Incremental Benefits of Male HPV Vaccination: Accounting for Inequality in Population Uptake

Background

Vaccines against HPV16/18 are approved for use in females and males but most countries currently have female-only programs. Cultural and geographic factors associated with HPV vaccine uptake might also influence sexual partner choice; this might impact post-vaccination outcomes. Our aims were to examine the population-level impact of adding males to HPV vaccination programs if factors influencing vaccine uptake also influence partner choice, and additionally to quantify how this changes the post-vaccination distribution of disease between subgroups, using incident infections as the outcome measure.

Methods

A dynamic model simulated vaccination of pre-adolescents in two scenarios: 1) vaccine uptake was correlated with factors which also affect sexual partner choice (“correlated”); 2) vaccine uptake was unrelated to these factors (“unrelated”). Coverage and degree of heterogeneity in uptake were informed by observed data from Australia and the USA. Population impact was examined via the effect on incident HPV16 infections. The rate ratio for post-vaccination incident HPV16 in the lowest compared to the highest coverage subgroup (RR_L) was calculated to quantify between-group differences in outcomes.

Results

The population-level incremental impact of adding males was lower if vaccine uptake was “correlated”, however the difference in population-level impact was extremely small (<1%) in the Australia and USA scenarios, even under the conservative and extreme assumption that subgroups according to coverage did not mix at all sexually. At the subgroup level, “correlated” female-only vaccination resulted in RR_L = 1.9 (Australia) and 1.5 (USA) in females, and RR_L = 1.5 and 1.3 in males. “Correlated” both-sex vaccination increased RR_L to 4.2 and 2.1 in females and 3.9 and 2.0 in males in the Australia and USA scenarios respectively.

Conclusions

The population-level incremental impact of male vaccination is unlikely to be substantially impacted by feasible levels of heterogeneity in uptake. However, these findings emphasize the continuing importance of prioritizing high coverage across all groups in HPV vaccination programs in terms of achieving equality of outcomes.     

A genomic point-of-view on environmental factors influencing the human brain methylome

The etiologic paradigm of complex human disorders such as autism is that genetic and environmental risk factors are independent and additive, but the interactive effects at the epigenetic interface are largely ignored. Genomic technologies have radically changed perspective on the human genome and how the epigenetic interface may impact complex human disorders. Here, I review recent genomic, environmental and epigenetic findings that suggest a new paradigm of “integrative genomics” in which genetic variation in genomic size may be impacted by dietary and environmental factors that influence the genomic saturation of DNA methylation. Human genomes are highly repetitive, but the interface of large-scale genomic differences with environmental factors that alter the DNA methylome such as dietary folate is under-explored. In addition to obvious direct effects of some environmental toxins on the genome by causing chromosomal breaks, non-mutagenic toxin exposures correlate with DNA hypomethylation that can lead to rearrangements between repeats or increased retrotransposition. Since human neurodevelopment appears to be particularly sensitive to alterations in epigenetic pathways, a further focus will be on how developing neurons may be particularly impacted by even subtle alterations to DNA methylation and proposing new directions towards understanding the quixotic etiology of autism by integrative genomic approaches.Key words: DNA methylation, copy number variation, autism, neurodevelopment, genomics, epigenomics, epigenetics, folate, folic acid, environmental exposures, Alu, MeCP2, LINE-1     

Crack propagation in cortical bone is affected by the characteristics of the cement line: a parameter study using an XFEM interface damage model

Bulk properties of cortical bone have been well characterized experimentally, and potent toughening mechanisms, e.g., crack deflections, have been identified at the microscale. However, it is currently difficult to experimentally measure local damage properties and isolate their effect on the tissue fracture resistance. Instead, computer models can be used to analyze the impact of local characteristics and structures, but material parameters required in computer models are not well established. The aim of this study was therefore to identify the material parameters that are important for crack propagation in cortical bone and to elucidate what parameters need to be better defined experimentally. A comprehensive material parameter study was performed using an XFEM interface damage model in 2D to simulate crack propagation around an osteon at the microscale. The importance of 14 factors (material parameters) on four different outcome criteria (maximum force, fracture energy, crack length and crack trajectory) was evaluated using ANOVA for three different osteon orientations. The results identified factors related to the cement line to influence the crack propagation, where the interface strength was important for the ability to deflect cracks. Crack deflection was also favored by low interface stiffness. However, the cement line properties are not well determined experimentally and need to be better characterized. The matrix and osteon stiffness had no or low impact on the crack pattern. Furthermore, the results illustrated how reduced matrix toughness promoted crack penetration of the cement line. This effect is highly relevant for the understanding of the influence of aging on crack propagation and fracture resistance in cortical bone.

     

Identification of Phytoplankton from Flow Cytometry Data by Using Radial Basis Function Neural Networks

We describe here the application of a type of artificial neural network, the Gaussian radial basis function (RBF) network, in the identification of a large number of phytoplankton strains from their 11-dimensional flow cytometric characteristics measured by the European Optical Plankton Analyser instrument. The effect of network parameters on optimization is examined. Optimized RBF networks recognized 34 species of marine and freshwater phytoplankton with 91.5% success overall. The relative importance of each measured parameter in discriminating these data and the behavior of RBF networks in response to data from “novel” species (species not present in the training data) were analyzed.     

A model of naturalistic decision making in preference tests

Decisions as to whether to continue with an ongoing activity or to switch to an alternative are a constant in an animal’s natural world, and in particular underlie foraging behavior and performance in food preference tests. Stimuli experienced by the animal both impact the choice and are themselves impacted by the choice, in a dynamic back and forth. Here, we present model neural circuits, based on spiking neurons, in which the choice to switch away from ongoing behavior instantiates this back and forth, arising as a state transition in neural activity. We analyze two classes of circuit, which differ in whether state transitions result from a loss of hedonic input from the stimulus (an “entice to stay” model) or from aversive stimulus-input (a “repel to leave” model). In both classes of model, we find that the mean time spent sampling a stimulus decreases with increasing value of the alternative stimulus, a fact that we linked to the inclusion of depressing synapses in our model. The competitive interaction is much greater in “entice to stay” model networks, which has qualitative features of the marginal value theorem, and thereby provides a framework for optimal foraging behavior. We offer suggestions as to how our models could be discriminatively tested through the analysis of electrophysiological and behavioral data.     

USP9X Enhances the Polarity and Self-Renewal of Embryonic Stem Cell-derived Neural Progenitors

The substrate-specific deubiquitylating enzyme USP9X is a putative “stemness” gene expressed in many progenitor cell populations. To test its function in embryonic stem cell-derived neural progenitor/stem cells, we expressed USP9X from a Nestin promoter. Elevated USP9X levels resulted in two phenomena. First, it produced a dramatically altered cellular architecture wherein the majority (>80%) of neural progenitors was arranged into radial clusters. These progenitors expressed markers of radial glial cells and were highly polarized with adherens junction proteins (N-cadherin, β-catenin, and AF-6) and apical markers (Prominin1, atypical protein kinase C-ζ) as well as Notch, Numb, and USP9X itself, concentrated at the center. The cluster centers were also devoid of nuclei and so resembled the apical end-feet of radial progenitors in the neural tube. Second, USP9X overexpression caused a fivefold increase in the number of radial progenitors and neurons, in the absence of exogenous growth factors. 5-Bromo-2′-deoxyuridine labeling, as well as the examination of the brain lipid-binding protein:βIII-tubulin ratio, indicated that nestin-USP9X enhanced the self-renewal of radial progenitors but did not block their subsequent differentiation to neurons and astrocytes. nestin-USP9X radial progenitors reformed clusters after passage as single cells, whereas control cells did not, suggesting it aids the establishment of polarity. We propose that USP9X-induced polarization of these neural progenitors results in their radial arrangement, which provides an environment conducive for self-renewal.     

Calcium Wave Propagation in Networks of Endothelial Cells: Model-based Theoretical and Experimental Study

In this paper, we present a combined theoretical and experimental study of the propagation of calcium signals in multicellular structures composed of human endothelial cells. We consider multicellular structures composed of a single chain of cells as well as a chain of cells with a side branch, namely a “T” structure. In the experiments, we investigate the result of applying mechano-stimulation to induce signaling in the form of calcium waves along the chain and the effect of single and dual stimulation of the multicellular structure. The experimental results provide evidence of an effect of architecture on the propagation of calcium waves. Simulations based on a model of calcium-induced calcium release and cell-to-cell diffusion through gap junctions shows that the propagation of calcium waves is dependent upon the competition between intracellular calcium regulation and architecture-dependent intercellular diffusion.     

The Impact of Funding through the RF President’s Grants for Young Scientists (the field – Medicine) on Research Productivity: A Quasi-Experimental Study and a Brief Systematic Review

The impact of grants on research productivity has been investigated by a number of retrospective studies. The results of these studies vary considerably. The objective of my study was to investigate the impact of funding through the RF President’s grants for young scientists on the research productivity of awarded applicants. The study compared the number of total articles and citations for awarded and rejected applicants who in 2007 took part in competitions for young candidates of science (CoS’s) and doctors of science (DoS’s) in the scientific field of medicine. The bibliometric analysis was conducted for the period from 2003 to 2012 (five years before and after the competition). The source of bibliometric data is the eLIBRARY.RU database. The impact of grants on the research productivity of Russian young scientists was assessed using the meta-analytical approach based on data from quasi-experimental studies conducted in other countries. The competition featured 149 CoS’s and 41 DoS’s, out of which 24 (16%) and 22 (54%) applicants, respectively, obtained funding. No difference in the number of total articles and citations at baseline, as well as in 2008–2012, for awarded and rejected applicants was found. The combination of data from the Russian study and other quasi-experimental studies (6 studies, 10 competitions) revealed a small treatment effect – an increase in the total number of publications over a 4–5-year period after the competition by 1.23 (95% CI 0.48–1.97). However, the relationship between the number of total publications published by applicants before and after the competition revealed that this treatment effect is an effect of the “maturation” of scientists with a high baseline publication activity – not of grant funding.     

Investigating the Role of Assessment Method on Reports of Déjà Vu and Tip-of-the-Tongue States during Standard Recognition Tests

Déjà vu and tip-of-the-tongue (TOT) are retrieval-related subjective experiences whose study relies on participant self-report. In four experiments (ns = 224, 273, 123 and 154), we explored the effect of questioning method on reported occurrence of déjà vu and TOT in experimental settings. All participants carried out a continuous recognition task, which was not expected to induce déjà vu or TOT, but were asked about their experiences of these subjective states. When presented with contemporary definitions, between 32% and 58% of participants nonetheless reported experiencing déjà vu or TOT. Changing the definition of déjà vu or asking participants to bring to mind a real-life instance of déjà vu or TOT before completing the recognition task had no impact on reporting rates. However, there was an indication that changing the method of requesting subjective reports impacted reporting of both experiences. More specifically, moving from the commonly used retrospective questioning (e.g. “Have you experienced déjà vu?”) to free report instructions (e.g. “Indicate whenever you experience déjà vu.”) reduced the total number of reported déjà vu and TOT occurrences. We suggest that research on subjective experiences should move toward free report assessments. Such a shift would potentially reduce the presence of false alarms in experimental work, thereby reducing the overestimation of subjective experiences prevalent in this area of research.     

The Impact of Various Time Intervals on the Supragingival Plaque Dynamic Core Microbiome

ObjectiveThe aim of this study was to examine the influence of various time intervals on the composition of the supragingival plaque microbiome, especially the dynamic core microbiome, and to find a suitable observation interval for further studies on oral microbiota.ResultsA total of 359,565 qualified reads for 64 samples were generated for subsequent analyses, which represents 8,452 operational taxonomic units identified at 3% dissimilarity. The dynamic core microbiome detected in the current study included five phyla, 12 genera and 13 species. At the genus level, the relative abundance of bacterial communities under the “1 day,” “1 month,” and “3 months” intervals was clustered into sub-category. At the species level, the number of overlapping species remained stable between the “1 month” and “3 months” intervals, whereas the number of dynamic core species became stable within only 1 week.ConclusionsThis study emphasized the impact of different time intervals (days, weeks and months) on the composition, commonality and diversity of the supragingival microbiome. The analyses found that for various types of studies, the time interval of a month is more suitable for observing the general composition of the supragingival microbiome, and that a week is better for observing the dynamic core microbiome.     

MET Gene Copy Number Predicts Worse Overall Survival in Patients with Non-Small Cell Lung Cancer (NSCLC); A Systematic Review and Meta-Analysis

Objectives

MET is a receptor present in the membrane of NSCLC cells and is known to promote cell proliferation, survival and migration. MET gene copy number is a common genetic alteration and inhibition o MET emerges as a promising targeted therapy in NSCLC. Here we aim to combine in a meta-analysis, data on the effect of high MET gene copy number on the overall survival of patients with resected NSCLC.

Methods

Two independent investigators applied parallel search strategies with the terms “MET AND lung cancer”, “MET AND NSCLC”, “MET gene copy number AND prognosis” in PubMed through January 2014. We selected the studies that investigated the association of MET gene copy number with survival, in patients who received surgery.

Results

Among 1096 titles that were identified in the initial search, we retrieved 9 studies on retrospective cohorts with adequate retrievable data regarding the prognostic impact of MET gene copy number on the survival of patients with NSCLC. Out of those, 6 used FISH and the remaining 3 used RT PCR to assess the MET gene copy number in the primary tumor. We calculated the I² statistic to assess heterogeneity (I² = 72%). MET gene copy number predicted worse overall survival when all studies were combined in a random effects model (HR = 1.78, 95% CI 1.22–2.60). When only the studies that had at least 50% of adenocarcinoma patients in their populations were included, the effect was significant (five studies, HR 1.55, 95% CI 1.23–1.94). This was not true when we included only the studies with no more than 50% of the patients having adenocarcinoma histology (four studies HR 2.18, 95% CI 0.97–4.90).

Conclusions

Higher MET gene copy number in the primary tumor at the time of diagnosis predicts worse outcome in patients with NSCLC. This prognostic impact may be adenocarcinoma histology specific.     

Relative Impact of Multimorbid Chronic Conditions on Health-Related Quality of Life – Results from the MultiCare Cohort Study

Background

Multimorbidity has a negative impact on health-related quality of life (HRQL). Previous studies included only a limited number of conditions. In this study, we analyse the impact of a large number of conditions on HRQL in multimorbid patients without preselecting particular diseases. We also explore the effects of these conditions on the specific dimensions of HRQL.

Materials and Methods

This analysis is based on a multicenter, prospective cohort study of 3189 multimorbid primary care patients aged 65 to 85. The impact of 45 conditions on HRQL was analysed. The severity of the conditions was rated. The EQ-5D, consisting of 5 dimensions and a visual-analogue-scale (EQ VAS), was employed. Data were analysed using multiple ordinary least squares and multiple logistic regressions. Multimorbidity measured by a weighted count score was significantly associated with lower overall HRQL (EQ VAS), b = −1.02 (SE: 0.06). Parkinson’s disease had the most pronounced negative effect on overall HRQL (EQ VAS), b = −12.29 (SE: 2.18), followed by rheumatism, depression, and obesity. With regard to the individual EQ-5D dimensions, depression (OR = 1.39 to 3.3) and obesity (OR = 1.44 to 1.95) affected all five dimensions of the EQ-5D negatively except for the dimension anxiety/depression. Obesity had a positive effect on this dimension, OR = 0.78 (SE: 0.07). The dimensions “self-care”, OR = 4.52 (SE: 1.37) and “usual activities”, OR = 3.59 (SE: 1.0), were most strongly affected by Parkinson’s disease. As a limitation our sample may only represent patients with at most moderate disease severity.

Conclusions

The overall HRQL of multimorbid patients decreases with an increasing count and severity of conditions. Parkinson’s disease, depression and obesity have the strongest impact on HRQL. Further studies should address the impact of disease combinations which require very large sample sizes as well as advanced statistical methods.     

Is tau ready for admission to the prion club?

Aggregation-prone proteins associated with neurodegenerative disease, such as α synuclein and β amyloid, now appear to share key prion-like features with mammalian prion protein, such as the ability to recruit normal proteins to aggregates and to translocate between neurons. These features may shed light on the genesis of stereotyped lesion development patterns in conditions such as Alzheimer disease and Lewy Body dementia. We discuss the qualifications of tau protein as a possible “prionoid” mediator of lesion spread based on recent characterizations of the secretion, uptake and transneuronal transfer of human tau isoforms in a variety of tauopathy models, and in human patients. In particular, we consider (1) the possibility that prionoid behavior of misprocessed tau in neurodegenerative disease may involve other aggregation-prone proteins, including PrP itself, and (2) whether “prionlike” tau lesion propagation might include mechanisms other than protein-protein templating.     

Comparison of the Laboratory Standard Washing Using CIPAC Washing Agent and the Domestic Washing on Three Recommended Types of Long-Lasting Insecticidal Mosquito Nets

Background

One of the best ways to prevent malaria is the use of insecticide-treated bed nets. Manufacturers pursue easier, safer and more efficient nets. Hence, many studies on the efficacy and wash resistance using World Health Organization standards have been reported. The commonly used detergent is “Savon de Marseille”, because it closely resembles actually used soaps. At the 54^th Collaborative International Pesticides Analytical Council (CIPAC) Technical Meeting in 2010, it was suggested to replace it by a standardized “CIPAC washing agent”. The aim of this study was to investigate the difference between a laboratory hand washing simulation using the CIPAC washing agent (method-1) and a domestic washing (method-2) on different bed nets, as well as the effect of the drying process on the release of active ingredient.

Methods

Interceptor®, Permanet®2.0 and Netprotect® nets were used in three treatments, each repeated 20 times. The first treatment included method-1 washing and indoor drying. The second treatment included method-2 washing and indoor drying. The third treatment used method-2 washing and UV-drying. The residual insecticide contents were determined using gas chromatography.

Results

The washing procedure and the number of washes have a significant effect on the release of active ingredient. Statistically, the two washing methods have the same effect on removing the active ingredient from the Interceptor® and Permanet®2.0 net, but a significantly different influence on the Netprotect® nets. The drying process has no significant effect on the insecticide.

Conclusion

Both washing procedures affected the amount of insecticide remaining on nets independently of the impregnation technology. The active ingredient decreases with the number of washing cycles following an exponential or logarithmic model for coated nets. The laboratory hand washing simulation had more impact on the decrease of active ingredient content of the Netprotect® nets. All net types seemed to be effectively protected against UV-light.     

Substrate Compliance versus Ligand Density in Cell on Gel Responses

Substrate stiffness is emerging as an important physical factor in the response of many cell types. In agreement with findings on other anchorage-dependent cell lineages, aortic smooth muscle cells are found to spread and organize their cytoskeleton and focal adhesions much more so on “rigid” glass or “stiff” gels than on “soft” gels. Whereas these cells generally show maximal spreading on intermediate collagen densities, the limited spreading on soft gels is surprisingly insensitive to adhesive ligand density. Bell-shaped cell spreading curves encompassing all substrates are modeled by simple functions that couple ligand density to substrate stiffness. Although smooth muscle cells spread minimally on soft gels regardless of collagen, GFP-actin gives a slight overexpression of total actin that can override the soft gel response and drive spreading; GFP and GFP-paxillin do not have the same effect. The GFP-actin cells invariably show an organized filamentous cytoskeleton and clearly indicate that the cytoskeleton is at least one structural node in a signaling network that can override spreading limits typically dictated by soft gels. Based on such results, we hypothesize a central structural role for the cytoskeleton in driving the membrane outward during spreading whereas adhesion reinforces the spreading.     

Social media user’s knowledge on soil plant relationship in Saudi Arabia

The study aimed to investigate the soil-plant relationship by looking at knowledge levels of social media users. The study examined the relationship between the users’ characteristics and their knowledge on soil-plant relationship. Online survey was designed and distributed to gather the data. The number of response was received from 383 respondents where 375 participants provided completed information and the remaining eight responses were eliminated due to quality standards. The results show most of the participants (68.8%) are moderately depend on social media to acquire knowledge on soil-plant relationship and indicated “Twitter” as the highly utilized platform followed by the “Youtube”. Meanwhile, 48.8% of the participants indicated that social media have a high impact on their knowledge-based information on soil-plant relationship and agricultural contents. Inferential analysis shows there was a significant positive relationship (p < 0.01) between independent variables; Twitter, Youtube, Instagram, and Snapchat and the degree of trust on these platforms, and the level’s knowledge on soil-plant relationship (dependent variable). Only 13% of the variance accounted for the impact of social media on participants’ agricultural knowledge-base can be predicted from the combination of participants’ reliance on a set of social media platforms (Twitter, Instagram, Youtube, and Snapchat). The study revealed the trust and confidence of the users using social media on agricultural information/soil plant relationship had a medium effect in social and educational research.     

Re-Examination of Globally Flat Space-Time

In the following, we offer a novel approach to modeling the observed effects currently attributed to the theoretical concepts of “dark energy,” “dark matter,” and “dark flow.” Instead of assuming the existence of these theoretical concepts, we take an alternative route and choose to redefine what we consider to be inertial motion as well as what constitutes an inertial frame of reference in flat space-time. We adopt none of the features of our current cosmological models except for the requirement that special and general relativity be local approximations within our revised definition of inertial systems. Implicit in our ideas is the assumption that at “large enough” scales one can treat objects within these inertial systems as point-particles having an insignificant effect on the curvature of space-time. We then proceed under the assumption that time and space are fundamentally intertwined such that time- and spatial-translational invariance are not inherent symmetries of flat space-time (i.e., observable clock rates depend upon both relative velocity and spatial position within these inertial systems) and take the geodesics of this theory in the radial Rindler chart as the proper characterization of inertial motion. With this commitment, we are able to model solely with inertial motion the observed effects expected to be the result of “dark energy,” “dark matter,” and “dark flow.” In addition, we examine the potential observable implications of our theory in a gravitational system located within a confined region of an inertial reference frame, subsequently interpreting the Pioneer anomaly as support for our redefinition of inertial motion. As well, we extend our analysis into quantum mechanics by quantizing for a real scalar field and find a possible explanation for the asymmetry between matter and antimatter within the framework of these redefined inertial systems.     

Publication of Original Research in Urologic Journals – A Neglected Orphan?

The pathophysiologic mechanisms behind urologic disease are increasingly being elucidated. The object of this investigation was to evaluate the publication policies of urologic journals during a period of progressively better understanding and management of urologic disease. Based on the ISI Web of Knowledge Journal Citation Reports and the PubMed database, the number and percentage of original experimental, original clinical, review or commentarial articles published between 2002–2010 in six leading urologic journals were analyzed. “British Journal of Urology International”, “European Urology”, “Urologic Oncology-Seminars and Original Investigations” (“Urologic Oncology”), “Urology”, “The Journal of Urology”, and “World Journal of Urology” were chosen, because these journals publish articles in all four categories. The publication policies of the six journals were very heterogeneous during the time period from 2002 to 2010. The percentage of original experimental and original clinical articles, related to all categories, remained the same in “British Journal of Urology International”, “Urologic Oncology”, “Urology” and “The Journal of Urology”. The percentage of experimental reports in “World Journal of Urology” between 2002–2010 significantly increased from 10 to 20%. A distinct elevation in the percentage of commentarial articles accompanied by a reduction of clinical articles became evident in “European Urology” which significantly correlated with a large increase in the journal’s impact factor. No clearly superior policy could be identified with regard to a general increase in the impact factors from all the journals. The publication policy of urologic journals does not expressly reflect the increase in scientific knowledge, which has occurred over the period 2002–2010. One way of increasing the exposure of urologists to research and expand the interface between experimental and clinical research, would be to enlarge the percentage of experimental articles published. There is no indication that such policy would be detrimental to a journal’s impact factor.     

The Use of the Mercury Inhibition Test in the Recognition of Virulent Strains of Staphylococci in a Hospital Environment

The effect of mercury salts on 200 hospital strains of Staph. pyogenes was investigated. Two methods of performing the mercury inhibition test were compared, and the agar plate technique was found to be the more practical. An attempt was made to correlate the results of the test with antibiotic sensitivity tests, phage patterns and virulence tests. Resistance to mercury was found to be associated with antibiotic resistance, and the majority of the resistant strains were found in the lytic group III. No difference in virulence between mercury-resistant and mercury-sensitive strains could be demonstrated by intracerebral inoculation of mice. The mercury inhibition test may be useful as a screening test for “hospital staphylococci”.