Supplier selection under disaster uncertainty with joint procurement

Master of ScienceDepartment of Industrial & Manufacturing Systems EngineeringJessica L. Heier StammHealth care organizations must have enough supplies and equipment on hand to adequately respond to events such as terrorist attacks, infectious disease outbreaks, and natural disasters. This is achieved through a robust supply chain system. Nationwide, states are assessing their current supply chains to identify gaps that may present issues during disaster preparedness and response. During an assessment of the Kansas health care supply chain, a number of vulnerabilities were identified, one of which being supplier consolidation. Through mergers and acquisitions, the number of suppliers within the health care field has been decreasing over the years. This can pose problems during disaster response when there is a surge in demand and multiple organizations are relying on the same suppliers to provide equipment and supplies. This thesis explores the potential for joint procurement agreements to encourage supplier diversity by splitting purchasing among multiple suppliers. In joint procurement, two or more customers combine their purchases into one large order so that they can receive quantity discounts from a supplier. This research makes three important contributions to supplier selection under disaster uncertainty. The first of these is the development of a scenario-based supplier selection model under uncertainty with joint procurement. This optimization model can be used to observe customer purchasing decisions in various scenarios while considering the probability of disaster occurrence. Second, the model is applied to a set of experiments to analyze the results when supplier diversity is increased and when joint procurement is introduced. This leads to the third and final contribution: a set of recommendations for health care organization decision makers regarding ways to increase supplier diversity and decrease the risk of disruption associated with disaster occurrence

Peri-pubertal exposure to testicular hormones organizes response to novel environments and social behaviour in adult male rats

Funding was received from the Wellcome Trust ISSF (grant ID 097831/Z/11/Z) scheme, awarded to the University of St Andrews.Previous research has shown that exposure to testicular hormones during the peri-pubertal period of life has long-term, organizational effects on adult sexual behaviour and underlying neural mechanisms in laboratory rodents. However, the organizational effects of peri-pubertal testicular hormones on other aspects of behaviour and brain function are less well understood. Here, we investigated the effects of manipulating peri-pubertal testicular hormone exposure on later behavioural responses to novel environments and on hormone receptors in various brain regions that are involved in response to novelty. Male rodents generally spend less time in the exposed areas of novel environments than females, and this sex difference emerges during the peri-pubertal period. Male Lister-hooded rats (Rattus norvegicus) were castrated either before puberty or after puberty, then tested in three novel environments (elevated plus-maze, light–dark box, open field) and in an object/social novelty task in adulthood. Androgen receptor (AR), oestrogen receptor (ER1) and corticotropin-releasing factor receptor (CRF-R2) mRNA expression were quantified in the hypothalamus, hippocampus and medial amygdala. The results showed that pre-pubertally castrated males spent more time in the exposed areas of the elevated-plus maze and light–dark box than post-pubertally castrated males, and also confirmed that peri-pubertal hormone exposure influences later response to an opposite-sex conspecific. Hormone receptor gene expression levels did not differ between pre-pubertally and post-pubertally castrated males in any of the brain regions examined. This study therefore demonstrates that testicular hormone exposure during the peri-pubertal period masculinizes later response to novel environments, although the neural mechanisms remain to be fully elucidated.Publisher PDFPeer reviewe

Viral Replication, Persistence in Water and Genetic Characterization of Two Influenza A Viruses Isolated from Surface Lake Water

Water-borne transmission has been suggested as an important transmission mechanism for Influenza A (IA) viruses in wild duck populations; however, relatively few studies have attempted to detect IA viruses from aquatic habitats. Water-isolated viruses have rarely been genetically characterized and evaluation for persistence in water and infectivity in natural hosts has never been documented. In this study, we focused on two IA viruses (H3N8 and H4N6 subtypes) isolated from surface lake water in Minnesota, USA. We investigated the relative prevalence of the two virus subtypes in wild duck populations at the sampling site and their genetic relatedness to IA viruses isolated in wild waterbirds in North America. Viral persistence under different laboratory conditions (temperature and pH) and replication in experimentally infected Mallards (Anas platyrhynchos) were also characterized. Both viruses were the most prevalent subtype one year following their isolation in lake water. The viruses persisted in water for an extended time period at constant temperature (several weeks) but infectivity rapidly reduced under multiple freeze-thaw cycles. Furthermore, the two isolates efficiently replicated in Mallards. The complete genome characterization supported that these isolates originated from genetic reassortments with other IA viruses circulating in wild duck populations during the year of sampling. Based on phylogenetic analyses, we couldn't identify genetically similar viruses in duck populations in the years following their isolation from lake water. Our study supports the role for water-borne transmission for IA viruses but also highlights that additional field and experimental studies are required to support inter-annual persistence in aquatic habitats

DNA damage signalling from the placenta to foetal blood as a potential mechanism for childhood leukaemia initiation

Abstract For many diseases with a foetal origin, the cause for the disease initiation remains unknown. Common childhood acute leukaemia is thought to be caused by two hits, the first in utero and the second in childhood in response to infection. The mechanism for the initial DNA damaging event are unknown. Here we have used in vitro, ex vivo and in vivo models to show that a placental barrier will respond to agents that are suspected of initiating childhood leukaemia by releasing factors that cause DNA damage in cord blood and bone marrow cells, including stem cells. We show that DNA damage caused by in utero exposure can reappear postnatally after an immune challenge. Furthermore, both foetal and postnatal DNA damage are prevented by prenatal exposure of the placenta to a mitochondrially-targeted antioxidant. We conclude that the placenta might contribute to the first hit towards leukaemia initiation by bystander-like signalling to foetal haematopoietic cells

Risk of classic Kaposi sarcoma with exposures to plants and soils in Sicily

<p>Abstract</p> <p>Background</p> <p>Ecologic and in vitro studies suggest that exposures to plants or soil may influence risk of Kaposi sarcoma (KS).</p> <p>Methods</p> <p>In a population-based study of Sicily, we analyzed data on contact with 20 plants and residential exposure to 17 soils reported by 122 classic KS cases and 840 sex- and age-matched controls. With 88 KS-associated herpesvirus (KSHV) seropositive controls as the referent group, novel correlates of KS risk were sought, along with factors distinguishing seronegatives, in multinomial logistic regression models that included matching variables and known KS cofactors - smoking, cortisone use, and diabetes history. All plants were summed for cumulative exposure. Factor and cluster analyses were used to obtain scores and groups, respectively. Individual plants and soils in three levels of exposure with <it>P</it>_trend≤ 0.15 were retained in a backward elimination regression model.</p> <p>Results</p> <p>Adjusted for known cofactors, KS was not related to cumulative exposures to 20 plants [per quartile adjusted odds ratio (OR_adj) 0.96, 95% confidence interval (CI) 0.73 - 1.25, <it>P</it>_trend= 0.87], nor was it related to any factor scores or cluster of plants (<it>P </it>= 0.11 to 0.81). In the elimination regression model, KS risk was associated with five plants (<it>P</it>_trend= 0.02 to 0.10) and with residential exposure to six soils (<it>P</it>_trend= 0.01 to 0.13), including three soils (eutric regosol, chromic/pellic vertisol) used to cultivate durum wheat. None of the KS-associated plants and only one soil was also associated with KSHV serostatus. Diabetes was associated with KSHV seronegativity (OR_adj4.69, 95% CI 1.97 - 11.17), but the plant and soil associations had little effect on previous findings that KS risk was elevated for diabetics (OR_adj7.47, 95% CI 3.04 - 18.35) and lower for current and former smokers (OR_adj0.26 and 0.47, respectively, <it>P</it>_trend= 0.05).</p> <p>Conclusions</p> <p>KS risk was associated with exposure to a few plants and soils, but these may merely be due to chance. Study of the effects of durum wheat, which was previously associated with cKS, may be warranted.</p

Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting hypoxia inducible factor-1

ABSTRACT The resistance of hypoxic cells to conventional chemotherapy is well documented. Using both adenovirus-mediated gene delivery and small molecules targeting hypoxia-inducible factor-1 (HIF-1), we evaluated the impact of HIF-1 inhibition on the sensitivity of hypoxic tumor cells to etoposide. The genetic therapy exploited a truncated HIF-1␣ protein that acts as a dominant-negative HIF-1␣ (HIF-1␣-no-TAD). Its functionality was validated in six human tumor cell lines using HIF-1 reporter assays. An EGFP-fused protein demonstrated that the dominant-negative HIF-1␣ was nucleus-localized and constitutively expressed irrespective of oxygen tension. The small molecules studied were quinocarmycin monocitrate (KW2152), its analog 7-cyanoquinocarcinol (DX-52-1), and topotecan. DX-52-1 and topotecan have been previously established as HIF-1 inhibitors. HT1080 and HCT116 cells were treated with either AdHIF-1␣-no-TAD or nontoxic concentrations (0.1 M; ϽIC 10 ) of KW2152 and DX-52-1 and exposed to etoposide in air or anoxia (Ͻ0.01% oxygen). Topotecan inhibited HIF-1 activity only at cytotoxic concentrations and was not used in the combination study. Etoposide IC 50 values in anoxia were 3-fold higher than those in air for HT1080 (2.2 Ϯ 0.3 versus 0.7 Ϯ 0.2 M) and HCT116 (9 Ϯ 4 versus 3 Ϯ 2 M) cells. KW2152 and DX-52-1 significantly reduced the anoxic etoposide IC 50 in HT1080 cells, whereas only KW2152 yielded sensitization in HCT116 cells. In contrast, AdHIF-1␣-no-TAD (multiplicity of infection 50) ablated the anoxic resistance in both cell lines (IC 50 values: HT1080, 0.7 Ϯ 0.04 M; HCT116, 3 Ϯ 1 M). HIF-1␣-no-TAD expression inhibited HIF-1-mediated down-regulation of the proapoptotic protein Bid under anoxia. These data support the potential development of HIF-1 targeted approaches in combination with chemotherapy, where hypoxic cell resistance contributes to treatment failure

Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity

We are grateful to members of the D.S. laboratory and Dr. E. Fernández-Malavé for discussions and critical reading of the manuscript. We appreciate the support of A. Tomás-Loba, G. Sabio, P. Martín, A. Tsilingiri, A.R. Ramiro, C.L. Abram, C.A. Lowell, J.M. García-Lobo, M. Molina, and M.C. Rodríguez for providing reagents and support. We thank the staff at the Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) facilities for technical support. M.M.-L. received a Formación de Personal Universitario (FPU) fellowship (AP2010-5935) from the Spanish Ministerio de Educación. S.I. is funded by grant SAF2015-74561-JIN from the Spanish Ministerio de Ciencia, Innovación, y Universidades (MCIU) and Fondos Europeos de Desarrollo Regional (FEDER). G.D.B and D.M.R. are supported by the Wellcome Trust and the MRC Centre for Medical Mycology at the University of Aberdeen. S.L.L. is supported by the Swiss National Science Foundation (PP00P3_150758). Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from MCIU, the Agencia Estatal de Investigación, and FEDER; B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MCIU, and FEDER; the Acteria Foundation; the Constantes y Vitales prize (Atresmedia); La Marató de TV3 Foundation (201723); the European Commission (635122-PROCROP H2020), and the European Research Council (ERC-2016-Consolidator Grant 725091). The CNIC is supported by the MCIU and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).Peer reviewedPublisher PD

Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages

The pathogenic fungus Cryptococcus enters the human host via inhalation into the lung and is able to reside in a niche environment that is serum- (opsonin) limiting. Little is known about the mechanism by which nonopsonic phagocytosis occurs via phagocytes in such situations. Using a combination of soluble inhibitors of phagocytic receptors and macrophages derived from knockout mice and human volunteers, we show that uptake of nonopsonized Cryptococcus neoformans and C. gattii via the mannose receptor is dependent on macrophage activation by cytokines. However, although uptake of C. neoformans is via both dectin-1 and dectin-2, C. gattii uptake occurs largely via dectin-1. Interestingly, dectin inhibitors also blocked phagocytosis of unopsonized Cryptococci in wax moth (Galleria mellonella) larvae and partially protected the larvae from infection by both fungi, supporting a key role for host phagocytes in augmenting early disease establishment. Finally, we demonstrated that internalization of nonopsonized Cryptococci is not accompanied by the nuclear translocation of NF-κB or its concomitant production of proinflammatory cytokines such as TNF-α. Thus, nonopsonized Cryptococci are recognized by mammalian phagocytes in a manner that minimizes proinflammatory cytokine production and potentially facilitates fungal pathogenesis

Development and implementation of a highly-multiplexed SNP array for genetic mapping in maritime pine and comparative mapping with loblolly pine

<p>Abstract</p> <p>Background</p> <p>Single nucleotide polymorphisms (SNPs) are the most abundant source of genetic variation among individuals of a species. New genotyping technologies allow examining hundreds to thousands of SNPs in a single reaction for a wide range of applications such as genetic diversity analysis, linkage mapping, fine QTL mapping, association studies, marker-assisted or genome-wide selection. In this paper, we evaluated the potential of highly-multiplexed SNP genotyping for genetic mapping in maritime pine (<it>Pinus pinaster </it>Ait.), the main conifer used for commercial plantation in southwestern Europe.</p> <p>Results</p> <p>We designed a custom GoldenGate assay for 1,536 SNPs detected through the resequencing of gene fragments (707 <it>in vitro </it>SNPs/Indels) and from Sanger-derived Expressed Sequenced Tags assembled into a unigene set (829 <it>in silico </it>SNPs/Indels). Offspring from three-generation outbred (G2) and inbred (F2) pedigrees were genotyped. The success rate of the assay was 63.6% and 74.8% for <it>in silico </it>and <it>in vitro </it>SNPs, respectively. A genotyping error rate of 0.4% was further estimated from segregating data of SNPs belonging to the same gene. Overall, 394 SNPs were available for mapping. A total of 287 SNPs were integrated with previously mapped markers in the G2 parental maps, while 179 SNPs were localized on the map generated from the analysis of the F2 progeny. Based on 98 markers segregating in both pedigrees, we were able to generate a consensus map comprising 357 SNPs from 292 different loci. Finally, the analysis of sequence homology between mapped markers and their orthologs in a <it>Pinus taeda </it>linkage map, made it possible to align the 12 linkage groups of both species.</p> <p>Conclusions</p> <p>Our results show that the GoldenGate assay can be used successfully for high-throughput SNP genotyping in maritime pine, a conifer species that has a genome seven times the size of the human genome. This SNP-array will be extended thanks to recent sequencing effort using new generation sequencing technologies and will include SNPs from comparative orthologous sequences that were identified in the present study, providing a wider collection of anchor points for comparative genomics among the conifers.</p

Spread of Avian Influenza Viruses by Common Teal (Anas crecca) in Europe

Since the recent spread of highly pathogenic (HP) H5N1 subtypes, avian influenza virus (AIV) dispersal has become an increasing focus of research. As for any other bird-borne pathogen, dispersal of these viruses is related to local and migratory movements of their hosts. In this study, we investigated potential AIV spread by Common Teal (Anas crecca) from the Camargue area, in the South of France, across Europe. Based on bird-ring recoveries, local duck population sizes and prevalence of infection with these viruses, we built an individual-based spatially explicit model describing bird movements, both locally (between wintering areas) and at the flyway scale. We investigated the effects of viral excretion duration and inactivation rate in water by simulating AIV spread with varying values for these two parameters. The results indicate that an efficient AIV dispersal in space is possible only for excretion durations longer than 7 days. Virus inactivation rate in the environment appears as a key parameter in the model because it allows local persistence of AIV over several months, the interval between two migratory periods. Virus persistence in water thus represents an important component of contamination risk as ducks migrate along their flyway. Based on the present modelling exercise, we also argue that HP H5N1 AIV is unlikely to be efficiently spread by Common Teal dispersal only