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\"Understand the context of negotiations to achieve better resultsNegotiation has always been at the heart of solving problems at work. Yet today, when people in organizations are asked to do more with less, be responsive 24/7, and manage in rapidly changing environments, negotiation is more essential than ever. What has been missed in much of the literature of the past 30 years is that negotiations in organizations always take place within a context--of organizational culture, of prior negotiations, of power relationships--that dictates which issues are negotiable and by whom. When we negotiate for new opportunities or increased flexibility, we never do it in a vacuum. We challenge the status quo and we build out the path for others to negotiate those issues after us. In this way, negotiating for ourselves at work can create small wins that can grow into something bigger, for ourselves and our organizations. Seen in this way, negotiation becomes a tool for addressing ineffective practices and outdated assumptions, and for creating change.Small Wins, Big Gains offers practical advice for managing your own workplace negotiations: how to get opportunities, promotions, flexibility, buy-in, support, and credit for your work. It does so within the context of organizational dynamics, recognizing that to negotiate with someone who has more power adds a level of complexity. This is true when we negotiate with our managers, and it's also true for women and people of color who are even more likely to meet with resistance. Small Wins, Big Gains is rooted in real-life cases of professionals from a wide range of industries and organizations, both national and international. Strategies to get the other person to the table and engage in creative problem solving, even when they are reluctant to do so Tips on how to recognize opportunities to negotiate, bolster your confidence prior to the negotiation, turn 'asks' into a negotiation, and advance negotiations that get \"stuck\" A rich examination of research on negotiation, conflict management, and gender Videos that walk you through difficult negotiation scenarios step-by-step By using these strategies, you can negotiate successfully for your job and your career; in a larger field, you can also alter organizational practices and policies that impact others\"-- Provided by publisher.

Antimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin-susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen.

Addressing the transmission enigma of the neglected disease Buruli ulcer (BU) is a World Health Organization priority. In Australia, we have observed an association between mosquitoes harboring the causative agent, Mycobacterium ulcerans, and BU. Here we tested a contaminated skin model of BU transmission by dipping the tails from healthy mice in cultures of the causative agent, Mycobacterium ulcerans. Tails were exposed to mosquito (Aedes notoscriptus and Aedes aegypti) blood feeding or punctured with sterile needles. Two of 12 of mice with M. ulcerans contaminated tails exposed to feeding A. notoscriptus mosquitoes developed BU. There were no mice exposed to A. aegypti that developed BU. Eighty-eight percent of mice (21/24) subjected to contaminated tail needle puncture developed BU. Mouse tails coated only in bacteria did not develop disease. A median incubation time of 12 weeks, consistent with data from human infections, was noted. We then specifically tested the M. ulcerans infectious dose-50 (ID50) in this contaminated skin surface infection model with needle puncture and observed an ID50 of 2.6 colony-forming units. We have uncovered a biologically plausible mechanical transmission mode of BU via natural or anthropogenic skin punctures.

Nontuberculosis mycobacterial (NTM) infections are increasing in prevalence across the world. In many cases, treatment options for these infections are limited. However, there has been progress in recent years in the development of new antimycobacterial drugs. Here, we investigate the in vitro activity of SPR719, a novel aminobenzimidazole antibiotic and the active form of the clinical-stage compound, SPR720, against several isolates of Mycobacterium ulcerans , Mycobacterium marinum and Mycobacterium chimaera . We show that SPR719 is active against these NTM species with a MIC range of 0.125–4 μg/ml and that this compares favorably with the commonly utilized antimycobacterial antibiotics, rifampicin and clarithromycin. Our findings suggest that SPR720 should be further evaluated for the treatment of NTM infections.

Mycobacterium kansasii can cause serious pulmonary disease. It belongs to a group of closely-related species of non-tuberculous mycobacteria known as the M. kansasii complex (MKC). Here, we report a population genomics analysis of 358 MKC isolates from worldwide water and clinical sources. We find that recombination, likely mediated by distributive conjugative transfer, has contributed to speciation and on-going diversification of the MKC. Our analyses support municipal water as a main source of MKC infections. Furthermore, nearly 80% of the MKC infections are due to closely-related M. kansasii strains, forming a main cluster that apparently originated in the 1900s and subsequently expanded globally. Bioinformatic analyses indicate that several genes involved in metabolism (e.g., maintenance of the methylcitrate cycle), ESX-I secretion, metal ion homeostasis and cell surface remodelling may have contributed to M. kansasii ’s success and its ongoing adaptation to the human host. Mycobacterium kansasii can cause serious pulmonary disease. Here, the authors present a population genomics analysis of 358 environmental and clinical isolates from around the world, supporting the idea that municipal water is a main source of infection, and shedding light into the pathogen’s diversity and adaptation to the human host.

Buruli ulcer (BU) is a neglected tropical disease of skin and subcutaneous tissues caused by Mycobacterium ulcerans . BU-endemic areas are highly focal, and M . ulcerans transmission dynamics vary by setting. In Victoria, Australia, BU is an endemic vector-borne zoonosis, with mosquitoes and native possums implicated in transmission, and humans incidental hosts. Despite the importance of possums as wildlife reservoirs of M . ulcerans , knowledge of BU in these animals is limited. Opportunistic necropsy-based and active trap-and-release surveillance studies were conducted across Melbourne and Geelong, Victoria, to investigate BU in possums. Demographic data and biological samples were collected, and cutaneous lesions suggestive of BU were mapped. Samples were tested for the presence of M . ulcerans DNA by IS 2404 qPCR. The final dataset included 26 possums: 20 necropsied; 6 trapped and released. Most possums (77%) were common ringtails from inner Melbourne. Nine had ulcers, ranging from single and mild, to multiple and severe, exposing bones and tendons in three cases. M . ulcerans was confirmed in 73% (19/26) of examined possums: 8 with lesions and 11 without. Oral swabs were most frequently indicative of M . ulcerans infection status. Severely ulcerated possums had widespread systemic internal bacterial dissemination and were shedding M . ulcerans in faeces. The anatomical distribution of ulcers and PCR positivity of biological samples suggests possums may contract BU from bites of M . ulcerans -harbouring mosquitoes, traumatic skin wounds, ingestion of an unknown environmental source, and/or during early development in the pouch. Ringtail possums appear highly susceptible to infection with M . ulcerans and are important bacterial reservoirs in Victoria. Oral swabs should be considered for diagnosis or surveillance of infected possums. A One Health approach is needed to design and implement integrated interventions that reduce M . ulcerans transmission in Victoria, thereby protecting wildlife and humans from this emerging zoonotic disease.

Introduction Mycobacterium ulcerans (MU) causes Buruli ulcer (Buruli), a geographically restricted infection that can result in skin loss, contracture and permanent scarring. Lesion-location maps compiled from more than 640 cases in south eastern Australia suggest biting insects are likely involved in transmission, but it is unclear whether MU is brought by insects to humans or if MU is already on the skin and inoculation is an opportunistic event that need not be insect dependent. Methods We validated a PCR swab detection assay and defined its dynamic range using laboratory cultured M. ulcerans and fresh pigskin. We invited volunteers in Buruli-endemic and non-endemic areas to sample their skin surfaces with self-collected skin swabs tested by IS2404 quantitative PCR. Results Pigskin validation experiments established a limit-of-detection of 0.06 CFU/cm.sup.2 at a qPCR cycle threshold (Ct) of 35. Fifty-seven volunteers returned their self-collected kits of 4 swabs (bilateral ankles, calves, wrists, forearms), 10 from control areas and 47 from endemic areas. Collection was timed to coincide with the known peak-transmission period of Buruli. All swabs from human volunteers tested negative (Ct [greater than or equal to]35). Conclusions M. ulcerans was not detected on the skin of humans from highly Buruli endemic areas.

Reconstructing the evolutionary origins of Mycobacterium tuberculosis , the causative agent of human tuberculosis, has helped identify bacterial factors that have led to the tubercle bacillus becoming such a formidable human pathogen. Here we report the discovery and detailed characterization of an exceedingly slow growing mycobacterium that is closely related to M . tuberculosis for which we have proposed the species name Mycobacterium spongiae sp. nov., (strain ID: FSD4b-SM). The bacterium was isolated from a marine sponge, taken from the waters of the Great Barrier Reef in Queensland, Australia. Comparative genomics revealed that, after the opportunistic human pathogen Mycobacterium decipiens , M . spongiae is the most closely related species to the M . tuberculosis complex reported to date, with 80% shared average nucleotide identity and extensive conservation of key M . tuberculosis virulence factors, including intact ESX secretion systems and associated effectors. Proteomic and lipidomic analyses showed that these conserved systems are functional in FSD4b-SM, but that it also produces cell wall lipids not previously reported in mycobacteria. We investigated the virulence potential of FSD4b-SM in mice and found that, while the bacteria persist in lungs for 56 days after intranasal infection, no overt pathology was detected. The similarities with M . tuberculosis , together with its lack of virulence, motivated us to investigate the potential of FSD4b-SM as a vaccine strain and as a genetic donor of the ESX-1 genetic locus to improve BCG immunogenicity. However, neither of these approaches resulted in superior protection against M . tuberculosis challenge compared to BCG vaccination alone. The discovery of M . spongiae adds to our understanding of the emergence of the M . tuberculosis complex and it will be another useful resource to refine our understanding of the factors that shaped the evolution and pathogenesis of M . tuberculosis .

We describe two locally acquired cases of Mycobacterium ulcerans infection (Buruli ulcer) in the town of Batemans Bay on the east coast of New South Wales (NSW), Australia, 150 km north of Eden, the only other place in NSW where Buruli ulcer has likely been locally acquired. Genomic analysis showed that the bacterial isolates from the cases were identical but belonged to a phylogenetically distinct M. ulcerans clade that was most closely related to the isolate from the earlier case in Eden to the south. It is proposed that Batemans Bay is a new endemic focus of human Buruli ulcer transmission.

Buruli ulcer (BU) is an infection of subcutaneous tissue caused by Mycobacterium ulcerans . This bacterial infection affects the lives of thousands of people each year across West and Central Africa and Australia. Recent research showed that as few as 2–3 M. ulcerans are sufficient to cause infection. Unfortunately, earlier laboratory studies have used unrealistically high bacterial doses to test new vaccines or to understand host responses, compromising subsequent conclusions. This research is significant because it takes a fresh approach to develop an experimental animal infection model for BU that uses a carefully calibrated and realistic infectious dose. The findings from assessing this new infection model are the foundation for an ambitious new program to develop a controlled human infection model for M. ulcerans , a platform for developing new therapies to prevent and treat BU.