Sourcing for Quality: Cooperating with a Single Supplier or Developing Two Competing Suppliers?

Supplier efforts regarding product quality are an important issue in outsourcing and play a critical role in a manufacturer’s choice of sourcing strategy. Consider a manufacturer that wants to outsource the manufacturing of two substitute products to external suppliers. This paper studies the strategic interactions under two sourcing strategies: single and dual sourcing. A four-stage noncooperative game model is established to describe each member’s decisions. We further propose four decision scenarios: single sourcing with and without manufacturer quality investment sharing and dual sourcing when suppliers cooperate or do not cooperate on quality decisions. By the backward induction approach, we obtain analytical equilibrium solutions for each decision scenario. By comparing each pair of equilibrium profiles, we find that an appropriate proportion of quality investment sharing by the manufacturer can enable a cooperating strategy with a single supplier to be the dominant strategy. When the manufacturer does not want to share or does not want to share a relatively large portion of its supplier’s quality investment, it will always prefer to develop two competing suppliers when the cost of dual sourcing is sufficiently low. However, dual sourcing can be extremely risky for the manufacturer because the suppliers could provide a relatively low product quality level by cooperating on the quality decision to extract the manufacturer’s profit

THE APPLICATION OF NONLINEAR MIXED-EFFECTS MODELING TO THE OPTIMIZATION OF HIV TREATMENT IN SPECIAL POPULATIONS

The HIV-infected population is heterogeneous in terms of drug disposition and drug response to HIV treatment. Identifying subgroups of patients at risk of suboptimal therapeutic effects or toxicity is critical to maintain drug efficacy and safety. The objectives of this dissertation were to apply nonlinear mixed-effects modeling (NLME) methods to investigate the potential discrepancies in the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of two special populations, pregnant women and older patients, compared to the general HIV-infected population, and inform appropriate HIV treatment for these patients. In the investigation of lopinavir/ritonavir (LPV/RTV) unbound drug PK in twelve HIV-infected pregnant women, clearances of LPV and RTV during pregnancy demonstrated an exponential increase between 20-32 weeks of gestation. The unbound fractions of LPV/RTV were not significantly different between pregnancy and postpartum. Despite the increased LPV/RTV elimination in pregnancy, >90% effective LPV inhibitory quotient (IQ) values were predicted under the standard dosing (400/100 mg B.I.D.) with ≤4-fold increase in viral half inhibitory concentration (IC50), supporting the use of standard dosing in pregnant women with low-resistance virus. As viral susceptibility decreases (>10-fold increase in viral IC50), higher doses or alternative regimens should be considered. The effects of aging on ART PK were studied in the context of different aging surrogates and pharmacogenetics in ninety-one HIV-infected patients aged 18-72 years receiving either efavirenz (EFV)- or atazanavir/ritonavir (ATV/RTV)- containing regimens. A cellular aging biomarker, the expression of p16INK4a, was shown to be negatively associated with the unbound drug clearance of EFV, implying that cellular aging might predict slower EFV metabolism. No alterations in drug clearance or unbound fraction with aging were observed for ATV or RTV. Regarding the recovery of CD4+ T-cells, analyses of long-term data (up to 15 years on treatment) of 102 patients and short-term data (within 2 years) of 20 patients indicated that advanced age was significantly associated with a greater apparent elimination rate constant of CD4+ naïve T-cells. Simulation showed that the differences of median total CD4+ T-cell counts between younger (18-35 years) and older (≥50 years) age groups were 93, 137 and 145 cells/μL at year 1, 4 years and steady state after treatment, respectively, suggesting that advanced age may have a greater negative effect on the long-term CD4+ T-cell recovery. In summary, this dissertation demonstrates the power of NLME approaches in studying antiretroviral PK and PD, and provides insights for the optimization of HIV intervention in pregnant women and older patients.Doctor of Philosoph

Modeling mode choice behavior incorporating household and individual sociodemographics and travel attributes based on rough sets theory

Most traditional mode choice models are based on the principle of random utility maximization derived from econometric theory. Alternatively, mode choice modeling can be regarded as a pattern recognition problem reflected from the explanatory variables of determining the choices between alternatives. The paper applies the knowledge discovery technique of rough sets theory to model travel mode choices incorporating household and individual sociodemographics and travel information, and to identify the significance of each attribute. The study uses the detailed travel diary survey data of Changxing county which contains information on both household and individual travel behaviors for model estimation and evaluation. The knowledge is presented in the form of easily understood IF-THEN statements or rules which reveal how each attribute influences mode choice behavior. These rules are then used to predict travel mode choices from information held about previously unseen individuals and the classification performance is assessed. The rough sets model shows high robustness and good predictive ability. The most significant condition attributes identified to determine travel mode choices are gender, distance, household annual income, and occupation. Comparative evaluation with the MNL model also proves that the rough sets model gives superior prediction accuracy and coverage on travel mode choice modeling

Structural equation models to analyze activity participation, trip generation, and mode choice of low-income commuters

Low-income commuters have distinct activity-travel characteristics from non-low-income commuters. This study examines low-income commuters' activity-travel pattern for a better understanding the mechanism of activity participation and travel behaviour based on the travel survey data collected in Nanjing, China. Structural equations modelling (SEM) methodology was adopted to estimate the complex relationships among socio-demographics, accessibility, activity participation, trip generation and mode choice. Results show that strong relationships do exist among socio-demographics, activity engagement and travel behavior. Specifically, we can understand travel behaviour better by including activity participation endogenously in the model. Furthermore, it allows us to better forecast how increasing any one type of activity will affect demand for other activities, as well as trip generation and mode choice. Lastly, the results reveal the effects of accessibility variables on activity participation and travel behaviour in which population density measure has more ubiquitous effects. Findings in this study might provide insightful policy implications for improving the travel environment of the low-income commuters

Unconserved C terminal of human cytomegalovirus tegument protein pUL76 elicits nuclear aggresome formation and induces DNA damage in transfected cells

Background The HCMV UL76 gene is a member of UL24 family in herpes virus and encodes a highly conserved herpes virus protein. Inherited from common ancestor, members of Herpes_UL24 family encode proteins with a conserved N terminal and varied in C terminal region. To define which region (conserved N terminal or unconserved C terminal) of UL76 was responsible for its ability to induce DNA damage and aggresome formation, the wild-type UL76 gene and two deletion mutants were transfected to cells and analyzed by immunofluorescent staining, Western blotting and comet assay. Results We report that the EGFP-fusion proteins present as globular aggresomes and colocalize with γ-H2AX in cells transfected with either pEGFP-UL76 or pEGFP-UL76C. The relative expression level of γ-H2AX and percentage of cells with comet tails were elevated in pEGFP-UL76 or pEGFP-UL76C transfection groups compared to the control. Conclusion Our findings suggest that the unconserved C terminal (not the conserved N terminal) of pUL76 was sufficient to induce DNA damage and aggresome formation in transfected cells

Trajectory patterns of macronutrient intake and their associations with obesity, diabetes, and all-cause mortality: A longitudinal analysis over 25 years

Over the past decades, China has been undergoing rapid economic growth, which may have significantly influenced the dietary patterns and health status of the Chinese population. Our study aimed to assess the associations of potential macronutrient trajectory patterns with chronic diseases and all-cause mortality using the latent class trajectory model (LCTM) and the longitudinal data of the China Health and Nutrition Survey obtained between 1991 and 2015. A 24-hour diet recall was used to assess the dietary intake. The Poisson regression model was employed to investigate the correlations between trajectory patterns and chronic diseases and all-cause mortality. A total of 8115 participants were included in the final analysis. We explored four and three trajectory patterns for male and female populations, respectively. We found that a decreasing very high-carbohydrate trajectory together with a U-shape protein trajectory was associated with a higher risk of diabetes in the male population (odds ratio (OR): 2.23; 95% confidence interval (CI): 1.31–3.77). A similar pattern for moderate protein intake was also associated with the risk of diabetes in the female population (OR: 1.82; 95% CI: 1.18–2.79). In addition, we show that a decreasing low-carbohydrate trajectory and an increasing high-fat trajectory were associated with a lower risk of all-cause mortality (OR: 0.76; 95% CI: 0.60–0.96) and a higher risk of obesity (OR: 1.24; 95% CI: 1.05–1.47) in males. Our results shed light on some salient nutritional problems in China, particularly the dual challenges of undernutrition and overnutrition

Pharmacoeconomic analysis (CER) of Dulaglutide and Liraglutide in the treatment of patients with type 2 diabetes

AimTo evaluate the treatment effect Fand pharmacoeconomic value of Dugaglutide in women with type 2 diabetes.MethodsWomen (n=96) with type 2 diabetes recruited from June 2019 to December 2021 were randomized into two equal groups. The control group was treated with Liraglutide, and the observation group was treated with Dulaglutide, both for 24 weeks. The blood glucose levels, biochemical index, insulin resistance index (HOMA-IR), cost-effect ratio (CER), and drug safety were determined and compared between the two groups.ResultsBlood glucose levels, the biochemical index, and HOMA-IR were lower in both groups after the treatment (P < 0.05), and there was no statistical difference in the blood glucose levels, biochemical index and HOMA-IR between the two groups (P > 0.05). The CER levels did not differ statistically between the two groups (P > 0.05). Both the cost and the incidence of drug side effects during solution injection were lower in the observation group than in the control group after 24 weeks of treatment (P < 0.05).ConclusionBoth Dulaglutide and Liraglutide can reduce blood glucose levels, improve biochemical index, and HOMA-IR levels in women with type 2 diabetes. Dulaglutide is more cost-effective and safe.Clinical trial registrationhttps://www.chictr.org.cn/index.aspx, identifier ChiCTR1900026514

Efficacy of polyethylene glycol loxenatide versus insulin glargine on glycemic control in patients with type 2 diabetes: a randomized, open-label, parallel-group trial

Objective: This trial aimed to evaluate the glycemic control of polyethylene glycol loxenatide measured with continuous glucose monitoring (CGM) in patients with type 2 diabetes mellitus (T2DM), with the hypothesis that participants given PEG-Loxe would spend more time in time-in-range (TIR) than participants were given insulin glargine after 24 weeks of treatment.Methods: This 24-week, randomized, open-label, parallel-group study was conducted in the Department of Endocrine and Metabolic Diseases, Longhu Hospital, Shantou, China. Participants with T2DM, who were ≥45 years of age, HbA1c of 7.0%–11.0%, and treated at least 3 months with metformin were randomized (1:1) to receive PEG-Loxe or insulin glargine. The primary endpoint was TIR (blood glucose range: 3.9–10.0 mmol/L) during the last 2 weeks of treatment (weeks 22–24).Results: From March 2020 to April 2022, a total of 107 participants with T2DM were screened, of whom 78 were enrolled into the trial (n = 39 per group). At the end of treatment (weeks 22–24), participants given PEG-Loxe had a greater proportion of time in TIR compared with participants given insulin glargine [estimated treatment difference (ETD) of 13.4% (95% CI, 6.8 to 20.0, p < 0.001)]. The tight TIR (3.9–7.8 mmol/L) was greater with PEG-Loxe versus insulin glargine, with an ETD of 15.6% (95% CI, 8.9 to 22.4, p < 0.001). The time above range (TAR) was significantly lower with PEG-Loxe versus insulin glargine [ETD for level 1: −10.5% (95% CI: −14.9 to −6.0), p < 0.001; ETD for level 2: −4.7% (95% CI: −7.9 to −1.5), p = 0.004]. The time below range (TBR) was similar between the two groups. The mean glucose was lower with PEG-Loxe versus insulin glargine, with an ETD of −1.2 mmol/L (95% CI, −1.9 to −0.5, p = 0.001). The SD of CGM glucose levels was 1.88 mmol/L for PEG-Loxe and 2.22 mmol/L for insulin glargine [ETD -0.34 mmol/L (95% CI: −0.55 to −0.12), p = 0.002], with a similar CV between the two groups.Conclusion: The addition of once-weekly GLP-1RA PEG-Loxe to metformin was superior to insulin glargine in improving glycemic control and glycemic variability evaluated by CGM in middle-aged and elderly patients with T2DM

Association between gut microbiota and gastrointestinal cancer: a two-sample bi-directional Mendelian randomization study

BackgroundThe gut microbiome is closely related to gastrointestinal (GI) cancer, but the causality of gut microbiome with GI cancer has yet to be fully established. We conducted this two-sample Mendelian randomization (MR) study to reveal the potential causal effect of gut microbiota on GI cancer.Materials and methodsSummary-level genetic data of gut microbiome were derived from the MiBioGen consortium and the Dutch Microbiome Project. Summary statistics of six GI cancers were drawn from United Kingdom Biobank. Inverse-variance-weighted (IVW), MR-robust adjusted profile score (MR-RAPS), and weighted-median (WM) methods were used to evaluate the potential causal link between gut microbiota and GI cancer. In addition, we performed sensitivity analyses and reverse MR analyses.ResultsWe identified potential causal associations between 21 bacterial taxa and GI cancers (values of p < 0.05 in all three MR methods). Among them, phylum Verrucomicrobia (OR: 0.17, 95% CI: 0.05–0.59, p = 0.005) retained a strong negative association with intrahepatic cholangiocarcinoma after the Bonferroni correction, whereas order Bacillales (OR: 1.67, 95% CI: 1.23–2.26, p = 0.001) retained a strong positive association with pancreatic cancer. Reverse MR analyses indicated that GI cancer was associated with 17 microbial taxa in all three MR methods, among them, a strong inverse association between colorectal cancer and family Clostridiaceae1 (OR: 0.91, 95% CI: 0.86–0.96, p = 0.001) was identified by Bonferroni correction.ConclusionOur study implicates the potential causal effects of specific microbial taxa on GI cancer, potentially providing new insights into the prevention and treatment of GI cancer through specific gut bacteria