The impact of diagnostic microbiology on de-escalation of antimicrobial therapy in hospitalised adults.

BACKGROUND: Minimising antimicrobial overuse is needed to limit antimicrobial resistance. There is little evidence on how often microbiological testing informs antimicrobial de-escalation (e.g. stopping, shortening duration, switching to narrower spectrum or intravenous to oral switch) at 48-72 h "review and revise". We performed a patient level analysis of diagnostic microbiology and antimicrobial prescribing to determine the impact of microbiology results on antimicrobial review outcomes. METHODS: Antimicrobial prescribing data were collected for hospitalised adults from across Brighton and Sussex University Hospitals NHS Trust using routine monthly audits of prescribing practice from July 2016 to April 2017. Microbiology testing data for cultures of blood, urine, sputum and cerebrospinal fluid (CSF) were gathered from the hospital pathology database and linked to prescriptions with matching patient identification codes. Antimicrobial prescriptions were grouped into "prescription episodes" (PEs), defined as one or more antimicrobials prescribed to the same patient for the same indication. Medical records were reviewed for all PEs with positive microbiology and a randomised sample of those with negative results to assess the impact of the microbiology result on the antimicrobial prescription(s). RESULTS: After excluding topical and prophylactic prescriptions, data were available for 382 inpatient antimicrobial prescriptions grouped into 276 prescription episodes. 162/276 (59%) had contemporaneous microbiology sent. After filtering likely contaminants, 33/276 (12%) returned relevant positive results, of which 20/33 (61%) had antimicrobials changed from empiric therapy as a result with 6/33 (18%) prompting de-escalation. Positive blood and CSF tended to have greater impact than urine or sputum cultures. 124/276 (45%) PEs returned only negative microbiology, and this was documented in the medical notes less often (9/40, 23%) than positive results (28/33, 85%). Out of 40 reviewed PEs with negative microbiology, we identified just one (~ 3%) in which antimicrobials were unambiguously de-escalated following the negative result. CONCLUSIONS: The majority of diagnostic microbiology tests sent to inform clinical management yielded negative results. However, negative microbiology contributed little to clinical decision making about antimicrobial de-escalation, perhaps reflecting a lack of trust in negative results by treating clinicians. Improving the negative predictive value of currently available diagnostic microbiology could help hospital prescribers in de-escalating antimicrobial therapy

Inherent and benzo[a]pyrene-induced differential aryl hydrocarbon receptor signaling greatly affects life span, atherosclerosis, cardiac gene expression, and body and heart growth in mice

Little is known of the environmental factors that initiate and promote disease. The aryl hydrocarbon receptor (AHR) is a key regulator of xenobiotic metabolism and plays a major role in gene/environment interactions. The AHR has also been demonstrated to carry out critical functions in development and disease. A qualitative investigation into the contribution by the AHR when stimulated to different levels of activity was undertaken to determine whether AHR-regulated gene/environment interactions are an underlying cause of cardiovascular disease. We used two congenic mouse models differing at the Ahr gene, which encodes AHRs with a 10-fold difference in signaling potencies. Benzo[a]pyrene (BaP), a pervasive environmental toxicant, atherogen, and potent agonist for the AHR, was used as the environmental agent for AHR activation. We tested the hypothesis that activation of the AHR of different signaling potencies by BaP would have differential effects on the physiology and pathology of the mouse cardiovascular system. We found that differential AHR signaling from an exposure to BaP caused lethality in mice with the low-affinity AHR, altered the growth rates of the body and several organs, induced atherosclerosis to a greater extent in mice with the high-affinity AHR, and had a huge impact on gene expression of the aorta. Our studies also demonstrated an endogenous role for AHR signaling in regulating heart size. We report a gene/environment interaction linking differential AHR signaling in the mouse to altered aorta gene expression profiles, changes in body and organ growth rates, and atherosclerosis

Susceptibility to scrapie and disease phenotype in sheep: cross-PRNP genotype experimental transmissions with natural sources

<p>Abstract</p> <p>It has long been established that the sheep <it>Prnp</it> genotype influences the susceptibility to scrapie, and some studies suggest that it can also determine several aspects of the disease phenotype. Other studies, however, indicate that the source of infection may also play a role in such phenotype. To address this question an experiment was set up in which either of two different natural scrapie sources, AAS from AA₁₃₆ Suffolk and VVC from VV₁₃₆ Cheviot sheep, were inoculated into AA₁₃₆, VA₁₃₆ and VV₁₃₆ sheep recipients (<it>n</it> = 52). The immunohistochemical (IHC) profile of disease-associated PrP (PrP^d) accumulation in the brain of recipient sheep was highly consistent upon codon 136 homologous and semi-homologous transmission, but could be either similar to or different from those of the inoculum donors. In contrast, the IHC profiles were highly variable upon heterologous transmission (VVC to AA₁₃₆ and AAS to VV₁₃₆). Furthermore, sheep of the same <it>Prnp</it> genotype could exhibit different survival times and PrP^d profiles depending on the source of infection, and a correlation was observed between IHC and Western blot profiles. It was found that additional polymorphisms at codons 112 or 141 of AA₁₃₆ recipients resulted in a delayed appearance of clinical disease or even in protection from infection. The results of this study strongly suggest that the scrapie phenotype in sheep results from a complex interaction between source, donor and recipient factors, and that the <it>Prnp</it> genotype of the recipient sheep does not explain the variability observed upon codon 136 heterologous transmissions, arguing for other genetic factors to be involved.</p

Associations between sleep disturbance, cognitive functioning and work disability in Bipolar Disorder

Bipolar Disorder (BD) is associated with impairment in a number of areas including poor work functioning, often despite the remission of mood symptoms. The present study aimed to examine the role of sleep disturbance and cognitive functioning in occupational impairment in BD. Twenty-four euthymic BD participants and 24 healthy control participants completed a week of prospective assessment of sleep disruption via self-report and actigraphy, a battery of neuropsychological tests of executive functioning, working memory, and verbal learning, and assessments of work functioning. BD participants experienced significantly poorer cognitive functioning as well as greater months of unemployment and greater incidence of being fired than controls. Moderation analyses revealed that both poor sleep and cognitive functioning were associated with poor work performance in BD participants, but not control participants. Sleep and cognitive functioning may be impaired in euthymic BD and are associated with poor work functioning in this population. More research should be conducted to better understand how sleep and cognitive functioning may interact in BD

Roadless wilderness area determines forest elephant movements in the Congo Basin

A dramatic expansion of road building is underway in the Congo Basin fuelled by private enterprise, international aid, and government aspirations. Among the great wilderness areas on earth, the Congo Basin is outstanding for its high biodiversity, particularly mobile megafauna including forest elephants (Loxodonta africana cyclotis). The abundance of many mammal species in the Basin increases with distance from roads due to hunting pressure, but the impacts of road proliferation on the movements of individuals are unknown. We investigated the ranging behaviour of forest elephants in relation to roads and roadless wilderness by fitting GPS telemetry collars onto a sample of 28 forest elephants living in six priority conservation areas. We show that the size of roadless wilderness is a strong determinant of home range size in this species. Though our study sites included the largest wilderness areas in central African forests, none of 4 home range metrics we calculated, including core area, tended toward an asymptote with increasing wilderness size, suggesting that uninhibited ranging in forest elephants no longer exists. Furthermore we show that roads outside protected areas which are not protected from hunting are a formidable barrier to movement while roads inside protected areas are not. Only 1 elephant from our sample crossed an unprotected road. During crossings her mean speed increased 14-fold compared to normal movements. Forest elephants are increasingly confined and constrained by roads across the Congo Basin which is reducing effective habitat availability and isolating populations, significantly threatening long term conservation efforts. If the current road development trajectory continues, forest wildernesses and the forest elephants they contain will collapse