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Abstract Background In remote rural Tanzania, the rate of linkage into HIV care was estimated at 28% in 2014. This study explored facilitators and barriers to linkage to HIV care at individual/patient, health care provider, health system, and contextual levels to inform eventual design of interventions to improve linkage to HIV care. Methods We conducted a descriptive qualitative study nested in a cohort study of 1012 newly diagnosed HIV-positive individuals in Mbeya region between August 2014 and July 2015. We conducted 8 focus group discussions and 10 in-depth interviews with recently diagnosed HIV-positive individuals and 20 individual interviews with healthcare providers. Transcripts were analyzed inductively using thematic content analysis. The emergent themes were then deductively fitted into the four level ecological model. Results We identified multiple factors influencing linkage to care. HIV status disclosure, support from family/relatives and having symptoms of disease were reported to facilitate linkage at the individual level. Fear of stigma, lack of disclosure, denial and being asymptomatic, belief in witchcraft and spiritual beliefs were barriers identified at individual’s level. At providers’ level; support and good patient-staff relationship facilitated linkage, while negative attitudes and abusive language were reported barriers to successful linkage. Clear referral procedures and well-organized clinic procedures were system-level facilitators, whereas poorly organized clinic procedures and visit schedules, overcrowding, long waiting times and lack of resources were reported barriers. Distance and transport costs to HIV care centers were important contextual factors influencing linkage to care. Conclusion Linkage to HIV care is an important step towards proper management of HIV. We found that access and linkage to care are influenced positively and negatively at all levels, however, the individual-level and health system-level factors were most prominent in this setting. Interventions must address issues around stigma, denial and inadequate awareness of the value of early linkage to care, and improve the capacity of HIV treatment/care clinics to implement quality care, particularly in light of adopting the ‘Test and Treat’ model of HIV treatment and care recommended by the World Health Organization.

Recently, experiments on basic plasma physics issues for solving future problems in fusion energy have been performed on a Large Helical Device. There are several problems to be solved in future devices for fusion energy. Emerging issues in burning plasma are: alpha-channeling (ion heating by alpha particles), turbulence and transport in electron dominant heating helium ash exhaust, reduction of the divertor heat load. To solve these problems, understanding the basic plasma physics of (1) wave–particle interaction through (inverse) Landau damping, (2) characteristics of electron-scale (high- k ) turbulence, (3) ion mixing and the isotope effect, and (4) turbulence spreading and detachment, is necessary. This overview discusses the experimental studies on these issues and turbulent transport in multi-ion plasma and other issues in the appendix.

This paper presents the development of a simultaneous measurement method for fast neutron energy spectra and tritium production rates within mixed radiation fields using a single crystal chemical vapour deposition diamond detector combined with a lithium fluoride (LiF) foil. The method involves the separation of pulses with rectangular shapes and the determination of the depth position within the single crystal diamond (SCD) struck by fast neutrons or nuclear reaction products including recoil tritons from the LiF foil based on pulse width, extracting pulse events occurred at the specific bulk region and the surface region of the SCD. Subsequently, unfolding techniques were employed to analyse the energy deposition spectrum of pulses at the specific bulk region which are induced only by fast neutrons, allowing the deduction of the fast neutron energy spectrum. To evaluate the tritium production rate, the energy deposition spectrum of pulses from events occurring at the SCD surface facing the LiF foil was analysed. By estimating the energy deposition spectrum solely induced by fast neutrons striking the SCD surface and subtracting it from the energy deposition spectrum of events at the SCD surface, the contribution of energetic ions, such as recoil tritons generated by the ^6 Li(n, α ) ^3 H reaction in the LiF foil, was determined. The fast neutron flux and tritium production rate obtained through this study were consistent with particle transport calculations, demonstrating the successful development of a method suitable for performance testing of fusion reactor blankets.

Energetic ion anisotropy was observed by tangential sightline compact neutron energy spectrometers (CNESs) in tangential neutral beam heated deuterium plasmas in Large Helical Device. Significant upper and lower energy shifts in D–D neutron energy from 2.45 MeV were measured according to the beam ion injection directions and CNES sightline using a conventional liquid scintillation detector with the unfolding technique and a novel Cs _2 LiYCl _6 :Ce with a ^7 Li-enrichment (CLYC7) scintillation detector without unfolding. The observed neutron energy spectrum was compared with that predicted by a numerical simulation based on orbit following models. Numerical simulation revealed that the Doppler shift in D–D neutron energy results from energetic ion anisotropy.

Abstract The compact neutron emission spectrometer (CNES) having a tangential sightline was installed to observe a significant Doppler shift of the neutron energy due to the high-energy tangential neutral beam (NB) injections in the Large Helical Device (LHD) for understanding of the energy distribution of fast-ion. The CNES is based on a 1-inch diameter and 1-inch height EJ301 liquid scintillator coupled with a conventional 1-inch photomultiplier tube. The histogram of the integrated pulse signal (Q total) during different NBs heating phases measured by the CNES shows that the edge of Q total changes depending on NB directions. Using the simple derivative unfolding technique, the neutron energy spectra were unfolded from the measured Q total histogram. Peaks of the neutron energy shift to 2.0 MeV, 2.42 MeV, and 3.0 MeV according to the injection direction of NBs. The obtained neutron energy is almost consistent with the virgin deuterium-deuterium neutron energy evaluated by the simple two-body kinematics considering the sightline of CNES, NB injection angle, and NB injection energy.

Abstract A middle-sensitivity scintillating fiber detector (hereafter middle Sci-Fi detector) that works at a deuterium-tritium neutron flux of ~105-107 cm−2s−1 was utilized to measure secondary deuterium-tritium neutron emission rates with high temporal resolution at a total neutron emission rate of 1013 to 1015 n/s, where strong magnetohydrodynamic (MHD) instabilities were observed in the large helical device deuterium plasma experiments. The gain and angular characteristics of the middle Sci-Fi detector were evaluated in an accelerator-based deuterium-tritium neutron source in the intense 14 MeV neutron source facility at Osaka University. Observation of 1 MeV triton transport due to MHD instability was performed by a middle Sci-Fi detector whose deuterium-tritium neutron counting rate was approximately 20 times higher than that of the conventional Sci-Fi detector. Fusion-born triton transport due to energetic-particle-driven MHD instability was observed using the middle Sci-Fi detector due to its high detection efficiency and high discrimination ability of deuterium-tritium neutrons from the sea of deuterium-deuterium neutrons.

El suelo es un ente vivo, dinámico y a la vez vulnerable a la degradación, siempre y cuando no se maneje de manera sostenible ocasionando bajos rendimientos de los cultivos. El objetivo de la presente investigación fue determinar los efectos de las coberturas vegetales asociado al cultivo de maíz amiláceo en las propiedades del suelo: densidad aparente, humedad gravimétrica, pH y conductividad eléctrica del suelo, materia orgánica, estimación del aporte de nitrógeno cuando se incorpora la biomasa foliar y finalmente el rendimiento de maíz. El estudio se realizó bajo un diseño experimental de bloques completos al azar con cinco tratamientos: maíz sin cobertura (testigo), maíz con cobertura de trébol; maíz con cobertura de vicia; maíz con cobertura de vicia + avena y maíz con cobertura muerta-mulch. Los resultados demostraron que, el maíz asociado con coberturas de trébol, vicia y mulch (cobertura muerta) aumentó en 44%, 37% y 38% respectivamente el rendimiento (kg.ha-1) de grano de maíz amiláceo, comparados a la siembra de maíz sin ningún tipo de cobertura. Asimismo, el uso de coberturas de trébol, vicia y avena + vicia incrementan la materia orgánica del suelo y aporta al suelo 253; 163 y 149 kg.ha-1 de nitrógeno siempre y cuando la biomasa foliar de las coberturas se incorpora al suelo. Por lo tanto, la asociación maíz – trébol es la que presenta mejores resultados para incrementar los rendimientos bajo un manejo sostenible del suelo y bajo los principios de la agroecología.

The aim of this research was to study the feasibility of bremsstrahlung photon production in target bombarded by 1 GeV electrons. The calculations were performed by the Monte Carlo code MCNP. Six target materials with densities between 2 and 20 g/cm3 were studied. The bremsstrahlung photon flux is high for the target density above 8 g/cm3. Copper is the best target for 1 GeV electron beam due to high bremsstrahlung photon production, low scattering and low transmission electron flux. The copper target was altered to have different thicknesses between 0.01 and 2.5 cm. The results showed that the bremsstrahlung photon flux significantly increased when the target thickness increased from 0.01 to 1.5 cm. The angular distribution of the bremsstrahlung photons with angles between 0 and 120 degrees was determined for copper target. The maximum angle of the photon scattering was about 20 degree.

In a petrochemical plant, training new operators to operate plant safely and consistent is a need. Conventional training for operators relies on senior operators’ experience. When experience operator leaves or resigns, it will take longer duration to train new personnel to gain the equivalent experience of previous or senior operators. The operators control the plant by using Distributed Control System (DCS) as an interface and ensure the reliability and productivity of plant sustains. The more challenges they face, the more experience they gain. Most of the operators are trained by real time events they faced on the job but errors or plant upsets should be avoided. It is estimated that in the United States alone, 10 billion USD is lost annually in the process industry caused by errors when faced with plant upsets. Operator training plan is therefore the crucial step to reduce the losses as well as the risk of operating the plant. Operator Training Simulator (OTS) is an alternative solution to safely provide the operators with various realistic operational conditions of the plant, including start-up, shutdown, and emergency conditions. This article discusses on the methodology of building an OTS for Ethylene plant, that are beneficial for educating operator response when faced with critical process upsets and succeeding quicker start-up. A dynamic process model was developed to give accurate dynamic behaviour of the plant process mainly during start-up, shutdown and upset conditions. Testing and verification processes of the models such as Model Acceptance Test (MAT), Factory Acceptance Test (FAT) and Site Acceptance Test (SAT) were deliberated. Few issues or problems faced during the testing were also discussed. Based on the experience of developing the simulator, process model was developed using mass and energy balance method does not reflect the actual plant conditions. It might be suitable for commissioning a new plant. However, once the plant is started all the parameters need to be realigned to meet the actual plant data. Process model for existing plant should always apply the actual plant data as a primary data. Especially during MAT, FAT and SAT processes, experience of the panel man is the best input data to get the best output of the simulations.

Origanum vulgare L. was collected from Ardebil, Guilan and Mazandaran provinces to assess the fumigant toxicity of its extract and determine LC50 and LC95 values for different developmental stages of Callosobruchus maculatus F. and Tribolium confusum J. du Val. It was extracted by solvents including methanol and dichloromethane. Eggs, larvae and adult of both species were exposed to dichloromethane and methanol extracts of O. vulgare for 72 hours. LC50 and LC95 values of dichloromethane extract were calculated 2084.51 and 4991.24 µl/l air for adults of T. cofusum, and 2282.80 and 6684.71µl/l air for adults of C. maculatus, respectively. Also, LC50 and LC95 values of methanol extract were 1726.57 and 5395.60 µl/l air for adults of T. cofusum, and 2040.88 and 5607.77 µl/l air for adults of C. maculatus, respectively.

Abstract Background Like other countries, Tanzania instituted mobile and outreach testing approaches to address low HIV testing rates at health facilities and enhance linkage to care. Available evidence from hard-to-reach rural settings of Mbeya region, Tanzania suggests that clients testing HIV+ at facility-based sites are more likely to link to care, and to link sooner, than those testing at mobile sites. This paper (1) describes the populations accessing HIV testing at mobile/outreach and facility-based testing sites, and (2) compares processes and dynamics from testing to linkage to care between these two testing models from the same study context. Methods An explanatory sequential mixed-method study (a) reviewed records of all clients (n = 11,773) testing at 8 mobile and 8 facility-based testing sites over 6 months; (b), reviewed guidelines; (c) observed HIV testing sites (n = 10) and Care and Treatment Centers (CTCs) (n = 8); (d) applied questionnaires at 0, 3 and 6 months to a cohort of 1012 HIV newly-diagnosed clients from the 16 sites; and (e) conducted focus group discussions (n = 8) and in-depth qualitative interviews with cohort members (n = 10) and health care providers (n = 20). Results More clients tested at mobile/outreach than facility-based sites (56% vs 44% of 11,733, p

External urinary catheter devices used in hospitals can offer an alternative to indwelling urinary catheters. Prevalence and patient outcomes are not well understood. This multisite project involved point prevalence of device use in patients with labia on acute care units. All patients on included units with corresponding anatomy were observed for presence of device in addition to review of indication of use and chart audit. Device use was 28.8 %. Immobility was the leading indication, and most patients had severe dysfunction as to mobility. For most patients, level of mobility remained the same from admission to discharge. Many patients were either potentially physically able to mobilize out of bed to urinate or were likely continent. There was variation in suction setting and chart documentation. The project lacked a comparison group and collected limited patient information. Areas for future inquiry include prevalence and impact on mobility, continence, and skin integrity., Competing Interests: Declaration of competing interest none., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype co-segregating in 14 sarcoglycanopathy cases from 13 unrelated families from south Indian region with the likely pathogenic homozygous mutation c.544 T > G (p.Thr182Pro) in SGCB. Haplotype was reconstructed based on 10 polymorphic markers surrounding the c.544 T > G mutation in the cases and related family members as well as 150 unrelated controls from Indian populations using PLINK1.9. We identified haplotype H1 = G, A, G, T, G, G, A, C, T, G, T at a significantly higher frequency in cases compared to related controls and unrelated control Indian population. Upon segregation analysis within the family pedigrees, H1 is observed to co-segregate with c.544 T > G in a homozygous state in all the pedigrees of cases except one indicating a probable event of founder effect. Furthermore, Identical-by-descent and inbreeding coefficient analysis revealed relatedness among 33 new pairs of seemingly unrelated individuals from sarcoglycanopathy cohort and a higher proportion of homozygous markers, thereby indicating common ancestry. Since all these patients are from the south Indian region, we suggest this region to be a primary target of mutation screening in patients diagnosed with sarcoglycanopathy., (© 2023. Springer Nature Limited.)

Background: Collaboration between medical doctors and nurses in the provision of healthcare services has been there for decades. The concept of clinical pharmacy services as a main goal for pharmacy practice is relatively new and is yielding more positive results for healthcare providers (HCPs), patients, and the health system. This study assessed barriers and facilitators toward the integration of pharmacists in the provision of CPS in Tanzania., Methods: A qualitative study was conducted in five tertiary hospitals representing Tanzania mainland. Ten (10) focus group discussions (FGDs) with 83 HCPs and 14 in-depth interviews (IDIs) with hospital administrators in referral hospitals were conducted between August and September 2021. The experienced qualitative researchers moderated the IDIs and FGDs, and all discussions were audio-recorded. Finally, the audios were transcribed verbatim, and analysis was done using a thematic approach., Results: Limited skills, lack of confidence, poor communication, inferiority, and superiority behaviors among HCPs were among the mentioned barriers. Shortage of pharmacists, lack of in-job training, standard operating procedures (SOPs), and guidelines were also mentioned. The study noted the high acceptability of CPS by other HCPs, the positive perception of pharmacists, and the recognition of CPS by the Tanzania Pharmacy Act and regulation., Conclusion: The facilitators and barriers to the integration of pharmacists in the provision of CPS lie at the individual, health facility, and health system levels. Therefore, the study recommends in-job pharmacists training, fostering teamwork among HCPs, and development of CPS SoPs, and guidelines., (© 2023. The Author(s).)

For clinical diagnosis of enterohemorrhagic Escherichia coli (EHEC）, it needs to capture viable EHEC cells from stool sample in the view of medical fee points. However, there is no comprehensive solution for the detection of viable EHEC cells since there are wide variety of serotype and susceptibility against potassium tellurite which is commonly used for selective agent in selective medium for EHEC. In these background, EHEC Clear-HT System (EHEC-CHT）, a novel effective chromogenic medium system for screening comprehensive viable EHEC, was developed. When EHEC-CHT was assessed using 128 microbes including 49 clinical isolated EHEC strains, EHEC-CHT detected all 49 EHEC strains as typical blue-colored colony regardless of both serotype and susceptibility to potassium tellurite. EHEC-CHT was compared with Japanese commercially available tellurite-based EHEC selective media using 107 clinical patient stool samples. EHEC-CHT showed higher detection ratio than conventional tellurite-based selective media compared, and 7% improvement at least in detection ratio in this study.

The clinico-genetic architecture of sarcoglycanopathies in Indian patients is reported only as short series. In the present study, we aimed to investigate the clinical picture, genetic basis, and disease progression of patients genetically confirmed to have sarcoglycanopathy. Next-generation sequencing was performed in 68 probands with suspected sarcoglycanopathy. A total of 35 different variants were detected in the sarcoglycan genes in 68 probands (M = 37; age range, 5-50 years). Consanguinity was present in 44 families. Thirty-two variants are predicted to be pathogenic/likely pathogenic, among which 25 (78.13%) are reported, and 7 (21.87%) are novel. The clinical diagnosis was confirmed in a total of 64 (94.12%) probands with biallelic variations [SGCA(n=18); SGCB(n=34); SGCG(n=7); SGCD(n=5)]. The most common mutation was c.544A > C (p.Thr182Pro) in SGCB, and detected in 20 patients (29.42%). The majority of pathogenic mutations are homozygous (n = 30; 93.75%). Variants in 4 cases are of uncertain significance. Thirty-three patients lost ambulation at a mean age of 15.12 ± 9.47 years, after 7.76 ± 5.95 years into the illness. Only 2 patients had cardiac symptoms, and one had respiratory muscle involvement. The results from this study suggest that mutations in SGCB are most common, followed by SGCA, SGCG, and SGCD. The novel variations identified in this study expand the mutational spectrum of sarcoglycanopathies. To the best of our knowledge, this is the first study from India to describe a large cohort of genetically confirmed patients with sarcoglycanopathy and report its disease progression., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein-based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods., Methods: Whole-exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM-related genes using variant calling and stringent variant filtration process. Subsequently, in silico homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants., Results: A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients (n = 12/22) in the CMD group and 35% patients (n = 5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild-type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis., Conclusion: The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling., (© 2020 European Academy of Neurology.)

Retrocaval ureter or circumcaval ureter is a rare congenital abnormality arising from dysgenesis of the inferior vena cava (IVC) that results in the right ureter coursing behind and medial to the IVC. The ideal nomenclature for the anomaly is preureteral vena cava, keeping in mind the aberrant embryology. It can result in hydronephrosis and is a rare cause of long-standing cyclical pain abdomen. Ultrasound, intravenous urography, nuclear scintigraphy, computed tomography urography (CTU) and magnetic resonance urography (MRU) have been used in the diagnosis of this abnormality but CTU, with its ability to depict the abnormality in three dimensions gives the most "wholesome" solution to its diagnosis. When symptomatic, the condition is treated surgically, either by laparoscopic or open surgery. The characteristic imaging findings that can help clinch the diagnosis are described as a reminder for this infrequently encountered cause for pain abdomen and hydronephrosis.

Background: Pathway discovery from gene expression data can provide important insight into the relationship between signaling networks and cancer biology. Oncogenic signaling pathways are commonly inferred by comparison with signatures derived from cell lines. We use the Molecular Apocrine subtype of breast cancer to demonstrate our ability to infer pathways directly from patients' gene expression data with pattern analysis algorithms., Methods: We combine data from two studies that propose the existence of the Molecular Apocrine phenotype. We use quantile normalization and XPN to minimize institutional bias in the data. We use hierarchical clustering, principal components analysis, and comparison of gene signatures derived from Significance Analysis of Microarrays to establish the existence of the Molecular Apocrine subtype and the equivalence of its molecular phenotype across both institutions. Statistical significance was computed using the Fasano & Franceschini test for separation of principal components and the hypergeometric probability formula for significance of overlap in gene signatures. We perform pathway analysis using LeFEminer and Backward Chaining Rule Induction to identify a signaling network that differentiates the subset. We identify a larger cohort of samples in the public domain, and use Gene Shaving and Robust Bayesian Network Analysis to detect pathways that interact with the defining signal., Results: We demonstrate that the two separately introduced ER- breast cancer subsets represent the same tumor type, called Molecular Apocrine breast cancer. LeFEminer and Backward Chaining Rule Induction support a role for AR signaling as a pathway that differentiates this subset from others. Gene Shaving and Robust Bayesian Network Analysis detect interactions between the AR pathway, EGFR trafficking signals, and ErbB2., Conclusion: We propose criteria for meta-analysis that are able to demonstrate statistical significance in establishing molecular equivalence of subsets across institutions. Data mining strategies used here provide an alternative method to comparison with cell lines for discovering seminal pathways and interactions between signaling networks. Analysis of Molecular Apocrine breast cancer implies that therapies targeting AR might be hampered if interactions with ErbB family members are not addressed.

In this paper, we investigate the pharmacokinetics and effect of doxorubicin and cisplatin in vascularized tumors through two-dimensional simulations. We take into account especially vascular and morphological heterogeneity as well as cellular and lesion-level pharmacokinetic determinants like P-glycoprotein (Pgp) efflux and cell density. To do this we construct a multi-compartment PKPD model calibrated from published experimental data and simulate 2-h bolus administrations followed by 18-h drug washout. Our results show that lesion-scale drug and nutrient distribution may significantly impact therapeutic efficacy and should be considered as carefully as genetic determinants modulating, for example, the production of multidrug-resistance protein or topoisomerase II. We visualize and rigorously quantify distributions of nutrient, drug, and resulting cell inhibition. A main result is the existence of significant heterogeneity in all three, yielding poor inhibition in a large fraction of the lesion, and commensurately increased serum drug concentration necessary for an average 50% inhibition throughout the lesion (the IC(50) concentration). For doxorubicin the effect of hypoxia and hypoglycemia ("nutrient effect") is isolated and shown to further increase cell inhibition heterogeneity and double the IC(50), both undesirable. We also show how the therapeutic effectiveness of doxorubicin penetration therapy depends upon other determinants affecting drug distribution, such as cellular efflux and density, offering some insight into the conditions under which otherwise promising therapies may fail and, more importantly, when they will succeed. Cisplatin is used as a contrast to doxorubicin since both published experimental data and our simulations indicate its lesion distribution is more uniform than that of doxorubicin. Because of this some of the complexity in predicting its therapeutic efficacy is mitigated. Using this advantage, we show results suggesting that in vitro monolayer assays using this drug may more accurately predict in vivo performance than for drugs like doxorubicin. The nonlinear interaction among various determinants representing cell and lesion phenotype as well as therapeutic strategies is a unifying theme of our results. Throughout it can be appreciated that macroscopic environmental conditions, notably drug and nutrient distributions, give rise to considerable variation in lesion response, hence clinical resistance. Moreover, the synergy or antagonism of combined therapeutic strategies depends heavily upon this environment.

Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically assess advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we review a multiscale, i.e., from the molecular to the gross tumor scale, mathematical and computational "first-principle" approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We review the feasibility of this methodology that, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as a phenotype-diagnostic tool to predict collective and individual tumor cell invasion of surrounding tissue. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior.

The complex, constantly evolving and multifaceted nature of cancer has made it difficult to identify unique molecular and pathophysiological signatures for each disease variant, consequently hindering development of effective therapies. Mathematical modeling and computer simulation are tools that can provide a robust framework to better understand cancer progression and response to chemotherapy. Successful therapeutic agents must overcome biological barriers occurring at multiple space and time scales and still reach targets at sufficient concentrations. A multiscale computer simulator founded on the integration of experimental data and mathematical models can provide valuable insights into these processes and establish a technology platform for analyzing the effectiveness of chemotherapeutic drugs, with the potential to cost-effectively and efficiently screen drug candidates during the drug-development process.

Platforms that allow parallel, quantitative analysis of single cells will be integral to realizing the potential of postgenomic biology. In stem cell biology, the study of clonal stem cells in multiwell formats is currently both inefficient and time-consuming. Thus, to investigate low-frequency events of interest, large sample sizes must be interrogated. We report a simple, versatile, and efficient micropatterned arraying system conducive to the culture and dynamic monitoring of stem cell proliferation. This platform enables: 1) parallel, automated, long-term ( approximately days to weeks), live-cell microscopy of single cells in culture; 2) tracking of individual cell fates over time (proliferation, apoptosis); and 3) correlation of differentiated progeny with founder clones. To achieve these goals, we used microfabrication techniques to create an array of approximately 10,000 microwells on a glass coverslip. The dimensions of the wells are tunable, ranging from 20 to >500 microm in diameter and 10-500 microm in height. The microarray can be coated with adhesive proteins and is integrated into a culture chamber that permits rapid (approximately min), addressable monitoring of each well using a standard programmable microscope stage. All cells share the same media (including paracrine survival signals), as opposed to cells in multiwell formats. The incorporation of a coverslip as a substrate also renders the platform compatible with conventional, high-magnification light and fluorescent microscopy. We validated this approach by analyzing the proliferation dynamics of a heterogeneous adult rat neural stem cell population. Using this platform, one can further interrogate the response of distinct stem cell subpopulations to microenvironmental cues (mitogens, cell-cell interactions, and cell-extracellular matrix interactions) that govern their behavior. In the future, the platform may also be adapted for the study of other cell types by tailoring the surface coatings, microwell dimensions, and culture environment, thereby enabling parallel investigation of many distinct cellular responses., (Copyright 2004 Wiley Periodicals, Inc.)