Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank.

Increased albuminuria indicates underlying glomerular pathology and is associated with worse renal disease outcomes, especially in diabetic kidney disease. Many single nucleotide polymorphisms (SNPs), associated with albuminuria, could be potentially useful to construct polygenic risk scores (PRSs) for kidney disease. We investigated the diagnostic accuracy of SNPs, previously associated with albuminuria-related traits, on albuminuria and renal injury in the UK Biobank population, with a particular interest in diabetes. Multivariable logistic regression was used to evaluate the influence of 91 SNPs on urine albumin-to-creatinine ratio (UACR)-related traits and kidney damage (any pathology indicating renal injury), stratifying by diabetes. Weighted PRSs for microalbuminuria and UACR from previous studies were used to calculate the area under the receiver operating characteristic curve (AUROC). CUBN-rs1801239 and DDR1-rs116772905 were associated with all the UACR-derived phenotypes, in both the overall and non-diabetic cohorts, but not with kidney damage. Several SNPs demonstrated different effects in individuals with diabetes compared to those without. SNPs did not improve the AUROC over currently used clinical variables. Many SNPs are associated with UACR or renal injury, suggesting a role in kidney dysfunction, dependent on the presence of diabetes in some cases. However, individual SNPs or PRSs did not improve the diagnostic accuracy for albuminuria or renal injury compared to standard clinical variables.

Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease.

Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes.

Global evidence on falls and subsequent social isolation in older adults: a scoping review.

BACKGROUND: Falls are a leading cause of injury-related hospitalizations among adults aged 65 years and older and may result in social isolation. OBJECTIVE: To summarise evidence on falls and subsequent social isolation and/or loneliness in older adults through a scoping review. ELIGIBILITY CRITERIA: Studies were eligible for inclusion if the population had a mean age of 60 years or older, they examined falls and subsequent social isolation, loneliness, fear of falling or risk factors and were primary studies (eg, experimental, quasi-experimental, observational and qualitative). SOURCES OF EVIDENCE: MEDLINE, CINAHL, Embase, Ageline and grey literature from inception until 11 January 2021. CHARTING METHODS: A screening and charting form was developed and pilot-tested. Subsequently, two reviewers screened citations and full-text articles, and charted the evidence. RESULTS: After screening 4993 citations and 304 full-text articles, 39 studies were included in this review. Participants had a history of falling (range: 11% to 100%). Most studies were conducted in Europe (44%) and North America (33%) and were of the cross-sectional study design (66.7%), in the community (79%). Studies utilised 15 different scales. Six studies examined risk factors for social isolation and activity restriction associated with fear of falling. Six studies reported mental health outcomes related to falls and subsequent social isolation. CONCLUSIONS: Consistency in outcome measurement is recommended, as multiple outcomes were used across the included studies. Further research is warranted in this area, given the ageing population and the importance of falls and social isolation to the health of older adults. SCOPING REVIEW REGISTRATION NUMBER: 10.17605/OSF.IO/2R8HM.

The effects of physical activity on cortisol and sleep: A systematic review and meta-analysis.

BACKGROUND: Managing stress and having good quality sleep are inter-related factors that are essential for health, and both factors seem to be affected by physical activity. Although there is an established bidirectional relationship between stress and sleep, remarkably few studies have been designed to examine the effects of physical activity on cortisol, a key biomarker for stress, and sleep. Research is particularly scarce in older people despite both sleep and cortisol changing with age. This systematic literature review addresses this gap. METHODS: A systematic review was conducted following the PRISMA guidelines. Original, peer-reviewed records of intervention studies such as randomized controlled trials (RCTs) and non-RCTs with relevant control groups were eligible for inclusion. The Participant, Intervention, Comparison, Outcome (PICO) characteristics were (1) adults or older adults (2) physical activity programmes of any duration, (3) controls receiving no intervention or controls included in a different programme, (4) cortisol measurement, and subjective or objective measures of sleep. RESULTS: Ten original studies with low-to-moderate risk of bias were included. Findings from this review indicated with moderate- and low-certainty evidence, respectively, that physical activity was an effective strategy for lowering cortisol levels (SMD [95% CI] = -0.37 [-0.52, -0.21] p < .001) and improving sleep quality (SMD [95% CI] = -0.30 [-0.56, -0.04], p = .02). Caution is needed to generalize these findings to the general population, as included trials were predominantly participants with breast cancer, included few males and no older adults. CONCLUSION: Cortisol regulation and sleep quality are intertwined, and physical activity programmes could improve both in several ways. Further, physical activity may benefit adults with long term conditions or current poor (mental) health states the most, although more research is needed to support this claim fully. Few intervention studies have examined the inter-relationship between cortisol and sleep outcomes in males or older adults, indicating fruitful enquiry for future research.

Interventions for social isolation in older adults who have experienced a fall: a systematic review.

OBJECTIVES: The objective of our systematic review was to identify the effective interventions to prevent or mitigate social isolation and/or loneliness in older adults who experienced a fall. DESIGN: Systematic review. DATA SOURCES: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Ageline were searched (from inception to February 2020). METHODS: Studies were eligible if they described any intervention for social isolation in older adults living in a community setting who experienced a fall, and reported outcomes related to social isolation or loneliness.Two independent reviewers screened citations, abstracted data and appraised risk of bias using the Cochrane risk of bias tool. The results were summarised descriptively. RESULTS: After screening 4069 citations and 55 full-text articles, four studies were included. The four studies varied in study design, including a randomised controlled trial, non-randomised controlled trial, an uncontrolled before-after study and a quasiexperimental study. Interventions varied widely, and included singing in a choir, a patient-centred, interprofessional primary care team-based approach, a multifactorial assessment targeting fall risk, appropriate medication use, loneliness and frailty, and a community-based care model that included comprehensive assessments and multilevel care coordination. Outcome measures varied and included scales for loneliness, social isolation, social interaction, social networks and social satisfaction. Mixed results were found, with three studies reporting no differences in social isolation or loneliness after the intervention. Only the multifactorial assessment intervention demonstrated a small positive effect on loneliness compared with the control group after adjustment (B=-0.18, 95% CI -0.35 to -0.02). CONCLUSIONS: Few studies examined the interventions for social isolation or loneliness in older adults who experienced a fall. More research is warranted in this area. PROSPERO REGISTRATION NUMBER: CRD42020198487.

Utilising social media within incident response programmes.

Humans are social creatures that learn from observing others. Until this century, the reach of social learning was confined to small groups or locales. However, the pervasive adoption of social media platforms has provided the means to augment social learning and empower virtual groups by transcending geographic and time boundaries. The broad adoption of social media across all demographic groups gives augmented social learning potentially broad applications, including within the realm of incident response. This article will discuss how augmented social learning can be a powerful tool to manage communications during high-impact 'black swan' events that require speed and agility when disseminating information, and for which no standard incident response 'playbook' is available.

Ready, set, bake: Using the 'Great British Bake Off' to learn important lessons in incidence response.

Adults learn from experiences, be they lived or virtual. In the latter case, television programming offers a variety of opportunities for virtual learning. Indeed, while some people regard 'reality television' as no more than simple entertainment, the manner in which participants tackle complex situations can in fact provide opportunities for learning. 'The Great British Bake Off' (GBBO) provides a case in point, due to the striking parallels between it and the incidence response process. Both involve executing complex processes in abbreviated timeframes with numerous opportunities for failure. Just like no two 'bakes' are alike, no two incident response events run identically. GBBO bakers and incident response practitioners need to be knowledgable, agile and prepared to manage in a variety of circumstances. This paper offers insights into enhancing incident response using the GBBO as a model for performing incident response. Please note: in the US GBBO is known as 'The Great British Baking Show'.

Genetic Strategies to Understand Human Diabetic Nephropathy: In Silico Strategies for Molecular Data-Association Studies.

Multiple genetic strategies are available to help improve understanding of diabetic nephropathy. This chapter provides detailed methodology for a single-nucleotide polymorphism association study and meta-analysis, using a protocol suitable for targeted SNP or genome-wide association studies, to identify genetic risk factors for diabetic nephropathy.

The Challenges of Chromosome Y Analysis and the Implications for Chronic Kidney Disease.

The role of chromosome Y in chronic kidney disease (CKD) remains unknown, as chromosome Y is typically excluded from genetic analysis in CKD. The complex, sex-specific presentation of CKD could be influenced by chromosome Y genetic variation, but there is limited published research available to confirm or reject this hypothesis. Although traditionally thought to be associated with male-specific disease, evidence linking chromosome Y genetic variation to common complex disorders highlights a potential gap in CKD research. Chromosome Y variation has been associated with cardiovascular disease, a condition closely linked to CKD and one with a very similar sexual dimorphism. Relatively few sources of genetic variation in chromosome Y have been examined in CKD. The association between chromosome Y aneuploidy and CKD has never been explored comprehensively, while analyses of microdeletions, copy number variation, and single-nucleotide polymorphisms in CKD have been largely limited to the autosomes or chromosome X. In many studies, it is unclear whether the analyses excluded chromosome Y or simply did not report negative results. Lack of imputation, poor cross-study comparability, and requirement for separate or additional analyses in comparison with autosomal chromosomes means that chromosome Y is under-investigated in the context of CKD. Limitations in genotyping arrays could be overcome through use of whole-chromosome sequencing of chromosome Y that may allow analysis of many different types of genetic variation across the chromosome to determine if chromosome Y genetic variation is associated with CKD.

Genetic Susceptibility to Chronic Kidney Disease - Some More Pieces for the Heritability Puzzle.

Chronic kidney disease (CKD) is a major global health problem with an increasing prevalence partly driven by aging population structure. Both genomic and environmental factors contribute to this complex heterogeneous disease. CKD heritability is estimated to be high (30-75%). Genome-wide association studies (GWAS) and GWAS meta-analyses have identified several genetic loci associated with CKD, including variants in UMOD, SHROOM3, solute carriers, and E3 ubiquitin ligases. However, these genetic markers do not account for all the susceptibility to CKD, and the causal pathways remain incompletely understood; other factors must be contributing to the missing heritability. Less investigated biological factors such as telomere length; mitochondrial proteins, encoded by nuclear genes or specific mitochondrial DNA (mtDNA) encoded genes; structural variants, such as copy number variants (CNVs), insertions, deletions, inversions and translocations are poorly covered and may explain some of the missing heritability. The sex chromosomes, often excluded from GWAS studies, may also help explain gender imbalances in CKD. In this review, we outline recent findings on molecular biomarkers for CKD (telomeres, CNVs, mtDNA variants, sex chromosomes) that typically have received less attention than gene polymorphisms. Shorter telomere length has been associated with renal dysfunction and CKD progression, however, most publications report small numbers of subjects with conflicting findings. CNVs have been linked to congenital anomalies of the kidney and urinary tract, posterior urethral valves, nephronophthisis and immunoglobulin A nephropathy. Information on mtDNA biomarkers for CKD comes primarily from case reports, therefore the data are scarce and diverse. The most consistent finding is the A3243G mutation in the MT-TL1 gene, mainly associated with focal segmental glomerulosclerosis. Only one GWAS has found associations between X-chromosome and renal function (rs12845465 and rs5987107). No loci in the Y-chromosome have reached genome-wide significance. In conclusion, despite the efforts to find the genetic basis of CKD, it remains challenging to explain all of the heritability with currently available methods and datasets. Although additional biomarkers have been investigated in less common suspects such as telomeres, CNVs, mtDNA and sex chromosomes, hidden heritability in CKD remains elusive, and more comprehensive approaches, particularly through the integration of multiple -"omics" data, are needed.

Using agility to combat cyber attacks.

Some incident response practitioners feel that they have been locked in a battle with cyber criminals since the popular adoption of the internet. Initially, organisations made great inroads in preventing and containing cyber attacks. In the last few years, however, cyber criminals have become adept at eluding defence security technologies and rapidly modifying their exploit strategies for financial or political gains. Similar to changes in military combat tactics, cyber criminals utilise distributed attack cells, real-time communications, and rapidly mutating exploits to minimise the potential for detection. Cyber criminals have changed their attack paradigm. This paper describes a new incident response paradigm aimed at combating the new model of cyber attacks with an emphasis on agility to increase the organisation's ability to respond rapidly to these new challenges.

You say you want an evolution (of your risk management programme).

Living organisms must evolve to continue to exist, let alone thrive. This situation is especially true when organisms are faced with a challenging environment, such as the risk management landscape. Risk management organisations need to adopt a continuous adaptation strategy to manage the dynamic threat landscape and build resilience into the risk management function. However, risk management teams do not have the luxury of being able to wait for adaptations to occur naturally because of the rapid rate of change. Risk management organisations should consider embracing strategic evolution to continuously transform their teams to handle new challenges created by societal and technological trends.

The FireWork air quality forecast system with near-real-time biomass burning emissions: Recent developments and evaluation of performance for the 2015 North American wildfire season.

UNLABELLED: Environment and Climate Change Canada's FireWork air quality (AQ) forecast system for North America with near-real-time biomass burning emissions has been running experimentally during the Canadian wildfire season since 2013. The system runs twice per day with model initializations at 00 UTC and 12 UTC, and produces numerical AQ forecast guidance with 48-hr lead time. In this work we describe the FireWork system, which incorporates near-real-time biomass burning emissions based on the Canadian Wildland Fire Information System (CWFIS) as an input to the operational Regional Air Quality Deterministic Prediction System (RAQDPS). To demonstrate the capability of the system we analyzed two forecast periods in 2015 (June 2-July 15, and August 15-31) when fire activity was high, and observed fire-smoke-impacted areas in western Canada and the western United States. Modeled PM2.5 surface concentrations were compared with surface measurements and benchmarked with results from the operational RAQDPS, which did not consider near-real-time biomass burning emissions. Model performance statistics showed that FireWork outperformed RAQDPS with improvements in forecast hourly PM2.5 across the region; the results were especially significant for stations near the path of fire plume trajectories. Although the hourly PM2.5 concentrations predicted by FireWork still displayed bias for areas with active fires for these two periods (mean bias [MB] of -7.3 µg m(-3) and 3.1 µg m(-3)), it showed better forecast skill than the RAQDPS (MB of -11.7 µg m(-3) and -5.8 µg m(-3)) and demonstrated a greater ability to capture temporal variability of episodic PM2.5 events (correlation coefficient values of 0.50 and 0.69 for FireWork compared to 0.03 and 0.11 for RAQDPS). A categorical forecast comparison based on an hourly PM2.5 threshold of 30 µg m(-3) also showed improved scores for probability of detection (POD), critical success index (CSI), and false alarm rate (FAR). IMPLICATIONS: Smoke from wildfires can have a large impact on regional air quality (AQ) and can expose populations to elevated pollution levels. Environment and Climate Change Canada has been producing operational air quality forecasts for all of Canada since 2009 and is now working to include near-real-time wildfire emissions (NRTWE) in its operational AQ forecasting system. An experimental forecast system named FireWork, which includes NRTWE, has been undergoing testing and evaluation since 2013. A performance analysis of FireWork forecasts for the 2015 wildfire season shows that FireWork provides significant improvements to surface PM2.5 forecasts and valuable guidance to regional forecasters and first responders.

The potential and realized spread of wildfires across Canada.

Given that they can burn for weeks or months, wildfires in temperate and boreal forests may become immense (eg., 10(0) - 10(4) km(2) ). However, during the period within which a large fire is 'active', not all days experience weather that is conducive to fire spread; indeed most of the spread occurs on a small proportion (e.g., 1 - 15 days) of not necessarily consecutive days during the active period. This study examines and compares the Canada-wide patterns in fire-conducive weather ('potential' spread) and the spread that occurs on the ground ('realized' spread). Results show substantial variability in distributions of potential and realized spread days across Canada. Both potential and realized spread are higher in western than in eastern Canada; however, whereas potential spread generally decreases from south to north, there is no such pattern with realized spread. The realized-to-potential fire-spread ratio is considerably higher in northern Canada than in the south, indicating that proportionally more fire-conducive days translate into fire progression. An exploration of environmental correlates to spread show that there may be a few factors compensating for the lower potential spread in northern Canada: a greater proportion of coniferous (i.e., more flammable) vegetation, lesser human impacts (i.e., less fragmented landscapes), sufficient fire ignitions, and intense droughts. Because a linear relationship exists between the frequency distributions of potential spread days and realized spread days in a fire zone, it is possible to obtain one from the other using a simple conversion factor. Our methodology thus provides a means to estimate realized fire spread from weather-based data in regions where fire databases are poor, which may improve our ability to predict future fire activity.

Alanine transaminase rather than abdominal ultrasound alone is an important investigation to justify cholecystectomy in patients presenting with acute pancreatitis.

OBJECTIVES: The aims of this study were to investigate the predictive value of an elevated level of alanine transaminase (ALT) for biliary acute pancreatitis (AP) and to reconsider the role of abdominal ultrasound (AUS). METHODS: All patients admitted to Christchurch Public Hospital with AP between July 2005 and December 2008 were identified from a prospectively collected database. Peak ALT within 48 h of presentation was recorded. Aetiology was determined on the basis of history, AUS and other relevant investigations. RESULTS: A total of 543 patients met the inclusion criteria. Patients with biliary AP had significantly higher median (range) ALT than those with non-biliary causes (200 units/l [63-421 units/l] vs. 33 units/l [18-84 units/l]; P < 0.001). An ALT level of >300 units/l had a sensitivity of 36%, specificity of 94%, positive predictive value of 87% and positive likelihood ratio of 5.6 for gallstones. An elevated ALT and negative AUS had a probability of 21-80% for gallstones. CONCLUSIONS: An elevated ALT strongly supports a diagnosis of gallstones in AP. Abdominal ultrasound effectively confirms this diagnosis; however, a negative ultrasound in the presence of a raised ALT does not exclude gallstones. In some patients consideration could be given to proceeding to laparoscopic cholecystectomy based on ALT alone.