Effectiveness of mRNA Covid-19 Vaccine among U.S. Health Care Personnel.

BACKGROUND: The prioritization of U.S. health care personnel for early receipt of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), allowed for the evaluation of the effectiveness of these new vaccines in a real-world setting. METHODS: We conducted a test-negative case-control study involving health care personnel across 25 U.S. states. Cases were defined on the basis of a positive polymerase-chain-reaction (PCR) or antigen-based test for SARS-CoV-2 and at least one Covid-19-like symptom. Controls were defined on the basis of a negative PCR test for SARS-CoV-2, regardless of symptoms, and were matched to cases according to the week of the test date and site. Using conditional logistic regression with adjustment for age, race and ethnic group, underlying conditions, and exposures to persons with Covid-19, we estimated vaccine effectiveness for partial vaccination (assessed 14 days after receipt of the first dose through 6 days after receipt of the second dose) and complete vaccination (assessed ≥7 days after receipt of the second dose). RESULTS: The study included 1482 case participants and 3449 control participants. Vaccine effectiveness for partial vaccination was 77.6% (95% confidence interval [CI], 70.9 to 82.7) with the BNT162b2 vaccine (Pfizer-BioNTech) and 88.9% (95% CI, 78.7 to 94.2) with the mRNA-1273 vaccine (Moderna); for complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine effectiveness was similar in subgroups defined according to age (<50 years or ≥50 years), race and ethnic group, presence of underlying conditions, and level of patient contact. Estimates of vaccine effectiveness were lower during weeks 9 through 14 than during weeks 3 through 8 after receipt of the second dose, but confidence intervals overlapped widely. CONCLUSIONS: The BNT162b2 and mRNA-1273 vaccines were highly effective under real-world conditions in preventing symptomatic Covid-19 in health care personnel, including those at risk for severe Covid-19 and those in racial and ethnic groups that have been disproportionately affected by the pandemic. (Funded by the Centers for Disease Control and Prevention.).

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

Sex-dependent differences in vulnerability to early risk factors for posttraumatic stress disorder: results from the AURORA study.

BACKGROUND: Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD. METHODS: As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men. RESULTS: Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects. CONCLUSIONS: Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.

Structural inequities contribute to racial/ethnic differences in neurophysiological tone, but not threat reactivity, after trauma exposure.

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms.

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

SARS-CoV-2 Serosurveys: How Antigen, Isotype and Threshold Choices Affect the Outcome.

BACKGROUND: Evaluating the performance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological assays and clearly articulating the utility of selected antigens, isotypes, and thresholds is crucial to understanding the prevalence of infection within selected communities. METHODS: This cross-sectional study, implemented in 2020, screened PCRconfirmed coronavirus disease 2019 patients (n 86), banked prepandemic and negative samples (n 96), healthcare workers and family members (n 552), and university employees (n 327) for antiSARS-CoV-2 receptor-binding domain, trimeric spike protein, and nucleocapsid protein immunoglobulin (Ig)G and IgA antibodies with a laboratory-developed enzyme-linked immunosorbent assay and tested how antigen, isotype and threshold choices affected the seroprevalence outcomes. The following threshold methods were evaluated: (i) mean 3 standard deviations of the negative controls; (ii) 100 specificity for each antigen-isotype combination; and (iii) the maximal Youden index. RESULTS: We found vastly different seroprevalence estimates depending on selected antigens and isotypes and the applied threshold method, ranging from 0.0 to 85.4. Subsequently, we maximized specificity and reported a seroprevalence, based on more than one antigen, ranging from 9.3 to 25.9. CONCLUSIONS: This study revealed the importance of evaluating serosurvey tools for antigen-, isotype-, and threshold-specific sensitivity and specificity, to interpret qualitative serosurvey outcomes reliably and consistently across studies.

Hippocampal Threat Reactivity Interacts with Physiological Arousal to Predict PTSD Symptoms.

Hippocampal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat-sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma (N=116, 76 Female), we found that PTSD symptoms at 2-weeks were associated with decreased hippocampal responses to threat as assessed with functional magnetic resonance imaging (fMRI). Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of Fear Potentiated Startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function, due to increases in fear-potentiated arousal.Significance StatementAlterations in hippocampal function linked to threat-related arousal are reliably associated with post-traumatic stress disorder (PTSD); however, how these alterations relate to the sequelae of trauma-related symptoms is unknown. Prior models based on non-trauma samples suggest that arousal may impact hippocampal neurophysiology leading to maladaptive behavior. Here we show that decreased hippocampal threat sensitivity interacts with fear-potentiated startle to predict PTSD symptoms. Specifically, individuals with high fear-potentiated startle and low, transient hippocampal threat sensitivity showed the greatest PTSD symptomology. These findings bridge literatures of threat-related arousal and hippocampal function to better understand PTSD risk.

Derivation and Validation of a Brief Emergency Department-Based Prediction Tool for Posttraumatic Stress After Motor Vehicle Collision.

STUDY OBJECTIVE: To derive and initially validate a brief bedside clinical decision support tool that identifies emergency department (ED) patients at high risk of substantial, persistent posttraumatic stress symptoms after a motor vehicle collision. METHODS: Derivation (n=1,282, 19 ED sites) and validation (n=282, 11 separate ED sites) data were obtained from adults prospectively enrolled in the Advancing Understanding of RecOvery afteR traumA study who were discharged from the ED after motor vehicle collision-related trauma. The primary outcome was substantial posttraumatic stress symptoms at 3 months (Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 ≥38). Logistic regression derivation models were evaluated for discriminative ability using the area under the curve and the accuracy of predicted risk probabilities (Brier score). Candidate posttraumatic stress predictors assessed in these models (n=265) spanned a range of sociodemographic, baseline health, peritraumatic, and mechanistic domains. The final model selection was based on performance and ease of administration. RESULTS: Significant 3-month posttraumatic stress symptoms were common in the derivation (27%) and validation (26%) cohort. The area under the curve and Brier score of the final 8-question tool were 0.82 and 0.14 in the derivation cohort and 0.76 and 0.17 in the validation cohort. CONCLUSION: This simple 8-question tool demonstrates promise to risk-stratify individuals with substantial posttraumatic stress symptoms who are discharged to home after a motor vehicle collision. Both external validation of this instrument, and work to further develop more accurate tools, are needed. Such tools might benefit public health by enabling the conduct of preventive intervention trials and assisting the growing number of EDs that provide services to trauma survivors aimed at promoting psychological recovery.

Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation.

OBJECTIVE: This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer's disease (AD) pathogenesis. DESIGN: We analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors. RESULTS: Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-ß plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients' gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPß/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors' microbiota transplants. CONCLUSIONS: These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

Aging, Frailty, and the Microbiome-How Dysbiosis Influences Human Aging and Disease.

The human gut microbiome is a collection of bacteria, protozoa, fungi, and viruses that coexist in our bodies and are essential in protective, metabolic, and physiologic functions of human health. Gut dysbiosis has traditionally been linked to increased risk of infection, but imbalances within the intestinal microbial community structure that correlate with untoward inflammatory responses are increasingly recognized as being involved in disease processes that affect many organ systems in the body. Furthermore, it is becoming more apparent that the connection between gut dysbiosis and age-related diseases may lie in how the gut microbiome communicates with both the intestinal mucosa and the systemic immune system, given that these networks have a common interconnection to frailty. We therefore discuss recent advances in our understanding of the important role the microbiome plays in aging and how this knowledge opens the door for potential novel therapeutics aimed at shaping a less dysbiotic microbiome to prevent or treat age-related diseases.

Socio-demographic and trauma-related predictors of depression within eight weeks of motor vehicle collision in the AURORA study.

BACKGROUND: This is the first report on the association between trauma exposure and depression from the Advancing Understanding of RecOvery afteR traumA(AURORA) multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. METHODS: We focus on participants presenting at EDs after a motor vehicle collision (MVC), which characterizes most AURORA participants, and examine associations of participant socio-demographics and MVC characteristics with 8-week depression as mediated through peritraumatic symptoms and 2-week depression. RESULTS: Eight-week depression prevalence was relatively high (27.8%) and associated with several MVC characteristics (being passenger v. driver; injuries to other people). Peritraumatic distress was associated with 2-week but not 8-week depression. Most of these associations held when controlling for peritraumatic symptoms and, to a lesser degree, depressive symptoms at 2-weeks post-trauma. CONCLUSIONS: These observations, coupled with substantial variation in the relative strength of the mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated in more in-depth analyses of the rich and evolving AURORA database to find new targets for intervention and new tools for risk-based stratification following trauma exposure.

Socio-demographic and trauma-related predictors of PTSD within 8 weeks of a motor vehicle collision in the AURORA study.

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively associated with participant sex (female), low socioeconomic status (education and income), and several self-report indicators of MVC severity. Most of these associations were entirely mediated by peritraumatic symptoms and, to a lesser degree, ASD, suggesting that the first 2 weeks after trauma may be a uniquely important time period for intervening to prevent and reduce risk of PTSD. This observation, coupled with substantial variation in the relative strength of mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated with more in-depth analyses of the rich and evolving AURORA data.

Prior histories of posttraumatic stress disorder and major depression and their onset and course in the three months after a motor vehicle collision in the AURORA study.

BACKGROUND: A better understanding of the extent to which prior occurrences of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) predict psychopathological reactions to subsequent traumas might be useful in targeting posttraumatic preventive interventions. METHODS: Data come from 1306 patients presenting to 29 U.S. emergency departments (EDs) after a motor vehicle collision (MVC) in the advancing understanding of recovery after trauma study. Patients completed self-reports in the ED and 2-weeks, 8-weeks, and 3-months post-MVC. Associations of pre-MVC probable PTSD and probable MDE histories with subsequent 3-months post-MVC probable PTSD and probable MDE were examined along with mediation through intervening peritraumatic, 2-, and 8-week disorders. RESULTS: 27.6% of patients had 3-month post-MVC probable PTSD and/or MDE. Pre-MVC lifetime histories of these disorders were not only significant (relative risk = 2.6-7.4) but were dominant (63.1% population attributable risk proportion [PARP]) predictors of this 3-month outcome, with 46.6% prevalence of the outcome among patients with pre-MVC disorder histories versus 9.9% among those without such histories. The associations of pre-MVC lifetime disorders with the 3-month outcome were mediated largely by 2- and 8-week probable PTSD and MDE (PARP decreasing to 22.8% with controls for these intervening disorders). Decomposition showed that pre-MVC lifetime histories predicted both onset and persistence of these intervening disorders as well as the higher conditional prevalence of the 3-month outcome in the presence of these intervening disorders. CONCLUSIONS: Assessments of pre-MVC PTSD and MDE histories and follow-ups at 2 and 8 weeks could help target early interventions for psychopathological reactions to MVCs.

The AURORA Study: a longitudinal, multimodal library of brain biology and function after traumatic stress exposure.

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, postconcussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large-scale (n = 5000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for 1 year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.

Interim Estimates of Vaccine Effectiveness of Pfizer-BioNTech and Moderna COVID-19 Vaccines Among Health Care Personnel - 33 U.S. Sites, January-March 2021.

Throughout the COVID-19 pandemic, health care personnel (HCP) have been at high risk for exposure to SARS-CoV-2, the virus that causes COVID-19, through patient interactions and community exposure (1). The Advisory Committee on Immunization Practices recommended prioritization of HCP for COVID-19 vaccination to maintain provision of critical services and reduce spread of infection in health care settings (2). Early distribution of two mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) to HCP allowed assessment of the effectiveness of these vaccines in a real-world setting. A test-negative case-control study is underway to evaluate mRNA COVID-19 vaccine effectiveness (VE) against symptomatic illness among HCP at 33 U.S. sites across 25 U.S. states. Interim analyses indicated that the VE of a single dose (measured 14 days after the first dose through 6 days after the second dose) was 82% (95% confidence interval [CI] = 74%-87%), adjusted for age, race/ethnicity, and underlying medical conditions. The adjusted VE of 2 doses (measured ≥7 days after the second dose) was 94% (95% CI = 87%-97%). VE of partial (1-dose) and complete (2-dose) vaccination in this population is comparable to that reported from clinical trials and recent observational studies, supporting the effectiveness of mRNA COVID-19 vaccines against symptomatic disease in adults, with strong 2-dose protection.

Reduction of Inappropriate Antibiotic Use and Improved Outcomes by Implementation of an Algorithm-Based Clinical Guideline for Nonpurulent Skin and Soft Tissue Infections.

STUDY OBJECTIVE: Clinicians currently do not reliably adhere to antibiotic treatment guidelines, resulting in unnecessary patient exposure to broad-spectrum antimicrobials. Our objective is to determine whether a treatment intervention for the management of nonpurulent skin and soft tissue infections increases clinician adherence and improves patient outcomes. METHODS: Between January 1 and December 31, 2017, patients presenting to 2 emergency departments (EDs) and who had received a diagnosis of a nonpurulent skin and soft tissue infection were enrolled and assigned to a pre- or postintervention cohort with a treatment intervention implemented on June 1. Primary outcomes were percentage of ED providers following the guidelines and percentage of patients admitted to the hospital. Secondary outcomes were patient self-reported treatment failure and hospital readmission. RESULTS: There were 1,360 patients, 665 in the preintervention and 695 in the postintervention cohorts. After algorithm implementation, guideline adherence increased (43.0% versus 55.1%; P<.001) and number of patients admitted to the hospital declined (36.5% versus 12.0%; P<.001). In addition, patients reported fewer treatment failures (26.8% versus 16.5%; P=.02) and fewer readmissions (22.3% versus 12.7%; P=.013). After multivariate adjustment, guideline adherence increased by 22% (adjusted relative risk [RR] 1.22; 95% confidence interval [CI] 1.10 to 1.37), whereas hospital admissions were reduced by 26% (adjusted RR 0.74; 95% CI 0.64 to 0.87). In addition, the risks of treatment failure and readmission were reduced by 46% (adjusted RR 0.64; 95% CI 0.43 to 0.97) and 45% (adjusted RR 0.55; 95% CI 0.34 to 0.87), respectively. CONCLUSION: Among patients with a nonpurulent skin and soft tissue infection, implementing an easy-to-follow treatment algorithm can reduce unnecessary antibiotic exposure by increasing clinician guideline adherence while reducing patient treatment failure rates.

Macrolide Resistance in Cases of Community-Acquired Bacterial Pneumonia in the Emergency Department.

BACKGROUND: Emergency physicians are under pressure to prescribe an antibiotic early in the treatment course of a patient with community-acquired pneumonia (CAP). Macrolides are recommended first-line empirical therapy for the outpatient treatment of CAP in patients without associated comorbidities; however, resistance rates to macrolides in the United States are on the rise. OBJECTIVE: This review considers macrolide use for CAP in the emergency department by reviewing the microbiologic environment in the United States and whether macrolides can overcome in vitro resistance during actual clinical use. Alternatives to macrolides for CAP are briefly discussed. DISCUSSION: Resistance to macrolides is now above 25% in all regions of the United States, and resistance to other antibiotics is also on the rise. The failure of outpatient macrolide treatment for CAP because of resistance rates increases the burden of the disease both in terms of the patient and health economics. No definitive answer is available on whether macrolides will achieve treatment success despite infection with in vitro resistant strains. When selecting a therapy, a balance needs to be struck between spectrum of activity targeted against the probable etiology (including atypical pathogens) for respiratory tract infections and the need for first-time success. CONCLUSIONS: Currently available macrolides are now facing resistance rates that cloud their recommendation as a first-line treatment for CAP. Clinicians need a better understanding of their own local resistance rates, while hospitals need to do a better job in describing low- and high-level resistance rates to better inform their physicians.

Elderly patients are at increased risk for treatment failure in outpatient management of purulent skin infections.

OBJECTIVE: Current Infectious Disease Society of America (IDSA) guidelines for the management of purulent skin or soft tissue infections do not account for patient age in treatment recommendations. The study objective was to determine if age was associated with outpatient treatment failure for purulent skin infection after adjusting for IDSA treatment guidelines. METHODS: We conducted a multicenter retrospective study of adult patients treated for a purulent skin infection and discharged home from four emergency departments between April and September 2014. Patients were followed for one month to assess for treatment failure (defined as need for a change in antibiotics, surgical intervention, or hospitalization). We used multivariable logistic regression to examine the role of patient age on treatment failure adjusting for demographic variables (gender, race), comorbidities and severity of infection. RESULTS: A total of 467 patients met inclusion criteria (mean age 37.9years [SD 14.0], 48.2% of whom were women). Overall, 12.4% failed initial therapy. Patients 65years and older (n=35) were almost 4 times more likely to fail initial ED therapy in follow-up compared with younger patients (adjusted Odds Ratio (OR) 3.87, 95% Confidence Interval (CI) 1.24-12.10). After adjustment, for every 10years of advancing age there was a 43% increased odds of failing initial treatment (OR 1.43 95% CI 1.09-1.88). CONCLUSION: Elderly patients with purulent skin infections, whose providers followed the 2014 IDSA guidelines, were more likely to fail initial treatment than younger patients. This study suggests that there is a need to re-evaluate treatment guidelines in elderly patients.

Telomeric ORFs (TLOs) in Candida spp. Encode mediator subunits that regulate distinct virulence traits.

The TLO genes are a family of telomere-associated ORFs in the fungal pathogens Candida albicans and C. dubliniensis that encode a subunit of the Mediator complex with homology to Med2. The more virulent pathogen C. albicans has 15 copies of the gene whereas the less pathogenic species C. dubliniensis has only two (CdTLO1 and CdTLO2). In this study we used C. dubliniensis as a model to investigate the role of TLO genes in regulating virulence and also to determine whether TLO paralogs have evolved to regulate distinct functions. A C. dubliniensis tlo1Δ/tlo2Δ mutant is unable to form true hyphae, has longer doubling times in galactose broth, is more susceptible to oxidative stress and forms increased levels of biofilm. Transcript profiling of the tlo1Δ/tlo2Δ mutant revealed increased expression of starvation responses in rich medium and retarded expression of hypha-induced transcripts in serum. ChIP studies indicated that Tlo1 binds to many ORFs including genes that exhibit high and low expression levels under the conditions analyzed. The altered expression of these genes in the tlo1Δ/tlo2Δ null mutant indicates roles for Tlo proteins in transcriptional activation and repression. Complementation of the tlo1Δ/tlo2Δ mutant with TLO1, but not TLO2, restored wild-type filamentous growth, whereas only TLO2 fully suppressed biofilm growth. Complementation with TLO1 also had a greater effect on doubling times in galactose broth. The different abilities of TLO1 and TLO2 to restore wild-type functions was supported by transcript profiling studies that showed that only TLO1 restored expression of hypha-specific genes (UME6, SOD5) and galactose utilisation genes (GAL1 and GAL10), whereas TLO2 restored repression of starvation-induced gene transcription. Thus, Tlo/Med2 paralogs encoding Mediator subunits regulate different virulence properties in Candida spp. and their expansion may account for the increased adaptability of C. albicans relative to other Candida species.