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.

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.

An open challenge to advance probabilistic forecasting for dengue epidemics.

A wide range of research has promised new tools for forecasting infectious disease dynamics, but little of that research is currently being applied in practice, because tools do not address key public health needs, do not produce probabilistic forecasts, have not been evaluated on external data, or do not provide sufficient forecast skill to be useful. We developed an open collaborative forecasting challenge to assess probabilistic forecasts for seasonal epidemics of dengue, a major global public health problem. Sixteen teams used a variety of methods and data to generate forecasts for 3 epidemiological targets (peak incidence, the week of the peak, and total incidence) over 8 dengue seasons in Iquitos, Peru and San Juan, Puerto Rico. Forecast skill was highly variable across teams and targets. While numerous forecasts showed high skill for midseason situational awareness, early season skill was low, and skill was generally lowest for high incidence seasons, those for which forecasts would be most valuable. A comparison of modeling approaches revealed that average forecast skill was lower for models including biologically meaningful data and mechanisms and that both multimodel and multiteam ensemble forecasts consistently outperformed individual model forecasts. Leveraging these insights, data, and the forecasting framework will be critical to improve forecast skill and the application of forecasts in real time for epidemic preparedness and response. Moreover, key components of this project-integration with public health needs, a common forecasting framework, shared and standardized data, and open participation-can help advance infectious disease forecasting beyond dengue.

Risk Factors for Healthcare Personnel Infection With Endemic Coronaviruses (HKU1, OC43, NL63, 229E): Results from the Respiratory Protection Effectiveness Clinical Trial (ResPECT).

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a large risk to healthcare personnel (HCP). Quantifying the risk of coronavirus infection associated with workplace activities is an urgent need. METHODS: We assessed the association of worker characteristics, occupational roles and behaviors, and participation in procedures with the risk of endemic coronavirus infection among HCP who participated in the Respiratory Protection Effectiveness Clinical Trial (ResPECT), a cluster randomized trial to assess personal protective equipment to prevent respiratory infections and illness conducted from 2011 to 2016. RESULTS: Among 4689 HCP seasons, we detected coronavirus infection in 387 (8%). HCP who participated in an aerosol-generating procedure (AGP) at least once during the viral respiratory season were 105% (95% confidence interval, 21%-240%) more likely to be diagnosed with a laboratory-confirmed coronavirus infection. Younger individuals, those who saw pediatric patients, and those with household members <5 years of age were at increased risk of coronavirus infection. CONCLUSIONS: Our analysis suggests that the risk of HCP becoming infected with an endemic coronavirus increases approximately 2-fold with exposures to AGPs. Our findings may be relevant to the coronavirus disease 2019 (COVID-19) pandemic; however, SARS-CoV-2, the virus that causes COVID-19, may differ from endemic coronaviruses in important ways. CLINICAL TRIALS REGISTRATION: NCT01249625.

Evaluating the ALERT algorithm for local outbreak onset detection in seasonal infectious disease surveillance data.

Estimation of epidemic onset timing is an important component of controlling the spread of seasonal infectious diseases within community healthcare sites. The Above Local Elevated Respiratory Illness Threshold (ALERT) algorithm uses a threshold-based approach to suggest incidence levels that historically have indicated the transition from endemic to epidemic activity. In this paper, we present the first detailed overview of the computational approach underlying the algorithm. In the motivating example section, we evaluate the performance of ALERT in determining the onset of increased respiratory virus incidence using laboratory testing data from the Children's Hospital of Colorado. At a threshold of 10 cases per week, ALERT-selected intervention periods performed better than the observed hospital site periods (2004/2005-2012/2013) and a CUSUM method. Additional simulation studies show how data properties may effect ALERT performance on novel data. We found that the conditions under which ALERT showed ideal performance generally included high seasonality and low off-season incidence.

N95 Respirators vs Medical Masks for Preventing Influenza Among Health Care Personnel: A Randomized Clinical Trial.

Importance: Clinical studies have been inconclusive about the effectiveness of N95 respirators and medical masks in preventing health care personnel (HCP) from acquiring workplace viral respiratory infections. Objective: To compare the effect of N95 respirators vs medical masks for prevention of influenza and other viral respiratory infections among HCP. Design, Setting, and Participants: A cluster randomized pragmatic effectiveness study conducted at 137 outpatient study sites at 7 US medical centers between September 2011 and May 2015, with final follow-up in June 2016. Each year for 4 years, during the 12-week period of peak viral respiratory illness, pairs of outpatient sites (clusters) within each center were matched and randomly assigned to the N95 respirator or medical mask groups. Interventions: Overall, 1993 participants in 189 clusters were randomly assigned to wear N95 respirators (2512 HCP-seasons of observation) and 2058 in 191 clusters were randomly assigned to wear medical masks (2668 HCP-seasons) when near patients with respiratory illness. Main Outcomes and Measures: The primary outcome was the incidence of laboratory-confirmed influenza. Secondary outcomes included incidence of acute respiratory illness, laboratory-detected respiratory infections, laboratory-confirmed respiratory illness, and influenzalike illness. Adherence to interventions was assessed. Results: Among 2862 randomized participants (mean [SD] age, 43 [11.5] years; 2369 [82.8%]) women), 2371 completed the study and accounted for 5180 HCP-seasons. There were 207 laboratory-confirmed influenza infection events (8.2% of HCP-seasons) in the N95 respirator group and 193 (7.2% of HCP-seasons) in the medical mask group (difference, 1.0%, [95% CI, -0.5% to 2.5%]; P = .18) (adjusted odds ratio [OR], 1.18 [95% CI, 0.95-1.45]). There were 1556 acute respiratory illness events in the respirator group vs 1711 in the mask group (difference, -21.9 per 1000 HCP-seasons [95% CI, -48.2 to 4.4]; P = .10); 679 laboratory-detected respiratory infections in the respirator group vs 745 in the mask group (difference, -8.9 per 1000 HCP-seasons, [95% CI, -33.3 to 15.4]; P = .47); 371 laboratory-confirmed respiratory illness events in the respirator group vs 417 in the mask group (difference, -8.6 per 1000 HCP-seasons [95% CI, -28.2 to 10.9]; P = .39); and 128 influenzalike illness events in the respirator group vs 166 in the mask group (difference, -11.3 per 1000 HCP-seasons [95% CI, -23.8 to 1.3]; P = .08). In the respirator group, 89.4% of participants reported "always" or "sometimes" wearing their assigned devices vs 90.2% in the mask group. Conclusions and Relevance: Among outpatient health care personnel, N95 respirators vs medical masks as worn by participants in this trial resulted in no significant difference in the incidence of laboratory-confirmed influenza. Trial Registration: ClinicalTrials.gov Identifier: NCT01249625.

Carotenoid-based coloration in cichlid fishes.

Animal colors play important roles in communication, ecological interactions and speciation. Carotenoid pigments are responsible for many yellow, orange and red hues in animals. Whereas extensive knowledge on the proximate mechanisms underlying carotenoid coloration in birds has led to testable hypotheses on avian color evolution and signaling, much less is known about the expression of carotenoid coloration in fishes. Here, we promote cichlid fishes (Perciformes: Cichlidae) as a system in which to study the physiological and evolutionary significance of carotenoids. Cichlids include some of the best examples of adaptive radiation and color pattern diversification in vertebrates. In this paper, we examine fitness correlates of carotenoid pigmentation in cichlids and review hypotheses regarding the signal content of carotenoid-based ornaments. Carotenoid-based coloration is influenced by diet and body condition and is positively related to mating success and social dominance. Gaps in our knowledge are discussed in the last part of this review, particularly in the understanding of carotenoid metabolism pathways and the genetics of carotenoid coloration. We suggest that carotenoid metabolism and transport are important proximate mechanisms responsible for individual and population-differences in cichlid coloration that may ultimately contribute to diversification and speciation.

Exposure to 17α-ethinylestradiol decreases motility and ATP in sperm of male fighting fish Betta splendens.

The synthetic estrogen 17α-ethinylestradiol (EE2) is an endocrine-disrupting chemical released into aquatic environments from sewage treatment facilities. We tested the effects of two environmentally relevant concentrations of waterborne EE2, 10 and 100 ng L(-1) , on reproductive endpoints in the teleost fish Betta splendens. In the first experiment, testes were removed from males and sperm were exposed to EE2 directly through the activation water. Direct exposure to EE2 had no effect on any measure of sperm swimming performance. In the second experiment, we exposed sexually mature male B. splendens to EE2 using a semi-static exposure protocol for 4 weeks. There were no significant treatment effects in the 10 ng L(-1) treatment group, but at the 100 ng L(-1) dose we found that fish had smaller gonads and reduced sperm swimming velocity. When allowed to interact freely with female conspecifics, males exposed to 100 ng L(-1) EE2 built smaller nests and showed a nonsignificant decrease in fertilization success. To investigate further the potential mechanism underlying the decrease in sperm quality, we repeated the chronic exposure experiment and analyzed the ATP content of sperm from fish in each treatment group. We found that males exposed to 100 ng L(-1) of EE2 had fewer moles of ATP per sperm than did fish in the other two treatment groups, suggesting that a decrease in intracellular ATP caused a reduction in sperm swimming velocity. The current study adds to the growing body of literature that indicates the risks to aquatic organisms of exposure to environmentally relevant concentrations of EE2.

Dietary carotenoids do not improve motility or antioxidant capacity in cichlid fish sperm.

Carotenoids may act as antioxidants under many circumstances. We examined the importance of carotenoids as antioxidants in the gonads of male convict cichlids (Amatitlania nigrofasciata), a species in which males lack the carotenoid-based breeding coloration that characterizes females. Male fish were fed one of four diets that included different combinations of xanthophyll and carotene carotenoids, and then we measured carotenoid concentration of the gonads, gonadosomatic index (GSI), sperm motility, and the antioxidant capacity of the gonads. Significant differences were found in gonadal carotenoid content among treatment groups, suggesting that dietary carotenoids were indeed sequestered in the gonads. There were no differences among diet groups, however, in GSI, sperm motility, or gonadal antioxidant capacity. These findings suggest that carotenoids are required only in small amounts in the testes of male convict cichlids or that they play a limited role in protecting sperm from oxidative damage.

Safety of Oral and Topical Nonsteroidal Anti-Inflammatory Drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to manage mild to moderate pain. While limited use is appropriate for many patients, there are safety concerns with use in certain patient populations or with long-term use of these agents. Topical NSAIDs may provide analgesic benefits while decreasing the overall risks of adverse effects. This article will review safety information for both oral and topical NSAIDs.

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.

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.

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.

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.

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.

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.

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.

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.