Data mining of gene arrays for biomarkers of survival in ovarian cancer

The expected five-year survival rate from a stage III ovarian cancer diagnosis is a mere 22%; this applies to the 7000 new cases diagnosed yearly in the UK. Stratification of patients with this heterogeneous disease, based on active molecular pathways, would aid a targeted treatment improving the prognosis for many cases. While hundreds of genes have been associated with ovarian cancer, few have yet been verified by peer research for clinical significance. Here, a meta-analysis approach was applied to two care fully selected gene expression microarray datasets. Artificial neural networks, Cox univariate survival analyses and T-tests identified genes whose expression was consistently and significantly associated with patient survival. The rigor of this experimental design increases confidence in the genes found to be of interest. A list of 56 genes were distilled from a potential 37,000 to be significantly related to survival in both datasets with a FDR of 1.39859 × 10−11, the identities of which both verify genes already implicated with this disease and provide novel genes and pathways to pursue. Further investigation and validation of these may lead to clinical insights and have potential to predict a patient’s response to treatment or be used as a novel target for therapy

Exoanal ultrasound of the anal sphincter: normal anatomy and sphincter defects

To describe the sonographic appearance of normal anal sphincter anatomy and sphincter defects evaluated with a conventional 5 MHz convex transducer placed on the perineum. Design Prospective, single-blind study. Setting Department of Obstetrics and Gynecology, University of Michigan Medical Center, USA. Population Twenty-five women with symptoms of faecal incontinence, 11 asymptomatic nulliparous women, and 32 asymptomatic parous women. Methods A convex scanner was placed on the perineum with the woman in lithotomy position. Images were taken at three levels of the sphincter canal. Pictures were evaluated by two examiners who were blinded to the case history of the women and to the results of each other for the presence or absence of sphincter defects. Main outcome measures Description of anal sphincter appearance on endoanal ultrasound. Reproducibilty of the evaluation of sphincter defects. Results The internal anal sphincter is visible as a hypoechoic circle; the external anal sphincter shows a hyperechoic pattern. Proximally the sling of the puborectalis muscle is visible. Sphincter defects were detected in 20 women. In all five women who subsequently underwent surgery, the presence and location of the defect was confirmed at the time of surgery. Examiners were in agreement 100% of the time on the presence or absence of internal defects. They disagreed in one patient on the presence of an external defect. Conclusion Exoanal ultrasound provides information on normal anatomy and on defects of the anal sphincter.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75125/1/j.1471-0528.1997.tb12056.x.pd

The association between failed quit attempts and increased levels of psychological distress in smokers in a large New Zealand cohort

<p>Abstract</p> <p>Background</p> <p>Although the association between smoking status and poorer mental health has been well documented, the association between quit status and psychological distress is less clear. The aim of the present study is to investigate the association of smoking status and quit status with psychological distress.</p> <p>Methods</p> <p>Data for this study is from a single year of the Survey of Families, Income and Employment (SoFIE) conducted in New Zealand (2004/05) (n = 18,525 respondents). Smoking status and quit status were treated as exposure variables, and psychological distress (Kessler-10) was treated as the outcome variable. Logistic regression analyses were performed to determine the association of smoking with psychological distress in the whole adult population and quit status with psychological distress in the ex- and current-smoking population.</p> <p>Results</p> <p>Current smokers had higher rates of high and very high psychological distress compared to never smokers (adjusted odds ratio (aOR) = 1.45; 95% CI: 1.24-1.69). Unsuccessful quitters had much higher levels of high to very high levels of psychological distress (16%) than any other group. Moreover, compared to long-term ex-smokers, unsuccessful quitters had a much higher odds of high to very high levels of psychological distress (aOR = 1.73; 95% CI: 1.36-2.21).</p> <p>Conclusion</p> <p>These findings suggest that the significant association between smoking and psychological distress might be partly explained by increased levels of psychological distress among current smokers who made a quit attempt in the last year. This issue needs further study as it has implications for optimising the design of quitting support.</p

Gene Expression Profiling during Early Acute Febrile Stage of Dengue Infection Can Predict the Disease Outcome

Background: We report the detailed development of biomarkers to predict the clinical outcome under dengue infection. Transcriptional signatures from purified peripheral blood mononuclear cells were derived from whole-genome gene-expression microarray data, validated by quantitative PCR and tested in independent samples. Methodology/Principal Findings: The study was performed on patients of a well-characterized dengue cohort from Recife, Brazil. The samples analyzed were collected prospectively from acute febrile dengue patients who evolved with different degrees of disease severity: classic dengue fever or dengue hemorrhagic fever (DHF) samples were compared with similar samples from other non-dengue febrile illnesses. The DHF samples were collected 2-3 days before the presentation of the plasma leakage symptoms. Differentially-expressed genes were selected by univariate statistical tests as well as multivariate classification techniques. The results showed that at early stages of dengue infection, the genes involved in effector mechanisms of innate immune response presented a weaker activation on patients who later developed hemorrhagic fever, whereas the genes involved in apoptosis were expressed in higher levels. Conclusions/Significance: Some of the gene expression signatures displayed estimated accuracy rates of more than 95%, indicating that expression profiling with these signatures may provide a useful means of DHF prognosis at early stages of infection. © 2009 Nascimento et al

Variation in the COVID-19 infection-fatality ratio by age, time, and geography during the pre-vaccine era: a systematic analysis

Background The infection-fatality ratio (IFR) is a metric that quantifies the likelihood of an individual dying once infected with a pathogen. Understanding the determinants of IFR variation for COVID-19, the disease caused by the SARS-CoV-2 virus, has direct implications for mitigation efforts with respect to clinical practice, non-pharmaceutical interventions, and the prioritisation of risk groups for targeted vaccine delivery. The IFR is also a crucial parameter in COVID-19 dynamic transmission models, providing a way to convert a population's mortality rate into an estimate of infections.Methods We estimated age-specific and all-age IFR by matching seroprevalence surveys to total COVID-19 mortality rates in a population. The term total COVID-19 mortality refers to an estimate of the total number of deaths directly attributable to COVID-19. After applying exclusion criteria to 5131 seroprevalence surveys, the IFR analyses were informed by 2073 all-age surveys and 718 age-specific surveys (3012 age-specific observations). When seroprevalence was reported by age group, we split total COVID-19 mortality into corresponding age groups using a Bayesian hierarchical model to characterise the non-linear age pattern of reported deaths for a given location. To remove the impact of vaccines on the estimated IFR age pattern, we excluded age-specific observations of seroprevalence and deaths that occurred after vaccines were introduced in a location. We estimated age-specific IFR with a non-linear meta-regression and used the resulting age pattern to standardise all-age IFR observations to the global age distribution. All IFR observations were adjusted for baseline and waning antibody-test sensitivity. We then modelled age-standardised IFR as a function of time, geography, and an ensemble of 100 of the top-performing covariate sets. The covariates included seven clinical predictors (eg, age-standardised obesity prevalence) and two measures of health system performance. Final estimates for 190 countries and territories, as well as subnational locations in 11 countries and territories, were obtained by predicting age-standardised IFR conditional on covariates and reversing the age standardisation.Findings We report IFR estimates for April 15, 2020, to January 1, 2021, the period before the introduction of vaccines and widespread evolution of variants. We found substantial heterogeneity in the IFR by age, location, and time. Age-specific IFR estimates form a J shape, with the lowest IFR occurring at age 7 years (0-0023%, 95% uncertainty interval [UI] 0-0015-0-0039) and increasing exponentially through ages 30 years (0-0573%, 0-0418-0-0870), 60 years (1-0035%, 0-7002-1-5727), and 90 years (20-3292%, 14-6888-28-9754). The countries with the highest IFR on July 15, 2020, were Portugal (2-085%, 0-946-4-395), Monaco (1-778%, 1-265-2-915), Japan (1-750%, 1-302-2-690), Spain (1-710%, 0-991-2-718), and Greece (1-637%, 1-155-2-678). All-age IFR varied by a factor of more than 30 among 190 countries and territories.After age standardisation, the countries with the highest IFR on July 15, 2020, were Peru (0-911%, 0-636-1-538), Portugal (0-850%, 0-386-1-793), Oman (0-762%, 0-381-1-399), Spain (0-751%, 0-435-1-193), and Mexico (0-717%, 0-426-1-404). Subnational locations with high IFRs also included hotspots in the UK and southern and eastern states of the USA. Sub-Saharan African countries and Asian countries generally had the lowest all-age and age-standardised IFRs. Population age structure accounted for 74% of logit-scale variation in IFRs estimated for 39 in-sample countries on July 15, 2020. A post-hoc analysis showed that high rates of transmission in the care home population might account for higher IFRs in some locations. Among all countries and territories, we found that the median IFR decreased from 0-466% (interquartile range 0-223-0-840) to 0-314% (0-143-0-551) between April 15, 2020, and Jan 1, 2021.Interpretation Estimating the IFR for global populations helps to identify relative vulnerabilities to COVID-19. Information about how IFR varies by age, time, and location informs clinical practice and non-pharmaceutical interventions like physical distancing measures, and underpins vaccine risk stratification. IFR and mortality risk form a J shape with respect to age, which previous research, such as that by Glynn and Moss in 2020, has identified to be a common pattern among infectious diseases. Understanding the experience of a population with COVID-19 mortality requires consideration for local factors; IFRs varied by a factor of more than 30 among 190 countries and territories in this analysis. In particular, the presence of elevated age-standardised IFRs in countries with well resourced health-care systems indicates that factors beyond health-care capacity are important. Potential extenuating circumstances include outbreaks among care home residents, variable burdens of severe cases, and the population prevalence of comorbid conditions that increase the severity of COVID-19 disease. During the pre-vaccine period, the estimated 33% decrease in median IFR over 8 months suggests that treatment for COVID-19 has improved over time. Estimating IFR for the pre-vaccine era provides an important baseline for describing the progression of COVID-19 mortality patterns.Funding Bill &amp; Melinda Gates Foundation, J Stanton, T Gillespie, and J and E Nordstrom Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

Role of the Chemokine Receptors CCR1, CCR2 and CCR4 in the Pathogenesis of Experimental Dengue Infection in Mice

Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. Recent clinical data have shown an association between levels of different chemokines in plasma and severity of dengue. We evaluated the role of CC chemokine receptors CCR1, CCR2 and CCR4 in an experimental model of DENV-2 infection in mice. Infection of mice induced evident clinical disease and tissue damage, including thrombocytopenia, hemoconcentration, lymphopenia, increased levels of transaminases and pro-inflammatory cytokines, and lethality in WT mice. Importantly, infected WT mice presented increased levels of chemokines CCL2/JE, CCL3/MIP-1α and CCL5/RANTES in spleen and liver. CCR1-/- mice had a mild phenotype with disease presentation and lethality similar to those of WT mice. In CCR2-/- mice, lethality, liver damage, levels of IL-6 and IFN-γ, and leukocyte activation were attenuated. However, thrombocytopenia, hemoconcentration and systemic TNF-α levels were similar to infected WT mice. Infection enhanced levels of CCL17/TARC, a CCR4 ligand. In CCR4-/- mice, lethality, tissue injury and systemic inflammation were markedly decreased. Despite differences in disease presentation in CCR-deficient mice, there was no significant difference in viral load. In conclusion, activation of chemokine receptors has discrete roles in the pathogenesis of dengue infection. These studies suggest that the chemokine storm that follows severe primary dengue infection associates mostly to development of disease rather than protection

The Neuronal Correlates of Digits Backward Are Revealed by Voxel-Based Morphometry and Resting-State Functional Connectivity Analyses

Digits backward (DB) is a widely used neuropsychological measure that is believed to be a simple and effective index of the capacity of the verbal working memory. However, its neural correlates remain elusive. The aim of this study is to investigate the neural correlates of DB in 299 healthy young adults by combining voxel-based morphometry (VBM) and resting-state functional connectivity (rsFC) analyses. The VBM analysis showed positive correlations between the DB scores and the gray matter volumes in the right anterior superior temporal gyrus (STG), the right posterior STG, the left inferior frontal gyrus and the left Rolandic operculum, which are four critical areas in the auditory phonological loop of the verbal working memory. Voxel-based correlation analysis was then performed between the positive rsFCs of these four clusters and the DB scores. We found that the DB scores were positively correlated with the rsFCs within the salience network (SN), that is, between the right anterior STG, the dorsal anterior cingulate cortex and the right fronto-insular cortex. We also found that the DB scores were negatively correlated with the rsFC within an anti-correlation network of the SN, between the right posterior STG and the left posterior insula. Our findings suggest that DB performance is related to the structural and functional organizations of the brain areas that are involved in the auditory phonological loop and the SN

In quest of a systematic framework for unifying and defining nanoscience

This article proposes a systematic framework for unifying and defining nanoscience based on historic first principles and step logic that led to a “central paradigm” (i.e., unifying framework) for traditional elemental/small-molecule chemistry. As such, a Nanomaterials classification roadmap is proposed, which divides all nanomatter into Category I: discrete, well-defined and Category II: statistical, undefined nanoparticles. We consider only Category I, well-defined nanoparticles which are >90% monodisperse as a function of Critical Nanoscale Design Parameters (CNDPs) defined according to: (a) size, (b) shape, (c) surface chemistry, (d) flexibility, and (e) elemental composition. Classified as either hard (H) (i.e., inorganic-based) or soft (S) (i.e., organic-based) categories, these nanoparticles were found to manifest pervasive atom mimicry features that included: (1) a dominance of zero-dimensional (0D) core–shell nanoarchitectures, (2) the ability to self-assemble or chemically bond as discrete, quantized nanounits, and (3) exhibited well-defined nanoscale valencies and stoichiometries reminiscent of atom-based elements. These discrete nanoparticle categories are referred to as hard or soft particle nanoelements. Many examples describing chemical bonding/assembly of these nanoelements have been reported in the literature. We refer to these hard:hard (H-n:H-n), soft:soft (S-n:S-n), or hard:soft (H-n:S-n) nanoelement combinations as nanocompounds. Due to their quantized features, many nanoelement and nanocompound categories are reported to exhibit well-defined nanoperiodic property patterns. These periodic property patterns are dependent on their quantized nanofeatures (CNDPs) and dramatically influence intrinsic physicochemical properties (i.e., melting points, reactivity/self-assembly, sterics, and nanoencapsulation), as well as important functional/performance properties (i.e., magnetic, photonic, electronic, and toxicologic properties). We propose this perspective as a modest first step toward more clearly defining synthetic nanochemistry as well as providing a systematic framework for unifying nanoscience. With further progress, one should anticipate the evolution of future nanoperiodic table(s) suitable for predicting important risk/benefit boundaries in the field of nanoscience