Natural products from reconstructed bacterial genomes of the Middle and Upper Paleolithic.

Major advances over the past decade in the field of ancient DNA are providing access to past paleogenomic diversity, but the diverse functions and biosynthetic capabilities of this growing paleome remain largely elusive. We investigated the dental calculus of 12 Neanderthals and 52 anatomically modern humans ranging from 100,000 years ago to the present and reconstructed 459 bacterial metagenome-assembled genomes. We identified a biosynthetic gene cluster shared by seven Middle and Upper Paleolithic individuals that allows for the heterologous production of a class of previously unknown metabolites that we name "paleofurans." This paleobiotechnological approach demonstrates that viable biosynthetic machinery can be produced from the preserved genetic material of ancient organisms, allowing access to natural products from the Pleistocene and providing a promising area for natural product exploration.

S-Adenosylmethionine (SAM)-Dependent Methyltransferase MftM is Responsible for Methylation of the Redox Cofactor Mycofactocin.

Mycobacteria produce several unusual cofactors that contribute to their metabolic versatility and capability to survive in different environments. Mycofactocin (MFT) is a redox cofactor involved in ethanol metabolism. The redox-active core moiety of mycofactocin is derived from the short precursor peptide MftA, which is modified by several maturases. Recently, it has been shown that the core moiety is decorated by a ß-1,4-glucan chain. Remarkably, the second glucose moiety of the oligosaccharide chain was found to be 2-O-methylated in Mycolicibacterium smegmatis. The biosynthetic gene responsible for this methylation, however, remained elusive, and no methyltransferase gene was part of the MFT biosynthetic gene cluster. Here, we applied reverse genetics to identify the gene product of MSMEG_6237 (mftM) as the SAM-dependent methyltransferase was responsible for methylation of the cofactor in M. smegmatis. According to metabolic analysis and comparative genomics, the occurrence of methylated MFT species was correlated with the presence of mftM homologues in the genomes of mycofactocin producers. This study revealed that the pathogen Mycobacterium tuberculosis does not methylate mycofactocins. Interestingly, mftM homologues co-occur with both mycofactocin biosynthesis genes as well as the putative mycofactocin-dependent alcohol dehydrogenase Mdo. We further showed that mftM knock-out mutants of M. smegmatis suffer from a prolonged lag phase when grown on ethanol as a carbon source. In addition, in vitro digestion of the glucose chain by cellulase suggested a protective function of glucan methylation. These results close an important knowledge gap and provide a basis for future studies into the physiological functions of this unusual cofactor modification.

Domino C-C/C-O bond formation: palladium-catalyzed regioselective synthesis of 7-iodobenzo[b]furans using 1,2,3-triiodobenzenes and benzylketones.

A facile and efficient synthesis of 7-iodobenzo[b]furan derivatives via a highly regioselective tandem α-arylation/intramolecular O-arylation of 5-substituted-1,2,3-triiodobenzenes and benzylketones is described. Remarkably, the α-arylation coupling reactions initiate exclusively at the least sterically-hindered position of the triiodoarene, which results in a highly chemoselective transformation. The highest yields were observed in reactions between electron-poor 1,2,3-triiodoarenes and electron-rich benzylketones, yet the optimized reaction conditions were found to be tolerant to a wide range of different functional groups. This unprecedent synthesis of 7-iodobenzo[b]furans from 1,2,3-triiodobenzenes is scalable, general in scope, and provides easy access to valuable precursors for other chemical transformations.

Lumos: a statewide linkage programme in Australia integrating general practice data to guide system redesign.

Objective: With ageing of the Australian population, more people are living longer and experiencing chronic or complex health conditions. The challenge is to have information that supports the integration of services across the continuum of settings and providers, to deliver person-centred, seamless, efficient and effective healthcare. However, in Australia, data are typically siloed within health settings, precluding a comprehensive view of patient journeys. Here, we describe the establishment of the Lumos programme-the first statewide linked data asset across primary care and other settings in Australia and evaluate its representativeness to the census population. Methods and analysis: Records extracted from general practices throughout New South Wales (NSW), Australia's most populous state, were linked to patient records from acute and other settings. Innovative privacy and security technologies were employed to facilitate ongoing and regular updates. The marginal demographic distributions of the Lumos cohort were compared with the NSW census population by calculating multiple measures of representation to evaluate its generalisability. Results: The first Lumos programme data extraction linked 1.3 million patients' general practice records to other NSW health system data. This represented 16% of the NSW population. The demographic distribution of patients in Lumos was >95% aligned to that of the NSW population in the calculated measures of representativeness. Conclusion: The Lumos programme delivers an enduring, regularly updated data resource, providing unique insights about statewide, cross-setting healthcare utilisation. General practice patients represented in the Lumos data asset are representative of the NSW population overall. Lumos data can reliably be used to identify at-risk regions and groups, to guide the planning and design of health services and to monitor their impact throughout NSW.

Synthesis of Allylboranes via Cu(I)-Catalyzed B-H Insertion of Vinyldiazoacetates into Phosphine-Borane Adducts.

Cu(I) catalysts enable C-B bond formation via direct insertion of vinyldiazoacetates into B-H bonds of borane-phosphine Lewis adducts to form phosphine-protected allylboranes under mild conditions. The resulting allylborane-phosphine Lewis adducts can be used in the diastereoselective allylation of aldehydes directly without the need for removal of the phosphine. The allylation reaction proceeds with high diastereoselectivity and yields 5,6-disubstituted dihydropyranones after treatment with an appropriate acid.

Palladium-catalyzed highly regioselective mono and double Sonogashira cross-coupling reactions of 5-substituted-1,2,3-triiodobenzene under ambient conditions.

An efficient synthesis of 2,3-diiodinated diphenylacetylene and iodinated meta-terphenylacetylene derivatives through highly regioselective mono and double Sonogashira cross-coupling reactions of 5-substituted-1,2,3-triiodobenzene is reported. Significantly, the regioselectivity of coupling reactions is exclusively performed at the terminal C-I bonds, the less sterically hindered and the most regioactive positions. The highest isolated yields were achieved from reactions of electron-poor/neutral 1,2,3-triiodoarene and electron-rich arylacetylene derivatives. The use of 2.0 equiv. of arylacetylenes in one-pot fashion afforded the iodinated meta-terphenylacetylenes in excellent site selectivity and in good isolated yields. Different functional groups were found to be suitable under optimized conditions. This report discloses the first method to synthesize hitherto unknown 2,3-diiodinated diphenylacetylenes and iodinated meta-terphenylacetylenes that is facile, highly regioselective, general in scope and produces remarkable building blocks for other chemical transformations.

Assessing the effectiveness of decision aids for decision making in prostate cancer testing: a systematic review.

BACKGROUND: Prostate cancer is a leading disease affecting men worldwide. Conflicting evidence within the literature provides little guidance to men contemplating whether or not to be screened for prostate cancer. This systematic review aimed to determine whether decision aids about early detection of prostate cancer improve patient knowledge and decision making about whether to undergo prostate-specific antigen testing. METHODS: Medline, EMBASE, CINAHL, PsychINFO, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment databases up until March 2014 were searched. All included randomised controlled trials were assessed for methodological quality. Clinical selection and assessment heterogeneity among studies prevented the pooling of data for meta-analyses. Descriptive analyses of all included studies and comparison were performed. RESULTS: A total of 13 randomised controlled trials met the inclusion criteria. Significant heterogeneity was present for the design and implementation of decision aids including comparative interventions and outcomes. Eight studies were of a low methodological quality, with the remaining five of medium quality. Improvements in patient knowledge following use of a decision aid were demonstrated by 11 of the 13 included studies. Seven of 10 studies demonstrated a reduction in decisional conflict/distress. Three of four studies demonstrated no difference between a decision aid and information only in reducing decisional uncertainty. Three of five studies demonstrated an increase in decisional satisfaction with use of a decision aid. CONCLUSIONS: Decision aids increase patient knowledge and confidence in decision making about prostate cancer testing. Further research into effective methods of implementation is needed. Copyright © 2015 John Wiley & Sons, Ltd.

Opioid prescribing pitfalls: medicolegal and regulatory issues.

Inappropriate opioid prescribing can lead to patient harm as well as a medicolegal risk to prescribers. Prescribers need to be familiar with the indications, contraindications and harms associated with opioids. When prescribing opioids, doctors must be aware of their clinical, ethical and legal responsibilities, particularly the legislative requirements in their state. Failure to comply with these can result in disciplinary action. To avoid potential conflict with differing state regulations on opioid prescribing, doctors should advise patients to get their prescription dispensed in the same state in which it was written.

"CAM-creep": medical practitioners, professional discipline and integrative medicine.

This article examines the problem of applying disciplinary standards to the practice of integrative medicine. The article examines the structure of the National Law and discusses examples of when medical practitioners have been found to have breached professional standards because of their use of complementary and alternative medicine. The article argues there is a danger in medical practitioners who move away from the principles of evidence-based practice and informed consent in their adoption of integrative medicine. The authors posit a concept of "CAM-creep", situations where practitioners abandon medical professional standards in favour of ones from complementary and alternative medicine.