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Vaccination is an important epidemic intervention strategy. Resource limitations and an imperative for efficient use of public resources drives a need for optimal allocation of vaccines within a population. For a disease causing severe illness in particular members of a population, an effective strategy to reduce illness might be to vaccinate those vulnerable with a vaccine that reduces the chance of catching a disease. However, it is not clear that this is the best strategy, and it is generally unclear how the difference between various vaccine strategies changes depending on population characteristics, vaccine mechanisms and allocation objective. In this paper we develop a conceptual mathematical model to consider strategies for vaccine allocation, prior to the establishment of community transmission. By extending the SEIR model to incorporate a range of vaccine mechanisms and disease characteristics, we simulate the impact of vaccination on a population with two sub-groups of differing characteristics. We then compare the outcomes of optimal and suboptimal vaccination strategies for a range of public health objectives using numerical optimisation. Our comparison serves to demonstrate that the difference between vaccinating optimally and suboptimally may be dependent on vaccine mechanism, diseases characteristics, and objective considered. We find that better resources do not guarantee better outcomes. Allocating optimally with lesser vaccine resources can produce a better outcome than allocating good vaccine resources suboptimally, dependent on vaccine mechanisms, disease characteristics and objective considered. Through a principled model-based process, this work highlights the importance of designing effective vaccine allocation strategies. This design process requires models that incorporate known biological characteristics, realistic parameters based on data analysis, etc. Overall, we see that allocation of resources can be just as crucial to the success of a vaccination strategy as the strength of resources available.

PURPOSE: To compare various suture anchor designs with and without calcium phosphate (CaP) augmentation in an osteoporotic foam block model and decorticated proximal humerus cadaveric model. METHODS: This was a controlled biomechanical study, consisting of 2 parts: (1) an osteoporotic foam block model (0.12 g/cc; n = 42) and (2) a matched pair cadaveric humeral model (n = 24). Suture anchors selected were an all-suture anchor, PEEK (polyether ether ketone)-threaded anchor, and a biocomposite-threaded anchor. For each study arm, one half the samples were first filled with injectable CaP and the other half were not augmented with CaP. For the cadaveric portion, the PEEK- and biocomposite-threaded anchors were assessed. Biomechanical testing consisted of a stepwise, increasing load protocol for a total of 40 cycles, followed by ramp to failure. RESULTS: For the foam block model, the average load to failure for anchors with CaP was significantly greater when compared with anchor fixation augmented without CaP; the all-suture anchor was 135.2 ± 20.2 N versus 83.3 ± 10.3 N (P = .0006); PEEK was 131 ± 34.3 N versus 58.5 ± 16.8 N (P = .001); and biocomposite was 182.2 ± 64.2 N versus 80.8 ± 17.4 N (P = .004). For the cadaveric model, the average load to failure for anchors augmented with CaP was again greater than anchor fixation without CaP; PEEK anchors went from 41.1 ± 21.1 N to 193.6 ± 63.9 N (P = .0034) and biocomposite anchors went from 70.9 ± 26.6 N to 143.2 ± 28.9 N (P = .004). CONCLUSIONS: Augmenting various suture anchors with CaP has shown to significantly increase pull-out strength and stiffness in an osteoporotic foam block and time zero cadaveric bone model. CLINICAL RELEVANCE: Rotator cuff tears are common in the elderly patients, in whom poor bone quality jeopardizes treatment success. Exploring methods that increase the strength of fixation in osteoporotic bone to improve outcomes in this patient population is important.

Birmingham New Street railway station in the UK has recently undergone a substantial redevelopment at a cost of more than £600 million. However, the unique underground tunnel geography of the platforms has remained virtually unchanged, which means that diesel exhaust gases are effectively trapped causing a daily build-up of air pollution in the station. A new ventilation system has been installed consisting of 98 bi-directional fans that are meant to disperse any air pollution out of the station. Unfortunately, the fans were triggered by carbon dioxide levels that do not significantly correlate with more serious air pollutants such as nitrogen oxides. In August 2018, new workplace exposure limits (WELs) were introduced for nitrogen monoxide (NO) and nitrogen dioxide (NO2). However, during a recent measurement campaign, one of the new WELs would have been exceeded on most days. Network Rail has undertaken to introduce a number of interventions, including the installation of new nitrogen monoxide/dioxide sensors to drive the ventilation system together with new sonic wind sensors, encouraging train operating companies to switch off idling diesel engines and encouraging more electric/hybrid trains.

Sharing data across institutions is critical to improving care for children who are using long-term mechanical ventilation (LTMV). Mechanical ventilation data are complex and poorly standardized. This lack of data standardization is a major barrier to data sharing.We aimed to describe current ventilator data in the electronic health record (EHR) and propose a framework for standardizing these data using a common data model (CDM) across multiple populations and sites.We focused on a cohort of patients with LTMV dependence who were weaned from mechanical ventilation (MV). We extracted and described relevant EHR ventilation data. We identified the minimum necessary components, termed "Clinical Ideas," to describe MV from time of initiation to liberation. We then utilized existing resources and partnered with informatics collaborators to develop a framework for incorporating Clinical Ideas into the PEDSnet CDM based on the Observational Medical Outcomes Partnership (OMOP).We identified 78 children with LTMV dependence who weaned from ventilator support. There were 25 unique device names and 28 unique ventilation mode names used in the cohort. We identified multiple Clinical Ideas necessary to describe ventilator support over time: device, interface, ventilation mode, settings, measurements, and duration of ventilation usage per day. We used Concepts from the SNOMED-CT vocabulary and integrated an existing ventilator mode taxonomy to create a framework for CDM and OMOP integration.The proposed framework standardizes mechanical ventilation terminology and may facilitate efficient data exchange in a multisite network. Rapid data sharing is necessary to improve research and clinical care for children with LTMV dependence.

Regulating the central CO2-fixing enzyme Rubisco is as complex as its ancient reaction mechanism and involves interaction with a series of cofactors and auxiliary proteins that activate catalytic sites and maintain activity. A key component among the regulatory mechanisms is the binding of sugar phosphate derivatives that inhibit activity. Removal of inhibitors via the action of Rubisco activase is required to restore catalytic competency. In addition, specific phosphatases dephosphorylate newly released inhibitors, rendering them incapable of binding to Rubisco catalytic sites. The best studied inhibitor is 2-carboxy-d-arabinitol 1-phosphate (CA1P), a naturally occurring nocturnal inhibitor that accumulates in most species during darkness and low light, progressively binding to Rubisco. As light increases, Rubisco activase removes CA1P from Rubisco, and the specific phosphatase CA1Pase dephosphorylates CA1P to CA, which cannot bind Rubisco. Misfire products of Rubisco’s complex reaction chemistry can also act as inhibitors. One example is xylulose-1,5-bisphosphate (XuBP), which is dephosphorylated by XuBPase. Here we revisit key findings related to sugar phosphate derivatives and their specific phosphatases, highlighting outstanding questions and how further consideration of these inhibitors and their role is important for better understanding the regulation of carbon assimilation.

When confined within an optical cavity, light can exert strong radiation pressure forces. Combined with dynamical backaction, this enables important processes such as laser cooling, and applications ranging from precision sensors to quantum memories and interfaces. However, the magnitude of radiation pressure forces is constrained by the energy mismatch between photons and phonons. Here, we overcome this barrier using entropic forces arising from the absorption of light. We show that entropic forces can exceed the radiation pressure force by eight orders of magnitude, and demonstrate this using a superfluid helium third-sound resonator. We develop a framework to engineer the dynamical backaction from entropic forces, applying it to achieve phonon lasing with a threshold three orders of magnitude lower than previous work. Our results present a pathway to exploit entropic forces in quantum devices, and to study nonlinear fluid phenomena such as turbulence and solitons., Main text is 10 pages, 5 figures. Supplements is 21 pages, 11 figures

Enhancers play a crucial role in regulating gene expression and their functional status can be queried with cell type precision using using single-cell (sc)ATAC-seq. To facilitate analysis of such data, we developed Enhlink, a novel computational approach that leverages single -cell signals to infer linkages between regulatory DNA sequences, such as enhancers and promoters. Enhlink uses an ensemble strategy that integrates cell-level technical covariates to control for batch effects and biological covariates to infer robust condition-specific links and their associatedp-values. It can integrate simultaneous gene expression and chromatin accessibility measurements of individual cells profiled by multi-omic experiments for increased specificity. We evaluated Enhlink using simulated and real scATAC-seq data, including those paired with physical enhancer-promoter links enumerated by promoter capture Hi-C and with multi-omic scATAC-/RNA-seq data we generated from the mouse striatum. These examples demonstrated that our method outperforms popular alternative strategies. In conjunction with eQTL analysis, Enhlink revealed a putative super-enhancer regulating key cell type-specific markers of striatal neurons. Taken together, our analyses demonstrate that Enhlink is accurate, powerful, and provides features that can lead to novel biological insights.

OBJECTIVES To describe outpatient respiratory outcomes and center-level variability among children with severe bronchopulmonary dysplasia (BPD) who require tracheostomy and long-term mechanical ventilation. METHODS Retrospective cohort of subjects with severe BPD, born between 2016 and 2021, who received tracheostomy and were discharged on home ventilator support from 12 tertiary care centers participating in the BPD Collaborative Outpatient Registry. Timing of key respiratory events including time to tracheostomy placement, initial hospital discharge, first outpatient clinic visit, liberation from the ventilator, and decannulation were assessed using Kaplan-Meier analysis. Differences between centers for the timing of events were assessed via log-rank tests. RESULTS There were 155 patients who met inclusion criteria. Median age at the time of the study was 32 months. The median age of tracheostomy placement was 5 months (48 weeks’ postmenstrual age). The median ages of hospital discharge and first respiratory clinic visit were 10 months and 11 months of age, respectively. During the study period, 64% of the subjects were liberated from the ventilator at a median age of 27 months and 32% were decannulated at a median age of 49 months. The median ages for all key events differed significantly by center (P ≤ .001 for all events). CONCLUSIONS There is wide variability in the outpatient respiratory outcomes of ventilator-dependent infants and children with severe BPD. Further studies are needed to identify the factors that contribute to variability in practice among the different BPD outpatient centers, which may include inpatient practices.

BackgroundThe genesis of SMAC mimetic drugs is founded on the observation that many cancers amplify IAP proteins to facilitate their survival, and therefore removal of these pathways would re-sensitize the cells towards apoptosis. It has become increasingly clear that SMAC mimetics also interface with the immune system in a modulatory manner. Suppression of IAP function by SMAC mimetics activates the non-canonical NF-κB pathway which can augment T cell function, opening the possibility of using SMAC mimetics to enhance immunotherapeutics.MethodsWe have investigated the SMAC mimetic LCL161, which promotes degradation of cIAP-1 and cIAP-2, as an agent for delivering transient costimulation to engineered BMCA-specific human TAC T cells. In doing so we also sought to understand the cellular and molecular effects of LCL161 on T cell biology.ResultsLCL161 activated the non-canonical NF-κB pathway and enhanced antigen-driven TAC T cell proliferation and survival. Transcriptional profiling from TAC T cells treated with LCL161 revealed differential expression of costimulatory and apoptosis-related proteins, namely CD30 and FAIM3. We hypothesized that regulation of these genes by LCL161 may influence the drug’s effects on T cells. We reversed the differential expression through genetic engineering and observed impaired costimulation by LCL161, particularly when CD30 was deleted. While LCL161 can provide a costimulatory signal to TAC T cells following exposure to isolated antigen, we did not observe a similar pattern when TAC T cells were stimulated with myeloma cells expressing the target antigen. We questioned whether FasL expression by myeloma cells may antagonize the costimulatory effects of LCL161. Fas-KO TAC T cells displayed superior expansion following antigen stimulation in the presence of LCL161, suggesting a role for Fas-related T cell death in limiting the magnitude of the T cell response to antigen in the presence of LCL161.ConclusionsOur results demonstrate that LCL161 provides costimulation to TAC T cells exposed to antigen alone, however LCL161 did not enhance TAC T cell anti-tumor function when challenged with myeloma cells and may be limited due to sensitization of T cells towards Fas-mediated apoptosis.

The invasive emerald ash borer (Agrilus planipennis) causes damages to street trees estimated to reach US$ 900 million over the next 30 years.Although millions of dollars are spent annually to control this species, such approaches are often based on heuristics. Here, we reveal an optimal management strategy to protect urban trees in North America from A. planipennis. To achieve this, we embedded a pest dispersal model within a mixed integer programming framework. We discovered that optimized strategies consistently outperformed those based on heuristics, potentially resulting in the protection of an additional nearly one million street trees and savings of $ 627 million. Critically, the best management strategies always relied on quarantines and biological control (constituting 83-95% and 5-17% of the project budget, respectively), in contrast with current practices, which have shifted responsibility for quarantines to state authorities. Our findings serve to inform future pest control efforts, and can potentially protect many more trees from this invasive species.

Genetic background drives phenotypic variability in pluripotent stem cells (PSCs). Most studies to date have used transcript abundance as the primary molecular readout of cell state in PSCs. We performed a comprehensive proteogenomics analysis of 190 genetically diverse mouse embryonic stem cell (mESC) lines. The quantitative proteome is highly variable across lines, and we identified pluripotency-associated pathways that were differentially activated in the proteomics data that were not evident in transcriptome data from the same lines. Integration of protein abundance to transcript levels and chromatin accessibility revealed broad co-variation across molecular layers as well as shared and unique drivers of quantitative variation in pluripotency-associated pathways. Quantitative trait locus (QTL) mapping localized the drivers of these multi-omic signatures to genomic hotspots. This study reveals post-transcriptional mechanisms and genetic interactions that underlie quantitative variability in the pluripotent proteome and provides a regulatory map for mESCs that can provide a basis for future mechanistic studies.

Since the emergence of SARS-CoV-2 (COVID-19), there have been multiple waves of infection and multiple rounds of vaccination rollouts. Both prior infection and vaccination can prevent future infection and reduce severity of outcomes, combining to form hybrid immunity against COVID-19 at the individual and population level. Here, we explore how different combinations of hybrid immunity affect the size and severity of near-future Omicron waves. To investigate the role of hybrid immunity, we use an agent-based model of COVID-19 transmission with waning immunity to simulate outbreaks in populations with varied past attack rates and past vaccine coverages, basing the demographics and past histories on the World Health Organization (WHO) Western Pacific Region (WPR). We find that if the past infection immunity is high but vaccination levels are low, then the secondary outbreak with the same variant can occur within a few months after the first outbreak; meanwhile, high vaccination levels can suppress near-term outbreaks and delay the second wave. Additionally, hybrid immunity has limited impact on future COVID-19 waves with immune-escape variants. Enhanced understanding of the interplay between infection and vaccine exposure can aid anticipation of future epidemic activity due to current and emergent variants, including the likely impact of responsive vaccine interventions.

Inflammation causes pain by shifting the balance of ionic currents in nociceptors toward depolarization, leading to hyperexcitability. The ensemble of ion channels within the plasma membrane is regulated by processes including biogenesis, transport, and degradation. Thus, alterations in ion channel trafficking may influence excitability. Sodium channel Na V 1.7 and potassium channel K V 7.2 promote and oppose excitability in nociceptors, respectively. We used live-cell imaging to investigate mechanisms by which inflammatory mediators (IM) modulate the abundance of these channels at axonal surfaces through transcription, vesicular loading, axonal transport, exocytosis, and endocytosis. Inflammatory mediators induced a Na V 1.7-dependent increase in activity in distal axons. Further, inflammation increased the abundance of Na V 1.7, but not of K V 7.2, at axonal surfaces by selectively increasing channel loading into anterograde transport vesicles and insertion at the membrane, without affecting retrograde transport. These results uncover a cell biological mechanism for inflammatory pain and suggest Na V 1.7 trafficking as a potential therapeutic target.

Precisely controlling the size of engineered biomolecules and pharmaceutical compounds is often critical to their function. Standard methods for size characterization, such as dynamic light scattering or size exclusion chromatography, can be sample intensive and may not provide the sensitivity needed for mass- or concentration-limited biological systems. Taylor dispersion analysis (TDA) is a proven analytical method for direct, calibration-free size determination which utilizes only nL-pL sample volumes. In TDA, diffusion coefficients, which are mathematically transformed to hydrodynamic radii, are determined by characterizing band broadening of an analyte under well-controlled laminar flow conditions. Here, we describe the design and development of a 3D printed instrument for TDA, which is the first such instrument to offer dual-point laser-induced fluorescence (LIF) detection. The instrument utilized a fully 3D printed eductor as a vacuum source for precise and stable pressure-driven flow within a capillary, evidenced by a linear response in generated static pressure to applied gas pressure (

von Willebrand factor (VWF) plays a key role in normal hemostasis, and deficiencies of VWF lead to clinically significant bleeding. We sought to identify novel modifiers of VWF levels in endothelial colony-forming cells (ECFCs) using single-cell RNA sequencing (scRNA-seq). ECFCs were isolated from patients with low VWF levels (plasma VWF antigen levels between 30 and 50 IU/dL) and from healthy controls. Human umbilical vein endothelial cells were used as an additional control cell line. Cells were characterized for their Weibel Palade body (WPB) content and VWF release. scRNA-seq of all cell lines was performed to evaluate for gene expression heterogeneity and for candidate modifiers of VWF regulation. Candidate modifiers identified by scRNA-seq were further characterized with small-interfering RNA (siRNA) experiments to evaluate for effects on VWF. We observed that ECFCs derived from patients with low VWF demonstrated alterations in baseline WPB metrics and exhibit impaired VWF release. scRNA-seq analyses of these endothelial cells revealed overall decreased VWF transcription, mosaicism of VWF expression, and genes that are differentially expressed in low VWF ECFCs and control endothelial cells (control ECs). An siRNA screen of potential VWF modifiers provided further evidence of regulatory candidates, and 1 such candidate, FLI1, alters the transcriptional activity of VWF. In conclusion, ECFCs from individuals with low VWF demonstrate alterations in their baseline VWF packaging and release compared with control ECs. scRNA-seq revealed alterations in VWF transcription, and siRNA screening identified multiple candidate regulators of VWF.

For infants with the most severe forms of chronic lung disease, regardless of etiology, chronic mechanical ventilation can provide stability, reduce acute respiratory events, and alleviate increased work of breathing. This approach prioritizes the baby's growth and development during early life. Once breathing comfortably, these infants can tolerate developmental therapies with the goal of achieving the best neurocognitive outcomes possible.

Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers. We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains. Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge. Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD.· Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..

Indirect contact with contaminated surfaces is a potential transmission route for COVID-19. Therefore, it is necessary to investigate convenient and inexpensive surface sanitization methods, such as HOCl, against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 surrogate, Phi6 (~ 7 log PFU/mL), was prepared in artificial saliva and tripartite matrices, spot inoculated (8–12 spots, 100 µL) on 25 cm2 coupons of either stainless steel or vinyl, and allowed to dry for 45 min. The coupons were sprayed with ~ 3 mL of either 500 ppm or 1,000 ppm HOCl. Exposure times were 0 s (control), 5 s, 30 s, or 60 s. Samples were eluted with 2 mL of Dey-Engley neutralizing broth by 5x repeated pipetting and plated via the double agar overlay assay. Statistical analysis was completed in R using a generalized linear model with Quasipoisson error approximations. Time, concentration, surface type, and inoculum matrix were all significant contributors to log reduction at P = 0.05. Significant three-way interactions were observed for 1000 ppm, vinyl, and 60 s (P = 0.03) and 1000 ppm, tripartite, and 60s (P = 0.0121). A significant two-way interaction between vinyl and 60 s was also observed (P = 0.0168). Overall, increased HOCl concentration and exposure time led to increased Phi6 reduction. Notably, the highest estimated mean log reduction was 3.31 (95% CI: 3.14, 3.49) for stainless steel at 60 s and 1,000 ppm HOCl in artificial saliva, indicating that this method of sanitization may not adequately reduce enveloped viruses to below infective thresholds.

Background aims T cells engineered with synthetic receptors have delivered powerful therapeutic results for patients with relapsed/refractory hematologic malignancies. The authors have recently described the T-cell antigen coupler (TAC) receptor, which co-opts the endogenous T-cell receptor (TCR) and activates engineered T cells in an HLA-independent manner. Here the authors describe the evolution of a next-generation TAC receptor with a focus on developing a TAC-engineered T cell for multiple myeloma. Methods To optimize the TAC scaffold, the authors employed a bona fide antigen-binding domain derived from the B-cell maturation antigen-specific monoclonal antibody C11D5.3, which has been used successfully in the clinic. The authors first tested humanized versions of the UCHT1 domain, which is used by the TAC to co-opt the TCR. The authors further discovered that the signal peptide affected surface expression of the TAC receptor. Higher density of the TAC receptor enhanced target binding in vitro, which translated into higher levels of Lck at the immunological synapse and stronger proliferation when only receptor–ligand interactions were present. Results The authors observed that the humanized UCHT1 improved surface expression and in vivo efficacy. Using TAC T cells derived from both healthy donors and multiple myeloma patients, the authors determined that despite the influence of receptor density on early activation events and effector function, receptor density did not impact late effector functions in vitro, nor did the receptor density affect in vivo efficacy. Conclusions The modifications to the TAC scaffold described herein represent an important step in the evolution of this technology, which tolerates a range of expression levels without impacting therapeutic efficacy.