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Changes in the 'shape' of risk (ie sources, nature, triggers, scale, rapidity and severity of consequences) relating to supply chains pose challenges for risk management and the underpinning discipline domains such as Operations Research that have traditionally provided guidance and support. The aim is to evaluate these challenges, specifically in the context of supply chain risk management and to consider new approaches to support management. An overall Supply Chain Risk Management Framework is constructed, comprising five components--risk drivers, risk management influencers, decision maker characteristics, risk management responses and performance outcomes. The focus is towards the risk management influencers, recognizing that other components have been investigated elsewhere in the operations literature. Four elements are identified within this risk management component, two conventional elements, rewards and risks, and two new elements, timescale and portfolio effects. An empirical case example is employed to illustrate these issues of risk management in the manufacturing sector and to evaluate the approaches employed to manage risk and performance. The conclusion drawn is that the proposed Supply Chain Risk Management Framework with the inclusion of the risk management influencers component provides a more robust description of the factors that affect the nature of the risk management responses in particular situations. This also demonstrates the need for the Operations Research discipline to evolve a more diverse set of risk management tools and approaches (ie both quantitative and qualitative) to effectively address the diversity of issues and contexts. doi: 10.1057/palgrave.jors.2602412 Published online 4 April 2007 Keywords: supply chain risk; risk management framework

Objective: The aim of this analysis was to assess the rate and extent of systemic availability of inhaled fluticasone propionate (FP) from 2 dry powder systems (Diskhaler and Diskus) and a metered-dose inhaler (MDI) by deconvolution analysis. Methods: The inhalation devices were evaluated in 3 separate studies with identical protocols. 12 healthy male volunteers were randomised to receive FP given as a 1000µg inhaled dose and 250µg by intravenous infusion according to a double-blind double-dummy crossover design. The bioavailability of FP after inhalation represents absorption of the drug from the lungs, since the bioavailability of the swallowed portion of the inhaled dose is negligible. Results: When corrected for the bioavailability (of FP) achieved by each inhalation device, the rate of absorption of FP over the first 2 hours was rapid from all devices. The mean time for absorption of 50% of the bioavailable dose was 1.6, 2.4, and 2.2 hours for the Diskhaler, Diskus and MDI, respectively. Thereafter, absorption from each device was prolonged, with approximately 10% of the dose remaining in the lungs 12 hours after inhalation. Conclusion: Irrespective of the inhalation device used, the prolonged absorption of FP into the systemic circulation indicates a long residence time in the lungs. [ABSTRACT FROM AUTHOR]

Objective: DMDC (2'-deoxy-2'-methylidenecytidine) is a potential antitumour deoxycytidine analogue of cytosine arabinoside. The major dose-limiting toxicity of DMDC is haematological depression, particularly neutropenia, and therefore quantitative exposure–toxicity relationships for DMDC are warranted. Methods: Data on the survival fraction at nadir of leukocytes, neutrophils and platelets from 66 patients receiving a once-daily regimen and 85 patients receiving a twice-daily regimen of DMDC were related to DMDC concentration–time profiles using area under the plasma concentration–time curve (AUC), threshold and general models. A semiphysiological model of neutrophils versus time after DMDC administration included transient compartments to imitate the differentiation stages in the bone marrow. Results: The relationship between plasma DMDC concentration–time profiles and the haematological toxicity at nadir was best described using an AUC-dependent model with separate functions for once- and twice-daily dosing, indicating schedule dependence of DMDC effects, even if differences in treatment duration had a similar explanatory value. Twice-daily dosing was associated with greater toxic effects than once-daily dosing. The AUC required for a 70% reduction in the neutrophils was 16 mgh/l and 4.2 mg·h/l for the once- and twice-daily regimens, respectively. The semiphysiological model included nine proliferating transient compartments that were sensitive to DMDC in a schedule-dependent manner, five non-mitotic, non-sensitive compartments and one compartment for circulating neutrophils. Conclusions: The haematological toxicity of DMDC is schedule dependent. The survival fractions of leukocytes, neutrophils and platelets are predicted to be lower when given on a twice-daily regimen than on a once-daily regimen. A semiphysiological model with transient compartments successfully described the entire time course of neutropenia after DMDC administration. [ABSTRACT FROM AUTHOR]

The in vivo antitumor activity of etoposide and mitozolomide was assessed in nude mice bearing a xenograft (CC3) of human gestational choriocarcinoma. Both agents demonstrated, at best, marginal activity observed as a delay in tumour growth. This lack of sensitivity suggests that the CC3 xenograft is not a good model for selection of agents for clinical evaluation in gestational choriocarcinoma. Plasma and tissue concentrations of etoposide and mitozolomide were measured in nude mice. Drug concentrations found in tumour tissue were 60% and 30% of plasma levels for mitozolomide and etoposide respectively. Etoposide and mitozolomide activity was also evaluated in vitro with another choriocarcinoma cell line (JAR). Maximum cell-kill was achieved after exposure to etoposide 0.05-1 microgram/ml for 3-24 h. In vitro response to etoposide demonstrates the importance of exposure time in determining cytotoxicity. In contrast, mitozolomide at concentrations from 1-100 micrograms/ml did not have a marked effect against JAR after exposure for 3-24 h. [ABSTRACT FROM AUTHOR]

BACKGROUND: Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. The results of clinical trials suggest that it is effective and well tolerated. OBJECTIVES: The goals of this study were to determine the absolute bioavailability of an oral dose of rosuvastatin and to describe the intravenous pharmacokinetics of rosuvastatin in healthy volunteers. METHODS: This was a randomized, open-label, 2-way crossover study consisting of 2 trial days separated by a > or =7-day washout period. Healthy male adult volunteers were given a single oral dose of rosuvastatin 40 mg on one trial day and an intravenous infusion of rosuvastatin 8 mg over 4 hours on the other. Pharmacokinetic and tolerability assessments were conducted up to 96 hours after dosing. A 3-compartment pharmacokinetic model was fitted to the plasma concentration-time profiles obtained for each volunteer after intravenous dosing. RESULTS: Ten white male volunteers entered and completed the trial. Their mean age was 35.7 years (range, 21-51 years), their mean height was 177 cm (range, 169-182 cm), and their mean body weight was 77.6 kg (range, 68-85 kg). The absolute oral bioavailability of rosuvastatin was estimated to be 20.1%,and the hepatic extraction ratio was estimated to be 0.63. The mean volume of distribution at steady state was 134 L. Renal clearance accounted for approximately 28% of total plasma clearance (48.9 L/h). Single oral and intravenous doses of rosuvastatin were well tolerated in this small number of healthy male volunteers. CONCLUSIONS: The absolute oral bioavailability of rosuvastatin in these 10 healthy volunteers was approximately 20%, and absorption was estimated to be 50%. The volume of distribution at steady state was consistent with extensive distribution of rosuvastatin to the tissues. The modest absolute oral bioavailability and high hepatic extraction of rosuvastatin are consistent with first-pass uptake into the liver after oral dosing. Rosuvastatin was cleared by both renal and nonrenal routes; tubular secretion was the predominant renal process. [ABSTRACT FROM AUTHOR]

Background: According to epidemiological transition theory, cardiovascular disease (CVD) risk shifts down the socioeconomic distribution with economic development., Methods: We tested this hypothesis using nationally representative data on 88,559 individuals aged 40-80 years from 57 low- and middle-income countries (LMICs). We used measured risk factors to estimate the 10-year probability of a CVD event (CVD risk) and proxied socioeconomic status (SES) by years of education. We used a concentration index to measure socioeconomic inequality in CVD risk and decomposed it into risk factor contributions. We estimated associations CVD risk and inequality in that risk with gross national income (GNI) per capita (pc)., Results: We estimated that a 1% higher GNI pc was associated with higher mean CVD risk of 0.0265 percentage points (pp) (95% CI: 0.0169-0.0361) among females and 0.0150 pp (0.0082-0.0219) among males. All risk factors, except systolic blood pressure (SBP) and smoking among females, were positively associated with GNI pc. In most countries, lower SES was associated with higher CVD risk. Age, SBP, diabetes (females only) and smoking (males particularly) contributed most to this inequality, while inequality in total cholesterol was mostly in the opposite direction. Lower SES individuals tended to have relatively higher CVD risk at higher GNI pc, particularly among females. This was due to differences in the distributions of SBP and, for females, age and diabetes., Conclusions: Economic development was associated with higher and more unequal CVD risk, which may warrant shifting targeting of CVD primary prevention to socially disadvantaged groups., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Bacterial infection of the intervertebral disc can lead to vertebral endplate edema known as Modic changes, with associated chronic low back pain. Oral antimicrobial therapy has shown efficacy but relies on prolonged dosing and may not be optimal in terms of patient outcome, side effects, or antibiotic stewardship. There is no antibiotic formulation approved for intradiscal administration. Here, we describe the development and preclinical characterization of a formulation of linezolid, a suspension of 50 mg/mL micronized powder, for intradiscal administration., Methods: Micronization, particle size analysis, Franz cell diffusion assays, ex vivo bioassay, and estimates of gelling temperature were used to optimize the composition and properties of the formulation. Performance of the formulation was assessed using sheep to characterize the pharmacokinetics and a model of intradiscal infection was developed to demonstrate efficacy. Suitability for human administration was demonstrated in a Good Laboratory Practice (GLP) local tolerance study., Results: Micronized linezolid, formulated as a powder suspension using a vehicle containing poloxamer 407 and iohexol, provided a temperature-dependent radio-opaque gel that was suitable for image-guided percutaneous intradiscal administration. Efficacy in a sheep model of intradiscal Staphylococcus aureus infection was demonstrated. The formulation provides a high level of sheep disc tissue exposure, with C max of 6500 μg/g and limited systemic exposure, with a plasma C max of 0.04 μg/mL per 0.1 mL dose (5 mg of linezolid). Deconvolution of plasma linezolid pharmacokinetics correlated with linezolid remaining in the disc over time. Observations from a GLP local tolerance study with the linezolid formulation were of a minor nature and related to the intradiscal administration procedure., Conclusions: Linezolid can be formulated for image-guided percutaneous intradiscal administration. The formulation is now in a Phase 1b clinical trial to evaluate safety, pharmacokinetics, and efficacy in patients with CLBP and suspected bacterial infection., Competing Interests: SG and LGC declare a financial interest and salary from Persica Pharmaceuticals Ltd., a clinical‐stage company developing intradiscally administered antibiotics to treat chronic low back pain (CLBP). Other authors work for contract research organizations contracted to provide expertise and services and their organizations received payment from Persica Pharmaceuticals Ltd. for the work detailed in this manuscript. Other authors declare no financial interests relevant to the manuscript., (© 2024 Persica Pharmaceuticals Ltd. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Background: Bacterial infection of the intervertebral disc is difficult to treat because the tissue is usually not vascularized and systemic antibiotic therapy may not reach optimal antibacterial exposure. Here we characterize the safety, tolerability, and pharmacokinetics of PP353, a suspension of micronized linezolid, formulated for direct intervertebral disc administration., Methods: The safety, tolerability, and pharmacokinetics of an intradiscal administration of PP353, was assessed in Part A of a Phase 1b study and consisted of a single injection of study drug (3 mL of PP353 and 150 mg linezolid). Clinical assessment included initial safety and tolerability of PP353 with continued follow-up for 12 months. Assessment of linezolid concentration in plasma samples enabled characterization of the pharmacokinetics. Deconvolution of systemic linezolid was used to estimate intervertebral disc linezolid concentration., Results: Intradiscal administration of 3 mL of PP353 (linezolid 50 mg/mL) to the nucleus pulposus was well tolerated with no reported study treatment-related severe or serious adverse events and resulted in an average geometric mean linezolid plasma C max of 1300 ng/mL at 7.27 h post-administration. The linezolid plasma C max observed with intradiscal PP353 is approximately 10% that observed with a standard oral or iv administration of 600 mg linezolid. Pharmacokinetic deconvolution estimated that a single dose of PP353 (150 mg linezolid) provided intradiscal bactericidal concentration of linezolid for 96 h and bacteriostatic exposure for up to 120 h after dosing., Conclusion: Intradiscal administration of 3 mL of PP353 is well-tolerated and based on the pharmacokinetics following a single injection, a two-dose regimen of PP353 (150 mg linezolid) on Day 1 and Day 5 ± 1 was selected to explore safety, tolerability, pharmacokinetics, and efficacy in Part B of the Persica 002 study., Competing Interests: SG, SR, and LGC declare a financial interest and salary from Persica Pharmaceuticals Ltd., a company developing intradiscally administered antibiotics to treat chronic low back pain (CLBP) in clinical trials. Other authors work for research organizations contracted to provide expertise and services and their organizations received payment from Persica Pharmaceuticals Ltd. for the work detailed in this manuscript. ST, RS, AG, PD, DH, CB, PC, RD, SS, CS, and GS declare no financial interests relevant to the manuscript., (© 2024 Persica Pharmaceuticals Ltd. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Nonketotic hyperglycinemia due to deficient glycine cleavage enzyme activity causes a severe neonatal epileptic encephalopathy. Current therapies based on mitigating glycine excess have only limited impact. An animal model with postnatal phenotyping is needed to explore new therapeutic approaches. We developed a Gldc p.Ala394Val mutant model and bred it to congenic status in two colonies on C57Bl/6J (B6) and J129X1/SvJ (J129) backgrounds. Mutant mice had reduced P-protein and enzyme activity indicating a hypomorphic mutant. Glycine levels were increased in blood and brain regions, exacerbated by dietary glycine, with higher levels in female than male J129 mice. Birth defects were more prevalent in mutant B6 than J129 mice, and hydrocephalus was more frequent in B6 (40%) compared to J129 (none). The hydrocephalus rate was increased by postnatal glycine challenge in B6 mice, more so when delivered from the first neonatal week than from the fourth. Mutant mice had reduced weight gain following weaning until the eighth postnatal week, which was exacerbated by glycine loading. The electrographic spike rate was increased in mutant mice following glycine loading, but no seizures were observed. The alpha/delta band intensity ratio was decreased in the left cortex in female J129 mice, which were less active in an open field test and explored less in a Y-maze, suggesting an encephalopathic effect. Mutant mice showed no evidence of memory dysfunction. This partial recapitulation of human symptoms and biochemistry will facilitate the evaluation of new therapeutic approaches with an early postnatal time window likely most effective., (© 2024 SSIEM.)

Background: Globally, non-communicable diseases (NCDs) are the leading cause of mortality and morbidity placing a huge burden on individuals, families and health systems, especially in low- and middle-income countries (LMICs). This rising disease burden calls for policy responses that engage the entire health care system. This study aims to synthesize evidence on how people with NCDs choose their healthcare providers in LMICs, and the outcomes of these choices, with a focus on private sector delivery., Methods: A systematic search for literature following PRISMA guidelines was conducted. We extracted and synthesised data on the determinants and outcomes of private health care utilisation for NCDs in LMICs. A quality and risk of bias assessment was performed using the Mixed Methods Appraisal Tool (MMAT)., Results: We identified 115 studies for inclusion. Findings on determinants and outcomes were heterogenous, often based on a particular country context, disease, and provider. The most reported determinants of seeking private NCD care were patients having a higher socioeconomic status; greater availability of services, staff and medicines; convenience including proximity and opening hours; shorter waiting times and perceived quality. Transitioning between public and private facilities is common. Costs to patients were usually far higher in the private sector for both inpatient and outpatient settings. The quality of NCD care seems mixed depending on the disease, facility size and location, as well as the aspect of quality assessed., Conclusion: Given the limited, mixed and context specific evidence currently available, adapting health service delivery models to respond to NCDs remains a challenge in LMICs. More robust research on health seeking behaviours and outcomes, especially through large multi-country surveys, is needed to inform the effective design of mixed health care systems that effectively engage both public and private providers., Trial Registration: PROSPERO registration number CRD42022340059 ., (© 2024. The Author(s).)

Long waiting times have been a persistent policy issue in the United Kingdom that the COVID-19 pandemic has exacerbated. This study analyses the causal effect of hospital spending on waiting times in England using a first-differences panel approach and an instrumental variable strategy to deal with residual concerns for endogeneity. We use data from 2014 to 2019 on waiting times from general practitioner referral to treatment (RTT) measured at the level of local purchasers (known as Clinical Commissioning Groups). We find that increases in hospital spending by local purchasers of 1% reduce median RTT waiting time for patients whose pathway ends with a hospital admission (admitted pathway) by 0.6 days but the effect is not statistically significant at 5% level (only at the 10% level). We also find that higher hospital spending does not affect the RTT waiting time for patients whose pathway ends with a specialist consultation (non-admitted pathway). Nor does higher spending have a statistically significant effect on the volume of elective activity for either pathway. Our findings suggest that higher spending is no guarantee of higher volumes and lower waiting times, and that additional mechanisms need to be put in place to ensure that increased spending benefits elective patients., (© 2023 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Introduction: The burden of non-communicable diseases (NCDs) has increased substantially in low- and middle-income countries (LMICs), and adapting health service delivery models to address this remains a challenge. Many patients with NCD seek private care at different points in their encounters with the health system, but the determinants and outcomes of these choices are insufficiently understood. The proposed systematic review will help inform the governance of mixed health systems towards achieving the goal of universal health coverage. This protocol details our intended methodological and analytical approaches, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)., Methods and Analysis: Following the PRISMA approach, this systematic review will develop a descriptive synthesis of the determinants and outcomes of private healthcare utilisation for NCDs in LMICs. The databases Embase, Medline, Web of Science Core Collection, EconLit, Global Index Medicus and Google Scholar will be searched for relevant studies published in English between period 1 January 2010 and 30 June 2022 with additional searching of reference lists. The study selection process will involve a title-abstract and full-text review, guided by clearly defined inclusion and exclusion criteria. A quality and risk of bias assessment will be done for each study using the Mixed Methods Appraisal Tool., Ethics and Dissemination: Ethical approval is not required because this review is based on data collected from publicly available materials. The results will be published in a peer-reviewed journal and presented at related scientific events., Prospero Registration Number: CRD42022340059., Competing Interests: Competing interests: None declared., (© World Health Organization 2023. Licensee BMJ.)