Cost-Effectiveness of Alternative Uses of Polyvalent Meningococcal Vaccines in Niger: An Agent-Based Transmission Modeling Study.

Background. Despite the introduction of an effective serogroup A conjugate vaccine (MenAfriVac™), sporadic epidemics of other Neisseria meningitidis serogroups remain a concern in Africa. Polyvalent meningococcal conjugate (PMC) vaccines may offer alternatives to current strategies that rely on routine infant vaccination with MenAfriVac plus, in the event of an epidemic, district-specific reactive campaigns using polyvalent meningococcal polysaccharide (PMP) vaccines. Methods. We developed an agent-based transmission model of N. meningitidis in Niger to compare the health effects and costs of current vaccination practice and 3 alternatives. Each alternative replaces MenAfriVac in the infant vaccination series with PMC and either replaces PMP with PMC for reactive campaigns or implements a one-time catch up campaign with PMC for children and young adults. Results. Over a 28-year period, replacement of MenAfriVac with PMC in the infant immunization series and of PMP in reactive campaigns would avert 63% of expected cases (95% prediction interval 49%-75%) if elimination of serogroup A is not followed by serogroup replacement. At a PMC price of $4/dose, this would cost $1412 ($81-$3510) per disability-adjusted life-year (DALY) averted. If serogroup replacement occurs, the cost-effectiveness of this strategy improves to $662 (cost-saving, $2473) per DALY averted. Sensitivity analyses accounting for incomplete laboratory confirmation suggest that a catch-up PMC campaign would also meet standard cost-effectiveness thresholds. Limitations. The assumption that polyvalent vaccines offer similar protection against all serogroups is simplifying. Conclusions. The use of PMC vaccines to replace MenAfriVac in routine infant immunization and in district-specific reactive campaigns would have important health benefits and is likely to be cost-effective in Niger. An additional PMC catch-up campaign would also be cost-effective if we account for incomplete laboratory reporting.

GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine.

The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients' outcome.

An online analytical processing multi-dimensional data warehouse for malaria data.

Database URL: https://dw.vecnet.org/datawarehouse/.

A spatial agent-based model of Anopheles vagus for malaria epidemiology: examining the impact of vector control interventions.

BACKGROUND: Malaria, being a mosquito-borne infectious disease, is still one of the most devastating global health issues. The malaria vector Anopheles vagus is widely distributed in Asia and a dominant vector in Bandarban, Bangladesh. However, despite its wide distribution, no agent based model (ABM) of An. vagus has yet been developed. Additionally, its response to combined vector control interventions has not been examined. METHODS: A spatial ABM, denoted as ABM[Formula: see text], was designed and implemented based on the biological attributes of An. vagus by modifying an established, existing ABM of Anopheles gambiae. Environmental factors such as temperature and rainfall were incorporated into ABM[Formula: see text] using daily weather profiles. Real-life field data of Bandarban were used to generate landscapes which were used in the simulations. ABM[Formula: see text] was verified and validated using several standard techniques and against real-life field data. Using artificial landscapes, the individual and combined efficacies of existing vector control interventions are modeled, applied, and examined. RESULTS: Simulated female abundance curves generated by ABM[Formula: see text] closely follow the patterns observed in the field. Due to the use of daily temperature and rainfall data, ABM[Formula: see text] was able to generate seasonal patterns for a particular area. When two interventions were applied with parameters set to mid-ranges, ITNs/LLINs with IRS produced better results compared to the other cases. Moreover, any intervention combined with ITNs/LLINs yielded better results. Not surprisingly, three interventions applied in combination generate best results compared to any two interventions applied in combination. CONCLUSIONS: Output of ABM[Formula: see text] showed high sensitivity to real-life field data of the environmental factors and the landscape of a particular area. Hence, it is recommended to use the model for a given area in connection to its local field data. For applying combined interventions, three interventions altogether are highly recommended whenever possible. It is also suggested that ITNs/LLINs with IRS can be applied when three interventions are not available.

Translation, Revision, and Validation of the Diabetes Distress Scale for Indonesian Type 2 Diabetic Outpatients with Various Types of Complications.

OBJECTIVES: To translate, revise, and validate the Diabetes Distress Scale (DDS) instrument for Indonesian type 2 diabetes mellitus (T2DM) outpatients with various complications. METHODS: Participants were recruited from four hospitals and two primary health care centers. The study was performed with forward and backward translations, an adaptation testing with a small subset of participants, and validation analysis. Factor analysis with maximum likelihood estimation and promax rotation was then used to investigate the instrument structure. Internal consistency among the items was estimated using Cronbach α for each domain of the DDS. RESULTS: In total, 324 participants (246 from the hospitals and 78 from the primary health care centers) were involved in this study. To improve participant comprehension of the exact meaning of questions, examples of daily activities for patients with T2DM (e.g., diet, exercise, and adherence to therapy) were added to some questions after the translation and revision procedures. The factor analysis revealed a correlation among the four factors ranging from 0.40 to 0.67. The factor loadings of selected items from the four factors ranged from 0.41 to 0.98. The order of the four factors in the factor analysis was as follows: interpersonal distress, emotional burden, physician distress, and regimen distress. The internal consistency for the four domains ranged from 0.78 to 0.83. The instrument resulting from this study was labeled "DDS17 Bahasa Indonesia." CONCLUSIONS: The DDS17 Bahasa Indonesia provides an initial psychometric validation study, factor structure, and internal consistency for assessing the distress of Indonesian T2DM outpatients. Use of this instrument in future research and clinical trials is recommended for the Indonesian context.

An agent-based model of the population dynamics of Anopheles gambiae.

BACKGROUND: Agent-based models (ABMs) have been used to model the behaviour of individual mosquitoes and other aspects of malaria. In this paper, a conceptual entomological model of the population dynamics of Anopheles gambiae and the agent-based implementations derived from it are described. Hypothetical vector control interventions (HVCIs) are implemented to target specific activities in the mosquito life cycle, and their impacts are evaluated. METHODS: The core model is described in terms of the complete An. gambiae mosquito life cycle. Primary features include the development and mortality rates in different aquatic and adult stages, the aquatic habitats and oviposition. The density- and age-dependent larval and adult mortality rates (vector senescence) allow the model to capture the age-dependent aspects of the mosquito biology. Details of hypothetical interventions are also described. RESULTS: Results show that with varying coverage and temperature ranges, the hypothetical interventions targeting the gonotrophic cycle stages produce higher impacts than the rest in reducing the potentially infectious female (PIF) mosquito populations, due to their multi-hour mortality impacts and their applicability at multiple gonotrophic cycles. Thus, these stages may be the most effective points of target for newly developed and novel interventions. A combined HVCI with low coverage can produce additive synergistic impacts and can be more effective than isolated HVCIs with comparatively higher coverages. It is emphasized that although the model described in this paper is designed specifically around the mosquito An. gambiae, it could effectively apply to many other major malaria vectors in the world (including the three most efficient nominal anopheline species An. gambiae, Anopheles coluzzii and Anopheles arabiensis) by incorporating a variety of factors (seasonality cycles, rainfall, humidity, etc.). Thus, the model can essentially be treated as a generic Anopheles model, offering an excellent framework for such extensions. The utility of the core model has also been demonstrated by several other applications, each of which investigates well-defined biological research questions across a variety of dimensions (including spatial models, insecticide resistance, and sterile insect techniques).

A test of agent-based models as a tool for predicting patterns of pathogen transmission in complex landscapes.

BACKGROUND: Landscape complexity can mitigate or facilitate host dispersal, influencing patterns of pathogen transmission. Spatial transmission of pathogens through landscapes, therefore, presents an important but not fully elucidated aspect of transmission dynamics. Using an agent-based model (LiNK) that incorporates GIS data, we examined the effects of landscape information on the spatial patterns of host movement and pathogen transmission in a system of long-tailed macaques and their gut parasites. We first examined the role of the landscape to identify any individual or additive effects on host movement. We then compared modeled dispersal distance to patterns of actual macaque gene flow to both confirm our model's predictions and to understand the role of individual land uses on dispersal. Finally, we compared the rate and the spread of two gastrointestinal parasites, Entamoeba histolytica and E. dispar, to understand how landscape complexity influences spatial patterns of pathogen transmission. RESULTS: LiNK captured emergent properties of the landscape, finding that interaction effects between landscape layers could mitigate the rate of infection in a non-additive way. We also found that the inclusion of landscape information facilitated an accurate prediction of macaque dispersal patterns across a complex landscape, as confirmed by Mantel tests comparing genetic and simulated dispersed distances. Finally, we demonstrated that landscape heterogeneity proved a significant barrier for a highly virulent pathogen, limiting the dispersal ability of hosts and thus its own transmission into distant populations. CONCLUSIONS: Landscape complexity plays a significant role in determining the path of host dispersal and patterns of pathogen transmission. Incorporating landscape heterogeneity and host behavior into disease management decisions can be important in targeting response efforts, identifying cryptic transmission opportunities, and reducing or understanding potential for unintended ecological and evolutionary consequences. The inclusion of these data into models of pathogen transmission patterns improves our understanding of these dynamics, ultimately proving beneficial for sound public health policy.

Examining the impact of larval source management and insecticide-treated nets using a spatial agent-based model of Anopheles gambiae and a landscape generator tool.

BACKGROUND: Agent-based models (ABMs) have been used to estimate the effects of malaria-control interventions. Early studies have shown the efficacy of larval source management (LSM) and insecticide-treated nets (ITNs) as vector-control interventions, applied both in isolation and in combination. However, the robustness of results can be affected by several important modelling assumptions, including the type of boundary used for landscapes, and the number of replicated simulation runs reported in results. Selection of the ITN coverage definition may also affect the predictive findings. Hence, by replication, independent verification of prior findings of published models bears special importance. METHODS: A spatially-explicit entomological ABM of Anopheles gambiae is used to simulate the resource-seeking process of mosquitoes in grid-based landscapes. To explore LSM and replicate results of an earlier LSM study, the original landscapes and scenarios are replicated by using a landscape generator tool, and 1,800 replicated simulations are run using absorbing and non-absorbing boundaries. To explore ITNs and evaluate the relative impacts of the different ITN coverage schemes, the settings of an earlier ITN study are replicated, the coverage schemes are defined and simulated, and 9,000 replicated simulations for three ITN parameters (coverage, repellence and mortality) are run. To evaluate LSM and ITNs in combination, landscapes with varying densities of houses and human populations are generated, and 12,000 simulations are run. RESULTS: General agreement with an earlier LSM study is observed when an absorbing boundary is used. However, using a non-absorbing boundary produces significantly different results, which may be attributed to the unrealistic killing effect of an absorbing boundary. Abundance cannot be completely suppressed by removing aquatic habitats within 300 m of houses. Also, with density-dependent oviposition, removal of insufficient number of aquatic habitats may prove counter-productive. The importance of performing large number of simulation runs is also demonstrated. For ITNs, the choice of coverage scheme has important implications, and too high repellence yields detrimental effects. When LSM and ITNs are applied in combination, ITNs' mortality can play more important roles with higher densities of houses. With partial mortality, increasing ITN coverage is more effective than increasing LSM coverage, and integrating both interventions yields more synergy as the densities of houses increase. CONCLUSIONS: Using a non-absorbing boundary and reporting average results from sufficiently large number of simulation runs are strongly recommended for malaria ABMs. Several guidelines (code and data sharing, relevant documentation, and standardized models) for future modellers are also recommended.

Increased use of multidisciplinary treatment modalities adds little to the outcome of rectal cancer treated by optimal total mesorectal excision.

PURPOSE: Total mesorectal excision (TME) is the standard surgical treatment for rectal cancer. The roles of chemotherapy and radiotherapy have become more defined, accompanied by improvements in preoperative staging and histopathological assessment. We analyse our ongoing results in the light of changing patterns of treatment over consecutive time periods. METHODS: In total, 151 consecutive patients underwent potentially curative rectal excision for cancer in a single institution. Management and outcomes were compared between 1993-1999 and 2000-2007 which corresponded with the restructuring of the regional oncological services. RESULTS: We found an increase in patients treated with neoadjuvant chemoradiotherapy after 1999 (20/89 vs 1/62, p < 0.001). There was an increase in the mean number of lymph nodes examined (11.9 vs 9.4, p = 0.037). The locoregional recurrence rate was 5.3%. The rates were not significantly different between the two study periods [4/89 (4.5%) 1999-2007 vs 4/62 (6.5%) 1993-1999, p = 0.597]. There was no statistical difference in overall or disease-free survival in the time periods examined. CONCLUSIONS: Increasing use of neoadjuvant therapy and concomitant improvement in lymph node assessment did not translate into a concurrent reduction in the local recurrence, disease-free and overall survival rates. Our results demonstrate the enduring benefit of specialist training in TME in the outcome of rectal cancer surgery. This observational study suggests that low local recurrence rates are surrogate markers for improved overall and disease-free survival. Multidisciplinary team practice should be examined and made cost effective according to the individual unit's local recurrence rate in the light of this and other reports.

Lupeol, a triterpene, inhibits early responses of tumor promotion induced by benzoyl peroxide in murine skin.

The modulating effect of Lupeol [lup-20(29)-en-3 beta -ol], a triterpene found in many fruits and medicinal plants, on benzoyl peroxide-induced tumor promotion responses or tumor promotion in murine skin is described. Benzoyl peroxide is an effective cutaneous tumor promoter acting through the generation of oxidative stress, the induction of ornithine decarboxylase activity and the enhancement of DNA synthesis. Benzoyl peroxide treatment increases cutaneous microsomal lipid peroxidation and hydrogen peroxide generation. The activity of the cutaneous antioxidant enzymes, namely catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase, is decreased and levels of cutaneous glutathione are depleted. Benzoyl peroxide treatment also induces ornithine decarboxylase activity and enhances [3H]thymidine uptake in DNA synthesis. Prophylactic treatment of mice with lupeol (0.75 and 1.5 mg per animal) 1 hour before benzoyl peroxide treatment resulted in a diminution of benzoyl peroxide-mediated damage. The susceptibility of cutaneous microsomal membrane to lipid peroxidation and hydrogen peroxide generation was significantly reduced (P< 0.01 and P< 0.01, respectively). In addition, depleted levels of glutathione and inhibited activity of antioxidant enzymes were recovered to a significant level (P< 0.01, P< 0.05 and P< 0.01, respectively). Similarly, the elevated ornithine decarboxylase activity and enhanced thymidine uptake in DNA synthesis were inhibited significantly (P< 0.05) in a dose-dependent manner. The protective effect of lupeol was dose dependent in all parameters. The results suggest that lupeol is an effective skin chemopreventive agent that may suppress benzoyl peroxide-induced cutaneous toxicity.