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UNLABELLED: Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate Coccidioides infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth in vitro and determined IC50 values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease. IMPORTANCE: Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways.

Samarium hexaboride is an anomaly, having many exotic and seemingly mutually incompatible properties. It was proposed to be a mixed-valent semiconductor, and later a topological Kondo insulator, and yet has a Fermi surface despite being an insulator. We propose a new and unified understanding of SmB6 centered on the hitherto unrecognized dynamical bonding effect: the coexistence of two Sm-B bonding modes within SmB6 , corresponding to different oxidation states of the Sm. The mixed valency arises in SmB6 from thermal population of these distinct minima enabled by motion of B. Our model simultaneously explains the thermal valence fluctuations, appearance of magnetic Fermi surface, excess entropy at low temperatures, pressure-induced phase transitions, and related features in Raman spectra and their unexpected dependence on temperature and boron isotope.

A statewide genomic surveillance system for invasive Group A Streptococcus was implemented in Arizona in June 2019, resulting in 1046 isolates being submitted for genomic analysis to characterize emm types and identify transmission clusters. Eleven of the 32 identified distinct emm types comprised >80% of samples, with 29.7% of all isolates being typed as emm 49 (and its genetic derivative emm 151). Phylogenetic analysis initially identified an emm 49 genomic cluster of 4 isolates that rapidly expanded over subsequent months (June 2019 to February 2020). Public health investigations identified epidemiologic links with 3 different long-term care facilities, resulting in specific interventions. Unbiased genomic surveillance allowed for identification and response to clusters that would have otherwise remained undetected. [ABSTRACT FROM AUTHOR]

Cardiovascular and reproductive health of women have been going hand in hand since the dawn of time, yet links have been poorly studied. Still, once basis of their connections started to be established, it depended on local regional abilities and level of progressive thinking to afford women comprehensive care beyond the “bikini medicine”. Further research identified different associations rendering more conditions sex-specific and launching therefore a slow, yet initial turn around in clinical trials’ concept as the majority of global cardiovascular guidelines rely on the results of research conducted on a very modest percentage of women and even less on the women of color. Currently, the concept of women’s heart centers varies depending on the local demographics’ guided needs, available logistics driven by budgeting and societal support of a broad-minded thinking environment, free of bias for everyone: from young adults questioning their gender identity, via women of reproductive age both struggling to conceive or keep working part time when healthy and line of work permits it during pregnancy, up to aging and the elderly. Using “Investigate-Educate-Advocate-Legislate” as the four pillars of advancing cardiovascular care of women, we aimed to summarize standing of women’s health in Serbia, present ongoing projects and propose actionable solutions for the future.

Coccidioides immitis is a rare but emerging fungal pathogen in Washington, USA; Only the south-central region of Washington has been established as an area to which Coccidioides spp. are endemic; [...]

Historical risk assessment forms for a sample of 173 males with a history of violent offending and under supervision by Merseyside Youth Offending Services (YOS) were investigated. Subsequent arrest records were scrutinised in order to obtain a better understanding of the relationship of social and psychological risk factors to offending behavior. The mean age of the sample at the point of contact with YOS was 16.01 (SD = 1.37) with a range between 12 and 18 years. Assault was associated with solo expressive offending, a history of domestic violence, low school attendance and an inability to control impulsivity and aggression. Robbery was associated instrumental and escalated violent offending, psychological disorders, and deviant groups, including family criminal involvement. Risk assessments by professionals and the young people indicated that substance misuse co-occurred with robbery. The findings suggest that solo offenders commit the majority of violent offences and that targeted interventions should distinguish between expressive and instrumental offending. [ABSTRACT FROM AUTHOR]