Adapting lean methodology towards surgical tray rationalisation in inguinoscrotal day case surgery in the republic of Ireland.

INTRODUCTION: Lean methodologies have been used successfully in both industry and healthcare to reduce waste. The operating room (OR) and central supplies department (CSD) are areas associated with high hospital costs. The aim of this study was to employ Lean methodologies to support the rationalisation of surgical trays in paediatric inguinoscrotal surgery in order to reduce instrument wastage, processing times and overall costs in a European setting. METHODS: This was a prospective, pilot observation and implementation study using Lean methodology including DMAIC (Define, Measure, Analyse, Improve and Control) cycles. Relevant tray set-up included trays for boys ≥12 months age undergoing open elective inguinoscrotal surgery. A comparative analysis of two phases, pre and post-standardization was then carried out with respect to operating times, instrument set-up times, tray weights, and costs. Instruments that were used <40% of the time were eliminated from the surgical tray. RESULTS: Rationalization of the inguinoscrotal tray led to a 34.7% reduction in tray size, with a concomitant time-reduction of >2 min per case. The average overall instrument utilisation rate increased from 56% to 80% across users. Cost savings were projected at €5380.40 per annum based on current changes. There were no differences in operative time, or adverse outcomes. DISCUSSION: At the hospital level, the reduction in variation, and rationalisation of this single surgical tray could lead to both operational (Tray assembly process; Operating rooms; Ergonomic functionality) as well as economic (Sterilisation; Instrument repair; Purchases) financial and ergonomic improvements for the healthcare system. The reduction in time taken to count and sterilise instruments can lead to a potential manpower saving involving a redistribution of activities to other areas which may require them. CONCLUSION: Surgical tray rationalisation is emerging Lean concept with overlap across a number of specialities, and represents a technique by which to manage costs, and improve supply chain efficiency without any adverse effect in patient healthcare outcomes.

Anti-Ro52/TRIM21 is independently associated with pulmonary arterial hypertension and mortality in a cohort of systemic sclerosis patients.

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement.Method: The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses.Results: Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications.Conclusion: Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

Microbial community changes in a female rat model of Rett syndrome.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that is predominantly caused by alterations of the methyl-CpG-binding protein 2 (MECP2) gene. Disease severity and the presence of comorbidities such as gastrointestinal distress vary widely across affected individuals. The gut microbiome has been implicated in neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) as a regulator of disease severity and gastrointestinal comorbidities. Although the gut microbiome has been previously characterized in humans with RTT compared to healthy controls, the impact of MECP2 mutation on the composition of the gut microbiome in animal models where the host and diet can be experimentally controlled remains to be elucidated. By evaluating the microbial community across postnatal development as behavioral symptoms appear and progress, we have identified microbial taxa that are differentially abundant across developmental timepoints in a zinc-finger nuclease rat model of RTT compared to WT. We have additionally identified p105 as a key translational timepoint. Lastly, we have demonstrated that fecal SCFA levels are not altered in RTT rats compared to WT rats across development. Overall, these results represent an important step in translational RTT research.

Factors affecting the growth of infants diagnosed with cystic fibrosis by newborn screening.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) improves nutritional outcomes. Despite early dietetic intervention some children fail to grow optimally. We report growth from birth to 2 years in a cohort of children diagnosed with CF by NBS and identify the variables that influence future growth. METHODS: One hundred forty-four children were diagnosed with CF by the West Midlands Regional NBS laboratory between November 2007 and October 2014. All anthropometric measurements and microbiology results from the first 2 years were collated as was demographic and CF screening data. Classification modelling was used to identify the key variables in determining future growth. RESULTS: Complete data were available on 129 children. 113 (88%) were pancreatic insufficient (PI) and 16 (12%) pancreatic sufficient (PS). Mean birth weight (z score) was 3.17 kg (- 0.32). There was no significant difference in birth weight (z score) between PI and PS babies: 3.15 kg (- 0.36) vs 3.28 kg (- 0.05); p = 0.33. By the first clinic visit the difference was significant: 3.42 kg (- 1.39) vs 4.60 kg (- 0.48); p < 0.0001. Weight and height remained lower in PI infants in the first year of life. In the first 2 years of life, 18 (14%) infants failed to regain their birth weight z score. The median time to achieve a weight z score of - 2, - 1 and 0 was 18, 33 and 65 weeks respectively. The median times to reach the same z scores for height were 30, 51 and 90 weeks. Birth weight z score, change in weight z score from birth to first clinic, faecal elastase, isolation of Pseudomonas aeruginosa, isolation of Staphylococcus aureus and sweat chloride were the variables identified by the classification models to predict weight and height in the first and second year of life. CONCLUSIONS: Babies with CF have a lower birth weight than the healthy population. For those diagnosed with CF by NBS, the weight difference between PI and PS babies was not significantly different at birth but became so by the first clinic visit. The presence of certain factors, most already identifiable at the first clinic visit can be used to identify infant at increased risk of poor growth.

Can We Accurately Predict Cost Effectiveness Without Access to Overall Survival Data? The Case Study of Nivolumab in Combination with Ipilimumab for the Treatment of Patients with Advanced Melanoma in England.

BACKGROUND: Nivolumab with ipilimumab (the Regimen) is the first immuno-oncology combination treatment to demonstrate long-term clinical benefit for advanced melanoma patients. We evaluated the cost effectiveness of the Regimen in this population, with and without the availability of overall survival (OS) data. METHODS: A partitioned survival model and a Markov state-transition model were developed to estimate the lifetime costs and benefits of the Regimen versus ipilimumab. These models were built with and without the availability of OS data, as only progression-free survival data were available from the head-to-head, phase III trial against ipilimumab at the time of the National Institute for Health and Care Excellence (NICE) submission. Patient utilities and resource use data were sourced from trial data or the literature. RESULTS: Incremental cost-effectiveness ratios (ICERs) and absolute costs were similar between the models with and without OS data, but the model with OS data generated more than 1 additional quality-adjusted life-year (QALY) across both treatment arms. In both models, based on list prices, the Regimen was the most cost-effective treatment. CONCLUSIONS: The analyses show that the Regimen is a cost-effective treatment for advanced melanoma patients in England, and methods to overcome the lack of OS can give reasonable estimates of QALYs gained and ICERs.

Correction to: Can We Accurately Predict Cost Effectiveness Without Access to Overall Survival Data? The Case Study of Nivolumab in Combination with Ipilimumab for the Treatment of Patients with Advanced Melanoma in England.

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Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Nutrient composition and retention in whole turkeys with and without added solution.

Whole turkeys sold in retail outlets are typically processed with added solutions to improve their taste and tenderness. The purpose of this study was to evaluate the nutrient composition of whole turkeys with and without added solution, and to update the nutrient profile of turkey for the USDA National Nutrient Database for Standard Reference. Eleven pairs of turkeys with added solution were obtained from statistically representative retail outlets using a nationwide sampling plan developed for USDA's National Food and Nutrient Analysis Program; 4 pairs of turkeys without added solution were purchased from local food outlets. Turkeys were roasted to an internal temperature of 165°F (74°C). Values of selected nutrients in light and dark meat, including skin, were determined by USDA approved laboratories using quality assurance protocols. Both raw and cooked turkeys, with and without added solution, were compared by one-way and 2-way factorial ANOVA. The results showed a significant interaction for fat (P < 0.0001) and zinc (P = 0.0070) between turkeys that were raw and cooked and those prepared with or without added solution. Fat was higher in raw turkeys with added solution compared to without added solution. Similarly, sodium, phosphorus, and calcium values were significantly higher in turkeys with added solution (P < 0.05) than in turkeys without added solution. Data from this study will be useful for developing strategies to address sodium-related health issues, nutrition monitoring, consumption surveys, and policy development.

p16INK4a , a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV-Infected Subjects.

The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a , a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV-Infected Subjects With Aging Biomarkers.

Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m2 . No alterations in drug clearance or unbound fraction with age, frailty, or p16INK4a expression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.

Model-Based Analysis of Unbound Lopinavir Pharmacokinetics in HIV-Infected Pregnant Women Supports Standard Dosing in the Third Trimester.

Physiological changes during pregnancy can affect drug pharmacokinetics. Here we present a population pharmacokinetic model to describe the longitudinal change of unbound lopinavir/ritonavir (LPV/RTV) PK parameters with gestational age, and to predict unbound LPV concentrations under different dosing regimens. The changes in apparent intrinsic clearances of LPV and RTV during pregnancy are described using an exponential function of gestational age. The unbound fractions of LPV/RTV are not significantly different between pregnancy and postpartum. Simulation reveals that despite increases in LPV intrinsic clearance, effective LPV inhibitory quotient (IQ) values are predicted with the standard dosing (400/100 mg b.i.d.) in >90% of simulations, with ≤4-fold increase in viral IC50. As viral susceptibility decreases, higher doses increase the likelihood of efficacy. With ≥40-fold increases in IC50, IQs suggest alternate regimens be considered. This approach refines previous LPV PK reports, and supports that standard dosing is effective with susceptible virus.

Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.

OBJECTIVE: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

Nutrient database improvement project: Separable components and proximate composition of raw and cooked retail cuts from the beef loin and round.

Beef nutrition research has become increasingly important domestically and internationally for the beef industry and its consumers. The objective of this study was to analyze the nutrient composition of ten beef loin and round cuts to update the nutrient data in the USDA National Nutrient Database for Standard Reference. Seventy-two carcasses representing a national composite of Yield Grade, Quality Grade, sex classification, and genetic type were identified from six regions across the U.S. Beef short loins, strip loins, tenderloins, inside rounds, and eye of rounds (NAMP # 173, 175, 190A, 169A, and 171C) were collected from the selected carcasses and shipped to three university meat laboratories for storage, retail fabrication, and raw/cooked analysis of nutrients. Sample homogenates from each animal were analyzed for proximate composition. These data provide updated information regarding the nutrient status of beef, in addition, to determining the influence of Quality Grade, Yield Grade, and sex classification on nutrient composition.

Nutrient database improvement project: the influence of USDA quality and yield grade on the separable components and proximate composition of raw and cooked retail cuts from the beef chuck.

This study was designed to provide updated information on the separable components, cooking yields, and proximate composition of retail cuts from the beef chuck. Additionally, the impact the United States Department of Agriculture (USDA) Quality and Yield Grade may have on such factors was investigated. Ultimately, these data will be used in the USDA - Nutrient Data Laboratory's (NDL) National Nutrient Database for Standard Reference (SR). To represent the current United States beef supply, seventy-two carcasses were selected from six regions of the country based on USDA Yield Grade, USDA Quality Grade, gender, and genetic type. Whole beef chuck primals from selected carcasses were shipped to three university laboratories for subsequent retail cut fabrication, raw and cooked cut dissection, and proximate analyses. The incorporation of these data into the SR will improve dietary education, product labeling, and other applications both domestically and abroad, thus emphasizing the importance of accurate and relevant beef nutrient data.

Nutrient database improvement project: the influence of U.S.D.A. Quality and Yield Grade on the separable components and proximate composition of raw and cooked retail cuts from the beef rib and plate.

Beef nutrition is important to the worldwide beef industry. The objective of this study was to analyze proximate composition of eight beef rib and plate cuts to update the USDA National Nutrient Database for Standard Reference (SR). Furthermore, this study aimed to determine the influence of USDA Quality Grade on the separable components and proximate composition of the examined retail cuts. Carcasses (n=72) representing a composite of Yield Grade, Quality Grade, gender and genetic type were identified from six regions across the U.S. Beef plates and ribs (IMPS #109 and 121C and D) were collected from the selected carcasses and shipped to three university meat laboratories for storage, retail fabrication, cooking, and dissection and analysis of proximate composition. These data provide updated information regarding the nutrient content of beef and emphasize the influence of common classification systems (Yield Grade and Quality Grade) on the separable components, cooking yield, and proximate composition of retail beef cuts.

Pharmacokinetics of two common antiretroviral regimens in older HIV-infected patients: a pilot study.

OBJECTIVES: The pharmacokinetics (PK) of antiretrovirals (ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir (TFV)/emtricitabine (FTC)/efavirenz (EFV) and TFV/FTC/atazanavir (ATV)/ritonavir (RTV)] in older nonfrail HIV-infected patients are presented. METHODS: HIV-infected subjects ≥ 55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [PBMCs; for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography-ultraviolet detection (LC-UV) or liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration-time curve over 24 h (AUC0-24h ) and maximal concentration (Cmax )]. These parameters were compared with historical values from the general HIV-infected population. RESULTS: Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8-13% decreased TFV AUC0-24h and Cmax , and 19-78% increased FTC and RTV AUC0-24h and Cmax . Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax . Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects. CONCLUSIONS: This study demonstrates that the PK of these ARVs are altered by 5-78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients.

Rosuvastatin reduced deep vein thrombosis in ApoE gene deleted mice with hyperlipidemia through non-lipid lowering effects.

INTRODUCTION: Statins, particularly rosuvastatin, have recently become relevant in the setting of venous thrombosis. The objective of this study was to study the non-lipid lowering effects of rosuvastatin in venous thrombosis in mice with hyperlipidemia. MATERIALS AND METHODS: An inferior vena cava ligation model of venous thrombosis in mice was utilized. Saline or 5mg/kg of rosuvastatin was administered by gavage 48hs previous to thrombosis. Blood, the inferior vena cava, thrombus, and liver were harvested 3, 6hours, and 2days post-thrombosis. Thrombus weight, inflammatory markers, and plasminogen activator inhibitor-1 expression and plasma levels were measured. Also, neutrophil migration to the IVC was assessed. RESULTS: Rosuvastatin significantly decreased thrombus weight, plasminogen activator inhibitor-1 expression and plasma levels, expression of molecules related to the interleukin-6 pathway, and neutrophil migration into the vein wall. CONCLUSIONS: This work supports the beneficial effects of rosuvastatin on venous thrombosis in mice with hyperlipidemia, due to its non-lipid lowering effects.

Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer.

Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management.