Sylvatic host associations of Triatominae and implications for Chagas disease reservoirs: a review and new host records based on archival specimens.

BACKGROUND: The 152 extant species of kissing bug include important vectors of the debilitating, chronic, and often fatal Chagas disease, which affects several million people mainly in Central and South America. An understanding of the natural hosts of this speciose group of blood-feeding insects has and will continue to aid ongoing efforts to impede the spread of Chagas disease. However, information on kissing bug biology is piecemeal and scattered, developed using methods with varying levels of accuracy over more than 100 years. Existing host records are heavily biased towards well-studied primary vector species and are derived from primarily three different types of observations, associational, immunological or DNA-based, with varying reliability. METHODS: We gather a comprehensive and unparalleled number of sources reporting host associations via rigorous targeted searches of publication databases to review all known natural, or sylvatic, host records including information on how each record was collected. We integrate this information with novel host records obtained via attempted amplification and sequencing of a ∼160 base pair (bp) region of the vertebrate 12S mitochondrial gene from the gastrointestinal tract of 64 archival specimens of Triatominae representing 19 species collected primarily in sylvatic habitats throughout the southern United States and Central and South America during the past 10 years. We show the utility of this method for uncovering novel and under-studied groups of Triatominae hosts, as well as detecting the presence of the Chagas disease pathogen via Polymerase Chain Reaction (PCR) of a ∼400 bp sequence of the trypanosome 18S gene. RESULTS: New host associations for several groups of arboreal mammals were determined including sloths, New World monkeys, coatis, arboreal porcupines and, for the first time as a host of any Triatominae, tayras. A thorough review of previously documented sylvatic hosts, organized by triatomine species and the type of observation (associational, antibody-based, or DNA-based), is presented in a phylogenetic context and highlights large gaps in our knowledge of Triatominae biology. CONCLUSION: The application of DNA-based methods of host identification towards additional species of Triatominae, including rarely collected species that may require use of archival specimens, is the most efficient and promising way to resolve recognized shortfalls.

Patient Centricity and Pharmaceutical Companies: Is It Feasible?

Various health care bodies (regulatory, health technology assessment, academia, health care providers, scientific journals) request patient input in their decision-making processes. This represents a shift from disease-centered to patient-centered approaches to health care. What does this "patient centricity" mean for the pharmaceutical industry? A panel of senior pharmaceutical industry representatives discussed the following key issues: why the pharmaceutical industry needs to be part of the patient-centric movement; how the industry can become patient-centric; and what a patient-centric company actually does. We summarize the panel's point of view on these key questions. The industry's role has been to develop the science and medicines for prevention or treatment of disease. In response to changes in the current health care environment, the industry should focus its efforts on initiatives that will improve impact and value for patients and carers. True patient centricity requires a change in the industry's cultural mindset, an increase in public trust, clearer roles and responsibilities within pharmaceutical organizations, openness to learn from others, and a framework to measure success. There are examples of industry engagement with patients throughout the drug discovery and development process. Patient-reported outcomes are becoming increasingly important endpoints in trials; they capture information of relevance to patients, identify preferences, and better inform treatment decision making. Understanding the patient experience can improve disease management at critical points in the disease course. The future of patient centricity lies in coordinated efforts by and alignment of multiple health care stakeholders, which can only be achieved through collaborations and consortia, with the industry playing a key role.

Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis.

IMPORTANCE: Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in patients with multiple myeloma (MM). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods. OBJECTIVE: To evaluate the utility of MRD detection in patients with newly diagnosed MM. DATA SOURCES: A Medline search was conducted for articles published in English between January 1990 and January 2016. STUDY SELECTION: Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in 20 or more patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis. DATA EXTRACTION AND SYNTHESIS: Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form. MAIN OUTCOMES AND MEASURES: The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other prespecified research questions were addressed qualitatively. RESULTS: Fourteen studies (n = 1273) provided data on the impact of MRD on PFS, and 12 studies (n = 1100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). An MRD-negative status was associated with significantly better PFS overall (hazard ratio [HR], 0.41; 95% CI, 0.36-0.48; P < .001) and in studies specifically looking at CR patients (HR, 0.44; 95% CI, 0.34-0.56; P < .001). Overall survival was also favorable in MRD-negative patients overall (HR, 0.57; 95% CI, 0.46-0.71; P < .001) and in CR patients (HR, 0.47; 95% CI, 0.33-0.67; P < .001). Tests of heterogeneity found no significant differences among the studies for PFS and OS. CONCLUSIONS AND RELEVANCE: Minimal residual disease-negative status after treatment for newly diagnosed MM is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of MM.

The sunshine act and medical publications: Guidance from professional medical associations.

OBJECTIVE: To review guidance from professional medical associations to physicians on the Sunshine Act, with a focus on industry support for medical publications. METHODS: Using 'Sunshine Act' as a search term, we searched PubMed (dates February 2013 to November 2014) and the 'grey literature' using Google and Google Scholar. Online information was extracted from websites of pre-identified professional medical associations. RESULTS: Some professional medical associations have published peer-reviewed recommendations, position statements or general advice on their websites and in journals around the Sunshine Act. Associations also provided broad online educational resources for physicians. There was universal agreement between peer-reviewed publications, including guidelines, for the need for full transparency and disclosure of industry support. Surveys by some professional associations showed variance in opinion on the forecasted impact of the Sunshine Act on physician-industry relationships. There was scarce information specifically related to reporting requirements for industry-supported medical publications. CONCLUSIONS: There is a shortage of information for physicians from professional associations regarding the Sunshine Act and support for medical publications. Due to the lack of clear guidance regarding support for publications, there are presently varying interpretations of the Sunshine Act. The literature debates the potential impact of the Sunshine Act and expresses some concerns that physician-enabled innovation in drug development may be hindered.

Modeling and simulation of preclinical cardiac safety: towards an integrative framework.

Despite an impressive battery of preclinical cardiac electrophysiology experimental models and the assessment of QT during clinical trials, the risk of Torsades de Pointes (TdP), a potentially lethal ventricular arrhythmia, remains among the common reasons for drug market withdrawal or lack of approval. Due to the low prevalence of TdP, development of statistical evidence that other clinical markers could be better predictors of TdP has proven challenging. Preclinical studies have provided a deeper understanding of torsadogenic mechanisms and potential pro-arrhythmic markers to assess. Translating these preclinical insights into a quantitative clinical risk assessment remains challenging because of (i) species differences in cardiac electrophysiology and drug pharmacokinetics; and (ii) the inability to measure clinically specific cardiac electrophysiology metrics, and therefore ascertain the full predictive value of earlier preclinical components of the risk assessment process. The integrative capacity of cardiac electrophysiology modeling to span time and length scales may provide a quantitative and predictive framework, to complement expert-based preclinical-to-clinical cardiac risk assessment process. In this review, we present salient elements of this risk assessment process and describe essential components of cardiac electrophysiology modeling, to propose that a progressive integration of mechanistic components into a common quantitative framework may help improve the predictability of drug-induced TdP risk.

Parabolic relationship between plasma triacylglycerols and LDL-cholesterol in familial combined hyperlipidaemia: the multiple-type hyperlipidaemia explained?

FCHL (familial combined hyperlipidaemia) is a highly prevalent genetic lipid disorder that accounts for a substantial number of premature cardiovascular events. To date, FCHL has been complicated by the different lipid phenotypes that are present within one family and one individual patient over time. In the present study, we hypothesized that a parabolic relationship between plasma triacylglycerols (triglycerides) and LDL (low-density lipoprotein)-cholesterol can explain this so-called 'multiple-type hyperlipidaemia' in FCHL. Our hypothesis was tested in two well-documented FCHL cohorts [Maastricht (n=145) and Nijmegen (n=299)] that were followed over a 5-year interval. Three groups were constructed depending on plasma triacylglycerols: group A (individuals with both measurements below 1.5 mmol/l), group B (one measurement below and one measurement above 1.5 mmol/l) and group C (both measurement above 1.5 mmol/l). In both male, but not female, cohorts, a significant positive relationship between plasma triacylglycerols and LDL-cholesterol was observed in group A (P=0.02 for Maastricht cohort and P=0.001 for the Nijmegen cohort), a significant negative relationship in group C (P=0.01 for Maastricht cohort and P=0.02 for the Nijmegen cohort), and a relationship intermediate to group A and C in group B. In contrast, both apoB (apolipoprotein B) levels and the prevalence of cardiovascular disease were related with plasma triacylglycerols in a more linear fashion. In conclusion, a parabolic relationship between plasma triacylglycerols and LDL-cholesterol explains the 'multiple-type hyperlipidaemia' in FCHL. In addition, the linear relationship between triacylglycerols and both apoB levels and the prevalence of cardiovascular disease substantiate the use of apoB instead of LDL-cholesterol in the diagnosis of FCHL and the prediction of cardiovascular disease.

Fatty liver is an integral feature of familial combined hyperlipidaemia: relationship with fat distribution and plasma lipids.

Overproduction of VLDL (very-low-density lipoprotein) particles is an important cause of FCHL (familial combined hyperlipidaemia). It has been shown recently that VLDL production is driven by the amount of hepatic fat. The present study was conducted to determine the prevalence of fatty liver in relation to the different fat compartments and lipid parameters in FCHL. A total of 68 FCHL patients, 110 normolipidaemic relatives and 66 spouses underwent ultrasound of the abdominal region to estimate the amount of subcutaneous, visceral and hepatic fat. Skinfold callipers were used to measure subcutaneous fat of the biceps, triceps, subscapular and supra-iliacal regions. Fatty liver was observed in 18% of the spouses, 25% of the normolipidaemic relatives and 49% of the FCHL patients. After adjustment for age, gender and body mass index, the prevalence of fatty liver was significantly higher in FCHL patients compared with spouses [OR (odds ratio), 3.1; P=0.03], and also in the normolipidaemic relatives compared with spouses (OR, 4.0; P=0.02), whereas no differences were observed between FCHL patients and normolipidaemic relatives (OR, 0.8; P=0.58). In the normolipidaemic relatives and FCHL patients combined, both visceral fat mass and subcutaneous abdominal fat were independent predictors of fatty liver (P<0.001 for both fat compartments; FCHL status corrected). Of interest, fatty liver stages were correlated with both VLDL-apoB (apolipoprotein B) and VLDL-triacylglycerols (triglycerides) in a representative subset (n=69) of patients and relatives (r(2)=0.12, P=0.006; and r(2)=0.18, P=0.001 respectively). These results show that fatty liver is a central aspect of FCHL, i.e. patients and normolipidaemic relatives. Both visceral and subcutaneous adiposity contribute to its 3-4-fold higher risk in FCHL.

Pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor lumiracoxib in the lipopolysaccharide-stimulated rat air pouch model.

PURPOSE: To investigate the pharmacodynamic behaviour of the selective cyclooxygenase-2 inhibitor, lumiracoxib, in the rat air pouch. METHODS: Air pouches were injected with lipopolysaccharide to stimulate prostaglandin E2 (PGE2) production 1h after lumiracoxib treatment. Pouch fluid samples were collected 6 or 24 h after lumiracoxib administration to measure PGE2 levels. Lumiracoxib concentrations in pouch fluid and plasma were measured by mass spectrometry. RESULTS: Oral administration of lumiracoxib resulted in dose-dependent inhibition of PGE2 production 6 and 24 h post-dose. The estimated ED50 values for inhibition of PGE2 production were 0.1 and 2.0 mg/kg at 6 and 24 h, respectively. Lumiracoxib concentrations in plasma and pouch fluid increased in proportion to dose. There was a strong positive correlation between lumiracoxib concentrations in plasma and pouch fluid compartments. Lumiracoxib concentrations were higher in plasma than in pouch fluid 6 h post-dose, but at 24 h post-dose, pouch fluid concentrations were > or =4-fold greater than plasma concentrations. CONCLUSIONS: Lumiracoxib readily enters the air pouch and persists in this extravascular compartment for a longer period of time than in plasma. This distribution profile may contribute to the ability of lumiracoxib to inhibit PGE2 production up to 24 h after dosing.

An integrated approach for inference and mechanistic modeling for advancing drug development.

An important challenge facing researchers in drug development is how to translate multi-omic measurements into biological insights that will help advance drugs through the clinic. Computational biology strategies are a promising approach for systematically capturing the effect of a given drug on complex molecular networks and on human physiology. This article discusses a two-pronged strategy for inferring biological interactions from large-scale multi-omic measurements and accounting for known biology via mechanistic dynamical simulations of pathways, cells, and organ- and tissue level models. These approaches are already playing a role in driving drug development by providing a rational and systematic computational framework.

Prothrombotic markers in familial combined hyperlipidemia: evidence of endothelial cell activation and relation to metabolic syndrome.

BACKGROUND: Familial combined hyperlipidemia (FCHL) is characterized by a varied expression of hypertriglyceridemia and hypercholesterolemia within a family, and a high risk of premature coronary artery disease. The present study evaluated a number of potential prothrombotic markers in familial combined hyperlipidemia, and studied their relationship to the hypercholesterolemic (Fredrickson type IIa) and hypertriglyceridemic (IIb and IV) phenotypes. METHODS AND RESULTS: Selected prothrombotic markers were studied in 68 subjects: 34 hyperlipidemic subjects with familial combined hyperlipidemia and 34 controls. FCHL patients exhibited significantly higher Thrombin-Antithrombin complex (TAT), activated coagulation factor XII (F XIIa), von Willebrand Factor (vWF), Plasminogen Activator Inhibitor-1 (PAI-1) and tissue derived Plasminogen Activator (t-PA) values in comparison to controls. Within the subgroup of familial combined hyperlipidemia subjects, elevated PAI-1 activity and soluble Thrombomodulin levels were particularly associated with features of the metabolic syndrome, including hyperinsulinemia, hypertriglyceridemia and predominance of small dense low density lipoprotein (LDL). CONCLUSIONS: A general pattern of activated blood coagulation and endothelial activation is present in all hyperlipidemic subjects studied, independent of metabolic phenotype. In those familial combined hyperlipidemia subjects with features of the metabolic syndrome, impaired fibrinolysis can provide an additional cardiovascular risk factor.

A distributed-parameter model for formaldehyde uptake and disposition in the rat nasal lining.

DNA-protein cross-links (DPX) serve as a dosimeter for inhaled formaldehyde and are associated with tumor induction in rat nasal passages after chronic exposure to 6 ppm and above. To determine the role of epithelium-specific morphometry in formaldehyde-induced patterns of injury, we developed a mathematical model that links airflow-driven formaldehyde uptake with DPX formation in regions of the rat nose with high and low tumor incidence. A three-dimensional, anatomically accurate computational fluid dynamics model of rat nasal airflow and inhaled gas uptake was integrated with a physiologically based mathematical model incorporating tissue thickness, formaldehyde diffusion, its removal by enzymatic and nonenzymatic processes, and DNA distribution in the nasal mucosa to predict DPX formation. The model implicitly incorporates the reversible conversion of formaldehyde to methylene glycol. Where possible, parameter values were taken from the literature or estimated using published correlations. The Michaelis-Menten kinetic constants Vmax and Km, as well as a first-order constant for formaldehyde removal, were left as fitted parameters. The resultant model fit to the experimentally measured DPX in the high- and low-tumor-incidence regions of the rat nasal passages was very good. Sensitivity analysis indicates that among the fitted parameters, model fits are most sensitive to Vmax and that predictions were sensitive to changes in tissue thickness when all other parameters are held constant. The model structure facilitates extrapolation to primates and humans and application to other soluble, reactive gases.