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GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients.
No full textOBJECTIVES
The homozygous GH receptor (GHR) pseudoexon (6Ψ) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Ψ-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this.
METHODS
6Ψ-GHR and WT-GHR mRNA transcripts of 4 6Ψ patient (height SDS -4.2 to -3.1) and 1 control fibroblasts were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6Ψ patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing.
RESULTS
RT-PCR confirmed 6Ψ-GHR transcript in the 6Ψ patients but not control. 6Ψ-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Ψ:WT transcript ratios ranged from 29-71:1 for patients 1-4 and correlated negatively with height SDS (R=-0.85; p<0.001). Eight deleterious variants in 6 genes were detected but the number of gene hits did not correlate with the degree of SS in individual 6Ψ patients.
CONCLUSION
Variable amounts of 6Ψ- and WT-GHR transcripts were identified in 6Ψ patients but no 6Ψ transcript was present in the control. Higher 6Ψ:WT GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation
Working Collaboratively: Outcomes of Geriatrician Input in Older Patients Undergoing Emergency Laparotomy in a District General Hospital.
No full textWith the increasing median age of survival in the UK, there is an increased burden on the provision of medical and surgical care to the population. The 2010 National Confidential Enquiry into Patient Outcome and Death report, "An Age Old Problem," emphasizes the early involvement of surgical and geriatric consultant input to improve perioperative care in older patients. This study describes the development of a Geriatric Surgical Liaison Service aimed at providing consultant-led geriatrician support to improve the outcomes of older patients undergoing Emergency Laparotomy (EL). The primary outcome is the reduction in length of stay (LOS) compared to baseline data prior to geriatrician involvement. The service was designed to include one clinical session involving a consultant geriatrician and two and a half days with a junior doctor in a week. Data was collected prospectively from February 2018 till July 2018 for surgical patients aged ≥ 70 years, who underwent EL, had an inpatient stay of more than seven days, and who were diagnosed with delirium or incurred inpatient falls (intervention group). Baseline data, prior to geriatrician involvement, were collected retrospectively for EL patients aged ≥ 70 years from December 2015 until May 2016. Length of stay and 30-day mortality were also compared between the two cohorts undergoing EL. A total of 69 patients were included in the intervention group; 45 patients underwent EL and their mean LOS was 17.5 days, which was reduced from 22.5 days prior to geriatrician involvement (n=57). There was no difference in median length of stay and 30-day mortality between the retrospective baseline group and the intervention groups. In the intervention group, 8.5% of patients had a new medical diagnosis and 26.8% of patients were offered follow-ups. Although statistically not significant (p=0.40), a shorter stay in hospital by five days can potentially have a positive impact on patient outcomes by reducing psychosocial, cognitive, and functional deconditioning. This would also improve patient flow, release capacity, and waiting times and would be of benefit to the financially strained National Health Service (NHS). Overall, our study suggests that a collaborative, consultant-led geriatric service can improve the management of older surgical patients by potentially reducing length of stay, identifying high-risk patients, and facilitating early and appropriate specialty input alongside adequate and required outpatient follow-up
Thermonuclease test accuracy is preserved in methicillin-resistant isolates.
No full textThe gene encodes a thermonuclease which is present in but not in coagulase-negative staphylococci (CoNS) and is the target of the rapid phenotypic thermonuclease test. The effect of gene variation in methicillin-resistant (MRSA) on the performance of PCR testing has been noted, although there are no reports about the effect of MRSA on the activity of the thermonuclease enzyme. Our goals were to examine the sensitivity and specificity of the thermonuclease test used to distinguish from CoNS cultured from blood. In addition, we aimed to assess differences in the sensitivity, specificity and accuracy of the thermonuclease test between methicillin-sensitive (MSSA) and MRSA isolates. We performed a retrospective analysis of 1404 isolates. Each isolate from a positive blood culture was identified as a Gram-positive coccus by microscopy then analysed with the thermonuclease test (Southern Group Laboratory) prior to confirmatory identification using VITEK microbial identification platforms (bioMérieux) and cefoxitin disc diffusion testing. Of 1331 samples included in the final analysis, 189 were thermonuclease-positive, of which 176 were identified as . Of the 1142 thermonuclease-negative samples, 13 were finally identified as , giving a sensitivity of 93.1 % (95 % confidence interval [CI] 88.5-96.3) and specificity of 98.9 % (95 % CI 98.1-99.4). Of the nine proven MRSA samples, eight were thermonuclease-positive, giving a sensitivity of 88.9 % (95 % CI 51.8-99.7). Thermonuclease test accuracy for MSSA and MRSA isolates was 98.1 % (95 % CI 97.2-98.8) versus 98.8 % (95 % CI 98.0-99.3), respectively. In the era of increasing use of molecular-based microbiology assays, the thermonuclease test remains a simple, inexpensive and robust test for the presumptive identification of cultured from blood, irrespective of methicillin sensitivity
Quality improvement in vascular access: The role of patient-reported outcome measures.
No full textQuality improvement initiatives should be aimed to enhance clinical outcomes, service delivery and quality of life for patients. For patients reliant on haemodialysis, vascular access is a lifeline. Survival differences relating to the type of vascular access are evident and many initiatives have focussed on increasing absolute rates of arteriovenous fistulas and/or decreasing central venous catheter use. While these have achieved some success quantitatively, the qualitative effects are less obvious. The aims of this review article are to explore the concepts of quality of care in vascular access. There is a paucity of studies into the effects of vascular access on the quality of life of dialysis patients, and where studies have been performed, generalised patient-reported outcome measures have been used. To facilitate the implementation of quality improvement programmes specifically for vascular access requires suitable tools. While existing patient-reported outcome measures may be applicable to vascular access, it is likely that these will require further evaluation, and the development of vascular access-specific patient-reported outcome measures may be required
A 16-year Longitudinal Cohort Study of Incidence and Bacteriology of Necrotising Fasciitis in England.
No full textBACKGROUND
Necrotising fasciitis (NF) is a rapidly progressive, destructive soft tissue infection with high mortality. The primary aim of this study was to evaluate the incidence and mortality of NF amongst patients admitted to English National Health Service (NHS) hospitals. The secondary aims included the identification of risk factors for mortality and causative pathogens.
METHODS
The Hospital Episodes Statistics database identified patients with NF admitted to English NHS Trusts from 1/1/2002 to 31/12/2017. Information on patient demographics, co-morbid conditions, microbiology specimens, surgical intervention and in-hospital mortality was collected. Uni- and multivariable analyses were performed to investigate factors related to in-hospital mortality.
RESULTS
A total of 11,042 patients were diagnosed with NF. Age-standardised incidence rose from 9 per million in 2002 to 21 per million in 2017 (annual percentage change = 6.9%). Incidence increased with age and was higher in men. Age-standardised mortality rate remained at 16% over the study period, while in-hospital mortality declined. On multivariable analysis, the following factors were associated with increased risk of in-hospital mortality: emergency admission, female sex, history of congestive heart failure, peripheral vascular disease, chronic kidney disease and cancer. Admission year and diabetes, which was significantly prevalent at 27%, were not associated with increased risk of mortality. Gram-positive pathogens, particularly Staphylococci, decreased over the study period with a corresponding increase in Gram-negative pathogens, predominantly E. coli.
CONCLUSION
The incidence of NF increased markedly from 2002 to 2017 although in-hospital mortality did not change. There was a gradual shift in the causative organisms from Gram-positive to Gram-negative
Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for PD-L1 Testing In Non-Small Cell Lung Cancer.
No full textRATIONALE
PD-L1 expression on cancer cells is a clinically important biomarker to select NSCLC patients for treatment with PD-1/PD-L1 inhibitors. Clinical trials of immunotherapy in patients with non-small cell lung cancer have required histology for PD-L1 testing, while in clinical practice cytology samples are commonly acquired in patients with advanced disease.
OBJECTIVES
This study investigates sampling adequacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for PD-L1 testing when compared to other methods. Furthermore, the relationship between clinico-pathological characteristics and PD-L1 expression in the study population have been examined.
METHODS
Five hundred seventy-seven NSCLC specimens were analysed from consecutive patients with NSCLC across six centres in United Kingdom and one in the United States between January 2015 and December 2016.
MAIN RESULTS
In the EBUS-TBNA group (189 specimens), the overall percentage of patients with successful PD-L1 testing was 94.7%. There was no significant difference in sampling adequacy with other methods of tissue acquisition. Older subjects had higher failure rates of PD-L1 testing (OR= 1.06, p=0.008). In multivariate analysis, advanced N-stage (p=0.048) and presence of brain metastasis (p<0.001) were associated with high PD-L1 expression.
CONCLUSION
This large multicenter study shows that EBUS-TBNA provides samples adequate for PD-L1 testing and that advanced N stage and the presence of brain metastasis are associated with high PD-L1 expression
Corrigendum to 'EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort Under the Auspices of the EAU-ESMO Guidelines Committees' [European Urology 77 (2020) 223-250].
No full textResponse to eculizumab in patients with myasthenia gravis recently treated with chronic IVIg: a subgroup analysis of REGAIN and its open-label extension study.
No full textBackground
In the phase III eculizumab for refractory generalized myasthenia gravis REGAIN study [ClinicalTrials.gov identifier: NCT01997229] and its open-label extension (OLE) [ClinicalTrials.gov identifier: NCT02301624], patients with treatment-refractory antiacetylcholine receptor antibody-positive generalized myasthenia gravis had clinically meaningful improvements with eculizumab placebo. This subgroup analysis evaluated data from patients with a recent history of chronic intravenous immunoglobulin (IVIg) use before study entry.
Methods
The subgroup comprised patients who had received IVIg at least four times in 1 year, with at least one IVIg treatment cycle during the 6 months before the first REGAIN study dose. Data from REGAIN and the OLE were analyzed. Response to eculizumab placebo was assessed using four validated, disease-specific measures. Incidences of exacerbations and safety endpoints were recorded.
Results
The subgroup had similar patient and disease characteristics as the overall REGAIN population. Clinical assessments showed sustained eculizumab efficacy during REGAIN and the OLE over 18 months. Patients receiving placebo in REGAIN experienced rapid improvements in assessment scores when treated with eculizumab in the OLE. There was a lower rate of disease exacerbations with eculizumab than with placebo during REGAIN, and eculizumab was well tolerated.
Conclusion
Eculizumab treatment, compared with placebo, results in meaningful clinical improvements and fewer disease exacerbations for patients who previously received chronic IVIg.
Trial registration
REGAIN [ClinicalTrials.gov identifier: NCT01997229]; REGAIN open-label extension [ClinicalTrials.gov identifier: NCT02301624]
