'Low' faecal immunochemical test (FIT) colorectal cancer: a 4-year comparison of the Nottingham '4F' protocol with FIT10 in symptomatic patients.

AIM: The aim of this work was to evaluate colorectal cancer (CRC) outcomes after 'low' (sub-threshold) faecal immunochemical test (FIT) results in symptomatic patients tested in primary care. METHOD: This work comprised a retrospective audit of 35 289 patients with FIT results who had consulted their general practitioner with lower gastrointestinal symptoms and had subsequent CRC diagnoses. The Rapid Colorectal Cancer Diagnosis pathway was introduced in November 2017 to allow incorporation of FIT into clinical practice. The local '4F' protocol combined FIT results with blood tests and digital rectal examination (DRE): FIT, full blood count, ferritin and finger [DRE]. The outcome used was detection rates of CRC, missed CRC and time to diagnosis in local 4F protocols for patients with a subthreshold faecal haemoglobin (fHb) result compared with thresholds of 10 and 20 µg Hb/g faeces. RESULTS: A single threshold of 10 µg Hb/g faeces identifies a population in whom the risk of CRC is 0.2%, but this would have missed 63 (10.5%) of 599 CRCs in this population. The Nottingham 4F protocol would have missed fewer CRCs [42 of 599 (7%)] despite using a threshold of 20 µg Hb/g faeces for patients with normal blood tests. Subthreshold FIT results in patients subsequently diagnosed with a palpable rectal tumour yielded the longest delays in diagnosis. CONCLUSION: A combination of FIT with blood results and DRE (the 4F protocol) reduced the risk of missed or delayed diagnosis. Further studies on the impact of such protocols on the diagnostic accuracy of FIT are expected. The value of adding blood tests to FIT may be restricted to specific parts of the fHb results spectrum.

A Computational Study of Dynamic Obstruction in Type B Aortic Dissection.

A serious complication in aortic dissection is dynamic obstruction of the true lumen (TL). Dynamic obstruction results in malperfusion, a blockage of blood flow to a vital organ. Clinical data reveal that increases in central blood pressure promote dynamic obstruction. However, the mechanisms by which high pressures result in TL collapse are underexplored and poorly understood. Here, we developed a computational model to investigate biomechanical and hemodynamical factors involved in Dynamic obstruction. We hypothesize that relatively small pressure gradient between TL and false lumen (FL) are sufficient to displace the flap and induce obstruction. An idealized fluid-structure interaction model of type B aortic dissection was created. Simulations were performed under mean cardiac output while inducing dynamic changes in blood pressure by altering FL outflow resistance. As FL resistance increased, central aortic pressure increased from 95.7 to 115.3 mmHg. Concurrent with blood pressure increase, flap motion was observed, resulting in TL collapse, consistent with clinical findings. The maximum pressure gradient between TL and FL over the course of the dynamic obstruction was 4.5 mmHg, consistent with our hypothesis. Furthermore, the final stage of dynamic obstruction was very sudden in nature, occurring over a short time (<1 s) in our simulation, consistent with the clinical understanding of this dramatic event. Simulations also revealed sudden drops in flow and pressure in the TL in response to the flap motion, consistent with first stages of malperfusion. To our knowledge, this study represents the first computational analysis of potential mechanisms driving dynamic obstruction in aortic dissection.

Four-year experience of paediatric penetrating injuries: findings from a paediatric major trauma centre in the UK.

AIM: To review the experience of penetrating injury and its subsequent imaging and to discuss imaging strategies in overall trauma management in a paediatric major trauma centre. MATERIALS AND METHODS: A retrospective, single-centre study was conducted over a 4-year period (1/1/16-31/12/19) of children (<16 years old) presenting to the Emergency Department with penetrating trauma. Clinical, radiographic, and demographic data were analysed using descriptive statistics. RESULTS: Fifty-eight patients in >60 attendances were reviewed. Most (44/60, 73%) underwent some imaging, with almost half (28/60, 47%) having both computed tomography (CT) and radiography. Of cases with only a single injury site (35/60, 58%), CT was performed in 19/35 (54%) with 13/19 (68%) covering more than one body area. Of the multi-injury site cases (26/60, 42%), CT was performed in 16/25 (64%) with 14/16 (88%) involving multiple body areas. The most common injuries were solid-organ lacerations and soft-tissue and vascular injuries according to body site involved. CONCLUSION: Contrast-enhanced CT across multiple body parts should be performed for multiple stab wounds or visible injuries involving the torso. Isolated penetrating injuries may only require CT of a single body part unless the entry wound crosses body parts. An imaging algorithm is suggested, which may be applicable to other paediatric trauma units.

A pas de deux of osteoporosis and sarcopenia: osteosarcopenia.

The musculoskeletal conditions osteoporosis and sarcopenia are highly prevalent in older adults. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone, whereas sarcopenia is identified by the loss of muscle strength, function and mass. Osteoporosis represents a major health problem contributing to millions of fractures worldwide on an annual basis, whereas sarcopenia is associated with a range of adverse physical and metabolic outcomes. They both affect physical and social function, confidence and quality of life as well as contributing to high health-care costs worldwide. Osteosarcopenia is the term given when both conditions occur concomitantly and it has been suggested that interactions between these two conditions may accelerate individual disease progression as co-existence of osteoporosis and sarcopenia is associated with higher morbidity from falls, fracture, disability as well as mortality. In this review, we will outline the epidemiology, pathogenesis and clinical consequences of osteosarcopenia and discuss available management strategies.

Approaches to the diagnosis and prevention of frailty.

An individual who is living with frailty has impairments in homeostasis across several body systems and is more vulnerable to stressors that may ultimately predispose them to negative health-related outcomes, disability and increased healthcare use. Approximately a quarter of individuals aged > 85 years are living with frailty and as such the identification of those who are frail is a public health priority. Given that the syndrome of frailty is defined by progressive and gradual loss of physiological reserves there is much scope to attempt to modify the trajectory of the frailty syndrome via physical activity and nutritional interventions. In this review we give an up to date account on the identification of frailty in clinical practice and offer insights into physical activity and nutritional strategies that may be beneficial to modify or reverse the frailty syndrome.

A systematic review of the provision and efficacy of patient and carer information and support (PCIS) interventions for patients with dementia and their informal carers.

BACKGROUND: The NHS dementia strategy identifies patient and carer information and support (PCIS) as a core component of gold-standard dementia care. This is the first systematic review of PCIS, performed to analyse the literature and evidence for these interventions. AIMS: To systematically review literature evaluating the effectiveness of the provision of PCIS for people with dementia and their informal carers, in inpatient and outpatient settings. METHODS: Searches of four online biomedical databases, accessed in September 2018. Studies were selected if they were: relating to people with dementia or their informal carers, based in inpatient or outpatient settings, published in English-language peer-reviewed journals no earlier than the year 2000 and assessed dementia-related information or social support interventions, by measuring qualitative or quantitative carer or patient-reported outcomes. Standardised data extraction and quality appraisal forms were used. RESULTS: 7 of 43 full-text papers analysed were eligible for analysis. 3 papers were different arms of one original study. Trends were present in the quantitative results towards reduced patient and carer depression and anxiety and the themes in the qualitative analysis were in favour of the intervention. CONCLUSIONS: The studies analysed were too heterogeneous in design, population and outcomes measured to make a conclusive opinion about the efficacy of these interventions. It is surprising that for such a common condition, a gold-standard evidence-based intervention and standardised delivery for provision of PCIS for people living with dementia in the UK does not exist. Further research is therefore vital.

COVID-19 and associations with frailty and multimorbidity: a prospective analysis of UK Biobank participants.

BACKGROUND: Frailty and multimorbidity have been suggested as risk factors for severe COVID-19 disease. AIMS: We investigated, in the UK Biobank, whether frailty and multimorbidity were associated with risk of hospitalisation with COVID-19. METHODS: 502,640 participants aged 40-69 years at baseline (54-79 years at COVID-19 testing) were recruited across UK during 2006-10. A modified assessment of frailty using Fried's classification was generated from baseline data. COVID-19 test results (England) were available for 16/03/2020-01/06/2020, mostly taken in hospital settings. Logistic regression was used to discern associations between frailty, multimorbidity and COVID-19 diagnoses, after adjusting for sex, age, BMI, ethnicity, education, smoking and number of comorbidity groupings, comparing COVID-19 positive, COVID-19 negative and non-tested groups. RESULTS: 4510 participants were tested for COVID-19 (positive = 1326, negative = 3184). 497,996 participants were not tested. Compared to the non-tested group, after adjustment, COVID-19 positive participants were more likely to be frail (OR = 1.4 [95%CI = 1.1, 1.8]), report slow walking speed (OR = 1.3 [1.1, 1.6]), report two or more falls in the past year (OR = 1.3 [1.0, 1.5]) and be multimorbid (≥ 4 comorbidity groupings vs 0-1: OR = 1.9 [1.5, 2.3]). However, similar strength of associations were apparent when comparing COVID-19 negative and non-tested groups. However, frailty and multimorbidity were not associated with COVID-19 diagnoses, when comparing COVID-19 positive and COVID-19 negative participants. DISCUSSION AND CONCLUSIONS: Frailty and multimorbidity do not appear to aid risk stratification, in terms of positive versus negative results of COVID-19 testing. Investigation of the prognostic value of these markers for adverse clinical sequelae following COVID-19 disease is urgently needed.

Widespread covariation of early environmental exposures and trait-associated polygenic variation.

Although gene-environment correlation is recognized and investigated by family studies and recently by SNP-heritability studies, the possibility that genetic effects on traits capture environmental risk factors or protective factors has been neglected by polygenic prediction models. We investigated covariation between trait-associated polygenic variation identified by genome-wide association studies (GWASs) and specific environmental exposures, controlling for overall genetic relatedness using a genomic relatedness matrix restricted maximum-likelihood model. In a UK-representative sample (n = 6,710), we find widespread covariation between offspring trait-associated polygenic variation and parental behavior and characteristics relevant to children's developmental outcomes-independently of population stratification. For instance, offspring genetic risk for schizophrenia was associated with paternal age (R2 = 0.002; P = 1e-04), and offspring education-associated variation was associated with variance in breastfeeding (R2 = 0.021; P = 7e-30), maternal smoking during pregnancy (R2 = 0.008; P = 5e-13), parental smacking (R2 = 0.01; P = 4e-15), household income (R2 = 0.032; P = 1e-22), watching television (R2 = 0.034; P = 5e-47), and maternal education (R2 = 0.065; P = 3e-96). Education-associated polygenic variation also captured covariation between environmental exposures and children's inattention/hyperactivity, conduct problems, and educational achievement. The finding that genetic variation identified by trait GWASs partially captures environmental risk factors or protective factors has direct implications for risk prediction models and the interpretation of GWAS findings.

Anastomotic leak and cancer-specific outcomes after curative rectal cancer surgery: a systematic review and meta-analysis.

BACKGROUND: The aim of the present study was to perform a systematic review and meta-analysis of cancer-specific outcomes after curative rectal cancer surgery comparing anastomotic leak (AL) with no leak. METHODS: PubMed, Medline and Embase databases were searched to identify studies comparing cancer-specific outcomes after rectal cancer surgery in patients with AL and without. A meta-analysis with a random-effects model was used to calculate pooled odds ratios (OR) and confidence intervals (CI) for each outcome measure. RESULTS: A total of 18 studies were included for meta-analysis, comprising a total of 18,039 patients after curative rectal resection (1764 AL, 16,275 without AL). The overall rate of AL was 9.8%. After AL and excluding 30-day mortality there was an increased risk of local recurrence (OR 1.50; CI 1.23, 1.82), worse overall survival (OR 0.69; CI 0.60-0.81), decreased disease free survival (OR 0.51; CI 0.36-0.73) and cancer specific survival (OR 0.71; CI 0.54-0.94). Distant recurrence (OR 1.10; CI 0.89-1.37) and overall recurrence (OR 1.33; CI 0.64-2.76) were not significantly different between the two groups. CONCLUSIONS: AL may negatively impact cancer-specific outcomes after curative rectal cancer surgery and could be considered an independent negative prognostic factor.

An unusual suspect for heart failure.

A 71-year old retired missionary presented with a 2- week history of increasing dyspnoea, orthopnoea, and peripheral oedema. The patient had no previous significant past medical history. On clinical examination, his heart sounds were dual and his jugular venous pressure was elevated to 7cm. On chest auscultation there were bilateral crepitations at his lung bases.

An unusual suspect for heart failure.

Constrictive pericarditis though an uncommon diagnosis is a potentially reversible form of heart failure (with surgical pericardiectomy) and hence is imperative to diagnose. Diagnosis is dependent on a high index of clinical suspicion and further testing with appropriate cardiac investigations including cardiac imaging with invasive cardiac catheterisation as the gold standard.

Regulation of the ß-Adrenergic Receptor Signaling Pathway in Sustained Ligand-Activated Preconditioning.

Sustained ligand-activated preconditioning (SLP), induced with chronic opioid receptor (OR) agonism, enhances tolerance to ischemia/reperfusion injury in young and aged hearts. Underlying mechanisms remain ill-defined, although early data implicate phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) during the induction phase, and ß 2-adrenoceptor (ß 2-AR), Gs alpha subunit (Gα s), and protein kinase A (PKA) involvement in subsequent cardioprotection. Here, we tested for induction of a protective ß 2-AR/Gα s/PKA signaling axis with SLP to ascertain whether signaling changes were PI3K-dependent (by sustained cotreatment with wortmannin), and whether the downstream PKA target Rho kinase (ROCK) participates in subsequent cardioprotection (by acute treatment with fasudil). A protected phenotype was evident after 5 days of OR agonism (using morphine) in association with increased membrane versus reduced cytosolic levels of total and phosphorylated ß 2-ARs; increased membrane and cytosolic expression of 52 and 46 kDa Gα s isoforms, respectively; and increased phosphorylation of PKA and Akt. Nonetheless, functional sensitivities of ß 2-ARs and adenylyl cyclase were unchanged based on concentration-response analyses for formoterol, fenoterol, and 6-[3-(dimethylamino)propionyl]-forskolin. Protection with SLP was not modified by ROCK inhibition, and changes in ß 2-AR, Gα s, and PKA expression appeared insensitive to PI3K inhibition, although 5 days of wortmannin alone exerted unexpected effects on signaling (also increasing membrane ß 2-AR and PKA expression/phosphorylation and Gα s levels). In summary, sustained OR agonism upregulates cardiac membrane ß 2-AR expression and phosphorylation in association with increased Gα s subtype levels and PKA phosphorylation. While Akt phosphorylation was evident, PI3K activity appears nonessential to OR upregulation of the ß 2-AR signal axis. This opioidergic remodeling of ß 2-AR signaling may explain ß 2-AR, Gα s, and PKA dependence of SLP protection.

Multi-polygenic score approach to trait prediction.

A primary goal of polygenic scores, which aggregate the effects of thousands of trait-associated DNA variants discovered in genome-wide association studies (GWASs), is to estimate individual-specific genetic propensities and predict outcomes. This is typically achieved using a single polygenic score, but here we use a multi-polygenic score (MPS) approach to increase predictive power by exploiting the joint power of multiple discovery GWASs, without assumptions about the relationships among predictors. We used summary statistics of 81 well-powered GWASs of cognitive, medical and anthropometric traits to predict three core developmental outcomes in our independent target sample: educational achievement, body mass index (BMI) and general cognitive ability. We used regularized regression with repeated cross-validation to select from and estimate contributions of 81 polygenic scores in a UK representative sample of 6710 unrelated adolescents. The MPS approach predicted 10.9% variance in educational achievement, 4.8% in general cognitive ability and 5.4% in BMI in an independent test set, predicting 1.1%, 1.1%, and 1.6% more variance than the best single-score predictions. As other relevant GWA analyses are reported, they can be incorporated in MPS models to maximize phenotype prediction. The MPS approach should be useful in research with modest sample sizes to investigate developmental, multivariate and gene-environment interplay issues and, eventually, in clinical settings to predict and prevent problems using personalized interventions.

A genome-wide association study for extremely high intelligence.

We used a case-control genome-wide association (GWA) design with cases consisting of 1238 individuals from the top 0.0003 (~170 mean IQ) of the population distribution of intelligence and 8172 unselected population-based controls. The single-nucleotide polymorphism heritability for the extreme IQ trait was 0.33 (0.02), which is the highest so far for a cognitive phenotype, and significant genome-wide genetic correlations of 0.78 were observed with educational attainment and 0.86 with population IQ. Three variants in locus ADAM12 achieved genome-wide significance, although they did not replicate with published GWA analyses of normal-range IQ or educational attainment. A genome-wide polygenic score constructed from the GWA results accounted for 1.6% of the variance of intelligence in the normal range in an unselected sample of 3414 individuals, which is comparable to the variance explained by GWA studies of intelligence with substantially larger sample sizes. The gene family plexins, members of which are mutated in several monogenic neurodevelopmental disorders, was significantly enriched for associations with high IQ. This study shows the utility of extreme trait selection for genetic study of intelligence and suggests that extremely high intelligence is continuous genetically with normal-range intelligence in the population.

A systematic review of specialist inpatient dementia care services versus standard inpatient dementia care in acute hospitals.

BACKGROUND: Specialist inpatient dementia units (SIDU) have been developed to address adverse outcomes often experienced by people living with dementia admitted to acute hospitals. However, the evidence base of their effectiveness remains limited. AIM: To review the current literature to establish the comparative effectiveness of acute hospital SIDU vs. standard ward care (SWC). METHODS: We did an online search of 12 biomedical databases from inception to 31st October 2017. Studies of inpatients with any form of dementia in acute hospitals, published in English language peer-reviewed journals, using experimental, observational or qualitative study designs, comparing SIDU with SWC and which measured any qualitative or quantitative outcome of the patient or carer experience were included in the search criteria. We used a standardised data extraction and appraisal form. RESULTS: Three of 46 full-text studies evaluated were suitable for analysis. Due to study heterogeneity, pooled odds ratios were only possible for mortality [OR 1.06 (CI 1.0-1.4)]. Otherwise, a narrative synthesis was performed. Although quantitative measures of length of stay, mortality and behavioural and psychiatric symptoms of dementia are not significantly lower, SIDU are associated with greater patient and carer satisfaction, reduced readmission rates, more accurate and comprehensive assessment processes, documentation of resuscitation decisions, and increased rates of discharge to the patient's own home. CONCLUSIONS: Although SIDU may be associated with improved care outcomes, the current evidence of their effectiveness is markedly limited. Further research and service evaluation of SIDU as a method for providing high-quality dementia care in acute NHS Trusts is needed. PROSPERO: CRD42017078364.

How is vasospasm screening using transcranial Doppler associated with delayed cerebral ischemia and outcomes in aneurysmal subarachnoid hemorrhage?

BACKGROUND: Delayed cerebral ischemia (DCI) is an independent predictor of an unfavorable outcome after aneurysmal subarachnoid hemorrhage (aSAH). Many centers, but not all, use transcranial Doppler (TCD) to screen for vasospasm to help predict DCI. We used the United Kingdom and Ireland Subarachnoid Haemorrhage (UKISAH) Registry to see if outcomes were better in centers that used TCD to identify vasospasm compared to those that did not. METHODS: TCD screening practices were ascertained by national survey in 13 participating centers of the UKISAH. The routine use of TCD was reported by 5 "screening" centers, leaving 7 "non-screening" centers. Using a cross-sectional cohort study design, prospectively collected data from the UKISAH Registry was used to compare DCI diagnosis and favorable outcome (Glasgow Outcome Score 4 or 5) at discharge based on reported screening practice. RESULTS: A cohort of 2028 aSAH patients treated ≤ 3 days of hemorrhage was analyzed. DCI was diagnosed in 239/1065 (22.4%) and 220/963 (22.8%) of patients in non-screening and screening centers respectively while 847/1065 (79.5%) and 648/963 (67.2%) achieved a favorable outcome. Odds ratios adjusted for age, injury severity, comorbidities, need for cerebrospinal fluid diversion, and re-bleed returned neutral odds of diagnosing DCI of 0.90 (95% CI 0.72-1.12; p value = 0.347) in screening units compared to those of non-screening units but significantly decreased odds of achieving a favorable outcome 0.56 (95% CI 0.42-0.82; p value < 0.001). CONCLUSIONS: Centers that screened for vasospasm using TCD had poorer in-hospital outcomes and similar rates of DCI diagnosis compared to centers that did not.

The ability of spore formers to degrade milk proteins, fat, phospholipids, common stabilizers, and exopolysaccharides.

Spore formers are common spoilage-causing microorganisms in dairy products; however, their modes of spoilage (proteolysis, lipolysis, etc.) have not been described in detail for cultured dairy products such as sour cream and yogurt. The objective of the present study was to test the ability of spore-forming strains isolated from dairy environments for their spoilage-causing activities at typical sour cream (24°C) and yogurt (42°C) fermentation temperatures. A total of 25 spore-forming strains were isolated from different sources, including raw milk, pasteurizer balance tank, biofilms formed on heat exchangers, and milk powder. These strains were tested for proteolytic and lipolytic activities and for their ability to degrade phospholipids, common stabilizers (starch, gelatin, xanthan gum, pectin), and exopolysaccharides (EPS) at sour cream and yogurt fermentation temperatures. A higher percentage of positive strains was observed for selected activities at yogurt fermentation temperature compared with sour cream fermentation temperature. Identified proteolytic spore-forming strains, based on a skim milk agar method, were subsequently quantified for their level of proteolysis using non-casein nitrogen (NCN) content and sodium dodecyl sulfate-PAGE (SDS-PAGE). The proteolytic strains that showed the highest levels of proteolysis (highest percentages of NCN content) at 24°C were Bacillus mojavensis BC, Bacillus cereus DBC, Bacillus subtilis DBC, B. mojavensis DBC1, and Paenibacillus polymyxa DBC1. At 42°C the strains with the highest levels of proteolysis (highest percentages of NCN content) were B. subtilis DBC, B. mojavensis BC, B. mojavensis DBC1, B. cereus DBC, and Bacillus licheniformis DBC6. Results of SDS-PAGE demonstrated that proteolytic strains had primarily hydrolyzed ß- and κ-CN. A viscometric method was used to evaluate the susceptibility of exopolysaccharides (EPS) to degradation by selected spore formers. This method helped to determine that EPS produced by commercial yogurt and sour cream cultures is susceptible to degradation by spore formers present in dairy environments.

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation.

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

Muscle Mass, Muscle Morphology and Bone Health Among Community-Dwelling Older Men: Findings from the Hertfordshire Sarcopenia Study (HSS).

Sarcopenia and osteoporosis are associated with poor health outcomes in older people. Relationships between muscle and bone have typically been reported at a functional or macroscopic level. The aims of this study were to describe the relationships between muscle morphology and bone health among participants of the Hertfordshire Sarcopenia Study (HSS). 105 older men, mean age 72.5 (SD 2.5) years, were recruited into the HSS. Whole body lean mass as well as appendicular lean mass, lumbar spine and femoral neck bone mineral content (BMC) and bone mineral density (BMD) were obtained through dual-energy X-ray absorptiometry scanning. Percutaneous biopsy of the vastus lateralis was performed successfully in 99 participants. Image analysis was used to determine the muscle morphology variables of slow-twitch (type I) and fast-twitch (type II) myofibre area, myofibre density, capillary and satellite cell (SC) density. There were strong relationships between whole and appendicular lean body mass in relation to femoral neck BMC and BMD (r ≥ 0.43, p < 0.001). Type II fibre area was associated with both femoral neck BMC (r = 0.27, p = 0.01) and BMD (r = 0.26, p = 0.01) with relationships robust to adjustment for age and height. In unadjusted analysis, SC density was associated with whole body area (r = 0.30, p = 0.011) and both BMC (r = 0.26, p = 0.031) and area (r = 0.29, p = 0.017) of the femoral neck. We have demonstrated associations between BMC and changes in muscle at a cellular level predominantly involving type II myofibres. Interventions targeted at improving muscle mass, function and quality may improve overall musculoskeletal health. Larger studies that include women are needed to explore these relationships further.

Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits.

BACKGROUND: Exposure of the developing brain to propofol results in cognitive deficits. Recent data suggest that inhibition of neuronal apoptosis does not prevent cognitive defects, suggesting mechanisms other than neuronal apoptosis play a role in anaesthetic neurotoxicity. Proper neuronal growth during development is dependent upon growth cone morphology and axonal transport. Propofol modulates actin dynamics in developing neurones, causes RhoA-dependent depolymerisation of actin, and reduces dendritic spines and synapses. We hypothesised that RhoA inhibition prevents synaptic loss and subsequent cognitive deficits. The present study tested whether RhoA inhibition with the botulinum toxin C3 (TAT-C3) prevents propofol-induced synapse and neurite loss, and preserves cognitive function. METHODS: RhoA activation, growth cone morphology, and axonal transport were measured in neonatal rat neurones (5-7 days in vitro) exposed to propofol. Synapse counts (electron microscopy), dendritic arborisation (Golgi-Cox), and network connectivity were measured in mice (age 28 days) previously exposed to propofol at postnatal day 5-7. Memory was assessed in adult mice (age 3 months) previously exposed to propofol at postnatal day 5-7. RESULTS: Propofol increased RhoA activation, collapsed growth cones, and impaired retrograde axonal transport of quantum dot-labelled brain-derived neurotrophic factor, all of which were prevented with TAT-C3. Adult mice previously treated with propofol had decreased numbers of total hippocampal synapses and presynaptic vesicles, reduced hippocampal dendritic arborisation, and infrapyramidal mossy fibres. These mice also exhibited decreased hippocampal-dependent contextual fear memory recall. All anatomical and behavioural changes were prevented with TAT-C3 pre-treatment. CONCLUSION: Inhibition of RhoA prevents propofol-mediated hippocampal neurotoxicity and associated cognitive deficits.