On the potential for discontinuing atovaquone-proguanil (AP) ad-hoc post-exposure and other abbreviated AP-regimens: Pharmacology, pharmacokinetics and perspectives

According to current guidelines, atovaquone-proguanil (AP) malaria chemoprophylaxis should be taken once daily starting one day before travel and continued for seven days post-exposure. However, drug-sparing regimens, including discontinuing AP after leaving malaria-endemic areas are cost-saving and probably more attractive to travelers, and may thus enhance adherence. AP has causal prophylactic effects, killing malaria parasites during the hepatic stage. If early hepatic stages were already targeted by AP, AP could possibly be discontinued upon return. Pharmacokinetic data and studies on drug-sparing AP regimens suggest this to be the case. Nevertheless, the evidence is weak and considered insufficient to modify current recommendations. Field trials require large numbers of travelers and inherently suffer from the lack of a control group. Safely-designed controlled human malaria infection trials could significantly reduce study participant numbers and safely establish an effective AP abbreviated regimen which we propose as the optimal trial design to test this concept

Combinatorial Exploration of Novel Transparent Conducting Oxide Materials

High-throughput combinatorial approaches have been used for the discovery and optimization of transparent conducting oxide (TCO) materials for PV applications. We report on current investigations in In-Zn-O, In-Ti-O and In-Mo-O systems. The InZnO system is shown to be amorphous in the best conducting range with a conductivity of ~ 3000 Ω-cm-1 for 50%-70% In/Zn. The amorphous InZnO films are very smooth (2..ANG.. rms). In-Ti-O is found to be an excellent high-mobility TCO with mobilities of greater than 80 cm2/v-sec and conductivities of more than 6000 Ω-cm-1 for sputtered thin film materials

Proposed Route to Thin Film Crystal Si Using Biaxially Textured Foreign Template Layers

We have developed a new approach to growing photovoltaic-quality crystal silicon (c-Si) films on glass. Other approaches to film c-Si focus on increasing grain size in order to reduce the deleterious effects of grain boundaries. Instead, we have developed an approach to align the silicon grains biaxially (both in and out of plane) so that 1) grain boundaries are "low-angle" and have less effect on the electronic properties of the material and 2) subsequent epitaxial thickening is simplified. They key to our approach is the use of a foreign template layer that can be grown with biaxial texture directly on glass

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility

Background: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. Methods: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. Results: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. Conclusions: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts

Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk

Measuring underreporting and under-ascertainment in infectious disease datasets: a comparison of methods

Gibbons CL, Mangen M-JJ, Plaß D, et al. Measuring underreporting and under-ascertainment in infectious disease datasets: a comparison of methods. BMC Public Health. 2014;14(1): 147.Background: Efficient and reliable surveillance and notification systems are vital for monitoring public health and disease outbreaks. However, most surveillance and notification systems are affected by a degree of underestimation (UE) and therefore uncertainty surrounds the 'true' incidence of disease affecting morbidity and mortality rates. Surveillance systems fail to capture cases at two distinct levels of the surveillance pyramid: from the community since not all cases seek healthcare (under-ascertainment), and at the healthcare-level, representing a failure to adequately report symptomatic cases that have sought medical advice (underreporting). There are several methods to estimate the extent of under-ascertainment and underreporting. Methods: Within the context of the ECDC-funded Burden of Communicable Diseases in Europe (BCoDE)-project, an extensive literature review was conducted to identify studies that estimate ascertainment or reporting rates for salmonellosis and campylobacteriosis in European Union Member States (MS) plus European Free Trade Area (EFTA) countries Iceland, Norway and Switzerland and four other OECD countries (USA, Canada, Australia and Japan). Multiplication factors (MFs), a measure of the magnitude of underestimation, were taken directly from the literature or derived (where the proportion of underestimated, under-ascertained, or underreported cases was known) and compared for the two pathogens. Results: MFs varied between and within diseases and countries, representing a need to carefully select the most appropriate MFs and methods for calculating them. The most appropriate MFs are often disease-,country-, age-, and sex-specific. Conclusions: When routine data are used to make decisions on resource allocation or to estimate epidemiological parameters in populations, it becomes important to understand when, where and to what extent these data represent the true picture of disease, and in some instances (such as priority setting) it is necessary to adjust for underestimation. MFs can be used to adjust notification and surveillance data to provide more realistic estimates of incidence