FRD will alter the gut microbiome, influence immune populations, and negatively impact disease in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To test this, we fed C57BL/6 mice either an FRD or normal feed for 4 or 12 wk and analyzed the effect of an FRD on gut microbiota, immune populations, and EAE. An FRD significantly influenced the gut microbiota, with reduced abundance of beneficial bacteria and enrichment of potentially proinflammatory bacteria. We also observed immune modulation in the gut and periphery. Of particular interest was a population of Helios-RORγt+Foxp3+CD4+ T cells that was enriched in the small intestine lamina propria of FRD-fed mice. However, despite gut microbiota and immune modulations, we observed only a subtle effect of an FRD on EAE severity. Overall, our data suggest that in C57Bl6/J mice, an FRD modulates the gut microbiota and immune system without significantly impacting myelin oligodendrocyte glycoprotein 35-55/CFA-induced EAE.

Measuring esophageal compliance using functional lumen imaging probe to assess remodeling in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is associated with fibrostenotic remodeling that can be objectively assessed using the functional lumen imaging probe (FLIP). This is typically done using a metric called distensibility plateau (DP). We aimed to describe a novel measure of compliance of the esophageal body and evaluate the associated clinical characteristics in EoE. METHODS: One hundred seventy-one adult patients with EoE (mean (SD) age 38 (12) years), 31% female and 35 healthy, asymptomatic controls who completed 16-cm functional luminal imaging probe (FLIP) during endoscopy, were evaluated in a cross-sectional study. The esophageal body DP and compliance were measured using a customized analysis program, with compliance calculated as (Δ esophageal body volume)/(Δ pressure) between two FLIP-filled volumes. RESULTS: In controls, the median (5-95th percentile) DP was 19.8 mm (17.9-21) and esophageal body compliance was 0.37 ml/mmHg (0.18-1.1), which was greater than in EoE (DP 19 (11-21)), compliance 0.19 (0.02-0.71), p-values <0.001. Among EoE patients, 70 (41%) had normal compliance (>0.2 ml/mmHg) and normal DP (>17 mm); 11 (6%) had normal compliance and reduced DP; 34 (20%) had reduced compliance and normal DP; and 56 (33%) had reduced compliance and reduce DP. Patients with both reduced compliance and DP had the greatest proportion of severe rings (61% with EREFS score 2-3) and stricture (100%). CONCLUSION: FLIP provides an objective evaluation of biomechanical properties of the esophageal wall that appears enhanced by complementary application of metrics of DP and esophageal body compliance.

Cross-sectional association between systemic metal concentrations and immune markers in patients with total joint arthroplasty.

Total joint arthroplasty (TJA) implants are composed of metal components. Although they are regarded safe, the long-term immunological effects of chronic exposure to the specific implant materials are unknown. We recruited 115 hip and/or knee TJA patients (mean age 68 years) who provided a blood draw for measurement of chromium, cobalt, titanium concentrations, inflammatory markers and systemic distribution of immune cells. We examined differences between the immune markers and the systemic concentrations of chromium, cobalt and titanium. CD66-b neutrophils, early natural killer cells (NK), and eosinophils were present in higher percentages in patients with chromium and cobalt concentrations greater than the median. The opposite pattern was observed with titanium where the percentages of CD66-b neutrophils, early NK, and eosinophils were higher in patients with undetectable titanium. Cobalt concentrations were positively correlated with a higher percentage of gamma delta T cells. Both chromium and cobalt concentrations were positively correlated with higher percentages of plasmablasts. Titanium concentrations were positively correlated with higher CD4 effector memory T cells, regulatory T cell count and Th1 CD4 helper cells. In this exploratory study, we observed altered distribution of immune cells in TJA patients with elevated systemic metal concentrations. Although these correlations were not strong, these exploratory findings warrant further investigation into the role of increased metals circulating in blood and its role in immune modulation.

Correlation of Blood Metal Concentrations with Cognitive Scores and Neuroimaging Findings in Patients with Total Joint Arthroplasty.

Total joint arthroplasty (TJA) implants are composed of metals, ceramics, and/or polyethylene. Studies suggest that the debris released from metal implants may possess neurotoxic properties with reports of neuropsychiatric symptoms and memory deficits, which could be relevant to Alzheimer's disease and related dementias. This exploratory study examined the cross-sectional correlation of blood metal concentrations with cognitive performance and neuroimaging findings in a convenience sample of 113 TJA patients with history of elevated blood metal concentrations of either titanium, cobalt and/or chromium. Associations with neuroimaging measures were observed but not with cognitive scores. Larger studies with longitudinal follow-up are warranted.

Teaching the History of Applied Behavior Analysis.

Incorporating historical readings and discussion into applied behavior-analytic coursework may be an important strategy for developing well-rounded behavior analysts. However, little guidance is available to instructors interested in teaching the history of applied behavior analysis. This article describes how the history of behavior analysis can be incorporated into a course on applied behavior analysis to achieve this goal. The history of punishment/aversives in behavior analysis will be provided as an example of how the history of behavior analysis can be embedded into applied coursework. The historical interaction between the culture at large (i.e., the culture beyond behavior analysis) and behavior-analytic literature and events related to punishment will be described because both affect the field and have led to the current state of practice. History related to early ethical standards, early experimental analysis of behavior literature, the backlash against early applied behavior analysis, and the field of behavior analysis' response to the backlash is discussed.

Leading the Charge: A Look Inside the Behavior Analysis in Practice Emergency Series of Publications on Systemic Racism and Police Brutality.

This article introduces the "Behavior Analysis in Practice Emergency Series of Publications on Systemic Racism and Police Brutality." After the murder of George Floyd, the behavior analytic community was charged to respond in the spirit of Dr. Martin Luther King's challenge to social scientists. The charge of Dr. King was to explain real life phenomena negatively affecting the Black community. This series covered a wide range of topics with the intent of creating solutions that may be used to address remnants of the overarching impact of systemic racism and anti-Blackness. In this editorial, we provide an overview of the major themes of the accepted articles, some personal accounts of the editorial team, context for the special issue, discuss the contributions of the included articles, and a discussion of the areas in need of further work.

Dietary Isoflavones Alter Gut Microbiota and Lipopolysaccharide Biosynthesis to Reduce Inflammation.

The etiopathogenesis of multiple sclerosis (MS) is strongly affected by environmental factors such as diet and the gut microbiota. An isoflavone-rich (ISO) diet was previously shown to reduce the severity of MS in the animal model experimental autoimmune encephalomyelitis (EAE). Translation of this concept to clinical trial where dietary isoflavones may be recommended for MS patients will require preliminary evidence that providing the isoflavone-rich diet to people with MS (PwMS) who lack phytoestrogen-metabolizing bacteria has beneficial effects. We have previously shown that the gut microbiota of PwMS resembles the gut microbiota of mice raised under a phytoestrogen-free (phyto-free) diet in that it lacks phytoestrogen-metabolizing bacteria. To investigate the effects of phytoestrogens on the microbiota inflammatory response and EAE disease severity we switched the diet of mice raised under a phyto-free (PF) diet to an isoflavone-rich diet. Microbiota analysis showed that the change in diet from one that is ISO to one that is PF reduces beneficial bacteria such as Bifidobacterium species. In addition we observed functional differences in lipopolysaccharide (LPS) biosynthesis pathways. Moreover LPS extracted from feces of mice fed an ISO diet induced increased production of anti-inflammatory cytokines from bone marrow-derived macrophages relative to fecal-LPS isolated from mice fed a PF diet. Eventually mice whose diet was switched from a PF diet to an ISO diet trended toward reduced EAE severity and mortality. Overall we show that an isoflavone-rich diet specifically modulates LPS biosynthesis of the gut microbiota imparts an anti-inflammatory response and decreases disease severity.

Participant assent in behavior analytic research: Considerations for participants with autism and developmental disabilities.

Obtaining assent from potential research participants is an important component of research for reasons related to ethics compliance, self-determination, and choice. However, unique issues arise when working with populations who cannot assent through traditional means, such as individuals with Autism Spectrum Disorder (ASD) and related developmental disabilities (DD). The purpose of this paper is to review and discuss assent practices within behavior-analytic research to identify strategies that can be used to obtain assent from potential participants with ASD and DDs. We began with a descriptive literature review of behavior-analytic articles that included the term "assent" to identify what practices behavior analysts have used to obtain assent from participants. In short, very few articles that clearly addressed assent procedures were identified. Thus, we propose a model for gaining assent when working with individuals with ASD and DDs.

An Evaluation of Multiple SAFMEDS Procedures.

Lindsley developed the "say all fast minute every day shuffled" (SAFMEDS) procedure in the late 1970s to enhance the typical use of flash cards (Graf & Auman, 2005). The acronym specifically guides the learner's behavior when using flash cards. A review of SAFMEDS research indicates its successful use with children, college students, and older adults with and without disabilities. The literature also indicates that SAFMEDS procedures are not well documented and have multiple variations, limiting practitioners' ability to know what procedures to use and when. The purpose of this study was to evaluate the effects of a basic SAFMEDS procedure and four supplementary SAFMEDS procedures on the rates of correct and incorrect responding to unfamiliar Russian words and Chinese characters in college students. The results of the study suggest that the basic SAFMEDS procedure produced some learning (i.e., increases in correct responding and decreases in incorrect responding), but all of the supplementary procedures led to greater increases in the number of correct responses per 1-min timing. Further research evaluating differences in performance across the supplementary procedures is warranted.

Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis.

The gut microbiota is a potential environmental factor that influences the development of multiple sclerosis (MS). We and others have demonstrated that patients with MS and healthy individuals have distinct gut microbiomes. However, the pathogenic relevance of these differences remains unclear. Previously, we showed that bacteria that metabolize isoflavones are less abundant in patients with MS, suggesting that isoflavone-metabolizing bacteria might provide protection against MS. Here, using a mouse model of MS, we report that an isoflavone diet provides protection against disease, which is dependent on the presence of isoflavone-metabolizing bacteria and their metabolite equol. Notably, the composition of the gut microbiome in mice fed an isoflavone diet exhibited parallels to healthy human donors, whereas the composition in those fed an isoflavone-free diet exhibited parallels to patients with MS. Collectively, our study provides evidence that dietary-induced gut microbial changes alleviate disease severity and may contribute to MS pathogenesis.

Safety of Irreversible Electroporation Ablation of the Pancreas.

OBJECTIVES: To evaluate the safety of irreversible electroporation (IRE) on swine pancreatic tissue including its effects on peripancreatic vessels, bile ducts, and bowel. METHODS: Eighteen Yorkshire pigs underwent IRE ablation of the pancreas successfully and without clinical complications. Contrast-enhanced computed tomography angiography and laboratory studies before the IRE ablation with follow-up computed tomography angiography, laboratory testing, and pathological examination up to 4 weeks postablation were performed. RESULTS: In a subset of cases, anatomic peripancreatic vessel narrowing was seen by 1 week postablation, persisting at 4 weeks postablation, without apparent functional impairment of blood flow. Laboratory studies revealed elevated amylase and lipase at 24 hours post-IRE, suggestive of acute pancreatitis, which normalized by 4 weeks post-IRE. There was extensive pancreatic tissue damage 24 hours after IRE with infiltration of immune cells, which was gradually replaced by fibrotic tissue. Ductal regeneration without loss of pancreatic acinar tissue and glandular function was observed at 1 and 4 weeks postablation. CONCLUSIONS: In our study, we demonstrated and confirmed the safety and minimal complications of IRE ablation in the pancreas and its surrounding vital structures. These results show the potential of IRE as an alternative treatment modality in patients with pancreatic cancer, especially those with locally advanced disease.