Trypanosoma cruzi CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hit

Enzyme sterol 14α-demethylase (CYP51) is a well-established target for anti-fungal therapy and is a prospective target for Chagas' disease therapy. We previously identified a chemical scaffold capable of delivering a variety of chemical structures into the CYP51 active site. In this work the binding modes of several second generation compounds carrying this scaffold were determined in high-resolution co-crystal structures with CYP51 of Mycobacterium tuberculosis. Subsequent assays against CYP51 in Trypanosoma cruzi, the agent of Chagas' disease, demonstrated that two of the compounds bound tightly to the enzyme. Both were tested for inhibitory effects against T. cruzi and the related protozoan parasite Trypanosoma brucei. One of the compounds had potent, selective anti–T. cruzi activity in infected mouse macrophages. This compound is currently being evaluated in animal models of Chagas' disease. Discrimination between T. cruzi and T. brucei CYP51 by the inhibitor was largely based on the variability of a single amino acid residue at a critical position in the active site. Our work is aimed at rational design of potent and highly selective CYP51 inhibitors with potential to become therapeutic drugs. Drug selectivity to prevent host–pathogen cross-reactivity is pharmacologically important, because CYP51 is present in human host

Comparison of Anterior Segment Optical Tomography Parameters Measured Using a Semi-Automatic Software to Standard Clinical Instruments

10.1371/journal.pone.0065559PLoS ONE86

Measuring quality of life in rheumatic conditions

Musculoskeletal disorders often have associated pain, functional impairment and work disability, and, not surprisingly, are the most common reasons for utilizing healthcare resources. Rheumatoid arthritis (RA) and fibromyalgia (FM) are causes of musculoskeletal pain and disability. Research indicates that there is a widespread impact of RA and FM on physical, psychological and social factors in affected individuals, and thus, outcome measures that encompass multiple aspects of quality of life are needed. Generic measures of quality of life identify associations between physical conditions and mental health and highlight the need to address psychological functioning to ultimately improve the individuals’ quality of life

Effects of Health Insurance on Perceived Quality of Care Among Latinos in the United States

There is suggestive evidence that lower rates of health insurance coverage increases the gaps in quality and access to care among Latinos as compared with non-Latino whites. In order to examine these potential disparities, we assessed the effects of insurance coverage and multiple covariates on perceived quality of care. To assess the distribution of perceived quality of care received in a national Latino population sample, and the role of insurance in different patient subgroups. Telephone interviews conducted between 2007 and 2008 using the Pew Hispanic Center/Robert Wood Johnson Foundation Latino Health Surveys (Waves 1 and 2). Randomly selected Latino adults aged ≥18 years living in the United States. Pearson χ2 tests identified associations among various demographic variables by quality of care ratings (poor, fair, good, excellent) for the insured and uninsured (Wave 1: N = 3545). Subgroup analyses were conducted among Wave 2 participants reporting chronic conditions (N = 1067). Bivariate and multivariate analyses were conducted to estimate the effects of insurance, demographic variables and consumer characteristics on quality of care. Insurance availability had an odds ratio of 1.47 (95% CI, 1.22–1.76) net of confounders in predicting perceived quality of care among Latinos. The largest gap in rates of excellent/good ratings occurred among the insured with eight or more doctor visits compared to the uninsured (76.2% vs. 54.6%, P < .05). Future research can gain additional insights by examining the impact of health insurance on processes of care with a refined focus on specific transactions between consumers and providers’ support staff and physicians guided by the principles of patient-centered care

The changing seroepidemiology of enterovirus 71 infection among children and adolescents in Singapore

<p>Abstract</p> <p>Background</p> <p>Enterovirus 71 (EV71) has caused recurrent epidemics of hand, foot and mouth disease among children in Singapore. Between August 2008 and July 2010, we conducted a survey to estimate the seroprevalence of EV71 infection among children and adolescents aged 1-17 years. We compared our EV71 seroepidemiologic findings with a previous study conducted in 1996-1997.</p> <p>Methods</p> <p>The survey involved the prospective collection of 1,200 residual sera from Singapore residents aged 1-17 years in two hospitals. Neutralizing antibodies to EV71 were detected by the microneutralization test. The geometric mean titer (GMT) of EV71 antibodies and 95% confidence intervals (CI) were calculated and compared by age groups. Statistical significance was taken as <it>P </it>< 0.05.</p> <p>Results</p> <p>The overall EV71 antibody prevalence was 26.9% (95% CI: 24.5-29.5%). It increased significantly from 14.3% in children aged 1-6 years to 27.8% in those aged 7-12 years, and reached 38.8% in adolescents aged 13-17 years. The seroconversion rate differed by about 12% between the consecutive age groups. The GMT of EV71 antibodies was higher among primary school children aged 7-12 years in our study than that among the 6-12 year age group in the 1996-1997 study.</p> <p>Conclusions</p> <p>Higher antibody titers were observed in children aged 1-6 years than those in the other two age groups, indicating that most of the infections had been acquired during early childhood. EV71 infection is common among children and adolescents in Singapore, with 39% infected by the time they are in secondary school (13-17 years of age).</p

Teacher led school-based surveillance can allow accurate tracking of emerging infectious diseases - evidence from serial cross-sectional surveys of febrile respiratory illness during the H1N1 2009 influenza pandemic in Singapore

10.1186/1471-2334-12-336BMC Infectious Diseases12-BIDM

PTEN as a Prognostic and Predictive Marker in Postoperative Radiotherapy for Squamous Cell Cancer of the Head and Neck

BACKGROUND: Tumor suppressor PTEN is known to control a variety of processes related to cell survival, proliferation, and growth. PTEN expression is considered as a prognostic factor in some human neoplasms like breast, prostate, and thyroid cancer. METHODOLOGY/PRINCIPAL FINDINGS: In this study we analyzed the influence of PTEN expression on the outcome of a randomized clinical trial of conventional versus 7-days-a-week postoperative radiotherapy for squamous cell cancer of the head and neck. The patients with cancer of the oral cavity, oropharynx, and larynx were randomized to receive 63 Gy in fractions of 1.8 Gy given 5 days a week (CF) or 7 days a week (p-CAIR). Out of 279 patients enrolled in the study, 147 paraffin blocks were available for an immunohistochemical assessment of PTEN. To evaluate the prognostic value of PTEN expression and the effect of fractionation relative to PTEN, the data on the outcome of a randomized clinical trial were analyzed. Tumors with a high intensity of PTEN staining had significant gain in the loco-regional control (LRC) from p-CAIR (5-year LRC 92.7% vs. 70.8%, for p-CAIR vs. CF, p = 0.016, RR = 0.26). By contrast, tumors with low intensity of PTEN did not gain from p-CAIR (5-year LRC 56.2% vs. 47.2%, p = 0.49, RR = 0.94). The intensity of PTEN highly affected the LRC in a whole group of 147 patients (5-year LRC 80.9% vs. 52.3% for high vs. low PTEN, p = 0.0007, RR = 0.32). In multivariate Cox analysis, including neck node involvement, EGFR, nm23, Ki-67, p53, cyclin D1, tumor site and margins, PTEN remained an independent predictor of LRC (RR = 2.8 p = 0.004). CONCLUSIONS/SIGNIFICANCE: These results suggest that PTEN may serve as a potent prognostic and predictive marker in postoperative radiotherapy for high-risk squamous cell cancer of the head and neck

Solid-state fermentation of oil palm frond petiole for lignin peroxidase and xylanase-rich cocktail production

In current practice, oil palm frond leaflets and stems are re-used for soil nutrient recycling, while the petioles are typically burned. Frond petioles have high commercialization value, attributed to high lignocellulose fiber content and abundant of juice containing free reducing sugars. Pressed petiole fiber is the subject of interest in this study for the production of lignocellulolytic enzyme. The initial characterization showed the combination of 0.125 mm frond particle size and 60% moisture content provided a surface area of 42.3 m2/g, porosity of 12.8%, and density of 1.2 g/cm3, which facilitated fungal solid-state fermentation. Among the several species of Aspergillus and Trichoderma tested, Aspergillus awamori MMS4 yielded the highest xylanase (109 IU/g) and cellulase (12 IU/g), while Trichoderma virens UKM1 yielded the highest lignin peroxidase (222 IU/g). Crude enzyme cocktail also contained various sugar residues, mainly glucose and xylose (0.1–0.4 g/L), from the hydrolysis of cellulose and hemicellulose. FT-IR analysis of the fermented petioles observed reduction in cellulose crystallinity (I900/1098), cellulose–lignin (I900/1511), and lignin–hemicellulose (I1511/1738) linkages. The study demonstrated successful bioconversion of chemically untreated frond petioles into lignin peroxidase and xylanase-rich enzyme cocktail under SSF condition

Acceptance and Perception of Artificial Intelligence Usability in Eye Care (APPRAISE) for Ophthalmologists: A Multinational Perspective

Background: Many artificial intelligence (AI) studies have focused on development of AI models, novel techniques, and reporting guidelines. However, little is understood about clinicians' perspectives of AI applications in medical fields including ophthalmology, particularly in light of recent regulatory guidelines. The aim for this study was to evaluate the perspectives of ophthalmologists regarding AI in 4 major eye conditions: diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD) and cataract. Methods: This was a multi-national survey of ophthalmologists between March 1st, 2020 to February 29th, 2021 disseminated via the major global ophthalmology societies. The survey was designed based on microsystem, mesosystem and macrosystem questions, and the software as a medical device (SaMD) regulatory framework chaired by the Food and Drug Administration (FDA). Factors associated with AI adoption for ophthalmology analyzed with multivariable logistic regression random forest machine learning. Results: One thousand one hundred seventy-six ophthalmologists from 70 countries participated with a response rate ranging from 78.8 to 85.8% per question. Ophthalmologists were more willing to use AI as clinical assistive tools (88.1%, n = 890/1,010) especially those with over 20 years' experience (OR 3.70, 95% CI: 1.10–12.5, p = 0.035), as compared to clinical decision support tools (78.8%, n = 796/1,010) or diagnostic tools (64.5%, n = 651). A majority of Ophthalmologists felt that AI is most relevant to DR (78.2%), followed by glaucoma (70.7%), AMD (66.8%), and cataract (51.4%) detection. Many participants were confident their roles will not be replaced (68.2%, n = 632/927), and felt COVID-19 catalyzed willingness to adopt AI (80.9%, n = 750/927). Common barriers to implementation include medical liability from errors (72.5%, n = 672/927) whereas enablers include improving access (94.5%, n = 876/927). Machine learning modeling predicted acceptance from participant demographics with moderate to high accuracy, and area under the receiver operating curves of 0.63–0.83. Conclusion: Ophthalmologists are receptive to adopting AI as assistive tools for DR, glaucoma, and AMD. Furthermore, ML is a useful method that can be applied to evaluate predictive factors on clinical qualitative questionnaires. This study outlines actionable insights for future research and facilitation interventions to drive adoption and operationalization of AI tools for Ophthalmology

Study of FoxA Pioneer Factor at Silent Genes Reveals Rfx-Repressed Enhancer at Cdx2 and a Potential Indicator of Esophageal Adenocarcinoma Development

Understanding how silent genes can be competent for activation provides insight into development as well as cellular reprogramming and pathogenesis. We performed genomic location analysis of the pioneer transcription factor FoxA in the adult mouse liver and found that about one-third of the FoxA bound sites are near silent genes, including genes without detectable RNA polymerase II. Virtually all of the FoxA-bound silent sites are within conserved sequences, suggesting possible function. Such sites are enriched in motifs for transcriptional repressors, including for Rfx1 and type II nuclear hormone receptors. We found one such target site at a cryptic “shadow” enhancer 7 kilobases (kb) downstream of the Cdx2 gene, where Rfx1 restricts transcriptional activation by FoxA. The Cdx2 shadow enhancer exhibits a subset of regulatory properties of the upstream Cdx2 promoter region. While Cdx2 is ectopically induced in the early metaplastic condition of Barrett's esophagus, its expression is not necessarily present in progressive Barrett's with dysplasia or adenocarcinoma. By contrast, we find that Rfx1 expression in the esophageal epithelium becomes gradually extinguished during progression to cancer, i.e, expression of Rfx1 decreased markedly in dysplasia and adenocarcinoma. We propose that this decreased expression of Rfx1 could be an indicator of progression from Barrett's esophagus to adenocarcinoma and that similar analyses of other transcription factors bound to silent genes can reveal unanticipated regulatory insights into oncogenic progression and cellular reprogramming