Discovery of Imidazo[1,2-a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis.

The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.

Enhancing PHC nurses diabetes care.

Primary care settings are shouldering more of the care associatea with increasing rates of diabetes. Waikato's diabetes service is ensuring nurses working in these settings have the right skills and knowledge to provide quality care.

Sharps management in hospital: an audit of equipment, practice and awareness.

The safe handling and disposal of needles and other sharp instruments forms part of an overall strategy to protect staff, patients and visitors from exposure to blood-borne pathogens. As with many infection prevention and control policies, the assessment and management of the risks associated with the use of sharps is paramount, and safe systems of work and engineering controls must be in place to minimize any identified risks. The use of sharps in hospitals should be avoided where possible; when their use is essential, particular care is required in handling and disposal - if possible, use safer sharps devices. An audit of sharps management was undertaken to observe equipment, practice and awareness. The audit reported very positive results. However, some areas needed further review to improve practice. The infection control team implemented an action plan as a result of the audit and set about initiating measures for training and awareness. It is necessary to audit sharps management routinely to have an accurate assessment of current practice and prevent occupational exposure to blood-borne pathogens.

Best evidence topic report. Kocher's or Milch's technique for reduction of anterior shoulder dislocations.

A short cut review was carried out to establish whether Kocher's or Milch's technique was better at reducing shoulder dislocations. A total of 304 papers were found of which one answered the three part question. The clinical bottom line is that the individual preference of physicians for either Kocher's or Milch's method of reduction is not supported by the evidence.

Best evidence topic report. Intranasal naloxone in suspected opioid overdose.

A short cut review was carried out to establish whether intransasal naloxone is effective in suspected opiate overdose. 596 papers were screened, of which eight presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that it is likely that intranasal Naloxone is a safe and effective first line prehospital intervention in reversing the effects of an Opioid overdose and helping to reduce the risk of needle stick injury. A large, well conducted trial into it's usage is however required to confirm this.