Definitions of progression in chronic kidney disease-predictors and relationship to renal replacement therapy in a population cohort with a 6 year follow-up

Background. Chronic kidney disease (CKD) is common, important and associated with increased healthcare needs due to CKD progression. Definitions of renal disease progression are multiple, and not always comparable. A measure of 'progression' directly comparable with renal replacement therapy (RRT) initiation would identify 'progressors' in research and for healthcare planning.Methods. The Grampian Laboratory Outcomes Morbidity and Mortality Study (GLOMMS-I) is a community cohort with CKD from 2003, followed up to June 2009 for (i) RRT initiation and (ii) 'progression': sustained reduction in estimated glomerular filtration rate (eGFR) by 15 mL/min/1.73 m(2) (equivalent to CKD stage change), or to <10 mL/min/1.73 m(2), whichever occurs first. Predictors were baseline demographics and comorbidity. The use of the Kidney Disease: Improving Global Outcomes-2012 progression definition was also explored.Results. Two thousand two hundred and eighty-nine and 1044 had Stage 3 and 4 CKD, 44% were males. Overall, RRT initiation and progression rates were 0.97 and 3.50 per 100 patient-years (py). Females had significantly lower progression and RRT initiation rates. The progression rate was not dependent on CKD stage [incidence rate ratio (IRR) for Stage 4 (versus Stage 3) 0.9 (95% CI 0.8-1.2)], whereas the RRT initiation rate was [IRR 5.6 (95% CI 3.8-8.2)]. Increased proteinuria was associated with both greater RRT initiation and progression rates.Conclusions. Progression and RRT initiation rate ratios allow comparison of predictors of these outcomes. Higher rates of both in males suggest that greater RRT initiation rate is biological rather than due to preferential treatment. Similar progression but very different RRT initiation rates in Stage 3 and 4 CKD suggests that CKD stage effect on RRT initiation is a function of endpoint proximity rather than faster renal function deterioration.Background. Chronic kidney disease (CKD) is common, important and associated with increased healthcare needs due to CKD progression. Definitions of renal disease progression are multiple, and not always comparable. A measure of 'progression' directly comparable with renal replacement therapy (RRT) initiation would identify 'progressors' in research and for healthcare planning.Methods. The Grampian Laboratory Outcomes Morbidity and Mortality Study (GLOMMS-I) is a community cohort with CKD from 2003, followed up to June 2009 for (i) RRT initiation and (ii) 'progression': sustained reduction in estimated glomerular filtration rate (eGFR) by 15 mL/min/1.73 m(2) (equivalent to CKD stage change), or to <10 mL/min/1.73 m(2), whichever occurs first. Predictors were baseline demographics and comorbidity. The use of the Kidney Disease: Improving Global Outcomes-2012 progression definition was also explored.Results. Two thousand two hundred and eighty-nine and 1044 had Stage 3 and 4 CKD, 44% were males. Overall, RRT initiation and progression rates were 0.97 and 3.50 per 100 patient-years (py). Females had significantly lower progression and RRT initiation rates. The progression rate was not dependent on CKD stage [incidence rate ratio (IRR) for Stage 4 (versus Stage 3) 0.9 (95% CI 0.8-1.2)], whereas the RRT initiation rate was [IRR 5.6 (95% CI 3.8-8.2)]. Increased proteinuria was associated with both greater RRT initiation and progression rates.Conclusions. Progression and RRT initiation rate ratios allow comparison of predictors of these outcomes. Higher rates of both in males suggest that greater RRT initiation rate is biological rather than due to preferential treatment. Similar progression but very different RRT initiation rates in Stage 3 and 4 CKD suggests that CKD stage effect on RRT initiation is a function of endpoint proximity rather than faster renal function deterioration

2010-2011 Philharmonia Season Program

Philharmonia No. 1 October 9, 2010 at 7:30 PM and October 10, 2010 at 4:00 PM Albert-George Schram, music director and conductor ; Elmar Oliveira, violin Feierlicher Einzug der Ritter des Johanniterordens / Richard Strauss, arranged by Karl Kramer -- Violin Concerto in E Minor, op. 64 / Felix Mendelssohn -- Symphony No. 5 in C-sharp Minor / Gustav Mahler Philharmonia No. 2 November 6, 2010 at 7:30 PM and November 7, 2010 at 4:00 PM Albert-George Schram, music director and conductor ; Tao Lin, piano Overture to Ruslan and Lyudmila / Mikhail Glinka -- Piano Concerto No. 25 in C Major, K. 503 / Wolfgang Amadeus Mozart -- Symphohy No. 2 in D Major, op. 43 / Jean Sibelius Philharmonia No. 3 December 4, 2010 at 7:30 PM and December 5, 2010 at 4:00 PM Concerto Competition Winners Philharmonia No. 4 January 29, 2011 at 7:30 PM and January 30, 2011 at 4:00 PM Gunther Schuller, guest conductor ; Lisa Leonard, piano ; Marc Reese, trumpet Die Vorstellung des Chaos from Die Schöpfung (The Representation of Chaos from the Creation) / Joseph Haydn -- Concerto for Piano, Trumpet and Strings in C Minor, op. 35 / Dmitri Shostakovich -- Symphony No. 3 in F Major, op. 90 / Johannes Brahms Philharmonia No. 5 February 19, 2011 at 7:30 PM and February 20, 2011 at 4:00 PM Jon Robertson, guest conductor ; Roberta Rust, piano Piano Concerto No. 5 in E-flat Major, op. 73 ( Emperor ) / Ludwig van Beethoven -- Symphony No. 6 in D Major, op. 60 / Antonín Dvořák Philharmonia No. 6 March 26, 2011 at 7:30 PM and March 27, 2011 at 4:00 PM Albert-George Schram, music director ; Amanda Hall, soprano ; Christin-Marie Hill, mezzo-soprano ; Scott Ramsey, tenor ; Wayne Shepperd, bass-baritone ; Joshua Habermann, Master Chorale of South Florida artistic director and conductor ; Master Chorale of South Florida Messa da Requiem / Giusepe Verdihttps://spiral.lynn.edu/conservatory_philharmonia/1022/thumbnail.jp

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Quantifying neutralising antibody responses against SARS-CoV-2 in dried blood spots (DBS) and paired sera

The ongoing SARS-CoV-2 pandemic was initially managed by non-pharmaceutical interventions such as diagnostic testing, isolation of positive cases, physical distancing and lockdowns. The advent of vaccines has provided crucial protection against SARS-CoV-2. Neutralising antibody (nAb) responses are a key correlate of protection, and therefore measuring nAb responses is essential for monitoring vaccine efficacy. Fingerstick dried blood spots (DBS) are ideal for use in large-scale sero-surveillance because they are inexpensive, offer the option of self-collection and can be transported and stored at ambient temperatures. Such advantages also make DBS appealing to use in resource-limited settings and in potential future pandemics. In this study, nAb responses in sera, venous blood and fingerstick blood stored on filter paper were measured. Samples were collected from SARS-CoV-2 acutely infected individuals, SARS-CoV-2 convalescent individuals and SARS-CoV-2 vaccinated individuals. Good agreement was observed between the nAb responses measured in eluted DBS and paired sera. Stability of nAb responses was also observed in sera stored on filter paper at room temperature for 28 days. Overall, this study provides support for the use of filter paper as a viable sample collection method to study nAb responses.</p

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348