Background: Vaccines are one of the most important public health successes in last century. Besides effectiveness in reducing the morbidity and mortality from many infectious diseases, a successful vaccine program also requires a rigorous assessment on their safety. Due to the limitations of adverse event (AE) data from clinical trials and post-approval surveillance systems, novel computational approaches are needed to organize, visualize, and analyze such high-dimensional complex data. Results: In this paper, we proposed a network-based approach to investigate the vaccine-AE association network from the Vaccine AE Reporting System (VAERS) data. Statistical summary was calculated using the VAERS raw data and represented in the Resource Description Framework (RDF). The RDF graph was leveraged for network analysis. Specifically, we compared network properties of (1) vaccine - adverse event association network based on reports collected over a 23 year period as well as each year; and (2) sex-specific vaccine-adverse event association network. We observed that (1) network diameter and average path length don’t change dramatically over a 23-year period, while the average node degree of these networks changes due to the different number of reports during different periods of time; (2) vaccine - adverse event associations derived from different sexes show sex-associated patterns in sex-specific vaccine-AE association networks. Conclusions: We have developed a network-based approach to investigate the vaccine-AE association network from the VAERS data. To our knowledge, this is the first time that a network-based approach was used to identify sex-specific association patterns in a spontaneous reporting system database. Due to unique limitations of such passive surveillance systems, our proposed network-based approaches have the potential to summarize and analyze the associations in passive surveillance systems by (1) identifying nodes of importance, irrespective of whether they are disproportionally reported; (2) providing guidance on sex-specific recommendations in personalized vaccinology.
In female m ammals, one of the two X chromosomes in each cell is transcriptionally silenced in order to achieve dosage compensation between the genders in a process called X chromosome inactivation. The master regulator of this process is the long non-coding RNA Xist. During X-inactivation, Xist accumulates in cis on the future inactive X chromosome, triggering a cascade of events that provoke the stable silencing of the entire chromosome, with relatively few genes remaining active. How Xist spreads, what are its binding sites, how it recruits silencing factors and how it induces a specific topological and nuclear organization of the chromatin all remain largely unanswered questions. Recent studies have improved our understanding of Xist localization and the proteins with which it interacts, allowing a reappraisal of ideas about Xist function. We discuss recent advances in our knowledge of Xist-mediated silencing, focusing on Xist spreading, the nuclear organization of the inactive X chromosome, recruitment of the polycomb complex and the role of the nuclear matrix in the process of X chromosome inactivation.
Background: Autopsy studies of HIV/AIDS-related hospital deaths in sub-Saharan Africa reveal frequent failure of pre-mortem diagnosis of tuberculosis (TB), which is found in 34–64 % of adult cadavers. We determined the overall prevalence and predictors of TB among consecutive unselected HIV-positive adults requiring acute hospital admission and the comparative diagnostic yield obtained by screening urine and sputum samples obtained on day 1 of admission with Xpert MTB/RIF (Xpert). Methods: To determine overall TB prevalence accurately, comprehensive clinical sampling (sputum, urine, blood plus other relevant samples) was done and TB was defined by detection of Mycobacterium tuberculosis in any sample using Xpert and/or mycobacterial liquid culture. To evaluate a rapid screening strategy, we compared the diagnostic yield of Xpert testing sputum samples and urine samples obtained with assistance from a respiratory study nurse in the first 24 h of admission. Results: Unselected HIV-positive acute adult new medical admissions (n = 427) who were not receiving TB treatment were enrolled irrespective of clinical presentation or symptom profile. From 2,391 cultures and Xpert tests done (mean, 5.6 tests/patient) on 1,745 samples (mean, 4.1 samples/patient), TB was diagnosed in 139 patients (median CD4 cell count, 80 cells/μL). TB prevalence was very high (32.6 %; 95 % CI, 28.1–37.2 %; 139/427). However, patient symptoms and risk factors were poorly predictive for TB. Overall, ≥1 non-respiratory sample(s) tested positive in 115/139 (83 %) of all TB cases, including positive blood cultures in 41/139 (29.5 %) of TB cases. In the first 24 h of admission, sputum (spot and/or induced samples) and urine were obtainable from 37.0 % and 99.5 % of patients, respectively (P <0.001). From these, the proportions of total TB cases (n = 139) that were diagnosed by Xpert testing sputum, urine or both sputum and urine combined within the first 24 h were 39/139 (28.1 %), 89/139 (64.0 %) and 108/139 (77.7 %) cases, respectively (P <0.001). Conclusions: The very high prevalence of active TB and its non-specific presentation strongly suggest the need for routine microbiological screening for TB in all HIV-positive medical admissions in high-burden settings. The incremental diagnostic yield from Xpert testing urine was very high and this strategy might be used to rapidly screen new admissions, especially if sputum is difficult to obtain.
Background: Non-adherence to Antiretroviral Treatment (ART) is strongly associated with virologic rebound and drug resistance. Studies have shown that the most frequently mentioned reason for missing ART doses is the forgetfulness of patients to take their medications on time. Therefore using communication devices as reminder tools, for example alarms, pagers, text messages and telephone calls could improve adherence to ART. The aim of this study is to measure access to cellphones, willingness to receive text message medication reminders and to identify associated factors of ART patients at the University of Gondar Hospital, in North West Ethiopia. Methods: An institution based cross sectional quantitative study was conducted among 423 patients on ART during April 2014. Data were collected using structured interviewer-administered questionnaires. Data entry and analysis were done using Epi-Info version 7 and SPSS version 20 respectively. Descriptive statistics and multivariable logistic regression analysis were used to describe the characteristic of the sample and identify factors associated with the willingness to receive text message medication reminders. Results: A total of 415 (98 % response rate) respondents participated in the interview. The majority of respondents 316 (76.1 %) owned a cellphone, and 161(50.9 %) were willing to receive text message medication reminders. Positively associated factors to the willingness were the following: Younger age group (AOR = 5.18, 95 % CI: [1.69, 15.94]), having secondary or higher education (AOR = 4.61, 95 % CI: [1.33, 16.01]), using internet (AOR = 3.94, 95 % CI: [1.67, 9.31]), not disclosing HIV status to anyone other than HCP (Health Care Provider) (AOR = 3.03, 95 % CI: [1.20, 7.61]), availability of radio in dwelling (AOR = 2.74 95 % CI: [1.27, 5.88]), not answering unknown calls (AOR = 2.67, 95 % CI: [1.34, 5.32]), use of cellphone alarm as medication reminder (AOR = 2.22, 95%CI [1.09, 4.52]), and forgetting to take medications (AOR = 2.13, 95 % CI: [1.14, 3.96]). Conclusions: A high proportion of respondents have a cell phone and are willing to use it as medication reminders. Age, educational status and using internet were the main factors that are significantly associated with the willingness of patients to receive text message medication reminders.
Background: Mesenchymal stromal cells (MSCs) are considered an important therapeutic tool in cancer therapy. They possess intrinsic therapeutic potential and can also be in vitro manipulated and engineered to produce therapeutic molecules that can be delivered to the site of diseases, through their capacity to home pathological tissues. We have recently demonstrated that MSCs, upon in vitro priming with anti-cancer drug, become drug-releasing mesenchymal cells (Dr-MCs) able to strongly inhibit cancer cells growth. Methods: Murine mesenchymal stromal cells were loaded with Paclitaxel (Dr-MCsPTX) according to a standardized procedure and their ability to inhibit the growth of a murine B16 melanoma was verified by in vitro assays. The anti-metastatic activity of Dr-MCsPTX was then studied in mice injected i.v. with B16 melanoma cells that produced lung metastatic nodules. Lung nodules were counted under a dissecting stereomicroscope and metastasis investigated by histological analysis. Results: We found that three i.v. injections of Dr-MCsPTX on day 5, 10 and 15 after tumor injection almost completely abolished B16 lung metastasis. Dr-MCsPTX arrested into lung by interacting with endothelium and migrate toward cancer nodule through a complex mechanism involving primarily mouse lung stromal cells (mL-StCs) and SDF-1/CXCR4/CXCR7 axis. Conclusions: Our results show for the first time that Dr-MCsPTX are very effective to inhibit lung metastasis formation. Actually, a cure for lung metastasis in humans is mostly unlikely and we do not know whether a therapy combining engineered MSCs and Dr-MCs may work synergistically. However, we think that our approach using Dr-MCs loaded with PTX may represent a new valid and additive therapeutic tool to fight lung metastases and, perhaps, primary lung cancers in human.
IntroductionScreening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment. Methods: We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS. Results: We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013). Conclusions: CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.
Background: Egress is a vital step in the life cycle of Toxoplasma gondii which attracts attentions of many groups. Previous studies have shown that exogenous nitric oxide (NO) stimulates the early egress of T. gondii from infected peritoneal macrophages, a kind of immune cells. However, because Toxoplasma forms cysts in brain and muscle tissues, the development of autonomous immunity in non-immune cells is vital for limiting parasite burden and cyst formation. Therefore, we attempted to investigate whether exogenous NO could induce the early egress of T. gondii from infected non-immune cells. Methods: T. gondii tachyzoites were cultured in human foreskin fibroblast (HFF) cells and were then treated with NO released by sodium nitroferricyanide (III) dihydrate (SNP). The egressed parasites were analysed by flow cytometry. Results: The results showed that NO induced the early egress of parasites from HFF cells before completing their intracellular life cycles. We also found that the occurrence of egress was dependent on intracellular calcium (Ca 2+ ) levels and the mobility of the parasite. Compared with freshly isolated tachyzoites, the developmental ability and virulence of egressed tachyzoites presented no difference. Conclusions: Taken together, our findings demonstrate a novel assay for the analysis of egress signalling mechanisms and an avenue of parasite clearance by hosts of T. gondii.
Background: Despite the prevalence of CDH23 mutations in East Asians, its large size hinders investigation. The pathologic mutation p.P240L in CDH23 is common in East Asians. However, whether this mutation represents a common founder or a mutational hot spot is unclear. The prevalence of CDH23 mutations with prelingual severe-to-profound sporadic or autosomal recessive sensorineural hearing loss (arSNHL) is unknown in Koreans. Methods: From September 2010 to October 2014, children with severe-to-profound sporadic or arSNHL without phenotypic markers, and their families, were tested for mutations in connexins GJB2, GJB6 and GJB3. Sanger sequencing of CDH23 p.P240L was performed on connexin-negative samples without enlarged vestibular aqueducts (EVA), followed by targeted resequencing of 129 deafness genes, including CDH23, unless p.P240L homozygotes were detected in the first screening. Four p.P240L-allele-linked STR markers were genotyped in 40 normal-hearing control subjects, and the p.P240L carriers in the hearing-impaired cohort, to identify the haplotypes. Results: Four (3.1 %) of 128 children carried two CDH23 mutant alleles, and SLC26A4 and GJB2 accounted for 18.0 and 17.2 %, respectively. All four children showed profound nonsyndromic SNHL with minimal residual hearing. Interestingly, all had at least one p.P240L mutant allele. Analysis of p.P240L-linked STR markers in these children and other postlingual hearing-impaired adults carrying p.P240L revealed that p.P240L was mainly carried on a single haplotype. Conclusions: p.P240L contributed significantly to Korean pediatric severe arSNHL with a strong founder effect, with implications for future phylogenetic studies. Screening for p.P240L as a first step in GJB2-negative arSNHL Koreans without EVA is recommended.
Background: Abnormalities in potassium levels can lead to several clinical difficulties in trauma patients admitted to the ICU. However, the significance of potassium abnormalities soon after admission in trauma patients has not yet been clearly delineated. The objective of this study was to describe the plasma potassium abnormalities in trauma patients on admission and to examine the clinical outcomes associated with these abnormalities. Methods: We performed a retrospective observational study of plasma potassium levels in trauma patients admitted to the Fukuyama City Hospital between January 1, 2010 and December 31, 2013. Five hundred twenty consecutive trauma patients were included and categorized into six groups according to their plasma potassium level on admission (<3.0, 3.0–<3.5, 3.5–<4.0, 4.0–<4.5, 4.5–<5.0, and ≥5.0 mEq/L). After adjusting for covariates, including age, gender, the Revised Trauma Score, and the Injury Severity Score, logistic regression analysis was used to examine the association between plasma potassium levels and outcomes, including life-saving interventions and in-hospital mortality. Results: Two hundred twenty-seven patients (43.7 %) presented with hypokalemia (<3.5 mEq/L), while seven patients (1.3 %) presented with hyperkalemia (≥5.0 mEq/L). Patients in the lowest potassium group (<3.0 mEq/L, n = 36 [6.9 %]) were significantly associated with craniotomy (adjusted odds ratio 5.25 [95 % confidence interval 2.06–13.40]; p < 0.001) and showed an increased trend toward in-hospital mortality. In the second lowest potassium group (3.0–< 3.5 mEq/L, n = 191 [36.7 %]), the adjusted odds ratio for craniotomy was significantly higher (2.03 [95 % confidence interval 1.01–4.07]; p = 0.048) compared to the reference group. Conclusions: Trauma patients presenting with hypokalemia (<3.5 mEq/L) on admission may be associated with severe head trauma requiring life-saving craniotomy.
Background: The amphipod and microsporidian diversity in freshwaters of a heterogeneous urban region in Germany was assessed. Indigenous and non-indigenous host species provide an ideal framework to test general hypotheses on potentially new host-parasite interactions, parasite spillback and spillover in recently invaded urban freshwater communities. Methods: Amphipods were sampled in 17 smaller and larger streams belonging to catchments of the four major rivers in the Ruhr Metropolis (Emscher, Lippe, Ruhr, Rhine), including sites invaded and not invaded by non-indigenous amphipods. Species were identified morphologically (hosts only) and via DNA barcoding (hosts and parasites). Prevalence was obtained by newly designed parasite-specific PCR assays. Results: Three indigenous and five non-indigenous amphipod species were detected. Gammarus pulex was further distinguished into three clades (C, D and E) and G. fossarum more precisely identified as type B. Ten microsporidian lineages were detected, including two new isolates (designated as Microsporidium sp. nov. RR1 and RR2). All microsporidians occurred in at least two different host clades or species. Seven genetically distinct microsporidians were present in non-invaded populations, six of those were also found in invaded assemblages. Only Cucumispora dikerogammari and Dictyocoela berillonum can be unambiguously considered as non-indigenous co-introduced parasites. Both were rare and were not observed in indigenous hosts. Overall, microsporidian prevalence ranged from 50 % (in G. roeselii and G. pulex C) to 73 % (G. fossarum) in indigenous and from 10 % (Dikerogammarus villosus) to 100 % (Echinogammarus trichiatus) in non-indigenous amphipods. The most common microsporidians belonged to the Dictyocoela duebenum- /D. muelleri- complex, found in both indigenous and non-indigenous hosts. Some haplotype clades were inclusive for a certain host lineage. Conclusions: The Ruhr Metropolis harbours a high diversity of indigenous and non-indigenous amphipod and microsporidian species, and we found indications for an exchange of parasites between indigenous and non-indigenous hosts. No introduced microsporidians were found in indigenous hosts and prevalence of indigenous parasites in non-indigenous hosts was generally low. Therefore, no indication for parasite spillover or spillback was found. We conclude that non-indigenous microsporidians constitute only a minimal threat to the native amphipod fauna. However, this might change e.g. if C. dikerogammari adapts to indigenous amphipod species or if other hosts and parasites invade.