Clinical and ethical challenges in undertaking LIMPRINT in vulnerable populations

Background and study objective: To estimate the prevalence of CO and wounds within two vulnerable populations a male, high security prison in the East Midlands (UK) and residential and nursing homes in the UK and Australia. Methods and results: Methods for screening for chronic oedema (CO) and wounds were adapted from the main LIMPRINT methodology. Prison population. In total, 195 inmates were recruited with 22(11%) having CO. While the majority were white Caucasian (156 / 83.4%) a further 20 (10.7%) were dark skinned with 11 (5.95%) from other minority populations. Co-morbidities included 123 (63%) smokers, 22 (11%) alcohol dependant, 60 (31%) with mental health problems and 35 (18%) a history of self- harm. Only three had a current wound with 30 (16%) having had a traumatic stab wound. Residential and nursing homes (UK and Australia): In the UK, the total population available for inclusion was 189 with only 137(73%) recruited. Seventy two of the 137 (52%) suffered from CO and a further 16 (23%) had a history of cellulitis. Results from the Australian residential care facilities have been published in full. In summary, of the 37 participants 20 (54%) experienced CO with 25 (68%) having co-morbidities and 11 (30%) having a concurrent wound. Conclusion: Obtaining an accurate picture of the prevalence and impact of CO in vulnerable populations is extremely challenging due issues of access and consent. Lack of reliable data for these populations will contribute to poor service provision

Prespecified Risk Criteria Facilitate Adequate Discharge and Long-Term Outcomes After Transfemoral Transcatheter Aortic Valve Implantation

Background Despite the availability of guidelines for the performance of transcatheter aortic valve implantation (TAVI), current treatment pathways vary between countries and institutions, which impact on the mean duration of postprocedure hospitalization. Methods and Results This was a prospective, multicenter registry of 502 patients to validate the appropriateness of discharge timing after transfemoral TAVI, using prespecified risk criteria from FAST-TAVI (Feasibility and Safety of Early Discharge After Transfemoral [TF] Transcatheter Aortic Valve Implantation), based on hospital events within 1-year after discharge. The end point-a composite of all-cause mortality, vascular access-related complications, permanent pacemaker implantation, stroke, cardiac rehospitalization, kidney failure, and major bleeding-was reached in 27.0% of patients (95% CI, 23.3-31.2) within 1 year after intervention; 7.5% (95% CI, 5.5-10.2) had in-hospital complications before discharge and 19.6% (95% CI, 16.3-23.4) within 1 year after discharge. Overall mortality within 1 year after discharge was 7.3% and rates of cardiac rehospitalization 13.5%, permanent pacemaker implantation 4.2%, any stroke 1.8%, vascular-access-related complications 0.7%, life-threatening bleeding 0.7%, and kidney failure 0.4%. Composite events within 1 year after discharge were observed in 18.8% and 24.3% of patients with low risk of complications/early (≤3 days) discharge and high risk and discharged late (>3 days) (concordant discharge), respectively. Event rate in patients with discordant discharge was 14.3% with low risk but discharged late and increased to 50.0% in patients with high risk but discharged in ≤3 days. Conclusions The FAST-TAVI risk assessment provides a tool for appropriate, risk-based discharge that was validated with the 1-year event rate after transfemoral TAVI. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT02404467

Prevalence and risk factors for chronic edema in U.K. community nursing services

Background and study design: Chronic edema (CO) is believed to be a major clinical problem within community nursing services in the UK. This study was undertaken as part of the LIMPRINT international study to determine the number of people with chronic oedema and its impact on health services. Methods and Results: Three urban based community nursing services participated in the UK with prospective evaluation over 4 weeks of all patients receiving nursing care using a questionnaire-based interview and clinical assessment using the LIMPRINT tools. Of the total 2,541 assessed 1,440 (56.7%) were considered to have CO, comprising Leicester City (768/ 1298 (59.2%), Nottingham West (124/ 181 (68.5%)) and Nottingham City (548/1062 (51.6%)). The mean age for women with CO was 78.6 (SD 12.8) years and for men 72.9 (SD14.5). More patients with CO suffered from diabetes (32.1% versus 27.9%, p=0.027), heart failure/ ischaemic heart disease (27.3% versus 14.0%, p<0.001) and peripheral arterial occlusive disease (5.5% versus 1.9%, p<0.001). By far the greatest association was with the presence of a wound (73.6% versus 37.9%, p<0.001). Cellulitis affected 628 (24.7%) and 688 (47.8%) had a concurrent leg ulcer. Rates of reduced mobility (71.6% versus 61.9%) and obesity were higher in those with CO. Six independent factors associated with chronic oedema were service location, age, ethnicity, obesity, heart failure and the presence of a wound. Conclusion: Chronic oedema is a major and growing health care problem within primary care that has been previously unrecognised and requires effective service provision

Alternative splicing and nonsense-mediated decay regulate telomerase reverse transcriptase (TERT) expression during virus-induced lymphomagenesis in vivo

<p>Abstract</p> <p>Background</p> <p>Telomerase activation, a critical step in cell immortalization and oncogenesis, is partly regulated by alternative splicing. In this study, we aimed to use the Marek's disease virus (MDV) T-cell lymphoma model to evaluate TERT regulation by splicing during lymphomagenesis <it>in vivo</it>, from the start point to tumor establishment.</p> <p>Results</p> <p>We first screened cDNA libraries from the chicken MDV lymphoma-derived MSB-1 T- cell line, which we compared with B (DT40) and hepatocyte (LMH) cell lines. The chTERT splicing pattern was cell line-specific, despite similar high levels of telomerase activity. We identified 27 alternative transcripts of chicken TERT (chTERT). Five were in-frame alternative transcripts without <it>in vitro </it>telomerase activity in the presence of viral or chicken telomerase RNA (vTR or chTR), unlike the full-length transcript. Nineteen of the 22 transcripts with a premature termination codon (PTC) harbored a PTC more than 50 nucleotides upstream from the 3' splice junction, and were therefore predicted targets for nonsense-mediated decay (NMD). The major PTC-containing alternatively spliced form identified in MSB1 (ie10) was targeted to the NMD pathway, as demonstrated by UPF1 silencing. We then studied three splicing events separately, and the balance between in-frame alternative splice variants (d5f and d10f) plus the NMD target i10ec and constitutively spliced chTERT transcripts during lymphomagenesis induced by MDV indicated that basal telomerase activity in normal T cells was associated with a high proportion of in-frame non functional isoforms and a low proportion of constitutively spliced chTERT. Telomerase upregulation depended on an increase in active constitutively spliced chTERT levels and coincided with a switch in alternative splicing from an in-frame variant to NMD-targeted variants.</p> <p>Conclusions</p> <p>TERT regulation by splicing plays a key role in telomerase upregulation during lymphomagenesis, through the sophisticated control of constitutive and alternative splicing. Using the MDV T-cell lymphoma model, we identified a chTERT splice variant as a new NMD target.</p

Analysis of Strain State and Cracking of Cocnrete Sleepers

Prestressed concrete sleepers are the most common type of the sleepers used on the railroad. They serve as rail supports and absorb loads induced by trains. Sleepers are important for the durability and safety of the railroad and are exposed to various loads and an agressive environment during exploitation. Therefore, different types of appearing damage can determine their reliability. The article briefly discusses possible causes of damage and the deterioration of prestressed concrete sleepers. End cracking and damage at the rail seat was determined during the inspection of used sleepers. Therefore, the strain state and cracking of the rail seat of the sleeper was analysed under static and dynamic loads. The paper provides the obtained results of experimental research of used and new sleepers

siRNA–Mediated Methylation of Arabidopsis Telomeres

Chromosome termini form a specialized type of heterochromatin that is important for chromosome stability. The recent discovery of telomeric RNA transcripts in yeast and vertebrates raised the question of whether RNA–based mechanisms are involved in the formation of telomeric heterochromatin. In this study, we performed detailed analysis of chromatin structure and RNA transcription at chromosome termini in Arabidopsis. Arabidopsis telomeres display features of intermediate heterochromatin that does not extensively spread to subtelomeric regions which encode transcriptionally active genes. We also found telomeric repeat–containing transcripts arising from telomeres and centromeric loci, a portion of which are processed into small interfering RNAs. These telomeric siRNAs contribute to the maintenance of telomeric chromatin through promoting methylation of asymmetric cytosines in telomeric (CCCTAAA)n repeats. The formation of telomeric siRNAs and methylation of telomeres relies on the RNA–dependent DNA methylation pathway. The loss of telomeric DNA methylation in rdr2 mutants is accompanied by only a modest effect on histone heterochromatic marks, indicating that maintenance of telomeric heterochromatin in Arabidopsis is reinforced by several independent mechanisms. In conclusion, this study provides evidence for an siRNA–directed mechanism of chromatin maintenance at telomeres in Arabidopsis