Structured benefit-risk assessment: a review of key publications and initiatives on frameworks and methodologies.

Introduction The conduct of structured benefit-risk assessment (BRA) of pharmaceutical products is a key area of interest for regulatory agencies and the pharmaceutical industry. However, the acceptance of a standardized approach and implementation are slow. Statisticians play major roles in these organizations, and have a great opportunity to be involved and drive the shaping of future BRA. Method We performed a literature search of recent reviews and initiatives assessing BRA methodologies, and grouped them to assist those new to BRA in learning, understanding, and choosing methodologies. We summarized the key points and discussed the impact of this emerging field on various stakeholders, particularly statisticians in the pharmaceutical industry. Results We provide introductory, essential, special interest, and further information and initiatives materials that direct readers to the most relevant materials, which were published between 2000 and 2013.  Based on recommendations in these materials we supply a toolkit of advocated BRA methodologies. Discussion Despite initiatives promoting these methodologies, there are still barriers, one of which being the lack of a consensus on the most appropriate methodologies among stakeholders. However, this opens up opportunities, for statisticians in the pharmaceutical industry especially, to champion appropriate BRA methodology use throughout the pharmaceutical product lifecycle. Conclusions This article may serve as a starting point for discussions and to reach a mutual consensus for methodology selection in a particular situation. Regulators and pharmaceutical industry should continue to collaborate to develop and take forward BRA methodologies, and by clear communication develop a mutual understanding of the key issues. Copyright © 2015 John Wiley & Sons, Ltd

Relative luminosity measurement of the LHC with the ATLAS forward calorimeter

In this paper it is shown that a measurement of the relative luminosity changes at the LHC may be obtained by analysing the currents drawn from the high voltage power supplies of the electromagnetic section of the forward calorimeter of the ATLAS detector. The method was verified with a reproduction of a small section of the ATLAS forward calorimeter using proton beams of known beam energies and variable intensities at the U-70 accelerator at IHEP in Protvino, Russia. The experimental setup and the data taking during a test beam run in April 2008 are described in detail. A comparison of the measured high voltage currents with reference measurements from beam intensity monitors shows a linear dependence on the beam intensity. The non-linearities are measured to be less than 0.5 % combining statistical and systematic uncertainties.Comment: 16 page

Allele frequencies of BRAFV600 mutations in primary melanomas and matched metastases and their relevance for BRAF inhibitor therapy in metastatic melanoma

Background: The detection of BRAFV600 mutations in patients with metastatic melanoma is important because of the availability of BRAF inhibitor therapy. However, the clinical relevance of the frequency of BRAFV600 mutant alleles is unclear. Patients and Methods: Allele frequencies of BRAFV600 mutations were analyzed byultra-deepnext-generation sequencing in formalin-fixed, paraffin-embedded melanoma tissue (75 primary melanomas and 88 matched metastases). In a second study, pretreatment specimens from 76 patients who received BRAF inhibitors were retrospectively analyzed, and BRAFV600 allele frequencies were correlated with therapeutic results. Results: Thirty-five patients had concordantly BRAF-positive and 36 (48%) patients had concordantly BRAF-negative primary melanomas and matched metastases, and four patients had discordant samples with low allele frequencies (3.4–5.2%). Twenty-six of 35 patients with concordant samples had BRAFV600E mutations, three of whom had additional mutations (V600K in two patients and V600R in one) and nine patients had exclusively non-V600E mutations (V600K in eight patients and V600E -c.1799_1800TG > AA- in one patient). The frequency of mutated BRAFV600 alleles was similar in the primary melanoma and matched metastasis in 27/35 patients, but differed by >3-fold in 8/35 of samples. BRAFV600E allele frequencies in pretreatment tumor specimens were not significantly correlated with treatment outcomes in 76 patients with metastatic melanoma who were treated with BRAF inhibitors. Conclusions: BRAFV600 mutation status and allele frequency is consistent in the majority of primary melanomas and matched metastases. A small subgroup of patients has double mutations. BRAFV600 allele frequencies are not correlated with the response to BRAF inhibitors

Implementation of Point-of-Care Diagnostics Leads to Variable Uptake of Syphilis, Anemia and CD4+ T-Cell Count Testing in Rural Maternal and Child Health Clinics

Introduction: Anemia, syphilis and HIV are high burden diseases among pregnant women in sub-Saharan Africa. A quasi-experimental study was conducted in four health facilities in Southern Mozambique to evaluate the effect of point-of-care technologies for hemoglobin quantification, syphilis testing and CD4+ T-cell enumeration performed within maternal and child health services on testing and treatment coverage, and assessing acceptability by health workers. Methods: Demographic and testing data on women attending first antenatal care services were extracted from existing records, before (2011; n = 865) and after (2012; n = 808) introduction of point-of-care testing. Study outcomes per health facility were compared using z-tests (categorical variables) and Wilcoxon rank-sum test (continuous variables), while inverse variance weights were used to adjust for possible cluster effects in the pooled analysis. A structured acceptability-assessment interview was conducted with health workers before (n = 22) and after (n = 19). Results: After implementation of point-of-care testing, there was no significant change in uptake of overall hemoglobin screening (67.9% to 83.0%; p = 0.229), syphilis screening (80.8% to 87.0%; p = 0.282) and CD4+ T-cell testing (84.9% to 83.5%; p = 0.930). Initiation of antiretroviral therapy for treatment eligible women was similar in the weighted analysis before and after, with variability among the sites. Time from HIV diagnosis to treatment initiation decreased (median of 44 days to 17 days; p\u3c0.0001). A generally good acceptability for point-of-care testing was seen among health workers. Conclusions: Point-of-care CD4+ T-cell enumeration resulted in a decreased time to initiation of antiretroviral therapy among treatment eligible women, without significant increase in testing coverage. Overall hemoglobin and syphilis screening increased. Despite the perception that point-of-care technologies increase access to health services, the variability in results indicate the potential for detrimental effects in some settings. Local context needs to be considered and services restructured to accommodate innovative technologies in order to improve service delivery to expectant mothers

High HIV incidence in the postpartum period sustains vertical transmission in settings with generalized epidemics: A cohort study in Southern Mozambique

Introduction: Acute infection with HIV in the postpartum period results in a high risk of vertical transmission through breastfeeding. A study was done to determine the HIV incidence rate and associated risk factors among postpartum women in Southern Mozambique, where HIV prevalence among pregnant women is 21%. Methods: A prospective cohort study was conducted in six rural health facilities in Gaza and Maputo provinces from March 2008 to July 2011. A total of 1221 women who were HIV-negative on testing at delivery or within two months postpartum were recruited and followed until 18 months postpartum. HIV testing, collection of dried blood spot samples and administration of a structured questionnaire to women were performed every three months. Infant testing by DNA-PCR was done as soon as possible after identification of a new infection in women. HIV incidence was estimated, and potential risk factors at baseline were compared using Poisson regression. Results: Data from 957 women were analyzed with follow-up after the enrolment visit, with a median follow-up of 18.2 months. The HIV incidence in postpartum women is estimated at 3.20/100 women-years (95% CI: 2.30–4.46), with the highest rate among 18- to 19-year-olds (4.92 per 100 women-years; 95% CI: 2.65–9.15). Of the new infections, 14 (34%) were identified during the first six months postpartum, 11 (27%) between 6 and 12 months and 16 (39%) between 12 and 18 months postpartum. Risk factors for incident HIV infection include young age, low number of children, higher education level of the woman\u27s partner and having had sex with someone other than one\u27s partner. The vertical transmission was 21% (95% CI: 5–36) among newly infected women. Conclusions: Incidence of HIV is high among breastfeeding women in Southern Mozambique, contributing to increasing numbers of HIV-infected infants. Comprehensive primary prevention strategies targeting women of reproductive age, particularly pregnant and postpartum women and their partners, will be crucial for the elimination of paediatric AIDS in Africa

Cost-effective Paper-based Diagnostic Using Split Proteins to Detect Yeast Infections

The common yeast infection, vulvovaginal candidiasis, affects three out of four women throughout their lifetime and can be spread to their child in the form of oral candidiasis (thrush). This disease is caused by the fungal pathogen Candida albicans, which is also a major cause of systemic candidiasis, a rarer but deadly disease with up to a 49% lethality rate. Current widely-used diagnostic methods include cell cultures, pH tests, and antibody detection, to assist effective treatment. Despite availability of various diagnostic methods, there is no inexpensive, rapid, and accurate way to detect C. albicans infection. This project aims to develop a paper-based diagnostic test for C. albicans that is, cost-effective, quick, and precise. The test detects the specific biomarkers farnesol and tyrosol produced by C. albicans by binding them to the split proteins pqsR and tyrosinase, respectively. Upon binding, a split horseradish peroxidase catalyzes and produces an amplified colorimetric signal by oxidizing the substrate tetramethylbenzidine (TMB) turning the paper blue. This test will produce a colorimetric output for a simple-to-understand diagnosis without any infrastructure. We predict that this device can give a response in under 2 minutes while costing around an estimated 10 cents per device This test may provide a way for an easy and cheap way to diagnose candidiasis worldwide, reducing the abuse of antifungals and provide an accurate way to treat vulvovaginal candidiasis and systemic candidiasis

Cost-effective Paper-based Diagnostic Using Split Proteins to Detect Yeast Infections

The common yeast infection, vulvovaginal candidiasis, affects three out of four women throughout their lifetime and can be spread to their child in the form of oral candidiasis (thrush). This disease is caused by the fungal pathogen Candida albicans, which is also a major cause of systemic candidiasis, a rarer but deadly disease with up to a 49% lethality rate. Current widely-used diagnostic methods include cell cultures, pH tests, and antibody detection, to assist effective treatment. Despite availability of various diagnostic methods, there is no inexpensive, rapid, and accurate way to detect C. albicans infection. This project aims to develop a paper-based diagnostic test for C. albicans that is, cost-effective, quick, and precise. The test detects the specific biomarkers farnesol and tyrosol produced by C. albicans by binding them to the split proteins pqsR and tyrosinase, respectively. Upon binding, a split horseradish peroxidase catalyzes and produces an amplified colorimetric signal by oxidizing the substrate tetramethylbenzidine (TMB) turning the paper blue. This test will produce a colorimetric output for a simple-to-understand diagnosis without any infrastructure. We predict that this device can give a response in under 2 minutes while costing around an estimated 10 cents per device This test may provide a way for an easy and cheap way to diagnose candidiasis worldwide, reducing the abuse of antifungals and provide an accurate way to treat vulvovaginal candidiasis and systemic candidiasis

Risk factors for incomplete vaccination and missed opportunity for immunization in rural Mozambique

<p>Abstract</p> <p>Background</p> <p>Inadequate levels of immunization against childhood diseases remain a significant public health problem in resource-poor areas of the globe. Nonetheless, the reasons for incomplete vaccination and non-uptake of immunization services are poorly understood. This study aimed at finding out the reasons for non-vaccination and the magnitude of missed opportunities for vaccination in children less than two years of age in a rural area in southern Mozambique.</p> <p>Methods</p> <p>Mothers of children under two years of age (N = 668) were interviewed in a cross-sectional study. The Road-to-Health card was utilized to check for completeness and correctness of vaccination schedule as well as for identifying the appropriate use of all available opportunities for vaccination. The chi-square test and the logistic regression were used for statistical analysis.</p> <p>Results</p> <p>We found that 28.2% of the children had not completed the vaccination program by two years of age, 25.7% had experienced a missed opportunity for vaccination and 14.9% were incorrectly vaccinated. Reasons for incomplete vaccination were associated with accessibility to the vaccination sites, no schooling of mothers and children born at home or outside Mozambique.</p> <p>Conclusion</p> <p>Efforts to increase vaccination coverage should take into account factors that contribute to the incomplete vaccination status of children. Missed opportunities for vaccination and incorrect vaccination need to be avoided in order to increase the vaccine coverage for those clients that reach the health facility, specially in those countries where health services do not have 100% of coverage.</p

The potential role of podoplanin in tumour invasion

Podoplanin is a small mucin-like transmembrane protein, widely expressed in various specialised cell types throughout the body. Here, we revisit the mechanism of podoplanin-mediated tumour invasion. We compare molecular pathways leading to single and collective cell invasion and discuss novel distinct concepts of tumour cell invasion