Modelling Pricing Policy Based on Shelf-Life of Non Homogeneous Available-To-Promise in Fruit Supply Chains

[EN] Fruit Supply Chains (SCs) are influenced by uncontrollable natural factors causing heterogeneity in their products, as regards certain attributes that are relevant to customers and vary over time because of the shelf-life. As a consequence customers should be served not only with the required quantity and due date as usual, but also with the quality, freshness and homogeneity specified in their orders. The order promising process (OPP) is based on the uncommitted availability of homogeneous product quantities in planned lots (ATP) that are uncertain. Therefore, there is a risk of not being reliable in the commitments because of discrepancies between the real and planned homogeneous quantities. Furthermore, due to the shelf-life (SL), serving customers with the freshest product introduce the risk of increasing waste because of the aging process. To efficiently manage these risks, this work proposes a mathematical model for handling the heterogeneous ATP in fruit SCs and a pricing policy based on the product SL in the moment of delivery. In order to illustrate the application of the modelling approach, a short numerical example is introduced. The example evidences a conflictive situation when optimizing the assignation of homogeneous ATP between serving orders with fresh and more valuable product, what could lead to increase the risk of having waste because of expiration, and consequently, more costs and less profit.This research has been supported by the Ministry of Science, Technology and Telecommunications, government of Costa Rica (MICITT), through the program of innovation and human capital for competitiveness (PINN) (PED-019-2015-1).Grillo-Espinoza, H.; Alemany Díaz, MDM.; Ortiz Bas, Á. (2016). Modelling Pricing Policy Based on Shelf-Life of Non Homogeneous Available-To-Promise in Fruit Supply Chains. IFIP Advances in Information and Communication Technology. 480:608-617. https://doi.org/10.1007/978-3-319-45390-3_52S608617480Alarcon, F., Alemany, M.M.E., Lario, F.C., Oltra, R.F.: The lack of homogeneity in the product (LHP) in the ceramic tile industry and its impact on the reallocation of inventories. Boletin Soc. Espanola Ceram. Vidr. 50, 49–57 (2011). doi: 10.3989/cyv.072011Alemany, M.M.E., Grillo, H., Ortiz, A., Fuertes-Miquel, V.S.: A fuzzy model for shortage planning under uncertainty due to lack of homogeneity in planned production lots. Appl. Math. Model. (2015). doi: 10.1016/j.apm.2014.12.057Alemany, M.M.E., Lario, F.-C., Ortiz, A., Gomez, F.: Available-To-Promise modeling for multi-plant manufacturing characterized by lack of homogeneity in the product: an illustration of a ceramic case. Appl. Math. Model. 37, 3380–3398 (2013). doi: 10.1016/j.apm.2012.07.022Blanco, A.M., Masini, G., Petracci, N., Bandoni, J.A.: Operations management of a packaging plant in the fruit industry. J. Food Eng. 70, 299–307 (2005). doi: 10.1016/j.jfoodeng.2004.05.075Grillo, H., Alemany, M.M.E., Ortiz, A.: A review of mathematical models for supporting the order promising process under Lack of Homogeneity in Product and other sources of uncertainty. Comput. Ind. Eng. 91, 239–261 (2016)Kilic, O.A., van Donk, D.P., Wijngaard, J., Tarim, S.A.: Order acceptance in food processing systems with random raw material requirements. Spectrum 32, 905–925 (2010). doi: 10.1007/s00291-010-0213-4Lin, J.T., Hong, I.H., Wu, C.H., Wang, K.S.: A model for batch available-to-promise in order fulfillment processes for TFT-LCD production chains. Comput. Ind. Eng. 59, 720–729 (2010). doi: 10.1016/j.cie.2010.07.026Maihami, R., Karimi, B.: Optimizing the pricing and replenishment policy for non-instantaneous deteriorating items with stochastic demand and promotional efforts. Comput. Oper. Res. 51, 302–312 (2014). doi: 10.1016/j.cor.2014.05.022Mundi, M.I., Alemany, M.M.E., Poler, R., Fuertes-Miquel, V.S.: Fuzzy sets to model master production effectively in Make to Stock companies with Lack of Homogeneity in the Product. Fuzzy Sets Syst. 293, 95–112 (2016). http://dx.doi.org/10.1016/j.fss.2015.06.009Tsao, Y.-C., Sheen, G.-J.: Dynamic pricing, promotion and replenishment policies for a deteriorating item under permissible delay in payments. Part Spec. Issue Top. Real-Time Supply Chain Manag. 35, 3562–3580 (2008). doi: 10.1016/j.cor.2007.01.02

Home parenteral nutrition with an omega-3-fatty-acid-enriched MCT/LCT lipid emulsion in patients with chronic intestinal failure (the HOME study):study protocol for a randomized, controlled, multicenter, international clinical trial

BACKGROUND: Home parenteral nutrition (HPN) is a life-preserving therapy for patients with chronic intestinal failure (CIF) indicated for patients who cannot achieve their nutritional requirements by enteral intake. Intravenously administered lipid emulsions (ILEs) are an essential component of HPN, providing energy and essential fatty acids, but can become a risk factor for intestinal-failure-associated liver disease (IFALD). In HPN patients, major effort is taken in the prevention of IFALD. Novel ILEs containing a proportion of omega-3 polyunsaturated fatty acids (n-3 PUFA) could be of benefit, but the data on the use of n-3 PUFA in HPN patients are still limited. METHODS/DESIGN: The HOME study is a prospective, randomized, controlled, double-blind, multicenter, international clinical trial conducted in European hospitals that treat HPN patients. A total of 160 patients (80 per group) will be randomly assigned to receive the n-3 PUFA-enriched medium/long-chain triglyceride (MCT/LCT) ILE (Lipidem/Lipoplus® 200 mg/ml, B. Braun Melsungen AG) or the MCT/LCT ILE (Lipofundin® MCT/LCT/Medialipide® 20%, B. Braun Melsungen AG) for a projected period of 8 weeks. The primary endpoint is the combined change of liver function parameters (total bilirubin, aspartate transaminase and alanine transaminase) from baseline to final visit. Secondary objectives are the further evaluation of the safety and tolerability as well as the efficacy of the ILEs. DISCUSSION: Currently, there are only very few randomized controlled trials (RCTs) investigating the use of ILEs in HPN, and there are very few data at all on the use of n-3 PUFAs. The working hypothesis is that n-3 PUFA-enriched ILE is safe and well-tolerated especially with regard to liver function in patients requiring HPN. The expected outcome is to provide reliable data to support this thesis thanks to a considerable number of CIF patients, consequently to broaden the present evidence on the use of ILEs in HPN. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03282955. Registered on 14 September 2017

A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity.

Background AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants.Methods We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity.Results Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations.Conclusions These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis

Comparing the costs and outcomes of an integrated twin compression screw (ITCS) nail with standard of care using a single lag screw or a single helical blade cephalomedullary nail in patients with intertrochanteric hip fractures

© 2018 The Author(s). Background: Surgical treatment is the optimal strategy for managing intertrochanteric fractures as it allows for early rehabilitation and functional recovery. The purpose of the study was to assess the cost-effectiveness of commonly used cephalomedullary nails for the treatment of unstable intertrochanteric hip fractures. Methods: A decision analytic model was developed from a US payer's perspective using clinical data from a pairwise meta-analysis of randomised controlled trials (RCTs) and comparative observational studies comparing the integrated twin compression screw (ITCS) nail versus two single-screw or blade cephalomedullary nails [single lag screw (SLS) nail and single helical blade (SHB) nail]. The model considered a cohort of 1000 patients with a mean age of 76, as reported in the clinical studies over a 1-year time period. Cost data was obtained from the Center for Medicare and Medicaid Services website and published literature and adjusted for inflation. One-way and probabilistic sensitivity analyses were conducted to assess the effect of uncertainty in model parameters on model conclusions. Results: The model estimated 0.546 quality-adjusted life years (QALYs) and 0.78 complications avoided by using the ITCS nail and 0.455 QALYs and 0.67 complications avoided for the standard of care, using SLS or SHB nails. The cost per patient was $34,336 for patients treated with an ITCS nail and$37,036 for patients treated with the standard of care respectively, resulting in a cost saving of $2700 in favour of the ITCS nail. More savings were observed when the ITCS nail was compared to the SHB ($3280 per patient) and SLS ($1652 per patient). The findings were robust to a range of both one-way and the probabilistic sensitivity analyses. Conclusion: In conclusion, the ITCS nail can be considered a cost saving intervention in patients undergoing intertrochanteric fracture fixation with an intramedullary device. Clinicians and policy makers should be encouraged to adopt healthcare technologies such as ITCS that will help them to provide quality healthcare despite falling budgets

Research trends in combinatorial optimization

Acknowledgments This work has been partially funded by the Spanish Ministry of Science, Innovation, and Universities through the project COGDRIVE (DPI2017-86915-C3-3-R). In this context, we would also like to thank the Karlsruhe Institute of Technology. Open access funding enabled and organized by Projekt DEAL.Peer reviewedPublisher PD

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Fibrous dysplasia of bone: a clinicopathologic review

Harsh Mohan1, Preeti Mittal1, Irneet Mundi1, Sudhir Kumar21Department of Pathology, 2Department of Orthopedics, Government Medical College, Sector 32, Chandigarh, IndiaAbstract: Fibrous dysplasia of the bones is an uncommon congenital skeletal disorder that is found equally in both genders and is not inherited. Its etiology has been linked to an activating mutation of Gsα and the downstream effects of the resultant increase in cAMP. Fibrous dysplasia is categorized as either monostotic or polyostotic, and may occur as a component of McCune-Albright syndrome or the rare Mazabraud syndrome. Long bones, skull bones, and ribs are the most commonly affected bones. The radiological picture is somewhat variable, including a ground-glass appearance, expansion of the bone, and sclerosis surrounding the lesion. Histologically, fibrous dysplasia shows irregularly-shaped trabeculae of immature, woven bone in a background of variably cellular, loosely arranged fibrous stroma. It may be complicated by pathologic fracture, and rarely by malignant transformation. This review examines interesting issues surrounding the etiology of fibrous dysplasia, its clinical and laboratory manifestations, radiological picture, utility of bone biopsy, gross and microscopic pathology, complications, and its differential diagnostic considerations.Keywords: fibrous dysplasia, McCune-Albright syndrome, monostotic form, polyostotic for