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Abstract Background A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG‐157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG‐157 and immune checkpoint inhibitors. Methods CCL23, UM‐SCC1 (human), and SCCVII (HPV−), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG‐157, anti‐PD‐1, and anti‐CTLA‐4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi‐color flow cytometry, immunohistochemistry, and RNA‐seq analysis. Fecal microbiome was analyzed by 16S rRNA sequence. Results Among the eight treatment groups, APG‐157 + anti‐CTLA‐4 demonstrated the best tumor growth suppression (p = 0.0065 compared to the control), followed by anti‐PD‐1 + anti‐CTLA‐4 treatment group (p = 0.48 compared to the control). Immunophenotype showed over 30% of CD8+ T cells in APG‐157 + anti‐CTLA‐4 group compared to 4%–5% of CD8+ T cells for the control group. Differential gene expression analysis revealed that APG‐157 + anti‐CTLA‐4 group showed an enriched set of genes for inflammatory response and apoptotic signaling pathways. The fecal microbiome analysis showed a substantial difference of lactobacillus genus among groups, highest for APG‐157 + anti‐CTLA‐4 treatment group. We were unable to perform correlative studies for MEER model as there was tumor growth suppression with all treatment conditions, except for the untreated control group. Conclusions The results indicate that APG‐157 and immune checkpoint inhibitor combination treatment could potentially lead to improved tumor control.

Disease-free planting stocks and formal certification systems are critical for the profitable production of vegetatively propagated crops. Propagation through seed tubers is the standard and preferred process for potato production. Seed tuber certification systems are used in the United States and throughout the world to mitigate degeneration and promote the use of high-quality planting stocks. Seed certification uses molecular and serological diagnostic methods for stock testing. While the molecular assays available are well-validated and offer high sensitivity, the rapidly evolving pathogens they target routinely develop mutations that allow them to evade detection. Examples of these limitations are the potato diseases soft rot and blackleg, caused by Pectobacterium and Dickeya species. These diseases are challenging for current diagnostics tools because of high pathogen genomic variability, identical symptom development, and co-infections. Given the rapidly changing genetics of soft rot and blackleg bacteria, metagenomic sequencing should be adopted as a tool for routine validation of currently accepted diagnostic methods, and for the development of new diagnostic assays. We propose metagenome sequencing usage to enhance the diagnostic capabilities and complement molecular epidemiology approaches. We envision that metagenomics will accelerate diagnosis, shorten response time to outbreaks caused by unknown microorganisms, and provide more accurate and sustainable management strategies for seed certification programs. [Figure: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

BackgroundSelf-reported diplopia is described in up to one-third of Parkinson’s disease (PD) patients.ObjectiveThe purpose of our study was to expand our understanding of the mechanistic underpinnings of diplopia in PD. We hypothesize that the time-based control of eye alignment and increased eye deviation under binocular viewing will be related to the fusion-initiating and fusion-maintaining component deficits of disparity-driven vergence in PD.MethodsWe used high-resolution video-oculography to measure eye alignment under binocular and monocular viewing and disparity-driven vergence in 33 PD and 10 age-matched healthy participants. We computed eye deviation and time-based control of eye alignment, occurrence of conjugate saccadic eye movements, latency and gain of vergence (fusion initiation), and variance of eye position at the end of dynamic vergence (fusion maintenance).ResultsWe categorized PD subjects into three groups, considering their time-based control of eye alignment as compared to healthy controls in binocular viewing. Group 1 = 45% had good control and spent >80% of the time when the eyes were well-aligned, Group 2 = 26% had intermediate control and spent 5% of the time when the eyes were well-aligned, and Group 3 = 29% had very poor control with increased eye deviation majority of the times (20%) than Group 1 (13%) and controls (0%) trials. No significant difference was found in the Unified Parkinson’s Disease Rating Scale (UPDRS—a tool to measure the severity of PD) values between the three PD groups (Group 1 = 33.69 ± 14.22, Group 2 = 38.43 ± 22.61, and Group 3 = 23.44 ± 1, p > 0.05).ConclusionThe majority of PD subjects within our cohort had binocular dysfunction with increased eye deviation under monocular viewing and disparity-driven vergence deficits. PD subjects with intermediate or poor control of eye deviation under binocular viewing had greater fusion-initiating and fusion-maintaining vergence deficits. The study highlights the importance of assessing binocular dysfunction in PD subjects independent of the severity of motor symptoms.

Rapid, specific, and sensitive identification of microbial pathogens is critical to infectious disease diagnosis and surveillance. Classical culture-based methods can be applied to a broad range of pathogens but have long turnaround times. Molecular methods, such as PCR, are time-effective but are not comprehensive and may not detect novel strains. Metagenomic shotgun next-generation sequencing (NGS) promises specific identification and characterization of any pathogen (viruses, bacteria, fungi, and protozoa) in a less biased way. Despite its great potential, NGS has yet to be widely adopted by clinical microbiology laboratories due in part to the absence of standardized workflows. Here, we describe a sample-to-answer workflow called PanGIA (Pan-Genomics for Infectious Agents) that includes simplified, standardized wet-lab procedures and data analysis with an easy-to-use bioinformatics tool. PanGIA is an end-to-end, multi-use workflow that can be used for pathogen detection and related applications, such as biosurveillance and biothreat detection. We performed a comprehensive survey and assessment of current, commercially available wet-lab technologies and open-source bioinformatics tools for each workflow component. The workflow includes total nucleic acid extraction from clinical human whole blood and environmental microbial forensic swabs as sample inputs, host nucleic acid depletion, dual DNA and RNA library preparation, shotgun sequencing on an Illumina MiSeq, and sequencing data analysis. The PanGIA workflow can be completed within 24 h and is currently compatible with bacteria and viruses. Here, we present data from the development and application of the clinical and environmental workflows, enabling the specific detection of pathogens associated with bloodstream infections and environmental biosurveillance, without the need for targeted assay development.

Given the prevalence of mental health issues for both educators and adolescents in rural Montana, this project is designed to help mitigate the impact of stressors by providing coping strategies linked to improvements in overall mental health outcomes for teachers, which may ultimately lead to improved co-regulation of students and classroom climate. The immediate goal of this pilot study was to measure physical and mental health outcomes of educators resulting from a remotely-delivered trauma-informed yoga intervention. Findings suggest improvements in participants’ depression and anxiety levels, trauma symptoms, sleep quality, and non-significant changes in heart rate variability and cortisol levels.

BackgroundThe midline is an imaginary line that isolates the left and right parts of the body. Crossing the midline infers that a body part (eg, hand or foot) can spontaneously move over to the opposite side of the body to perform an action. A child who has difficulty crossing the midline can physically perform actions that cross the center of the body; however, they do not intuitively cross the midline when challenged with a task that requires this movement, as their perceptual components prevent them from engaging on the contralateral side. This requires treatment from an occupational therapist. Owing to the recent COVID-19 pandemic, access to therapeutic sessions was not possible or reduced, putting the responsibility for treatment on caretakers at home. Caretakers do not have the knowledge and skills to provide treatment, and occupational therapists do not receive adequate feedback from caretakers on the child’s progress. ObjectiveThe first objective is to adapt a simple serious game, or applied game, into a telehealth solution. Children will play the game at home under the supervision of a caretaker, and the results will be stored on the web. Occupational therapists can monitor progress via a web-based dashboard, receive additional valuable feedback about the child’s behavior during treatment, and easily adapt the game to target specific needs. The second objective is to evaluate whether the implemented telehealth solution is feasible as a treatment option for midline crossing difficulties and thus fit for purpose. MethodsTo meet the first objective, engineering and game development stakeholders formed a team with an occupational therapist, and through a collaborative design process combined with an agile programming approach, a telehealth solution was designed to assist remote monitoring of the serious gameplay. For the second objective, 6 different occupational therapists were introduced to the game, had the opportunity to play the game, and then provided feedback regarding the feasibility, benefits, and applicability of the system during structured interviews. ResultsA telehealth system was designed aimed to address this problem. All results are saved on the web and accessed by occupational therapists via a dashboard. In addition, observed behavioral information is also saved. During the interviews, occupational therapists indicated that the dashboard would support their treatment plan and was indeed a feasible solution. ConclusionsThe feedback from the occupational therapists for this telehealth solution suggests a feasible method to treat midline crossing problems remotely. The therapists commented on the convenience of integrating both assessment and treatment into the same application, as it assists them when grading a child. The therapists collectively agreed that the quantitative aspect the serious game creates by providing measurable and standardized data proves advantageous when compared with traditional methods of assessment and treatment.

Abstract Background Preclinical and clinical evidence supports the concept of bidirectional brain-gut microbiome interactions. We aimed to determine if subgroups of irritable bowel syndrome (IBS) subjects can be identified based on differences in gut microbial composition, and if there are correlations between gut microbial measures and structural brain signatures in IBS. Methods Behavioral measures, stool samples, and structural brain images were collected from 29 adult IBS and 23 healthy control subjects (HCs). 16S ribosomal RNA (rRNA) gene sequencing was used to profile stool microbial communities, and various multivariate analysis approaches were used to quantitate microbial composition, abundance, and diversity. The metagenomic content of samples was inferred from 16S rRNA gene sequence data using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). T1-weighted brain images were acquired on a Siemens Allegra 3T scanner, and morphological measures were computed for 165 brain regions. Results Using unweighted Unifrac distances with hierarchical clustering on microbial data, samples were clustered into two IBS subgroups within the IBS population (IBS1 (n = 13) and HC-like IBS (n = 16)) and HCs (n = 23) (AUROC = 0.96, sensitivity 0.95, specificity 0.67). A Random Forest classifier provided further support for the differentiation of IBS1 and HC groups. Microbes belonging to the genera Faecalibacterium, Blautia, and Bacteroides contributed to this subclassification. Clinical features distinguishing the groups included a history of early life trauma and duration of symptoms (greater in IBS1), but not self-reported bowel habits, anxiety, depression, or medication use. Gut microbial composition correlated with structural measures of brain regions including sensory- and salience-related regions, and with a history of early life trauma. Conclusions The results confirm previous reports of gut microbiome-based IBS subgroups and identify for the first time brain structural alterations associated with these subgroups. They provide preliminary evidence for the involvement of specific microbes and their predicted metabolites in these correlations.

Microsaccades shift the image on the fovea and counteract visual fading. They also serve as an optimal sampling strategy while viewing complex visual scenes. Microsaccade production relies on the amount of retinal error or acuity demand of a visual task. The goal of this study was to assess the effects of blur induced by uncorrected refractive error on visual search. Eye movements were recorded in fourteen healthy subjects with uncorrected and corrected refractive error while they performed a) visual fixation b) blank-scene viewing c) visual search (spot the difference) tasks. Microsaccades, saccades, correctly identified differences and reaction times were analyzed. The frequency of microsaccades and correctly identified differences were lower in the uncorrected refractive error during visual search. No similar change in microsaccades was seen during blank-scene viewing and gaze holding tasks. These findings suggest that visual blur, hence the precision of an image on the fovea, has an important role in calibrating the amplitude of microsaccades during visual scanning.

OBJECTIVE:A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions play an important role in human health and disease, including hedonic food intake and obesity. We performed a tripartite network analysis based on graph theory to test the hypothesis that microbiota-derived fecal metabolites are associated with connectivity of key regions of the brain's extended reward network and clinical measures related to obesity. METHODS:DTI and resting state fMRI imaging was obtained from 63 healthy subjects with and without elevated body mass index (BMI) (29 males and 34 females). Subjects submitted fecal samples, completed questionnaires to assess anxiety and food addiction, and BMI was recorded. RESULTS:The study results demonstrate associations between fecal microbiota-derived indole metabolites (indole, indoleacetic acid, and skatole) with measures of functional and anatomical connectivity of the amygdala, nucleus accumbens, and anterior insula, in addition to BMI, food addiction scores (YFAS) and anxiety symptom scores (HAD Anxiety). CONCLUSIONS:The findings support the hypothesis that gut microbiota-derived indole metabolites may influence hedonic food intake and obesity by acting on the extended reward network, specifically the amygdala-nucleus accumbens circuit and the amygdala-anterior insula circuit. These cross sectional, data-driven results provide valuable information for future mechanistic studies.

This article approaches the characterization of the heroine in Esther 2:1-20 from three perspectives: her status prior to her meeting with the king; her status after meeting with the king; and a literary analogy between her and Ahasuerus.