Selective Depletion of Staphylococcus aureus Restores the Skin Microbiome and Accelerates Tissue Repair after Injury.

Our skin is home to a diverse community of commensal microorganisms integral to cutaneous function. However, microbial dysbiosis and barrier perturbation increase the risk of local and systemic infection. Staphylococcus aureus is a particularly problematic bacterial pathogen, with high levels of antimicrobial resistance and direct association with poor healing outcome. Innovative approaches are needed to selectively kill skin pathogens, such as S aureus, without harming the resident microbiota. In this study, we provide important data on the selectivity and efficacy of an S aureus-targeted endolysin (XZ.700) within the complex living skin/wound microbiome. Initial cross-species comparison using Nanopore long-read sequencing identified the translational potential of porcine rather than murine skin for human-relevant microbiome studies. We therefore performed an interventional study in pigs to assess the impact of endolysin administration on the microbiome. XZ.700 selectively inhibited endogenous porcine S aureus in vivo, restoring microbial diversity and promoting multiple aspects of wound repair. Subsequent mechanistic studies confirmed the importance of this microbiome modulation for effective healing in human skin. Taken together, these findings strongly support further development of S aureus-targeted endolysins for future clinical management of skin and wound infections.

A Bayesian Motivated Two-Sample Test Based on Kernel Density Estimates.

A new nonparametric test of equality of two densities is investigated. The test statistic is an average of log-Bayes factors, each of which is constructed from a kernel density estimate. Prior densities for the bandwidths of the kernel estimates are required, and it is shown how to choose priors so that the log-Bayes factors can be calculated exactly. Critical values of the test statistic are determined by a permutation distribution, conditional on the data. An attractive property of the methodology is that a critical value of 0 leads to a test for which both type I and II error probabilities tend to 0 as sample sizes tend to ∞. Existing results on Kullback-Leibler loss of kernel estimates are crucial to obtaining these asymptotic results, and also imply that the proposed test works best with heavy-tailed kernels. Finite sample characteristics of the test are studied via simulation, and extensions to multivariate data are straightforward, as illustrated by an application to bivariate connectionist data.

Pre-Clinical Assessment of Single-Use Negative Pressure Wound Therapy During In Vivo Porcine Wound Healing.

Objective: Traditional negative pressure wound therapy (tNPWT) systems can be large and cumbersome, limiting patient mobility and adversely affecting quality of life. PICO™, a no canister single-use system, offers a lightweight, portable alternative to tNPWT, with improved clinical performance. The aim of this study was to determine the potential mechanism(s) of action of single-use NPWT (sNPWT) versus tNPWT. Approach: sNPWT and tNPWT were applied to an in vivo porcine excisional wound model, following product use guidelines. Macroscopic, histological, and biochemical analyses were performed at defined healing time points to assess multiple aspects of the healing response. Results: Wounds treated with single-use negative pressure displayed greater wound closure and increased reepithelialization versus those treated with traditional negative pressure. The resulting granulation tissue was more advanced with fewer neutrophils, reduced inflammatory markers, more mature collagen, and no wound filler-associated foreign body reactions. Of note, single-use negative pressure therapy failed to induce wound edge epithelial hyperproliferation, while traditional negative pressure therapy compromised periwound skin, which remained inflamed with high transepidermal water loss; features not observed following single-use treatment. Innovation: Single-use negative pressure was identified to improve multiple aspects of healing versus traditional negative pressure treatment. Conclusion: This study provides important new insight into the differing mode of action of single-use versus traditional negative pressure and may go some way to explaining the improved clinical outcomes observed with single-use negative pressure therapy.

Effects of the no interruption zone on distraction levels, withdrawal times, and adenoma detection rates of colonoscopy.

BACKGROUND: The creation of no interruption zones (NIZs) reduces medical errors by reducing distraction levels on hospital wards. To date, the effect of a NIZ during colonoscopy has not been evaluated. AIMS: Assess the effects of a NIZ during colonoscopy, on distraction levels, withdrawal times, and adenoma detection rates (ADRs). METHODS: This was a non-randomized prospective study of screening colonoscopies at a teaching hospital. The intervention, a NIZ, was created by limiting conversations to the care of the patient undergoing the procedure and posting a "do not disturb" sign during the withdrawal phase of colonoscopy. Distraction levels, withdrawal times, and ADRs were analyzed at baseline and after the NIZ. RESULTS: The implementation of the NIZ leads to a significant reduction of high-distraction-level environments (13.1 vs. 5.1 %; p < 0.0001). There was a significant decrease in withdrawal time with NIZs; (10.6 vs. 9.9 min, p = 0.0038). There was no significant difference in ADRs (38 % baseline vs. 36 % NIZs, respectively; p = 0.33). CONCLUSIONS: Creation of a NIZ was associated with a significant decrease in high-distraction environments and shorter withdrawal times with no significant change in ADRs. Further studies are needed to evaluate whether lower distraction levels in an endoscopy suite translate to improved quality measures.

BK virus as a potential co-factor for HPV in the development of cervical neoplasia.

Cervical cancer is the third most common type of cancer in women worldwide. A persistent infection with high risk (HR) human papillomavirus (HPV) is necessary for cervical cancer to occur. However, the great majority of women that are infected with HR-HPV will not develop cervical cancer, indicating that HR-HPV alone is not adequate to drive the development of cervical cancer, suggesting the involvement of cofactors. The BK polyomavirus (BKV) establishes latency near cervical tissue in the urogenital tract and is frequently detected in the urine, especially in immunosuppressed patients, and hence may coexist with HR-HPV. Current experimental evidence indicates that both HR-HPV and BKV are capable of altering cell-cycle control and inhibit apoptosis. Therefore, they may act additively or synergistically to promote malignant transformation. We hypothesize that BKV is a co-factor for HR-HPV in cervical cancer. In this study, we examined 249 cervical swabs that were submitted for routine HR-HPV screening test in the Molecular Diagnostics Laboratory at the University of Texas Medical Branch (UTMB). Our results showed that 107 samples contained HR-HPV at an overall rate of 43% (107/249); BKV was present in 4 (3.7%) of the 107 HR-HPV positive specimens and in 12 (8.5%) of the 142 HR-HPV negative samples with an overall positive rate of 6.4% (16/249). Although there was no statistical significance between HR-HPV and BKV co-infection (P=0.19, Fisher's exact test), our results support the hypothesis that BKV can co-exist with HR-HPV in cervical specimens.

Local and omnibus goodness-of-fit tests in classical measurement error models.

We consider functional measurement error models, i.e. models where covariates are measured with error and yet no distributional assumptions are made about the mismeasured variable. We propose and study a score-type local test and an orthogonal series-based, omnibus goodness-of-fit test in this context, where no likelihood function is available or calculated-i.e. all the tests are proposed in the semiparametric model framework. We demonstrate that our tests have optimality properties and computational advantages that are similar to those of the classical score tests in the parametric model framework. The test procedures are applicable to several semiparametric extensions of measurement error models, including when the measurement error distribution is estimated non-parametrically as well as for generalized partially linear models. The performance of the local score-type and omnibus goodness-of-fit tests is demonstrated through simulation studies and analysis of a nutrition data set.

Density Estimation in Several Populations With Uncertain Population Membership.

We devise methods to estimate probability density functions of several populations using observations with uncertain population membership, meaning from which population an observation comes is unknown. The probability of an observation being sampled from any given population can be calculated. We develop general estimation procedures and bandwidth selection methods for our setting. We establish large-sample properties and study finite-sample performance using simulation studies. We illustrate our methods with data from a nutrition study.

Bias properties of Bayesian statistics in finite mixture of negative binomial regression models in crash data analysis.

Factors that cause heterogeneity in crash data are often unknown to researchers and failure to accommodate such heterogeneity in statistical models can undermine the validity of empirical results. A recently proposed finite mixture for the negative binomial regression model has shown a potential advantage in addressing the unobserved heterogeneity as well as providing useful information about features of the population under study. Despite its usefulness, however, no study has been found to examine the performance of this finite mixture under various conditions of sample sizes and sample-mean values that are common in crash data analysis. This study investigated the bias associated with the Bayesian summary statistics (posterior mean and median) of dispersion parameters in the two-component finite mixture of negative binomial regression models. A simulation study was conducted using various sample sizes under different sample-mean values. Two prior specifications (non-informative and weakly-informative) on the dispersion parameter were also compared. The results showed that the posterior mean using the non-informative prior exhibited a high bias for the dispersion parameter and should be avoided when the dataset contains less than 2,000 observations (even for high sample-mean values). The posterior median showed much better bias properties, particularly at small sample sizes and small sample means. However, as the sample size increases, the posterior median using the non-informative prior also began to exhibit an upward-bias trend. In such cases, the posterior mean or median with the weakly-informative prior provided smaller bias. Based on simulation results, guidelines about the choice of priors and the summary statistics to use are presented for different sample sizes and sample-mean values.

Hypertrichosis of vellus hairs of the malar region after unilateral treatment with bimatoprost.

PURPOSE: To report hypertrichosis and increased pigmentation of vellus hairs of the malar region associated with topical bimatoprost usage. DESIGN: Interventional case report METHODS: In a female Hispanic patient with open-angle glaucoma, hypertrichosis, and increased pigmentation of the vellus hairs of the malar region developed after 8 weeks of unilateral treatment with bimatoprost. Increased growth of eyelashes was also noted. RESULTS: Bimatoprost was discontinued, with the intention of monitoring for resolution of hypertrichosis. The patient epilated the hair because of poor cosmetic appearance. Two months after epilating the hair, growth did not recur. CONCLUSIONS: Increased hair growth in the malar region can be an early side effect of topical use of ocular bimatoprost.

The role of oxidised regenerated cellulose/collagen in wound repair: effects in vitro on fibroblast biology and in vivo in a model of compromised healing.

Irrespective of underlying chronic wound pathology, delayed wound healing is normally characterised by impaired new tissue formation at the site of injury. It is thought that this impairment reflects both a reduced capacity to synthesize new tissue and the antagonistic activities of high levels of proteinases within the chronic wound environment. Historically, wound dressings have largely been passive devices that offer the wound interim barrier function and establish a moist healing environment. A new generation of devices, designed to interact with the wound and promote new tissue formation, is currently being developed and tested. This study considers one such device, oxidised regenerated cellulose (ORC) /collagen, in terms of its ability to promote fibroblast migration and proliferation in vitro and to accelerate wound repair in the diabetic mouse, a model of delayed wound healing. ORC/collagen was found to promote both human dermal fibroblasts proliferation and cell migration. In vivo studies considered the closure and histological characteristics of diabetic wounds treated with ORC/collagen compared to those of wounds given standard treatment on both diabetic and non-diabetic mice. ORC/collagen was found to significantly accelerate diabetic wound closure and result in a measurable improvement in the histological appearance of wound tissues. As the diabetic mouse is a recognised model of impaired healing, which may share some characteristics of human chronic wounds, the results of this in vivo study, taken together with those relating the positive effects of ORC/collagen in vitro, may predict the beneficial use of this device in the clinical setting.

RUST FUNGI AND HOST PLANT COEVOLUTION: DO PRIMITIVE HOSTS HARBOR PRIMITIVE PARASITES?

Abstract- The classical view of rust phylogeny is that rusts found on ferns and conifers are primitive, while rusts that parasitize angiosperms are advanced. This belief was based on the theory that primitive hosts harbor primitive parasites; that is, it assumed coevolution (co-speciation) of hosts and parasites. A cladistic analysis of 30 genera and 28 characters representative of the major patterns of rust fungi diversity is presented. The results of this analysis suggest that tropical short-cycle rusts on angiosperms form the cladistically basal group of rusts, while the rusts on conifers and ferns (Melampsoraceae sensu lato) form a nested terminal clade. These results suggest that rusts and their hosts have not undergone a long period of parallel cladogenesis (co-speciation); host transfer has probably been at least as frequent as co-speciation. The cladograms indicate evolutionary trends of spore stages and life history: urediniospores evidently preceded the evolution of aeciospores and pycniospores within Uredinales, and heteroecism is a derived condition which evolved at least several times. This study stresses the importance of making use of independent cladistic analyses of both host and parasite in order to test assumptions of coevolution and host transfer.