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Mycobacterium tuberculosis transmission through solid organ transplantation has been well described, but transmission through transplanted tissues is rare. We investigated a tuberculosis outbreak in the USA linked to a bone graft product containing live cells derived from a single deceased donor.In this outbreak report, we describe the management and severity of the outbreak and identify opportunities to improve tissue transplant safety in the USA. During early June, 2021, the US Centers for Disease Control and Prevention (CDC) worked with state and local health departments and health-care facilities to locate and sequester unused units from the recalled lot and notify, evaluate, and treat all identified product recipients. Investigators from CDC and the US Food and Drug Administration (FDA) reviewed donor screening and tissue processing. Unused product units from the recalled and other donor lots were tested for the presence of M tuberculosis using real-time PCR (rt PCR) assays and culture. M tuberculosis isolates from unused product and recipients were compared using phylogenetic analysis.The tissue donor (a man aged 80 years) had unrecognised risk factors, symptoms, and signs consistent with tuberculosis. Bone was procured from the deceased donor and processed into 154 units of bone allograft product containing live cells, which were distributed to 37 hospitals and ambulatory surgical centres in 20 US states between March 1 and April 2, 2021. From March 3 to June 1, 2021, 136 (88%) units were implanted into 113 recipients aged 24-87 years in 18 states (some individuals received multiple units). The remaining 18 units (12%) were located and sequestered. 87 (77%) of 113 identified product recipients had microbiological or imaging evidence of tuberculosis disease. Eight product recipients died 8-99 days after product implantation (three deaths were attributed to tuberculosis after recognition of the outbreak). All 105 living recipients started treatment for tuberculosis disease at a median of 69 days (IQR 56-81) after product implantation. M tuberculosis was detected in all eight sequestered unused units tested from the recalled donor lot, but not in lots from other donors. M tuberculosis isolates from unused product and recipients were more than 99·99% genetically identical.Donor-derived transmission of M tuberculosis via bone allograft resulted in substantial morbidity and mortality. All prospective tissue and organ donors should be routinely assessed for tuberculosis risk factors and clinical findings. When these are present, laboratory testing for M tuberculosis should be strongly considered.None.

In 2015, data released by the Association of American Medical Colleges (AAMC) showed that there were more Black men applying and matriculating to medical school in 1978 than 2014. The representation of Black men in medicine is a troubling workforce issue that was identified by the National Academies of Sciences, Engineering, and Medicine as a national crisis. While premedical pathway programs have contributed to increased workforce diversity, alone they are insufficient to accelerate change. In response, the AAMC and the National Medical Association launched a new initiative in August 2020, the Action Collaborative for Black Men in Medicine, to address the systems factors that influence the trajectory to medicine for Black men. The authors provide a brief overview of the educational experiences of Black boys and men in the United States and, as members of the Action Collaborative, describe their early work. Using research, data, and collective lived experiences, the Action Collaborative identified premedical and academic medicine systems factors that represented opportunities for change. The premedical factors include financing and funding, information access, pre-health advisors, the Medical College Admission Test, support systems, foundational academics, and alternative career paths. The academic medicine factors include early identification, medical school recruitment and admissions, and leadership accountability. The authors offer several points of intervention along the medical education continuum, starting as early as elementary school through medical school matriculation, for institutional leaders to address these factors as part of their diversity strategy. The authors also present the Action Collaborative's process for leveraging collective impact to build an equity-minded action agenda focused on Black men. They describe their initial focus on pre-health advising and leadership accountability and next steps to develop an action agenda. Collective impact and coalition building will facilitate active, broad engagement of partners across sectors to advance long-term systems change.

Objectives. To assess SARS-CoV-2 transmission within a correctional facility and recommend mitigation strategies. Methods. From April 29 to May 15, 2020, we established the point prevalence of COVID-19 among incarcerated persons and staff within a correctional facility in Arkansas. Participants provided respiratory specimens for SARS-CoV-2 testing and completed questionnaires on symptoms and factors associated with transmission. Results. Of 1647 incarcerated persons and 128 staff tested, 30.5% of incarcerated persons (range by housing unit = 0.0%–58.2%) and 2.3% of staff tested positive for SARS-CoV-2. Among those who tested positive and responded to symptom questions (431 incarcerated persons, 3 staff), 81.2% and 33.3% were asymptomatic, respectively. Most incarcerated persons (58.0%) reported wearing cloth face coverings 8 hours or less per day, and 63.3% reported close contact with someone other than their bunkmate. Conclusions. If testing remained limited to symptomatic individuals, fewer cases would have been detected or detection would have been delayed, allowing transmission to continue. Rapid implementation of mass testing and strict enforcement of infection prevention and control measures may be needed to mitigate spread of SARS-CoV-2 in this setting.

The complex interactions between the 2019 coronavirus disease (COVID-19) pandemic, structural racism, and mental health inequities have led to devastating health, economic, and social consequences. The intersection of these three conditions, which meets criteria for a syndemic (synergistic epidemics), presents numerous policy challenges-and opportunities. Addressing these issues in a unified manner, using a syndemic theory approach, can lead to significant progress and effective solutions for otherwise intransigent problems in society. This article proposes steps that can be taken to protect "essential workers" and other "vulnerable" populations; engage and empower communities; optimize community-led crisis response interventions; improve data collection about the intersection of COVID-19, structural racism, and mental health inequities; support school-based interventions; expand financial supports for mental health service delivery; expand health care insurance coverage to increase access and lower out-of-pocket costs; and promote workforce diversity. Emphasis on local, state, and federal policy interventions that prioritize equity and justice and focus on collective health and well-being will ultimately lead us on a more sustainable and equitable path.

Antibiotic resistance among gram-negative bacteria continues to rise globally at an alarming rate. New vaccines that prevent bacterial infections and reduce antibiotic use could provide a potential solution to these problems. This study focused on development of an investigational vaccine to prevent recurrent urinary traction infections (UTI) caused by gram-negative bacteria that use type 1 pili to adhere to, invade, and colonize human bladders. The vaccine antigen is FimH, an adhesin protein on the tip of type 1 pili with a lectin binding domain that enables attachment to glycoproteins on mammalian bladders. This was a phase 1, open-label, dose escalation study evaluating the vaccine in 67 healthy women with and without histories of recurrent UTI. The objectives of the study were to evaluate the safety, tolerability, and immunogenicity of different dosages of the antigen and adjuvant of the vaccine. All dosages were well-tolerated and a low incidence of systemic reactions occurred. No serious adverse events related to the vaccine were reported. The vaccine induced both binding and functional antibodies. The women with histories of recurrent UTI demonstrated greater than 150-fold increases in antibodies against the N-terminal region of FimH. Based on the results of this phase 1 study, this vaccine is proceeding to a double-blind, randomized, placebo-controlled phase 2 study. If this vaccine is successful in future studies, it could potentially prevent millions of recurrent UTI globally and reduce the development of antibiotic resistance.

Recurrent urinary tract infections (rUTI) are a serious disease associated with morbidities and mortality. Resistance to the standard of care antibiotics is now widespread because of the continued use of antibiotics among people who suffer from rUTI. We are therefore developing a vaccine to prevent recurrences among patients with rUTI. The antigen of the vaccine is FimH, a bacterial adhesin protein, and the vaccine is adjuvanted with a TLR-4 agonist. In a Phase 1 clinical study evaluating the vaccine, immunized individuals produced FimH-binding antibodies. Here we describe the optimization, qualification, and use of an assay to assess the functionality of these anti-FimH antibodies. The suitability of the assay for its intended purpose was demonstrated by selectivity, specificity, sensitivity, and intra-assay and inter-assay precision. The acceptance criteria were achieved for all parameters including intra-assay precision with ≤10% relative standard deviations and inter-assay precision with ≤25% relative standard deviations. The results presented herein suggest this functional assay will be important for supporting the vaccine’s efficacy in future human studies. Furthermore and of great significance, these results prove that vaccine-induced functional antibodies can be elicited in rUTI patients against an essential virulence factor, FimH.

Background Nucleic acid amplification (NAA) tests rapidly detect Mycobacterium tuberculosis complex directly from clinical specimens, providing valuable results for those evaluated for tuberculosis. Methods We analyzed characteristics of cases with NAA testing performed, compared cases with positive and negative NAA test results, and calculated turnaround time and time-to-treatment for all verified cases reported to the National Tuberculosis Surveillance System in the United States during 2011–2017. Results Among 67,082 verified tuberculosis cases with NAA testing information, 30,820 (45.9%) were reported as not having a NAA test performed; the proportion without NAA testing declined annually, from 60.5% in 2011 to 33.6% in 2017. Of 67,082 verified cases, 27,912 (41.6%) had positive, 8,215 (12.2%) had negative, and 135 (0.2%) had indeterminate NAA test results. Among the 33,937 cases with an acid-fast-bacilli–smear-positive result, 70.9% (24,093) had a NAA test performed; 38.0% (11,490) of the 30,244 with an acid-fast-bacilli–smear-negative result had a NAA test performed. Although sputum was the most common specimen type tested, 79.8% (7,023 of 8,804) of non-sputum specimen types had a positive NAA test result. Overall, 63.7% of cases with laboratory testing had NAA test results reported Conclusions Our analyses demonstrate increased NAA test utilization between 2011 and 2017. However, a large proportion of cases did not have a NAA test performed, reflecting challenges in broader uptake, suggesting an opportunity to expand use of this diagnostic methodology.

Background: Prior studies have documented racial and ethnic differences in mental healthcare utilization, and extensively in outpatient treatment and prescription medication usage for mental health disorders. However, limited studies have investigated racial and ethnic differences in length of inpatient stay (LOS) in patients with and without Serious and Persistent Mental Illness. Understanding racial and ethnic differences in LOS is necessary given that longer stays in hospital are associated with adverse health outcomes, which in turn contribute to health inequities. Objective: To examine racial and ethnic differences in length of stay among patients with and without serious and persistent mental illness (SPMI) and how these differences vary in two age cohorts: patients aged 18 to 64 and patients aged 65+. Methods: This study employed a retrospective cohort design to address the research objective, using the 2018 Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample. After merging the 2018 National Inpatient Sample’s Core and Hospital files, Generalized Linear Model (GLM), adjusting for covariates, was applied to examine associations between race and ethnicity, and length of stay for patients with and without SPMI. Results: Overall, patients from racialized groups were likely to stay longer than White patients regardless of severe mental health status. Of all races and ethnicities examined, Asian patients had the most extended stays in both age cohorts: 8.69 days for patients with SPMI and 5.73 days for patients without SPMI in patients aged 18 to 64 years and 8.89 days for patients with SPMI and 6.05 days for patients without SPMI in the 65+ cohort. For individuals aged 18 to 64, differences in length of stay were significantly pronounced in Asian patients (1.6 days), Black patients (0.27 days), and Native American patients/patients from other races (0.76 days) if they had SPMI. For individuals aged 65 and older, Asian patients (1.09 days) and Native American patients/patients from other races (0.45 days) had longer inpatient stays if they had SPMI. Conclusion: Racial and ethnic differences in inpatient length of stay were most pronounced in Asian patients with and without SPMI. Further studies are needed to understand the mechanism(s) for these differences.

Background: With the rapid development of new advanced molecular detection methods, identification of new genetic mutations conferring pathogen resistance to an ever-growing variety of antimicrobial substances will generate massive genomic datasets for public health and clinical laboratories. Keeping up with specialized standard coding for these immense datasets will be extremely challenging. This challenge prompted our effort to create a common molecular resistance Logical Observation Identifiers Names and Codes (LOINC) panel that can be used to report any identified antimicrobial resistance pattern. Objective: To develop and utilize a common molecular resistance LOINC panel for molecular drug susceptibility testing (DST) data exchange in the U.S. National Tuberculosis Surveillance System using California Department of Public Health (CDPH) and New York State Department of Health as pilot sites. Methods: We developed an interface and mapped incoming molecular DST data to the common molecular resistance LOINC panel using Health Level Seven (HL7) v2.5.1 Electronic Laboratory Reporting (ELR) message specifications through the Orion Health™ Rhapsody Integration Engine v6.3.1. Results: Both pilot sites were able to process and upload/import the standardized HL7 v2.5.1 ELR messages into their respective systems; albeit CDPH identified areas for system improvements and has focused efforts to streamline the message importation process. Discussion: The common molecular resistance LOINC panel is designed to be generalizable across other resistance genes and ideally also applicable to other disease domains. Conclusion: The study demonstrates that it is possible to exchange molecular DST data across the continuum of disparate healthcare information systems in integrated public health environments using the common molecular resistance LOINC panel. Keywords: Data Exchange Formats, Electronic Laboratory Reporting, Health Information Exchange, LOINC, Health Level Seven, Public Health Surveillance.

This article offers a brief history of mental health policies that have shaped current inequities in health care financing and service delivery. Mental health has a unique position within the health care system given the pervasive nature of stigma associated with illness; race and ethnicity often amplify this burden. The acknowledgment of disparities in mental health and the development of policies that address the needs of minority groups are relatively recent phenomena. Highlighted are legislative actions that have influenced reforms of the health care landscape. This text outlines opportunities to advance a targeted, community-based approach to mental health policy development.

OBJECTIVES: Capacity for safe and independent living (SAIL) refers to an individual’s ability to solve problems associated with everyday life and perform activities necessary for living independently. Little guidance exists on the assessment of capacity for SAIL among nursing home residents. As a result, capacity for SAIL is not fully considered in the development of discharge plans to ensure safety and independence in the community. We reasoned that this problem could be addressed with the Making and Executing Decisions for Safe and Independent Living (MEDSAIL) tool, developed to screen for capacity for SAIL among community-dwelling older adults. In this report, we describe findings on the validity of the MEDSAIL when used with nursing home residents. DESIGN: Prospective cross-sectional pilot study. SETTING AND PARTICIPANTS: Twenty-four residents of a Veterans Health Affairs Community Living Center (CLC; nursing home); exclusion criteria were cognitive impairment too severe to complete the protocol, diagnosis of serious mental illness or developmental disability, inability to hear, or inability to communicate verbally. METHODS: Participants completed 2 assessments: the MEDSAIL interview administered by a research assistant and the criterion standard capacity interview administered by a geriatric psychiatrist. We examined internal consistency, divergent validity, and criterion-based validity. RESULTS: Five of 7 MEDSAIL scenarios approximated acceptable levels of internal consistency (α >0.70). MEDSAIL scores were highly positively correlated with criterion standard capacity determination (0.88, P=.001), and the Wilcoxon rank-sum test statistic for the 2 assessments was also statistically significant (P =.001). CONCLUSIONS AND IMPLICATIONS: MEDSAIL has promise as a user-friendly brief screening tool for use by nursing home staff to understand resident capacity for SAIL. This information can be used in the development of discharge plans to keep the resident safe and independent in the community. In addition, tailoring the MEDSAIL scenarios specifically to the nursing home setting may further enhance the tool’s validity and utility in this new application. Published by Elsevier Inc. on behalf of AMDA – The Society for Post-Acute and Long-Term Care Medicine.

Drug-resistant tuberculosis poses a persistent public health threat. The ReSeqTB platform is a collaborative, curated knowledgebase, designed to standardize and aggregate global Mycobacterium tuberculosis complex (MTBC) variant data from whole genome sequencing (WGS) with phenotypic drug susceptibility testing (DST) and clinical data. We developed a unified analysis variant pipeline (UVP) ( https://github.com/CPTR-ReSeqTB/UVP ) to identify variants and assign lineage from MTBC sequence data. Stringent thresholds and quality control measures were incorporated in this open source tool. The pipeline was validated using a well-characterized dataset of 90 diverse MTBC isolates with conventional DST and DNA Sanger sequencing data. The UVP exhibited 98.9% agreement with the variants identified using Sanger sequencing and was 100% concordant with conventional methods of assigning lineage. We analyzed 4636 publicly available MTBC isolates in the ReSeqTB platform representing all seven major MTBC lineages. The variants detected have an above 94% accuracy of predicting drug based on the accompanying DST results in the platform. The aggregation of variants over time in the platform will establish confidence-graded mutations statistically associated with phenotypic drug resistance. These tools serve as critical reference standards for future molecular diagnostic assay developers, researchers, public health agencies and clinicians working towards the control of drug-resistant tuberculosis.

Objective Paclitaxel, a microtubule inhibitor, is subject to tumor resistance while treating high-grade serous ovarian and uterine cancer. This study aims to directly compare the effects of SQ1274, a novel microtubule inhibitor that binds to the colchicine-binding site on tubulin, and paclitaxel in high-grade serous ovarian and uterine cancer cell lines both in vitro and in vivo. Methods We assessed the sensitivity of ovarian (OVCAR8) and uterine (ARK1) cancer cell lines to SQ1274 and paclitaxel using XTT assays. We used western blot and quantitative real-time PCR to analyze changes in AXL RNA and protein expression by SQ1274 and paclitaxel. Differences in cell-cycle arrest and apoptosis were investigated using flow cytometry. Finally, we treated ovarian and uterine xenograft models with vehicle, paclitaxel, or SQ1274. Results First, we demonstrate that SQ1274 has a much lower IC50 than paclitaxel in both ARK1 (1.26 nM vs. 15.34 nM, respectively) and OVCAR8 (1.34 nM vs. 10.29 nM, respectively) cancer cell lines. Second, we show SQ1274 decreases both RNA and protein expression of AXL. Third, we show that SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel. Finally, we report that SQ1274 more effectively inhibits tumor growth in vivo compared to paclitaxel. Conclusions SQ1274 presents as a viable alternative to paclitaxel for treating ovarian and uterine cancer. This study supports the development of SQ1274 as a chemotherapeutic to treat ovarian and uterine cancer.

Tuberculosis is the primary infectious disease killer worldwide, with a growing threat from multidrug-resistant cases. Unfortunately, classic growth-based phenotypic drug susceptibility testing (DST) remains difficult, costly, and time consuming, while current rapid molecular testing options are limited by the diversity of antimicrobial-resistant genotypes that can be detected at once. Next-generation sequencing (NGS) offers the opportunity for rapid, comprehensive DST without the time or cost burden of phenotypic tests and can provide useful information for global surveillance. As access to NGS expands, it will be important to ensure that results are communicated clearly, consistent, comparable between laboratories, and associated with clear guidance on clinical interpretation of results. In this viewpoint article, we summarize 2 expert workshops regarding a standardized report format, focusing on relevant variables, terminology, and required minimal elements for clinical and laboratory reports with a proposed standardized template for clinical reporting NGS results for Mycobacterium tuberculosis., An expert consensus process was used to develop a standardized framework for reporting and communicating clinically relevant next-generation sequencing data from Mycobacterium tuberculosis for guiding drug treatment options.

Objectives: Public health laboratories (PHLs) provide essential services in the diagnosis and surveillance of diseases of public health concern, such as tuberculosis. Maintaining access to high-quality laboratory testing is critical to continued disease detection and decline of tuberculosis cases in the United States. We investigated the practical experience of sharing tuberculosis testing services between PHLs through the Shared Services Project. Methods: The Shared Services Project was a 9-month-long project funded through the Association of Public Health Laboratories and the Centers for Disease Control and Prevention during 2012-2013 as a one-time funding opportunity to consortiums of PHLs that proposed collaborative approaches to sharing tuberculosis laboratory services. Submitting PHLs maintained testing while simultaneously sending specimens to reference laboratories to compare turnaround times. Results: During the 9-month project period, 107 Mycobacterium tuberculosis complex submissions for growth-based drug susceptibility testing and molecular detection of drug resistance testing occurred among the 3 consortiums. The median transit time for all submissions was 1.0 day. Overall, median drug susceptibility testing turnaround time (date of receipt in submitting laboratory to result) for parallel testing performed in house by submitting laboratories was 31.0 days; it was 43.0 days for reference laboratories. The median turnaround time for molecular detection of drug resistance results was 1.0 day (mean = 2.8; range, 0-14) from specimen receipt at the reference laboratories. Conclusions: The shared services model holds promise for specialized tuberculosis testing. Sharing of services requires a balance among quality, timeliness, efficiency, communication, and fiscal costs.

Capacity for safe and independent living (SAIL) refers to an individual’s ability to solve problems associated with everyday life and perform activities necessary to live independently. Little guidance exists on the assessment of capacity for SAIL among nursing home residents. As a result, capacity for SAIL is not fully considered in the development of discharge plans to ensure safety and independence in the community. The Making and Executing Decisions for Safe and Independent Living (MEDSAIL) tool was developed to screen for capacity for SAIL among community-dwelling older adults. In this cross sectional pilot study, we tested the validity of MEDSAIL for use with nursing home residents. Participants were twenty-four residents of a Veterans Health Affairs nursing home. Exclusion criteria were cognitive impairment too severe to complete the protocol, diagnosis of serious mental illness or developmental disability, inability to hear, and inability to communicate verbally. Participants completed two assessments: the MEDSAIL interview administered by a research assistant and the criterion standard capacity interview administered by a geriatric psychiatrist. We examined internal consistency, convergent validity, divergent validity, and criterion-based validity. Five of seven MEDSAIL scenarios approximated acceptable levels of internal consistency (α>0.70). MEDSAIL scores were positively correlated with the criterion standard (0.88, p=0.001), and the Wilcoxon Rank Sum Test statistic was also statistically significant (p=0.001). MEDSAIL has promise as a user-friendly brief screening tool in nursing homes to understand resident capacity for SAIL and to inform development of discharge plans to keep the resident safe and independent in the community.

Numerous studies have addressed the mesoscale features within extratropical cyclones (ETCs) that are responsible for the most destructive winds, though few have utilized surface observation data, and most are based on case studies. By using a 39-station UK surface observation network, coupled with in-depth analysis of the causes of extreme gusts during the period 2008–2014, we show that larger-scale features (warm and cold conveyer belts) are most commonly associated with the top 1% of UK gusts but smaller-scale features generate the most extreme winds. The cold conveyor belt is far more destructive when joining the momentum of the ETC, rather than earlier in its trajectory, ahead of the approaching warm front. Sting jets and convective lines account for two thirds of severe surface gusts in the UK.

The first total synthesis of bifidenone, a novel natural tubulin polymerization inhibitor, has been achieved in 12 steps starting from commercially available 1,4-dioxaspiro[4.5]decan-8-one. The synthesis includes a newly developed method to generate the dihydrobenzodioxolone core by palladium-catalyzed aerobic dehydrogenation. The three stereocenters were installed with an AD-mix-β dihydroxylation step followed by a late-stage palladium-catalyzed decarboxylation-allylation procedure. The absolute stereochemistry of 3 was determined via 13a by single-crystal X-ray analysis.

Economically feasible systems for heterologous production of complex secondary metabolites originating from difficult to cultivate species are in demand since Escherichia coli and Saccharomyces cerevisiae are not always suitable for expression of plant and animal genes. An emerging oilseed crop, Camelina sativa, has recently been engineered to produce novel oil profiles, jet fuel precursors, and small molecules of industrial interest. To establish C. sativa as a system for the production of medicinally relevant compounds, we introduced four genes from Veratrum californicum involved in steroid alkaloid biosynthesis. Together, these four genes produce verazine, the hypothesized precursor to cyclopamine, a medicinally relevant steroid alkaloid whose analogs are currently being tested for cancer therapy in clinical trials. The future supply of this potential cancer treatment is uncertain as V. californicum is slow-growing and not amendable to cultivation. Moreover, the complex stereochemistry of cyclopamine results in low-yield syntheses. Herein, we successfully engineered C. sativa to synthesize verazine, as well as other V. californicum secondary metabolites, in seed. In addition, we have clarified the stereochemistry of verazine and related V. californicum metabolites.

10 Pages, 1 Figure, 3 Tables. Supplementary information: http://dx.doi.org/10.1038/s41598-018-33731-1, Drug-resistant tuberculosis poses a persistent public health threat. The ReSeqTB platform is a collaborative, curated knowledgebase, designed to standardize and aggregate global Mycobacterium tuberculosis complex (MTBC) variant data from whole genome sequencing (WGS) with phenotypic drug susceptibility testing (DST) and clinical data. We developed a unified analysis variant pipeline (UVP) ( https://github.com/CPTR-ReSeqTB/UVP ) to identify variants and assign lineage from MTBC sequence data. Stringent thresholds and quality control measures were incorporated in this open source tool. The pipeline was validated using a well-characterized dataset of 90 diverse MTBC isolates with conventional DST and DNA Sanger sequencing data. The UVP exhibited 98.9% agreement with the variants identified using Sanger sequencing and was 100% concordant with conventional methods of assigning lineage. We analyzed 4636 publicly available MTBC isolates in the ReSeqTB platform representing all seven major MTBC lineages. The variants detected have an above 94% accuracy of predicting drug based on the accompanying DST results in the platform. The aggregation of variants over time in the platform will establish confidence-graded mutations statistically associated with phenotypic drug resistance. These tools serve as critical reference standards for future molecular diagnostic assay developers, researchers, public health agencies and clinicians working towards the control of drug-resistant tuberculosis., This study was supported by the Bill & Melinda Gates Foundation under grant agreement OPP1115887 to C-Path for developing the ReSeqTB drug resistance data sharing platform and under grant agreement FIND OPP1115209 to address how to score mutations in the ReSeqTB data sharing platform initiative. The South African MRC and the EDCTP support K. Dheda. I. Comas is supported by the Ministerio de Economía y Competitividad (Spanish Government) research grant SAF2016-77346-R and the European Research Council (ERC) (638553-TB-ACCELERATE). L. Chindelevitch acknowledges support by NSERC, Genome Canada, and the Sloan Foundation. Use of trade names is for identification only and does not constitute endorsement by the US Department of Health and Human Services, the US Public Health Service, or the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency.

Ethambutol (EMB) is used as a part of drug regimens for treatment of tuberculosis (TB). Susceptibility ofMycobacterium tuberculosiscomplex (MTBC) isolates to EMB can be discerned by DNA sequencing to detect mutations in theembBgene associated with resistance. US Public Health Laboratories (PHL) primarily use growth-based drug susceptibility test (DST) methods to determine EMB resistance. The Centers for Disease Control and Prevention (CDC) provides a service for molecular detection of drug resistance (MDDR) by DNA sequencing and concurrent growth-based DST using agar proportion. PHL and CDC test results were compared for 211 MTBC samples submitted to CDC from September 2009 through February 2011. Concordance between growth-based DST results from PHL and CDC was 88.2%. A growth-based comparison of 39 samples, where anembBmutation associated with EMB resistance was detected, revealed a higher percentage of EMB resistance by CDC (84.6%) than by PHL (59.0%) which was significant (Pvalue = 0.002). Discordance between all growth-based test results from PHL and CDC was also significant (Pvalue = 0.003). Most discordance was linked to false susceptibility using the BACTEC™MGIT™960 (MGIT) growth-based system. Our analysis supports coalescing growth-based and molecular results for an informed interpretation of potential EMB resistance.

Various Staphylococcus species have been demonstrated to play important roles on the skin, including causing disease and protecting the host from pathogens. Although culture-based studies have isolated various Staphylococcus spp. from feline skin, very little is known regarding the species-level communities on the host.To describe the species-level staphylococcal communities inhabiting the skin of healthy cats and cats with allergic dermatitis.Skin swabs from the ear canal and groin of 11 healthy and 10 allergic (nonlesional) cats were obtained.DNA was extracted from the skin swabs and used for next-generation sequencing targeting the V1-3 region of the 16S rRNA gene. Following a standard microbiota analysis of the sequencing data, species-level assignment for the staphylococcal sequences were obtained using a staphylococci-specific database.Staphylococcus spp. had similar relative abundance in healthy and allergic samples. The most abundant staphylococcal species were S. epidermidis in healthy samples, and S. felis and S. capitis in allergic samples. The composition of staphylococcal communities, as well as relative abundance of Staphylococcus spp., was variable between body sites and individual cats sampled.These results demonstrate that diverse staphylococcal communities inhabit the skin of healthy and allergic cats, and provide a starting point for further research into the importance of Staphylococcus spp. in feline allergic skin disease.Plusieurs espèces de Staphylococcus ont montré un rôle important dans la peau, dont la cause de maladies ou la protection de l’hôte des pathogènes. Bien que les études basées sur les cultures aient permis d’isoler le nombreuses Staphylococcus spp. de la peau de chat, on en sait très peu sur les niveaux d’espèces de communautés de l’hôte. HYPOTHÈSES/OBJECTIFS: Décrire les communautés staphylococciques de niveau d’espèce occupant la peau de chats sains et de chats avec dermatites allergiques.Des écouvillons cutanés des conduits auriculaires et du nez de 11 chats sains et 10 chats allergiques (non lésionnels) ont été obtenus. MATÉRIELS ET MÉTHODES: L’ADN a été extrait d’écouvillons cutanés et utilisés pour le séquençage de dernière génération ciblant la région V1-3 du gène ARNr 16s. Suivant une analyse de microbiote standard des données de séquençage, la désignation des niveaux d’espèce pour les séquences staphylococciques ont été obtenues à l’aide de données spécifiques de staphylocoques. RÉSULTATS: Staphylococcus spp. était présent en quantité relative similaire pour les échantillons sains et allergiques. Les espèces de staphylocoques les plus abondantes étaient S. epidermidis dans les échantillons sains, et S. felis et S. capitis dans les échantillons allergiques. La composition des communautés de staphylocoques, ainsi que la quantité relative de Staphylococcus spp., était variable entre les sites corporels et entre les chats prélevés.Ces résultats démontrent que les communautés de staphylocoques diverses occupent la peau de chat sain et allergique et fournit un point de départ pour des recherches supplémentaires sur l’importance de Staphylococcus spp. dans les dermatoses allergiques félines.INTRODUCCIÓN: se ha demostrado que varias especies de Staphylococcus desempeñan papeles importantes en la piel, incluyendo causar enfermedades y proteger al huésped de los patógenos. Aunque los estudios basados ​​en cultivos han aislado varios Staphylococcus spp. de piel felina, se sabe muy poco sobre las comunidades a nivel de especie en el hospedador felino. HIPÓTESIS/OBJETIVOS: describir las comunidades estafilocócicas a nivel de especie que habitan la piel de gatos sanos y gatos con dermatitis alérgica. ANIMALES: se obtuvieron hisopos de piel del canal auditivo y de la ingle de 11 gatos sanos y 10 gatos alérgicos (sin lesiones). MÉTODOS Y MATERIALES: se extrajo el DNA de hisopos de la piel y se usó en secuenciación de próxima generación dirigida a la región V1-3 del gen 16s rRNA. Después de un análisis estándar de microbiota de los datos de secuenciación, se obtuvo la asignación a nivel de especie para las secuencias estafilocócicas utilizando una base de datos específica de estafilococos. RESULTADOS: Staphylococcus spp. tuvo abundancia relativa similar en muestras sanas y alérgicas. Las especies de estafilococos más abundantes fueron S. epidermidis en muestras sanas y S. felis y S. capitis en muestras alérgicas. La composición de las comunidades de estafilococos, así como la abundancia relativa de Staphylococcus spp., fue variable entre las zonas del cuerpo y en los gatos individuales muestreados. CONCLUSIONES Y RELEVANCIA CLÍNICA: estos resultados demuestran que diversas comunidades de estafilococos habitan en la piel de gatos sanos y alérgicos, y proporcionan un punto de partida para futuras investigaciones sobre la importancia de Staphylococcus spp. en la enfermedad cutánea alérgica felina.Es konnte gezeigt werden, dass verschiedene Staphylococcus Spezies eine wichtige Rolle auf der Haut spielen, so verursachen sie auch Erkrankungen und schützen den Wirt vor Krankheitserregern. Obwohl mittels Kultur-basierten Studien verschiedene Staphylococcus spp. von Katzenhaut isoliert werden konnten, ist sehr wenig bekannt über die Spezies-Level Arten auf dem Wirt.Die Beschreibung der Staphylokokken Spezies-Level Arten, die die Haut gesunder Katzen und die Haut von Katzen mit allergischer Dermatitis bewohnen.Es wurden Hauttupfer aus dem Ohrkanal und der Inguinalgegend von 11 gesunden und 10 allergischen (nicht-läsionalen) Katzen genommen.Es wurde DNA von den Hauttupfern extrahiert und für die Next-Generation Sequenzierung verwendet, welche auf die V1-3 Region des 16s rRNA Gens abzielte. Nach einer Standard Mikrobiota Analyse der Sequenzierungsdaten wurden Spezies-Level Zuordnungen der Staphylokokken Sequenzen mittels einer Staphylokokken-spezifischen Datenbank erzielt.Staphylococcus spp. zeigte eine ähnliche relative Häufigkeit bei gesunden wie auch bei allergischen Proben. Die am häufigsten vorkommende Staphylokokken Spezies waren S. epidermidis bei gesunden Proben und S. felis und S. capitis bei allergischen Proben. Die Zusammensetzung der Staphylokokken Arten sowie die relative Menge an Staphylococcus spp. war zwischen den verschiedenen Körperstellen und den individuellen Katzen, von denen Proben entnommen wurden, unterschiedlich.Diese Ergebnisse zeigen, dass diverse Staphylokokkenarten die Haut gesunder und allergischer Katzen bewohnen und stellen einen Ansatz für die weitere Forschung über die Wichtigkeit der Staphylococcus spp. bei Katzen mit allergischer Hauterkrankung dar.Várias espécies de Staphylococcustêm demonstrado desempenhar papéis importantes na pele, incluindo causar doenças e proteger o hospedeiro de patógenos. Embora estudos baseados em cultura tenham isolado diversos Staphylococcus spp. da pele de felinos, muito pouco se sabe sobre as comunidades em nível de espécie no hospedeiro. HIPÓTESE/OBJETIVOS: Descrever as comunidades estafilocócicas em nível de espécie que habitam a pele de gatos saudáveis e gatos com dermatite alérgica.Foram obtidos swabs de pele do conduto auditivo e virilha de 11 gatos saudáveis e 10 alérgicos (alesionais). MÉTODOS E MATERIAIS: O DNA foi extraído dos swabsde pele e utilizado para o sequenciamento de nova geração da região V1-3 do gene 16S rRNA. A partir uma análise de dados de microbiota padronizada para dados de sequenciamento, a atribuição em nível de espécie para as sequências estafilocócicas foi obtida usando um banco de dados específico para estafilococos.Staphylococcus spp. teve abundância relativa semelhante em amostras de gatos saudáveis e de alérgicos. As espécies estafilocócicas mais abundantes foram S. epidermidis em amostras de saudáveis e S. felis e S. capitis em amostras de alérgicos. A composição das comunidades estafilocócicas, bem como a abundância relativa de Staphylococcus spp., foi variável entre os locais do corpo e individualmente entre os gatos amostrados. CONCLUSÕES E RELEVÂNCIA CLÍNICA: Esses resultados demonstram que diversas comunidades estafilocócicas habitam a pele de gatos saudáveis e alérgicos e fornecem um ponto de partida para pesquisas futuras sobre a importância de Staphylococcus spp. na dermatite alérgica felina.背景: 様々なブドウ球菌種が、疾患の発生や病原体からの宿主の保護など、皮膚に重要な役割を果たすことが実証されている。培養ベースの研究は、猫の皮膚から様々なブドウ球菌属を分離しているが、宿主における種レベルのコミュニティについてはほとんど知られていない。 仮説/目的: 本研究の目的は、健常猫およびアレルギー性皮膚炎の猫の皮膚に生息する種レベルのブドウ球菌コミュニティについて説明することであった。 供試動物: 健常猫11頭およびアレルギー（非病変部位）猫11頭の外耳道および鼠径部の皮膚スワブを採取した。 材料と方法: 皮膚スワブからDNAを抽出し、16s rRNA遺伝子のV1-3領域をターゲットとした次世代シーケンシングを使用した。シーケンスデータの標準的な微生物叢解析に続いて、ブドウ球菌固有のデータベースを使用し、ブドウ球菌シーケンスに対する種レベルの割当を取得した。 結果: ブドウ球菌属は健常およびアレルギーサンプルで同様の相対量を有していた。最も豊富なブドウ球菌種は、健常サンプルではS.epidermidis、アレルギーサンプルではS.felisおよびS.capitisであった。ブドウ球菌コミュニティの組成およびブドウ球菌属の相対量は、身体部位および採取した個々の猫間で変動した。 結論と臨床的関連性: 本研究結果は、様々なブドウ球菌コミュニティが健常およびアレルギー猫の皮膚に生息していることを示しており、猫のアレルギー性皮膚疾患におけるブドウ球菌属の重要性に関するさらなる研究の出発点を提供している。.背景: 已证实各种葡萄球菌在皮肤上发挥重要作用，包括引起疾病和保护宿主免受病原体的影响。尽管从猫皮肤分离培养的研究发现了各种葡萄球菌，但对该宿主身上菌种水平的群落仍知之甚少。 假设/目的: 常驻在健康猫和过敏性皮炎猫皮肤上的葡萄球菌，对其菌种水平上的群落进行描述。 动物: 对11只健康猫和10只过敏（无病变）猫的耳道和腹股沟皮肤棉签采样。 方法和材料: 从皮肤棉签样本中提取DNA，使用针对16s rRNA基因V1-3区的新一代测序。对测序数据进行标准微生物群分析后，利用葡萄球菌特异性数据库，获得菌种水平上的葡萄球菌序列。 结果: 健康和过敏猫的葡萄球菌相对丰度很相似。在健康样本的葡萄球菌中，丰度最高的菌种为表皮葡萄球菌，过敏样本中为猫链球菌和头葡萄球菌。葡萄球菌的群落组成，以及葡萄球菌的相对丰度，在不同采样的身体部位和个体猫之间存在差异。 结论和临床相关性: 这些结果表明，健康和过敏猫皮肤上存在不同的葡萄球菌群落，并为猫过敏性皮肤病中的葡萄球菌，对其进一步研究的重要性提供了起点。.

Many human diseases, including cystic fibrosis lung infections, are caused or exacerbated by bacterial biofilms. Specialized modes of motility, including swarming and twitching, allow gram-negative bacteria to spread across surfaces and form biofilms. Compounds that inhibit these motilities could slow the spread of biofilms, thereby allowing antibiotics to work better. We previously demonstrated that a set of plant-derived triterpenes, including oleanolic acid and ursolic acid, inhibit formation of Escherichia coli and Pseudomonas aeruginosa biofilms, and alter expression of genes involved in chemotaxis and motility. In the present study, we have prepared a series of analogs of oleanolic acid. The analogs were evaluated against clinical isolates of E. coli and P. aeruginosa in biofilm formation assays and swarming assays. From these analogs, compound 9 was selected as a lead compound for further development. Compound 9 inhibits E. coli biofilm formation at 4 µg/mL; it also inhibits swarming at ≤1 µg/mL across multiple clinical isolates of P. aeruginosa, E. coli, Burkholderia cepacia, and Salmonella enterica, and at

Bifidenone is a novel natural tubulin polymerization inhibitor that exhibits antiproliferative activity against a range of human cancer cell lines, making it an attractive candidate for development. A synthetic route was previously developed to alleviate supply constraints arising from its isolation in microgram quantities from a Gabonese tree. Using that previously published route, we present here 42 analogues that were synthesized to examine the structure-activity relationship of bifidenone derivatives. In addition to in vitro cytotoxicity data, data from murine xenograft and pharmacokinetic studies were used to evaluate the analogues. Compounds 45b and 46b were found to demonstrate promising efficacy in murine xenograft experiments, and 46b had significantly more potent in vitro antiproliferative activity against taxane-resistant cell lines compared to that of paclitaxel.

Continued progress in addressing challenges associated with detection and management of tuberculosis requires new diagnostic tools. These tools must be able to provide rapid and accurate information for detecting resistance to guide selection of the treatment regimen for each patient. To achieve this goal, globally representative genotypic, phenotypic, and clinical data are needed in a standardized and curated data platform. A global partnership of academic institutions, public health agencies, and nongovernmental organizations has been established to develop a tuberculosis relational sequencing data platform (ReSeqTB) that seeks to increase understanding of the genetic basis of resistance by correlating molecular data with results from drug susceptibility testing and, optimally, associated patient outcomes. These data will inform development of new diagnostics, facilitate clinical decision making, and improve surveillance for drug resistance. ReSeqTB offers an opportunity for collaboration to achieve improved patient outcomes and to advance efforts to prevent and control this devastating disease.

The compass plant, Silphium laciniatum, is an iconic perennial plant of the North American tallgrass prairie. The plants of the tallgrass prairie historically have been subjected to a number of biological and environmental stresses. Among the adaptations developed by S. laciniatum is a large deep taproot. An investigation of the secondary metabolites found in the root of a S. laciniatum specimen has led to the identification of 15 new terpenoids (3-8, 10-17, and 22), which were screened for cytotoxic activity in the NCI-H460 human large-cell lung carcinoma cell line.

Grindelia robusta or gumweed, is a medicinal herb of the sunflower family that forms a diverse suite of diterpenoid natural products. Its major constituents, grindelic acid and related grindelane diterpenoids accumulate in a resinous exudate covering the plants' surfaces, most prominently the unopened composite flower. Recent studies demonstrated potential pharmaceutical applications for grindelic acid and its synthetic derivatives. Mining of the previously published transcriptome of G. robusta flower tissue identified two additional diterpene synthases (diTPSs). We report the in vitro and in vivo functional characterization of an ent-kaurene synthase of general metabolism (GrTPS4) and a class II diTPS (GrTPS2) of specialized metabolism that converts geranylgeranyl diphosphate (GGPP) into labda-7,13E-dienyl diphosphate as verified by nuclear magnetic resonance (NMR) analysis. Tissue-specific transcript abundance of GrTPS2 in leaves and flowers accompanied by the presence of an endocyclic 7,13 double bond in labda-7,13E-dienyl diphosphate suggest that GrTPS2 catalyzes the first committed reaction in the biosynthesis of grindelic acid and related grindelane metabolites. With the formation of labda-7,13E-dienyl diphosphate, GrTPS2 adds an additional function to the portfolio of monofunctional class II diTPSs, which catalytically most closely resembles the bifunctional labda-7,13E-dien-15-ol synthase of the lycopod Selaginella moellendorffii. Together with a recently identified functional diTPS pair of G. robusta producing manoyl oxide, GrTPS2 lays the biosynthetic foundation of the diverse array of labdane-related diterpenoids in the genus Grindelia. Knowledge of these natural diterpenoid metabolic pathways paves the way for developing biotechnology approaches toward producing grindelic acid and related bioproducts.

Steroid alkaloids have been shown to elicit a wide range of pharmacological effects that include anticancer and antifungal activities. Understanding the biosynthesis of these molecules is essential to bioengineering for sustainable production. Herein, we investigate the biosynthetic pathway to cyclopamine, a steroid alkaloid that shows promising antineoplastic activities. Supply of cyclopamine is limited, as the current source is solely derived from wild collection of the plant Veratrum californicum. To elucidate the early stages of the pathway to cyclopamine, we interrogated a V. californicum RNA-seq dataset using the cyclopamine accumulation profile as a predefined model for gene expression with the pattern-matching algorithm Haystack. Refactoring candidate genes in Sf9 insect cells led to discovery of four enzymes that catalyze the first six steps in steroid alkaloid biosynthesis to produce verazine, a predicted precursor to cyclopamine. Three of the enzymes are cytochromes P450 while the fourth is a γ-aminobutyrate transaminase; together they produce verazine from cholesterol.

Plants, fungi, and bacteria synthesize the aromatic amino acids: l-phenylalanine, l-tyrosine, and l-tryptophan. Chorismate mutase catalyzes the branch point reaction of phenylalanine and tyrosine biosynthesis to generate prephenate. In Arabidopsis thaliana, there are two plastid-localized chorismate mutases that are allosterically regulated (AtCM1 and AtCM3) and one cytosolic isoform (AtCM2) that is unregulated. Previous analysis of plant chorismate mutases suggested that the enzymes from early plants (i.e. bryophytes/moss, lycophytes, and basal angiosperms) formed a clade distinct from the isoforms found in flowering plants; however, no biochemical information on these enzymes is available. To understand the evolution of allosteric regulation in plant chorismate mutases, we analyzed a basal lineage of plant enzymes homologous to AtCM1 based on sequence similarity. The chorismate mutases from the moss/bryophyte Physcomitrella patens (PpCM1 and PpCM2), the lycophyte Selaginella moellendorffii (SmCM), and the basal angiosperm Amborella trichopoda (AmtCM1 and AmtCM2) were characterized biochemically. Tryptophan was a positive effector for each of the five enzymes examined. Histidine was a weak positive effector for PpCM1 and AmtCM1. Neither tyrosine nor phenylalanine altered the activity of SmCM; however, tyrosine was a negative regulator of the other four enzymes. Phenylalanine down-regulates both moss enzymes and AmtCM2. The 2.0 Å X-ray crystal structure of PpCM1 in complex with the tryptophan identified the allosteric effector site and reveals structural differences between the R- (more active) and T-state (less active) forms of plant chorismate mutases. Molecular insight into the basal plant chorismate mutases guides our understanding of the evolution of allosteric regulation in these enzymes.

The pursuit of structurally novel compounds has led to the isolation of a series of neolignans (2–6), for which the structures have been determined from microgram quantities using microcryoprobe NMR technology. Compounds 2–6 provided some unexpectedly clear structure–activity relationship data, with compound 2 demonstrating significantly more potency in the in vitro cytotoxicity assay than the other analogues. Further screening found that compound 2 induces apoptosis with activation of caspase 3/7. The NCI Compare algorithm suggested that compound 2 acts through the inhibition of tubulin/microtubule dynamics. Compound 2 was confirmed to be a tubulin polymerization inhibitor that binds directly to tubulin.

The lack of capacity to provide laboratory confirmation of a diagnosis of tuberculosis disease (TB) is contributing to enormous gaps in the ability to find, treat and follow TB patients. WHO estimates that globally only about 57% of the notified new cases of pulmonary TB in 2012 and about 19% of rifampicin-resistant TB cases were laboratory confirmed. The Cepheid Xpert(®) MTB/RIF assay has been credited with revolutionizing laboratory testing to aid in the diagnosis of TB and rifampicin-resistant TB. This semi-automated test can detect both the causative agent of TB and mutations that confer rifampicin resistance from clinical specimens within 2 h after starting the test. In this article, we review the performance of the test, its pathway to regulatory approval and endorsement, guidelines for its use and lessons learned from the implementation of the test in low-burden, high-resource countries and in high-burden, low-resource countries.

Summary Marrubium vulgare (Lamiaceae) is a medicinal plant whose major bioactive compounds, marrubiin and other labdane–related furanoid diterpenoids, have potential applications as anti–diabetics, analgesics or vasorelaxants. Metabolite and transcriptome profiling of M. vulgare leaves identified five different candidate diterpene synthases (diTPSs) of the TPS–c and TPS–e/f clades. We describe the in vitro and in vivo functional characterization of the M. vulgare diTPS family. In addition to MvEKS ent–kaurene synthase of general metabolism, we identified three diTPSs of specialized metabolism: MvCPS3 (+)-copalyl diphosphate synthase, and the functional diTPS pair MvCPS1 and MvELS. In a sequential reaction, MvCPS1 and MvELS produce a unique oxygenated diterpene scaffold 9,13-epoxy-labd-14-ene en route to marrubiin and an array of related compounds. In contrast with previously known diTPSs that introduce a hydroxyl group at carbon C–8 of the labdane backbone, the MvCPS1-catalyzed reaction proceeds via oxygenation of an intermediate carbocation at C–9, yielding the bicyclic peregrinol diphosphate. MvELS belongs to a subgroup of the diTPS TPS–e/f clade with unusual βα–domain architecture. MvELS is active in vitro and in vivo with three different prenyl diphosphate substrates forming the marrubiin precursor 9,13-epoxy-labd-14-ene, as identified by nuclear magnetic resonance (NMR) analysis, manoyl oxide and miltiradiene. MvELS fills a central position in the biosynthetic system that forms the foundation for the diverse repertoire of Marrubium diterpenoids. Co-expression of MvCPS1 and MvELS in engineered E. coli and Nicotiana benthamiana offers opportunities for producing precursors for an array of biologically active diterpenoids.

Species extinction is tantamount to loss of chemical diversity, and so it is important to seize all opportunities to study species on the brink of extinction. Such studies are often hampered by the limited material available, but that obstacle is surmountable through collaboration with botanical gardens and advances in instrumentation. The goldenrod Solidago shortii is one example of an endangered species native to the United States. From S. shortii, one known diterpene (1), two new diterpenes (2 and 3), and three new hydrolysis products (4-6) are described. This work was made possible through collaboration with the Missouri Botanical Garden and with the use of highly sensitive microcryoprobe NMR technology for structure elucidation and VCD spectroscopy for the determination of absolute configuration.

Six chromene stilbenoids and one chromane stilbenoid were isolated from the African tree Hymenocardia acida. Several were moderately active against methicillin-resistant Staphylococcus aureus clinical isolate MRSA-108, including hymenocardichromanic acid, which was active at 8 μg/ml. None had IC50 values

The first study of the chemical constituents of Combretum inflatum has resulted in the isolation of seven new acetylated dammarane-type bisdesmosides (1-7). Their structures were determined from microgram quantities on hand using Bruker BioSpin TCI 1.7 mm MicroCryoProbe technology, ESIMS, and comparison to data found in the literature. Compounds 1-7 were screened for inhibition of an Escherichia coli strain UTI89 biofilm, MRSA inhibition, and cytotoxicity in NCI-H460 human lung cancer cells. Compounds 3-7 reduced the growth of MRSA at 16 μg/mL by 71-45%, and compound 7 had an IC₅₀ value of 3.9 μM in NCI-H460.

Prostate cancer mortality rates are highest among men of African ancestry in the United States and globally. Environmental exposures and ancestry-related factors may influence tumor biology and induce a more aggressive disease in this population. Here, we summarize the most recent advances in our understanding of race/ethnic differences in the tumor biology of prostate cancer with an emphasis on the excess disease burden among African-Americans.Results from several DNA methylation studies showed an increased prevalence in DNA hypermethylation at disease-related loci in tumors from African-American patients compared with tumors from European-American patients. Analyses of genome-wide gene expression in prostate tumors revealed frequent alterations in the expression of genes related to immunobiology among the African-American patients, consistent with immune response differences between them and their European-American counterparts. Lastly, population differences in the frequency of oncogenic erythroblast transformation-specific family of transcription factors (ETS)-related gene rearrangements were evaluated in three studies that showed that these alterations manifest themselves most commonly in tumors from men of European ancestry, but are significantly less frequent in men of African ancestry, whereas least common in men of Asian ancestry.Analysis of tumor markers indicates that tumor biological differences may exist between prostate cancer patients of African ancestry and those of European or Asian ancestry. These differences could affect disease aggressiveness and response to therapy.