ABSTRACT
Background: The widespread emergence of antibiotic resistance including MDR in Gram-negative bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium. Objectives: To create a novel drug-Fc conjugate (DFC) that can be delivered at sustained and prolonged levels while simultaneously activating the host immune response to combat MDR Gram-negative infections. Methods: The Cloudbreak™ platform was used to develop DFCs consisting of a targeting moiety (TM) (a polymyxin-derived dimer) attached via a non-cleavable linker to an effector moiety (EM) (the Fc domain of human IgG1). In vitro activities of the DFCs were assessed by MIC testing. Neutropenic mouse models of thigh infection, septicaemia and pneumonia were used to evaluate in vivo efficacy. Pharmacokinetics were evaluated in mice and cynomolgus monkeys. Results: A single prophylactic dose of our lead DFC, CTC-177, resulted in significantly decreased bacterial burdens and reduced inflammation comparable to daily treatment with colistin in septicaemia and pneumonia mouse models. Furthermore, CTC-177 prophylaxis was able to restore colistin efficacy in colistin-resistant septicaemia, reducing bacterial burdens beyond the limit of detection. Finally, CTC-177 displayed a long terminal half-life of over 24 and 65 h in mice and cynomolgus monkeys, respectively. Conclusions: These data support the continued development of Cloudbreak™ DFCs as broad-spectrum prophylactic agents against Gram-negative infections.
ABSTRACT
Stressors inherent to training and stemming from the learning environment are associated with high rates of burnout, depression, and mental health problems in health professions students (HPS). There is evidence that disadvantaged or stigmatized groups are particularly affected. These problems not only impact students after graduation but may also have detrimental effects on patient outcomes. Resilience, conceptualized as the process of adapting well in the face of adversity, has inspired an increasing number of interventions aimed at addressing those problems in HPS. These interventions have mostly targeted individual students and their psychological traits while ignoring social and structural factors that may enhance or undermine individual resilience. To address this gap in the literature, the authors reviewed the evidence for psychosocial determinants of resilience and proposed a model inspired by the social determinants of health literature and the "upstream-downstream" metaphor. In this theoretical paper, the authors propose that upstream determinants such adverse childhood experiences and socioeconomic and sociodemographic markers of disadvantage have a direct effect on psychological adjustment and an indirect effect mediated by resilience. Additionally, the authors propose that the institutional downstream drivers of learning environment, social support, and sense of belonging moderate the direct and indirect effects of the upstream determinants on psychological adjustment. Future research should test these hypotheses and gather evidence that may guide the development of interventions. The authors present their model as part of a comprehensive response to recent calls to action to address diversity, equity and inclusion in health professions education.
Subject(s)
Resilience, Psychological , Students, Health Occupations , Humans , Emotional Adjustment , Social Determinants of Health , Social Support , Health OccupationsABSTRACT
OBJECTIVE: To examine pain treatment preferences before and after participation in an N-of-1 trial. STUDY DESIGN AND SETTING: In this observational study nested within a randomized trial, we examined chronic pain patients' preferences before and after treatment in relation to N-of-1 trial results; assessed the influence of different schemes for defining comparative "superiority" on potential conclusions; and generated classification trees illustrating the relationship between pre-treatment preferences, N-of-1 trial results, and post-treatment preferences. RESULTS: Treatment preferences differed pre- and post-trial for 40% of participants. The proportion of patients whose N-of-1 trials demonstrated "superiority" of one treatment regimen over the other varied depending on how superiority was defined and ranged from 24% (using criteria that required statistically significant differences between regimens) to 62% (when relying only on differences in point estimates). Regardless of criteria for declaring treatment superiority, nearly three-fourths of patients with equivocal N-of-1 trial results nevertheless expressed definite preferences post-trial. CONCLUSION: A large segment of patients undergoing N-of-1 trials for chronic pain altered their treatment preferences. However, the direction of preference change did not necessarily correspond to the N-of-1 results. More research is needed to understand how patients use N-of-1 trial results, why preferences are "sticky" even in the face of personalized data, and how patients and clinicians might be educated to use N-of-1 trial results more informatively.
Subject(s)
Analgesics/therapeutic use , Chronic Pain/drug therapy , Musculoskeletal Pain/drug therapy , Pain Management/methods , Pain Management/standards , Patient Preference/psychology , Patient Preference/statistics & numerical data , Aged , Decision Making, Shared , Female , Humans , Male , Middle Aged , Pain Management/statistics & numerical dataABSTRACT
OBJECTIVE: Alarming rates of anxiety and burnout in pre-clinical health profession trainees are now challenged by additional COVID-19 stressors. This study explored COVID-related stressors among first-year medical, physician assistant, nurse practitioner, and veterinary medical students. The authors examined associations between resilience, news monitoring, and COVID stress. METHODS: Students completed an online questionnaire that included the Brief Resilience Scale at their matriculation in August 2019. Survey results were linked to demographic information collected by all schools. A follow-up survey in May 2020 included original questions on COVID-19 stressors and news monitoring. Statistical analyses included descriptive statistics and multivariable linear regression models. RESULTS: Across schools, 74% (266/360) provided consent for the 2019 survey, and 76% (201/264) responded to COVID-19 questions in the follow-up 2020 survey. Students were "extremely" or "very" concerned about family members getting infected (n = 71, 76% School of Medicine (SOM); n = 31, 76% School of Nursing (SON); n = 50, 75% School of Veterinary Medicine (SVM)) and curriculum schedule changes (n = 72, 78%, SOM; n = 28, 68% SON; n = 52, 79% SVM). Greater frequency of COVID news monitoring was associated with greater COVID-related stress (p = 0.02). Higher resilience at matriculation was associated with lower COVID-related stress ten months later (p < 0.001). CONCLUSIONS: Amid COVID-19 uncertainty, health science schools should address the immense student stress regarding curriculum disruptions. The results of this study underscore the powerful role of resilience in protecting against stress not only during the known academic rigor of health professions training but also during unprecedented crises.
Subject(s)
COVID-19 , Students, Medical , Anxiety , Health Occupations , Humans , SARS-CoV-2 , Surveys and QuestionnairesABSTRACT
The ultrasonic emission of the biosonar systems of bats, such as Old World leaf-nosed bats (family Hipposideridae) and the related horseshoe bats (family Rhinolophidae), is characterized by a unique dynamics where baffle shapes ('noseleaves') deform while diffracting the outgoing wave packets. As of now, nothing comparable to this dynamics has been used in any related engineering application (e.g. sonar or radar). Prior work with simple concave baffle shapes has demonstrated the impact of the dynamics on the emission characteristics, but it has remained unclear whether this was simply due to the change in aperture size or also influenced by the geometrical shape detail. Hence, it has also remained unclear whether it would be possible to further enhance the time-variant effects reported so far through different static and dynamic geometries. To address this issue, we have created a dynamic emission baffle with biomimetic shape detail modeled after Pratt's roundleaf bats (Hipposideros pratti). The impact of the dynamic deformation of the shape on the time-variant emission characteristics was evaluated by virtue of the gradient magnitude and the entropy in the gradient orientation. The results have shown that the dynamics results in much larger gradients in signal representation, which change jointly over direction and time.