Comprehensive geriatric assessment in perioperative care: a protocol for a systematic review and qualitative synthesis

INTRODUCTION: Comprehensive geriatric assessment (CGA) is an intervention that has been deployed in the perioperative setting with the aim to improve outcomes for older patients admitted to hospital. Older patients undergoing surgery are more likely to have postoperative complications, a longer hospital stay and be discharged to a care facility. Despite the increasing application of this intervention within surgical services, the evidence for CGA remains limited in this group. The aim of this systematic review is to describe CGA as in intervention applied to surgical populations in randomised controlled trials (RCTs) as well as the outcomes assessed. METHODS AND ANALYSIS: A systematic search of RCTs of CGA in surgery will be run in Embase, Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Cochrane library. Further articles will be identified from reference lists in relevant studies found in the search. A narrative synthesis will be undertaken outlining specialties included, detailed descriptions of the intervention and outcomes. ETHICS AND DISSEMINATION: No ethical approval is required. The results of this review will be published and used as the basis of work to optimise this intervention for future trials in surgical populations. PROSPERO REGISTRATION NUMBER: This review is registered with PROSPERO CRD42020221797

Novel dehydroepiandrosterone troche supplementation improves the serum androgen profile of women undergoing in vitro fertilization

Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in the circulation and has potent multifunctional activity. Epidemiological evidence suggests that levels of serum DHEA decrease with advancing age, and this has been associated with onset or progression of various age-related ailments, including cognitive decline and dementia, cardiovascular disease, and obesity. Consequently, these findings have sparked intense research interest in DHEA supplementation as an “antiaging” therapy. Currently, DHEA is being used by 25% of in vitro fertilization (IVF) clinicians as an adjuvant in assisted reproductive programs, yet the therapeutic benefit of DHEA is unclear. Here, we examined the use of novel DHEA-containing oral troches in patients undertaking IVF and investigated the impact of these troches on their serum androgen profile. This retrospective study determined the androgen profile of 31 IVF patients before (baseline) and after DHEA supplementation (with DHEA). Baseline serum measurements of testosterone (total and free), DHEA sulfate (DHEAS), sex hormone-binding globulin (SHBG), and androstenedione were made before and after supplementation. Each patient received DHEA troches containing 25 mg of micronized DHEA, and troches were administered sublingually twice daily for a period of no greater than 4 months. Adjuvant treatment with DHEA boosted the serum concentration of a number of androgen-related analytes, including total and free testosterone, androstenedione, and DHEAS, while serum SHBG remained unchanged. Supplementation also significantly increased the free-androgen index in IVF patients. Interestingly, the increase in serum analyte concentration following DHEA supplementation was found to be dependent on body mass index (BMI), but not individual age.Patients with the lowest BMI (30.0 kg/m2) tended to have lower androgen responses following DHEA supplementation, but these were not statistically different from the corresponding baseline level. This method of DHEA administration results in a similar enhancement of testosterone, DHEAS, and androstenedione levels in comparison with other methods of administration. Furthermore, we showed that BMI significantly influences DHEA uptake and metabolism, and that BMI should be carefully considered during dosage calculation to ensure a significant and robust androgen-profile boost

Structure of an atypical periplasmic adaptor from a multidrug efflux pump of the spirochete Borrelia burgdorferi.

Periplasmic adaptor proteins are essential components of bacterial tripartite multidrug efflux pumps. Here we report the 2.35 Å resolution crystal structure of the BesA adaptor from the spirochete Borrelia burgdorferi solved using selenomethionine derivatized protein. BesA shows the archetypal linear, flexible, multi-domain architecture evident among proteobacteria and retains the lipoyl, β-barrel and membrane-proximal domains that interact with the periplasmic domains of the inner membrane transporter. However, it lacks the α-hairpin domain shown to establish extensive coiled-coil interactions with the periplasmic entrance helices of the outer membrane-anchored TolC exit duct. This has implications for the modelling of assembled tripartite efflux pumps.This is the final published version. It is available from the publisher here: http://www.sciencedirect.com/science/article/pii/S0014579313005206

Structure of the periplasmic adaptor protein from a major facilitator superfamily (MFS) multidrug efflux pump.

Periplasmic adaptor proteins are key components of bacterial tripartite efflux pumps. The 2.85 Å resolution structure of an MFS (major facilitator superfamily) pump adaptor, Aquifex aeolicus EmrA, shows linearly arranged α-helical coiled-coil, lipoyl, and β-barrel domains, but lacks the fourth membrane-proximal domain shown in other pumps to interact with the inner membrane transporter. The adaptor α-hairpin, which binds outer membrane TolC, is exceptionally long at 127 Å, and the β-barrel contains a conserved disordered loop. The structure extends the view of adaptors as flexible, modular components that mediate diverse pump assembly, and suggests that in MFS tripartite pumps a hexamer of adaptors could provide a periplasmic seal.This work was supported by grants from the UK Medical Research Council and The Wellcome Trust to C.H. and V.KThis is the advanced access version of the article, distributed under a Creative Commons Attribution License. It can also be found on the publisher's website at: http://www.sciencedirect.com/science/article/pii/S0014579314005195

Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition

Klebsiella pneumoniae carbapenemase-2 (KPC-2) is a serine-β-lactamase (SBL) capable of hydrolysing almost all β-lactam antibiotics. We compare KPC-2 inhibition by vaborbactam, a clinically-approved monocyclic boronate, and VNRX-5133 (taniborbactam), a bicyclic boronate in late-stage clinical development. Vaborbactam inhibition is slowly reversible, whereas taniborbactam has an off-rate indicating essentially irreversible complex formation and a 15-fold higher on-rate, although both potentiate β-lactam activity against KPC-2-expressing K. pneumoniae. High resolution X-ray crystal structures reveal closely related binding modes for both inhibitors to KPC-2, with differences apparent only in positioning of the endocyclic boronate ester oxygen. The results indicate the bicyclic boronate scaffold as both an efficient, long-lasting, KPC-2 inhibitor and capable of supporting further iterations that may improve potency against specific enzyme targets and pre empt the emergence of inhibitor resistant KPC-2 variants