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IntroductionThe purpose of this study was to examine the influence of nutritional intake on visual perceptual-cognitive performance (VCP) in young healthy adults.MethodsNinety-eight healthy men (n = 38) and women (n = 60) aged 18–33 years participated and maintained their usual dietary intake throughout the study. VCP was measured using the NeuroTracker™ CORE (NT) 3-Dimensional (3-D) software program (15 training sessions) over a 15-day period. Food logs and extensive lifestyle measures including body composition, cardiovascular health, sleep and exercise patterns, and general readiness to perform were collected. Mean intake from 10 food logs collected over the 15 days were analyzed using Nutribase software. Statistical analyses were performed in SPSS using repeated measures ANOVA including significant covariates when appropriate.ResultsMales consumed significantly more calories, macronutrients, cholesterol, choline, and zinc and performed significantly better on VCP than the females. Participants who consumed more than 40% of kcals from carbohydrates (p = 0.038), less than 24% of kcals from protein (p = 0.009), more than 2,000 μg/day lutein/zeaxanthin or more than 1.8 mg/ day vitamin B2 performed significantly better on VCP than those who consumed less than those amounts, respectively.DiscussionVCP is an important dimension of cognitive function and in the present study is influenced by higher carbohydrate, lutein/ zeaxanthin, and vitamin B2 dietary intake while high protein consumption and the female sex negatively impacted VCP.

Abstract Background Zonulin is observed in animal models to regulate intestinal permeability and influenced by dietary intake, gut microbiota, and inflammation. We conducted a secondary analysis of a randomized controlled crossover trial (NCT03582306) in individuals with a BMI greater than 30 kg/m2 and high habitual red meat intake and low habitual green leafy vegetable (GLV) intake. Methods Participants were provided with frozen GLV during the first or last four weeks (immediate or delayed intervention) of the twelve-week trial. Biological and anthropometric measures were taken at the beginning and at each four-week interval. A subset of 20 participants was selected for this secondary analysis of the intestinal permeability and inflammation-related biomarkers: serum and fecal zonulin; serum lipopolysaccharide binding protein (LBP), Alpha-1-acid glycoprotein 1 (ORM-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and C-reactive protein; 8-hydroxy-2'-deoxyguanosine (8OHdG) and plasma Vitamin K1 as a marker of protocol adherence. Nutrient and food group intake from two-24-h dietary recalls collected at each time point were assessed. Fecal microbiota was measured by 16 s rRNA PCR sequencing. Changes in biological markers, dietary factors, and microbial taxa were assessed with Wilcoxon Sign Ranks Tests. Exploratory analyses of the relationship between changes in outcome variables were conducted with Spearman correlations. Results No changes in serum and fecal zonulin and serum LBP were observed. Plasma Vitamin K (p = 0.005) increased, while plasma 8OHdG (p = 0.023) decreased during the intervention compared to the control. The only dietary factors that changed significantly were increases during intervention in Vitamin K and Dark GLV (p

Background: Muscle-invasive bladder cancer (MIBC) remains undertreated despite multiple potentially curative options. Both radical cystectomy (RC) with or without neoadjuvant chemotherapy and trimodal therapy (TMT), including transurethral resection of bladder tumor followed by chemoradiotherapy, are standard treatments. Objective: To evaluate real-world clinical outcomes of RC with neoadjuvant chemotherapy (RC-NAC), RC without NAC, TMT with National Comprehensive Cancer Network guideline–preferred radiosensitizing chemotherapy including cisplatin or mitomycin-C and 5-fluorouracil (pTMT), and TMT with nonpreferred chemotherapy (npTMT). Design, setting, and participants: US veterans with nonmetastatic MIBC (T2-4aN0-3M0) were studied. Outcome measurements and statistical analysis: Overall mortality (OM) was evaluated with multivariable Cox proportional hazard model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. Salvage cystectomy rates were obtained by chart review. Results and limitations: Overall 2306 patients were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 163 (7%) with pTMT, and 165 (7%) with npTMT. On multivariable analysis, pTMT was associated with similar OM (hazard ratio [HR] 1.19; 95% confidence interval [CI] 0.94–1.50; p = 0.15) and BCSM (HR 1.34; 95% CI 0.99–1.83; p = 0.06) to RC-NAC; npTMT was associated with worse OM (HR 1.30; 95% CI 1.04–1.61; p = 0.02) and BCSM (HR 1.45; 95% CI 1.09–1.94; p = 0.01). RC without NAC was associated with similar OM (HR 1.08; 95% CI 0.95–1.24; p = 0.24) and BCSM (HR 1.02; 95% CI 0.86–1.21; p = 0.79). When stratified by age, among patients ≥65 yr of age, treatment with pTMT was associated with similar OM (HR 1.14; 95% CI 0.87–1.50; p = 0.35) and BCSM (HR 1.11; 95% CI 0.76–1.62; p = 0.60). Among patients

In the last decade, the number of full-time registered dietitians (RDs) serving intercollegiate athletes in the United States has more than quadrupled. However, many student athletes may be at increased risk of nutrition-related problems that impact physical and academic performance, which include inadequate macronutrients, inadequate micronutrients, and excessive macronutrients. This narrative review reports the current literature to date on nutrition-related knowledge in collegiate athletes and the impact of sports RDs on student athletes’ nutrition knowledge and behaviors. To date, only observational and quasi-experimental studies have been published with regard to changes in nutrition knowledge and behaviors in NCAA athletes. While these studies report benefits of the RD as a member of the interdisciplinary student athlete support team, more well-designed randomized control trials are warranted to determine benefits related to health outcomes and sport-specific performance outcomes.

Green leafy vegetables (GLV) may reduce the risk of red meat (RM)-induced colonic DNA damage and colorectal cancer (CRC). We previously reported the primary outcomes (feasibility) of a 12-week randomized controlled crossover trial in adults with habitual high RM and low GLV intake with body mass index (BMI) > 30 kg/m2 (NCT03582306). Herein, our objective was to report a priori secondary outcomes. Participants were recruited and enrolled in 2018, stratified by gender, and randomized to two arms: immediate intervention group (IG, n = 26) or delayed intervention group (DG, n = 24). During the 4 week intervention period, participants were provided with frozen GLV and counseled to consume 1 cooked cup equivalent daily. Participants consumed their normal diet for the remaining 8 weeks. At each of four study visits, anthropometrics, stool, and blood were taken. Overall, plasma Vitamin K1 (0.50 ± 1.18 ng/mL, p < 0.001) increased, while circulating 8OHdG (−8.52 ± 19.05 ng/mL, p < 0.001), fecal 8OHdG (−6.78 ± 34.86 ng/mL, p < 0.001), and TNFα (−16.95 ± 60.82 pg/mL, p < 0.001) decreased during the GLV intervention compared to control periods. Alpha diversity of fecal microbiota and relative abundance of major taxa did not differ systematically across study periods. Further investigation of the effects of increased GLV intake on CRC risk is warranted.

Preclinical and observational research suggests green leafy vegetables (GLVs) may reduce the risk of red meat (RM)-induced colonic DNA damage and colon cancer (CC). We sought to determine the feasibility of a high GLV dietary intervention in adults with an increased risk of CC (NCT03582306) via a 12-week randomized controlled crossover trial. Participants were randomized to immediate or delayed (post-4-week washout) intervention groups. During the 4-week intervention period, participants were given frozen GLVs and counseled to consume one cooked cup equivalent daily. The primary outcomes were: accrual—recruiting 50 adults in 9 months; retention—retaining 80% of participants at completion; and adherence—meeting GLV intake goals on 90% of days. Adherence data were collected twice weekly and 24-h dietary recalls at each time point provided nutrient and food group measures. The Food Acceptability Questionnaire (FAQ) was completed to determine acceptability. On each of the four study visits, anthropometrics, stool, saliva, and blood were obtained. Fifty adults were recruited in 44 days. Participants were 48 ± 13 years of age, 62% female, and 80% Caucasian, with an average BMI at screening of 35.9 ± 5.1. Forty-eight (96%) participants were retained and completed the study. During the intervention phase, participants consumed GLVs on 88.8% of days; the adherence goal of one cup was met on 73.2% of days. Dietary recall-derived Vitamin K and GLVs significantly increased for all participants during the intervention periods. Overall satisfaction did not differ between intervention and control periods (p = 0.214). This feasibility trial achieved accrual, retention and acceptability goals, but fell slightly short of the benchmark for adherence. The analysis of biological specimens will determine the effects of GLVs on gut microbiota, oxidative DNA damage, and inflammatory cytokines.

Objective: Osteoarthritis (OA) exposes all joint tissues to physiologic stresses, increasing the need to clear apoptotic cells from tissues, including the synovium. We undertook this study to assess the burden of apoptotic cells in synovial tissue in patients with late-stage knee OA and to investigate whether OA impairs the macrophage-mediated clearance of apoptotic cells via efferocytosis., Methods: Synovial tissue was collected from individuals with healthy knees and patients with late-stage knee OA during arthroplasty. Synovial apoptotic cell burden was assessed by immunofluorescence for cleaved caspase 3. Efferocytosis of apoptotic Jurkat cells by CD14+ synovial tissue macrophages and peripheral blood-derived macrophages was quantified using immunofluorescence microscopy. Effects of OA on macrophage-mediated efferocytosis were modeled by stimulating blood-derived macrophages with synovial fluid collected from individuals with healthy knees and patients with early- or late-stage knee OA., Results: Patients with late-stage knee OA had more apoptotic synovial cells compared to healthy individuals. There was a marked reduction in the fraction of synovial tissue macrophages engaging in efferocytosis and the quantity of material efferocytosed by individual macrophages in OA patients. Blood-derived macrophages exposed to synovial fluid from patients with knee OA recapitulated the defective efferocytosis, with the greatest effect from patients with early-stage knee OA and higher disease activity (pain and inflammation)., Conclusion: Apoptotic cells accumulate in the synovium of patients with late-stage knee OA. Our results suggest that OA impairs critical homeostatic functions of synovial macrophages, leading to accumulation of apoptotic cells., (© 2022 American College of Rheumatology.)

As countries graduate from low-income to middle-income status, many face losses in development assistance for health and must 'transition' to greater domestic funding of their health response. If improperly managed, donor transitions in middle-income countries (MICs) could present significant challenges to global health progress. No prior knowledge synthesis has comprehensively surveyed how donor transitions can affect health systems in MICs. We conducted a scoping review using a structured search strategy across five academic databases and 37 global health donor and think tank websites for literature published between January 1990 and October 2018. We used the World Health Organization health system 'building blocks' framework to thematically synthesize and structure the analysis. Following independent screening, 89 publications out of 11 236 were included for data extraction and synthesis. Most of this evidence examines transitions related to human immunodeficiency virus/Acquired Immune Deficiency Syndrome (AIDS; n = 45, 50%) and immunization programmes (n = 14, 16%), with a focus on donors such as the Global Fund to Fight AIDS, Tuberculosis and Malaria (n = 26, 29%) and Gavi, the Vaccine Alliance (n = 15, 17%). Donor transitions are influenced by the actions of both donors and country governments, with impacts on every component of the health system. Successful transition experiences show that leadership, planning, and pre-transition investments in a country's financial, technical, and logistical capacity are vital to ensuring smooth transition. In the absence of such measures, shortages in financial resources, medical product and supply stock-outs, service disruptions, and shortages in human resources were common, with resulting implications not only for programme continuation, but also for population health. Donor transitions can affect different components of the health system in varying and interconnected ways. More rigorous evaluation of how donor transitions can affect health systems in MICs will create an improved understanding of the risks and opportunities posed by donor exits., (© The Author(s) 2022. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

Male gametogenesis involves both mitotic divisions to amplify germ cell progenitors that gradually differentiate and meiotic divisions. Centrosomal regulation is essential for both types of divisions, with centrioles remaining tightly paired during the interphase. Here, we generated and characterized the phenotype of mutant mice devoid of Cep250/C-Nap1 , a gene encoding for a docking protein for fibers linking centrioles, and characterized their phenotype. The Cep250 -/- mice presented with no major defects, apart from male infertility due to a reduction in the spermatogonial pool and the meiotic blockade. Spermatogonial stem cells expressing Zbtb16 were not affected, whereas the differentiating spermatogonia were vastly lost. These cells displayed abnormal γ H2AX-staining, accompanied by an increase in the apoptotic rate. The few germ cells that survived at this stage, entered the meiotic prophase I and were arrested at a pachytene-like stage, likely due to synapsis defects and the unrepaired DNA double-strand breaks. In these cells, centrosomes split up precociously, with γ -tubulin foci being separated whereas these were closely associated in wild-type cells. Interestingly, this lack of cohesion was also observed in wild-type female meiocytes, likely explaining the normal fertility of Cep250 -/- female mice. Taken together, this study proposes a specific requirement of centrosome cohesion in the male germline, with a crucial role of CEP250 in both differentiating spermatogonia and meiotic spermatocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Floriot, Bellutti, Castille, Moison, Messiaen, Passet, Boulanger, Boukadiri, Tourpin, Beauvallet, Vilotte, Riviere, Péchoux, Bertaud, Vilotte and Livera.)

Hypertension is a recognized comorbidity for COVID-19. The association of antihypertensive medications with outcomes in patients with hypertension is not fully described. However, angiotensin-converting enzyme 2 (ACE2), responsible for host entry of the novel coronavirus (SARS-CoV-2) leading to COVID-19, is postulated to be upregulated in patients taking angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Here, we evaluated the occurrence of pulmonary adverse drug events (ADEs) in patients with hypertension receiving ACEIs/ARBs to determine if disparities exist between individual drugs within the respective classes using data from the FDA Spontaneous Reporting Systems. For this purpose, we proposed the proportional reporting ratio to provide a statistical summary for the commonality of an ADE for a specific drug as compared to the entire database for drugs in the same or other classes. In addition, a statistical procedure, multiple logistic regression analysis, was employed to correct hidden confounders when causative covariates are underreported or untrusted to correct analyses of drug-ADE combinations. To date, analyses have been focused on drug classes rather than individual drugs which may have different ADE profiles depending on the underlying diseases present. A retrospective analysis of thirteen pulmonary ADEs showed significant differences associated with quinapril and trandolapril, compared to other ACEIs and ARBs. Specifically, quinapril and trandolapril were found to have a statistically significantly higher incidence of pulmonary ADEs compared with other ACEIs as well as ARBs (P < 0.0001) for group comparison (i.e., ACEIs vs. ARBs vs. quinapril vs. trandolapril) and (P ≤ 0.0007) for pairwise comparison (i.e., ACEIs vs. quinapril, ACEIs vs. trandolapril, ARBs vs. quinapril, or ARBs vs. trandolapril). This study suggests that specific members of the ACEI antihypertensive class (quinapril and trandolapril) have a significantly higher cluster of pulmonary ADEs.

Background: Ghana's shift from low-income to middle-income status will make it ineligible to receive concessional aid in the future. While transition may be a reflection of positive changes in a country, such as economic development or health progress, a loss of support from donor agencies could have negative impacts on health system performance and population health. We aimed to identify key challenges and opportunities that Ghana will face in dealing with aid transition, specifically from the point of view of country-level stakeholders., Methods: We conducted key informant interviews with 18 stakeholders from the government, civil society organisations and donor agencies in Ghana using a semistructured interview guide. We performed directed content analysis of the interview transcripts to identify key themes related to anticipated challenges and opportunities that might result from donor transitions., Results: Overall, stakeholders identified challenges more frequently than opportunities. All stakeholders interviewed believe that Ghana will face substantial challenges due to donor transitions. Challenges include difficulty filling financial gaps left by donors, the shifting of national priorities away from the health sector, lack of human resources for health, interrupted care for beneficiaries of donor-funded health programmes, neglect of vulnerable populations and loss of the accountability mechanisms that are linked with donor financing. However, stakeholders also identified key opportunities that transitions might present, including efficiency gains, increased self-determination and self-sufficiency, enhanced capacity to leverage domestic resources and improved revenue mobilisation., Conclusion: Stakeholders in Ghana believe transitioning away from aid for health presents both challenges and opportunities. The challenges could be addressed by conducting a transition readiness assessment, identifying health sector priorities, developing a transition plan with a budget to continue critical health programmes and mobilising greater political commitment to health. The loss of aid could be turned into an opportunity to integrate vertical programmes into a more comprehensive health system., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34 + cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in KDM6A and two heterozygous mutations in TET2 in the founding clone and a secondary KRAS (G12D) mutation. CD34 + cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the KRAS (G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease., (Copyright© 2020 Ferrata Storti Foundation.)

Background: The current scenario of newborn screening is changing as DNA studies are being included in the programs of several countries. Severe combined immunodeficiency (SCID) disorders can be detected using quantitative PCR assays to measure T-cell receptor excision circles (TRECs), a byproduct of correct T-cell development. However, in addition to SCID, other T-cell-deficient phenotypes such as 22q11.2 deletion syndrome 22q11.2 duplication syndrome, CHARGE syndrome, and trisomy 21 are detected., Methods: We present our experience with the detection of 22q11.2 deletion syndrome and 22q11.2 duplication syndrome in a series of 103,903 newborns included in the newborn screening program of Catalonia (Spain)., Results: Thirty newborns tested were positive (low TREC levels) and five were found to have copy number variations at the 22q11 region (4 deletions and 1 duplication) when investigated with array comparative genomic hybridization technology and MLPA., Conclusion: Newborn screening for SCID enables detection of several conditions, such as 22q syndromes, which should be managed by prompt, proactive approaches with adequate counseling for families by a multidisciplinary team., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: Osteochondrosis (OC(D)) is a juvenile osteo-articular disorder affecting several mammalian species. In horses, OC(D) is considered as a multifactorial disease and has been described as a focal disruption of endochondral ossification leading to the development of osteoarticular lesions. Nevertheless, OC(D) physiopathology is poorly understood. Affected horses may present joint swelling, stiffness and lameness. Thus, OC(D) is a major concern for the equine industry. Our study was designed as an integrative approach using omics technologies for the identification of constitutive defects in epiphyseal cartilage and/or subchondral bone associated with the development of primary lesions to further understand OC(D) pathology. This study compared samples from non-affected joints (hence lesion-free) from OC(D)-affected foals (n = 5, considered predisposed samples) with samples from OC-free foals (n = 5) considered as control samples. Consequently, results are not confounded by changes associated with the evolution of the lesion, but focus on altered constitutive molecular mechanisms. Comparative proteomics and micro computed tomography analyses were performed on predisposed and OC-free bone and cartilage samples. Metabolomics was also performed on synovial fluid from OC-free, OC(D)-affected and predisposed joints., Results: Two lesion subtypes were identified: OCD (lesion with fragment) and OC (osteochondral defects). Modulated proteins were identified using omics technologies (2-DE proteomics) in cartilage and bone from affected foals compare to OC-free foals. These were associated with cellular processes including cell cycle, energy production, cell signaling and adhesion as well as tissue-specific processes such as chondrocyte maturation, extracellular matrix and mineral metabolism. Of these, five had already been identified in synovial fluid of OC-affected foals: ACTG1 (actin, gamma 1), albumin, haptoglobin, FBG (fibrinogen beta chain) and C4BPA (complement component 4 binding protein, alpha)., Conclusion: This study suggests that OCD lesions may result from a cartilage defect whereas OC lesions may be triggered by both bone and cartilage defects, suggesting that different molecular mechanisms responsible for the equine osteochondrosis lesion subtypes and predisposition could be due to a defect in both bone and cartilage. This study will contribute to refining the definition of OC(D) lesions and may improve diagnosis and development of therapies for horses and other species, including humans.

Thyroid hormone (T3) is required for postnatal skeletal growth. It exerts its effect by binding to nuclear receptors, TRs including TRα1 and TRβ1, which are present in most cell types. These cell types include chondrocytes and osteoblasts, the interactions of which are known to regulate endochondral bone formation. In order to analyze the respective functions of T3 stimulation in chondrocytes and osteoblasts during postnatal growth, we use Cre/loxP recombination to express a dominant-negative TRα1(L400R) mutant receptor in a cell-specific manner. Phenotype analysis revealed that inhibiting T3 response in chondrocytes is sufficient to reproduce the defects observed in hypothyroid mice, not only for cartilage maturation, but also for ossification and mineralization. TRα1(L400R) in chondrocytes also results in skull deformation. In the meantime, TRα1(L400R) expression in mature osteoblasts has no visible effect. Transcriptome analysis identifies a number of changes in gene expression induced by TRα1(L400R) in cartilage. These changes suggest that T3 normally cross talks with several other signaling pathways to promote chondrocytes proliferation, differentiation, and skeletal growth.

Background: Nanoparticle-protein corona complex formation involves absorption of protein molecules onto nanoparticle surfaces in a physiological environment. Understanding the corona formation process is crucial in predicting nanoparticle behavior in biological systems, including applications of nanotoxicology and development of nano drug delivery platforms., Method: This paper extends the modeling work in to derive a mathematical model describing the dynamics of nanoparticle corona complex formation from population balance equations. We apply nonlinear dynamics techniques to derive analytical results for the composition of nanoparticle-protein corona complex, and validate our results through numerical simulations., Results: The model presented in this paper exhibits two phases of corona complex dynamics. In the first phase, proteins rapidly bind to the free surface of nanoparticles, leading to a metastable composition. During the second phase, continuous association and dissociation of protein molecules with nanoparticles slowly changes the composition of the corona complex. Given sufficient time, composition of the corona complex reaches an equilibrium state of stable composition. We find analytical approximate formulae for metastable and stable compositions of corona complex. Our formulae are very well-structured to clearly identify important parameters determining corona composition., Conclusion: The dynamics of biocorona formation constitute vital aspect of interactions between nanoparticles and living organisms. Our results further understanding of these dynamics through quantitation of experimental conditions, modeling results for in vitro systems to better predict behavior for in vivo systems. One potential application would involve a single cell culture medium related to a complex protein medium, such as blood or tissue fluid.

Recent adulteration of milk products with melamine (ME) in several countries caused adverse health effects and even deaths in infants. Earlier, in 2007, contamination of pet food with ME and its related contaminants was associated with many clinical cases of canine and feline nephrotoxicity, and in some cases mortality. ME is a triazine compound that is often detected with other triazine analogs such as cyanuric acid. As is the custom in some livestock operations, the contaminated pet food was mixed with feed intended for the swine and poultry industry. This practice has raised several questions as to whether ME and its related triazines would adversely affect the health of these food animals, and whether meat products derived from swine and poultry could contain high-enough levels of these contaminants to warrant public health concern. Data for this review article were obtained from recent research efforts in our laboratory, peer-reviewed publications cited in PubMed, and information available at USDA, US FDA, and WHO websites. The primary issues discussed are related to (1) the chemistry and interactions between ME and its triazine analogs; (2) reported animal and human exposures with possible pathways through which ME can enter the human food chain; (3) mammalian toxicology; (4) comparative pharmacokinetics (PK) and modeling strategies used to predict residue levels; and (5) emerging issues and management strategies.

Christian perfection, the evangelical doctrine that gave rise to abstinence as it is understood and practiced in America, originated in Britain with John Wesley and the Methodists. We examine why that doctrine floundered in its country of origin, opening the door to a more pluralistic and evidence-based approach to problems such as alcohol and drug abuse. Although social and political factors were important (the stratification of British society stood in the way of holding everyone to the same moral standard, and the drink trade was far better organized than its American counterpart), Britain's intellectual elite also played a vital role, heaping ridicule on the temperance movement and subjecting it to a devastating critique.

The presence of antimicrobial agents in edible tissues of food-producing animals remains a major public health concern. Probabilistic modeling techniques incorporated into a physiologically based pharmacokinetic (PBPK) model were used to predict the amounts of sulfamethazine residues in edible tissues in swine. A PBPK model for sulfamethazine in swine was adapted to include an oral dosing route. The distributions for sensitive parameters were determined and were used in a Monte Carlo analysis to predict tissue residue times. Validation of the distributions was done by comparison of the results of a Monte Carlo analysis to those obtained with an external data set from the literature and an in vivo pilot study. The model was used to predict the upper limit of the 95% confidence interval of the 99th percentile of the population, as recommended by the U.S. Food and Drug Administration (FDA). The external data set was used to calculate the withdrawal time by using the tolerance limit algorithm designed by FDA. The withdrawal times obtained by both methods were compared to the labeled withdrawal time for the same dose. The Monte Carlo method predicted a withdrawal time of 21 days, based on the amounts of residues in the kidneys. The tolerance limit method applied to the time-limited data set predicted a withdrawal time of 12 days. The existing FDA label withdrawal time is 15 days. PBPK models can incorporate probabilistic modeling techniques that make them useful for prediction of tissue residue times. These models can be used to calculate the parameters required by FDA and explore those conditions where the established withdrawal time may not be sufficient.