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Cystic fibrosis is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance and progressive decline in lung function. The disease may start in the small airways; however, this is difficult to prove due to limited accessibility of the small airways with the current single photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of [68Ga] tagged macro-aggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down few minutes after delivery. Cystic fibrosis pig small airways cleared significantly less than non-CF pig small airways (non-CF 25.1±3.1% vs. CF 14.6±0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue UTP further impaired clearance (non-CF with UTP 20.9±0.3% vs. CF with UTP 13.0±1.8%). None of the cystic fibrosis pig treated with UTP (N = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.

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BACKGROUND: The management of pain after shoulder surgery typically includes the use of cryotherapy and the prescription of opioid analgesics. Much focus has been placed lately on the opioid epidemic, which in part is fueled by excessive prescription of opioid medication. Previous studies have found a combination of cryotherapy and compression effective at reducing analgesic consumption and increasing recovery in patients undergoing knee and spine surgery; however, efficacy in patients undergoing shoulder surgery has not been evaluated. PURPOSE: To evaluate the effectiveness of a cryo-pneumatic compression device on postoperative shoulder pain, narcotic use, and quality of life when compared with standard care cryotherapy. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: In total, 200 patients older than 18 years scheduled for unilateral shoulder surgery were enrolled. Patients were randomized to receive either postoperative cryo-pneumatic compression or standard care. The intervention group received a cryo-pneumatic device, while the standard care group received the treating surgeon's preferred method of postoperative care, including standard cryotherapy. Narcotic use was evaluated by the number of oral morphine milligram equivalents consumed during the postoperative period, as well as the time to cessation of narcotic use. Patient-reported outcome measures consisted of a numeric rating scale pain score, 36-item Short Form Survey, patient experience assessed using the net promoter score, and adverse events. Outcomes were evaluated at 2, 6, and 12 weeks postoperatively. RESULTS: Patients receiving cryo-pneumatic compression reported a significant decrease in opioid consumption when compared with standard care (oral morphine milligram equivalents median, 56.1 vs 112; P = .02468). A significant increase in self-reported function was seen in the cryo-pneumatic compression group at 2 weeks when compared with standard care (mean, 61.2 vs 54.2; P = .0412). CONCLUSION: In patients undergoing unilateral shoulder surgery, the use of cryotherapy with pneumatic compression, when compared with standard care, resulted in significantly decreased opioid consumption as well as increased function at 2 weeks. REGISTRATION: NCT04185064 (ClinicalTrials.gov identifier).

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Rationale: Cystic fibrosis is a genetic disorder characterized by recurrent airway infections, inflammation, and progressive decline in lung function. Autopsy and spirometry data suggest that cystic fibrosis may start in the small airways which, due to the fractal nature of the airways, account for most of the airway tree surface area. However, they are not easily accessible for testing. Objectives: Here, we tested the hypothesis that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Methods: Current mucociliary clearance assays are limited therefore we developed a dynamic positron emission tomography scan assay with high spatial and temporal resolution. Each study was accompanied by a high-resolution computed tomography scan that helped identify the thin outer region of the lung that contained small airways. Measurements and Main Results: Clearance of aerosolized [ 68 Ga]macro aggregated albumin from distal airways occurred within minutes after delivery and followed a two-phase process. In cystic fibrosis pigs, both early and late clearance rates were slower. Stimulation of the cystic fibrosis airways with the purinergic agonist UTP further impaired late clearance. Only 1 cystic fibrosis pig treated with UTP out of 6 cleared more than 20% of the delivered dose. Conclusions: These data indicate that mucociliary transport in the small airways is fast and can easily be missed if the acquisition is not fast enough. The data also indicate that mucociliary transport is impaired in small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.

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SARS-CoV-2 lipid nanoparticle mRNA vaccines continue to be administered as the predominant prophylactic measure to reduce COVID-19 disease pathogenesis. Quantifying the kinetics of the secondary immune response from subsequent doses beyond the primary series and understanding how dose-dependent immune waning kinetics vary as a function of age, sex, and various comorbidities remains an important question. We study anti-spike IgG waning kinetics in 152 individuals who received an mRNA-based primary series (first two doses) and a subset of 137 individuals who then received an mRNA-based booster dose. We find the booster dose elicits a 71-84% increase in the median Anti-S half life over that of the primary series. We find the Anti-S half life for both primary series and booster doses decreases with age. However, we stress that although chronological age continues to be a good proxy for vaccine-induced humoral waning, immunosenescence is likely not the mechanism, rather, more likely the mechanism is related to the presence of noncommunicable diseases, which also accumulate with age, that affect immune regulation. We are able to independently reproduce recent observations that those with pre-existing asthma exhibit a stronger primary series humoral response to vaccination than compared to those that do not, and further, we find this result is sustained for the booster dose. Finally, via a single-variate Kruskal-Wallis test we find no difference between male and female humoral decay kinetics, however, a multivariate approach utilizing  Least Absolute Shrinkage and Selection Operator (LASSO) regression for feature selection reveals a statistically significant (p < 1 × 10 - 3 ), albeit small, bias in favour of longer-lasting humoral immunity amongst males.

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The Covid-19 pandemic has prompted governments across the world to enforce a range of public health interventions. We introduce the Covid-19 Policy Response Canadian tracker (CPRCT) database that tracks and records implemented public health measures in every province and territory in Canada. The implementations are recorded on a four-level ordinal scale (0-3) for three domains, (Schools, Work, and Other), capturing differences in degree of response. The data-set allows the exploration of the effects of public health mitigation on the spread of Covid-19, as well as provides a near-real-time record in an accessible format that is useful for a diverse range of modeling and research questions.

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Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.

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BACKGROUND: Motor neuron disease (MND) is a fatal, progressive neurodegenerative disease that causes progressive weakening and wasting of limb, bulbar, thoracic and abdominal muscles. Clear evidence-based guidance on how psychological distress should be managed in people living with MND (plwMND) is lacking. Acceptance and Commitment Therapy (ACT) is a form of psychological therapy that may be particularly suitable for this population. However, to the authors' knowledge, no study to date has evaluated ACT for plwMND. Consequently, the primary aim of this uncontrolled feasibility study was to examine the feasibility and acceptability of ACT for improving the psychological health of plwMND. METHODS: PlwMND aged ≥ 18 years were recruited from 10 UK MND Care Centres/Clinics. Participants received up to 8 one-to-one ACT sessions, developed specifically for plwMND, plus usual care. Co-primary feasibility and acceptability outcomes were uptake (≥ 80% of the target sample [N = 28] recruited) and initial engagement with the intervention (≥ 70% completing ≥ 2 sessions). Secondary outcomes included measures of quality of life, anxiety, depression, disease-related functioning, health status and psychological flexibility in plwMND and quality of life and burden in caregivers. Outcomes were assessed at baseline and 6 months. RESULTS: Both a priori indicators of success were met: 29 plwMND (104%) were recruited and 76% (22/29) attended ≥ 2 sessions. Attrition at 6-months was higher than anticipated (8/29, 28%), but only two dropouts were due to lack of acceptability of the intervention. Acceptability was further supported by good satisfaction with therapy and session attendance. Data were possibly suggestive of small improvements in anxiety and psychological quality of life from baseline to 6 months in plwMND, despite a small but expected deterioration in disease-related functioning and health status. CONCLUSIONS: There was good evidence of acceptability and feasibility. Limitations included the lack of a control group and small sample size, which complicate interpretation of findings. A fully powered RCT to evaluate the clinical and cost-effectiveness of ACT for plwMND is underway. TRIAL REGISTRATION: The study was pre-registered with the ISRCTN Registry (ISRCTN12655391).

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Within-host SARS-CoV-2 modelling studies have been published throughout the COVID-19 pandemic. These studies contain highly variable numbers of individuals and capture varying timescales of pathogen dynamics; some studies capture the time of disease onset, the peak viral load and subsequent heterogeneity in clearance dynamics across individuals, while others capture late-time post-peak dynamics. In this study, we curate multiple previously published SARS-CoV-2 viral load data sets, fit these data with a consistent modelling approach, and estimate the variability of in-host parameters including the basic reproduction number, R0, as well as the best-fit eclipse phase profile. We find that fitted dynamics can be highly variable across data sets, and highly variable within data sets, particularly when key components of the dynamic trajectories (e.g. peak viral load) are not represented in the data. Further, we investigated the role of the eclipse phase time distribution in fitting SARS-CoV-2 viral load data. By varying the shape parameter of an Erlang distribution, we demonstrate that models with either no eclipse phase, or with an exponentially-distributed eclipse phase, offer significantly worse fits to these data, whereas models with less dispersion around the mean eclipse time (shape parameter two or more) offered the best fits to the available data across all data sets used in this work. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".

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We consider a general mathematical model for protein subunit vaccine with a focus on the MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2, and use the model to study immunological outcomes in the humoral and cell-mediated arms of the immune response from vaccination. The mathematical model is fit to vaccine clinical trial data. We elucidate the role of Interferon-γ and Interleukin-4 in stimulating the immune response of the host. Model results, and results from a sensitivity analysis, show that a balance between the TH1 and TH2 arms of the immune response is struck, with the TH1 response being dominant. The model predicts that two-doses of the vaccine at 28 days apart will result in approximately 85% humoral immunity loss relative to peak immunity approximately 6 months post dose 1.

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The lipid nanoparticle (LNP)-formulated mRNA vaccines BNT162b2 and mRNA-1273 are a widely adopted multi vaccination public health strategy to manage the COVID-19 pandemic. Clinical trial data has described the immunogenicity of the vaccine, albeit within a limited study time frame. Here, we use a within-host mathematical model for LNP-formulated mRNA vaccines, informed by available clinical trial data from 2020 to September 2021, to project a longer term understanding of immunity as a function of vaccine type, dosage amount, age, and sex. We estimate that two standard doses of either mRNA-1273 or BNT162b2, with dosage times separated by the company-mandated intervals, results in individuals losing more than 99% humoral immunity relative to peak immunity by 8 months following the second dose. We predict that within an 8 month period following dose two (corresponding to the original CDC time-frame for administration of a third dose), there exists a period of time longer than 1 month where an individual has lost more than 99% humoral immunity relative to peak immunity, regardless of which vaccine was administered. We further find that age has a strong influence in maintaining humoral immunity; by 8 months following dose two we predict that individuals aged 18-55 have a four-fold humoral advantage compared to aged 56-70 and 70+ individuals. We find that sex has little effect on the immune response and long-term IgG counts. Finally, we find that humoral immunity generated from two low doses of mRNA-1273 decays at a substantially slower rate relative to peak immunity gained compared to two standard doses of either mRNA-1273 or BNT162b2. Our predictions highlight the importance of the recommended third booster dose in order to maintain elevated levels of antibodies.

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SARS-CoV-2, the causative agent of COVID-19, has caused devastating health and economic impacts around the globe since its appearance in late 2019. The advent of effective vaccines leads to open questions on how best to vaccinate the population. To address such questions, we developed a model of COVID-19 infection by age that includes the waning and boosting of immunity against SARS-CoV-2 in the context of infection and vaccination. The model also accounts for changes to infectivity of the virus, such as public health mitigation protocols over time, increases in the transmissibility of variants of concern, changes in compliance to mask wearing and social distancing, and changes in testing rates. The model is employed to study public health mitigation and vaccination of the COVID-19 epidemic in Canada, including different vaccination programs (rollout by age), and delays between doses in a two-dose vaccine. We find that the decision to delay the second dose of vaccine is appropriate in the Canadian context. We also find that the benefits of a COVID-19 vaccination program in terms of reductions in infections is increased if vaccination of 15-19 year olds are included in the vaccine rollout.

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The prevailing abundance of full-length HIV type 1 (HIV-1) genome sequences provides an opportunity to revisit the standard model of HIV-1 group M (HIV-1/M) diversity that clusters genomes into largely nonrecombinant subtypes, which is not consistent with recent evidence of deep recombinant histories for simian immunodeficiency virus (SIV) and other HIV-1 groups. Here we develop an unsupervised nonparametric clustering approach, which does not rely on predefined nonrecombinant genomes, by adapting a community detection method developed for dynamic social network analysis. We show that this method (dynamic stochastic block model [DSBM]) attains a significantly lower mean error rate in detecting recombinant breakpoints in simulated data (quasibinomial generalized linear model (GLM), P<8×10−8), compared to other reference-free recombination detection programs (genetic algorithm for recombination detection [GARD], recombination detection program 4 [RDP4], and RDP5). When this method was applied to a representative sample of n = 525 actual HIV-1 genomes, we determined k = 29 as the optimal number of DSBM clusters and used change-point detection to estimate that at least 95% of these genomes are recombinant. Further, we identified both known and undocumented recombination hotspots in the HIV-1 genome and evidence of intersubtype recombination in HIV-1 subtype reference genomes. We propose that clusters generated by DSBM can provide an informative framework for HIV-1 classification.

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PURPOSE: Although distraction-based growing rods (GR) are the gold standard for the treatment of early onset scoliosis, they suffer from high failure rates. We have (1) performed a literature search to understand the deficiencies of the current protocols, (2) in vitro evaluation of GRs using our proposed protocol and performed a finite element (FE) model validation, and (3) identified key features which should be considered in mechanical testing setups. METHODS: PubMed, Embase, and Web of Science databases were searched for articles published on (a) in vivo animal, in vitro cadaveric, and biomechanical studies analyzing the use of GRs as well as (b) failure mechanisms and risk factors for GRs. Both FE and benchtop models of a proposed TGR test construct were developed and evaluated for two cases, long tandem connectors (LT), and side-by-side connectors (SBS). The test construct consisted of five polymer blocks representing vertebral bodies, joined with springs to simulate spinal stiffness. The superior and inferior blocks accepted the pedicle screw anchors, while the three middle blocks were floating. After the pedicle screws, rods, and connectors were assembled onto this construct, distraction was performed, mimicking scoliosis surgery. The resulting distracted constructs were then subjected to static compression-bending loading. Yield load and stiffness were calculated and used to verify/validate the FE results. RESULTS: From the literature search, key features identified as significant were axial and transverse connectors, contoured rods, and distraction, distraction being the most challenging feature to incorporate in testing. The in silico analyses, once they are validated, can be used as a complementing technique to investigate other anatomical features which are not possible in the mechanical setup (like growth/scoliosis curvature). Based on our experiment, the LT constructs showed higher stiffness and yield load compared to SBS (78.85 N/mm vs. 59.68 N/mm and 838.84 N vs. 623.3 N). The FE predictions were in agreement with the experimental outcomes (within 10% difference). The maximum von Mises stresses were predicted adjacent to the distraction site, consistent with the location of observed failures in vivo. CONCLUSION: The two-way approach presented in this study can lead to a robust prediction of the contributing factors to the in vivo failure.

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BACKGROUND: Palliative sedation and analgesia are employed in patients with refractory and intractable symptoms at the end of life to reduce their suffering by lowering their level of consciousness. The doctrine of double effect, a philosophical principle that justifies doing a "good action" with a potentially "bad effect," is frequently employed to provide an ethical justification for this practice. MAIN TEXT: We argue that palliative sedation and analgesia do not fulfill the conditions required to apply the doctrine of double effect, and therefore its use in this domain is inappropriate. Furthermore, we argue that the frequent application of the doctrine of double effect to palliative sedation and analgesia reflects physicians' discomfort with the complex moral, intentional, and causal aspects of end-of-life care. CONCLUSIONS: We are concerned that this misapplication of the doctrine of double effect can consequently impair physicians' ethical reasoning and relationships with patients at the end of life.

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COVID-19 seroprevalence changes over time, with infection, vaccination, and waning immunity. Seroprevalence estimates are needed to determine when increased COVID-19 vaccination coverage is needed, and when booster doses should be considered, to reduce the spread and disease severity of COVID-19 infection. We use an age-structured model including infection, vaccination and waning immunity to estimate the distribution of immunity to COVID-19 in the Canadian population. This is the first mathematical model to do so. We estimate that 60-80% of the Canadian population has some immunity to COVID-19 by late Summer 2021, depending on specific characteristics of the vaccine and the waning rate of immunity. Models results indicate that increased vaccination uptake in age groups 12-29, and booster doses in age group 50+ are needed to reduce the severity COVID-19 Fall 2021 resurgence.

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Aberrant redox signaling underlies the pathophysiology of many chronic metabolic diseases, including type 2 diabetes (T2D). Methodologies aimed at rebalancing systemic redox homeostasis have had limited success. A noninvasive, sustained approach would enable the long-term control of redox signaling for the treatment of T2D. We report that static magnetic and electric fields (sBE) noninvasively modulate the systemic GSH-to-GSSG redox couple to promote a healthier systemic redox environment that is reducing. Strikingly, when applied to mouse models of T2D, sBE rapidly ameliorates insulin resistance and glucose intolerance in as few as 3 days with no observed adverse effects. Scavenging paramagnetic byproducts of oxygen metabolism with SOD2 in hepatic mitochondria fully abolishes these insulin sensitizing effects, demonstrating that mitochondrial superoxide mediates induction of these therapeutic changes. Our findings introduce a remarkable redox-modulating phenomenon that exploits endogenous electromagneto-receptive mechanisms for the noninvasive treatment of T2D, and potentially other redox-related diseases.

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