Population based screening for chronic kidney disease: cost effectiveness study

Objective To determine the cost effectiveness of one-off population based screening for chronic kidney disease based on estimated glomerular filtration rate

The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis

Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor interacting protein (RIP) lcinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-gamma in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases

Kidney Function, Albuminuria and Life Expectancy

Background: Lower estimated glomerular filtration rate is associated with reduced life expectancy. Whether this association is modified by the presence or absence of albuminuria, another cardinal finding of chronic kidney disease, is unknown. Objective: Our objective was to estimate the life expectancy of middle-aged men and women with varying levels of eGFR and concomitant albuminuria. Design: A retrospective cohort study. Setting: A large population-based cohort identified from the provincial laboratory registry in Alberta, Canada. Participants: Adults aged ≥30 years who had outpatient measures of serum creatinine and albuminuria between May 1, 2002 and March 31, 2008. Measurements: Predictor : Baseline levels of kidney function identified from serum creatinine and albuminuria measurements. Outcomes : all cause mortality during the follow-up. Methods: Patients were categorized based on their estimated glomerular filtration rate (eGFR) (≥60, 45–59, 30–44, and 15–29 mL/min/1 · 73 m 2 ) as well as albuminuria (normal, mild, and heavy) measured by albumin-to-creatinine ratio or urine dipstick. The abridged life table method was applied to calculate the life expectancies of men and women from age 40 to 80 years across combined eGFR and albuminuria categories. We also categorized participants by severity of kidney disease (low risk, moderately increased risk. high risk, and very high risk) using the combination of eGFR and albuminuria levels. Results: Among men aged 50 years and with eGFR ≥60 mL/min/1.73 m 2 , estimated life expectancy was 24.8 (95% CI: 24.6–25.0), 17.5 (95% CI: 17.1–17.9), and 13.5 (95% CI: 12.6–14.3) years for participants with normal, mild and heavy albuminuria respectively. Life expectancy for men with mild and heavy albuminuria was 7.3 (95% CI: 6.9–7.8) and 11.3 (95% CI: 10.5–12.2) years shorter than men with normal proteinuria, respectively. A reduction in life expectancy was associated with an increasing severity of kidney disease; 24.8 years for low risk (95% CI: 24.6–25.0), 19.1 years for moderately increased risk (95% CI: 18.7–19.5), 14.2 years for high risk (95% CI: 13.5–15.0), and 9.6 years for very high risk (95% CI: 8.4–10.8). Among women of similar age and kidney function, estimated life expectancy was 28.9 (95% CI: 28.7–29.1), 19.8 (95% CI: 19.2–20.3), and 14.8 (95% CI: 13.5–16.0) years for participants with normal, mild and heavy albuminuria respectively. Life expectancy for women with mild and heavy albuminuria was 9.1 (95% CI: 8.5–9.7) and 14.2 (95% CI: 12.9–15.4) years shorter than the women with normal proteinuria, respectively. For women also a graded reduction in life expectancy was observed across the increasing severity of kidney disease; 28.9 years for low risk (95% CI: 28.7–29.1), 22.5 years for moderately increased risk (95% CI: 22.0–22.9), 16.5 years for high risk (95% CI: 15.4–17.5), and 9.2 years for very high risk (95% CI: 7.8–10.7). Limitations: Possible misclassification of long-term kidney function categories cannot be eliminated. Possibility of confounding due to concomitant comorbidities cannot be ruled out. Conclusion: The presence and degree of albuminuria was associated with lower estimated life expectancy for both gender and was especially notable in those with eGFR ≥30 mL/min/1.73 m 2 . Life expectancy associated with a given level of eGFR differs substantially based on the presence and severity of albuminuria

Pathophysiological implications of urinary peptides in hepatocellular carcinoma

SIMPLE SUMMARY: In this study, the application of capillary electrophoresis mass spectrometry enabled identification of 31 urinary peptides significantly associated with hepatocellular carcinoma diagnosis and prognosis. Further assessment of these peptides lead to prediction of cellular proteases involved in their development namely Meprin A subunit α and Kallikrein-6. Subsequent identification of the proteases was verified by immunohistochemistry in normal liver, cirrhosis and hepatocellular carcinoma. Histopathological assessment of the proteases revealed numerical gradient staining signifying their involvement in liver fibrosis and hepatocellular carcinoma formation. The discovered urinary peptides offered a potential noninvasive tool for diagnosis and prognosis of hepatocellular carcinoma. ABSTRACT: Hepatocellular carcinoma (HCC) is known to be associated with protein alterations and extracellular fibrous deposition. We investigated the urinary proteomic profiles of HCC patients in this prospective cross sectional multicentre study. 195 patients were recruited from the UK (Coventry) and Germany (Hannover) between 1 January 2013 and 30 June 2019. Out of these, 57 were HCC patients with a background of liver cirrhosis (LC) and 138 were non-HCC controls; 72 patients with LC, 57 with non-cirrhotic liver disease and 9 with normal liver function. Analysis of the urine samples was performed by capillary electrophoresis (CE) coupled to mass spectrometry (MS). Peptide sequences were obtained and 31 specific peptide markers for HCC were identified and further integrated into a multivariate classification model. The peptide model demonstrated 79.5% sensitivity and 85.1% specificity (95% CI: 0.81–0.93, p < 0.0001) for HCC and 4.1-fold increased risk of death (95% CI: 1.7–9.8, p = 0.0005). Proteases potentially involved in HCC progression were mapped to the N- and C-terminal sequence motifs of the CE-MS peptide markers. In silico protease prediction revealed that kallikrein-6 (KLK6) elicits increased activity, whilst Meprin A subunit α (MEP1A) has reduced activity in HCC compared to the controls. Tissue expression of KLK6 and MEP1A was subsequently verified by immunohistochemistry

The feasibility of using a parenting programme for the prevention of unintentional home injuries in the under-fives: A cluster randomised controlled trial

Background: Unintentional injury is the leading cause of preventable death of children over the age of 1 year in the UK and a major cause of attendance at emergency departments. Children having one injury are at increased risk of further injuries. Parenting programmes can reduce injuries in preschool children if delivered in the home and on a one-to-one basis. It is not known if group-based programmes delivered outside the home are effective. Objectives: To develop (1) a parenting programme to prevent recurrent unintentional home injuries in preschool children and (2) a tool for parents to report unintentional home injuries occurring to their preschool children. To assess the feasibility of delivering and evaluating the parenting programme through a cluster randomised controlled trial, specifically to (1) assess methods for the recruitment and retention of parents; (2) determine the training, equipment and facilities needed for the delivery of the programme; (3) establish appropriate primary and secondary outcome measures and methods for their collection; (4) determine how 'normal care' in a comparison arm should be defined; and (5) determine the resource utilisation and costing data that would need to be collected for the cost-effectiveness component of a future trial; and (6) produce estimates of effect sizes to inform sample size estimation for a main trial. Design: Feasibility multicentre, cluster, randomised, unblinded trial. Setting: Eight children's centres in Bristol and Nottingham, UK. Participants: Ninety-six parents of preschool children who had sustained an unintentional injury requiring medical attention in the previous 12 months. Interventions: The First-aid Advice and Safety Training (FAST) parent programme, comprising parenting support and skills combined with first aid and home safety advice. Main outcome measures: Parent-reported medically attended injuries in the index child and any preschool siblings sustained during a 6-month period of observation. Results: An 8-week parenting programme was produced, designed with participant-friendly, incrementally progressive content. A slimline, month-to-a-view injury calendar, spiral bound and suitable for hanging on a wall, was designed for parents to record injuries occurring to their preschool children during the 6-month period of observed time. Fifty-one parents were recruited (40 meeting eligibility criteria plus 11 following 'open invite' to participate); 15 parents completed the FAST parent programme and 49 provided data at baseline and during follow-up. Completion of the programme was significantly greater for participants using the 'open invite' approach (85%) than for those recruited using the original eligibility criteria (31%). Prototype resource use checklists, unit costs and total costs were developed for phases 0, 1 and 2 of the study for use in a future trial. Conclusions: This feasibility study has developed an innovative injury prevention intervention and a tool to record parent-reported injuries in preschool children. It was not feasible to recruit parents of children who had sustained a recent injury, or to ask health visitor teams to identify potential participants and to deliver the programme. A trial should target all families attending children's centres in disadvantaged areas. The intervention could be delivered by a health professional supported by a member of the children's centre team in a community setting. Trial registration: Current Controlled Trials ISRCTN03605270. Source of funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 3. See the NIHR Journals Library website for further project information. © Queen's Printer and Controller of HMSO 2014

Correction to:Methods for identifying 30 chronic conditions: application to administrative data

Following publication of the original manuscript [1], the authors noted several errors in Table 1. Details of the requested corrections are shown below

Overview of the Alberta Kidney Disease Network

<p>Abstract</p> <p>Background</p> <p>The Alberta Kidney Disease Network is a collaborative nephrology research organization based on a central repository of laboratory and administrative data from the Canadian province of Alberta.</p> <p>Description</p> <p>The laboratory data within the Alberta Kidney Disease Network can be used to define patient populations, such as individuals with chronic kidney disease (using serum creatinine measurements to estimate kidney function) or anemia (using hemoglobin measurements). The administrative data within the Alberta Kidney Disease Network can also be used to define cohorts with common medical conditions such as hypertension and diabetes. Linkage of data sources permits assessment of socio-demographic information, clinical variables including comorbidity, as well as ascertainment of relevant outcomes such as health service encounters and events, the occurrence of new specified clinical outcomes and mortality.</p> <p>Conclusion</p> <p>The unique ability to combine laboratory and administrative data for a large geographically defined population provides a rich data source not only for research purposes but for policy development and to guide the delivery of health care. This research model based on computerized laboratory data could serve as a prototype for the study of other chronic conditions.</p

A Next-generation Marker Genotyping Platform (AmpSeq) in Heterozygous Crops: A Case Study for Marker-assisted Selection in Grapevine

Marker-assisted selection (MAS) is often employed in crop breeding programs to accelerate and enhance cultivar development, via selection during the juvenile phase and parental selection prior to crossing. Next-generation sequencing and its derivative technologies have been used for genome-wide molecular marker discovery. To bridge the gap between marker development and MAS implementation, this study developed a novel practical strategy with a semi-automated pipeline that incorporates traitassociated single nucleotide polymorphism marker discovery, low-cost genotyping through amplicon sequencing (AmpSeq) and decision making. The results document the development of a MAS package derived from genotyping-by-sequencing using three traits (flower sex, disease resistance and acylated anthocyanins) in grapevine breeding. The vast majority of sequence reads ( ⩾99%) were from the targeted regions. Across 380 individuals and up to 31 amplicons sequenced in each lane of MiSeq data, most amplicons (83 to 87%) had o10% missing data, and read depth had a median of 220–244 × . Several strengths of the AmpSeq platform that make this approach of broad interest in diverse crop species include accuracy, flexibility, speed, high-throughput, lowcost and easily automated analysis

Impaired word and face recognition in older adults with type 2 diabetes

Background: Older adults with type 2 diabetes mellitus (DM2) exhibit accelerated decline in some domains of cognition, including verbal episodic memory. Few studies have investigated the influence of DM2 status in older adults on recognition memory for more complex stimuli, such as faces. Aims: In the present study, we sought to compare recognition memory performance for words, objects and faces under conditions of relatively low and high cognitive load. Methods: Healthy older adults with good glucoregulatory control (n = 13) and older adults with DM2 (n = 24) were administered recognition memory tasks in which stimuli (faces, objects and words) were presented under conditions of either i) low (stimulus presented without a background pattern), or ii) high (stimulus presented against a background pattern) cognitive load. Results: In a subsequent recognition phase, the DM2 group recognised fewer faces than healthy controls. Further, the DM2 group exhibited word recognition deficits in the low cognitive load condition. Conclusions: The recognition memory impairment observed in the patients with DM2 has clear implications for day-to-day functioning. While these deficits were not amplified under conditions of increased cognitive load, the present study emphasises that recognition memory impairment for both words and more complex stimuli, such as faces, are a feature of DM2 in older adults