Risk factors for postoperative delirium: An umbrella review of systematic reviews.

BACKGROUND: Postoperative delirium (POD) is associated with increased mortality, increased length of hospital stays and increased rates and severity of subsequent cognitive decline including dementia. A wide range of risk factors for POD have been suggested in the literature across multiple surgical specialities. However few are validated and no accurate prognostic models exist. We therefore aimed to map the existing evidence regarding risk factors for POD to help guide future research by undertaking an umbrella review of systematic reviews examining risk factors for POD in any context. MATERIALS AND METHODS: We systematically searched multiple medical databases for systematic reviews examining the risk factors for POD in adults undergoing any surgery. We then selected relevant reviews with minimal overlap in primary studies and extracted information about individual risk factors. RESULTS: Thirty-five relevant reviews were identified of which ten were in trauma and orthopaedic surgery patients (four exclusively examined hip fractures), five were in cardiac surgery patients, and four were in vascular surgery patients. Due to substantial overlap in reviews, eighteen reviews were analysed in detail finding the widely examined and consistent risk factors were increasing age, nursing home residency, pre-existing cognitive impairment, psychiatric disorders, cerebrovascular disease, end stage renal failure, low albumin, higher ASA score, and intra-operative blood transfusion. Many other risk factors were examined, but they were either not studied in multiple systematic reviews, or inconsistent either in results or in categorisation (which for many factors was heterogenous even within systematic reviews). There are also a large number of existing prognostic models, many of which remain unvalidated. CONCLUSION: Given the wealth of existing literature, future research should avoid simple risk factor evaluation except for novel candidates, validate existing prognostic models where possible, and instead focus on interventional research.

Increased case-finding and uptake of direct-acting antiviral treatment essential for micro-elimination of hepatitis C among people living with HIV: a national record linkage study.

OBJECTIVES: Micro-elimination of hepatitis C virus (HCV) in people living with HIV (PLHIV) and co-infected with HCV has been proposed as a key contribution to the overall goal of HCV elimination. While other studies have examined micro-elimination in HIV-treated cohorts, few have considered HCV micro-elimination among those not treated for HIV or at a national level. METHODS: Through data linkage of national and sentinel surveillance data, we examined the extent of HCV testing, diagnosis and treatment among a cohort of PLHIV in Scotland identified through the national database of HIV-diagnosed individuals, up to the end of 2017. RESULTS: Of 5018 PLHIV, an estimated 797 (15%) had never been tested for HCV and 70 (9%) of these had undiagnosed chronic HCV. The odds of never having been tested for HCV were the highest in those not on HIV treatment [adjusted odds ratio (aOR) = 7.21, 95% confidence interval (CI): 5.15-10.10). Overall HCV antibody positivity was 11%, and it was at its highest among people who inject drugs (49%). Most of those with chronic HCV (91%) had attended an HCV treatment clinic but only half had been successfully treated (54% for those on HIV treatment, 12% for those not) by the end of 2017. The odds of never having been treated for HCV were the highest in those not on HIV treatment (aOR = 3.60, 95% CI: 1.59-8.15). CONCLUSIONS: Our data demonstrate that micro-elimination of HCV in PLHIV is achievable but progress will require increased effort to engage and treat those co-infected, including those not being treated for their HIV.

A matched comparison study of hepatitis C treatment outcomes in the prison and community setting, and an analysis of the impact of prison release or transfer during therapy.

Prisoners are a priority group for hepatitis C (HCV) treatment. Although treatment durations will become shorter using directly acting antivirals (DAAs), nearly half of prison sentences in Scotland are too short to allow completion of DAA therapy prior to release. The purpose of this study was to compare treatment outcomes between prison- and community-based patients and to examine the impact of prison release or transfer during therapy. A national database was used to compare treatment outcomes between prison treatment initiates and a matched community sample. Additional data were collected to investigate the impact of release or transfer on treatment outcomes. Treatment-naïve patients infected with genotype 1/2/3/4 and treated between 2009 and 2012 were eligible for inclusion. 291 prison initiates were matched with 1137 community initiates: SVRs were 61% (95% CI 55%-66%) and 63% (95% CI 60%-66%), respectively. Odds of achieving a SVR were not significantly associated with prisoner status (P=.33). SVRs were 74% (95% CI 65%-81%), 59% (95% CI 42%-75%) and 45% (95% CI 29%-62%) among those not released or transferred, transferred during treatment, or released during treatment, respectively. Odds of achieving a SVR were significantly associated with release (P<.01), but not transfer (P=.18). Prison-based HCV treatment achieves similar outcomes to community-based treatment, with those not released or transferred during treatment doing particularly well. Transfer or release during therapy should be avoided whenever possible, using anticipatory planning and medical holds where appropriate.

Attendance at specialist hepatitis clinics and initiation of antiviral treatment among persons chronically infected with hepatitis C: examining the early impact of Scotland's Hepatitis C Action Plan.

Primary goals of the Hepatitis C Action Plan for Scotland Phase II (May 2008-March 2011) were to increase, among persons chronically infected with the hepatitis C (HCV) virus, attendance at specialist outpatient clinics and initiation on antiviral therapy. We evaluated progress towards these goals by comparing the odds, across time, of (a) first clinic attendance within 12 months of HCV diagnosis (n = 9747) and (b) initiation on antiviral treatment within 12 months of first attendance (n = 5736). Record linkage between the national HCV diagnosis (1996-2009) and HCV clinical (1996-2010) databases and logistic regression analyses were conducted for both outcomes. For outcome (a), 32% and 45% in the respective pre-Phase II (before 1 May 2008) and Phase II periods attended a specialist clinic within 12 months of diagnosis; the odds of attendance within 12 months increased over time (OR = 1.05 per year, 95% CI: 1.04-1.07), but was not significantly greater for persons diagnosed with HCV in the Phase II era, compared with the pre-Phase II era (OR = 1.1, 95% CI: 0.9-1.3), after adjustment for temporal trend. For outcome (b), 13% and 28% were initiated on treatment within 12 months of their first clinic attendance in the pre-Phase II and Phase II periods, respectively. Higher odds of treatment initiation were associated with first clinic attendance in the Phase II (OR = 1.9, 95% CI: 1.5-2.4), compared with the pre-Phase II era. Results were consistent with a positive impact of the Hepatitis C Action Plan on the treatment of chronically infected individuals, but further monitoring is required to confirm a sustained effect.

The contribution of the right supra-marginal gyrus to sequence learning in eye movements.

We investigated the role of the human right Supra-Marginal Gyrus (SMG) in the generation of learned eye movement sequences. Using MRI-guided transcranial magnetic stimulation (TMS) we disrupted neural activity in the SMG whilst human observers performed saccadic eye movements to multiple presentations of either predictable or random target sequences. For the predictable sequences we observed shorter saccadic latencies from the second presentation of the sequence. However, these anticipatory improvements in performance were significantly reduced when TMS was delivered to the right SMG during the inter-trial retention periods. No deficits were induced when TMS was delivered concurrently with the onset of the target visual stimuli. For the random version of the task, neither delivery of TMS to the SMG during the inter-trial period nor during the presentation of the target visual stimuli produced any deficit in performance that was significantly different from the no-TMS or control conditions. These findings demonstrate that neural activity within the right SMG is causally linked to the ability to perform short latency predictive saccades resulting from sequence learning. We conclude that neural activity in rSMG constitutes an instruction set with spatial and temporal directives that are retained and subsequently released for predictive motor planning and responses.

Proteomic approach for the detection of chicken mechanically recovered meat.

Mechanically recovered meat is cheaper than raw meat and thus has been incorporated into many meat-derived products. EU regulations exclude mechanically recovered meat from the definition of meat; as a consequence analytical procedures are needed to differentiate it from hand-deboned meat. The present pilot study has utilized a proteomic approach to find potential markers for the detection of chicken mechanically recovered meat. Intact proteins were extracted from raw meat and then analyzed with OFF-GEL electrophoresis followed by SDS-PAGE and identification of potential markers by nano-LC-MS/MS. It was shown that it is possible to extract, separate and identify key proteins from processed meat material. Potential chicken mechanically recovered meat markers--hemoglobin subunits and those similar to myosin-binding protein C were also identified.

Adult cerebellar mutism and cognitive-affective syndrome caused by cystic hemangioblastoma.

Cerebellar mutism is a rare phenomenon often described in children following surgical intervention in the posterior fossa. In this report we present a very unusual case of pre-operative cerebellar mutism in an adult in the context of cognitive-affective syndrome caused by cystic hemangioblastoma.

Increases in cell elongation, plastid compartment size and phytoene synthase activity underlie the phenotype of the high pigment-1 mutant of tomato.

A characteristic trait of the high pigment-1 ( hp-1) mutant phenotype of tomato ( Lycopersicon esculentum Mill.) is increased pigmentation resulting in darker green leaves and a deeper red fruit. In order to determine the basis for changes in pigmentation in this mutant, cellular and plastid development was analysed during leaf and fruit development, as well as the expression of carotenogenic genes and phytoene synthase enzyme activity. The hp-1 mutation dramatically increases the periclinal elongation of leaf palisade mesophyll cells, which results in increased leaf thickness. In addition, in both palisade and spongy mesophyll cells, the total plan area of chloroplasts per cell is increased compared to the wild type. These two perturbations in leaf development are the primary cause of the darker green hp-1 leaf. In the hp-1 tomato fruit, the total chromoplast area per cell in the pericarp cells of the ripe fruit is also increased. In addition, although expression of phytoene synthase and desaturase is not changed in hp-1 compared to the wild type, the activity of phytoene synthase in ripe fruit is 1.9-fold higher, indicating translational or post-translational control of carotenoid gene expression. The increased plastid compartment size in leaf and fruit cells of hp-1 is novel and provides evidence that the normally tightly controlled relationship between cell expansion and the replication and expansion of plastids can be perturbed and thus could be targeted by genetic manipulation.

Effect of the Cnr mutation on carotenoid formation during tomato fruit ripening.

The characteristic pigmentation of ripe tomato fruit is due to the deposition of carotenoid pigments. In tomato, numerous colour mutants exist. The Cnr tomato mutant has a colourless, non-ripening phenotype. In this work, carotenoid formation in the Cnr mutant has been studied at the biochemical level. The carotenoid composition of Ailsa Craig (AC) and Cnr leaves was qualitatively and quantitatively similar. However, Cnr fruits had low levels of total carotenoids and lacked detectable levels of phytoene and lycopene. The presence of normal tocopherols and ubiquinone-9 levels in the ripe Cnr fruits suggested that other biosynthetically related isoprenoids were unaffected by the alterations to carotenoid biosynthesis. In vitro assays confirmed the virtual absence of phytoene synthesis in the ripe Cnr fruit. Extracts from ripe fruit of the Cnr mutant also revealed a reduced ability to synthesise the carotenoid precursor geranylgeranyl diphosphate (GGPP). These results suggest that besides affecting the first committed step in carotenoid biosynthesis (phytoene synthase) the Cnr mutation also affects the formation of the isoprenoid precursor (GGPP).

Isomerization of lycopene in the gastric milieu.

There is considerable interest in the bioavailability of carotenoids from the diet and their bioactivity in vivo. Little is known, however, of the preabsorption events in the gastric lumen on the breakdown or isomerisation of dietary carotenoids. In this study the effects of the acidic environment found in the gastric milieu on lycopene have been investigated. The results show that under these conditions all-trans-lycopene is isomerised to cis-isomers, which may be implicated in enhanced absorption from the small intestine. Furthermore the pH, as well as the food matrix, seems to have an influence on the level of isomerisation of this carotenoid.

Technical advance: application of high-performance liquid chromatography with photodiode array detection to the metabolic profiling of plant isoprenoids.

The application of high-performance liquid chromatography (HPLC) using a C30 reverse-phase stationary matrix has enabled the simultaneous separation of carotenes, xanthophylls, ubiquinones, tocopherols and plastoquinones in a single chromatogram. Continuous photodiode array (PDA) detection ensured identification and quantification of compounds upon elution. Applications of the method to the characterization of transgenic and mutant tomato varieties with altered isoprenoid content, biochemical screening of Arabidopsis thaliana, and elucidation of the modes of action of bleaching herbicides are described to illustrate the versatility of the procedure.

Phytoene synthase from tomato (Lycopersicon esculentum) chloroplasts--partial purification and biochemical properties.

Phytoene synthase activity in tomato chloroplasts is membrane-associated, requiring treatment with high ionic strength buffer or mild non-ionic detergent for solubilisation. Using a combination of ammonium sulphate precipitation, cation and anion exchange, dye-ligand and hydrophobic interaction chromatography, phytoene synthase has been purified 600-fold from tomato (Lycopersion esculentum Mill.) chloroplasts. The native molecular mass of the enzyme was 43 kDa. with an isoelectric point of 4.6. Although phytoene synthase was functional in a monomeric state, under optimal native conditions it was associated with a large (at least 200 kDa) protein complex which contained other terpenoid enzymes such as isopentenyl diphosphate isomerase and geranylgeranyl diphosphate (GGPP) synthase. Both Mn2+ and ATP, in combination, were essential for catalytic activity; their effect was stochiometric from 0.5 to 2 mM, with Km values for Mn2+, ATP and the substrate GGPP of 0.4 mM, 2.0 mM and 5 microM, respectively. The detergents Tween 60 and Triton X-100 (0.1 w/v) stimulated (5-fold) enzyme activity, but lipids (crude chloroplast lipids and phospholipids) had no such effect and could not compensate for the absence of detergent. A number of metabolites with possible regulatory effects were investigated, including beta-carotene, which reduced enzyme activity in vitro some 2-fold. A comparison of phytoene synthase activity from partially purified chloroplast and chromoplast preparations indicated biochemical differences.

Elevation of the provitamin A content of transgenic tomato plants.

Tomato products are the principal dietary sources of lycopene and major source of beta-carotene, both of which have been shown to benefit human health. To enhance the carotenoid content and profile of tomato fruit, we have produced transgenic lines containing a bacterial carotenoid gene (crtI) encoding the enzyme phytoene desaturase, which converts phytoene into lycopene. Expression of this gene in transgenic tomatoes did not elevate total carotenoid levels. However, the beta-carotene content increased about threefold, up to 45% of the total carotenoid content. Endogenous carotenoid genes were concurrently upregulated, except for phytoene synthase, which was repressed. The alteration in carotenoid content of these plants did not affect growth and development. Levels of noncarotenoid isoprenoids were unchanged in the transformants. The phenotype has been found to be stable and reproducible over at least four generations.

Is lycopene beneficial to human health?

Since humans cannot synthesise carotenoids de novo, we depend upon the diet exclusively for the source of these micronutrients. Although the necessity for beta-carotene, as the precursor of vitamin A has been recognised for many years, it is lycopene that has attracted substantial interest more recently. Lycopene is the red-coloured carotenoid predominantly found in tomato fruit, but in few other fruits or vegetables. It has claimed that it may alleviate chronic diseases such as cancers and coronary heart disease. This possibility has been studied extensively, by epidemiological studies and biochemical investigations of its properties and its bioavailability from tomato-based diets. This article summarises the current state of knowledge of the properties of lycopene, its possible role in human health and areas for future research.

Isomerization of dietary lycopene during assimilation and transport in plasma.

Diets of individuals were supplemented with tomatoes, either cooked or as tomato pureé in order to compare uptake of lycopene from intact and homogenized fruit tissue matrices. Following a diet containing cooked tomatoes over three consecutive 7-day periods, little change in the carotenoid levels in plasma lipoproteins occurred. In contrast, a diet supplemented with concentrated tomato pureé, over a 2 week period, caused a significant (p < 0.05) increase in lycopene levels in plasma, showing that the lycopene within intact cells is less bioavailable than that from processed tissue. The isomeric composition of plasma lycopene was significantly different to that of the ingested pureé. A number of cis-isomers (predominantly 5-cis, 13-cis and 9-cis-) were detected in plasma, that are not present in the lycopene from pureé. The significance of the increase in lycopene following dietary supplementation with respect to bioavailability and the causes of isomerization are discussed.

Phytoene synthase-2 enzyme activity in tomato does not contribute to carotenoid synthesis in ripening fruit.

The characteristic yellow fruit phenotype of the r,r mutant and Psy-1 (phytoene synthase-1) antisense tomatoes is due to a mutated or down-regulated phytoene synthase protein, respectively, resulting in the virtual absence of carotenoids. Based on detailed carotenoid determinations Psy-1 appeared to barely contribute to the formation of carotenoids in chloroplast-containing tissues. Despite the virtual absence of carotenoids in ripe fruit the formation of phytoene in vitro was detected in fruit of both mutants. When [14C]isopentenyl pyrophosphate (IPP) was used as the substrate for phytoene synthase a reduction (e.g. r,r mutant, 5-fold) in the formation of phytoene was observed with an accumulation (e.g. r,r mutant, 2-fold) of the immediate precursor geranylgeranyl pyrophosphate (GGPP). Contrastingly, reduced phytoene synthase activity was not detected when [3H]GGPP was used as the substrate. The profile of phytoene formation during ripening was also different in the down-regulated mutants compared to the wild-type. Using specific primers, RT-PCR analysis detected the presence of Psy-2 transcripts in the down-regulated mutants and wild-type throughout fruit development and ripening. These data were supported by the detection of phytoene synthase protein on western blots. Both GGPP formation and phytoene desaturation were elevated in these mutants. Therefore, it appears that despite the absence of carotenoids in ripe fruit, both the mutants have the enzymic capability to synthesize carotenoids in this tissue. Implications of the data with respect to the regulation of carotenoid formation and the channelling of prenyl lipid precursors in tomato (and its potential manipulation) are discussed.