A Model of Gastric Mucosal pH Regulation: Extending Sensitivity Analysis Using Sobol' Indices to Understand Higher Moments.

Several recent theoretical studies have indicated that a relatively simple secretion control mechanism in the epithelial cells lining the stomach may be responsible for maintaining a neutral (healthy) pH adjacent to the stomach wall, even in the face of enormous electrodiffusive acid transport from the interior of the stomach. Subsequent work used Sobol' Indices (SIs) to quantify the degree to which this secretion mechanism is "self-regulating" i.e. the degree to which the wall pH is held neutral as mathematical parameters vary. However, questions remain regarding the nature of the control that specific parameters exert over the maintenance of a healthy stomach wall pH. Studying the sensitivity of higher moments of the statistical distribution of a model output can provide useful information, for example, how one parameter may skew the distribution towards or away from a physiologically advantageous regime. In this work, we prove a relationship between SIs and the higher moments and show how it can potentially reduce the cost of computing sensitivity of said moments. We define γ -indices to quantify sensitivity of variance, skewness, and kurtosis to the choice of value of a parameter, and we propose an efficient strategy that uses both SIs and γ -indices for a more comprehensive sensitivity analysis. Our analysis uncovers a control parameter which governs the "tightness of control" that the secretion mechanism exerts on wall pH. Finally, we discuss how uncertainty in this parameter can be reduced using expert information about higher moments, and speculate about the physiological advantage conferred by this control mechanism.

Bayesian estimation of Pseudomonas aeruginosa viscoelastic properties based on creep responses of wild type, rugose, and mucoid variant biofilms.

Pseudomonas aeruginosa biofilms are relevant for a variety of disease settings, including pulmonary infections in people with cystic fibrosis. Biofilms are initiated by individual bacteria that undergo a phenotypic switch and produce an extracellular polymeric slime (EPS). However, the viscoelastic characteristics of biofilms at different stages of formation and the contributions of different EPS constituents have not been fully explored. For this purpose, we develop and parameterize a mathematical model to study the rheological behavior of three biofilms - P. aeruginosa wild type PAO1, isogenic rugose small colony variant (RSCV), and mucoid variant biofilms against a range of experimental data. Using Bayesian inference to estimate these viscoelastic properties, we quantify the rheological characteristics of the biofilm EPS. We employ a Monte Carlo Markov Chain algorithm to estimate these properties of P. aeruginosa variant biofilms in comparison to those of wild type. This information helps us understand the rheological behavior of biofilms at different stages of their development. The mechanical properties of wild type biofilms change significantly over time and are more sensitive to small changes in their composition than the other two mutants.

Hematologic markers of distant metastases and poor prognosis in gynecological cancers.

BACKGROUND: Despite the recent progress in the development of anti-cancer drugs, the treatment of metastatic tumors is usually ineffective. The systemic inflammatory response performs key roles in different stages of the carcinogenesis process including metastasis. The high neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) were found to be associated with poor survival rates in the majority of solid tumors. However, only a few studies were conducted to further investigate this association in patients with advanced gynecological cancers. METHODS: Clinical data from 264 patients with FIGO stage III and IV gynecological (endometrial, ovarian and cervical) cancers treated at King Hussein Cancer Center (Amman-Jordan) from 2006 to 2012 were retrospectively reviewed. We examined the association between absolute neutrophil count (ANC), absolute monocyte count (AMC), MLR, PLR, and NLR with distant metastases, overall survival and event-free survival in gynecological cancers. For survival analysis, Receiver Operating Characteristic (ROC) curve analysis was operated to determine the optimal cutoff values. RESULTS: Patients with high baseline NLR (≥4.1) had more baseline distant metastases than patients with low baseline NLR (< 4.1), (p-value 0.045). Patients with high baseline AMC (≥560) had more distant metastases in comparison to patients with low baseline AMC (< 560), (p-value 0.040). Furthermore, Patients with high baseline PLR (≥0.3) had more distant metastases in comparison to patients with low baseline PLR (< 0.3), (p-value 0.025). Additionally, patients with high baseline ANC (≥5700) had worse overall survival compared to the patients with low baseline ANC (< 5700), (p-value 0.015). Also, patients with high baseline AMC (≥490) had worse overall survival compared to the patients with low baseline AMC (< 490), (p-value 0.044). CONCLUSION: Different hematologic markers obtained from a cheap test (CBC) could potentially be used to predict the presence of distant metastases thus used as prognostic indices in gynecological cancers.

A framework for model analysis across multiple experiment regimes: Investigating effects of zinc on Xylella fastidiosa as a case study.

Mathematical models are ubiquitous in analyzing dynamical biological systems. However, it might not be possible to explicitly account for the various sources of uncertainties in the model and the data if there is limited experimental data and information about the biological processes. The presence of uncertainty introduces problems with identifiability of the parameters of the model and determining appropriate regions to explore with respect to sensitivity and estimates of parameter values. Since the model analysis is likely dependent on the numerical estimates of the parameters, parameter identifiability should be addressed beforehand to capture biologically relevant parameter space. Here, we propose a framework which uses data from different experiment regimes to identify a region in the parameter space over which subsequent mathematical analysis can be conducted. Along with building confidence in the parameter estimates, it provides us with variations in the parameters due to changes in the experimental conditions. To determine significance of these variations, we conduct global sensitivity analysis, allowing us to make testable hypothesis for effects of changes in the experimental conditions on the biological system. As a case study, we develop a model for growth dynamics and biofilm formation of a bacterial plant pathogen, and use our framework to identify possible effects of zinc on the bacterial populations in different metabolic states. The framework reveals underlying issues with parameter identifiability and identifies a suitable region in the parameter space, sensitivity analysis over which informs us about the parameters that might be affected by addition of zinc. Moreover, these parameters prove to be identifiable in this region.

Short-Term Antiretroviral Treatment Recommendations Based on Sensitivity Analysis of a Mathematical Model for HIV Infection of CD4âºΤ Cells.

HIV infection is one of the most difficult infections to control and manage. The most recent recommendations to control this infection vary according to the guidelines used (US, European, WHO) and are not patient-specific. Unfortunately, no two individuals respond to infection and treatment quite the same way. The purpose of this paper is to make use of the uncertainty and sensitivity analysis to investigate possible short-term treatment options that are patient-specific. We are able to identify the most significant parameters that are responsible for ART outcome and to formulate some insights into the ART success.

Combining Two Methods of Global Sensitivity Analysis to Investigate MRSA Nasal Carriage Model.

We apply two different sensitivity techniques to a model of bacterial colonization of the anterior nares to better understand the dynamics of Staphylococcus aureus nasal carriage. Specifically, we use partial rank correlation coefficients to investigate sensitivity as a function of time and identify a reduced model with fewer than half of the parameters of the full model. The reduced model is used for the calculation of Sobol' indices to identify interacting parameters by their additional effects indices. Additionally, we found that the model captures an interesting characteristic of the biological phenomenon related to the initial population size of the infection; only two parameters had any significant additional effects, and these parameters have biological evidence suggesting they are connected but not yet completely understood. Sensitivity is often applied to elucidate model robustness, but we show that combining sensitivity measures can lead to synergistic insight into both model and biological structures.

Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.

Uncertainties in parameter values in microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of vaginal microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization.

Novel approach of treating Gorham-Stout disease in the humerus--Case report and review of literature.

Gorham-Stout disease or the so-called vanishing bone syndrome is a rare disorder characterized by intra-osseous proliferation of vascular channels resulting in destruction and resorption of the osseous matrix. The exact pathology of this disease showed no evidence of malignant, neuropathic, or infectious components involved in the causation of this disorder except for the culprit of lympho-vascular malformations in the bone. The mechanism of bone resorption is yet to be clarified. The clinical presentation of Gorham's disease varies according to the organ of involvement. Patients diagnosed with Gorham's disease in the bone may initially present with insidious onset of dull aching pain, progressive weakness, or pathologic fractures as the initial presentation. Gorham's disease is progressive in most patients; yet it can be self-limiting in a few reported cases. The axes of treating this disease as reported in the literature include the use of medical treatment, surgical intervention, radiotherapy and/or the combination of any them. However, there is no consensus about the most effective approach for treating this rare disease. The challenge in this disease lies in both: how to diagnose and how to treat. Our novel approach combined surgical intervention, medication and radiotherapy as a treatment of Graham-Stout disease in the humerus, and showed no progression of the disease our case.

Optimal unified combination rule in application of Dempster-Shafer theory to lung cancer radiotherapy dose response outcome analysis.

Our previous study demonstrated the application of the Dempster-Shafer theory of evidence to dose/volume/outcome data analysis. Specifically, it provided Yager's rule to fuse data from different institutions pertaining to radiotherapy pneumonitis versus mean lung dose. The present work is a follow-on study that employs the optimal unified combination rule, which optimizes data similarity among independent sources. Specifically, we construct belief and plausibility functions on the lung cancer radiotherapy dose outcome datasets, and then apply the optimal unified combination rule to obtain combined belief and plausibility, which bound the probabilities of pneumonitis incidence. To estimate the incidence of pneumonitis at any value of mean lung dose, we use the Lyman-Kutcher-Burman (LKB) model to fit the combined belief and plausibility curves. The results show that the optimal unified combination rule yields a narrower uncertainty range (as represented by the belief-plausibility range) than Yager's rule, which is also theoretically proven.

Mathematical Model for MRSA Nasal Carriage.

An interesting biological phenomenon that is a factor for the spread of antibiotic-resistant strains, such as MRSA, is human nasal carriage. Here, we evaluate several biological hypotheses for this problem in an effort to better understand and narrow the scope of the dominant factors that allow these bacteria to persist in otherwise healthy individuals. First, we set up and analyze a simple PDE model created to generally mimic the interactions of the microbes and nasal immune response. This includes looking at different types of diffusion and chemotaxis terms as well as different boundary conditions. Then, using sensitivity analysis, we walk through several biological hypotheses and compare to the model's results looking for persistent infection scenarios indicated by the model's bacteria component surviving over time.

Global sensitivity analysis used to interpret biological experimental results.

Modeling host/pathogen interactions provides insight into immune defects that allow bacteria to overwhelm the host, mechanisms that allow vaccine strategies to be successful, and illusive interactions between immune components that govern the immune response to a challenge. However, even simplified models require a fairly high dimensional parameter space to be explored. Here we use global sensitivity analysis for parameters in a simple model for biofilm infections in mice. The results indicate which parameters are insignificant and are 'frozen' to yield a reduced model. The reduced model replicates the full model with high accuracy, using approximately half of the parameter space. We used the sensitivity to investigate the results of the combined biological and mathematical experiments for osteomyelitis. We are able to identify parts of the compartmentalized immune system that were responsible for each of the experimental outcomes. This model is one example for a technique that can be used generally.

Use of human surplus biospecimens in research: a survey from a cancer centre.

Little is known about the public's views on the use of human biospecimens for research in the Eastern Mediterranean Region. A study at a cancer centre in Amman, Jordan, assessed patients' perceptions about the use of blood and tissue samples obtained during clinical care and the use of these in research. A self-administered questionnaire was distributed to a sample of 205 adult cancer patients. Almost all patients (98.0%) accepted the use of their surplus blood samples and archived tissue in research if they consented, with about one-third requesting a specific opt-in consent. Most patients (82.9%) also agreed to donate a blood sample for research purposes only, 84.9% were interested to know the results of that research, but with a specific opt-in consent, and 81.0% accepted sending their samples to research laboratories abroad, even without specific consent. Patients' views on the potential use of the surplus biospecimens in research were largely concordant with the international literature.

Use of human surplus biospecimens in research: a survey from a cancer centre

قليلة هي معارفنا حول آراء الناس عن استخدام العينات البيولوجية البشرية في البحوث في إقليم شرق المتوسط. وقد أجريت هذه الدراسة في مركز للسرطان في عمان، الأردن، لتقييم إدراك المرضى لاستخدام الدم والعينات النسيجية التي يتم الحصول عليها خال الرعاية السريرية واستخدام ذلك في البحوث، وذلك من خال استبيان ذاتي تم توزيعه على عينة تضم 205 من مرضى السرطان البالغين. وافق جميع المرضى تقريبا [98.0 % منهم]على استخدام ما يفيض عن الحاجة من عينات الدم والنماذج النسجية المحفوظة، في البحوث إذا ما طلب الباحثون موافقتهم على ذلك، كما أن ما يقرب من الثلث طلبوا نمطا نوعيا من الموافقة المقيدة. كما وافق معظم المرضى [82.9 % منهم]على التبرع بعينات الدم لأغراض البحوث فقط، وكان 84.9 % منهم مهتمين بمعرفة نتائج تلك البحوث، ولكن مع موافقة مقيدة، بينا وافق 81.0 % منهم على إرسال العينات المأخوذة منهم إلى مختبرات خارج البلاد، حتى بدون موافقة خاصة منهم. وقد تبين أن وجهات نظر المرضى حول الاستخدام المحتمل للعينات البيولوجية الفائضة عن الحاجة في البحوث تتوافق مع ما هو منشور على الصعيد الدولي

ABSTRACT Little is known about the public’s views on the use of human biospecimens for research in the Eastern Mediterranean Region. A study at a cancer centre in Amman, Jordan, assessed patients’ perceptions about the use of blood and tissue samples obtained during clinical care and the use of these in research. A self-administered questionnaire was distributed to a sample of 205 adult cancer patients. Almost all patients (98.0%) accepted the use of their surplus blood samples and archived tissue in research if they consented, with about one-third requesting a specific opt-in consent. Most patients (82.9%) also agreed to donate a blood sample for research purposes only, 84.9% were interested to know the results of that research, but with a specific opt-in consent, and 81.0% accepted sending their samples to research laboratories abroad, even without specific consent. Patients’ views on the potential use of the surplus biospecimens in research were largely concordant with the international literature.

RÉSUMÉ Il existe peu d'informations sur l'opinion du public quant à l'utilisation d'échantillons biologiques humains pour la recherche dans la Région de la Méditerranée orientale. Une étude menée dans un centre anticancer à Amman (Jordanie) a évalué les perceptions des patients concernant l'utilisation des échantillons de sang et de tissu recueillis pendant des soins cliniques et leur utilisation pour la recherche. Un autoquestionnaire a été distribué à un échantillon de 205 patients adultes atteints de cancer. Presque tous les patients (98,0 %) acceptaient l'utilisation des échantillons de sang et de tissus excédentaires conservés pour la recherche, après leur consentement, et environ un tiers exigeait une demande de consentement spécifique. La plupart des patients (82,9 %) consentaient également à faire un don de sang à des fins de recherche uniquement, tandis que 84,9 % souhaitaient connaître les résultats de cette recherche après un consentement spécifique, et 81,0 % acceptaient que leurs échantillons soient envoyés à des laboratoires de recherche à l'étranger, même sans consentement spécifique. Le point de vue des patients sur l'utilisation potentielle des échantillons biologiques excédentaires pour la recherche concordait en grande partie avec les points de vue présentés dans la littérature internationale.

Choroidal metastases as the sole initial presentation of metastatic lung cancer: case report and review of literature.

BACKGROUND: Choroidal metastasis as an initial presenting feature of metastatic lung cancer is exceedingly rare. External beam radiotherapy (EBRT) is an effective and widely accepted therapeutic modality. However, data addressing the effectiveness of other treatment strategies is limited. Herein, we present a patient with choroidal metastases secondary to lung cancer and review the relevant literature. CASE REPORT: A 25-year-old male presented with deterioration of vision. His evaluation revealed bilateral choroidal metastasis secondary to adenocarcinoma of the lung. Unfortunately, his vision continued to deteriorate despite treatment with EBRT and chemotherapy. CONCLUSION: Metastatic lung cancer can manifest with choroidal metastasis as an initial presentation.

Choroidal metastasis as the sole initial presentation of metastatic lung cancer.

Choroidal metastasis as an initial presenting feature of metastatic lung cancer is exceedingly rare. External beam radiotherapy (EBRT) is an effective and widely accepted therapeutic modality. However, data addressing the effectiveness of other treatment strategies is limited. We present a patient with choroidal metastases secondary to lung cancer and review the relevant literature. A 25-year-old male presented with deterioration of vision. His evaluation revealed bilateral choroidal metastasis secondary to adeno- carcinoma of the lung. Unfortunately, his vision continued to deteriorate despite treatment with EBRT and chemotherapy. Choroidal metastasis as an initial presentation of metastatic lung cancer is exceedingly rare, as only 30 cases have been reported. EBRT and systemic chemotherapy are effective therapeutic modalities. This case report could prove helpful to clinicians faced with a similar exceedingly rare scenario.

Radiological findings in gliosarcoma. A single institution experience.

Gliosarcomas are rare tumors with a poor prognosis composed of intermingled malignant glial and sarcoma elements with an estimated incidence of 1.8-8.0% of all malignant astrocytic neoplasms. We aimed to review the imaging findings in eight patients with gliosarcoma who were treated in our center between 2002 and 2010. The diagnosis was confirmed by morphological and immunohistochemical stains. This study, to the best of our knowledge, is the largest describing the imaging manifestations of this tumor. Although our study revealed no unique radiological features for gliosarcoma, it is important to note that they all demonstrated either dural or ependymal involvement or both. Calcification, hemorrhage or cystic components are described with a tendency for a ring enhancement pattern. Interestingly pre-existing benign looking lesions and associated remotely located small meningiomas are also described.

Snake bite envenomation: experience at King Abdulaziz Medical City, Riyadh.

We surveyed the records of 21 of the 28 snakebite victims seen at King Fahad National Guard Hospital in Riyadh over the 20-year period 1986-2005. The most common symptoms were local pain and swelling and the most common signs oedema and tenderness. Neurotoxicity was not noted in any case. Coagulopathy was recorded for 14/21 patients (66.7%) and 5/19 (26.4%) had leukocytosis. All patients were given tetanus toxoid (100%) and 20 (95.2%) received antivenom. Blood products were administered in 2 cases and prophylactic antibiotics in 10 (47.6%). No allergic reaction to antivenom was reported.