Search

Type 1 diabetes (T1D) is increasing in incidence and predictable with measurement of serum islet autoantibodies (iAb) years prior to clinical disease onset. Identifying iAb positive individuals reduces diabetic ketoacidosis and identifies individuals for T1D prevention trials. However, large scale screening for iAb remains challenging as assays have varying sensitivities and specificities, insulin autoantibodies remain difficult to measure and venipuncture is generally required to obtain serum. We developed an approach to reliably measure all four major iAb, including insulin autoantibodies, from dried blood spots (DBS) on filter-paper. By spiking iAb positive serum into iAb negative whole blood in a dose titration, we optimized the conditions for autoantibody elution from filter paper as measured by fluid phase radioimmunoassays. After assessing stability of measuring iAb from DBS over time, we then screened iAb from DBS and the corresponding serum in new-onset T1D (n = 52), and controls (n = 72) which included first-degree relatives of T1D patients. iAb measured from eluted DBS in new-onset T1D strongly correlated with serum measurements (R2 = 0.96 for mIAA, GADA = 0.94, IA-2A = 0.85, ZnT8A = 0.82, p<0.01 for each autoantibody). There were no false positives in control subjects, and 5/6 with previously unknown iAb positivity in sera were detected using DBS. With further validation, measuring iAb from DBS can be a reliable method to screen for T1D risk. [ABSTRACT FROM AUTHOR]

Moderate-to-severe psoriasis is associated with significant comorbidity, an impaired quality of life, and increased medical costs, including those associated with treatments. Systematic reviews (SRs) and meta-analyses (MAs) of randomized clinical trials are considered two of the best approaches to the summarization of high-quality evidence. However, methodological bias can reduce the validity of conclusions from these types of studies and subsequently impair the quality of decision making. As co-authorship is among the most well-documented forms of research collaboration, the present study aimed to explore whether authors’ collaboration methods might influence the methodological quality of SRs and MAs of psoriasis. Methodological quality was assessed by two raters who extracted information from full articles. After calculating total and per-item Assessment of Multiple Systematic Reviews (AMSTAR) scores, reviews were classified as low (0-4), medium (5-8), or high (9-11) quality. Article metadata and journal-related bibliometric indices were also obtained. A total of 741 authors from 520 different institutions and 32 countries published 220 reviews that were classified as high (17.2%), moderate (55%), or low (27.7%) methodological quality. The high methodological quality subnetwork was larger but had a lower connection density than the low and moderate methodological quality subnetworks; specifically, the former contained relatively fewer nodes (authors and reviews), reviews by authors, and collaborators per author. Furthermore, the high methodological quality subnetwork was highly compartmentalized, with several modules representing few poorly interconnected communities. In conclusion, structural differences in author-paper affiliation network may influence the methodological quality of SRs and MAs on psoriasis. As the author-paper affiliation network structure affects study quality in this research field, authors who maintain an appropriate balance between scientific quality and productivity are more likely to develop higher quality reviews. [ABSTRACT FROM AUTHOR]

Background: Sponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website. Objectives: This study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis. Methods: Available data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy. Results: FDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The “signal” in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical. Conclusion: There was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias). [ABSTRACT FROM AUTHOR]

Objective: Studies suggest that parenteral MTX may be more efficacious than the oral form at equivalent doses for the treatment of rheumatoid arthritis. We carried out a meta-analysis to compare the efficacy of oral versus parenteral MTX in RA. Methods: PubMed, Web of Science and Embase were systematically searched from inception to June 8th 2017 and reviewed following PRISMA 2009 guidelines, by two independent reviewers. To be included, trials had to study adults with RA randomized to the same dose of either oral or parenteral MTX. The primary endpoint was ACR20 at 6 months. Intention-to-treat analysis results were used when possible. Data from direct comparisons between oral and parenteral methotrexate quantitatively analyzed using maximum likelihood random effects meta-analysis. Relative treatment effects were generated as an odds ratio [OR] (OR>1 indicated a benefit for parenteral therapy). Results: The search yielded 357 papers or abstracts. After review of titles or abstracts and full text papers, we found 4 that met inclusion criteria with 703 patients randomized. Dose of MTX started at 15mg/week and increased up to 25mg/week. The summary OR for achieving ACR20 using parenteral vs. oral MTX was 3.02 (95% CI 1.41, 6.46), with no significant difference in the risk for all adverse events. Conclusion: Parenteral MTX therapy had significantly higher odds than oral MTX of achieving reduction in disease activity. We propose that parenteral MTX is more effective than weekly oral MTX; its widespread use may lead to better control of disease and a decrease in demand for biologic agents. [ABSTRACT FROM AUTHOR]

Citation metrics are widely used and misused. We have created a publicly available database of 100,000 top scientists that provides standardized information on citations, h-index, coauthorship-adjusted hm-index, citations to papers in different authorship positions, and a composite indicator. Separate data are shown for career-long and single-year impact. Metrics with and without self-citations and ratio of citations to citing papers are given. Scientists are classified into 22 scientific fields and 176 subfields. Field- and subfield-specific percentiles are also provided for all scientists who have published at least five papers. Career-long data are updated to end of 2017 and to end of 2018 for comparison. [ABSTRACT FROM AUTHOR]

In epidemiology, gerontology, human development and the social sciences, age-period-cohort (APC) models are used to study the variability in trajectories of change over time. A well-known issue exists in simultaneously identifying age, period and birth cohort effects, namely that the three characteristics comprise a perfectly collinear system. That is, since age = period−cohort, only two of these effects are estimable at a time. In this paper, we introduce an alternative framework for considering effects relating to age, period and birth cohort. In particular, instead of directly modeling age in the presence of period and cohort effects, we propose a risk modeling approach to characterize age-related risk (i.e., a hybrid of multiple biological and sociological influences to evaluate phenomena associated with growing older). The properties of this approach, termed risk-period-cohort (RPC), are described in this paper and studied by simulations. We show that, except for pathological circumstances where risk is uniquely determined by age, using such risk indices obviates the problem of collinearity. We also show that the size of the chronological age effect in the risk prediction model associates with the correlation between a risk index and chronological age and that the RPC approach can satisfactorily recover cohort and period effects in most cases. We illustrate the advantages of RPC compared to traditional APC analysis on 27496 individuals from NHANES survey data (2005–2016) to study the longitudinal variability in depression screening over time. Our RPC method has broad implications for examining processes of change over time in longitudinal studies. [ABSTRACT FROM AUTHOR]

Background: In economic analyses of HIV interventions, South Africa is often used as a case in point, due to the availability of good epidemiological and programme data and the global relevance of its epidemic. Few analyses however use locally relevant cost data. We reviewed available cost data as part of the South African HIV Investment Case, a modelling exercise to inform the optimal use of financial resources for the country’s HIV programme. Methods: We systematically reviewed publication databases for published cost data covering a large range of HIV interventions and summarised relevant unit costs (cost per person receiving a service) for each. Where no data was found in the literature, we constructed unit costs either based on available information regarding ingredients and relevant public-sector prices, or based on expenditure records. Results: Only 42 (5%) of 1,047 records included in our full-text review reported primary cost data on HIV interventions in South Africa, with 71% of included papers covering ART. Other papers detailed the costs of HCT, MMC, palliative and inpatient care; no papers were found on the costs of PrEP, social and behaviour change communication, and PMTCT. The results informed unit costs for 5 of 11 intervention categories included in the Investment Case, with the remainder costed based on ingredients (35%) and expenditure data (10%). Conclusions: A large number of modelled economic analyses of HIV interventions in South Africa use as inputs the same, often outdated, cost analyses, without reference to additional literature review. More primary cost analyses of non-ART interventions are needed. [ABSTRACT FROM AUTHOR]

Co-diagnosis of HIV and tuberculosis presents a treatment dilemma. Starting both treatments at the same time can cause a flood of immune response called immune reconstitution inflammatory syndrome (IRIS) which can be lethal. But, how long to delay HIV treatment is less understood. In 2011, based on the conclusions of three separate studies, WHO recommended starting HIV treatment earlier for those with later HIV disease progression. This paper conducts a replication study of one of the three studies, by Havlir and colleagues. Using their publicly available data, we were able to replicate most of the results presented in the original paper. In our measurement and estimation analyses we use different estimation techniques to assess the robustness of the results. We find that adjusting for loss to follow-up does not affect the main results of the paper. However, an ANCOVA estimation and an instrumental variable model weaken the main result of the paper of better outcomes with early HIV treatment only for those who are sicker, reducing significance from the 5% to the 10% level. A change-point analysis also detects no changes in effect by timing of HIV treatment initiation or different thresholds of CD4 count for the primary outcome. This result suggests that the choice of start time for HIV treatment initiation should be based on other factors including potential drug interactions, overlapping side effects, a high pill burden and severity of illness rather than CD4 threshold and preset timeframes. While we caution against overgeneralizing, the result of this replication is aligned with more recent studies that show no evidence that early initiation of HIV treatment reduces mortality for any patients. [ABSTRACT FROM AUTHOR]

Understanding expression levels of proteins and their interactions is a key factor to diagnose and explain the Down syndrome which can be considered as the most prevalent reason of intellectual disability in human beings. In the previous studies, the expression levels of 77 proteins obtained from normal genotype control mice and from trisomic Ts65Dn mice have been analyzed after training in contextual fear conditioning with and without injection of the memantine drug using statistical methods and machine learning techniques. Recent studies have also pointed out that there may be a linkage between the Down syndrome and the immune system. Thus, the research presented in this paper aim at in silico identification of proteins which are significant to the learning process and the immune system and to derive the most accurate model for classification of mice. In this paper, the features are selected by implementing forward feature selection method after preprocessing step of the dataset. Later, deep neural network, gradient boosting tree, support vector machine and random forest classification methods are implemented to identify the accuracy. It is observed that the selected feature subsets not only yield higher accuracy classification results but also are composed of protein responses which are important for the learning and memory process and the immune system. [ABSTRACT FROM AUTHOR]

Cholera rapid diagnostic tests (RDT) could play a central role in outbreak detection and surveillance in low-resource settings, but their modest performance has hindered their broad adoption. The addition of an enrichment step may improve test specificity. We describe the results of a prospective diagnostic evaluation of the Crystal VC RDT (Span Diagnostics, India) with enrichment step and of culture, each compared to polymerase chain reaction (PCR), during a cholera outbreak in South Sudan. RDTs were performed on alkaline peptone water inoculated with stool and incubated for 4–6 hours at ambient temperature. Cholera culture was performed from wet filter paper inoculated with stool. Molecular detection of Vibrio cholerae O1 by PCR was done from dry Whatman 903 filter papers inoculated with stool, and from wet filter paper supernatant. In August and September 2015, 101 consecutive suspected cholera cases were enrolled, of which 36 were confirmed by PCR. The enriched RDT had 86.1% (95% CI: 70.5–95.3) sensitivity and 100% (95% CI: 94.4–100) specificity compared to PCR as the reference standard. The sensitivity of culture versus PCR was 83.3% (95% CI: 67.2–93.6) for culture performed on site and 72.2% (95% CI: 54.8–85.8) at the international reference laboratory, where samples were tested after an average delay of two months after sample collection, and specificity was 98.5% (95% CI: 91.7–100) and 100% (95% CI: 94.5–100), respectively. The RDT with enrichment showed performance comparable to that of culture and could be a sustainable alternative to culture confirmation where laboratory capacity is limited. [ABSTRACT FROM AUTHOR]

Established cell lines are widely used in research, however an appealing question is the comparability of the cells between various laboratories, their characteristics and stability in time. Problematic is also the cell line misidentification, genetic and phenotypic shift or Mycoplasma contamination which are often forgotten in research papers. The monocyte/macrophage-like cell line RAW 264.7 has been one of the most commonly used myeloid cell line for more than 40 years. Despite its phenotypic and functional stability is often discussed in literature or at various scientific discussion panels, their stability during the consecutive passages has not been confirmed in any solid study. So far, only a few functional features of these cells have been studied, for example their ability to differentiate into osteoclasts. Therefore, in the present paper we have investigated the phenotype and functional stability of the RAW 264.7 cell line from passage no. 5 till passage no. 50. We found out that the phenotype (expression of particular macrophage-characteristic genes and surface markers) and functional characteristics (phagocytosis and NO production) of RAW 264.7 cell line remains stable through passages: from passage no. 10 up to passage no. 30. Overall, our results indicated that the RAW 264.7 cell line should not be used after the passage no. 30 otherwise it may influence the data reliability. [ABSTRACT FROM AUTHOR]

Kaempferol (kae) and its glycosides are widely distributed in nature and show multiple bioactivities, yet few reports have compared them. In this paper, we report the antitumor, antioxidant and anti-inflammatory activity differences of kae, kae-7-O-glucoside (kae-7-O-glu), kae-3-O-rhamnoside (kae-3-O-rha) and kae-3-O-rutinoside (kae-3-O-rut). Kae showed the highest antiproliferation effect on the human hepatoma cell line HepG2, mouse colon cancer cell line CT26 and mouse melanoma cell line B16F1. Kae also significantly inhibited AKT phosphorylation and cleaved caspase-9, caspase-7, caspase-3 and PARP in HepG2 cells. A kae-induced increase in DPPH and ABTS radical scavenging activity, inhibition of concanavalin A (Con A)-induced activation of T cell proliferation and NO or ROS production in LPS-induced RAW 264.7 macrophage cells were also seen. Kae glycosides were used to produce kae via environment-friendly enzymatic hydrolysis. Kae-7-O-glu and kae-3-O-rut were hydrolyzed to kae by β-glucosidase and/or α-L-rhamnosidase. This paper demonstrates the application of enzymatic catalysis to obtain highly biologically active kae. This work provides a novel and efficient preparation of high-value flavone-related products. [ABSTRACT FROM AUTHOR]

In a previous paper we showed that the yeast Pichia pastoris X-33 grown in parboiled rice effluent supplemented with glycerol byproduct from the biodiesel industry improved the quality of the effluent. In this paper we show the validation of this yeast (PPE) as probiotic for broilers. Its effect on feed efficiency and immunomodulation was compared with the same yeast grown in yeast peptone dextrose medium (PPY), with Saccharomyces boulardii (SBY) and with the controls fed unsupplemented feed (CON). One-day-old female chicks were vaccinated against infectious bursal disease (IBD) and the titers of anti-IBD antibodies were measured by ELISA. PPE group had the highest mean titres on days 14 and 28 (p<0,05), and at 28 days, 64% of the animals showed seroconvertion. The PPE group also showed the best weight gains at 42 days of age, that, on days 7, 14 and 21 were 19%, 15%, and 8.7% higher, respectively, than the control group. The best feed conversion, 8.2% higher than the control group, was obtained by PPY at 42 days. Histopathological studies did not detect any undesirable effects in the supplemented animals. We concluded that Pichia pastoris X-33 when grown in effluents of the rice parboiling industry supplemented with glycerol byproduct from the biodiesel has probiotic properties for poultry. [ABSTRACT FROM AUTHOR]

Background: Quality improvement collaboratives (QICs) have been used to improve health care for decades. Evidence on QIC effectiveness has been reported, but systematic reviews to date have little information from low- and middle-income countries (LMICs). Objective: To assess the effectiveness of QICs in LMICs. Methods: We conducted a systematic review following Cochrane methods, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for quality of evidence grading, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement for reporting. We searched published and unpublished studies between 1969 and March 2019 from LMICs. We included papers that compared usual practice with QICs alone or combined with other interventions. Pairs of reviewers independently selected and assessed the risk of bias and extracted data of included studies. To estimate strategy effectiveness from a single study comparison, we used the median effect size (MES) in the comparison for outcomes in the same outcome group. The primary analysis evaluated each strategy group with a weighted median and interquartile range (IQR) of MES values. In secondary analyses, standard random-effects meta-analysis was used to estimate the weighted mean MES and 95% confidence interval (CI) of the mean MES of each strategy group. This review is registered with PROSPERO (International Prospective Register of Systematic Reviews): CRD42017078108. Results: Twenty-nine studies were included; most (21/29, 72.4%) were interrupted time series studies. Evidence quality was generally low to very low. Among studies involving health facility-based health care providers (HCPs), for “QIC only”, effectiveness varied widely across outcome groups and tended to have little effect for patient health outcomes (median MES less than 2 percentage points for percentage and continuous outcomes). For “QIC plus training”, effectiveness might be very high for patient health outcomes (for continuous outcomes, median MES 111.6 percentage points, range: 96.0 to 127.1) and HCP practice outcomes (median MES 52.4 to 63.4 percentage points for continuous and percentage outcomes, respectively). The only study of lay HCPs, which used “QIC plus training”, showed no effect on patient care-seeking behaviors (MES -0.9 percentage points), moderate effects on non-care-seeking patient behaviors (MES 18.7 percentage points), and very large effects on HCP practice outcomes (MES 50.4 percentage points). Conclusions: The effectiveness of QICs varied considerably in LMICs. QICs combined with other invention components, such as training, tended to be more effective than QICs alone. The low evidence quality and large effect sizes for QIC plus training justify additional high-quality studies assessing this approach in LMICs. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) induces B-cell proliferation with high efficiency through expression of latent proteins and microRNAs. This process takes place in vivo soon after infection, presumably to expand the virus reservoir, but can also induce pathologies, e.g. an infectious mononucleosis (IM) syndrome after primary infection or a B-cell lymphoproliferation in immunosuppressed individuals. In this paper, we investigated the growth characteristics of EBV-infected B-cells isolated from transplant recipients or patients with IM. We found that these cells grew and withstood apoptosis at highly variable rates, suggesting that the expansion rate of the infected B-cells widely varies between individuals, thereby influencing the size of the B-cell reservoir and the ability to form tumors in infected individuals. All viruses investigated were type 1 and genetically close to western strains. EBV-infected B-cells expressed the transforming EBV latent genes and microRNAs (miRNAs) at variable levels. We found that the B-cell growth rates positively correlated with the BHRF1 miRNA levels. Comparative studies showed that infected B-cells derived from transplant recipients with iEBVL on average expressed higher levels of EBV miR-BHRF1 miRNAs and grew more rapidly than B-cells from IM patients, suggesting infection by more transforming viruses. Altogether, these findings suggest that EBV infection has a highly variable impact on the B-cell compartment that probably reflects the genetic diversity of both the virus and the host. It also demonstrates the unexpected finding that B-cells from different individuals can grow at different speed under the influence of the same virus infection. [ABSTRACT FROM AUTHOR]

Prophylactic interventions such as vaccine allocation are some of the most effective public health policy planning tools. The supply of vaccines, however, is limited and an important challenge is to optimally allocate the vaccines to minimize epidemic impact. This resource allocation question (which we refer to as VID) has multiple dimensions: when, where, to whom, etc. Most of the existing literature in this topic deals with the latter (to whom), proposing policies that prioritize individuals by age and disease risk. However, since seasonal influenza spread has a typical spatial trend, and due to the temporal constraints enforced by the availability schedule, the when and where problems become equally, if not more, relevant. In this paper, we study the VID problem in the context of seasonal influenza spread in the United States. We develop a national scale metapopulation model for influenza that integrates both short and long distance human mobility, along with realistic data on vaccine uptake. We also design GA, a greedy algorithm for allocating the vaccine supply at the state level under temporal constraints and show that such a strategy improves over the current baseline of pro-rata allocation, and the improvement is more pronounced for higher vaccine efficacy and moderate flu season intensity. Further, the resulting strategy resembles a ring vaccination applied spatiallyacross the US. [ABSTRACT FROM AUTHOR]

Objective: Systematic Review was used to evaluate the efficacy and safety of Dalfampridine (DAP) in the treatment of Mobility Disability (MS) in patients with Multiple Sclerosis. Methods: Clinical randomized controlled studies about DAP and placebo in the treatment of Mobility Disability in patients with Multiple Sclerosis until March 2019 were explored by searching Embase, PubMed, Cochrane, Web of Knowledge, and ClinicalTrials.gov. Literature screening, data extraction, quality assessment, and statistical analysis were performed by using Stata 14.0. Results: 10 papers were included in the meta-analysis, and the number of patients was 2100. In conclusion, the application of DAP in clinical can significantly improve the Mobility Disability of patients [OR = 2.73, 95%CI (1.66, 4.50), P<0.001, I2 = 74.1%] and boost the mobility speed of patients in Timing 24 Minute Walk Test (T24FW) [SMD = 3,08, 95%CI(1,58, 4.58), P<0.001, I2 = 98.7%]. There are no significant differences of the incidence of adverse events [RR = 1.06, 95%CI (0.99, 1.14), P = 0.928, I2 = 0.0%] and urinary tract infection [RR = 1.21, 95%CI(0.91, 1.60), P = 0.145, I2 = 37.2%] between the DAP test group (Doses≤10 mg) and the placebo control group, and the incidence of adverse events [RR = 1.14, 95%CI(1.02, 1.28), P = 0.793, I2 = 0.0%] and urinary tract infection[RR = 3.05, 95%CI(1.04, 8.99), P = 0.680, I2 = 0.0%] for the DAP test group (Doses>10 mg) is a litter higher than the placebo control group. Conclusion: DAP can effectively improve Mobility Disability in patients with Multiple Sclerosis, which is safe and reliable in specific DAP usage doses. [ABSTRACT FROM AUTHOR]

The main goal of this paper is to study the effects of (1) trust in government medical experts and (2) proximity to a recent disease outbreak on vaccine propensity. More specifically, we explore how these variables affect attitudes with regards to measles. Using original survey data, collected in January/February 2017, we obtain three main empirical findings. First, contrary to our expectations, an individual’s proximity to a recent measles outbreak has no independent effect on vaccination attitudes. Second, corroborating previous studies in the field, we find that trust in institutions such as the CDC has a positive effect on our dependent variable. Third, there is a significant interactive relationship between proximity and trust in governmental medical experts. While distance from a previous measles outbreak has no effect on vaccination attitudes for respondents with medium or high levels of trust, the variable exerts a negative effect for subjects with little confidence in government medical experts. In other words: low-trust individuals who live farther away from a recent measles outbreak harbor less favorable views about vaccination for this particular disease than low-trust respondents who live close to an affected area. This implies that citizens who are skeptical of the CDC and similar institutions base their vaccination decision-making to some degree on whether or not a given disease occurs in close vicinity to their community. [ABSTRACT FROM AUTHOR]

B-spline functions are widely used in many industrial applications such as computer graphic representations, computer aided design, computer aided manufacturing, computer numerical control, etc. Recently, there exist some demands, e.g. in reverse engineering (RE) area, to employ B-spline curves for non-trivial cases that include curves with discontinuous points, cusps or turning points from the sampled data. The most challenging task in these cases is in the identification of the number of knots and their respective locations in non-uniform space in the most efficient computational cost. This paper presents a new strategy for fitting any forms of curve by B-spline functions via local algorithm. A new two-step method for fast knot calculation is proposed. In the first step, the data is split using a bisecting method with predetermined allowable error to obtain coarse knots. Secondly, the knots are optimized, for both locations and continuity levels, by employing a non-linear least squares technique. The B-spline function is, therefore, obtained by solving the ordinary least squares problem. The performance of the proposed method is validated by using various numerical experimental data, with and without simulated noise, which were generated by a B-spline function and deterministic parametric functions. This paper also discusses the benchmarking of the proposed method to the existing methods in literature. The proposed method is shown to be able to reconstruct B-spline functions from sampled data within acceptable tolerance. It is also shown that, the proposed method can be applied for fitting any types of curves ranging from smooth ones to discontinuous ones. In addition, the method does not require excessive computational cost, which allows it to be used in automatic reverse engineering applications. [ABSTRACT FROM AUTHOR]

Background: To be meaningful, a core outcome set (COS) should be relevant to all stakeholders including patients and carers. This review aimed to explore the methods by which patients and carers have been included as participants in COS development exercises and, in particular, the use and reporting of qualitative methods. Methods: In August 2015, a search of the Core Outcomes Measures in Effectiveness Trials (COMET) database was undertaken to identify papers involving patients and carers in COS development. Data were extracted to identify the data collection methods used in COS development, the number of health professionals, patients and carers participating in these, and the reported details of qualitative research undertaken. Results: Fifty-nine papers reporting patient and carer participation were included in the review, ten of which reported using qualitative methods. Although patients and carers participated in outcome elicitation for inclusion in COS processes, health professionals tended to dominate the prioritisation exercises. Of the ten qualitative papers, only three were reported as a clear pre-designed part of a COS process. Qualitative data were collected using interviews, focus groups or a combination of these. None of the qualitative papers reported an underpinning methodological framework and details regarding data saturation, reflexivity and resource use associated with data collection were often poorly reported. Five papers reported difficulty in achieving a diverse sample of participants and two reported that a large and varied range of outcomes were often identified by participants making subsequent rating and ranking difficult. Conclusions: Consideration of the best way to include patients and carers throughout the COS development process is needed. Additionally, further work is required to assess the potential role of qualitative methods in COS, to explore the knowledge produced by different qualitative data collection methods, and to evaluate the time and resources required to incorporate qualitative methods into COS development. [ABSTRACT FROM AUTHOR]

The collection of immunoglobulin genes in an individual’s germline, which gives rise to B cell receptors via recombination, is known to vary significantly across individuals. In humans, for example, each individual has only a fraction of the several hundred known V alleles. Furthermore, the currently-accepted set of known V alleles is both incomplete (particularly for non-European samples), and contains a significant number of spurious alleles. The resulting uncertainty as to which immunoglobulin alleles are present in any given sample results in inaccurate B cell receptor sequence annotations, and in particular inaccurate inferred naive ancestors. In this paper we first show that the currently widespread practice of aligning each sequence to its closest match in the full set of IMGT alleles results in a very large number of spurious alleles that are not in the sample’s true set of germline V alleles. We then describe a new method for inferring each individual’s germline gene set from deep sequencing data, and show that it improves upon existing methods by making a detailed comparison on a variety of simulated and real data samples. This new method has been integrated into the partis annotation and clonal family inference package, available at , and is run by default without affecting overall run time. [ABSTRACT FROM AUTHOR]

The subset of pro-inflammatory B cells, called late memory, tissue-like or double negative (DN), accumulates in the blood of elderly individuals. Here we show that DN B cells do not proliferate and do not make antibodies to influenza antigens, but they secrete antibodies with autoimmune reactivity, in agreement with their membrane phenotype (CD95+CD21-CD11c+) and their spontaneous expression of the transcription factor T-bet. These cells also increase in the blood of individuals with obesity and autoimmune diseases, but causative mechanisms and signaling pathways involved are known only in part. In the present paper we compare frequencies and metabolic requirements of these cells in the blood of healthy individuals of different ages and in the blood and the subcutaneous adipose tissue (SAT) of individuals with obesity. Results show that DN B cells from young individuals have minimal metabolic requirements, DN B cells from elderly and obese individuals utilize higher amounts of glucose to perform autoimmune antibody production and enroll in aerobic glycolysis to support their function. DN B cells from the SAT have the highest metabolic requirements as they activate oxidative phosphorylation, aerobic glycolysis and fatty acid oxidation. DN B cells from the SAT also show the highest levels of ROS and the highest levels of phosphorylated AMPK (5’-AMP activated kinase) and Sestrin 1, both able to mitigate stress and cell death. This metabolic advantage drives DN B cell survival and function (secretion of autoimmune antibodies). [ABSTRACT FROM AUTHOR]

Streptococcus pneumonia is an important human pathogen that causes various severe diseases such as pneumonia, otitis and meningitis. Vaccination against S. pneumoniae is implemented in many developed countries. The presently used vaccines are safe, well tolerated but relatively expensive and require modification due to the immunological changes of the epidemic strains. This paper describes the development of a new pneumococcal vaccine candidate for immunization on mucosal surfaces. For this purpose the antigens of chimeric protein PSPF, previously suggested for an injectable S. pneumoniae vaccine, were expressed on the surface of the live probiotic strain Enterococcus faecium L3. Experiments on laboratory mice vaccinated with live bacteria demonstrated the appearance of the specific IgA and IgG which provide protection against the lethal S. pneumoniae infection. [ABSTRACT FROM AUTHOR]

Microscopic examination of peripheral blood plays an important role in the field of diagnosis and control of major diseases. Peripheral leukocyte recognition by manual requires medical technicians to observe blood smears through light microscopy, using their experience and expertise to discriminate and analyze different cells, which is time-consuming, labor-intensive and subjective. The traditional systems based on feature engineering often need to ensure successful segmentation and then manually extract certain quantitative and qualitative features for recognition but still remaining a limitation of poor robustness. The classification pipeline based on convolutional neural network is of automatic feature extraction and free of segmentation but hard to deal with multiple object recognition. In this paper, we take leukocyte recognition as object detection task and apply two remarkable object detection approaches, Single Shot Multibox Detector and An Incremental Improvement Version of You Only Look Once. To improve recognition performance, some key factors involving these object detection approaches are explored and the detection models are generated using the train set of 14,700 annotated images. Finally, we evaluate these detection models on test sets consisting of 1,120 annotated images and 7,868 labeled single object images corresponding to 11 categories of peripheral leukocytes, respectively. A best mean average precision of 93.10% and mean accuracy of 90.09% are achieved while the inference time is 53 ms per image on a NVIDIA GTX1080Ti GPU. [ABSTRACT FROM AUTHOR]

Control problem in a biological system is the problem of finding an interventional policy for changing the state of the biological system from an undesirable state, e.g. disease, into a desirable healthy state. Boolean networks are utilized as a mathematical model for gene regulatory networks. This paper provides an algorithm to solve the control problem in Boolean networks. The proposed algorithm is implemented and applied on two biological systems: T-cell receptor network and Drosophila melanogaster network. Results show that the proposed algorithm works faster in solving the control problem over these networks, while having similar accuracy, in comparison to previous exact methods. Source code and a simple web service of the proposed algorithm is available at . [ABSTRACT FROM AUTHOR]

Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies—F4, F6, F7, and F9—are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 μM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development. [ABSTRACT FROM AUTHOR]

Background: The cestode Taenia solium causes the neglected (zoonotic) tropical disease cysticercosis, a leading cause of preventable epilepsy in endemic low and middle-income countries. Transmission models can inform current scaling-up of control efforts by helping to identify, validate and optimise control and elimination strategies as proposed by the World Health Organization (WHO). Methodology/Principal findings: A systematic literature search was conducted using the PRISMA approach to identify and compare existing T. solium transmission models, and related Taeniidae infection transmission models. In total, 28 modelling papers were identified, of which four modelled T. solium exclusively. Different modelling approaches for T. solium included deterministic, Reed-Frost, individual-based, decision-tree, and conceptual frameworks. Simulated interventions across models agreed on the importance of coverage for impactful effectiveness to be achieved. Other Taeniidae infection transmission models comprised force-of-infection (FoI), population-based (mainly Echinococcus granulosus) and individual-based (mainly E. multilocularis) modelling approaches. Spatial structure has also been incorporated (E. multilocularis and Taenia ovis) in recognition of spatial aggregation of parasite eggs in the environment and movement of wild animal host populations. Conclusions/Significance: Gaps identified from examining the wider Taeniidae family models highlighted the potential role of FoI modelling to inform model parameterisation, as well as the need for spatial modelling and suitable structuring of interventions as key areas for future T. solium model development. We conclude that working with field partners to address data gaps and conducting cross-model validation with baseline and longitudinal data will be critical to building consensus-led and epidemiological setting-appropriate intervention strategies to help fulfil the WHO targets. [ABSTRACT FROM AUTHOR]

Background: Asymptomatic Leishmania donovani infections outnumber clinical presentations, however the predictors for development of active disease are not well known. We aimed to identify serological, immunological and genetic markers for progression from L. donovani infection to clinical Visceral Leishmaniasis (VL). Methods: We enrolled all residents >2 years of age in 27 VL endemic villages in Bihar (India). Blood samples collected on filter paper on two occasions 6–12 months apart, were tested for antibodies against L. donovani with rK39-ELISA and DAT. Sero converters, (negative for both tests in the first round but positive on either of the two during the second round) and controls (negative on both tests on both occasions) were followed for three years. At the start of follow-up venous blood was collected for the following tests: DAT, rK39- ELISA, Quantiferon assay, SNP/HLA genotyping and L.donovani specific quantitative PCR. Results: Among 1,606 subjects enrolled,17 (8/476 seroconverters and 9/1,130 controls) developed VL (OR 3.1; 95% CI 1.1–8.3). High DAT and rK39 ELISA antibody titers as well as positive qPCR were strongly and significantly associated with progression from seroconversion to VL with odds ratios of 19.1, 30.3 and 20.9 respectively. Most VL cases arose early (median 5 months) during follow-up. Conclusion: We confirmed the strong association between high DAT and/or rK39 titers and progression to disease among asymptomatic subjects and identified qPCR as an additional predictor. Low predictive values do not warrant prophylactic treatment but as most progressed to VL early during follow-up, careful oberservation of these subjects for at least 6 months is indicated. [ABSTRACT FROM AUTHOR]

Blocking cytokine interleukin 10 (IL-10) at the time of immunisation enhances vaccine induced T cell responses and improves control of tumour cell growth in vivo. However, the effect of an IL-10 blockade on the biological function of macrophages has not been explored. In the current paper, a macrophage precursor cell line, U937 cells, was selected to investigate the differential expression of proteins and relevant cell signalling pathway changes, when stimulated with lipopolysaccharide (LPS) in the presence of antibodies to IL-10 or IL-10 receptor. We used a quantitative proteomic strategy to investigate variations in protein profiles of U937 cells following the treatments with LPS, LPS plus human anti-IL10 antibody and anti-IL10R antibody in 24hrs, respectively. The LPS treatment significantly activated actin-related cell matrix formation and immune response pathways. The addition of anti-IL10 and anti-IL10R antibody further promoted the immune response and potentially effect macrophage survival through PI3K/AKT signalling; however, the latter appeared to also upregulated oncogene XRCC5 and Cajal body associated processes. [ABSTRACT FROM AUTHOR]

Invasive cervical cancer is the most prevalent cancer among women in Sub-Saharan Africa. In 2013, the World Health Organization (WHO) emitted recommendations to start Highly Active Antiretroviral Therapy (HAART) regardless of CD4 count. Although HAART has been shown to reduce the prevalence of high-risk human papillomavirus (HR-HPV) genotypes, it is unclear whether it confers a protective effect specifically for HPV 16. This review summarizes the existing evidence regarding the effect of HAART on HPV 16 infection, as this genotype may not be influenced by immunity level and explores its implications for Sub Saharan Africa. A comprehensive literature review was undertaken and quality assessment was carried out on the selected papers. Four cohort studies and three cross-sectional studies were identified for which the overall quality score assessment ranged from weak/moderate (Score of 1.8) to strong (Score of 3). The evidence yielded by our review was conflicting. Thus, the high heterogeneity between study populations and results did not allow us to draw any firm conclusions as to whether HAART has an impact on HPV 16 acquisition/prevalence. As only three studies were conducted in Africa, there are insufficient grounds for solid comparison between geographic regions. In light of inadequate data, HPV unvaccinated women on HAART should still receive more frequent follow-up. [ABSTRACT FROM AUTHOR]

Objective: Clinical code sets are vital to research using routinely-collected electronic healthcare data. Existing code set engineering methods pose significant limitations when considering reproducible research. To improve the transparency and reusability of research, these code sets must abide by FAIR principles; this is not currently happening. We propose ‘term sets’, an equivalent alternative to code sets that are findable, accessible, interoperable and reusable. Materials and methods: We describe a new code set representation, consisting of natural language inclusion and exclusion terms (term sets), and explain its relationship to code sets. We formally prove that any code set has a corresponding term set. We demonstrate utility by searching for recently published code sets, representing them as term sets, and reporting on the number of inclusion and exclusion terms compared with the size of the code set. Results: Thirty-one code sets from 20 papers covering diverse disease domains were converted into term sets. The term sets were on average 74% the size of their equivalent original code set. Four term sets were larger due to deficiencies in the original code sets. Discussion: Term sets can concisely represent any code set. This may reduce barriers for examining and reusing code sets, which may accelerate research using healthcare databases. We have developed open-source software that supports researchers using term sets. Conclusion: Term sets are independent of clinical code terminologies and therefore: enable reproducible research; are resistant to terminology changes; and are less error-prone as they are shorter than the equivalent code set. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this paper was to describe the time trends in the prevalence of multimorbidity and polypharmacy in Flanders (Belgium) between 2000 and 2015, while controlling for age and sex. Methods: Data were available from Intego, a Flemish-Belgian general practice-based morbidity registration network. The practice population between 2000 and 2015 was used as the denominator, representing a mean of 159,946 people per year. Age and gender-standardised prevalence rates were used for the trends of multimorbidity and polypharmacy in the total population and for subgroups. Joinpoint regression analyses were used to analyse the time trends and breaks in trends, for the entire population as well as for specific age and sex groups. Results: Overall, in 2015, 22.7% of the population had multimorbidity, while the overall prevalence of polypharmacy was 20%. Throughout the study period the standardised prevalence rate of multimorbidity rose for both sexes and in all age groups. The largest relative increase in multimorbidity was observed in the younger age groups (up to the age of 50 years). The prevalence of polypharmacy showed a significant increase between 2000 and 2015 for all age groups except the youngest (0–25 years). Conclusion: For all adult age groups multimorbidity and polypharmacy are frequent, dynamic over time and increasing. This asks for both epidemiological and interventional studies to improve the management of the resulting complex care. [ABSTRACT FROM AUTHOR]

We generalize the notion of λ-superstrings, presented in a previous paper, to the notion of weighted λ-superstrings. This generalization entails an important improvement in the applications to vaccine designs, as it allows epitopes to be weighted by their immunogenicities. Motivated by these potential applications of constructing short weighted λ-superstrings to vaccine design, we approach this problem in two ways. First, we formalize the problem as a combinatorial optimization problem (in fact, as two polynomially equivalent problems) and develop an integer programming (IP) formulation for solving it optimally. Second, we describe a model that also takes into account good pairwise alignments of the obtained superstring with the input strings, and present a genetic algorithm that solves the problem approximately. We apply both algorithms to a set of 169 strings corresponding to the Nef protein taken from patiens infected with HIV-1. In the IP-based algorithm, we take the epitopes and the estimation of the immunogenicities from databases of experimental epitopes. In the genetic algorithm we take as candidate epitopes all 9-mers present in the 169 strings and estimate their immunogenicities using a public bioinformatics tool. Finally, we used several bioinformatic tools to evaluate the properties of the candidates generated by our method, which indicated that we can score high immunogenic λ-superstrings that at the same time present similar conformations to the Nef virus proteins. [ABSTRACT FROM AUTHOR]

Background: In 2015, the World Health Organization (WHO) updated the global methodology for assessing and reducing missed opportunities for vaccination (MOV), when eligible children have contact with the health system but are not vaccinated. This paper presents the results of two pilot assessments conducted in Chad and Malawi. Methods: Using the ten-step global WHO MOV strategy, we purposively selected districts and health facilities, with non-probabilistic sampling of <24 month old children for exit interviews of caregivers and self-administered knowledge, attitudes, and practices (KAP) surveys of health workers. MOV were calculated based on a child’s documented vaccination history (i.e., from a home-based record (HBR) or a health facility vaccination register), including selected vaccines in the national schedule. Results: Respondents included caregivers of 353 children in Chad and of 580 children in Malawi. Among those with documented vaccination history, 82% (195/238) were eligible for vaccination in Chad and 47% (225/483) in Malawi. Among eligible children, 51% (99/195) in Chad, and 66% (149/225) in Malawi had one or more MOV on the survey date. During non-vaccination visits, 77% (24/31) of children eligible for vaccination in Chad and 92% (119/129) in Malawi had a MOV compared to 46% (75/164) and 31% (30/96) during vaccination visits, respectively. Among health workers, 92% in Chad and 88% in Malawi were unable to correctly identify valid contraindications for vaccination. Conclusion: The new MOV tool was able to characterize the type and potential causes of MOV. In both countries, the findings of the assessments point to two major barriers to full vaccination of eligible children—a lack of coordination between vaccination and curative health services and incomplete vaccination during vaccination visits. National immunization programs should explore tailored efforts to improve health worker practices and to increase vaccine delivery by making better use of existing health service contacts. [ABSTRACT FROM AUTHOR]

Background: Naja annulifera is a medically important venomous snake occurring in some of the countries in Sub-Saharan Africa. Accidental bites result in severe coagulation disturbances, systemic inflammation and heart damage, as reported in dogs, and death, by respiratory arrest, in humans. Despite the medical importance of N. annulifera, little is known about its venom composition and the pathogenesis of envenomation. In this paper, the toxic, inflammatory and immunogenic properties of N. annulifera venom were analyzed. Methodology/Principal findings: Venom proteomic analysis identified 79 different proteins, including Three Finger Toxins, Cysteine Rich Secretory Proteins, Metalloproteinases, Phospholipases A2 (PLA2), Hyaluronidase, L-amino-acid oxidase, Cobra Venom Factor and Serine Proteinase. The presence of PLA2, hyaluronidase, fibrinogenolytic and anticoagulant activities was detected using functional assays. The venom was cytotoxic to human keratinocytes. In an experimental murine model of envenomation, it was found that the venom induced local changes, such as swelling, which was controlled by anti-inflammatory drugs. Moreover, the venom caused death, which was preceded by systemic inflammation and pulmonary hemorrhage. The venom was shown to be immunogenic, inducing a strong humoral immune response, with the production of antibodies able to recognize venom components with high molecular weight and to neutralize its lethal activity. Conclusions/Significance: The results obtained in this study demonstrate that N. annulifera venom contains toxins able to induce local and systemic inflammation, which can contribute to lung damage and death. Moreover, the venom is immunogenic, an important feature that must be considered during the production of a therapeutic anti-N. annulifera antivenom. [ABSTRACT FROM AUTHOR]

Background: Although empirical evidence suggests that the adherence club model is more effective in retaining people living with HIV in antiretroviral treatment care and sustaining medication adherence compared to standard clinic care, it is poorly understood exactly how and why this works. In this paper, we examined and made explicit how, why and for whom the adherence club model works at a public health facility in South Africa. Methods: We applied an explanatory theory-building case study approach to examine the validity of an initial programme theory developed a priori. We collected data using a retrospective cohort quantitative design to describe the suppressive adherence and retention in care behaviours of patients on ART using Kaplan-Meier methods. In conjunction, we employed an explanatory qualitative study design using non-participant observations and realist interviews to gain insights into the important mechanisms activated by the adherence club intervention and the relevant contextual conditions that trigger the different mechanisms to cause the observed behaviours. We applied the retroduction logic to configure the intervention-context-actor-mechanism-outcome map to formulate generative theories. Results: A modified programme theory involving targeted care for clinically stable adult patients (18 years+) receiving antiretroviral therapy was obtained. Targeted care involved receiving quick, uninterrupted supply of antiretroviral medication (with reduced clinic visit frequencies), health talks and counselling, immediate access to a clinician when required and guided by club rules and regulations within the context of adequate resources, and convenient (size and position) space and proper preparation by the club team. When grouped for targeted care, patients feel nudged, their self-efficacy is improved and they become motivated to adhere to their medication and remain in continuous care. Conclusion: This finding has implications for understanding how, why and under what health system conditions the adherence club intervention works to improve its rollout in other contexts. [ABSTRACT FROM AUTHOR]

Agent-based models are a tool that can be used to better understand the dynamics of an infectious disease outbreak. An infectious disease outbreak is influenced by many factors including vaccination or immunity levels, population density, and the age structure of the population. We hypothesize that these factors along with interactions of factors and the actions of individuals would lead to outbreaks of different size and severity even in two towns that appear similar on paper. Thus, it is necessary to implement a model that is able to capture these interactions and the actions of individuals. Using openly available data we create a data-driven agent-based model to simulate the spread of an airborne infectious disease in an Irish town. Agent-based models have been known to produce results that include the emergence of patterns and behaviours that are not directly programmed into the model. Our model is tested by simulating an outbreak of measles that occurred in Schull, Ireland in 2012. We simulate the same outbreak in 33 different towns and look at the correlations between the model results and the town characteristics (population, area, vaccination rates, age structure) to determine if the results of the model are affected by interactions of those town characteristics and the decisions on the agents in the model. As expected our results show that the outbreaks are not strongly correlated with any of the main characteristics of the towns and thus the model is most likely capturing such interactions and the agent-based model is successful in capturing the differences in the outbreaks. [ABSTRACT FROM AUTHOR]

With the HIV-1 epidemic in southern Africa still rising, a prophylactic vaccine against the region’s most prolific subtype (subtype C) would be a significant step forward. In this paper we report on the effect of 2 different adjuvants, AddaVax and AlhydroGel, formulated with HIV-1 subtype C gp140, on the development of binding and neutralising antibody titres in rabbits. AddaVax is a squalene-based oil-in-water nano-emulsion (similar to MF59) which can enhance both cellular and humoral immune responses, whilst AlhydroGel (aluminium hydroxide gel) mainly drives a Th2 response. The gp140 gene tested was derived from the superinfecting virus (SU) from participant CAP256 in the CAPRISA 002 Acute infection cohort. The furin cleavage site of the Env protein was replaced with a flexible linker and an I559P mutation introduced. Lectin affinity purified soluble Env protein was mainly trimeric as judged by molecular weight using BN-PAGE and contained intact broadly neutralising epitopes for the V3-glycan supersite (monoclonal antibodies PGT128 and PGT135), the CD4 binding site (VRC01) and the V2-glycan (PG9) but not for the trimer-specific monoclonal antibodies PG16, PGT145 and CAP256-VRC26_08. When this soluble Env protein was tested in rabbits, AlhydroGel significantly enhanced soluble Env and V1V2 binding antibodies when compared to AddaVax. Finally, AlhydroGel resulted in significantly higher neutralization titres for a subtype C Tier 1A virus (MW965.26) and increased neutralization breadth to Tier 1A and 1B viruses. However, no autologous Tier 2 neutralisation was observed. These data suggest that adjuvant selection is critical for developing a successful vaccine and AlhydroGel should be further investigated. Additional purification of trimeric native-like CAP256 Env and/or priming with DNA or MVA might enhance the induction of neutralizing antibodies and possible Tier 2 HIV-1 neutralisation. [ABSTRACT FROM AUTHOR]

Plasma cell segmentation is the first stage of a computer assisted automated diagnostic tool for multiple myeloma (MM). Owing to large variability in biological cell types, a method for one cell type cannot be applied directly on the other cell types. In this paper, we present PCSeg Tool for plasma cell segmentation from microscopic medical images. These images were captured from bone marrow aspirate slides of patients with MM. PCSeg has a robust pipeline consisting of a pre-processing step, the proposed modified multiphase level set method followed by post-processing steps including the watershed and circular Hough transform to segment clusters of cells of interest and to remove unwanted cells. Our modified level set method utilizes prior information about the probability densities of regions of interest (ROIs) in the color spaces and provides a solution to the minimal-partition problem to segment ROIs in one of the level sets of a two-phase level set formulation. PCSeg tool is tested on a number of microscopic images and provides good segmentation results on single cells as well as efficient segmentation of plasma cell clusters. [ABSTRACT FROM AUTHOR]

Cystectomy is the removal of all or part of the urinary bladder. It has been observed that there is significant regrowth of the bladder after partial cystectomy and this has been proposed to be through regeneration of the organ. Regrowth of tissue in mammals has been proposed to involve compensatory mechanisms that share many characteristics of true regeneration, like the growth of specialized structures such as blood vessels or nerves. However, the overall structure of the normal organ is not achieved. Here we tested if bladder growth after subtotal cystectomy (STC, removal of 50% of the bladder) was compensatory or regenerative. To do this we subjected adult female mouse bladders to STC and assessed regrowth using several established cellular parameters including histological, gene expression, cytokine accumulation and cell proliferation studies. Bladder function was analyzed using cystometry and the voiding stain on paper (VSOP) technique. We found that STC bladders were able to increase their ability to hold urine with the majority of volume restoration occurring within the first two weeks. Regenerating bladders had thinner walls with less mean muscle thickness, and they showed increased collagen deposition at the incision as well as throughout the bladder wall suggesting that fibrosis was occurring. Cell populations differed in their response to injury with urothelial regeneration complete by day 7, but stromal and detrusor muscle still incomplete after 8wks. Cells incorporated EdU when administered at the time of surgery and tracing of EdU positive cells over time indicated that many newborn cells originate at the incision and move mediolaterally. Basal urothelial cells and bladder mesenchymal stem cells but not smooth muscle cells significantly incorporated EdU after STC. Since anti-inflammatory cytokines play a role in regeneration, we analyzed expressed cytokines and found that no anti-inflammatory cytokines were present in the bladder 1wk after STC. Our findings suggest that bladder regrowth after cystectomy is compensatory and functions to increase the volume that the bladder can hold. This finding sets the stage for understanding how the bladder responds to cystectomy and how this can be improved in patients after suffering bladder injury. [ABSTRACT FROM AUTHOR]

Measles is a highly transmissible disease and is one of the leading causes of death among young children under 5 globally. While the use of ongoing surveillance data and—recently—dynamic models offer insight on measles dynamics, both suffer notable shortcomings when applied to measles outbreak prediction. In this paper, we apply the Sequential Monte Carlo approach of particle filtering, incorporating reported measles incidence for Saskatchewan during the pre-vaccination era, using an adaptation of a previously contributed measles compartmental model. To secure further insight, we also perform particle filtering on an age structured adaptation of the model in which the population is divided into two interacting age groups—children and adults. The results indicate that, when used with a suitable dynamic model, particle filtering can offer high predictive capacity for measles dynamics and outbreak occurrence in a low vaccination context. We have investigated five particle filtering models in this project. Based on the most competitive model as evaluated by predictive accuracy, we have performed prediction and outbreak classification analysis. The prediction results demonstrate that this model could predict measles outbreak evolution and classify whether there will be an outbreak or not in the next month (Area under the ROC Curve of 0.89). We conclude that anticipating the outbreak dynamics of measles in low vaccination regions by applying particle filtering with simple measles transmission models, and incorporating time series of reported case counts, is a valuable technique to assist public health authorities in estimating risk and magnitude of measles outbreaks. It is to be emphasized that particle filtering supports estimation of (via sampling from) the entire state of the dynamic model—both latent and observable—for each point in time. Such approach offers a particularly strong value proposition for other pathogens with little-known dynamics, critical latent drivers, and in the context of the growing number of high-velocity electronic data sources. Strong additional benefits are also likely to be realized from extending the application of this technique to highly vaccinated populations. [ABSTRACT FROM AUTHOR]

B cells develop high affinity receptors during the course of affinity maturation, a cyclic process of mutation and selection. At the end of affinity maturation, a number of cells sharing the same ancestor (i.e. in the same “clonal family”) are released from the germinal center; their amino acid frequency profile reflects the allowed and disallowed substitutions at each position. These clonal-family-specific frequency profiles, called “substitution profiles”, are useful for studying the course of affinity maturation as well as for antibody engineering purposes. However, most often only a single sequence is recovered from each clonal family in a sequencing experiment, making it impossible to construct a clonal-family-specific substitution profile. Given the public release of many high-quality large B cell receptor datasets, one may ask whether it is possible to use such data in a prediction model for clonal-family-specific substitution profiles. In this paper, we present the method “Substitution Profiles Using Related Families” (SPURF), a penalized tensor regression framework that integrates information from a rich assemblage of datasets to predict the clonal-family-specific substitution profile for any single input sequence. Using this framework, we show that substitution profiles from similar clonal families can be leveraged together with simulated substitution profiles and germline gene sequence information to improve prediction. We fit this model on a large public dataset and validate the robustness of our approach on two external datasets. Furthermore, we provide a command-line tool in an open-source software package () implementing these ideas and providing easy prediction using our pre-fit models. [ABSTRACT FROM AUTHOR]

Anisakis simplex spp. sensitization rates have increased worldwide, with a significant impact on health-care systems. To date, no clear-cut diagnostic criteria and laboratory algorithm have been established, so anisakiasis still represents an under-reported health problem whose clinical manifestations, when present, mimic the much more common allergic and digestive disorders. Aim of the study was to systematically review the available literature on the prevalence of sensitization against Anisakis in the general population and in specific population groups, taking into account the impact of the different available diagnostic techniques on the epidemiological data. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, relevant papers reporting Anisakis sensitization epidemiological data were found covering a period ranging from 1996 to February 2017. Overall, 41 studies comprising 31,701 participants from eleven countries were included in the qualitative synthesis. General asymptomatic population resulted sensitized to Anisakis in 0.4 to 27.4% of cases detected by means of indirect ELISA or ImmunoCAP specific IgE detection, and between 6.6% and 19.6% of the samples by Skin prick test (SPT). Occupationally exposed workers (fishermen, fishmongers and workers of fish-processing industries) documented specific IgE between 11.7% and 50% of cases, whereas SPT positivity ranged between 8% and 46.4%. Symptomatic allergic patients to any kind of allergen were found to be positive to Anisakis specific IgE detection between 0.0% (in children with mastocytosis) to 81.3% (among adults with shellfish allergy). Results highlighted that hypersensitivity prevalence estimates varied widely according to geographical area, characteristics of the population studied, diagnostic criteria and laboratory assays. Further studies are needed to overcome the documented misdiagnosis by improving the diagnostic approach and, consequently, providing more affordable estimates in order to address public health interventions on populations at high risk of exposure to Anisakis and to tailor health services related to specific groups. [ABSTRACT FROM AUTHOR]

In palynology, the visual classification of pollen grains from different species is a hard task which is usually tackled by human operators using microscopes. Its complete automatization would save a high quantity of resources and provide valuable improvements especially for allergy-related information systems, but also for other application fields as paleoclimate reconstruction, quality control of honey based products, collection of evidences in criminal investigations or fabric dating and tracking. This paper presents three state-of-the-art deep learning classification methods applied to the recently published POLEN23E image dataset. The three methods make use of convolutional neural networks: the first one is strictly based on the idea of transfer learning, the second one is based on feature extraction and the third one represents a hybrid approach, combining transfer learning and feature extraction. The results from the three methods are indeed very good, reaching over 97% correct classification rates in images not previously seen by the models, where other authors reported around 70. [ABSTRACT FROM AUTHOR]

Case-control Genome-Wide Association Studies (GWAS) provide a rich resource for studying the genetic architecture of complex diseases. A key is to elucidate how the genetic effects vary by the environment, what is traditionally defined by Gene-Environment interactions (GxE). The overlooked complication is that multiple, distinct pathophysiologic mechanisms may lead to the same clinical diagnosis and often these mechanisms have distinct genetic bases. In this paper, we first show that using the clinically diagnosed status can lead to severely biased estimates of GxE interactions in situations when the frequency of the pathologic diagnosis of interest, as compared to other diagnoses, depends on the environment. We then propose a pseudo-likelihood solution to correct the bias. Finally, we demonstrate our method in extensive simulations and in a GWAS of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Background: Making inferences about measles distribution patterns at small area level is vital for more focal targeted intervention. However, in statistical literature, the analysis of originally collected data on one resolution with the purpose to make inferences on a different level of spatial resolution is referred to as the misalignment problem. In Namibia the measles data were available in aggregated format at regional level for the period 2005 to 2014. This leads to a spatial misalignment problem if the purpose is to make decisions at constituency level. Moreover, although data on risk covariates of measles could be obtained at constituency level, they were not available each year between 2005 and 2014. Thus, assuming that covariates were constant through the study period would induce measurement errors which might have effects on the analysis results. This paper presents a spatio-temporal model through a multi-step approach in order to deal with misalignment and measurement error. Methods: For the period 2005–2014, measles data from the Ministry of Health and Social Services (MoHSS) were analysed in two steps. First, a multi-step approach was applied to correct spatial misalignment in the data. Second, a classical measurement error model was fitted to account for measurement errors. The time effects were specified using a nonparametric formulation for the linear trend through first order random walk. An interaction between area and time was modelled through type I and type II interaction structures. Results: The study showed that there was high variation in measles risk across constituencies and as well as over the study period (2005–2014). Furthermore, the risk of measles was found to be associated with (i) the number of people aged between 0 and 24 years, (ii) the percentages of women aged 15–49 with an educational level more than secondary, (iii) the percentages of children age 12–23 months who received measles vaccine, (iv) the percentages of malnourished children under 5 years, and (vi) the measles cases for each previous year. Conclusion: The study showed some of the determinants of measles risk and revealed areas at high risk through disease mapping. Additionally, the study showed a non-linear temporal distribution of measles risk over the study period. Finally, it was shown that ignoring the measurement errors may yield misleading results. It was recommended that group and geographically targeted intervention, prevention and control strategies can be tailored on the basis these findings. [ABSTRACT FROM AUTHOR]

Background & Aims: Extended esophageal endoscopic submucosal dissection (ESD) is highly responsible for esophageal stricture. We conducted a comparative study in a porcine model to evaluate the effectiveness of adipose tissue-derived stromal cell (ADSC) double cell sheet transplantation. Methods: Twelve female pigs were treated with 5 cm long hemi-circumferential ESD and randomized in two groups. ADSC group (n = 6) received 4 double cell sheets of allogenic ADSC on a paper support membrane and control group (n = 6) received 4 paper support membranes. ADSC were labelled with PKH-67 fluorophore to allow probe-based confocal laser endomicroscopie (pCLE) monitoring. After 28 days follow-up, animals were sacrificed. At days 3, 14 and 28, endoscopic evaluation with pCLE and esophagography were performed. Results: One animal from the control group was excluded (anesthetic complication). Animals from ADSC group showed less frequent alimentary trouble (17% vs 80%; P = 0.08) and higher gain weight on day 28. pCLE demonstrated a compatible cell signal in 4 animals of the ADSC group at day 3. In ADSC group, endoscopy showed that 1 out of 6(17%) animals developed a severe esophageal stricture comparatively to 100% (5/5) in the control group; P = 0.015. Esophagography demonstrated a decreased degree of stricture in the ADSC group on day 14 (44% vs 81%; P = 0.017) and day 28 (46% vs 90%; P = 0.035). Histological analysis showed a decreased fibrosis development in the ADSC group, in terms of surface (9.7 vs 26.1 mm²; P = 0.017) and maximal depth (1.6 vs 3.2 mm; P = 0.052). Conclusion: In this model, transplantation of allogenic ADSC organized in double cell sheets after extended esophegeal ESD is strongly associated with a lower esophageal stricture’s rate. [ABSTRACT FROM AUTHOR]

Current estimates of the HIV epidemic indicate a decrease in the incidence of the disease in the undiagnosed subpopulation over the past 10 years. However, a lack of access to care has not been considered when modeling the population. Populations at high risk for contracting HIV are twice as likely to lack access to reliable medical care. In this paper, we consider three contributors to the HIV population dynamics: at-risk population exhaustion, lack of access to care, and usage of anti-retroviral therapy (ART) by diagnosed individuals. An extant problem in the mathematical study of this system is deriving parameter estimates due to a portion of the population being unobserved. We approach this problem by looking at the proportional change in the infected subpopulations. We obtain conservative estimates for the proportional change of the infected subpopulations using hierarchical Bayesian statistics. The estimated proportional change is used to derive epidemic parameter estimates for a system of stochastic differential equations (SDEs). Model fit is quantified to determine the best parametric explanation for the observed dynamics in the infected subpopulations. Parameter estimates derived using these methods produce simulations that closely follow the dynamics observed in the data, as well as values that are generally in agreement with prior understanding of transmission and diagnosis rates. Simulations suggest that the undiagnosed population may be larger than currently estimated without significantly affecting the population dynamics. [ABSTRACT FROM AUTHOR]

Triticum vulgare has been extensively used in traditional medicine thanks to its properties of accelerating tissue repair. The specific extract of Triticum vulgare manufactured by Farmaceutici Damor (TVE-DAMOR) is already present in some pharmaceutical formulations used in the treatment of decubitus ulcers, skin lesions and burns. It has been recently suggested that this Triticum vulgare extract may possess potential anti-inflammatory properties. In the light of these premises the aim of the present paper was to verify the anti-inflammatory role of TVE, using the LPS-stimulated microglia model of inflammation. In particular the effect of different concentrations of TVE on the release of several mediators of inflammation such as nitric oxide, IL-6, PGE2 and TNF alpha was evaluated. More important, the anti-inflammatory effect of TVE was confirmed also in primary rat microglia cultures. The results of the present study show that TVE exerts anti-inflammatory properties since it reduces the release of all the evaluated markers of inflammation, such as NO, IL6, TNF alpha and PGE2 in LPS-activated BV2 microglial cells. Intriguingly, TVE reduced microglia activation and NO release also in primary microglia. Indeed, to verify the pathway of modulation of the inflammatory markers reported above, we found that TVE restores the cytoplasmic expression of p65 protein, kwown as specific marker associated with activation of inflammatory response. The evidence for an inhibitory activity on inflammation of this specific extract of Triticum vulgare may open the way to the possibility of a therapeutical use of the Triticum vulgare extract as an anti-inflammatory compound in certain pathological states such as burns, decubitus ulcers, folliculitis and inflammation of peripheral nerve. [ABSTRACT FROM AUTHOR]

Titanium (Ti) and Ti-6 Aluminium-4 Vanadium alloys are the most common materials in implants composition but β type alloys are promising biomaterials because they present better mechanical properties. Besides the composition of biomaterial, many factors influence the performance of the biomaterial. For example, porous surface may modify the functional cellular response and accelerate osseointegration. This paper presents in vitro and in vivo evaluations of powder metallurgy-processed porous samples composed by different titanium alloys and pure Ti, aiming to show their potential for biomedical applications. The porous surfaces samples were produced with different designs to in vitro and in vivo tests. Samples were characterized with scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and elastic modulus analyses. Osteogenic cells from newborn rat calvaria were plated on discs of different materials: G1—commercially pure Ti group (CpTi); G2—Ti-6Al-4V alloy; G3—Ti-13 Niobium-13 Zirconium alloy; G4—Ti-35 Niobium alloy; G5—Ti-35 Niobium-7 Zirconium-5 Tantalum alloy. Cell adhesion and viability, total protein content, alkaline phosphatase activity, mineralization nodules and gene expression (alkaline phosphatase, Runx-2, osteocalcin and osteopontin) were assessed. After 2 and 4 weeks of implantation in rabbit tibia, bone ingrowth was analyzed using micro-computed tomography (μCT). EDS analysis confirmed the material production of each group. Metallographic and SEM analysis revealed interconnected pores, with mean pore size of 99,5μm and mean porosity of 42%, without significant difference among the groups (p>0.05). The elastic modulus values did not exhibit difference among the groups (p>0.05). Experimental alloys demonstrated better results than CpTi and Ti-6Al-4V, in gene expression and cytokines analysis, especially in early experimental periods. In conclusion, our data suggests that the experimental alloys can be used for biomedical application since they contributed to excellent cellular behavior and osseointegration besides presenting lower elastic modulus. [ABSTRACT FROM AUTHOR]