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A semiclassical method is presented for the calculation of Feshbach resonance positions and widths. This approach, based on semiclassical transfer matrices, relies only on relatively short trajectory fragments, thus avoiding problems associated with the long trajectories needed in more straightforward semiclassical techniques. Complex resonance energies are obtained from an implicit equation that is developed to compensate for the inaccuracy of the stationary phase approximation underlying the semiclassical transfer matrix applications. Although this treatment requires calculation of transfer matrices for complex energies, an initial value representation method makes it possible to extract such quantities from ordinary real-valued classical trajectories. This treatment is applied to obtain positions and widths for resonances in a model two-dimensional system, and the results are compared to those obtained from accurate quantum mechanical calculations. The semiclassical method successfully captures the irregular energy dependence of resonance widths that vary over a range of more than two orders of magnitude. An explicit semiclassical expression for the width of narrow resonances is also presented and serves as a simpler, useful approximation for many cases.

Simple fabrication and 3D-printing methods are used to generate tubes and filaments from self-assembled gels, which can be loaded in situ with gold nanoparticles, with the resulting gels encouraging stem cell proliferation.

LPS causes lysosome tubulation in macrophages and dendritic cells. The PI3K-Akt-mTOR pathway is necessary for LPS-induced lysosome tubulation, and mTOR is required for MHC-II presentation in dendritic cells. Evidence shows that mTOR may control lysosome tubulation by modulating microtubule motor activity through Arl8b., Macrophages and dendritic cells exposed to lipopolysaccharide (LPS) convert their lysosomes from small, punctate organelles into a network of tubules. Tubular lysosomes have been implicated in phagosome maturation, retention of fluid phase, and antigen presentation. There is a growing appreciation that lysosomes act as sensors of stress and the metabolic state of the cell through the kinase mTOR. Here we show that LPS stimulates mTOR and that mTOR is required for LPS-induced lysosome tubulation and secretion of major histocompatibility complex II in macrophages and dendritic cells. Specifically, we show that the canonical phosphatidylinositol 3-kinase–Akt–mTOR signaling pathway regulates LPS-induced lysosome tubulation independently of IRAK1/4 and TBK. Of note, we find that LPS treatment augmented the levels of membrane-associated Arl8b, a lysosomal GTPase required for tubulation that promotes kinesin-dependent lysosome movement to the cell periphery, in an mTOR-dependent manner. This suggests that mTOR may interface with the Arl8b-kinesin machinery. To further support this notion, we show that mTOR antagonists can block outward movement of lysosomes in cells treated with acetate but have no effect in retrograde movement upon acetate removal. Overall our work provides tantalizing evidence that mTOR plays a role in controlling lysosome morphology and trafficking by modulating microtubule-based motor activity in leukocytes.

N‐methyl‐D‐aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment‐resistant major depressive disorder. This phase I, randomized, multicenter, placebo‐controlled, five‐period, crossover, single‐dose study evaluated simulated driving performance of healthy participants (N = 107) after single doses of rapastinel slow intravenous (i.v.) bolus 900 and 1800 mg, alprazolam oral 0.75 mg (positive control), ketamine i.v. infusion 0.5 mg/kg (clinical comparator), and placebo ~ 45 min before driving. The primary end point was SD of lateral position (SDLP) during the 60‐min 100‐km simulated driving scenario. Additional measures of driving performance, sleepiness, and cognition were also evaluated. To assess effects over time, mean SDLP was calculated for each 10‐min interval of driving. Sensitivity of the assays was confirmed with alprazolam (all placebo comparisons p 0.5). Both rapastinel doses resulted in significantly less impaired driving compared to alprazolam or ketamine (all p

Whenever there is sufficient demand, companies generally prefer the full truckload (TL) option for long-distance transport, resulting in large and less frequent shipment operations that can be costly if inventory carrying costs are high. Less than truckload (LTL) is another option for transport when carrying costs are high and/or there is insufficient demand. Shipment consolidation provides another option that combines many of the benefits of both TL and LTL. Shipment consolidation is a cost-effective transport solution that combines different size shipments into a single truckload. Combining many loads as a single load brings together economies of scale and potential savings. Traditional routing techniques that minimize distance are not suitable for shipments that have different origins and destinations because it can be beneficial to travel further to minimize overall transport and inventory cost, or what is termed total logistics cost (TLC). Effective consolidation of multi-stop routes to minimize TLC requires routing procedures that are more computationally intensive to find beneficial combinations of loads into consolidated shipments. In this study, we have developed a saving-based procedure to determine consolidated route sequences that minimize the TLC of shipments. Twenty-one data sets were produced using real city coordinates and population densities in North Carolina to demonstrate the effectiveness of the procedure. The solutions of the proposed method are compared with the solutions of the traditional Clarke and Wright (C-W) algorithm. Although the traditional C-W algorithm provides very fast solution times, the proposed method has produced much better solution values.

PurposeThe study aims to investigate the impact of additive manufacturing (AM) on the performance of a spare parts supply chain with a particular focus on underlying spare part demand patterns.Design/methodology/approachThis work evaluates various AM-enabled supply chain configurations through Monte Carlo simulation. Historical demand simulation and intermittent demand forecasting are used in conjunction with a mixed integer linear program to determine optimal network nodal inventory policies. By varying demand characteristics and AM capacity this work assesses how to best employ AM capability within the network.FindingsThis research assesses the preferred AM-enabled supply chain configuration for varying levels of intermittent demand patterns and AM production capacity. The research shows that variation in demand patterns alone directly affects the preferred network configuration. The relationship between the demand volume and relative AM production capacity affects the regions of superior network configuration performance.Research limitations/implicationsThis research makes several simplifying assumptions regarding AM technical capabilities. AM production time is assumed to be deterministic and does not consider build failure probability, build chamber capacity, part size, part complexity and post-processing requirements.Originality/valueThis research is the first study to link realistic spare part demand characterization to AM supply chain design using quantitative modeling.

Delayed upper aerodigestive tract (UADT) perforation is a rare complication of anterior cervical spinal hardware. The purpose of this study was to investigate swallowing outcomes between treatment approaches for delayed UADT perforation. A retrospective chart review was performed on patients with anterior cervical hardware and delayed UADT perforation who were treated at a single tertiary care center between 2000 and 2020. Of the twelve patients identified, most patients presented with dysphagia (n = 9, 75%) and/or neck pain (n = 7, 58%). Perforations generally occurred at the level of C6 (n = 6, 50%) and C7 (n = 4, 33%) and spanned only one spinal level (n = 8, 67%). The majority (n = 8, 67%) of patients were past or current cigarette users. Operative approaches included primary repair (n = 5, 42%) and rotational flap (n = 4, 33%); the rotational flap harvest sites included supraclavicular fasciocutaneous (n = 2), infrahyoid muscle (n = 1), and sternocleidomastoid muscle (n = 1). While most patients demonstrated penetration and/or aspiration on first post-operative swallow study (n = 6), this resolved completely within a median time of 31 days. There were no differences in swallowing outcomes between repair approaches. Patient smoking history appears to be a clear risk factor for the development of delayed UADT perforation from anterior cervical spine hardware. A variety of techniques can be used to repair these perforations, and there were no differences in swallowing outcomes between repair approaches.

Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Here, we uncover the control mechanisms and physiological functions of Mir483 in vivo, by generating constitutive loss-of-function and over-expressing mice. Mir483 expression is imprinted and dependent on the Igf2 promoters and Igf2/H19 imprinting control region. Over-expression of Mir483 causes severe mid-gestation fetal, but not placental, growth restriction, and late lethality. Fetal death is prevented by restoring Mir483 to endogenous levels using an inducible transgenic system. Continuous postnatal Mir483 over-expression induces growth stunting, elevated hepatic lipid content, increased adiposity, reduced local and systemic IGF1 levels and increased GH. The growth phenotypes are rescued by IGF1 infusion. Our findings provide evidence for a novel functional antagonism between a growth-suppressor microRNA and its growth-promoter host gene, and suggest that Mir483 evolved to limit excessive tissue growth through repression of IGF ligand signalling.

Improvements in both liquid chromatography (LC) and mass spectrometry (MS) instrumentation have greatly enhanced proteomic and small molecule metabolomic analysis in recent years. Less focus has been on the improved capability to detect and quantify small bioactive peptides, even though the exact sequences of the peptide species produced can have important biological consequences. Endogenous bioactive peptide hormones, for example, are generated by the targeted and regulated cleavage of peptides from their prohormone sequence. This process may include organ specific variants, as proglucagon is converted to glucagon in the pancreas but glucagon-like peptide-1 (GLP-1) in the small intestine, with glucagon raising, whereas GLP-1, as an incretin, lowering blood glucose. Therefore, peptidomics workflows must preserve the structure of the processed peptide products to prevent the misidentification of ambiguous peptide species. The poor in vivo and in vitro stability of peptides in biological matrices is a major factor that needs to be considered when developing methods to study them. The bioinformatic analysis of peptidomics data sets requires the inclusion of specific post-translational modifications, which are critical for the function of many bioactive peptides. This review aims to discuss and contrast the various extraction, analytical, and bioinformatics approaches used for human peptidomics studies in a multitude of matrices.

BACKGROUND: Whereas data from the pre-pandemic era have demonstrated that tracheostomy can accelerate liberation from the ventilator, reduce need for sedation, and facilitate rehabilitation, concerns for healthcare worker safety have led to disagreement on tracheostomy placement in COVID-19 patients. Data on COVID-19 patients undergoing tracheostomy may inform best practices. Thus, we report a retrospective institutional cohort experience with tracheostomy in ventilated patients with COVID-19, examining associations between time to tracheostomy and duration of mechanical ventilation in relation to patient characteristics, clinical course, and survival. METHODS: Clinical data were extracted for all COVID-19 tracheostomies performed at a quaternary referral center from April-July 2020. Outcomes studied included mortality, adverse events, duration of mechanical ventilation, and time to decannulation. RESULTS: Among 64 COVID-19 tracheostomies (13% of COVID-19 hospitalizations), patients were 64% male and 42% African American, with a median age of 54 (range, 20–89). Median time to tracheostomy was 22 (range, 7–60) days and median duration of mechanical ventilation was 39.4 (range, 20–113) days. Earlier tracheostomy was associated with shortened mechanical ventilation (R(2)=0.4, P

One of the biggest challenges in designing a logistics network is predicting thedemand flows between all pairs of points in the network. Until recently, thegravity model was mainly used for estimating the demand flow between points.However, the gravity model uses historical data to estimate values for its multi-ple parameters and distance between pairs to forecast the demand flow. Distancevalues close to zero and unprecedented changes in demand flow data create nu-merical instability for the gravity model’s output. Hence, the proximity factor,a single parameter model that uses the relative ordering of pairs instead of dis-tance, was developed. In this paper, we systematically compare the proximityfactor and the gravity model. It is shown that the proximity factor is a robustand competitive alternative to the gravity model. According to our analysis,the proximity factor model can replace the gravity model in some applicationswhen no historical data is available to adjust the parameters of the latter.

We report the preparation of hybrid self-assembled microgel beads by combining the low molecular weight gelator (LMWG) DBS-CONHNH2 and the natural polysaccharide calcium alginate polymer gelator (PG). Microgel formulations based on LMWGs are extremely rare due to the fragility of the self-assembled networks and the difficulty of retaining any imposed shape. Our hybrid beads contain interpenetrated LMWG and PG networks, and are obtained by an emulsion method, allowing the preparation of spherical gel particles of controllable sizes with diameters in the mm or μm range. Microgels based on LMWG/alginate can be easily prepared with reproducible diameters, We report microgel beads with diameters of ca. 800 nm based on interpenetrating networks of a low-molecular-weight gelator and a polymer gelator, and demonstrate their use as heparin delivery vehicles to enhance stem cell growth.

Purpose This paper aims to investigate the current state, technological challenges, economic opportunities and future directions in the growing “indirect” hybrid manufacturing ecosystem, which integrates traditional metal casting with the production of tooling via additive manufacturing (AM) process including three-dimensional sand printing (3DSP) and printed wax patterns. Design/methodology/approach A survey was conducted among 100 participants from foundries and AM service providers across the USA to understand the current adoption of AM in metal casting as a function of engineering specifications, production demand, volume and cost metrics. In addition, current technological and logistical challenges that are encountered by the foundries are identified to gather insight into the future direction of this evolving supply chain. Findings One of the major findings from this study is that hard tooling costs (i.e. patterns/core boxes) are the greatest challenge in low volume production for foundries. Hence, AM and 3DSP offer the greatest cost-benefit for these low volume production runs as it does not require the need for hard tooling to produce much higher profit premium castings. It is evident that there are major opportunities for the casting supply chain to benefit from an advanced digital ecosystem that seamlessly integrates AM and 3DSP into foundry operations. The critical challenges for adoption of 3DSP in current foundry operations are categorized into as follows: capital cost of the equipment, which cannot be justified due to limited demand for 3DSP molds/cores by casting buyers, transportation of 3DSP molds and cores, access to 3DSP, limited knowledge of 3DSP, limitations in current design tools to integrate 3DSP design principles and long lead times to acquire 3DSP molds/cores. Practical implications Based on the findings of this study, indirect hybrid metal AM supply chains, i.e. 3DSP metal casting supply chains is proposed, as 3DSP replaces traditional mold-making in the sand casting process flow, no/limited additional costs and resources would be required for qualification and certification of the cast parts made from three-dimensional printed sand molds. Access to 3DSP resources can be addressed by establishing a robust 3DSP metal casting supply chain, which will also enable existing foundries to rapidly acquire new 3DSP-related knowledge. Originality/value This original survey from 100 small and medium enterprises including foundries and AM service providers suggests that establishing 3DSP hubs around original equipment manufacturers as a shared resource to produce molds and cores would be beneficial. This provides traditional foundries means to continue mass production of castings using existing hard tooling while integrating 3DSP for new complex low volume parts, replacement parts, legacy parts and prototyping.

Interleukin-34 (IL-34) is a cytokine that supports the viability and differentiation of macrophages. An important cytokine for the development of epidermal immunity, IL-34, is present and plays a role in the immunity of the oral environment. IL-34 has been linked to inflammatory periodontal diseases, which involve innate phagocytes, including macrophages. Whether IL-34 can alter the ability of macrophages to effectively interact with oral microbes is currently unclear. Using macrophages derived from human blood monocytes with either the canonical cytokine colony-stimulating factor (CSF)1 or IL-34, we compared the ability of the macrophages to phagocytose, kill, and respond through the production of cytokines to the periodontal keystone pathogen Porphyromonas gingivalis. While macrophages derived from both cytokines were able to engulf the bacterium equally, IL-34-derived macrophages were much less capable of killing internalized P. gingivalis. Of the macrophage cell surface receptors known to interact with P. gingivalis, dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin was found to have the largest variation between IL-34- and CSF1-derived macrophages. We also found that upon interaction with P. gingivalis, IL-34-derived macrophages produced significantly less of the neutrophil chemotactic factor IL-8 than macrophages derived in the presence of CSF1. Mechanistically, we identified that the levels of IL-8 corresponded with P. gingivalis survival and dephosphorylation of the major transcription factor NF-κB p65. Overall, we found that macrophages differentiated in the presence of IL-34, a dominant cytokine in the oral gingiva, have a reduced ability to kill the keystone pathogen P. gingivalis and may be susceptible to specific bacteria-mediated cytokine modification.

BackgroundCritically ill patients routinely receive antibiotics with activity against anaerobic gut bacteria. However, in other disease states and animal models, gut anaerobes are protective against pneumonia, organ failure and mortality. We therefore designed a translational series of analyses and experiments to determine the effects of anti-anaerobic antibiotics on the risk of adverse clinical outcomes among critically ill patients.MethodsWe conducted a retrospective single-centre cohort study of 3032 critically ill patients, comparing patients who did and did not receive early anti-anaerobic antibiotics. We compared intensive care unit outcomes (ventilator-associated pneumonia (VAP)-free survival, infection-free survival and overall survival) in all patients and changes in gut microbiota in a subcohort of 116 patients. In murine models, we studied the effects of anaerobe depletion in infectious (Klebsiella pneumoniaeandStaphylococcus aureuspneumonia) and noninfectious (hyperoxia) injury models.ResultsEarly administration of anti-anaerobic antibiotics was associated with decreased VAP-free survival (hazard ratio (HR) 1.24, 95% CI 1.06–1.45), infection-free survival (HR 1.22, 95% CI 1.09–1.38) and overall survival (HR 1.14, 95% CI 1.02–1.28). Patients who received anti-anaerobic antibiotics had decreased initial gut bacterial density (p=0.00038), increased microbiome expansion during hospitalisation (p=0.011) and domination by Enterobacteriaceae spp. (p=0.045). Enterobacteriaceae were also enriched among respiratory pathogens in anti-anaerobic-treated patients (p−16). In murine models, treatment with anti-anaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia (pConclusionsIn critically ill patients, early treatment with anti-anaerobic antibiotics is associated with increased mortality. Mechanisms may include enrichment of the gut with respiratory pathogens, but increased mortality is incompletely explained by infections alone. Given consistent clinical and experimental evidence of harm, the widespread use of anti-anaerobic antibiotics should be reconsidered.

The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy.This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used.We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5).This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Objective(s): To compare otolaryngology program director, house-staff, and medical student perspectives on the score reporting change of USMLE Step 1 to pass/fail. Methods: Separate electronic surveys were sent to program directors of ACGME-accredited otolaryngology programs (Cronbach’s alpha = .87), otolaryngology house-staff (Cronbach’s alpha = .91), and medical students interested in otolaryngology (Cronbach’s alpha = .76). Results: Among the 51 otolaryngology program directors that completed the survey (response rate of 46.8%), 17.6% favored reporting USMLE Step 1 as pass/fail. A majority believed the reporting change would make it more difficult to screen (74.5%) and objectively compare applicants (82.4%). Step 2 CK scores will be more important to most program directors due to the reporting change (83.7%). Of the 93 house-staff that completed surveys, most did not favor the reporting change (61.3%). Over half (54.0%) of the 87 medical students that completed surveys did not support the scoring change, and most (65.5%) did not feel that it would decrease anxiety around residency applications (65.5%). Most house-staff and medical students felt that the scoring change would put non-U.S. MD students at a disadvantage (65.6% of house-staff, 69.8% of medical students). Conclusion: Most survey respondents do not agree with the decision to report Step 1 as pass/fail. Despite its intended goals, most do not believe pass/fail Step 1 reporting will improve medical student well-being and believe it will put certain student populations at a greater disadvantage.

Mesenchymal stromal cell (MSC) heterogeneity clouds biological understanding and hampers their clinical development. In MSC cultures most commonly used in research and therapy, we have identified an MSC subtype characterised by CD317 expression (CD317pos(29.77±3.00% of the total MSC population), comprising CD317dim(28.10±4.60%) and CD317bright(1.67±0.58%) MSCs) and a constitutive interferon signature linked to human disease. We demonstrate that CD317posMSCs induced cutaneous tissue damage when applied a skin explant model of inflammation, whereas CD317negMSCs had no effect. Only CD317negMSCs were able to suppress proliferative cycles of activated human T cellsin vitro, whilst CD317posMSCs increased polarisation towards pro-inflammatory Th1 cells and CD317negcell lines did not. Using anin vivoperitonitis model, we found that CD317negand CD317posMSCs suppressed leukocyte recruitment but only CD317negMSCs suppressed macrophage numbers. Using MSC-loaded scaffolds implanted subcutaneously in immunocompromised mice we were able to observe tissue generation and blood vessel formation with CD317negMSC lines, but not CD317posMSC lines. Our evidence is consistent with the identification of an immune stromal cell, which is likely to contribute to specific physiological and pathological functions and influence clinical outcome of therapeutic MSCs.

The oral cavity is a complex environment constantly exposed to antigens from food and the oral microbiota. Innate immune cells play an essential role in maintaining health and homeostasis in the oral environment. However, these cells also play a significant role in disease progression. This review will focus on two innate phagocytes in the oral cavity: macrophages and neutrophils, and examine their roles during homeostasis and disease development, with a focus on periodontal disease and cancer. Macrophages have a well-known ability to polarize and be activated towards a variety of phenotypes. Several studies have found that macrophages’ polarization changes can play an essential role in maintaining health in the oral cavity and contribute to disease. Recent data also finds that neutrophils display phenotypic heterogeneity in the oral cavity. In both cases, we focus on what is known about how these cellular changes alter these immune cells’ interactions with the oral microbiota, including how such changes can lead to worsening, rather than improving, disease states.

Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/−p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat+/−p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat+/−p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat+/−p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat+/−p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.