Candida albicans selection for human commensalism results in substantial within-host diversity without decreasing fitness for invasive disease.

Candida albicans is a frequent colonizer of human mucosal surfaces as well as an opportunistic pathogen. C. albicans is remarkably versatile in its ability to colonize diverse host sites with differences in oxygen and nutrient availability, pH, immune responses, and resident microbes, among other cues. It is unclear how the genetic background of a commensal colonizing population can influence the shift to pathogenicity. Therefore, we examined 910 commensal isolates from 35 healthy donors to identify host niche-specific adaptations. We demonstrate that healthy people are reservoirs for genotypically and phenotypically diverse C. albicans strains. Using limited diversity exploitation, we identified a single nucleotide change in the uncharacterized ZMS1 transcription factor that was sufficient to drive hyper invasion into agar. We found that SC5314 was significantly different from the majority of both commensal and bloodstream isolates in its ability to induce host cell death. However, our commensal strains retained the capacity to cause disease in the Galleria model of systemic infection, including outcompeting the SC5314 reference strain during systemic competition assays. This study provides a global view of commensal strain variation and within-host strain diversity of C. albicans and suggests that selection for commensalism in humans does not result in a fitness cost for invasive disease.

Active compensation for changes in TDH3 expression mediated by direct regulators of TDH3 in Saccharomyces cerevisiae.

Genetic networks are surprisingly robust to perturbations caused by new mutations. This robustness is conferred in part by compensation for loss of a gene's activity by genes with overlapping functions, such as paralogs. Compensation occurs passively when the normal activity of one paralog can compensate for the loss of the other, or actively when a change in one paralog's expression, localization, or activity is required to compensate for loss of the other. The mechanisms of active compensation remain poorly understood in most cases. Here we investigate active compensation for the loss or reduction in expression of the Saccharomyces cerevisiae gene TDH3 by its paralog TDH2. TDH2 is upregulated in a dose-dependent manner in response to reductions in TDH3 by a mechanism requiring the shared transcriptional regulators Gcr1p and Rap1p. TDH1, a second and more distantly related paralog of TDH3, has diverged in its regulation and is upregulated by another mechanism. Other glycolytic genes regulated by Rap1p and Gcr1p show changes in expression similar to TDH2, suggesting that the active compensation by TDH3 paralogs is part of a broader homeostatic response mediated by shared transcriptional regulators.

Current practices in the management of central airway obstruction.

PURPOSE OF REVIEW: Airway obstruction continues to cause substantial pulmonary morbidity and mortality. We present a review of classic, current, and evolving management techniques, highlighting recently published studies on the topic. Recommendations have historically been primarily based on anecdotal experience, case reports, and retrospective studies, but more solid evidence has emerged in the last decade. RECENT FINDINGS: Novel endobronchial stents are being developed to mitigate the issues of stent migration, mucus plugging, fracture, and granulation tissue formation. Endobronchial drug delivery has become an active area of translational and clinical research, especially with regards to antineoplastic agents used for malignant airway stenosis. Even classic or updated techniques such as spray cryotherapy, injections of mitomycin-c, and balloon dilation have recently been examined in methodologically sound studies. Finally, recently published data have confirmed that patient breathlessness and quality of life improve significantly with therapeutic airway interventions. A multimodal and multidisciplinary approach to patient care is key to achieving the best outcomes. SUMMARY: The treatment of central airway stenosis is often multimodal and should focus on patient-centric factors, taking into account risks and benefits of the procedure, operator, and center expertise, and always occur in the context of a multidisciplinary approach. Evidence-based clinical research is increasingly driving patient management.

Levofloxacin prophylaxis for pediatric leukemia patients: Longitudinal follow-up for impact on health care-associated infections.

BACKGROUND: Bloodstream infections (BSIs) cause morbidity and mortality in pediatric patients with leukemia. Antibiotic prophylaxis during periods of chemotherapy-induced neutropenia may reduce the incidence of BSIs. PROCEDURE: A levofloxacin prophylaxis guideline was implemented for pediatric patients with acute myeloid leukemia and relapsed acute lymphoblastic leukemia. We conducted a retrospective cohort study over 4 years (2 years pre and 2 years post implementation) of the practice guideline to assess the impact on central line-associated bloodstream infections (CLABSI) and BSI events. Secondary outcomes included incidence of Clostridioides difficile-associated diarrhea, bacteremia due to multidrug-resistant organisms (MDRO), and bacteremia due to levofloxacin nonsusceptible organisms. STATA was used for data analysis. RESULTS: Sixty-three and 72 patients met inclusion criteria for the pre- and postimplementation cohorts, respectively. Demographics were similar between the groups. We observed 60 BSI events in the pre-group versus 49 events in the post-group (p = .1). Bacteremia due to Gram-negative rods (risk ratio [RR] 0.37 [0.21, 0.66], p < .001) and National Healthcare Safety Network (NHSN) CLABSIs (RR 0.62 [0.44, 0.89], p = .01) were significantly reduced in the postimplementation group. The incidences of C. difficile-associated diarrhea and MDRO bacteremia were similar between groups. However, we observed an increase in the incidence of BSI due to Gram-negative rods that were nonsusceptible to levofloxacin (RR 3.38 [0.72, 6.65], p < .001). CONCLUSION: Following implementation of a levofloxacin prophylaxis guideline, we observed a significant decrease in BSIs due to Gram-negative rods and NHSN CLABSIs. Vigilant monitoring of outcomes post guideline implementation is critical to track emergence of resistant organisms.

Empirical measures of mutational effects define neutral models of regulatory evolution in Saccharomyces cerevisiae.

Understanding how phenotypes evolve requires disentangling the effects of mutation generating new variation from the effects of selection filtering it. Tests for selection frequently assume that mutation introduces phenotypic variation symmetrically around the population mean, yet few studies have tested this assumption by deeply sampling the distributions of mutational effects for particular traits. Here, we examine distributions of mutational effects for gene expression in the budding yeast Saccharomyces cerevisiae by measuring the effects of thousands of point mutations introduced randomly throughout the genome. We find that the distributions of mutational effects differ for the 10 genes surveyed and are inconsistent with normality. For example, all 10 distributions of mutational effects included more mutations with large effects than expected for normally distributed phenotypes. In addition, some genes also showed asymmetries in their distribution of mutational effects, with new mutations more likely to increase than decrease the gene's expression or vice versa. Neutral models of regulatory evolution that take these empirically determined distributions into account suggest that neutral processes may explain more expression variation within natural populations than currently appreciated.

Esophageal contractile segment impedance from high-resolution impedance manometry correlates with mean nocturnal baseline impedance and acid exposure time from 24-hour pH-impedance monitoring.

Esophageal baseline impedance (BI) acquired during esophageal contraction (contractile segment impedance [CSI]) is proposed to improve BI accuracy in gastroesophageal reflux disease (GERD). We evaluated associations between CSI and conventional and novel GERD metrics. We analyzed high-resolution impedance manometry (HRIM) and ambulatory pH-impedance studies from 51 patients (58.6 ± 1.5 years; 26% F) with GERD symptoms studied off antisecretory therapy. Patients with achalasia or absent contractility were excluded. CSI (averaged across 10 swallows) and BI-HRIM (from the resting landmark phase) were acquired from the distal impedance sensors (distal sensor and 5 cm above the lower esophageal sphincter). Acid exposure time (AET) and mean nocturnal baseline impedance (MNBI) were calculated. Associations between CSI, BI-HRIM, MNBI, and AET were evaluated using correlation (Pearson) and receiver operating characteristic (ROC) analysis. Presenting symptoms included heartburn (67%), regurgitation (12%), cough (12%), and chest pain (10%). CSI-distal and CSI-5 each correlated with BI-HRIM, AET, and distal MNBI. Associations with AET were numerically stronger for CSI-distal (r = -0.46) and BI-HRIM-distal (r = -0.44) than CSI-5 (r = -0.33), BI-HRIM-5 (r = -0.28), or distal MNBI (r < -0.36). When compared to AET <4%, patients with AET >6% had significantly lower CSI-distal and BI-HRIM-distal values but not CSI-5, BI-HRIM-5, or MNBI. ROC areas under the curve for AET >6% were numerically higher for CSI-distal (0.81) than BI-HRIM-distal (0.77), distal MNBI (0.68-0.75), CSI-5 (0.68), or BI-HRIM-5 (0.68). CSI from HRIM studies inversely correlates with pathologic AET and has potential to augment the evaluation of GERD.

Effects of mutation and selection on plasticity of a promoter activity in Saccharomyces cerevisiae.

Phenotypic plasticity is an evolvable property of biological systems that can arise from environment-specific regulation of gene expression. To better understand the evolutionary and molecular mechanisms that give rise to plasticity in gene expression, we quantified the effects of 235 single-nucleotide mutations in the Saccharomyces cerevisiae TDH3 promoter (PTDH3 ) on the activity of this promoter in media containing glucose, galactose, or glycerol as a carbon source. We found that the distributions of mutational effects differed among environments because many mutations altered the plastic response exhibited by the wild-type allele. Comparing the effects of these mutations with the effects of 30 PTDH3 polymorphisms on expression plasticity in the same environments provided evidence of natural selection acting to prevent the plastic response in PTDH3 activity between glucose and galactose from becoming larger. The largest changes in expression plasticity were observed between fermentable (glucose or galactose) and nonfermentable (glycerol) carbon sources and were caused by mutations located in the RAP1 and GCR1 transcription factor binding sites. Mutations altered expression plasticity most frequently between the two fermentable environments, with mutations causing significant changes in plasticity between glucose and galactose distributed throughout the promoter, suggesting they might affect chromatin structure. Taken together, these results provide insight into the molecular mechanisms underlying gene-by-environment interactions affecting gene expression as well as the evolutionary dynamics affecting natural variation in plasticity of gene expression.

"Felony assault should stick:" Assaulted EMS responders' frustration and dissatisfaction with the legal system.

INTRODUCTION: The prevalence of violence to first responders is reported in ranges of approximately 40% to 90%. Pennsylvania has a felonious assault statute to address such violence, but the prosecutorial process has been noted to cause first-responder dissatisfaction. METHODS: An exploratory qualitative study using individual interviews with snowball sampling was conducted with the Philadelphia District Attorney's office to understand the prosecutorial process when a first responder is assaulted and injured in a line of duty. The Philadelphia Fire Department provided a list of first responders who sustained a work-related injury from a patient or bystander assault so that particular cases could be discussed during the interviews. RESULTS: Emergent themes fell into two categories: factors that lead to a charge (prosecutorial merit, intent, and victim investment), and the judge's discretion in sentencing ("part of the job" mentality, concern for the defendant, and the justice system's offender focus). Immediately actionable tertiary prevention recommendations for fire departments, labor unions, and district attorney's offices were developed. CONCLUSION: Violence against fire-based emergency medical service (EMS) responders is a persistent and preventable workplace hazard. While felonious assault statutes express society's value that it is unacceptable to harm a first responder, this study found that such statutes failed to provide satisfaction to victims and that support when going through the court process is lacking. Assaulted EMS responders, their employers, and labor unions would benefit from the recommendations provided herein to help them extract a stronger sense of procedural justice from the legal process.

Gene Expression Evolves under a House-of-Cards Model of Stabilizing Selection.

Divergence in gene regulation is hypothesized to underlie much of phenotypic evolution, but the role of natural selection in shaping the molecular phenotype of gene expression continues to be debated. To resolve the mode of gene expression, evolution requires accessible theoretical predictions for the effect of selection over long timescales. Evolutionary quantitative genetic models of phenotypic evolution can provide such predictions, yet those predictions depend on the underlying hypotheses about the distributions of mutational and selective effects that are notoriously difficult to disentangle. Here, we draw on diverse genomic data sets including expression profiles of natural genetic variation and mutation accumulation lines, empirical estimates of genomic mutation rates, and inferences of genetic architecture to differentiate contrasting hypotheses for the roles of stabilizing selection and mutation in shaping natural expression variation. Our analysis suggests that gene expression evolves in a domain of phenotype space well fit by the House-of-Cards (HC) model. Although the strength of selection inferred is sensitive to the number of loci controlling gene expression, the model is not. The consistency of these results across evolutionary time from budding yeast through fruit fly implies that this model is general and that mutational effects on gene expression are relatively large. Empirical estimates of the genetic architecture of gene expression traits imply that selection provides modest constraints on gene expression levels for most genes, but that the potential for regulatory evolution is high. Our prediction using data from laboratory environments should encourage the collection of additional data sets allowing for more nuanced parameterizations of HC models for gene expression.

Expecting the unexpected: A mixed methods study of violence to EMS responders in an urban fire department.

BACKGROUND: Struck by injuries experienced by females were observed to be higher compared to males in an urban fire department. The disparity was investigated while gaining a grounded understanding of EMS responder experiences from patient-initiated violence. METHODS: A convergent parallel mixed methods design was employed. Using a linked injury dataset, patient-initiated violence estimates were calculated comparing genders. Semi-structured interviews and a focus group were conducted with injured EMS responders. RESULTS: Paramedics had significantly higher odds for patient-initiated violence injuries than firefighters (OR 14.4, 95%CI: 9.2-22.2, P < 0.001). Females reported increased odds of patient-initiated violence injuries compared to males (OR = 6.25, 95%CI 3.8-10.2), but this relationship was entirely mediated through occupation (AOR = 1.64, 95%CI 0.94-2.85). Qualitative data illuminated the impact of patient-initiated violence and highlighted important organizational opportunities for intervention. CONCLUSIONS: Mixed methods greatly enhanced the assessment of EMS responder patient-initiated violence prevention.

A Strained 9-1-1 System and Threats to Public Health.

The goal of this study was to understand safety climate in the United States (U.S.) fire service, which responded to more than 31 million calls to the 9-1-1 emergency response system in 2013. The majority of those calls (68 %) were for medical assistance, while only 4 % of calls were fire-related, highlighting that the 9-1-1 system serves as a critical public health safety net. We conducted focus groups and interviews with 123 firefighters from 12 fire departments across the United States. Using an iterative analytic approach supported by NVivo 10 software, we developed consensus regarding key themes. Firefighters concurred that the 9-1-1 system is strained and increasingly called upon to deliver Emergency Medical Services (EMS) in the community. Much like the hospital emergency department, EMS frequently assists low-income and elderly populations who have few alternative sources of support. Firefighters highlighted the high volume of low-acuity calls that occupy much of their workload, divert resources from true emergencies, and lead to unwarranted occupational hazards like speeding to respond to non-serious calls. As a result, firefighters reported high occupational stress, low morale, and desensitization to community needs. Firefighters' called for improvements to the 9-1-1 system-the backbone of emergency response in the U.S.-including better systems of triage, more targeted use of EMS resources, continuing education to align with job demands, and a strengthened social safety net to address the persistent needs of poor and elderly populations.

Biased learning affects mate choice in a butterfly.

Early acquisition of mate preferences or mate-preference learning is associated with signal diversity and speciation in a wide variety of animal species. However, the diversity of mechanisms of mate-preference learning across taxa remains poorly understood. Using the butterfly Bicyclus anynana we uncover a mechanism that can lead to directional sexual selection via mate-preference learning: a bias in learning enhanced ornamentation, which is independent of preexisting mating biases. Naïve females mated preferentially with wild-type males over males with enhanced wing ornamentation, but females briefly exposed to enhanced males mated significantly more often with enhanced males. In contrast, females exposed to males with reduced wing ornamentation did not learn to prefer drab males. Thus, we observe both a learned change of a preexisting mating bias, and a bias in ability to learn enhanced male ornaments over reduced ornaments. Our findings demonstrate that females are able to change their preferences in response to a single social event, and suggest a role for biased learning in the evolution of visual sexual ornamentation.

Ligand-regulated heterodimerization of peroxisome proliferator-activated receptor α with liver X receptor α.

Peroxisome proliferator-activated receptor α (PPARα) and liver X receptor α (LXRα) are members of the nuclear receptor superfamily that function to regulate lipid metabolism. Complex interactions between the LXRα and PPARα pathways exist, including competition for the same heterodimeric partner, retinoid X receptor α (RXRα). Although data have suggested that PPARα and LXRα may interact directly, the role of endogenous ligands in such interactions has not been investigated. Using in vitro protein-protein binding assays, circular dichroism, and co-immunoprecipitation of endogenous proteins, we established that full-length human PPARα and LXRα interact with high affinity, resulting in altered protein conformations. We demonstrated for the first time that the affinity of this interaction and the resulting conformational changes could be altered by endogenous PPARα ligands, namely long chain fatty acids (LCFA) or their coenzyme A thioesters. This heterodimer pair was capable of binding to PPARα and LXRα response elements (PPRE and LXRE, respectively), albeit with an affinity lower than that of the respective heterodimers formed with RXRα. LCFA had little effect on binding to the PPRE but suppressed binding to the LXRE. Ectopic expression of PPARα and LXRα in mammalian cells yielded an increased level of PPRE transactivation compared to overexpression of PPARα alone and was largely unaffected by LCFA. Overexpression of both receptors also resulted in transactivation from an LXRE, with decreased levels compared to that of LXRα overexpression alone, and LCFA suppressed transactivation from the LXRE. These data are consistent with the hypothesis that ligand binding regulates heterodimer choice and downstream gene regulation by these nuclear receptors.

Inventory of state workers' compensation laws in the United States: first responder mental health.

We conducted a comprehensive review of state workers' compensation laws in the United States to evaluate the extent to which they support first responders with mental injury. Most state workers' compensation systems divide mental injuries into categories based on their presumed etiology: physical-mental, mental-physical, and mental-mental. Major differences exist among states as to which workers are eligible. Proving workplace causation can be difficult where no traumatic physical injuries exist. Latency periods, time limits, preexisting health conditions, restrictions as to types of condition covered, and complex chains of causation may make this burden, which falls on the claimant, even more challenging. Only nine (9) states enacted presumption of causation laws for mental health conditions to ease claimants' burden of proof. This contrasts starkly with presumption laws for chronic and infectious diseases. State decision-makers should create presumptions that mental health conditions in first responders are caused or significantly exacerbated by their stressful workplaces.

Levofloxacin prophylaxis for pediatric leukemia patients: monitoring of outcomes for sustained benefit and consequences.

Levofloxacin prophylaxis reduces bloodstream infections in neutropenic patients with acute myeloid leukemia or relapsed acute lymphoblastic leukemia. A retrospective, longitudinal cohort study compares incidence of bacteremia, multidrug-resistant organisms (MDRO), and Clostridioides difficile (CDI) between time periods of levofloxacin prophylaxis implementation. Benefits were sustained without increasing MDRO or CDI.

An updated analysis of safety climate and downstream outcomes in two convenience samples of U.S. fire departments (FOCUS 1.0 and 2.0 survey waves).

BACKGROUND: The Fire service Organizational Culture of Safety (FOCUS) survey is an assessment tool comprised of psychometrically validated metrics of safety climate, safety behavior, and downstream outcomes (organizational and injury) that are specific to the U.S. fire and rescue service. METHODS: This analysis consists of a descriptive summary of two independent survey waves (FOCUS 1.0 and 2.0). The fire departments included in these survey waves were from convenience sampling (n1.0 = 275; n2.0 = 170). In addition to department level characteristics, we examined individual level characteristics for firefighters and EMS providers in participating departments (n1.0 = 22,719; n2.0 = 16,882). We conducted regression analyses to examine the associations between safety climate and safety behaviors, organizational outcomes, and safety outcomes. All analyses were stratified by organization type (career, volunteer). RESULTS: Our analysis indicated that a majority of respondents were males (90.7%FOCUS 1.0; 90.4%FOCUS 2.0), non-officers (68.4%FOCUS 1.0; 66.4%FOCUS 2.0), and non-Hispanic Whites (70.8%FOCUS 1.0; 69.5%FOCUS 2.0). For both samples there was a higher prevalence of injuries among individuals in career departments (nFOCUS 1.0 = 3778 [17.5%]; nFOCUS 2.0 = 3072 [18.7%]) than volunteer departments (nFOCUS 1.0 = 103 [8.8%]; nFOCUS 2.0 = 34 [7.4%]). We observed an approximate 10-point difference between the mean scores of Management Commitment to Safety for career and volunteer departments in both samples. We observed associations for two organizational outcomes, Safety Behavior and Job Satisfaction, with Management Commitment to Safety and Supervisor Support for Safety overall and when stratified by organization type. We observed a decrease in the odds of injuries associated with a one-unit increase in Management Commitment to Safety (OR1.0 overall: 0.98, 95% CI 0.97-0.99; OR2.0 volunteer: 0.90, 95% CI 0.85-0.95) and Supervisor Support for Safety (OR1.0 overall: 0.95, 95% CI 0.93-0.97; OR1.0 career: 0.95, 95% CI 0.92-0.98). CONCLUSIONS: From our current study, and a prior analysis of a geographically stratified random sample of U.S. fire departments, we identified that from all the organizational outcomes, job satisfaction was most consistently associated with FOCUS safety climate. Further, firefighters in our samples consistently rated Supervisor Support for Safety higher than Management Commitment to Safety. Future interventions should support fire departments in improving their departmental Management Commitment to Safety and maintaining their Supervisor for Safety.

Self-reported health impacts of do-it-yourself air cleaner use in a smoke-impacted community.

Background: Smoke exposure from wildfires or residential wood burning for heat is a public health problem for many communities. Do-It-Yourself (DIY) portable air cleaners (PACs) are promoted as affordable alternatives to commercial PACs, but evidence of their effect on health outcomes is limited. Objective: Pilot test an evaluation of the effect of DIY PAC usage on self-reported symptoms, and investigate barriers and facilitators of PAC use, among members of a tribal community that routinely experiences elevated concentrations of fine particulate matter (PM2.5) from smoke. Methods: We conducted studies in Fall 2021 ("wildfire study"; N = 10) and Winter 2022 ("wood stove study"; N = 17). Each study included four sequential one-to-two-week phases: 1) initial, 2) DIY PAC usage ≥8 h/day, 3) commercial PAC usage ≥8 h/day, and 4) air sensor with visual display and optional PAC use. We continuously monitored PAC usage and indoor/outdoor PM2.5 concentrations in homes. Concluding each phase, we conducted phone surveys about participants' symptoms, perceptions, and behaviors. We analyzed symptoms associated with PAC usage and conducted an analysis of indoor PM2.5 concentrations as a mediating pathway using mixed effects multivariate linear regression. We categorized perceptions related to PACs into barriers and facilitators of use. Results: No association was observed between PAC usage and symptoms, and the mediation analysis did not indicate that small observed trends were attributable to changes in indoor PM2.5 concentrations. Small sample sizes hindered the ability to draw conclusions regarding the presence or absence of causal associations. DIY PAC usage was low; loud operating noise was a barrier to use. Discussion: This research is novel in studying health effects of DIY PACs during wildfire and wood smoke exposures. Such research is needed to inform public health guidance. Recommendations for future studies on PAC use during smoke exposure include building flexibility of intervention timing into the study design.

Barriers and facilitators of consumer use of nutrition labels at sit-down restaurant chains.

OBJECTIVE: Numerous localities have mandated that chain restaurants post nutrition information at the point of purchase. However, some studies suggest that consumers are not highly responsive to menu labelling. The present qualitative study explored influences on full-service restaurant customers' noticing and using menu labelling. DESIGN: Five focus groups were conducted with thirty-six consumers. A semi-structured script elicited barriers and facilitators to using nutrition information by showing excerpts of real menus from full-service chain restaurants. SETTING: Participants were recruited from a full-service restaurant chain in Philadelphia, Pennsylvania, USA, in September 2011. SUBJECTS: Focus group participants were mostly female, African American, with incomes <$US 60 000, mean age 36 years and education 14·5 years. At recruitment, 33 % (n 12) reported changing their order after seeing nutrition information on the menu. RESULTS: Three themes characterized influences on label use in restaurants: nutrition knowledge, menu design and display, and normative attitudes and behaviours. Barriers to using labels were low prior knowledge of nutrition; displaying nutrition information using codes; low expectations of the nutritional quality of restaurant food; and restaurant discounts, promotions and social influences that overwhelmed interest in nutrition and reinforced disinterest in nutrition. Facilitators were higher prior knowledge of recommended daily intake; spending time reading the menu; having strong prior interest in nutrition/healthy eating; and being with people who reinforced dietary priorities. CONCLUSIONS: Menu labelling use may increase if consumers learn a few key recommended dietary reference values, understand basic energy intake/expenditure scenarios and if chain restaurants present nutrition information in a user-friendly way and promote healthier items.