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Potent inhibitors of an essential microbial enzyme have been shown to be effective growth inhibitors of Candida albicans, a pathogenic fungus. C. albicans is the main cause of oropharyngeal candidiasis, and also causes invasive fungal infections, including systemic sepsis, leading to serious complications in immunocompromised patients. As the rates of drug-resistant fungal infections continue to rise novel antifungal treatments are desperately needed. The enzyme aspartate semialdehyde dehydrogenase (ASADH) is critical for the functioning of the aspartate biosynthetic pathway in microbes and plants. Because the aspartate pathway is absent in humans, ASADH has the potential to be a promising new target for antifungal research. Deleting the asd gene encoding for ASADH significantly decreases the survival of C. albicans, establishing this enzyme as essential for this organism. Previously developed ASADH inhibitors were tested against several strains of C. albicans to measure their possible therapeutic impact. The more potent inhibitors show a good correlation between enzyme inhibitor potency and fungal growth inhibition. Growth curves generated by incubating different C. albicans strains with varying enzyme inhibitor levels show significant slowing of fungal growth by these inhibitors against each of these strains, similar to the effect observed with a clinical antifungal drug. The most effective inhibitors also demonstrated relatively low cytotoxicity against a human epithelial cell line. Taken together, these results establish that the ASADH enzyme is a promising new target for further development as a novel antifungal treatment against C. albicans and related fungal species., (© 2020 Wiley Periodicals, Inc.)

Canavan disease (CD) is a fatal leukodystrophy caused by mutations in the aspA gene coding for the enzyme aspartoacylase. Insufficient catalytic activity by this enzyme leads to the accumulation of its substrate, N-acetyl-l-aspartate (NAA), and diminished production of acetate in brain oligodendrocytes of patients with CD. There is growing evidence that this accumulation of NAA is the cause of many of the developmental defects observed in these patients. NAA is produced in the brain by a transacetylation reaction catalyzed by aspartate N-acetyltransferase (ANAT), and this membrane-associated enzyme has recently been purified as a soluble maltose binding protein fusion. Designing selective inhibitors against ANAT has the potential to slow the accumulation of NAA and moderate these developmental defects, and this is the goal of this project. Several bisubstrate analog inhibitors of ANAT have been synthesized that have achieved nanomolar level binding affinities against this enzyme. Truncated versions and fragments of these bisubstrate analog inhibitors have identified the essential structural elements needed for high binding affinity. More drug-like versions of these inhibitors can now be built, based on these essential core structures., (© 2019 John Wiley & Sons Ltd.)

The aspartate pathway, uniquely found in plants and microorganisms, offers novel potential targets for the development of new antimicrobial drugs. Aspartate semialdehyde dehydrogenase (ASADH) catalyzes production of a key intermediate at the first branch point in this pathway. Several fungal ASADH structures have been determined, but the prior crystallization conditions had precluded complex formation with enzyme inhibitors. The first inhibitor-bound and cofactor-bound structures of ASADH from the pathogenic fungi Blastomyces dermatitidis have now been determined, along with a structural and functional comparison to other ASADH family members. The structure of this new ASADH is similar to the other fungal orthologs, but with some critical differences in the orientation of some active site functional groups and in the subunit interface region. The presence of this bound inhibitor reveals the first details about inhibitor binding interactions, and the flexible orientation of its aromatic ring provides helpful insights into the design of potentially more potent and selective antifungal compounds., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pathogenic fungi represent a growing threat to human health, with an increase in the frequency of drug-resistant fungal infections. Identifying targets from among the selected metabolic pathways that are unique to microbial species presents an opportunity to develop new antifungal agents against new and untested targets to combat this growth threat. Aspartate semialdehyde dehydrogenase (ASADH) catalyzes a key step in a uniquely microbial amino acid biosynthetic pathway and is essential for microbial viability. This enzyme, purified from four pathogenic fungal organisms ( Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Blastomyces dermatitidis), has been screened against fragment libraries to identify initial enzyme inhibitors. The binding of structural analogs of the most promising lead compounds was measured against these fungal ASADHs to establish important structure-activity relationships among these different inhibitor classes. The most potent of these inhibitors have been docked into structures of this fungal enzyme target to identify important structural elements that serve as critical binding determinants. Several inhibitors with low micromolar inhibition constants have been identified that showed selectivity against these related enzymes from different fungal species. Subsequent screening against a library of drugs and drug candidates identified some additional inhibitors containing a consistent set of functional groups required for fungal ASADH inhibition. Additional elaboration of these core structures will likely lead to more potent and selective inhibitors.

Aspartate-semialdehyde dehydrogenase (ASADH) functions at a critical junction in the aspartate biosynthetic pathway and represents a validated target for antimicrobial drug design. This enzyme catalyzes the NADPH-dependent reductive dephosphorylation of β-aspartyl phosphate to produce the key intermediate aspartate semialdehyde. The absence of this entire pathway in humans and other mammals will allow the selective targeting of pathogenic microorganisms for antimicrobial development. Here, the X-ray structure of a new form of ASADH from the pathogenic fungal species Aspergillus fumigatus has been determined. The overall structure of this enzyme is similar to those of its bacterial orthologs, but there are some critical differences both in biological assembly and in secondary-structural features that can potentially be exploited for the development of species-selective drugs with selective toxicity against infectious fungal organisms.

Objective: To assess the effects of rapid voluntary counselling and testing (VCT) for HIV on HIV incidence and uptake of HIV/AIDS services in people at high risk for HIV exposure., Design: Cochrane systematic review and meta-analysis., Data Sources: We searched PubMed, EMBASE, AIDSearch, LILACS, Global Health, Medline Africa, PsychInfo, CINAHL, Cochrane CENTRAL, Cochrane HIV/AIDS Group Specialized Register and grey literature from 1 January 2001 to 5 June 2014 without language restriction., Data Selection: We included controlled studies that compared rapid VCT with conventional testing among people at risk for HIV exposure., Data Extraction: Two reviewers extracted data. We used Cochrane risk of bias tool and GRADE criteria: risk of bias, inconsistency, indirectness, imprecision and publication bias. For observational studies we used the Newcastle-Ottawa Scale. We used the PRISMA-Equity reporting guideline., Results: From 2441 articles, we included 8 randomised controlled trials and 5 observational studies. Rapid VCT was associated with a threefold increase in HIV-testing uptake (relative risk (RR)=2.95 95% CI 1.69 to 5.16) and a twofold increase in the receipt of test results (RR=2.14, 95% CI 1.08 to 4.24). Women accepted testing more often than men in rapid VCT arm, but no differences in effect for age or socioeconomic status. Observational studies also showed rapid VCT led to higher rates of uptake of testing. Heterogeneity was high. A cluster-randomised trial reported an 11% reduction in HIV incidence in intervention communities (RR=0.89, 95% CI=0.63 to 1.24) over 3 years trial., Conclusions: Rapid VCT in health facilities and communities was associated with a large increase in HIV-testing uptake and receipt of results. This has implications for WHO guidelines. The routine use of rapid VCT may also help avoid human rights violations among marginalised populations where testing may occur without informed consent and where existing stigma may create barriers to testing., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Nepal has a distinct topography that makes reproductive health and family planning services difficult to access, particularly in remote mountain and hill regions where over a quarter of modern contraceptive users rely exclusively on vasectomy., Study Design: A three-level random intercept logistic regression analysis was applied on data from the 2011 Nepal Demographic and Health Survey to investigate the extent of influence of mobile family planning clinics on the odds of a male or a female sterilization, adjusting for relevant characteristics including ecological differences and random effects. The analyses included a sample of 2014 sterilization users, considering responses from currently married women of reproductive ages., Results: The odds of a male sterilization were significantly higher in a mobile clinic than those in a government hospital (odds ratio, 1.65; 95% confidence interval, 1.21-2.25). The effects remained unaltered and statistically significant after adjusting for sociodemographic and clustering effects. Random effects were highly significant, which suggest the extent of heterogeneity in vasectomy use at the community and district levels. The odds of vasectomy use in mobile clinics were significantly higher among couples residing in hill and mountain regions and among those with three or more sons or those with only daughters., Conclusion: Mobile clinics significantly increase the uptake of vasectomy in hard-to-reach areas of Nepal. Reproductive health interventions should consider mobile clinics as an effective strategy to improve access to male-based modern methods and enhance gender equity in family planning., Implications: Family planning interventions in hard-to-reach communities could consider mobile clinic as an effective strategy to promote male-based modern methods. Improving access to vasectomy could substantially reduce unmet need for family planning in countries experiencing rapid fertility transition., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose. Globalization is contributing to changes in health outcomes and healthcare use in many ways, including health professionals' practices. The objective of this study was to assess and compare global health competencies in rehabilitation students. Method. Online cross-sectional survey of physiotherapy and occupational therapy students from five universities within Ontario. We used descriptive statistics to analyze students' perceived knowledge, skills, and learning needs in global health. We used Chi-square tests, with significance set at P < 0.05, to compare results across professions. Results. One hundred and sixty-six students completed the survey. In general, both physiotherapy and occupational therapy students scored higher on the "relationship between work and health," "relationship between income and health," and "socioeconomic position (SEP) and impact on health" and lower on "Access to healthcare for low income nations," "mechanisms for why racial and ethnic disparities exist," and "racial stereotyping and medical decision making." Occupational therapy students placed greater importance on learning concerning social determinants of health (P = 0.03). Conclusion. This paper highlights several opportunities for improvement in global health education for rehabilitation students. Educators and professionals should consider developing strategies to address these needs and provide more global health opportunities in rehabilitation training programs.

The association between maternal smoking and adverse child health outcomes has not been systematically explored in less developed countries, especially in Nepal where over a quarter of women of reproductive age smoke tobacco products. This study aims to quantify the effect of maternal smoking on acute respiratory infection (ARI) symptoms among children aged below five years, using the 2001 Nepal Demographic and Health Survey. It is hypothesized that children born to mothers who smoke frequently are at higher risk of developing ARI symptoms. Four-level random intercept logistic regression models were used to disentangle the independent effect of maternal smoking on children's ARI symptoms, controlling for potential biological, socioeconomic, seasonal and spatial variables. Maternal smoking status had a significant effect on children's ARI symptoms; the effects were significantly higher (adjusted OR 1.41; 95% CI 1.02-1.96) among those born to mothers who smoked more frequently than their counterparts. Furthermore, a strong spatial pattern was evident in the prevalence of ARI symptoms, after adjusting for maternal smoking and relevant control variables. The findings underscore the importance of designing exclusive public health intervention measures to prevent tobacco smoking within households, for example through awareness campaigns highlighting the adverse effect of maternal smoking on child health.

Context: Contraceptive choices among men who want no more children have been little explored in South Asia, particularly in Nepal, where fertility rates have remained high over the last few decades., Methods: Using the 2001 Nepal Demographic and Health Survey couple data set, multinomial logistic regression analyses were conducted for 1,041 married men aged 20 or older who had at least one living child and wanted no more children. Regression models examined relationships between selected characteristics and men's reported contraceptive use, and predicted probabilities were estimated to assess interactions between ecological zone, family composition and method choice. The primary goal was to determine whether the number and sex of living children influenced contraceptive use., Results: Twenty-four percent of men who wanted no more children were not using any contraceptive method at the time of the survey, 30% reported that their wives were sterilized, 12% had had a vasectomy, 7% were using condoms and 27% used other temporary methods. The probability of relying on permanent methods was highest among men who had at least two living sons and lowest among those who had only daughters, while the probability of using no method was highest among those who had only daughters., Conclusion: In Nepal, men who report a desire to have no more children are likely to choose permanent methods only after they have two living sons.