A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD); however, the natural course of disease progression is heterogeneous between patients. This study aimed to develop a natural history model of ADPKD that predicted progression rates and long-term outcomes in patients with differing baseline characteristics. Methods: The ADPKD Outcomes Model (ADPKD-OM) was developed using available patient-level data from the placebo arm of the Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Study (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Multivariable regression equations estimating annual rates of ADPKD progression, in terms of total kidney volume (TKV) and estimated glomerular filtration rate, formed the basis of the lifetime patient-level simulation model. Outputs of the ADPKD-OM were compared against external data sources to validate model accuracy and generalisability to other ADPKD patient populations, then used to predict long-term outcomes in a cohort matched to the overall TEMPO 3:4 study population. Results: A cohort with baseline patient characteristics consistent with TEMPO 3:4 was predicted to reach ESRD at a mean age of 52 years. Most patients (85%) were predicted to reach ESRD by the age of 65 years, with many progressing to ESRD earlier in life (18, 36 and 56% by the age of 45, 50 and 55 years, respectively). Consistent with previous research and clinical opinion, analyses supported the selection of baseline TKV as a prognostic factor for ADPKD progression, and demonstrated its value as a strong predictor of future ESRD risk. Validation exercises and illustrative analyses confirmed the ability of the ADPKD-OM to accurately predict disease progression towards ESRD across a range of clinically-relevant patient profiles. Conclusions: The ADPKD-OM represents a robust tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics. In conjunction with clinical judgement, it has the potential to support decision-making in research and clinical practice

Widening access to cardiovascular healthcare: community screening among ethnic minorities in inner-city Britain – the Healthy Hearts Project

<p>Abstract</p> <p>Background</p> <p>The burden of cardiovascular disease (CVD) in Britain is concentrated in inner-city areas such as Sandwell, which is home to a diverse multi-ethnic population. Current guidance for CVD risk screening is not established, nor are there specific details for ethnic minorities. Given the disparity in equitable healthcare for these groups, we developed a 'tailored' and systematic approach to CVD risk screening within communities of the Sandwell locality. The key anticipated outcomes were the numbers of participants from various ethnic backgrounds attending the health screening events and the prevalence of known and undiagnosed CVD risk within ethnic groups.</p> <p>Methods</p> <p>Data was collected during 10 health screening events (September 2005 and July 2006), which included an assessment of raised blood pressure, overweight, hyperlipidaemia, impaired fasting glucose, smoking habit and the 10 year CVD risk score. Specific features of our approach included (i) community involvement, (ii) a clinician who could deliver immediate attention to adverse findings, and (iii) the use of an interpreter.</p> <p>Results</p> <p>A total of 824 people from the Sandwell were included in this study (47% men, mean age 47.7 years) from community groups such as the Gujarati Indian, Punjabi Indian, European Caucasian, Yemeni, Pakistani and Bangladeshi. A total of 470 (57%) individuals were referred to their General Practitioner with a report of an increased CVD score – undetected high blood pressure in 120 (15%), undetected abnormal blood glucose in 70 (8%), undetected raised total cholesterol in 149 (18%), and CVD risk management review in 131 (16%).</p> <p>Conclusion</p> <p>Using this systematic and targeted approach, there was a clear demand for this service from people of various ethnic backgrounds, of whom, one in two needed review from primary or secondary healthcare. Further work is required to assess the accuracy and clinical benefits of this community health screening approach.</p

Is chest CT useful in newborn screened infants with cystic fibrosis at 1 year of age?

Rationale: Sensitive outcome measures applicable in different centres to quantify and track early pulmonary abnormalities in infants with cystic fibrosis (CF) are needed both for clinical care and interventional trials. Chest CT has been advocated as such a measure yet there is no validated scoring system in infants. Objectives: The objectives of this study were to standardise CT data collection across multiple sites; ascertain the incidence of bronchial dilatation and air trapping in newborn screened (NBS) infants with CF at 1 year; and assess the reproducibility of Brody-II, the most widely used scoring system in children with CF, during infancy. Methods: A multicentre observational study of early pulmonary lung disease in NBS infants with CF at age 1 year using volume-controlled chest CT performed under general anaesthetic. Main results: 65 infants with NBS-diagnosed CF had chest CT in three centres. Small insignificant variations in lung recruitment manoeuvres but significant centre differences in radiation exposures were found. Despite experienced scorers and prior training, with the exception of air trapping, inter- and intraobserver agreement on Brody-II score was poor to fair (eg, interobserver total score mean (95% CI) κ coefficient: 0.34 (0.20 to 0.49)). Only 7 (11%) infants had a total CT score ≥12 (ie, ≥5% maximum possible) by either scorer. Conclusions: In NBS infants with CF, CT changes were very mild at 1 year, and assessment of air trapping was the only reproducible outcome. CT is thus of questionable value in infants of this age, unless an improved scoring system for use in mild CF disease can be developed

Modelling the impact of improving screening and treatment of chronic hepatitis C virus infection on future hepatocellular carcinoma rates and liver-related mortality.

BACKGROUND: The societal, clinical and economic burden imposed by the complications of chronic hepatitis C virus (HCV) infection - including cirrhosis and hepatocellular carcinoma (HCC) - is expected to increase over the coming decades. However, new therapies may improve sustained virological response (SVR) rates and shorten treatment duration. This study aimed to estimate the future burden of HCV-related disease in England if current management strategies remain the same and the impact of increasing diagnosis and treatment of HCV as new therapies become available. METHODS: A previously published model was adapted for England using published literature and government reports, and validated through an iterative process of three meetings of HCV experts. The impact of increasing diagnosis and treatment of HCV as new therapies become available was modelled and compared to the base-case scenario of continuing current management strategies. To assess the 'best case' clinical benefit of new therapies, the number of patients treated was increased by a total of 115% by 2018. RESULTS: In the base-case scenario, total viraemic (HCV RNA-positive) cases of HCV in England will decrease from 144,000 in 2013 to 76,300 in 2030. However, due to the slow progression of chronic HCV, the number of individuals with cirrhosis, decompensated cirrhosis and HCC will continue to increase over this period. The model suggests that the 'best case' substantially reduces HCV-related hepatic disease and HCV-related liver mortality by 2020 compared to the base-case scenario. The number of HCV-related HCC cases would decrease 50% by 2020 and the number progressing from infection to decompensated cirrhosis would decline by 65%. Therefore, compared to projections of current practices, increasing treatment numbers by 115% by 2018 would reduce HCV-related mortality by 50% by 2020. CONCLUSIONS: This analysis suggests that with current treatment practices the number of patients developing HCV-related cirrhosis, decompensated cirrhosis and HCC will increase substantially, with HCV-related liver deaths likely to double by 2030. However, increasing diagnosis and treatment rates could optimise the reduction in the burden of disease produced by the new therapies, potentially halving HCV-related liver mortality and HCV-related HCC by 2020

Clustered Gene Expression Changes Flank Targeted Gene Loci in Knockout Mice

Gene expression profiling using microarrays is a powerful technology widely used to study regulatory networks. Profiling of mRNA levels in mutant organisms has the potential to identify genes regulated by the mutated protein.Using tissues from multiple lines of knockout mice we have examined genome-wide changes in gene expression. We report that a significant proportion of changed genes were found near the targeted gene.The apparent clustering of these genes was explained by the presence of flanking DNA from the parental ES cell. We provide recommendations for the analysis and reporting of microarray data from knockout mice

Network-based social capital and capacity-building programs: an example from Ethiopia

<p>Abstract</p> <p>Introduction</p> <p>Capacity-building programs are vital for healthcare workforce development in low- and middle-income countries. In addition to increasing human capital, participation in such programs may lead to new professional networks and access to social capital. Although network development and social capital generation were not explicit program goals, we took advantage of a natural experiment and studied the social networks that developed in the first year of an executive-education Master of Hospital and Healthcare Administration (MHA) program in Jimma, Ethiopia.</p> <p>Case description</p> <p>We conducted a sociometric network analysis, which included all program participants and supporters (formally affiliated educators and mentors). We studied two networks: the Trainee Network (all 25 trainees) and the Trainee-Supporter Network (25 trainees and 38 supporters). The independent variable of interest was out-degree, the number of program-related connections reported by each respondent. We assessed social capital exchange in terms of resource exchange, both informational and functional. Contingency table analysis for relational data was used to evaluate the relationship between out-degree and informational and functional exchange.</p> <p>Discussion and evaluation</p> <p>Both networks demonstrated growth and inclusion of most or all network members. In the Trainee Network, those with the highest level of out-degree had the highest reports of informational exchange, χ²(1, <it>N </it>= 23) = 123.61, p < 0.01. We did not find a statistically significant relationship between out-degree and functional exchange in this network, χ²(1, <it>N </it>= 23) = 26.11, p > 0.05. In the Trainee-Supporter Network, trainees with the highest level of out-degree had the highest reports of informational exchange, χ²(1, <it>N </it>= 23) = 74.93, p < 0.05. The same pattern held for functional exchange, χ²(1, <it>N </it>= 23) = 81.31, p < 0.01.</p> <p>Conclusions</p> <p>We found substantial and productive development of social networks in the first year of a healthcare management capacity-building program. Environmental constraints, such as limited access to information and communication technologies, or challenges with transportation and logistics, may limit the ability of some participants to engage in the networks fully. This work suggests that intentional social network development may be an important opportunity for capacity-building programs as healthcare systems improve their ability to manage resources and tackle emerging problems.</p

RNF185, a Novel Mitochondrial Ubiquitin E3 Ligase, Regulates Autophagy through Interaction with BNIP1

Autophagy is an evolutionarily conserved catabolic process that allows recycling of cytoplasmic organelles, such as mitochondria, to offer a bioenergetically efficient pathway for cell survival. Considerable progress has been made in characterizing mitochondrial autophagy. However, the dedicated ubiquitin E3 ligases targeting mitochondria for autophagy have not been revealed. Here we show that human RNF185 is a mitochondrial ubiquitin E3 ligase that regulates selective mitochondrial autophagy in cultured cells. The two C-terminal transmembrane domains of human RNF185 mediate its localization to mitochondrial outer membrane. RNF185 stimulates LC3II accumulation and the formation of autophagolysosomes in human cell lines. We further identified the Bcl-2 family protein BNIP1 as one of the substrates for RNF185. Human BNIP1 colocalizes with RNF185 at mitochondria and is polyubiquitinated by RNF185 through K63-based ubiquitin linkage in vivo. The polyubiquitinated BNIP1 is capable of recruiting autophagy receptor p62, which simultaneously binds both ubiquitin and LC3 to link ubiquitination and autophagy. Our study might reveal a novel RNF185-mediated mechanism for modulating mitochondrial homeostasis through autophagy

The Lysosome and Intracellular Signalling.

In addition to being the terminal degradative compartment of the cell's endocytic and autophagic pathways, the lysosome is a multifunctional signalling hub integrating the cell's response to nutrient status and growth factor/hormone signalling. The cytosolic surface of the limiting membrane of the lysosome is the site of activation of the multiprotein complex mammalian target of rapamycin complex 1 (mTORC1), which phosphorylates numerous cell growth-related substrates, including transcription factor EB (TFEB). Under conditions in which mTORC1 is inhibited including starvation, TFEB becomes dephosphorylated and translocates to the nucleus where it functions as a master regulator of lysosome biogenesis. The signalling role of lysosomes is not limited to this pathway. They act as an intracellular Ca2+ store, which can release Ca2+ into the cytosol for both local effects on membrane fusion and pleiotropic effects within the cell. The relationship and crosstalk between the lysosomal and endoplasmic reticulum (ER) Ca2+ stores play a role in shaping intracellular Ca2+ signalling. Lysosomes also perform other signalling functions, which are discussed. Current views of the lysosomal compartment recognize its dynamic nature. It includes endolysosomes, autolysosome and storage lysosomes that are constantly engaged in fusion/fission events and lysosome regeneration. How signalling is affected by individual lysosomal organelles being at different stages of these processes and/or at different sites within the cell is poorly understood, but is discussed

Analysis of Thyroid Response Element Activity during Retinal Development

Thyroid hormone (TH) signaling components are expressed during retinal development in dynamic spatial and temporal patterns. To probe the competence of retinal cells to mount a transcriptional response to TH, reporters that included thyroid response elements (TREs) were introduced into developing retinal tissue. The TREs were placed upstream of a minimal TATA-box and two reporter genes, green fluorescent protein (GFP) and human placental alkaline phosphatase (PLAP). Six of the seven tested TREs were first tested in vitro where they were shown to drive TH-dependent expression. However, when introduced into the developing retina, the TREs reported in different cell types in both a TH-dependent and TH-independent manner, as well as revealed specific spatial patterns in their expression. The role of the known thyroid receptors (TR), TRα and TRβ, was probed using shRNAs, which were co-electroporated into the retina with the TREs. Some TREs were positively activated by TR+TH in the developing outer nuclear layer (ONL), where photoreceptors reside, as well as in the outer neuroblastic layer (ONBL) where cycling progenitor cells are located. Other TREs were actively repressed by TR+TH in cells of the ONBL. These data demonstrate that non-TRs can activate some TREs in a spatially regulated manner, whereas other TREs respond only to the known TRs, which also read out activity in a spatially regulated manner. The transcriptional response to even simple TREs provides a starting point for understanding the regulation of genes by TH, and highlights the complexity of transcriptional regulation within developing tissue

Caspase involvement in autophagy

Caspases are a family of cysteine proteases widely known as the principal mediators of the apoptotic cell death response, but considerably less so as the contributors to the regulation of pathways outside cellular demise. In regards to autophagy, the modulatory roles of caspases have only recently begun to be adequately described. In contrast to apoptosis, autophagy promotes cell survival by providing energy and nutrients through the lysosomal degradation of cytoplasmic constituents. Under basal conditions autophagy and apoptosis cross-regulate each other through an elaborate network of interconnections which also includes the interplay between autophagyrelated proteins (ATGs) and caspases. In this review we focus on the effects of this crosstalk at the cellular level, as we aim to concentrate the main observations from research conducted so far on the fine-tuning of autophagy by caspases. Several members of this protease-family have been found to directly interact with key ATGs involved in different tiers across the autophagic cascade. Therefore, we firstly outline the core mechanism of macroautophagy in brief. In an effort to emphasize the importance of the intricate cross-regulation of ATGs and caspases, we also present examples drawn from Drosophila and plant models regarding the contribution of autophagy to apoptotic cell death during normal development