Pain catastrophizing moderates changes in spinal control in response to noxiously induced low back pain

It is generally accepted that spine control and stability are relevant for the prevention and rehabilitation of low back pain (LBP). However, there are conflicting results in the literature in regards to how these variables are modified in the presence of LBP. The aims of the present work were twofold: (1) to use noxious stimulation to induce LBP in healthy individuals to assess the direct effects of pain on control (quantified by the time-dependent behavior of kinematic variance), and (2) to assess whether the relationship between pain and control is moderated by psychological features (i.e. pain catastrophizing (PC) and kinesiophobia). Participants completed three conditions (baseline, pain, recovery) during a task involving completion of 35 cycles of a repetitive unloaded spine flexion/extension movement. The neuromuscular control of spine movements was assessed during each condition using maximum finite-time Lyapunov exponents (λ). Nociceptive stimulus involved injection of hypertonic saline into the interspinous ligament, eliciting pain that was greater than baseline and recovery (p\ua

A Mechanism‐based Pharmacokinetic Model of Remdesivir Leveraging Interspecies Scaling to Simulate COVID‐19 Treatment in Humans

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak initiated the global COVID-19 pandemic resulting in 42.9 million confirmed infections and >1.1 million deaths worldwide as of October 26, 2020. Remdesivir is a broad-spectrum nucleotide prodrug shown to be effective against enzootic coronaviruses. The pharmacokinetics (PK) of remdesivir in plasma have recently been described. However, the distribution of its active metabolite nucleoside triphosphate (NTP) to the site of pulmonary infection is unknown in humans. Our objective was to use existing in vivo mouse PK data for remdesivir and its metabolites to develop a mechanism-based model to allometrically scale and simulate the human PK of remdesivir in plasma and NTP in lung homogenate. Remdesivir and GS-441524 concentrations in plasma and total phosphorylated nucleoside concentrations in lung homogenate from Ces1c-/- mice administered 25 or 50 mg/kg of remdesivir subcutaneously were simultaneously fit to estimate PK parameters. The mouse PK model was allometrically scaled to predict human PK parameters to simulate the clinically recommended 200 mg loading dose followed by 100 mg daily maintenance doses administered as 30-minute intravenous infusions. Simulations of unbound remdesivir concentrations in human plasma were below 2.48 μM, the 90% maximal inhibitory concentration for SARS-CoV-2 inhibition in vitro. Simulations of NTP in lung were below high efficacy in vitro thresholds. We have identified a need for alternative dosing strategies to achieve more efficacious concentrations of NTP in human lung, perhaps by reformulating remdesivir for direct pulmonary delivery

Pathways to Coastal Resiliency: The Adaptive Gradients Framework

Current and future climate-related coastal impacts such as catastrophic and repetitive flooding, hurricane intensity, and sea level rise necessitate a new approach to developing and managing coastal infrastructure. Traditional “hard” or “grey” engineering solutions are proving both expensive and inflexible in the face of a rapidly changing coastal environment. Hybrid solutions that incorporate natural, nature-based, structural, and non-structural features may better achieve a broad set of goals such as ecological enhancement, long-term adaptation, and social benefits, but broad consideration and uptake of these approaches has been slow. One barrier to the widespread implementation of hybrid solutions is the lack of a relatively quick but holistic evaluation framework that places these broader environmental and societal goals on equal footing with the more traditional goal of exposure reduction. To respond to this need, the Adaptive Gradients Framework was developed and pilot-tested as a qualitative, flexible, and collaborative process guide for organizations to understand, evaluate, and potentially select more diverse kinds of infrastructural responses. These responses would ideally include natural, nature-based, and regulatory/cultural approaches, as well as hybrid designs combining multiple approaches. It enables rapid expert review of project designs based on eight metrics called “gradients”, which include exposure reduction, cost efficiency, institutional capacity, ecological enhancement, adaptation over time, greenhouse gas reduction, participatory process, and social benefits. The framework was conceptualized and developed in three phases: relevant factors and barriers were collected from practitioners and experts by survey; these factors were ranked by importance and used to develop the initial framework; several case studies were iteratively evaluated using this technique; and the framework was finalized for implementation. The article presents the framework and a pilot test of its application, along with resources that would enable wider application of the framework by practitioners and theorists

Genetic Analysis of Anti-Amoebae and Anti-Bacterial Activities of the Type VI Secretion System in Vibrio cholerae

A type VI secretion system (T6SS) was recently shown to be required for full virulence of Vibrio cholerae O37 serogroup strain V52. In this study, we systematically mutagenized each individual gene in T6SS locus and characterized their functions based on expression and secretion of the hemolysin co-regulated protein (Hcp), virulence towards amoebae of Dictyostelium discoideum and killing of Escherichia coli bacterial cells. We group the 17 proteins characterized in the T6SS locus into four categories: twelve (VipA, VipB, VCA0109–VCA0115, ClpV, VCA0119, and VasK) are essential for Hcp secretion and bacterial virulence, and thus likely function as structural components of the apparatus; two (VasH and VCA0122) are regulators that are required for T6SS gene expression and virulence; another two, VCA0121 and valine-glycine repeat protein G 3 (VgrG-3), are not essential for Hcp expression, secretion or bacterial virulence, and their functions are unknown; the last group is represented by VCA0118, which is not required for Hcp expression or secretion but still plays a role in both amoebae and bacterial killing and may therefore be an effector protein. We also showed that the clpV gene product is required for Dictyostelium virulence but is less important for killing E. coli. In addition, one vgrG gene (vgrG-2) outside of the T6SS gene cluster was required for bacterial killing but another (vgrG-1) was not. However, a bacterial killing defect was observed when vgrG-1 and vgrG-3 were both deleted. Several genes encoded in the same putative operon as vgrG-1 and vgrG-2 also contribute to virulence toward Dictyostelium but have a smaller effect on bacterial killing. Our results provide new insights into the functional requirements of V. cholerae's T6SS in the context of secretion as well as killing of bacterial and eukaryotic phagocytic cells

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Atypical Disease after Bordetella pertussis Respiratory Infection of Mice with Targeted Disruptions of Interferon-γ Receptor or Immunoglobulin μ Chain Genes

Using a murine respiratory challenge model we have previously demonstrated a role for Th1 cells in natural immunity against Bordetella pertussis, but could not rule out a role for antibody. Here we have demonstrated that B. pertussis respiratory infection of mice with targeted disruptions of the genes for the IFN-γ receptor resulted in an atypical disseminated disease which was lethal in a proportion of animals, and was characterized by pyogranulomatous inflammation and postnecrotic scarring in the livers, mesenteric lymph nodes and kidneys. Viable virulent bacteria were detected in the blood and livers of diseased animals. An examination of the course of infection in the lung of IFN-γ receptor–deficient, IL-4–deficient and wild-type mice demonstrated that lack of functional IFN-γ or IL-4, cytokines that are considered to play major roles in regulating the development of Th1 and Th2 cells, respectively, did not affect the kinetics of bacterial elimination from the lung. In contrast, B cell–deficient mice developed a persistent infection and failed to clear the bacteria after aerosol inoculation. These findings demonstrate an absolute requirement for B cells or their products in the resolution of a primary infection with B. pertussis, but also define a critical role for IFN-γ in containing bacteria to the mucosal site of infection