Screening Carbon Nano Materials for Preventing Amyloid Protein Aggregation by Adopting a Facile Method.

The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aß), α-synuclein, mutant Huntingtin Protein (mHTT) and islet amyloid polypeptide (IAPP) among others are associated with disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Type 2 Diabetes (T2D), respectively. The dissolution of mature fibrils and toxic amyloidogenic intermediates, including oligomers, continues to be the pinnacle in the treatment of neurodegenerative disorders. Yet, methods to effectively and quantitatively report on the interconversion between amyloid monomers, oligomers and mature fibrils fall short. Here we describe a simplified method that implements the use of gel electrophoresis to address the transformation between soluble monomeric amyloid proteins and mature amyloid fibrils. The technique implements an optimized but well-known, simple, inexpensive, and quantitative assessment previously used to assess the oligomerization of amyloid monomers and subsequent amyloid fibrils. This method facilitates the screening of small molecules that disintegrate oligomers and fibrils into monomers, dimers, and trimers and/or retain amyloid proteins in their monomeric forms. Most importantly, our optimized method diminishes existing barriers associated with existing (alternative) techniques to evaluate fibril formation and intervention.

Screening Carbon Nano Materials for preventing amyloid protein aggregation by adopting a facile method.

The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aß), α-synuclein, mutant Huntingtin Protein (mHTT) and islet amyloid polypeptide (IAPP) among others is associated with disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Type 2 Diabetes (T2D), respectively. The dissolution of mature fibrils and toxic amyloidogenic intermediates including oligomers continues to be the pinnacle in the treatment of neurodegenerative disorders. Yet, methods to effectively, and quantitatively, report on the interconversion between amyloid monomers, oligomers and mature fibrils fall short. Here we describe a simplified method that implements the use of gel electrophoresis to address the transformation between soluble monomeric amyloid proteins and mature amyloid fibrils. The technique implements an optimized but well-known, simple, inexpensive and quantitative assessment previously used to assess the oligomerization of amyloid monomers and subsequent amyloid fibrils. This method facilitates the screening of small molecules that disintegrate oligomers and fibrils into monomers, dimers, and trimers and/or retain amyloid proteins in their monomeric forms. Most importantly, our optimized method diminishes existing barriers associated with existing (alternative) techniques to evaluate fibril formation and intervention.

Gender Disparity in Expression of Sarcopenia in Haemodialysis Recipients: Analysis from the FITNESS Cohort.

Background: There has been little exploration of the interplay between sarcopenia and frailty in haemodialysis, particularly regarding gender difference. We aimed to (1) assess whether ultrasound-derived low muscle mass (LMM) and sarcopenia are more common in male or female haemodialysis recipients; (2) assess whether age influences any observed gender difference, and (3) explore the interplay between sarcopenia, frailty, and gender in haemodialysis recipients. Methods: This was an exploratory analysis of a subgroup of adult prevalent (≥3 months) haemodialysis with frailty phenotype (FP) scores. Bilateral anterior thigh thickness (BATT) was obtained according to an established ultrasound protocol. Associations with frailty were explored via both linear and logistic regressions for BATT, LMM, and sarcopenia with a priori covariables, stratified by gender. Results: In total of 223 studies, participants had ultrasound measurements. Males showed greater prevalence of LMM. On adjusted analyses, LMM was associated with lower hand grip strength in males (ß = -4.17; 95% C.I. -7.57 to -0.77; P=0.02), but not females (ß = -1.88; 95% C.I. -5.41 to 1.64; P=0.29). LMM was also associated with slower walking speed in both males (ß = -0.115; 95% C.I. -0.258 to -0.013; P=0.03) and females (ß = -0.152; 95% C.I. -0.300 to -0.005; P=0.04). Sarcopenia was associated with greater odds of frailty on adjusted models in males (OR = 9.86; 95% C.I. 1.8 to 54.0; P=0.01), but not females (OR = 5.16; 95% C.I. 0.22 to 124; P=0.31). Conclusions: The clinical expression and significance of sarcopenia differ substantially between males and females on haemodialysis. Further work is required to elucidate underlying mechanisms and guide tailored treatment.

Resolving the soluble-to-toxic transformation of amyloidogenic proteins: A method to assess intervention by small-molecules.

The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aß), α-synuclein, mutant Huntingtin Protein (mHTT) and islet amyloid polypeptide (IAPP) among others is associated with disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Type 2 Diabetes (T2D), respectively. Conversely, the dissolution of mature fibrils and toxic amyloidogenic intermediates including oligomers remains the holy grail in the treatment of neurodegenerative disorders. Yet, methods to effectively, and quantitatively, report on the interconversion between amyloid monomers, oligomers and mature fibrils fall short. For the first time, we describe the use of gel electrophoresis to address the transformation between soluble monomeric amyloid proteins and mature amyloid fibrils. The technique permits rapid, inexpensive and quantitative assessment of the fraction of amyloid monomers that form intermediates and mature fibrils. In addition, the method facilitates the screening of small molecules that disintegrate oligomers and fibrils into monomers or retain amyloid proteins in their monomeric forms. Importantly, our methodological advance diminishes major existing barriers associated with existing (alternative) techniques to evaluate fibril formation and intervention.

Development of a UK core dataset for geriatric medicine research: a position statement and results from a Delphi consensus process.

BACKGROUND: There is lack of standardisation in assessment tools used in geriatric medicine research, which makes pooling of data and cross-study comparisons difficult. METHODS: We conducted a modified Delphi process to establish measures to be included within core and extended datasets for geriatric medicine research in the United Kingdom (UK). This included three complete questionnaire rounds, and one consensus meeting. Participants were selected from attendance at the NIHR Newcastle Biomedical Research Centre meeting, May 2019, and academic geriatric medicine e-mailing lists. Literature review was used to develop the initial questionnaire, with all responses then included in the second questionnaire. The third questionnaire used refined options from the second questionnaire with response ranking. RESULTS: Ninety-eight responses were obtained across all questionnaire rounds (Initial: 19, Second: 21, Third: 58) from experienced and early career researchers in geriatric medicine. The initial questionnaire included 18 questions with short text responses, including one question for responders to suggest additional items. Twenty-six questions were included in the second questionnaire, with 108 within category options. The third questionnaire included three ranking, seven final agreement, and four binary option questions. Results were discussed at the consensus meeting. In our position statement, the final consensus dataset includes six core domains: demographics (age, gender, ethnicity, socioeconomic status), specified morbidities, functional ability (Barthel and/or Nottingham Extended Activities of Daily Living), Clinical Frailty Scale (CFS), cognition, and patient-reported outcome measures (dependent on research question). We also propose how additional variables should be measured within an extended dataset. CONCLUSIONS: Our core and extended datasets represent current consensus opinion of academic geriatric medicine clinicians across the UK. We consider the development and further use of these datasets will strengthen collaboration between researchers and academic institutions.

Repurposing digoxin for geroprotection in patients with frailty and multimorbidity.

The geroscience hypothesis proposes biological hallmarks of ageing are modifiable. Increasing evidence supports targeting these hallmarks with therapeutics could prevent and ameliorate age-related conditions - collectively termed "geroprotector drugs". Cellular senescence is a hallmark with considerable potential to be modified with geroprotector drugs. Senotherapeutics are drugs that target cellular senescence for therapeutic benefit. Repurposing commonly used medications with secondary geroprotector properties is a strategy of interest to promote incorporation of geroprotector drugs into clinical practice. One candidate is the cardiac glycoside digoxin. Evidence in mouse models of pulmonary fibrosis, Alzheimer's disease, arthritis and atherosclerosis support digoxin as a senotherapeutic agent. Proposed senolytic mechanisms are upregulation of intrinsic apoptotic pathways and promoting intracellular acidification. Digoxin also appears to have a senomorphic mechanism - altering the T cell pool to ameliorate pro-inflammatory SASP. Despite being widely prescribed to treat atrial fibrillation and heart failure, often in multimorbid older adults, it is not known whether digoxin exerts senotherapeutic effects in humans. Further cellular and animal studies, and ultimately clinical trials with participation of pre-frail older adults, are required to identify whether digoxin has senotherapeutic effect at low dose. This paper reviews the biological mechanisms identified in preliminary cellular and animal studies that support repurposing digoxin as a geroprotector in patients with frailty and multimorbidity.

Ultrasound quadriceps muscle thickness is variably associated with frailty in haemodialysis recipients.

BACKGROUND: Ultrasonographic quantitation of quadriceps muscle mass is increasingly used for assessment of sarcopenia, but its relationship with frailty in haemodialysis recipients is not known. This study explores the relationship between ultrasound-derived bilateral anterior thigh thickness (BATT), sarcopenia, and frailty by common frailty tools (Frailty Phenotype [FP], Frailty Index [FI], Edmonton Frailty [EFS], and Clinical Frailty Scale [CFS]). METHODS: This was an exploratory analysis of a subgroup of adult prevalent (≥3 months) haemodialysis recipients deeply phenotyped for frailty. Ultrasound assessment of BATT was obtained with participants at an angle of ≤45°, with legs outstretched and knees resting at 10°-20°, according to an established protocol. Associations with frailty were explored via both linear and logistic regressions for BATT, Low Muscle Mass (LMM), and sarcopenia with stepwise adjustment for a priori covariables. RESULTS: In total 223 study participants had ultrasound measurements. Frailty ranged from 34% for FP to 58% for FI. BATT was associated with increasing frailty on simple linear regression by all frailty tools, but lost significance on addition of covariables. Upon dichotomising frailty tools into Frail/Not Frail, BATT was associated with frailty by all tools on univariable analyses, but only retained association for EFS on the fully adjusted model (OR 0.97, 95% C.I. 0.94-1.00, P = 0.05). CONCLUSIONS: Ultrasound measures of quadriceps thickness is variably associated with frailty in prevalent haemodialysis recipients, dependent upon the frailty tool used, but not independent of other variables. Further work is required to establish the added value of sarcopenia measurement in frail haemodialysis patients. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03071107 registered 06/03/2017.

Nutrition and Frailty: Opportunities for Prevention and Treatment.

Frailty is a syndrome of growing importance given the global ageing population. While frailty is a multifactorial process, poor nutritional status is considered a key contributor to its pathophysiology. As nutrition is a modifiable risk factor for frailty, strategies to prevent and treat frailty should consider dietary change. Observational evidence linking nutrition with frailty appears most robust for dietary quality: for example, dietary patterns such as the Mediterranean diet appear to be protective. In addition, research on specific foods, such as a higher consumption of fruit and vegetables and lower consumption of ultra-processed foods are consistent, with healthier profiles linked to lower frailty risk. Few dietary intervention studies have been conducted to date, although a growing number of trials that combine supplementation with exercise training suggest a multi-domain approach may be more effective. This review is based on an interdisciplinary workshop, held in November 2020, and synthesises current understanding of dietary influences on frailty, focusing on opportunities for prevention and treatment. Longer term prospective studies and well-designed trials are needed to determine the causal effects of nutrition on frailty risk and progression and how dietary change can be used to prevent and/or treat frailty in the future.

Effect of position and exercise on measurement of muscle quantity and quality: towards a standardised pragmatic protocol for clinical practice.

BACKGROUND: Ultrasonography is an emerging non-invasive bedside tool for muscle quantity/quality assessment; Bioelectrical Impedance Analysis (BIA) is an alternative non-invasive bedside measure of body composition, recommended for evaluation of sarcopenia in clinical practice. We set out to assess impact of position and exercise upon measures towards protocol standardisation. METHODS: Healthy volunteers aged 18-35 were recruited. Bilateral Anterior Thigh Thickness (BATT; rectus femoris and vastus intermedius), BATT: Subcutaneous Ratio (BATT:SCR), and rectus femoris echogenicity were measured using ultrasound and BIA was performed; 1) lying with upper body at 45° (Reclined), 2) lying fully supine at 180o (Supine), 3) sat in a chair with upper body at 90o (Sitting), and 4) after exercise Reclined. Variability of Skeletal Muscle Mass (SMM) by two different equations from BIA (SMM-Janssen, SMM-Sergi), phase angle, fat percentage, and total body (TBW), extracellular (ECW), and intracellular water (ICW) were assessed. RESULTS: Forty-four participants (52% female; mean 25.7 years-old (SD 5.0)) were recruited. BATT increased from Reclined to Sitting (+ 1.45 cm, 1.27-1.63), and after exercise (+ 0.51, 0.29-0.73). Echogenicity reduced from Reclined to Sitting (- 2.1, - 3.9 - -0.26). SMM-Sergi declined from Reclined to Supine (- 0.65 kg, - 1.08 - - 0.23) and after exercise (- 0.70 kg, - 1.27 - -0.14). ECW increased from Reclined to Sitting (+ 1.19 L, 0.04-2.35). There were no other statistically significant changes. CONCLUSION: Standardisation of protocols is especially important for assessment of muscle quantity by ultrasonography; BIA measurements may also vary dependent on the equations used. Where possible, participants should be rested prior to muscle ultrasonography and BIA, and flexion of the knees should be avoided.

COVID-19 and Acute Sarcopenia.

The COVID-19 pandemic has had a devastating global impact, with older adults being most at risk of death from the disease. However, acute sarcopenia occurs in survivors of COVID-19; older adults and the most critically unwell patients are the most at risk. Acute sarcopenia is an under-recognised condition of acute muscle insufficiency, defined by declines in muscle function and/or quantity within six months, usually following a stressor event. This commentary reviews definition and mechanisms of acute sarcopenia in COVID-19 and suggests recommendations for research and clinical practice. Research should now focus on the longer-term consequences of acute sarcopenia in patients who have suffered from COVID-19. At the same time, clinicians need to be increasingly aware of the condition, and measurements of muscle strength, quantity, and physical performance should be embedded into clinical practice. Clinicians should consider the risks of acute sarcopenia when weighing up the risks and benefits of treatment (e.g. dexamethasone), and instigate multidisciplinary treatment including dietetics input.

Frailty Is Associated With Neutrophil Dysfunction Which Is Correctable With Phosphoinositol-3-Kinase Inhibitors.

Neutrophil dysfunction has been described with age, appears exaggerated in infection, with altered phosphoinositol signaling a potential mechanism. However, functional aging is heterogeneous. Frailty is a negative health status and is more common in older adults. We hypothesized that neutrophil migration may be compromised in frailty, associated with the degree of frailty experienced by the older person. We compared measures of frailty, neutrophil function, and systemic inflammation in 40 young and 77 older community-dwelling adults in the United Kingdom. Systemic neutrophils exhibited an age-associated reduction in the accuracy of migration (chemotaxis) which was further blunted with frailty. The degree of migratory inaccuracy correlated with physical (adjusted hand grip strength) and cognitive (Stroop test) markers of frailty. Regression analysis demonstrated that age, Charlson comorbidity index, and frailty index were able to predict neutrophil chemotaxis. Reduced chemotaxis of neutrophils from frail adults could be reversed using selective PI3K inhibitors. Exposure of neutrophils from young adults to plasma from chronically inflamed frail older adults could not recapitulate the migratory deficit in vitro, and there were no relationships with systemic inflammation and neutrophil dysfunction. Frailty exaggerated the neutrophil deficits seen with advanced age but aspects of the frailty-associated deficit in neutrophil function are rescuable and thus potentially form a therapeutic target to improve outcomes from infection in older adults.

Bilateral Anterior Thigh Thickness: A New Diagnostic Tool for the Identification of Low Muscle Mass?

OBJECTIVES: To develop an ultrasonographic scanning protocol that included an assessment of muscle size [the proposed Bilateral Anterior Thigh Thickness (BATT)] and quality (echogenicity) to support the diagnosis of sarcopenia in a clinical setting. To determine the relationship of BATT and ultrasound echogenicity with physical function parameters of sarcopenia and test the reliability of ultrasound echogenicity measurements. DESIGN: Observational study. SETTING AND PARTICIPANTS: The BATT criteria were determined from a reference population of 113 healthy younger adults and tested in 39 healthy older adults and 31 frail older adults. METHODS: Ultrasonography was used to measure the thickness of rectus femoris and vastus intermedius bilaterally; the thickness measurements were summed to calculate the BATT. Diagnostic criteria for low muscle size were calculated from the reference population. Echogenicity was assessed using freeze-frame images. All individuals underwent anthropological, frailty, and physical performance assessments. RESULTS: The mean (standard deviation) BATTs for the subsamples were as follows: healthy young women (n = 54), 60.6 mm (±11.1); healthy young men (n = 59), 75.8 mm (±10.71); healthy older women (n = 27), 38.4 mm (±7.18); healthy older men (n = 13), 47.5 mm (±10.8); frail older women (n = 17), 29.2 mm (±11.4); and frail older men (n = 14), 27.3 mm (±13.9). The calculated cutoffs for low muscle size in older adults using the BATT criteria were 38.5 mm in women and 54.4 mm in men in this population. The BATT was correlated with grip strength (ρ = 0.750, P < .001 for women; ρ = 0.619, P < .001 for men) and walk speed (ρ = -0.599, P < .001 for women; ρ = -0.324, P = .003 for men). Ultrasound echogenicity increased with age and frailty. Lay sonographers were able to reliably reproduce the same muscle thickness measurements but not the same muscle echogenicity measurements. CONCLUSIONS/IMPLICATIONS: The data support the use of ultrasonography to identify low muscle size in sarcopenia. Ultrasonography provides a pragmatic diagnostic tool that is noninvasive, without radiation exposure, and usable in both community and hospital settings. The proposed BATT criteria could be used to identify low muscle size in clinical practice and research, and in this study have excellent correlation with physical parameters of muscle health. However, this now needs testing in a validation cohort. Ultrasound echogenicity has been demonstrated to be an important surrogate marker of muscle health, but difficulties with reproducibility preclude its widespread clinical use.

The challenges of muscle biopsy in a community based geriatric population.

OBJECTIVES: To describe the difficulties of obtaining muscle samples using a Bergstrom needle technique in a frail older adult population. The data were obtained from a study primarily investigating immunosenescence in frailty. An intended research technique was skeletal muscle biopsy in a small subset of participants to investigate muscle morphology and local inflammatory factors. RESULTS: Forty healthy older adults and 37 frail older adults were considered for a Bergstrom needle muscle biopsy. Of these, 17.5% of healthy older adults and 94.6% of the frail older adults had single or multiple participant factors resulting in a contra-indication to muscle biopsy. 40.7% of healthy older female participants were at risk of a failed muscle biopsy due to low muscle mass. Considering only muscle mass muscle biopsy would have been successful in 18.7% of the frail older women and 21.4% of the frail older men. In this population, muscle biopsy was not feasible because of contra-indications in the majority of participants. This questions whether a biopsy sample obtained from frail older individuals, is actually representative of this population and supports the need to disclose biopsy failure rate in this population.

Inflammation and neutrophil immunosenescence in health and disease: Targeted treatments to improve clinical outcomes in the elderly.

Despite increasing longevity, many old people are not in good health. There has been an increase in the prevalence of age-associated multi-morbidity (two or more chronic conditions in the same person). Also, severe infections, such as pneumonia, remain significant causes of mortality and morbidity in this aging group. Many chronic health conditions share risk factors such as increasing age, smoking, a sedentary life style and being part of a lower socioeconomic group. However, despite this, multi-morbidities often co-occur more commonly than would be predicted. This has led to the hypothesis that they share common underlying mechanisms. This is an important concept, for if it were true, treatments could be devised which target these common pathways and improve a number of age-associated health conditions. Many chronic illnesses associated with multi-morbidity and severe infections are characterized by an abnormal and sustained inflammatory response, with neutrophils being key effector cells in the pathological process. Studies have described aberrant neutrophil functions across these conditions, and some have highlighted potential mechanisms for altered cell behaviours which appear shared across disease states. It has been suggested that altered functions may represent neutrophil "senescence". This review considers how and why neutrophil functions change as the cell ages, and how and why neutrophil functions change as the host ages in health and disease and discusses whether neutrophil functions could be targeted to improve health outcomes in older adults.

Age-Related Anabolic Resistance of Myofibrillar Protein Synthesis Is Exacerbated in Obese Inactive Individuals.

Context: A diminished muscle anabolic response to protein nutrition may underpin age-associated muscle loss. Objective: To determine how chronological and biological aging influence myofibrillar protein synthesis (MyoPS). Design: Cross-sectional comparison. Setting: Clinical research facility. Participants: Ten older lean [OL: 71.7 ± 6 years; body mass index (BMI) ≤25 kg ⋅ m-2], 7 older obese (OO: 69.1 ± 2 years; BMI ≥30 kg ⋅ m-2), and 18 young lean (YL) individuals (25.5 ± 4 years; BMI ≤25 kg ⋅ m-2). Intervention: Skeletal muscle biopsies obtained during a primed-continuous infusion of l-[ring-13C6]-phenylalanine. Main Outcome Measures: Anthropometrics, insulin resistance, inflammatory markers, habitual diet, physical activity, MyoPS rates, and fiber-type characteristics. Results: Fat mass, insulin resistance, inflammation, and type II fiber intramyocellular lipid were greater, and daily step count lower, in OO compared with YL and OL. Postprandial MyoPS rates rose above postabsorptive values by ∼81% in YL (P < 0.001), ∼38% in OL (P = 0.002, not different from YL), and ∼9% in OO (P = 0.11). Delta change in postprandial MyoPS from postabsorptive values was greater in YL compared with OL (P = 0.032) and OO (P < 0.001). Absolute postprandial MyoPS rates and delta postprandial MyoPS change were associated with step count (r2 = 0.33; P = 0.015) and leg fat mass (r2 = 0.4; P = 0.006), respectively, in older individuals. Paradoxically, lean mass was similar between groups, and muscle fiber area was greater in OO vs OL (P = 0.002). Conclusion: Age-related muscle anabolic resistance is exacerbated in obese inactive individuals, with no apparent detriment to muscle mass.

Frailty and sarcopenia: The potential role of an aged immune system.

Frailty is a common negative consequence of ageing. Sarcopenia, the syndrome of loss of muscle mass, quality and strength, is more common in older adults and has been considered a precursor syndrome or the physical manifestation of frailty. The pathophysiology of both syndromes is incompletely described with multiple causes, inter-relationships and complex pathways proposed. Age-associated changes to the immune system (both immunesenescence, the decline in immune function with ageing, and inflammageing, a state of chronic inflammation) have been suggested as contributors to sarcopenia and frailty but a direct causative role remains to be established. Frailty, sarcopenia and immunesenescence are commonly described in older adults but are not ubiquitous to ageing. There is evidence that all three conditions are reversible and all three appear to share common inflammatory drivers. It is unclear whether frailty, sarcopenia and immunesenescence are separate entities that co-occur due to coincidental or potentially confounding factors, or whether they are more intimately linked by the same underlying cellular mechanisms. This review explores these possibilities focusing on innate immunity, and in particular associations with neutrophil dysfunction, inflammation and known mechanisms described to date. Furthermore, we consider whether the age-related decline in immune cell function (such as neutrophil migration), increased inflammation and the dysregulation of the phosphoinositide 3-kinase (PI3K)-Akt pathway in neutrophils could contribute pathogenically to sarcopenia and frailty.

Predicting outcome in older hospital patients with delirium: a systematic literature review.

OBJECTIVE: Delirium is a serious neuropsychiatric syndrome common in older hospitalised adults. It is associated with poor outcomes, however not all people with delirium have poor outcomes and the risk factors for adverse outcomes within this group are not well described. The objective was to report which predictors of outcome had been reported in the literature. METHODS: We performed a systematic review by an initial electronic database search of MEDLINE, Embase and PsycINFO using four key search criteria. These were: (1) participants with a diagnosis of delirium, (2) clearly defined outcome measures, (3) a clearly defined variable as predictor of outcomes and (4) participants in the general hospital, rehabilitation and care home settings, excluding intensive care. Studies were then selected in a systematic fashion using specific predetermined criteria by three reviewers. RESULTS: A total of 559 articles were screened, and 57 full text articles were assessed for eligibility. Twenty seven studies describing 18 different predictors of poor outcome were reported. The studies were rated by the Newcastle-Ottawa Score and were generally at low risk of bias. Four broad themes of predictor were identified; five delirium related predictors, two co-morbid psychiatric illness related predictors, eight patient related predictors and three biomarker related predictors. The most numerously described and clinically important appear to be the duration of the delirium episode, a hypoactive motor subtype, delirium severity and pre-existing psychiatric morbidity with dementia or depression. These are all associated with poorer delirium outcomes. CONCLUSION: Important predictors of poor outcomes in patients with delirium have been demonstrated. These could be used in clinical practice to focus direct management and guide discussions regarding prognosis. These results also demonstrate a number of key unknowns, where further research to explore delirium prognosis is recommended and is vital to improve understanding and management of this condition.

Innate immune cells in liver inflammation.

Innate immune system is the first line of defence against invading pathogens that is critical for the overall survival of the host. Human liver is characterised by a dual blood supply, with 80% of blood entering through the portal vein carrying nutrients and bacterial endotoxin from the gastrointestinal tract. The liver is thus constantly exposed to antigenic loads. Therefore, pathogenic microorganism must be efficiently eliminated whilst harmless antigens derived from the gastrointestinal tract need to be tolerized in the liver. In order to achieve this, the liver innate immune system is equipped with multiple cellular components; monocytes, macrophages, granulocytes, natural killer cells, and dendritic cells which coordinate to exert tolerogenic environment at the same time detect, respond, and eliminate invading pathogens, infected or transformed self to mount immunity. This paper will discuss the innate immune cells that take part in human liver inflammation, and their roles in both resolution of inflammation and tissue repair.

Spinal cord compression: to biopsy, or not to biopsy?

A patient presenting with acute spinal cord compression initially thought to be secondary to metastatic cancer based on magnetic resonance imaging alone is described. No primary tumour was identified on further imaging, and although deemed to be technically very difficult, surgical decompression was postponed in favour of obtaining a histological diagnosis. Histology confirmed a low grade non-Hodgkin's lymphoma, a diagnosis which would not have been considered had a biopsy not been undertaken. The correct curative treatment was subsequently initiated, and the patient responded well to localised radiotherapy and intrathecal methotrexate.