Simulation of the cost-effectiveness of malaria vaccines

<p>Abstract</p> <p>Background</p> <p>A wide range of possible malaria vaccines is being considered and there is a need to identify which vaccines should be prioritized for clinical development. An important element of the information needed for this prioritization is a prediction of the cost-effectiveness of potential vaccines in the transmission settings in which they are likely to be deployed. This analysis needs to consider a range of delivery modalities to ensure that clinical development plans can be aligned with the most appropriate deployment strategies.</p> <p>Methods</p> <p>The simulations are based on a previously published individual-based stochastic model for the natural history and epidemiology of <it>Plasmodium falciparum </it>malaria. Three different vaccine types: pre-erythrocytic vaccines (PEV), blood stage vaccines (BSV), mosquito-stage transmission-blocking vaccines (MSTBV), and combinations of these, are considered each delivered via a range of delivery modalities (Expanded Programme of Immunization – EPI-, EPI with booster, and mass vaccination combined with EPI). The cost-effectiveness ratios presented are calculated for four health outcomes, for assumed vaccine prices of US$2 or US$ 10 per dose, projected over a 10-year period.</p> <p>Results</p> <p>The simulations suggest that PEV will be more cost-effective in low transmission settings, while BSV at higher transmission settings. Combinations of BSV and PEV are more efficient than PEV, especially in moderate to high transmission settings, while compared to BSV they are more cost-effective in moderate to low transmission settings. Combinations of MSTBV and PEV or PEV and BSV improve the effectiveness and the cost-effectiveness compared to PEV and BSV alone only when applied with EPI and mass vaccinations. Adding booster doses to the EPI is unlikely to be a cost-effective alternative to delivering vaccines via the EPI for any vaccine, while mass vaccination improves effectiveness, especially in low transmission settings, and is often a more efficient alternative to the EPI. However, the costs of increasing the coverage of mass vaccination over 50% often exceed the benefits.</p> <p>Conclusion</p> <p>The simulations indicate malaria vaccines might be efficient malaria control interventions, and that both transmission setting and vaccine delivery modality are important to their cost-effectiveness. Alternative vaccine delivery modalities to the EPI may be more efficient than the EPI. Mass vaccination is predicted to provide substantial health benefits at low additional costs, although achieving high coverage rates can lead to substantial incremental costs.</p

A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release

Introduction The reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA). A central role of A2A and A3 adenosine receptors (ARs) in mechanisms of inflammation has been reported in different pathologies. The primary aim of this study was to investigate the A2A and A3ARs and their involvement in RA progression measured by Disease Activity Score in 28 or 44 joints (DAS28 or DAS). Methods ARs were analyzed by saturation binding assays, mRNA and Western blotting analysis in lymphocytes from early and established RA patients. The effect of A2A and A3AR agonists in nuclear factor kB (NF-kB) pathway was evaluated. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) release was carried out by A2A and A3AR activation. AR pharmacological regulation in matrix metalloproteinase-1 (MMP-1) and metalloproteinase-3 (MMP-3) release was also studied. Results In lymphocytes obtained from RA patients, A2A and A3ARs were up-regulated if compared with healthy controls. A2A and A3AR activation inhibited the NF-kB pathway and diminished inflammatory cytokines such as TNF-α, IL-1β and IL-6. A2A and A3AR agonists mediated a reduction of MMP-1 and MMP-3 release. A2A and A3AR density inversely correlated with DAS28 and DAS suggesting a direct role of the endogenous activation of these receptors in the control of RA joint inflammation. Conclusions Taken together these data demonstrate that the inflammatory and clinical responses in RA are regulated by A2A and A3ARs and support the use of A2A and/or A3AR agonists as novel and effective pharmacological treatment in RA patients

Country specific predictions of the cost-effectiveness of malaria vaccine RTS,S/AS01 in endemic Africa

RTS,S/AS01 is a safe and moderately efficacious vaccine considered for implementation in endemic Africa. Model predictions of impact and cost-effectiveness of this new intervention could aid in country adoption decisions.; The impact of RTS,S was assessed in 43 countries using an ensemble of models of Plasmodium falciparum epidemiology. Informed by the 32months follow-up data from the phase 3 trial, vaccine effectiveness was evaluated at country levels of malaria parasite prevalence, coverage of control interventions and immunization. Benefits and costs of the program incremental to routine malaria control were evaluated for a four dose schedule: first dose administered at six months, second and third - before 9months, and fourth dose at 27months of age. Sensitivity analyses around vaccine properties, transmission, and economic inputs were conducted.; If implemented in all 43 countries the vaccine has the potential to avert 123 (117;129) million malaria episodes over the first 10years. Burden averted averages 18,413 (range of country median estimates 156-40,054) DALYs per 100,000 fully vaccinated children with much variation across settings primarily driven by differences in transmission intensity. At a price of $5 per dose program costs average$39.8 per fully vaccinated child with a median cost-effectiveness ratio of $188 (range$78-$22,448) per DALY averted; the ratio is lower by one third -$136 (range $116-$220) - in settings where parasite prevalence in children aged 2-10years is at or above 10%.; RTS,S/AS01has the potential to substantially reduce malaria burden in children across Africa. Conditional on assumptions on price, coverage, and vaccine properties, adding RTS,S to routine malaria control interventions would be highly cost-effective. Implementation decisions will need to further consider feasibility of scaling up existing control programs, and operational constraints in reaching children at risk with the schedule

Functional connectivity measured with magnetoencephalography identifies persons with HIV disease

There is need for a valid and reliable biomarker for HIV Associated Neurocognitive Disorder (HAND). The purpose of the present study was to provide preliminary evidence of the potential utility of neuronal functional connectivity measures obtained using magnetoencephalography (MEG) to identify HIV-associated changes in brain function. Resting state, eyes closed, MEG data from 10 HIV-infected individuals and 8 seronegative controls were analyzed using mutual information (MI) between all pairs of MEG sensors to ..

Efecto del desarrollo de una cultura organizacional basada en valores sobre la competitividad de la empresa Cerámica San Lorenzo S.A.

Análisis cuantitativo, descriptivo, transversal y correlacional de diseño no experimental que tiene como objetivo determinar la asociación entre cultura organizacional basada en valores y la competitividad de la empresa Cerámica San Lorenzo S.A.C. Para comprobar que existe dicha asociación estadísticamente significativa se utilizó un cuestionario para medir la cultura organizacional basada en valores dentro de la empresa; y para medir la competitividad se aplicó los parámetros del diamante de Porter utilizando un check list tabulado. En consecuencia, se estableció que la empresa tiene una cultura organizacional fuerte basada en sus valores desarrollo del recurso humano, eficiencia y eficacia en los procesos, orientación a los resultados y compromiso con la calidad; y que las determinantes del Diamante hacen de la empresa Cerámica San Lorenzo, una empresa competitiva. Por lo tanto, se puede decir que si existe una asociación entre la cultura organizacional basada en valores y la competitividad de San Lorenzo. En este sentido, es el capital humano el que se alinea a la misión de la empresa, pone su esfuerzo para lograr los objetivos de la empresa, genera valor con la dirección y motivación de los líderes y aporta a la ventaja competitiva y a la competitividad frente a los competidores del sector de pisos y acabados para la construcción.Tesi

Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival

Abstract Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fibrosis, inflammation, and hypoxia, which activates HIF-1α to increase tumor cell metastasis and therapeutic resistance. Carbonic anhydrase IX (CA9) stabilizes intracellular pH following induction by HIF-1α. Redox effector factor-1 (APE1/Ref-1) is a multifunctional protein with redox signaling activity that converts certain oxidized transcription factors to a reduced state, enabling them to upregulate tumor-promoting genes. Our studies evaluate PDAC hypoxia responses and APE1/Ref-1 redox signaling contributions to HIF-1α-mediated CA9 transcription. Our previous studies implicated this pathway in PDAC cell survival under hypoxia. We expand those studies, comparing drug responses using patient-derived PDAC cells displaying differential hypoxic responses in 3D spheroid tumor-stroma models to characterize second generation APE1/Ref-1 redox signaling and CA9 inhibitors. Our data demonstrates that HIF-1α-mediated CA9 induction differs between patient-derived PDAC cells and that APE1/Ref-1 redox inhibition attenuates this induction by decreasing hypoxia-induced HIF-1 DNA binding. Dual-targeting of APE1/Ref-1 and CA9 in 3D spheroids demonstrated that this combination effectively kills PDAC tumor cells displaying drastically different levels of CA9. New APE1/Ref-1 and CA9 inhibitors were significantly more potent alone and in combination, highlighting the potential of combination therapy targeting the APE1-Ref-1 signaling axis with significant clinical potential

Competencias socioemocionales en la gestión de la empleabilidad de estudiantes universitarios: el estudio de caso de las carreras profesionales de Gestión y Alta Dirección y de Derecho de la Pontificia Universidad Católica del Perú en el 2017

La presente investigación profesional tiene como objetivo determinar la influencia de la relación de las competencias socioemocionales y la empleabilidad en la gestión por competencias de las facultades de Gestión y Alta Dirección y de Derecho de la Pontificia Universidad Católica del Perú y de las principales organizaciones empleadoras de los alumnos de ambas facultades en el año 2017. La aproximación de la investigación se realiza mediante el estudio de caso de las facultades de Gestión y Alta Dirección y de Derecho de la Pontificia Universidad Católica del Perú, las cuales se encuentran trabajando en la estructuración de planes de estudios que contemplen la formación por competencias, de manera que se le confiera la misma importancia que el mercado laboral le otorga a las competencias socioemocionales. En consecuencia, la presente investigación analiza la formación actual que imparten ambas facultades en sus estudiantes, así como las percepciones que tienen los estudiantes de ambas carreras profesionales sobre el nivel de competencias socioemocionales adquirido en la etapa universitaria y el nivel de competencias socioemocionales aplicado en las organizaciones en las que ellos se desempeñan, las cuales son contratas con el nivel de competencias socioemocionales requerido por las principales organizaciones empleadoras. El estudio se centra en 23 competencias socioemocionales que tienen su sustento teórico en el Diccionario de competencias laborales de Martha Alles. Como resultado de este estudio, se identificaron dos tipos de brechas existentes: 1) entre el nivel de competencias adquirido en la etapa universitaria y el nivel de competencias aplicado en el lugar de trabajo y 2) entre el nivel de competencias adquirido en la etapa universitaria y el nivel de competencias requerido por el mercado laboral. A partir de la identificación de estas brechas desagregadas por cada una de las facultades, se determinaron los márgenes de mejora en cada una de las 23 competencias que componen el estudio, los cuales se complementan con la información recolectada a través de entrevistas en profundidad a los principales actores involucrados. Todo ello con el propósito de que la presente investigación sirva de insumo para ambas facultades en estudio en la estructuración de un modelo formativo por competencias que mejore la empleabilidad de sus estudiantes.Tesi

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1–induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment