This paper develops a framework and solution methodology for optimizing the integration of production, inventory, and distribution for supplying retail demand locations from a production facility. ...Two mathematical programming-based heuristics are developed which use a relaxed mixed integer model to determine an initial solution. One approach uses set partitioning and another approach employs the concept of seed routes to determine an approximate solution and a vehicle routing metaheuristic is used to sequence routes for each time period in the planning horizon. A multi-iteration improvement procedure determines the final solution. The proposed multi-phase approach achieves many new best known solutions to test problems for this challenging supply chain optimization problem. Additionally, experiments are conducted to assess the inclusion of fixed vehicle costs and the impact on fleet size and solution quality.
The HLA-B27 gene is a major risk factor for clinical diseases including ankylosing spondylitis, acute anterior uveitis, reactive arthritis, and psoriatic arthritis, but its mechanism of risk ...enhancement is not completely understood. The gut microbiome has recently been shown to influence several HLA-linked diseases. However, the role of HLA-B27 in shaping the gut microbiome has not been previously investigated. In this study, we characterize the differences in the gut microbiota mediated by the presence of the HLA-B27 gene. We identified differences in the cecal microbiota of Lewis rats transgenic for HLA-B27 and human β2-microglobulin (hβ2m), compared with wild-type Lewis rats, using biome representational in situ karyotyping (BRISK) and 16S rRNA gene sequencing. 16S sequencing revealed significant differences between transgenic animals and wild type animals by principal coordinates analysis. Further analysis of the data set revealed an increase in Prevotella spp. and a decrease in Rikenellaceae relative abundance in the transgenic animals compared to the wild type animals. By BRISK analysis, species-specific differences included an increase in Bacteroides vulgatus abundance in HLA-B27/hβ2m and hβ2m compared to wild type rats. The finding that HLA-B27 is associated with altered cecal microbiota has not been shown before and can potentially provide a better understanding of the clinical diseases associated with this gene.
Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for ...small interfering RNA delivery, there are still challenges to use this formulation for mRNA delivery. LNPs are typically a mixture of a cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and a PEG-lipid. The structural characterization of mRNA-containing LNPs (mRNA-LNPs) is crucial for a full understanding of the way in which they function, but this information alone is not enough to predict their fate upon entering the bloodstream. The biodistribution and cellular uptake of LNPs are affected by their surface composition as well as by the extracellular proteins present at the site of LNP administration, e.g., apolipoproteinE (ApoE). ApoE, being responsible for fat transport in the body, plays a key role in the LNP’s plasma circulation time. In this work, we use small-angle neutron scattering, together with selective lipid, cholesterol, and solvent deuteration, to elucidate the structure of the LNP and the distribution of the lipid components in the absence and the presence of ApoE. While DSPC and cholesterol are found to be enriched at the surface of the LNPs in buffer, binding of ApoE induces a redistribution of the lipids at the shell and the core, which also impacts the LNP internal structure, causing release of mRNA. The rearrangement of LNP components upon ApoE incubation is discussed in terms of potential relevance to LNP endosomal escape.
Diffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown.
The goal ...of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging.
Data for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV1 > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV1 ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV1 percent predicted among other confounders.
In multivariable analyses, every 10% predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 P < .001; St. George’s Respiratory Questionnaire, 1.67 P < .001; Medical Outcomes Study Short Form 36 Physical Function, –0.89 P < .001), exercise performance (6-min walk distance, –45.35 feet; P < .001), and severe exacerbation rate (rate ratio, 1.14; P < .001). When categorized, severe impairment in Dlco alone, FEV1 alone, or both Dlco and FEV1 were associated with significantly worse morbidity compared with the reference group (P < .05 for all outcomes).
Impairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD.
Objective
To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients.
Participants
A ...multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine.
Design/methods
The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members.
Results
The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO
2
/FiO
2
< 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence).
Conclusions
Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.
Electrochemical energy storage (EES) devices are gaining ever greater prominence in the quest for global energy security. With increasing applications and widening scope, rechargeable battery ...technology is gradually finding avenues for more abundant and sustainable systems such as Na‐ion (NIB) and K‐ion batteries (KIB). Development of suitable electrode materials lies at the core of this transition. Organic redox‐active molecules are attractive candidates as negative electrode materials owing to their low redox potentials and the fact that they can be obtained from biomass. Also, the rich structural diversity allows integration into several solid‐state polymeric materials. Research in this domain is increasingly focused on deploying molecular engineering to address specific electrochemical limitations that hamper competition with rival materials. This Minireview aims to summarize the advances in both the electrochemical properties and the materials development of organic anode materials.
Sustainable electrodes: Sodium‐ion and potassium‐ion batteries are likely to contribute significantly in the upcoming years to global energy security. Sustainable electrode materials must be developed to enable this growth. Organic molecules are at the core of this technology and materials offering low‐voltage redox are improving. This Minireview tracks the progress and remaining challenges in this domain.
MV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored by noninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative ...patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 10(11) TCID50 (50% tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reduction and resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at all disease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infected plasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated cancer.
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Gold nanoparticles (AuNPs), which have been widely used for the delivery of photosensitizers for photodynamic therapy (PDT) of cancer, can be dispersed in aqueous solutions improving ...the delivery of the hydrophobic photosensitizer into the body. Furthermore, the large surface of AuNPs can be functionalized with a variety of ligands, including proteins, nucleic acids and carbohydrates, that allow selective targeting to cancer tissue. In this study, gold nanoparticles were functionalized with a mixed monolayer of a zinc phthalocyanine and a lactose derivative. For the first time, a carbohydrate was used with a dual purpose, as the stabilizing agent of the gold nanoparticles in aqueous solutions and as the targeting agent for breast cancer cells. The functionalization of the phthalocyanine-AuNPs with lactose led to the production of water-dispersible nanoparticles that are able to generate singlet oxygen and effect cell death upon irradiation. The targeting ability of lactose of the lactose-phthalocyanine functionalized AuNPs was studied in vitro towards the galectin-1 receptor on the surface of breast cancer cells. The targeting studies showed the exciting potential of lactose as a specific targeting agent for galactose-binding receptors overexpressed on breast cancer cells.
Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro-B-type ...natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification.
We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials.
We examined the prognostic value of plasma cell-related characteristics (ie, difference between involved and uninvolved light chain FLC-diff, marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β(2) microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets.
Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.
Dodecaphenyltetracene Xiao, Yonglong; Mague, Joel T.; Schmehl, Russell H. ...
Angewandte Chemie International Edition,
February 25, 2019, Letnik:
58, Številka:
9
Journal Article
Recenzirano
Dodecaphenyltetracene (4), the largest perphenylacene yet prepared, was synthesized from known tetraphenylfuran, hexaphenylisobenzofuran, and 1,2,4,5‐tetrabromo‐3,6‐diphenylbenzene in three steps. ...The X‐ray structure of the deep red, highly luminescent 4 shows it to be a D2‐symmetric molecule with an end‐to‐end twist of 97°. The central acene is encapsulated by the peripheral phenyl substituents, and as a result, the molecule is relatively unreactive and even displays reversible electrochemical oxidation and reduction.
Twist acene: Dodecaphenyltetracene, the largest perphenylacene yet prepared, was synthesized as a deep red, highly luminescent compound. Its X‐ray structure shows it to be a D2‐symmetric molecule with an end‐to‐end twist of 97°.
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