Identification of a potent and selective LAPTc inhibitor by RapidFire-Mass Spectrometry, with antichagasic activity.

BACKGROUND: Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and leads to ~10,000 deaths each year. Nifurtimox and benznidazole are the only two drugs available but have significant adverse effects and limited efficacy. New chemotherapeutic agents are urgently required. Here we identified inhibitors of the acidic M17 leucyl-aminopeptidase from T. cruzi (LAPTc) that show promise as novel starting points for Chagas disease drug discovery. METHODOLOGY/PRINCIPAL FINDINGS: A RapidFire-MS screen with a protease-focused compound library identified novel LAPTc inhibitors. Twenty-eight hits were progressed to the dose-response studies, from which 12 molecules inhibited LAPTc with IC50 < 34 µM. Of these, compound 4 was the most potent hit and mode of inhibition studies indicate that compound 4 is a competitive LAPTc inhibitor, with Ki 0.27 µM. Compound 4 is selective with respect to human LAP3, showing a selectivity index of >500. Compound 4 exhibited sub-micromolar activity against intracellular T. cruzi amastigotes, and while the selectivity-window against the host cells was narrow, no toxicity was observed for un-infected HepG2 cells. In silico modelling of the LAPTc-compound 4 interaction is consistent with the competitive mode of inhibition. Molecular dynamics simulations reproduce the experimental binding strength (-8.95 kcal/mol), and indicate a binding mode based mainly on hydrophobic interactions with active site residues without metal cation coordination. CONCLUSIONS/SIGNIFICANCE: Our data indicates that these new LAPTc inhibitors should be considered for further development as antiparasitic agents for the treatment of Chagas disease.

Prevalence of Refractive Error, Presbyopia, and Spectacle Coverage in Bogotá, Colombia: A Rapid Assessment of Refractive Error.

SIGNIFICANCE: Uncorrected refractive error is the leading cause of visual impairment; therefore, reducing its prevalence is important worldwide. For two decades, there has not been a comprehensive assessment of refractive error in Latin America. PURPOSE: The purpose of this study was to determine the current prevalence of refractive error, presbyopia, spectacle coverage, barriers to uptake refractive services, and spectacle correction in people 15 years and older in Bogotá, Colombia. METHODS: A cross-sectional community-based survey was conducted using 50 randomly selected clusters from 10 districts of Bogotá reflecting the socioeconomic status of the city. Respondents 15 years and older were interviewed and underwent standardized clinical eye examinations. Prevalence of uncorrected refractive error, spectacle coverage, and visual impairment were standardized to 2015 age-sex population distribution of Bogotá and further analyzed. RESULTS: A total of 2886 subjects (90% of 3206 eligible subjects) participated in the study; 39.1% were male and 60.9% were female in the age range of 15 to 96 years, with a median age of 46 years (interquartile range, 45 to 54 years). Age- and sex-standardized prevalence of visual impairment was 19.3% (95% confidence interval [CI], 17.8 to 20.8%). Prevalence of uncorrected refractive error was 12.5% (95% CI, 11.3 to 13.7%). Prevalence of presbyopia among participants 35 years and older was 55.2% (95% CI, 52.9 to 57.4%). Spectacle coverage was 50.9% for distance vision, and it was 33.9% for presbyopia. Main barrier to spectacle uptake was a limitation in affording spectacles because of economic factors (29.5%). CONCLUSIONS: This study provides a current estimate of refractive error using the Rapid Assessment of Refractive Error for Colombia and the Latin American region. The prevalence of uncorrected refractive error and presbyopia was high, and the barriers to spectacle uptake were higher in the lowest socioeconomic strata. The results obtained in the present study will help in making evidence-based decisions related to eye care service delivery in Colombia.

Teaching Helping Babies Breathe via Telehealth: A New Application in Rural Guatemala.

BACKGROUND: Helping Babies Breathe (HBB) is a neonatal resuscitation curriculum that teaches life-saving interventions utilized in the first minutes after birth, reducing morbidity and mortality. Traditionally, it requires in-person facilitators for didactic and hands-on training. OBJECTIVES: The aim of this study was to offer HBB to nurses and nursing students in Guatemala, with the lead facilitator presenting concepts via telehealth and in-person facilitators providing hands-on demonstration. METHODS: Learners completed pre- and post-tests that included the standard HBB knowledge check, as well as an assessment of the course teaching model. Learners also completed the standard Objective Structured Clinical Evaluations (OSCEs). RESULTS: Eighteen learners were included in the analysis. All but one learner (94%) passed the course, and the average percent improvement from the pre- to post-test was 12%. All learners achieved passing scores on the OSCEs. Learners responded positively to questions regarding the technology, connection with the instructor, and ability to ask questions. Ninety-four percent of the learners agreed with the statement "this lecture was as good via telehealth as in person." A cost analysis demonstrated approximately USD 3,979.00 in savings using telehealth compared to a standard in-person course. CONCLUSIONS: The telehealth model was successful in delivering course material to the learners and was well received. This model represents a cost-effective way to improve access to HBB. This study may not be generalizable to other populations, and the ability to use telehealth requires reliable internet connectivity, which may not be available in all settings. Further study and expansion of this pilot are needed to assess success in other settings.

To tell or not: parental thoughts on disclosure of urologic surgery to their child.

PURPOSE: Literature pertaining to surgical disclosure to the pediatric patient is lacking. We hypothesized parents would find it difficult to disclose urologic surgery to a child. MATERIALS AND METHODS: Parents of patients <5 years old undergoing urologic surgery were contacted for telephone survey. Parents were asked about future plans of surgical disclosure, comfort with disclosure, and any support received. RESULTS: 98 parents consented to study participation. 87% of surgeries were on the genitalia with 62% being minor genitalia surgery (i.e. circumcision). 70% of parents would tell their child about minor genital surgery while 84% would tell about major genital surgery (p=0.07). 4 of 20 parents of children undergoing hypospadias repair (major genital surgery) did not plan to tell their child about surgery. All parents of children undergoing non-genital surgery would tell. Of all parents planning to tell their children about surgery, only 14% were nervous. 34% of parents would find guidance in talking to their child helpful despite the majority (90%) stating no guidance had ever been provided. CONCLUSIONS: Parents seem comfortable discussing urologic surgeries with a child but about 1/3 would appreciate further counseling. 20% of parents of children undergoing hypospadias repair hope to avoid telling their child.

To tell or not: parental thoughts on disclosure of urologic surgery to their child

Literature pertaining to surgical disclosure to the pediatric patient is lacking. We hypothesized parents would find it difficult to disclose urologic surgery to a child.

Familial Oral Microbial Imbalance and Dental Caries Occurrence in Their Children.

OBJECTIVE: Develop a familial liability index for oral microbial status that reflects an imbalance of oral domains based on the presence of risk indicators in saliva, inter-proximal plaque, tongue, and throat. METHODS: Fifty-six mother-child pairs from Webster and Nicholas counties, West Virginia, USA, participated in this study. Saliva samples were assayed for mutans streptococci (MS), interproximal plaque samples for the BANA Test (BT) species, tongue swabs for BT, and throat swabs for any of the sentinel organisms (Staphylococcus aureus, Streptococcus pyogenes, and yeasts). The corresponding thresholds for a (+) risk indicator were, respectively, ≥105 CFU of MS salivary levels, one or more BT-(+) plaques (>105 CFU/mg of plaque of at least one of BT-(+) species), weak-(+) BT for a tongue swab (>104-<105), and >104 CFU/swab for any of the sentinel markers. RESULTS: The mean age of mothers and children was 41.6 and 14.6 years. Ninety-one % of both mothers and children had at least one (+) risk indicator. Overall, 76% of mother child-pairs had at least one (+) concordant oral microbial risk indicator. Accordingly, the relative risk (RR) of children having concordant results with their mothers was increased 1.36 (BT-plaque), 1.37 (BT-tongue), 0.94 (sentinel organisms) and 1.13 (MS) times. Principal component analysis revealed distinct sets of oral microbial risk indicators in mothers and children that correlated with dental caries prevalence rates in children. CONCLUSIONS: Mother-child pairs shared similarities of oral microbial risk indicators that allow for the development of a liability index that can elucidate caries in the children.