Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.

Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.

Prediction of Response Patterns during Conditional Discrimination Training across Data Recording Methods.

The effectiveness of an intervention is tied to the degree to which a program is implemented as described and the behavior analyst's ability to individualize the program based on client-specific factors. LeBlanc et al. (2020) found that training clinicians to use enhanced data sheets, which represent both the antecedent and response, resulted in greater procedural integrity when compared to standard data sheets. Additional benefits of enhanced data collection systems include the representation of potential error patterns, which may be used to modify the intervention program. The current study compared naïve participants' accuracy in predicting a client's performance when represented on standard and enhanced data sheets. Participants consistently identified error patterns on enhanced data sheets; however, performance did not differ across data collection methods when accurate responding or unpredictable controlling relations were shown. These findings suggest that enhanced measurement may facilitate the identification of error patterns during instruction for behavior analysts.

Simultaneous Prompting to Teach Intraverbal Synonyms to Struggling Readers.

In simultaneous prompting procedures, an immediate (i.e., 0-s) prompt is presented during all training trials, and transfer to the target discriminative condition is assessed during daily probes. Previous research suggests that simultaneous prompting procedures are efficacious and may produce acquisition in fewer errors to mastery when compared to prompt delay procedures. To date, only a single study on simultaneous prompting has included intraverbal targets. The current study evaluated the efficacy of a simultaneous prompting procedure on the acquisition of intraverbal synonyms for six children at risk for reading failure. Simultaneous prompting alone produced responding at mastery levels in seven of the 12 evaluations. Antecedent-based procedural modifications were effective in four of the five remaining evaluations. Errors were generally low for all but one participant. The current findings support the use of simultaneous prompting procedures when targeting intraverbals for young children exhibiting reading deficits.

Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis.

Immune checkpoint inhibitors (ICIs) target advanced malignancies with high efficacy but also predispose patients to immune-related adverse events like immune-mediated colitis (IMC). Given the association between gut bacteria with response to ICI therapy and subsequent IMC, fecal microbiota transplantation (FMT) represents a feasible way to manipulate microbial composition in patients, with a potential benefit for IMC. Here, we present a large case series of 12 patients with refractory IMC who underwent FMT from healthy donors as salvage therapy. All 12 patients had grade 3 or 4 ICI-related diarrhea or colitis that failed to respond to standard first-line (corticosteroids) and second-line immunosuppression (infliximab or vedolizumab). Ten patients (83%) achieved symptom improvement after FMT, and three patients (25%) required repeat FMT, two of whom had no subsequent response. At the end of the study, 92% achieved IMC clinical remission. 16S rRNA sequencing of patient stool samples revealed that compositional differences between FMT donors and patients with IMC before FMT were associated with a complete response after FMT. Comparison of pre- and post-FMT stool samples in patients with complete responses showed significant increases in alpha diversity and increases in the abundances of Collinsella and Bifidobacterium, which were depleted in FMT responders before FMT. Histologically evaluable complete response patients also had decreases in select immune cells , including CD8+ T cells, in the colon after FMT when compared with non-complete response patients (n = 4). This study validates FMT as an effective treatment strategy for IMC and gives insights into the microbial signatures that may play a critical role in FMT response.

Simultaneous Prompting to Teach Initial Listener Responses to a Child with Down Syndrome.

Simultaneous prompting procedures are infrequently published in the behavior analytic literature yet represent a potential method for promoting nearly errorless learning. No research on simultaneous prompting has targeted early skill repertoires for young children with developmental disabilities. The current study compared simultaneous prompting and constant prompt delay procedures on the acquisition of simple listener responses for a 4-year-old male with Down syndrome. Simultaneous prompting produced responding at mastery levels in less than one third of the total sessions required in the prompt delay condition and substantially fewer errors.

The Effect of CoQ10 supplementation on ART treatment and oocyte quality in older women.

A significant problem associated with assisted reproductive technologies (ART) is recurrent treatment failure which can be attributed to the age-associated decline in oocyte quality. Co-enzyme Q10 (CoQ10) is an antioxidant and essential component of the mitochondrial electron transport chain. It is reported that de novo CoQ10 production declines with ageing and coincides with age-related decline in fertility, leading to CoQ10 supplementation being advocated to enhance response to ovarian stimulation and improve oocyte quality. CoQ10 supplementation was found to improve fertilization rates, embryo maturation rates and embryo quality when used before and during in vitro fertilization (IVF) and in vitro maturation (IVM) treatment in women aged 31 and over. Regarding oocyte quality, CoQ10 was able to reduce high rates of chromosomal abnormalities and oocyte fragmentation, as well as improve mitochondrial function. Proposed mechanisms of CoQ10 function include restoration of reactive oxygen species imbalance, preventing DNA damage and oocyte apoptosis, as well as restoration of Krebs cycle downregulation from ageing. In this literature review, we provide an overview of the use of CoQ10 in improving the success of IVF and IVM in older women, and additionally assess the impact of CoQ10 on oocyte quality and discuss potential mechanisms of action by CoQ10 on the oocyte.

Mucocutaneous adverse events to immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Since the approval of ipilimumab in 2011, a total of nine ICIs have gained indications for various solid and hematologic malignancies. The expanding use of ICIs in oncology underscores the need for diagnosis and treatment expertise in immune related adverse events (irAE). Cutaneous toxicities are the earliest and most common irAE in this class of therapy. In addition to the more frequent reactions including vitiligo, lichenoid dermatitis, psoriasiform dermatitis, other less common skin toxicities including bullous dermatoses, neutrophilic dermatoses, and autoimmune dermato-rheumatologic diseases have been reported. Even though less than 3% of cutaneous irAEs (irCAEs) are classified as grade 3 or higher events, irCAEs can greatly impact quality of life. Appropriate management of irCAEs is critical to avoid unwarranted interruptions or discontinuation of lifesaving immunotherapy.

Detecting elder abuse in dermatology: A clinical and practical review.

The pace of aging in our population is dramatically increasing, raising concern for rising prevalence of elder abuse. Given the visual nature of the occupation, dermatologists can play a crucial role in identifying certain types of elder mistreatment, especially physical abuse, sexual abuse, and neglect. Nonetheless, many dermatologists report insufficient training in the diagnosis of elder abuse as well as appropriate interventions. This review article aims to synthesize and assess recent clinical, screening, and practical developments surrounding elder abuse. Implementation of some of these screening methods and recommendations in clinical practice and in dermatology residency curriculums could lead to increased awareness among physicians and improved patient outcomes. Like all other clinicians, dermatologists have a legal, moral, and ethical obligation to report suspicion of mistreatment and help suffering patients. Elder abuse is and will continue to be, an important issue that will require efforts from physicians across all fields to ensure the health and safety of patients.

Bacteroides ovatus alleviates dysbiotic microbiota-induced intestinal graft-versus-host disease.

Acute gastrointestinal intestinal GVHD (aGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation, and the intestinal microbiota is known to impact on its severity. However, an association between treatment response of aGI-GVHD and the intestinal microbiota has not been well-studied. In a cohort of patients with aGI-GVHD (n=37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and loss of Bacteroides ovatus from the microbiome. In a mouse model of carbapenem-aggravated GVHD, introducing Bacteroides ovatus reduced severity of GVHD and improved survival. Bacteroides ovatus reduced degradation of colonic mucus by another intestinal commensal, Bacteroides thetaiotaomicron, via its ability to metabolize dietary polysaccharides into monosaccharides, which then inhibit mucus degradation by Bacteroides thetaiotaomicron and reduce GVHD-related mortality.

Systemic Treatment of Cutaneous Adverse Events After Immune Checkpoint Inhibitor Therapy: A Review.

As treatment with immune checkpoint inhibitors (CPIs) for cancer increases, so has the incidence of immune-related cutaneous adverse events (irCAEs). These toxicities can significantly impact quality of life and may be dose-limiting. Current guidelines for irCAEs offer only corticosteroids or CPI discontinuation. Evidence supports biologic immunomodulatory therapies when corticosteroids fail or need avoidance. A review of literature from 2010 to 2020 yielded 45 articles, resulting in 185 irCAEs, including bullous pemphigoid-like eruption (n = 55), psoriasis/psoriasiform dermatitis (n = 41), and maculopapular rash (n = 31). Treatments included immunomodulators, intravenous immunoglobulin, aprepitant, acitretin, tetracyclines, and biologic agents. Overall, 92.3% of patients saw improvement or resolution of their rash. Bullous pemphigoid-like eruptions were treated with a tetracycline +/- niacinamide (94.7% success [18/19]), omalizumab (100% success [7/7]), and rituximab (100% success [10/10]). Although prospective research is required, this review provides a comprehensive list of successful, non-corticosteroid treatment options for irCAEs to improve compliance with lifesaving cancer therapy.

Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment.

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.

Control by Compound Antecedent Verbal Stimuli in the Intraverbal Relation.

Control by compound antecedent stimuli in verbal behavior represents an understudied but promising area of research. To date, reference to compound verbal stimulus control has generally only included descriptions of convergent multiple control. A sizeable experimental literature exists on the topic of compound stimulus control, which differs from convergent multiple control in that the stimulus elements often do not have a prior conditioning history (i.e., do not separately strengthen any response). The current study attempted to bridge the experimental and verbal behavior literatures by including a two-component antecedent verbal stimulus during intraverbal training for which neither component currently served an evocative function. Subsequent analyses of stimulus control suggested overshadowing by temporal location in the compound verbal stimulus and lack of emergence of the divergent intraverbal relation across all sets. Additional research is needed on compound stimulus control and verbal behavior researchers may be poised to answer several questions relevant to the experimental and verbal behavior literatures on the topic.

Mucus-degrading Bacteroides link carbapenems to aggravated graft-versus-host disease.

The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.

A retrospective chart review of management strategies for lichenoid eruptions associated with immune-checkpoint inhibitor therapy from a single institution.

Immune checkpoint inhibitors and their associated immune-related cutaneous adverse events are continuing to become a mainstay of cancer treatment regimens. While most rashes are mild and easily manageable, severe or persistent rashes like lichenoid dermatoses can significantly impact the quality of life and may require ICI cessation. Lichenoid dermatoses currently have no management guidelines beyond the use of topical or oral steroids. Our study is a single-institution retrospective chart review to characterize ICI-induced lichenoid eruptions, their treatments, and associated tumor response. We utilized natural language processing and our institutional medical record to identify patients with lichenoid eruptions on ICI therapy. One-hundred nineteen patients were identified, of which 108 rashes were characterized as lichenoid dermatitis and fifteen as lichenoid mucositis. Most patients presented with a diffuse distribution (86%, 101/117), with pruritus in lichenoid dermatoses (82%, 89/108) and pain in lichenoid mucositis (80%, 12/15). Successful treatments for lichenoid dermatitis included topical steroids (81%, 88/108), oral antihistamines (21%, 23/108), and oral steroids (15%, 16/108). Of lichenoid dermatitis patients, 21% (23/108) did not respond to treatment (7) or required oral steroids (16). Approximately 28% of patients who had lichenoid dermatitis had delay, reduction, or discontinuation of their ICI because of their irCAE. This descriptive study highlights the impact of lichenoid dermatitis on patients' ability to remain on ICI therapy and the need for more effective non-steroidal management strategies.

Impact of mandatory vaccination of healthcare personnel on rates of influenza and other viral respiratory pathogens.

OBJECTIVE: The implementation of mandatory influenza vaccination policies among healthcare personnel (HCP) is controversial. Thus, we examined the affect of mandatory influenza vaccination policies among HCP working in outpatient settings. SETTING: Four Veterans' Affairs (VA) health systems and three non-VA medical centers. METHODS: We analyzed rates of influenza and other viral causes of respiratory infections among HCP working in outpatient sites at 4 VA health systems without mandatory influenza vaccination policies and 3 non-VA health systems with mandatory influenza vaccination policies. RESULTS: Influenza vaccination was associated with a decreased risk of influenza (odds ratio, 0.17; 95% confidence interval [CI], 0.13-0.22) but an increased risk of other respiratory viral infections (incidence rate ratio, 1.26; 95% CI, 1.02-1.57). CONCLUSIONS: Our fitted regression models suggest that if influenza vaccination rates in clinics where vaccination was not mandated had equalled those where vaccine was mandated, HCP influenza infections would have been reduced by 52.1% (95% CI, 51.3%-53.0%). These observations, their possible causes, and additional strategies to reduce influenza and other viral respiratory illnesses among HCP working in ambulatory clinics warrant further investigation.

Preference for Alternative Communication Modality Based on Reinforcer Quality and Availability.

Preference for augmentative or alternative communication (AAC) systems has received growing interest in work with individuals with developmental disabilities. An individual may choose a modality based on technological (e.g., auditory-output) or aesthetic features of a system; however, it is ideal that functional features (i.e., effectiveness in producing a reinforcer) affect preference to a much greater extent. Prior research has treated preference as a static variable and may commonly report a lack of preference for a modality or control by irrelevant features of the assessment (e.g., position of the modality in an array). The current study assessed the preference for AAC modalities of a teenager with autism spectrum disorder and intellectual disability using a concurrent-chains procedure. This study extended prior research by including additional methods to ensure accurate assessment of preference (i.e., a control condition) and a reinforcer manipulation to determine whether preference was controlled by non-functional (e.g., aesthetic) or functional (i.e., reinforcer quality and availability) variables. Preference was found to be functionally related to reinforcer availability, including when rapidly alternated between modalities. Moreover, the participant consistently allocated responding away from the control condition. Implications for self-determination and suggestions for future research on preference for AAC systems are considered.

An Evaluation of Instructive Feedback During Mastered Demands.

The presentation of non-target stimuli during trial-based instruction is known as instructive feedback. Previous research on instructive feedback has shown that learners with developmental disabilities may acquire these additional (i.e., secondary) targets without further training. Embedding secondary targets during the review of previously mastered targets may be used to bolster instructional gains. The current study evaluated the efficacy of embedding secondary targets during maintenance sessions for a child with autism spectrum disorder. The participant's responding met the mastery criterion for two target sets presented during the consequence portion of maintenance trials. For the remaining five target sets, a more intrusive intervention was required. Additional research is needed to evaluate the conditions under which secondary targets may be acquired. Supplementary Information: The online version contains supplementary material available at 10.1007/s40616-022-00174-9.

Use of Indoor Tanning Diagnosis Codes in Claims Data.

The International Classification of Diseases: 10th Revision (effective from October 2015) included indoor tanning diagnosis codes for the first time. The majority of data on indoor tanning is self-reported. We used a large claims dataset to investigate the patients and settings in which indoor tanning International Classification of Diseases: 10th Revision codes are being used. We included encounters with the International Classification of Diseases: 10th Revision indoor tanning codes in Truven Health MarketScan data 2016-2018, which contain deidentified commercial insurance claims data for approximately 43 million patients. We used descriptive statistics to evaluate patient and encounter characteristics and normalized results using outpatient dermatology encounters. A total of 4,550 encounters were identified, 99.0% of which were outpatient, and 72.3% were with dermatology. Patients were majority female (85.0%) with ages ranging from 7 to 93. The Midwest region had the most indoor tanning encounters. Destruction of a premalignant lesion was performed in 15.1%, and biopsies were performed in 18.4% of encounters, suggesting that encounters may have been for skin cancer surveillance. Increased usage of indoor tanning International Classification of Diseases: 10th Revision codes in the coming years may strengthen the indoor tanning literature. Claims data are a potential tool to better understand patients who have a history of exposure to indoor tanning and their associated risk factors, comorbidities, behaviors, and healthcare utilization.