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Introduction: Biofilm is linked through a variety of mechanisms to the pathogenesis of chronic wounds. However, accurate biofilm detection is challenging, demanding highly specialized and technically complex methods rendering it unapplicable for most clinical settings. This study evaluated promising methods of bedside biofilm localization, fluorescence imaging of wound bacterial loads, and biofilm blotting by comparing their performance against validation scanning electron microscopy (SEM). Methods: In this clinical trial, 40 chronic hard-to-heal wounds underwent the following assessments: (1) clinical signs of biofilm (CSB), (2) biofilm blotting, (3) fluorescence imaging for localizing bacterial loads, wound scraping taken for (4) SEM to confirm matrix encased bacteria (biofilm), and (5) PCR (Polymerase Chain Reaction) and NGS (Next Generation Sequencing) to determine absolute bacterial load and species present. We used a combination of SEM and PCR microbiology to calculate the diagnostic accuracy measures of the CSB, biofilm blotting assay, and fluorescence imaging. Results: Study data demonstrate that 62.5% of wounds were identified as biofilm-positive based on SEM and microbiological assessment. By employing this method to determine the gold truth, and thus calculate accuracy measures for all methods, fluorescence imaging demonstrated superior sensitivity (84%) and accuracy (63%) compared to CSB (sensitivity 44% and accuracy 43%) and biofilm blotting (sensitivity 24% and accuracy 40%). Biofilm blotting exhibited the highest specificity (64%), albeit with lower sensitivity and accuracy. Using SEM alone as the validation method slightly altered the results, but all trends held constant. Discussion: This trial provides the first comparative assessment of bedside methods for wound biofilm detection. We report the diagnostic accuracy measures of these more feasibly implementable methods versus laboratory-based SEM. Fluorescence imaging showed the greatest number of true positives (highest sensitivity), which is clinically relevant and provides assurance that no pathogenic bacteria will be missed. It effectively alerted regions of biofilm at the point-of-care with greater accuracy than standard clinical assessment (CSB) or biofilm blotting paper, providing actionable information that will likely translate into enhanced therapeutic approaches and better patient outcomes.

Venous leg ulcers (VLUs) are traditionally managed with standard‐of‐care dressings, compression and appropriate adjunctive venous interventions for pathologic venous reflux. Due to pathophysiological complexity and underlying patient comorbidities, conducting randomised controlled trials to evaluate the comparative efficacy of advanced treatment modalities is difficult, as many patients would likely be excluded. This retrospective, pragmatic, real‐world evidence (RWE) study compared the healing outcomes of VLUs treated with either ovine forestomach matrix (OFM) (n = 312) or collagen/oxidised regenerated cellulose (ORC) (n = 239) in outpatient wound care centres. Unlike restrictive randomised controlled trials, minimal inclusion and exclusion criteria were applied to create two treatment cohorts that reflected the general VLU population. The incidence (%) of closure was greater in OFM‐treated VLUs at 12, 24 and 36 weeks, and this difference was significant at 24 and 36 weeks compared to collagen/ORC. Median time to wound closure was significantly faster (p = 0.045) in the OFM cohort (11.1 ± 0.6 weeks) compared to the collagen/ORC group (12.3 ± 1.0 weeks). Cox proportional hazards analysis demonstrated that OFM‐treated VLUs had a significantly greater probability of healing (up to ~40%). This RWE comparative efficacy study further substantiates the clinical benefit of OFM in the treatment of chronic wounds, such as VLU, in a real‐world patient cohort.

The retrospective pragmatic real‐world data (RWD) study compared the healing outcomes of diabetic foot ulcers (DFUs) treated with either ovine forestomach matrix (OFM) (n = 1150) or collagen/oxidised regenerated cellulose (ORC) (n = 1072) in out‐patient wound care centres. Median time to wound closure was significantly (P = .0015) faster in the OFM group (14.6 ± 0.5 weeks) relative to the collagen/ORC group (16.4 ± 0.7). A sub‐group analysis was performed to understand the relative efficacy in DFUs requiring longer periods of treatment and showed that DFUs treated with OFM healed up to 5.3 weeks faster in these challenging wounds. The percentage of wounds closed at 36 weeks was significantly improved in OFM treated DFUs relative to the collagen/ORC. A Cox proportional hazards analysis showed OFM‐treated wounds had a 18% greater probability of healing versus wounds managed with collagen/ORC, and the probability increased to 21% when the analysis was adjusted for multiple variables. This study represents the first large retrospective RWD analysis comparing OFM and collagen/ORC and supports the clinical efficacy of OFM in the treatment of DFUs.

Background Methods for near-real-time monitoring of new drugs in electronic healthcare data are needed. Objective In a novel application, we prospectively monitored ischemic, bleeding, and mortality outcomes among patients initiating prasugrel versus clopidogrel in routine care during the first 2 years following the approval of prasugrel. Methods Using the HealthCore Integrated Research Database, we conducted a prospective cohort study comparing prasugrel and clopidogrel initiators in the 6 months following the introduction of prasugrel and every 2 months thereafter. We identified patients who initiated antiplatelets within 14 days following discharge from hospitalizations for myocardial infarction (MI) or acute coronary syndrome. We matched patients using high-dimensional propensity scores (hd-PSs) and followed them for ischemic (i.e., MI and ischemic stroke) events, bleed (i.e., hemorrhagic stroke and gastrointestinal bleed) events, and all-cause mortality. For each outcome, we applied sequential alerting algorithms. Results We identified 1,282 eligible new users of prasugrel and 8,263 eligible new users of clopidogrel between September 2009 and August 2011. In hd-PS matched cohorts, the overall MI rate difference (RD) comparing prasugrel with clopidogrel was −23.1 (95 % confidence interval [CI] −62.8–16.7) events per 1,000 person-years and RDs were −0.5 (−12.9–11.9) and −2.8 (−13.2–7.6) for a composite bleed event outcome and death from any cause, respectively. No algorithms generated alerts for any outcomes. Conclusions Near-real-time monitoring was feasible and, in contrast to the key pre-marketing trial that demonstrated the efficacy of prasugrel, did not suggest that prasugrel compared with clopidogrel was associated with an increased risk of gastrointestinal and intracranial bleeding.

Under the United States Endangered Species Act, a species is granted protection if it is in danger of extinction throughout all or a significant portion of its range. Since 2016, the United States Fish and Wildlife Service has adopted a more analytical approach to determining significant portion of its range. Termed Species Status Assessment (SSA), this approach addresses whether loss of individuals from a portion of its range will influence at least one of the conservation biology principles of redundancy (ability to withstand catastrophic events), resiliency (ability to withstand stochastic events), and representation (ability to adapt over time to long-term changes in the environment). Using Sicklefin Redhorse (Moxostoma sp.), we illustrate the use of genetic data to evaluate each SSA metric. We sampled (n = 382) Sicklefin Redhorse from three major river basins throughout its contemporary distribution and estimated genetic parameters using ten microsatellite markers. Using STRUCTURE analyses, we showed that redundancy was three, but our approximate Bayesian computation analysis revealed that this value could be reduced to two if admixture, due to anthropogenic stressors of the 1900s, continues. We used estimates of effective population size (Ne) to measure resiliency and representation and found that all populations showed resiliency and representation with Ne ≥ 479. Genetic monitoring of the Little Tennessee and Tuckasegee populations will be necessary to assess the future status of redundancy for this species. Any reduction in redundancy would warrant further ESA evaluation.

Abstract Background Circuit-induced hemolysis is relatively common in extracorporeal membrane oxygenation (ECMO) patients. Intravascular release of cell-free hemoglobin can lead to complications and requires timely recognition. Validation of plasma free hemoglobin (PFH) measurement using a direct spectrophotometric method is presented. Methodology We evaluated a method modified from Kahn et al. (Ann Clin Lab Sci 1981;11:126–31) on a stand-alone spectrophotometer (Cary 60) and compared its performance to the semiquantitative H-index on an Abbott Alinity c, including precision, linearity, recovery, reference interval verification, interference, and stability. Method comparison was performed relative to the H-index and the same method on a different spectrophotometer (Beckman DU 720). Lipemia interference was performed on the Cary 60, Cary 3500, and Beckman DU 720. Surrogate biomarkers for hemolysis detection were also investigated in ECMO patients. Results The PFH method on the Cary 60 demonstrated imprecision ranging from 1% (96.0 mg/dL) to 4% (3.0 mg/dL), linearity to 100 mg/dL, and recovery >80% for values >2 mg/dL hemoglobin-spiked plasma. Dilution expanded the reportable range to the maximum dilution tested (1000 mg/dL). Lipemia interfered with PFH measurement by the direct method, but the same method on the Cary 3500 was resistant to lipemia. Bilirubin did not cause significant interference. Direct and H-index methods were comparable with a mean difference of 5.03 mg/dL (95% CI −1.38, 11.44). Lactate dehydrogenase was the most reliable surrogate biomarker for hemolysis. with AUC of 0.921 (0.894, 0.949) at >50 mg/dL. Conclusion PFH measurement by a direct spectrophotometric method is more precise and sensitive compared to the H-index; however, PFH measurement is susceptible to lipemia unless performed on a high-end spectrophotometer.

Maize (Zea mays, L.) breeding research in the public sector involves identifying novel genes, alleles, and breeding procedures that have promising commercial applications, but this role is stymied due to limited access to commercial quality lines and hybrids. Use of lines recently released from Plant Variety Protection (PVP) may be a solution. Our overall goal was to investigate the extent and nature of the allelic diversity in elite maize germplasm at the molecular level and gain insight into how this allelic diversity relates to the performance of superior hybrids. The specific objectives were to (i) characterize the genetic composition of 12 selected elite inbreds, (ii) evaluate these inbreds and their 66 F1 hybrids and segregating F1 derived F2 populations for an extensive number of leaf, tassel, and ear traits, including yield, and (iii) perform a statistical and quantitative genetic analysis to identify significant genetic variation thereof. Cluster analysis based on pedigree relationships and molecular markers indicated that the selected elite inbred parents are genetically diverse. Applying the Eberhart and Gardner general model we confirmed the presence of substantial additive, dominance, and epistatic variation in the elite germplasm selected and developed for this experiment. Experimental material derived from Ex‐PVP lines will be an important component of maize breeding research on increased productivity. In this research, hybrid mapping populations will prove to be invaluable for detection of nonadditive quantitative trait loci and association effects in yield related traits.

Background: Several efforts are under way to develop and test methods for prospective drug safety monitoring using large, electronic claims databases. Prospective monitoring systems must incorporate signalling algorithms and techniques to mitigate confounding in order to minimize false positive and false negative signals due to chance and bias. Objective: The aim of the study was to describe a prototypical targeted active safety monitoring system and apply the framework to three empirical examples. Methods: We performed sequential, targeted safety monitoring in three known drug/adverse event (AE) pairs: (i) paroxetine/upper gastrointestinal (UGI) bleed; (ii) lisinopril/angioedema; (iii) ciprofloxacin/Achilles tendon rupture (ATR). Data on new users of the drugs of interest were extracted from the HealthCore Integrated Research Database. New users were matched by propensity score to new users of comparator drugs in each example. Analyses were conducted sequentially to emulate prospective monitoring. Two signalling rules — a maximum sequential probability ratio test and an effect estimate-based approach — were applied to sequential, matched cohorts to identify signals within the system. Results: Signals were identified for all three examples: paroxetine/UGI bleed in the seventh monitoring cycle, within 2 calendar years of sequential data; lisinopril/angioedema in the second cycle, within the first monitoring year; ciprofloxacin/ATR in the tenth cycle, within the fifth year. Conclusion: In this proof of concept, our targeted, active monitoring system provides an alternative to systems currently in the literature. Our system employs a sequential, propensity score-matched framework and signalling rules for prospective drug safety monitoring and identified signals for all three adverse drug reactions evaluated.

Vascular contributions are now widely accepted to play a key role in many cases of dementia, including Alzheimer's disease (AD), that commonly manifest as cerebral small vessel diseases, including cerebral amyloid angiopathy (CAA). However, the mechanisms by which vascular contributions such as CAA contribute dementias such as AD are not well understood. This is due in part to the lack mouse models that develop robust CAA, hampering our ability to develop therapies that target vascular deficits. To address this, we have explored the use of distinct genetic contexts to enhance the face validity of mouse models for AD. We have previously identified the WSB/EiJ (WSB) strain as a model that shows increased susceptibility to CAA in the presence of the amyloid driver, compared to the commonly used C57BL/6J (B6) strain. Here, we now perform an in-depth characterization of WSB. and its WSB wild type (WT) counterpart, assessing male and female mice, at 4, 8, and 12 months of age (M). We show that WSB. mice show mild CAA at 8M, with robust CAA being apparent at 14M. Transcriptional profiling showed strong correlation to AMP-AD gene expression modules highlighting the human relevance of WSB. mice and predicted white matter deficits at 14M that was confirmed by immunofluorescence. PET/CT showed blood flow and metabolic deficits, and modifications in small vessel morphology in 8M WSB. compared to WSB WT mice. We tested whether cerebrovascular reactivity deficits in WSB WT mice may underly the susceptibility to CAA, but interestingly, they did not show age-dependent decline in reactivity that was observed in B6 mice. Finally, using an allelic series of humanized apolipoprotein E ( ), we show that increased the extent of CAA in WSB. mice, compared to and , but in a sex-dependent manner. Collectively, these data show the utility of the WSB strain to uncover mechanisms of vascular contributions to Alzheimer's disease and related dementias.