Mathematical model predicts anti-adhesion--antibiotic--debridement combination therapies can clear an antibiotic resistant infection

As antimicrobial resistance increases, it is crucial to develop new treatment strategies to counter the emerging threat. In this paper, we consider combination therapies involving conventional antibiotics and debridement, coupled with a novel anti-adhesion therapy, and their use in the treatment of antimicrobial resistant burn wound infections. Our models predict that anti-adhesion–antibiotic–debridement combination therapies can eliminate a bacterial infection in cases where each treatment in isolation would fail. Antibiotics are assumed to have a bactericidal mode of action, killing bacteria, while debridement involves physically cleaning a wound (e.g. with a cloth); removing free bacteria. Anti-adhesion therapy can take a number of forms. Here we consider adhesion inhibitors consisting of polystyrene microbeads chemically coupled to a protein known as multivalent adhesion molecule 7, an adhesin which mediates the initial stages of attachment of many bacterial species to host cells. Adhesion inhibitors competitively inhibit bacteria from binding to host cells, thus rendering them susceptible to removal through debridement. An ordinary differential equation model is developed and the antibiotic-related parameters are fitted against new in vitro data gathered for the present study. The model is used to predict treatment outcomes and to suggest optimal treatment strategies. Our model predicts that anti-adhesion and antibiotic therapies will combine synergistically, producing a combined effect which is often greater than the sum of their individual effects, and that anti-adhesion–antibiotic–debridement combination therapy will be more effective than any of the treatment strategies used in isolation. Further, the use of inhibitors significantly reduces the minimum dose of antibiotics required to eliminate an infection, reducing the chances that bacteria will develop increased resistance. Lastly, we use our model to suggest treatment regimens capable of eliminating bacterial infections within clinically relevant timescales

Retrospective Study of Midazolam Protocol for Prehospital Behavioral Emergencies

Introduction: Agitated patients in the prehospital setting pose challenges for both patient care and emergency medical services (EMS) provider safety. Midazolam is frequently used to control agitation in the emergency department setting; however, limited data exist in the prehospital setting. We describe our experience treating patients with midazolam for behavioral emergencies in a large urban EMS system. We hypothesized that using midazolam for acute agitation leads to improved clinical conditions without causing significant clinical deterioration.Methods: We performed a retrospective review of EMS patient care reports following implementation of a behavioral emergencies protocol in a large urban EMS system from February 2014–June 2016. For acute agitation, paramedics administered midazolam 1 milligram (mg) intravenous (IV), 5 mg intramuscular (IM), or 5 mg intranasal (IN). Results were analyzed using descriptive statistics, Levene’s test for assessing variance among study groups, and t-test to evaluate effectiveness based on route.Results: In total, midazolam was administered 294 times to 257 patients. Median age was 30 (interquartile range 24–42) years, and 66.5% were male. Doses administered were 1 mg (7.1%) and 5 mg (92.9%). Routes were IM (52.0%), IN (40.8%), and IV (7.1%). A second dose was administered to 37 patients. In the majority of administrations, midazolam improved the patient’s condition (73.5%) with infrequent adverse events (3.4%). There was no significant difference between the effectiveness of IM and IN midazolam (71.0% vs 75.4%; p = 0.24).Conclusion: A midazolam protocol for prehospital agitation was associated with reduced agitation and a low rate of adverse events

Resident-Led Physical Wellness Initiative Linked to Less Burnout for Emergency Physicians during COVID-19 Pandemic

Introduction: The COVID-19 pandemic has taken a significant toll on societal, physical, and psychological health. Emergency physicians (EPs) are susceptible to burnout under ordinary circumstances and may be particularly vulnerable during the pandemic. To reduce pandemic-related burnout, we implemented a residency-led physical wellness initiative and evaluated the effect on burnout among EPs. Methods: In the spring of 2020, we invited all resident and attending EPs in our department to participate in a four-week physical wellness initiative as part of a prospective study. After completing or opting out of this wellness initiative, EPs responded to an online survey comprised of five sections: demographics, participation, opinion on wellness initiative, opinion on the impact of COVID-19, and the Maslach Burnout Index (MBI-HSS). We stratified respondents by initiative participation, described the characteristics of each group, and then compared the perceived impact of COVID-19 and the MBI-HSS results between the two groups. Results: Out of 110 eligible participants, 57 EPs completed the survey (51.8%). Thirty-five respondents completed the wellness initiative. Few (37.1%) documented their progress, though most worked with accountability partners (85.7%). Most enrollees enjoyed participation (Likert Score 3.2-5, CI 2.9-3.5) and would participate again (3.3, CI 3.0-3.6). The reported effect of the COVID-19 pandemic on mental wellbeing was lower for participants, although this was not significant (2.1, CI 1.5-2.1 vs 2.4, CI 2.0-2.7, p=0.312). On the MBI-HSS, participants had a lower emotional exhaustion score (1.4, 95% CI 0.9-1.8) than non-participants (2.2, 95%CI 1.8-2.6, p=0.005). Conclusion: Participation in a residency-led, physical wellness initiative was linked to lower emotional exhaustion for EPs during the COVID-19 pandemic

Population Genetics of Bowhead Whales (Baleana mysticetus) in the Western Arctic

Bowhead whales (Balaena mysticetus) in the Bering, Chukchi, and Beaufort seas experienced a severe reduction as a result of commercial whaling in the 19th century. Since the cessation of commercial whaling, the population has recovered to a size that is approaching pre-whaling estimates. Inupiat and Yupik communities in northern and western Alaska hunt these Western Arctic (WA) bowheads along their migratory path during spring and fall. This hunting is regulated by the International Whaling Commission. Recent but preliminary analysis of available genetic data (207 whales and 10 microsatellite markers) raised the question of the presence of multiple, genetically distinct populations within the WA bowheads. Here we re-examined this question on the basis of a study of 414 whales and 22 newly developed microsatellite loci. We identified widespread departures from Hardy-Weinberg equilibrium; however, we were unable to detect significant evidence of multiple genetic populations within the WA bowheads that could explain this Hardy-Weinberg disequilibrium, particularly when compared to the strength of evidence for differentiation between WA bowheads and other populations from distant regions such as the Okhotsk Sea and eastern Canada. There was conclusive evidence of genetic differentiation among the three regions. The statistical rejection of panmixia within the WA improves our understanding of bowhead whale biology, and the lack of evidence for multiple populations within the WA enables risk-averse management of aboriginal hunting of Western Arctic bowhead whales.La population de baleines boréales (Balaena mysticetus) des mers de Béring, de Tchoukotka et de Beaufort a enregistré un grave déclin en raison de la pêche commerciale à la baleine au XIXe siècle. Depuis que la pêche commerciale à la baleine a cessé, la population de baleines boréales a connu un certain essor au point où elle approche maintenant les estimations de la taille qu’elle avait avant la pêche commerciale à la baleine. Les collectivités Inupiat et Yupik du nord et de l’ouest de l’Alaska chassent les baleines boréales de l’ouest de l’Arctique le long de leur voie de migration au printemps et à l’automne. La chasse est réglementée par l’International Whaling Commission. Des analyses récentes, bien que préliminaires, des données génétiques disponibles (207 baleines et 10 marqueurs microsatellites) ont soulevé la question de la présence de multiples populations génétiquement distinctes au sein de la population de baleines boréales de l’ouest de l’Alaska. Ici, nous avons réexaminé cette question en fonction de l’étude de 414 baleines et de 22 locis microsatellites nouvellement mis au point. Nous avons remarqué d’importantes déviations de l’équilibre de Hardy-Weinberg; toutefois, nous n’avons pas pu trouver de preuve significative de populations génétiques multiples au sein des baleines boréales de l’ouest de l’Alaska qui pourrait expliquer ce déséquilibre de Hardy-Weinberg, plus particulièrement en comparaison avec la force de la preuve de différenciation entre les baleines boréales de l’ouest de l’Arctique et d’autres populations de régions distantes telles que la mer d’Okhotsk et l’est du Canada. Il y avait des preuves concluantes de différenciation génétique entre les trois régions. Le rejet statistique de la panmixie au sein de l’ouest de l’Arctique améliore notre compréhension de la biologie des baleines boréales, et le manque de preuves de populations multiples dans l’ouest de l’Arctique donne lieu à la gestion de l’aversion au risque de la chasse à la baleine boréale de l’ouest de l’Arctique par les Autochtones

Targeting bacterial adherence inhibits multidrug-resistant Pseudomonas aeruginosa infection following burn injury

Classical antimicrobial drugs target proliferation and therefore place microbes under extreme selective pressure to evolve resistance. Alternative drugs that target bacterial virulence without impacting survival directly offer an attractive solution to this problem, but to date few such molecules have been discovered. We previously discovered a widespread group of bacterial adhesins, termed Multivalent Adhesion Molecules (MAMs) that are essential for initial binding of bacteria to host tissues and virulence. Thus, targeting MAM-based adherence is a promising strategy for displacing pathogens from host tissues and inhibiting infection. Here, we show that topical application of polymeric microbeads functionalized with the adhesin MAM7 to a burn infected with multidrug-resistant Pseudomonas aeruginosa substantially decreased bacterial loads in the wound and prevented the spread of the infection into adjacent tissues. As a consequence, the application of this adhesion inhibitor allowed for vascularization and wound healing, and maintained local and systemic inflammatory responses to the burn. We propose that MAM7-functionalized microbeads can be used as a topical treatment, to reduce bacterial attachment and hence prevent bacterial colonization and infection of wounds. As adhesion is not required for microbial survival, this anti-infective strategy has the potential to treat multidrug-resistant infections and limit the emergence of drug-resistant pathogens

Predictive modelling of a novel anti-adhesion therapy to combat bacterial colonisation of burn wounds

As the development of new classes of antibiotics slows, bacterial resistance to existing antibiotics is becoming an increasing problem. A potential solution is to develop treatment strategies with an alternative mode of action. We consider one such strategy: anti-adhesion therapy. Whereas antibiotics act directly upon bacteria, either killing them or inhibiting their growth, anti-adhesion therapy impedes the binding of bacteria to host cells. This prevents bacteria from deploying their arsenal of virulence mechanisms, while simultaneously rendering them more susceptible to natural and artificial clearance. In this paper, we consider a particular form of anti-adhesion therapy, involving biomimetic multivalent adhesion molecule 7 coupled polystyrene microbeads, which competitively inhibit the binding of bacteria to host cells. We develop a mathematical model, formulated as a system of ordinary differential equations, to describe inhibitor treatment of a Pseudomonas aeruginosa burn wound infection in the rat. Benchmarking our model against in vivo data from an ongoing experimental programme, we use the model to explain bacteria population dynamics and to predict the efficacy of a range of treatment strategies, with the aim of improving treatment outcome. The model consists of two physical compartments: the host cells and the exudate. It is found that, when effective in reducing the bacterial burden, inhibitor treatment operates both by preventing bacteria from binding to the host cells and by reducing the flux of daughter cells from the host cells into the exudate. Our model predicts that inhibitor treatment cannot eliminate the bacterial burden when used in isolation; however, when combined with regular or continuous debridement of the exudate, elimination is theoretically possible. Lastly, we present ways to improve therapeutic efficacy, as predicted by our mathematical model

Bacterial adhesion inhibitor prevents infection in a rodent surgical incision model

Surgical site infection risk continues to increase due to lack of efficacy in current standard of care drugs. New methods to treat or prevent antibiotic-resistant bacterial infections are needed. Multivalent Adhesion Molecules (MAM) are bacterial adhesins required for virulence. We developed a bacterial adhesion inhibitor using recombinant MAM fragment bound to polymer scaffold, mimicking MAM7 display on the bacterial surface. Here, we test MAM7 inhibitor efficacy to prevent Gram-positive and Gram-negative infections. Using a rodent model of surgical infection, incision sites were infected with antibiotic-resistant bioluminescent strains of Staphylococcus aureus or Pseudomonas aeruginosa. Infections were treated with MAM7 inhibitor or control suspension. Bacterial abundance was quantified for nine days post infection. Inflammatory responses and histology were characterized using fixed tissue sections. MAM7 inhibitor treatment decreased burden of S. aureus and P. aeruginosa below detection threshold. Bacterial load of groups treated with control were significantly higher than MAM7 inhibitor-treated groups. Treatment with inhibitor reduced colonization of clinically-relevant pathogens in an in vivo model of surgical infection. Use of MAM7 inhibitor to block initial adhesion of bacteria to tissue in surgical incisions may reduce infection rates, presenting a strategy to mitigate overuse of antibiotics to prevent surgical site infections

Can Genetic Analysis of Putative Blood Alzheimer’s Disease Biomarkers Lead to Identification of Susceptibility Loci?

Although 24 Alzheimer’s disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10-7. Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated

A Blood-Based Screening Tool for Alzheimer's Disease That Spans Serum and Plasma: Findings from TARC and ADNI

There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimer's disease (AD) at the population level.To generate and cross-validate a blood-based screener for AD that yields acceptable accuracy across both serum and plasma. status) data.Alzheimer's disease.11 proteins met our criteria and were utilized for the biomarker risk score. The random forest (RF) biomarker risk score from the TARC serum samples (training set) yielded adequate accuracy in the ADNI plasma sample (training set) (AUC = 0.70, sensitivity (SN) = 0.54 and specificity (SP) = 0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/Aβ ratio AUC = 0.92). However, the full algorithm yielded excellent accuracy (AUC = 0.88, SN = 0.75, and SP = 0.91). The likelihood ratio of having AD based on a positive test finding (LR+) = 7.03 (SE = 1.17; 95% CI = 4.49–14.47), the likelihood ratio of not having AD based on the algorithm (LR−) = 3.55 (SE = 1.15; 2.22–5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR) = 28.70 (1.55; 95% CI = 11.86–69.47).It is possible to create a blood-based screening algorithm that works across both serum and plasma that provides a comparable screening accuracy to that obtained from CSF analyses

Long COVID Clinical Phenotypes up to 6 Months After Infection Identified by Latent Class Analysis of Self-Reported Symptoms

BACKGROUND: The prevalence, incidence, and interrelationships of persistent symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection vary. There are limited data on specific phenotypes of persistent symptoms. Using latent class analysis (LCA) modeling, we sought to identify whether specific phenotypes of COVID-19 were present 3 months and 6 months post-infection. METHODS: This was a multicenter study of symptomatic adults tested for SARS-CoV-2 with prospectively collected data on general symptoms and fatigue-related symptoms up to 6 months postdiagnosis. Using LCA, we identified symptomatically homogenous groups among COVID-positive and COVID-negative participants at each time period for both general and fatigue-related symptoms. RESULTS: Among 5963 baseline participants (4504 COVID-positive and 1459 COVID-negative), 4056 had 3-month and 2856 had 6-month data at the time of analysis. We identified 4 distinct phenotypes of post-COVID conditions (PCCs) at 3 and 6 months for both general and fatigue-related symptoms; minimal-symptom groups represented 70% of participants at 3 and 6 months. When compared with the COVID-negative cohort, COVID-positive participants had higher occurrence of loss of taste/smell and cognition problems. There was substantial class-switching over time; those in 1 symptom class at 3 months were equally likely to remain or enter a new phenotype at 6 months. CONCLUSIONS: We identified distinct classes of PCC phenotypes for general and fatigue-related symptoms. Most participants had minimal or no symptoms at 3 and 6 months of follow-up. Significant proportions of participants changed symptom groups over time, suggesting that symptoms present during the acute illness may differ from prolonged symptoms and that PCCs may have a more dynamic nature than previously recognized