The accuracy and diagnostic value of gram staining joint aspirates in suspected joint infections.

BACKGROUND: Septic arthritis is a debilitating condition with prolonged treatment and adverse outcomes. A gram stain is often performed from the joint aspirate sample, followed by a definitive culture. In our study, we assessed the accuracy of gram staining for suspected septic arthritis and explored factors associated with positive culture growth and false negatives in the gram stain. METHODS: We retrospectively reviewed joint aspirates performed from 2015-2021 at a major trauma centre. Aspirates not cultured for septic arthritis were excluded. Data collected included aspirate site, gram stain and culture result delay, patient demographics, orthopaedic/rheumatological history, and comorbidities. Outcomes measured were gram stain sensitivity and specificity. Factors influencing positive cultures and false negative gram stain results were analysed using logistic regression. RESULTS: Of 408 joint aspirates meeting the criteria, 37 did not undergo initial gram staining. Gram stain sensitivity was 30.4%, specificity was 97.6%. The delay from aspirate to definitive gram stain and culture results was 1.1 and 5.4 days, respectively Logistic regression identified that prosthetic joint(p = 0.007), past joint infections(p = 0.006), arthritis(p < 0.001), hypertension(p = 0.007), diabetes(p = 0.019) were positively associated with positive cultures. Past joint infections(p = 0.004) were positively associated with false negative gram stain results. Patients on antibiotics during the aspirate had a higher risk of false negative gram stain results (OR = 5.538, 95%CI, 2.802-10.948; p < 0.001). CONCLUSIONS: In conclusion, the initial gram stain has limited sensitivity and caution should be exercised when interpreting negative results. Vigilance is crucial when the highlighted comorbidities or antibiotic use are present, to assess patients with potential joint infections.

MiniMovers: An Initial Pilot and Feasibility Study to Investigate the Impact of a Mobile Application on Children's Motor Skills and Parent Support for Physical Development.

The MiniMovers (MM) APP combines motor development theory with creativity expertise and has been designed to provide parents with developmentally appropriate activities to support children's motor skills. This study investigates how MiniMovers activities enabled parents to support their children's physical development. Families participated in an 8-week MM programme of activities from the MM APP (Mini, Mighty and Mega levels), with pre- and post-intervention data collected using multiple tools (e.g., motion capture system, force plate, eye-tracking glasses, and videos). Mixed research methods were applied among children (N = 8; aged 21-79 months) and their parents, providing quantitative analysis on children's performance (running, throwing, jumping, kicking, balancing and catching), as well as qualitative analysis on parents' attitude and behaviour (two-weekly feedback surveys and interviews). Lab-based measures showed significant improvements in run time, underarm throwing distance, and horizontal jump distance. Test of Gross Motor Development-3 showed a significant gain in running, underarm and overarm throwing, horizontal jump and kicking. Further, developmental stages indicated significant improvements in running, kicking and catching. Parents reported increased enjoyment and knowledge, children's enjoyment, independence and confidence. This pilot study provides support for the research and development of the MM App and suggests more research into the use of APPs to support home activities among families with young children.

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8.

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-ß plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.

Predictors for infection severity for open tibial fractures: major trauma centre perspective.

INTRODUCTION: Open diaphyseal tibial fractures are the most common long-bone fractures and require a rapid approach to prevent devastating complications. Current literature reports the outcomes of open tibial fractures. However, there is no robust, up-to-date research on the predictive indicators of infection severity in a large open tibial fracture patient cohort. This study investigated the predictive factors of superficial infections and osteomyelitis in open tibial fractures. MATERIALS AND METHODS: A retrospective analysis of the tibial fracture database was carried out from 2014 to 2020. Criteria for inclusion was any tibial fracture including tibial plateau, shaft, pilon or ankle, with an open wound at the fracture site. Exclusion criteria included patients with a follow-up period of less than 12 months and who are deceased. A total of 235 patients were included in our study, of which 154 (65.6%), 42 (17.9%), and 39 (16.6%) developed no infection, superficial infection, or osteomyelitis, respectively. Patient demographics, injury characteristics, fracture characteristics, infection status and management details were collected for all patients. RESULTS: On multivariate modelling, patients with BMI > 30 (OR = 2.078, 95%CI [1.145-6.317], p = 0.025), Gustilo-Anderson (GA) type III (OR = 6.120, 95%CI [1.995-18.767], p = 0.001), longer time to soft tissue cover (p = 0.006) were more likely to develop a superficial infection, and patients with wound contamination (OR = 3.152, 95%CI [1.079-9.207], p = 0.036), GA-3 (OR = 3.387,95%CI [1.103-10.405], p = 0.026), longer to soft tissue cover (p = 0.007) were more likely to develop osteomyelitis. Univariate analysis also determined that risk factors for superficial infection were: BMI > 35 (OR = 6.107, 95%CI [2.283-16.332], p = 0.003) and wound contamination (OR = 2.249, 95%CI [1.015-5.135], p = 0.047); whilst currently smoking (OR = 2.298, 95%CI [1.087-4.856], p = 0.025), polytrauma (OR = 3.212, 95%CI [1.556-6.629], p = 0.001), longer time to definitive fixation (p = 0.023) were for osteomyelitis. However, none of these reached significance in multivariate analysis. CONCLUSION: Higher GA classification is a significant risk factor for developing superficial infection and osteomyelitis, with a stronger association with osteomyelitis, especially GA 3C fractures. Predictors for superficial infection included BMI and time to soft tissue closure. Time to definitive fixation, time to soft tissue closure, and wound contamination were associated with osteomyelitis.

Immuno-epigenetic signature derived in saliva associates with the encephalopathy of prematurity and perinatal inflammatory disorders.

BACKGROUND: Preterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging outcomes in adult cohorts. However, the robustness of DNAm inflammatory scores in infancy, their relation to comorbidities of preterm birth characterised by inflammation, neonatal neuroimaging metrics of EoP, and saliva cross-tissue applicability are unknown. METHODS: Using salivary DNAm from 258 neonates (n = 155 preterm, gestational age at birth 23.28 - 34.84 weeks, n = 103 term, gestational age at birth 37.00 - 42.14 weeks), we investigated the impact of a DNAm surrogate for C-reactive protein (DNAm CRP) on brain structure and other clinically defined inflammatory exposures. We assessed i) if DNAm CRP estimates varied between preterm infants at term equivalent age and term infants, ii) how DNAm CRP related to different types of inflammatory exposure (maternal, fetal and postnatal) and iii) whether elevated DNAm CRP associated with poorer measures of neonatal brain volume and white matter connectivity. RESULTS: Higher DNAm CRP was linked to preterm status (-0.0107 ± 0.0008, compared with -0.0118 ± 0.0006 among term infants; p < 0.001), as well as perinatal inflammatory diseases, including histologic chorioamnionitis, sepsis, bronchopulmonary dysplasia, and necrotising enterocolitis (OR range |2.00 | to |4.71|, p < 0.01). Preterm infants with higher DNAm CRP scores had lower brain volume in deep grey matter, white matter, and hippocampi and amygdalae (ß range |0.185| to |0.218|). No such associations were observed for term infants. Association magnitudes were largest for measures of white matter microstructure among preterms, where elevated epigenetic inflammation associated with poorer global measures of white matter integrity (ß range |0.206| to |0.371|), independent of other confounding exposures. CONCLUSIONS: Inflammatory-related DNAm captures the allostatic load of inflammatory burden in preterm infants. Such DNAm measures complement biological and clinical metrics when investigating the determinants of neurodevelopmental differences.

A "bottom up" Health in All Policies program: Supporting local government wellbeing approaches.

ISSUE ADDRESSED: A wellbeing economy requires multiple inputs to enable the wholistic vision of a sustainable healthy population and planet. A Health in All Policies (HiAP) approach is a useful way to support policy makers and planners to implement the activities required to support a wellbeing economy. OUTLINE OF THE PROJECT: Aotearoa New Zealand's Government has explicitly set a path towards a wellbeing economy. Here, we report the utility of a HiAP approach in Greater Christchurch, the largest urban area in the South Island of New Zealand, to achieving the shared societal goals of a sustainable healthy population and environment. We use the World Health Organisation draft Four Pillars for HiAP implementation as a framework for discussion. SO WHAT?: The paper adds to the growing number of examples of city and regions supporting a wellbeing agenda, specifically focused on some of the successes and challenges for local HiAP practitioners working within a public health unit in influencing this work.

Airborne transmission: a new paradigm with major implications for infection control and public health.

Recognition of airborne transmission of SARS-CoV-2 and other respiratory viruses is a paradigm shift in the Infection Prevention and Control (IPC) field, contributed to by New Zealand's experience in Managed Isolation Quarantine Facilities (MIQF). Slowness to embrace this shift by the World Health Organization (WHO) and other international bodies highlights the importance of applying the precautionary principle and subjecting established theories to the same level of critical scrutiny as those challenging the status quo. Improving indoor air quality to reduce infection risk and provide other health benefits is a new frontier, requiring much additional work at both grassroots and policy levels. Existing technologies such as masks, air cleaners and opening windows can improve air quality of many environments now. To achieve sustained, comprehensive improvements in air quality that provide meaningful protection, we also need additional actions that do not rely on individual human's behaviour.

Inequalities in healthcare disruptions during the COVID-19 pandemic: evidence from 12 UK population-based longitudinal studies.

OBJECTIVES: We investigated associations between multiple sociodemographic characteristics (sex, age, occupational social class, education and ethnicity) and self-reported healthcare disruptions during the early stages of the COVID-19 pandemic. DESIGN: Coordinated analysis of prospective population surveys. SETTING: Community-dwelling participants in the UK between April 2020 and January 2021. PARTICIPANTS: Over 68 000 participants from 12 longitudinal studies. OUTCOMES: Self-reported healthcare disruption to medication access, procedures and appointments. RESULTS: Prevalence of healthcare disruption varied substantially across studies: between 6% and 32% reported any disruption, with 1%-10% experiencing disruptions in medication, 1%-17% experiencing disruption in procedures and 4%-28% experiencing disruption in clinical appointments. Females (OR 1.27; 95% CI 1.15 to 1.40; I2=54%), older persons (eg, OR 1.39; 95% CI 1.13 to 1.72; I2=77% for 65-75 years vs 45-54 years) and ethnic minorities (excluding white minorities) (OR 1.19; 95% CI 1.05 to 1.35; I2=0% vs white) were more likely to report healthcare disruptions. Those in a more disadvantaged social class were also more likely to report healthcare disruptions (eg, OR 1.17; 95% CI 1.08 to 1.27; I2=0% for manual/routine vs managerial/professional), but no clear differences were observed by education. We did not find evidence that these associations differed by shielding status. CONCLUSIONS: Healthcare disruptions during the COVID-19 pandemic could contribute to the maintenance or widening of existing health inequalities.

Plasma Myeloperoxidase as a Potential Biomarker of Patient Response to Anti-Dementia Treatment in Alzheimer's Disease.

BACKGROUND: Myeloperoxidase (MPO), a neutrophil-derived pro-inflammatory protein, co-localizes with amyloid-ß (Aß) plaques in Alzheimer's disease (AD). Anti-dementia treatment may facilitate efflux of Aß and associated plaque proteins from the brain to the peripheral circulation, therefore providing potential biomarkers for the monitoring of donor response to drug treatment. OBJECTIVE: We investigated the diagnostic utility of MPO as a biomarker of AD, and how anti-dementia treatment alters plasma MPO concentration. METHODS: Thirty-two AD patients were recruited, and plasma collected pre-drug administration (baseline), and 1- and 6-months post-treatment. All patients received cholinesterase inhibitors (ChEIs). At baseline and 6 months, patients underwent neuropsychological assessment. Forty-nine elderly healthy individuals with normal cognitive status served as controls. Plasma MPO concentration was measured by ELISA. RESULTS: AD drug naïve patients had similar plasma MPO concentration to their control counterparts (p > 0.05). Baseline MPO levels positively correlated with Neuropsychiatric Inventory score (r = 0.5080; p = 0.011) and carer distress (r = 0.5022; p = 0.012). Following 1-month ChEI treatment, 84.4% of AD patients exhibited increased plasma MPO levels (p < 0.001), which decreased at 6 months (p < 0.001). MPO concentration at 1 month was greatest in AD patients whose memory deteriorated during the study period (p = 0.028), and for AD patients with deterioration in Cornell assessment score (p = 0.044). CONCLUSION: Whereas baseline MPO levels did not differentiate between healthy and AD populations, baseline MPO positively correlated with initial Neuropsychiatric Inventory evaluation. Post-treatment, transient MPO upregulation in ChEI-treated patients may reflect worse therapeutic outcome. Further studies are required to assess the potential of plasma MPO as an AD therapeutic biomarker.

The UK Coronavirus Job Retention Scheme and smoking, alcohol consumption and vaping during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: Employment disruptions can impact smoking and alcohol consumption. During the COVID-19 pandemic, many countries implemented furlough schemes to prevent job loss. We examine how furlough was associated with smoking, vaping and alcohol consumption in the UK. METHODS: Data from 27,841 participants in eight UK adult longitudinal surveys were analysed. Participants self-reported employment status and current smoking, current vaping and alcohol consumption (>4 days/week or 5+ drinks per typical occasion) both before and during the early stages of the pandemic (April-July 2020). Risk ratios were estimated within each study using modified Poisson regression, adjusting for a range of potential confounders, including pre-pandemic behaviour. Findings were synthesised using random effects meta-analysis. RESULTS: Compared to stable employment and after adjustment for pre-pandemic characteristics, furlough was not associated with smoking (ARR = 1.05; 95% CI: 0.95-1.16; I2: 10%), vaping (ARR = 0.89; 95% CI: 0.74-1.08; I2: 0%) or drinking (ARR = 1.03; 95% CI: 0.94-1.13; I2: 48%). There were similar findings for no longer being employed, and stable unemployment, though this varied by sex: stable unemployment was associated with smoking for women (ARR = 1.35; 95% CI: 1.00-1.82; I2: 47%) but not men (0.84; 95% CI: 0.67-1.05; I2: 0%). No longer being employed was associated with vaping among women (ARR = 2.74; 95% CI: 1.59-4.72; I2: 0%) but not men (ARR = 1.25; 95% CI: 0.83-1.87; I2: 0%). CONCLUSIONS: We found no clear evidence of furlough or unemployment having adverse impacts on smoking, vaping or drinking behaviours during the early stages of the COVID-19 pandemic in the UK. Differences in risk compared to those who remained employed were largely explained by pre-pandemic characteristics.

A comparison of blood and brain-derived ageing and inflammation-related DNA methylation signatures and their association with microglial burdens.

Inflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in five post mortem brain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers ('epigenetic clocks'), and two inflammatory biomarkers (methylation proxies for C-reactive protein and interleukin-6) were compared across tissues and regions. Divergent associations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippocampus (ß range = 0.83-1.14, p ≤ 0.02). The inflammation-related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippocampus (ß = 1.32, p = 5 × 10-4 ); however, the only association identified between the blood- and brain-based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (ß = 0.40, p = 0.002). This work highlights a potential vulnerability of the hippocampus to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.

The UK Coronavirus Job Retention Scheme and diet, physical activity, and sleep during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: In March 2020, the UK implemented the Coronavirus Job Retention Scheme (furlough) to minimise job losses. Our aim was to investigate associations between furlough and diet, physical activity, and sleep during the early stages of the COVID-19 pandemic. METHODS: We analysed data on 25,092 participants aged 16-66 years from eight UK longitudinal studies. Changes in employment, including being furloughed, were based on employment status before and during the first lockdown. Health behaviours included fruit and vegetable consumption, physical activity, and sleep. Study-specific estimates obtained using modified Poisson regression, adjusting for socio-demographic characteristics and pre-pandemic health and health behaviours, were statistically pooled using random effects meta-analysis. Associations were also stratified by sex, age, and education. RESULTS: Across studies, between 8 and 25% of participants were furloughed. Compared to those who remained working, furloughed workers were slightly less likely to be physically inactive (RR = 0.85; [95% CI 0.75-0.97]; I 2 = 59%) and did not differ overall with respect to low fruit and vegetable consumption or atypical sleep, although findings for sleep were heterogenous (I 2 = 85%). In stratified analyses, furlough was associated with lower fruit and vegetable consumption among males (RR = 1.11; [1.01-1.22]; I 2 = 0%) but not females (RR = 0.84; [0.68-1.04]; I 2 = 65%). Considering changes in quantity, furloughed workers were more likely than those who remained working to report increases in fruit and vegetable consumption, exercise, and hours of sleep. CONCLUSIONS: Those furloughed exhibited similar health behaviours to those who remained in employment during the initial stages of the pandemic. There was little evidence to suggest that adoption of such social protection policies in the post-pandemic recovery period and during future economic crises had adverse effects on population health behaviours.

Pre-pandemic mental health and disruptions to healthcare, economic and housing outcomes during the COVID-19 pandemic: evidence from 12 UK longitudinal studies.

BACKGROUND: The COVID-19 pandemic has disrupted lives and livelihoods, and people already experiencing mental ill health may have been especially vulnerable. AIMS: Quantify mental health inequalities in disruptions to healthcare, economic activity and housing. METHOD: We examined data from 59 482 participants in 12 UK longitudinal studies with data collected before and during the COVID-19 pandemic. Within each study, we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to healthcare (medication access, procedures or appointments), economic activity (employment, income or working hours) and housing (change of address or household composition). Estimates were pooled across studies. RESULTS: Across the analysed data-sets, 28% to 77% of participants experienced at least one disruption, with 2.3-33.2% experiencing disruptions in two or more domains. We found 1 s.d. higher pre-pandemic psychological distress was associated with (a) increased odds of any healthcare disruptions (odds ratio (OR) 1.30, 95% CI 1.20-1.40), with fully adjusted odds ratios ranging from 1.24 (95% CI 1.09-1.41) for disruption to procedures to 1.33 (95% CI 1.20-1.49) for disruptions to prescriptions or medication access; (b) loss of employment (odds ratio 1.13, 95% CI 1.06-1.21) and income (OR 1.12, 95% CI 1.06 -1.19), and reductions in working hours/furlough (odds ratio 1.05, 95% CI 1.00-1.09) and (c) increased likelihood of experiencing a disruption in at least two domains (OR 1.25, 95% CI 1.18-1.32) or in one domain (OR 1.11, 95% CI 1.07-1.16), relative to no disruption. There were no associations with housing disruptions (OR 1.00, 95% CI 0.97-1.03). CONCLUSIONS: People experiencing psychological distress pre-pandemic were more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening mental health inequalities.

Epigenetic scores for the circulating proteome as tools for disease prediction.

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.

Although our genetic code does not change throughout our lives, our genes can be turned on and off as a result of epigenetics. Epigenetics can track how the environment and even certain behaviors add or remove small chemical markers to the DNA that makes up the genome. The type and location of these markers may affect whether genes are active or silent, this is, whether the protein coded for by that gene is being produced or not. One common epigenetic marker is known as DNA methylation. DNA methylation has been linked to the levels of a range of proteins in our cells and the risk people have of developing chronic diseases. Blood samples can be used to determine the epigenetic markers a person has on their genome and to study the abundance of many proteins. Gadd, Hillary, McCartney, Zaghlool et al. studied the relationships between DNA methylation and the abundance of 953 different proteins in blood samples from individuals in the German KORA cohort and the Scottish Lothian Birth Cohort 1936. They then used machine learning to analyze the relationship between epigenetic markers found in people's blood and the abundance of proteins, obtaining epigenetic scores or 'EpiScores' for each protein. They found 109 proteins for which DNA methylation patterns explained between at least 1% and up to 58% of the variation in protein levels. Integrating the 'EpiScores' with 14 years of medical records for more than 9000 individuals from the Generation Scotland study revealed 130 connections between EpiScores for proteins and a future diagnosis of common adverse health outcomes. These included diabetes, stroke, depression, various cancers, and inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease. Age-related chronic diseases are a growing issue worldwide and place pressure on healthcare systems. They also severely reduce quality of life for individuals over many years. This work shows how epigenetic scores based on protein levels in the blood could predict a person's risk of several of these diseases. In the case of type 2 diabetes, the EpiScore results replicated previous research linking protein levels in the blood to future diagnosis of diabetes. Protein EpiScores could therefore allow researchers to identify people with the highest risk of disease, making it possible to intervene early and prevent these people from developing chronic conditions as they age.

DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging.

BACKGROUND AND OBJECTIVES: To investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive outcomes. METHODS: At baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption, body mass index), and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation-serum C-reactive protein (CRP)-and an epigenetic measure (DNA methylation [DNAm] signature of CRP). Linear models were used to examine the inflammation-brain health associations; mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure, and cognitive functioning. RESULTS: We demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (ß = -0.197, 95% confidence interval [CI] -0.28 to -0.12, p FDR = 8.42 × 10-6), gray matter volume (ß = -0.200, 95% CI -0.28 to -0.12, p FDR = 1.66 × 10-5), and white matter volume (ß = -0.150, 95% CI -0.23 to -0.07, p FDR = 0.001) and regional brain atrophy. We also find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial, and memory) cognitive functioning and that brain structure partially mediates this CRP-cognitive association (up to 29.7%), dependent on lifestyle and health factors. DISCUSSION: These results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes that underlie differences in cognitive ability in later life and highlight the potential of DNAm proxies for indexing chronic inflammatory status. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a DNAm signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.

Detection of Amyloid-ß Fibrils Using Track-Etched Nanopores: Effect of Geometry and Crowding.

Several neurodegenerative diseases have been linked to proteins or peptides that are prone to aggregate in different brain regions. Aggregation of amyloid-ß (Aß) peptides is recognized as the main cause of Alzheimer's disease (AD) progression, leading to the formation of toxic Aß oligomers and amyloid fibrils. The molecular mechanism of Aß aggregation is complex and still not fully understood. Nanopore technology provides a new way to obtain kinetic and morphological aspects of Aß aggregation at a single-molecule scale without labeling by detecting the electrochemical signal of the peptides when they pass through the hole. Here, we investigate the influence of nanoscale geometry (conical and bullet-like shape) of a track-etched nanopore pore and the effect of molecular crowding (polyethylene glycol-functionalized pores) on Aß fibril sensing and analysis. Various Aß fibril samples that differed by their length were produced by sonication of fibrils obtained in the presence of epigallocatechin gallate. The conical nanopore functionalized with polyethylene glycol (PEG) 5 kDa is suitable for discrimination of the fibril size from relative current blockade. The bullet-like-shaped nanopore enhances the amplitude of the current and increases the dwell time, allowing us to well discern the fibrils. Finally, the nanopore crowded with PEG 20 kDa enhances the relative current blockade and increases the dwell time; however, the discrimination is not improved compared to the "bullet-shaped" nanopore.

Epigenetic predictors of lifestyle traits applied to the blood and brain.

Modifiable lifestyle factors influence the risk of developing many neurological diseases. These factors have been extensively linked with blood-based genome-wide DNA methylation, but it is unclear if the signatures from blood translate to the target tissue of interest-the brain. To investigate this, we apply blood-derived epigenetic predictors of four lifestyle traits to genome-wide DNA methylation from five post-mortem brain regions and the last blood sample prior to death in 14 individuals in the Lothian Birth Cohort 1936. Using these matched samples, we found that correlations between blood and brain DNA methylation scores for smoking, high-density lipoprotein cholesterol, alcohol and body mass index were highly variable across brain regions. Smoking scores in the dorsolateral prefrontal cortex had the strongest correlations with smoking scores in blood (r = 0.5, n = 14, P = 0.07) and smoking behaviour (r = 0.56, n = 9, P = 0.12). This was also the brain region which exhibited the largest correlations for DNA methylation at site cg05575921 - the single strongest correlate of smoking in blood-in relation to blood (r = 0.61, n = 14, P = 0.02) and smoking behaviour (r = -0.65, n = 9, P = 0.06). This suggested a particular vulnerability to smoking-related differential methylation in this region. Our work contributes to understanding how lifestyle factors affect the brain and suggest that lifestyle-related DNA methylation is likely to be both brain region dependent and in many cases poorly proxied for by blood. Though these pilot data provide a rarely-available opportunity for the comparison of methylation patterns across multiple brain regions and the blood, due to the limited sample size available our results must be considered as preliminary and should therefore be used as a basis for further investigation.

Characterising generalism in clinical practice: a systematic mixed studies review protocol.

BACKGROUND: Generalist physician care is associated with improved patient outcomes. Despite initiatives to promote generalism in educational settings, recruitment to generalist disciplines remains less than required to serve societal needs. Increasingly this impacts not just general practice but also generalist specialties such as internal medicine, surgery, and paediatrics. One potential factor for this deficit is a lack of explicit attention to generalism as a praxis, including clarifying key aspects of generalist expertise. AIM: To examine empirical clinical literature on generalism, and characterise how generalism is described and delivered by physicians in primary and secondary care. DESIGN & SETTING: A systematic mixed studies review (SMSR) including quantitative, qualitative, mixed-methods studies, and systematic reviews of physician generalist practice. METHOD: MEDLINE, Psycinfo, SocINDEX, Embase, Ovid HealthSTAR, Scopus, and Web of Science will be searched for English language studies from 1999 to present, using a structured search. Given study heterogeneity, quality appraisal will not be performed. Two reviewers will perform study selection for each study. Data extraction will focus on how generalism is defined and characterised, including the clinical care provided by generalists and patient experiences of generalist care. Quantitative and qualitative data will be summarised in tabular and narrative form. Convergent synthesis design will then be used to synthesise quantitative and qualitative data. CONCLUSION: Findings will characterise generalism and generalist practice from a grassroots clinical perspective. By identifying similarities and differences across generalist disciplines, this work will inform more focused educational initiatives on generalism at undergraduate and postgraduate level, including collaborations between generalist disciplines.