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Each year, the American Cancer Society publishes a summary of its guidelines for early cancer detection, data and trends in cancer screening rates, and select issues related to cancer screening. In this issue of the journal, the current American Cancer Society cancer screening guidelines are summarized, and the most current data from the National Health Interview Survey are provided on the utilization of cancer screening for men and women and on the adherence of men and women to multiple recommended screening tests.  相似文献   
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Volunteer infection studies using the induced blood stage malaria (IBSM) model have been shown to facilitate antimalarial drug development. Such studies have traditionally been undertaken in single‐dose cohorts, as many as necessary to obtain the dose‐response relationship. To enhance ethical and logistic aspects of such studies, and to reduce the number of cohorts needed to establish the dose‐response relationship, we undertook a retrospective in silico analysis of previously accrued data to improve study design. A pharmacokinetic (PK)/pharmacodynamic (PD) model was developed from initial fictive‐cohort data for OZ439 (mixing the data of the three single‐dose cohorts as: n = 2 on 100 mg, 2 on 200 mg, and 4 on 500 mg). A three‐compartment model described OZ439 PKs. Net growth of parasites was modeled using a Gompertz function and drug‐induced parasite death using a Hill function. Parameter estimates for the PK and PD models were comparable for the multidose single‐cohort vs. the pooled analysis of all cohorts. Simulations based on the multidose single‐cohort design described the complete data from the original IBSM study. The novel design allows for the ascertainment of the PK/PD relationship early in the study, providing a basis for rational dose selection for subsequent cohorts and studies.

Study Highlights
  • WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
☑ Volunteer infection studies are routinely used in antimalarial drug development to generate early pharmacokinetic/pharmacodynamic data for compounds.
  • WHAT QUESTION DID THIS STUDY ADDRESS?
☑ Can in silico analyses be used to suggest improvements to volunteer infection study designs?
  • WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
☑ Multiple dose adaptive trial designs can potentially reduce the number of cohorts needed to establish the dose‐response relationship in volunteer infection studies.
  • HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
☑ Real time data analyses can be used to recommend doses for adaptive volunteer infection studies.

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been recognized as a valuable system for defining the key pharmacokinetic (PK) and pharmacodynamic (PD) relationships for dose selection in antimalarial drug development. 1 , 2 , 3 , 4 , 5 , 6 , 7 In such studies, healthy volunteers are inoculated intravenously with a given quantity (with small variability) of Plasmodium‐infected red cells. Parasitemia is then followed by quantitative polymerase chain reaction until a prespecified treatment threshold is reached when the test drug is administered. Parasite and drug concentrations are then measured. These studies are conducted prior to phase II dose‐response (D‐R) trials and can be included in an integrated first‐in‐human study protocol, or after completion of the first‐in‐human PK and safety study. IBSM studies have been typically designed as flexible multiple cohort studies where each volunteer of one cohort receives a single dose of the same amount of drug (“single dose per cohort”). 2 , 3 , 4 , 5 After each cohort, a decision is made to stop or to add a cohort to test a lower or higher dose based on the response observed in the previous cohorts.For the multiple single‐dose‐per‐cohort design, the starting dose is typically selected based on safety and PK information from a phase I single ascending dose (SAD) study and, more recently, on preclinical data from a severe combined immunodeficient mouse model, with the dose selected on the basis of being best able to inform the D‐R relationship, rather than aiming for cure. This approach, where a single dose is tested in all subjects of the initial cohort, risks missing the dose likely to be most informative for defining the PK/PD relationship.An alternative approach is to spread a range of doses across a smaller number of subjects within the initial cohort and use PK/PD models developed based on data from this cohort to support dose selections of subsequent cohorts and studies. Using data from a previous study, 2 we undertook an in silico investigation of such an adaptive study design, aiming to reduce the number of subjects exposed to inefficacious doses, and to establish a D‐R relationship. This multiple‐dose‐groups‐per‐cohort design, referred to as the “2‐2‐4” design, is contrasted with the already implemented study design depicted in Figure  1 .Open in a separate windowFigure 1Comparison of standard and adaptive designs of IBSM studies. A/B/C, dose levels to be selected during the progress of the study based on pharmacokinetic/pharmacodynamic results of the initial cohort; CHMI, controlled human malaria infection; D‐R, dose‐response; IBSM, induced blood stage malaria infection; n, number of subjects at each dose.The objectives of this retrospective analysis were to: (i) compare PK/PD parameter estimates from the initial cohort of the 2‐2‐4 study design with the prior results from the data of the full study and (ii) propose a preliminary workflow to establish D‐R early in an IBSM study, and use modeling and simulation (M&S) to support dose selections for subsequent cohorts and later phase clinical trials.  相似文献   
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The succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle. Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis. Succinate accumulation inhibits 2‐oxoglutarate‐dependent dioxygenases, including DNA and histone demethylase enzymes and hypoxic gene response regulators. Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours. Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours. Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5‐year mortality of 50%. There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours. However, there is no consensus on when and how surveillance should be performed in children and young adults. Here, we address the question: “What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?”.  相似文献   
6.
Background: Substance abuse can cause a range of harmful secondary health consequences, including body weight changes. These remain poorly understood but can lead to metabolic disorders including obesity and diabetes. Energy balance is a function of the equation: energy balance?=?energy intake – energy expenditure; an imbalance to this equation results in body weight changes. Currently, in the clinical setting, changes to food intake (energy intake) are considered as the primary mediator of body weight changes related to substance abuse, reflected in the current treatment focus on nutritional intervention. The influence of substance abuse on energy expenditure receives less attention. The aim of this think-piece is to consider potential causes of body weight changes during active substance abuse and abstinence, by focussing on the components of the energy balance equation.

Methods: We discuss both human and animal studies on the effects of substance abuse on energy balance, with particular focus on animal models utilising pair-feeding, which enable investigation of energy balance whilst controlling for the effects of altered food intake.

Results: We demonstrate that whilst some drugs of abuse affect food intake, this effect is inconsistent. Furthermore, body weight changes do not match food intake changes.

Conclusion: We provide evidence that drugs of abuse can affect both energy intake and energy expenditure; contributing to the observed body weight changes. This think-piece highlights that treatment strategies for body weight changes related to substance abuse cannot focus solely on nutritional interventions, but should consider the impact of broader disruptions to energy balance.  相似文献   
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ABSTRACT

Collaborative ways of working have become increasingly important as healthcare adopts a more team-based approach to patient care. Interprofessional education (IPE) addresses some of the challenges associated with collaborative working and is increasingly offered to learners pre and post qualification. This article reports on a three-day IPE program designed to enable undergraduate health professional students develop interprofessional (IP) work readiness skills, knowledge, and values while undertaking clinical placement in a hospital setting. The curriculum built participant skills in culturally safe IP collaboration (IPC); focused on strategies for providing quality care to indigenous peoples and communities, and overtly linked IP competence to organizational mission and values. It highlighted the patient voice and displayed both the human cost of poor team communication and the comfort family members gained from watching united treating teams working with skill, compassion, and kindness. Twenty-four students from seven healthcare disciplines completed the program (N = 24). The Work Self-Efficacy Inventory (WS-Ei) and the Interprofessional Socialization and Valuing Scale (ISVS) assessed participant IP skills, knowledge, beliefs, values, attitudes, and confidence before and after program completion. A paired sample t-test showed an increase in mean scores in all responses on both scales. Results suggest that participation in the IPE program resulted in substantial shifts in knowledge, skills, and values as evidenced by changed assumptions and worldviews, enhanced knowledge and skills concerning IPC, improved understanding of other professional roles and increased confidence in managing workplace experiences.  相似文献   
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Transport of pollution from remote sources into the state of Texas has been shown by modeling techniques, satellite, and in situ data. Attaining a better understanding of the impact (i.e., temporally) of remote pollution sources will provide a more robust/quantifiable basis for State Implementation Plans (SIPs) that govern air quality. Utilizing Tropospheric Emission Spectrometer (TES) and Ozone Monitoring Instrument (OMI) and in situ data for ozone (O3) and nitrogen dioxide (NO2) and Hybrid Single-Particle Lagrangian Integrated Trajectory Model (HYSPLIT), we assess whether high-pollution events in Texas are primarily sourced locally (i.e., within Texas) or remotely. We focus on TES and OMI dates that exemplify high O3 and NO2, over Texas’s lower troposphere from August 5, 2006, to June 21, 2009. For all dates and altitudes, 4-day back trajectory analyses, exemplified by high TES O3, show that remotely sourced from the Gulf of Mexico, Southeast USA, Midwest USA, Northeast USA, the Atlantic Ocean, Pacific Ocean, Mexico to Texas. The only exception is air at 1 km on July 22, 2006, which shows that air at this altitude is sourced within Texas. Throughout half of the eastern portion of Texas, TES shows O3 enhancements in the boundary layer and OMI shows O3 and NO2 enhancements via tropospheric column profiles (O3 between 75 and 90 ppbv; NO2 ≥5.5 molecules cm?2). These enhancements complement the HYSPLIT 4-day trajectory analyses, which gives further indication that they are influenced by transport from remote sources. Dates with co-located satellite and in situ data (e.g., August 2, 2005) further exemplify the need to consider satellite and in situ data and modeling data/forecasts when creating SIPs for compliance with Environmental Protection Agency and the Texas Commission on Environmental Quality air quality standards. Despite the fact that quantifying local versus remote sources is in its early stages, Texas has become increasingly compliant with Environmental Protection Agency (EPA) regulations. Environmental Systems Research Institute’s ArcGIS exemplifies the noticeable decrease in the number of days that locales in Texas exceed EPA’s limit for O3. From 2005 to 2009, population standard deviation and standard error of the mean, and true sample deviation of the sample mean for O3 and NO2, at all 16 monitoring sites distributed throughout Texas, are temporally consistent and small—reinforcing the reliability of in situ data as they are consistent throughout. This investigation has global implications for regions within countries that enforce air quality mandates. Such governing bodies should consider utilizing data assimilation (of in situ data) for air quality prediction as a part of the governmental process that produces such laws. This could potentially keep regions more accountable for emissions both locally and far from high source points.  相似文献   
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