Author: Jason Curtis

Selection of endogenous control genes for normalising gene expression data derived from formalin-fixed paraffin-embedded tumour tissue (2020)

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Type of publication:
Journal article

Author(s):
Smith T.A.D.; AbdelKarem O.A.; Irlam-Jones J.J.; Lane B.; Valentine H.; Bibby B.A.S.; Choudhury A.; West C.M.L.; *Denley H.

Citation:
Scientific reports; Oct 2020; vol. 10 (no. 1)

Abstract:
Quantitative real time polymerase chain reaction (qPCR) data are normalised using endogenous control genes. We aimed to: (1) demonstrate a pathway to identify endogenous control genes for qPCR analysis of formalinfixed paraffin-embedded (FFPE) tissue using bladder cancer as an exemplar; and (2) examine the influence of probe length and sample age on PCR amplification and co-expression of candidate genes on apparent expression stability. RNA was extracted from prospective and retrospective samples and subject to qPCR using TaqMan human endogenous control arrays or single tube assays. Gene stability ranking was assessed using coefficient of variation (CoV), GeNorm and NormFinder. Co-expressed genes were identified from The Cancer Genome Atlas (TCGA) using the on-line gene regression analysis tool GRACE. Cycle threshold (Ct) values were lower for prospective (19.49+/-2.53) vs retrospective (23.8+/-3.32) tissues (p<0.001) and shorter vs longer probes. Co-expressed genes ranked as the most stable genes in the TCGA cohort by GeNorm when analysed together but ranked lower when analysed individually omitting co-expressed genes indicating bias. Stability values were<1.5 for the 20 candidate genes in the prospective cohort. As they consistently ranked in the top ten by CoV, GeNorm and Normfinder, UBC, RPLP0, HMBS, GUSB, and TBP are the most suitable endogenous control genes for bladder cancer qPCR.

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Results of a randomized phase III study of dysphagia-optimized intensity modulated radiotherapy (Do-IMRT) versus standard IMRT (S-IMRT) in head and neck cancer (2020)

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Type of publication:
Conference abstract

Author(s):
Nutting C.; Rooney K.; Foran B.; *Pettit L.; Beasley M.; Finneran L.; Roe J.; Tyler J.; Roques T.; Cook A.; Petkar I.; Bhide S.; Srinivasan D.; Boon C.; De Winton E.; Frogley R.; Mertens K.; Emson M.; Hall E.

Citation:
Journal of Clinical Oncology; 2020; vol. 38 (no. 15)

Abstract:
Background: Most newly diagnosed oro-& hypopharngeal cancers (OPC, HPC) are treated with (chemo)RT with curative intent but at the consequence of adverse effects on quality of life. CRUK/14/014 investigated if using Do-IMRT to reduce RT dose to the dysphagia/aspiration related structures (DARS) improved swallowing function compared to S-IMRT. Method(s): Patients with T1-4, N0-3, M0 OPC/HPC were randomised 1:1 to S-IMRT (65 Gray (Gy)/30 fractions (f) to primary&nodal tumour; 54Gy/30f to remaining pharyngeal subsite&nodal areas at risk of microscopic disease) or Do-IMRT. The volume of the superior∣dle pharyngeal constrictor muscle (PCM) (OPC) or inferior PCM (HPC) lying outside the high-dose target volume was set a mandatory mean dose constraint in Do-IMRT. Treatment allocation was by minimisation balanced by centre, use of induction/concomitant chemotherapy, tumour site&AJCC stage. Primary endpoint was mean MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after RT with 102 patients needed to detect a 10 point improvement (assuming S-IMRT score of 72, standard deviation (SD) 13.8; 90% power, 2-sided 5% alpha). Patients were blind to treatment allocation. Secondary endpoints included local control. Result(s): 112 patients (56 S-IMRT, 56 Do-IMRT) were randomised from 22 UK centres from 06/2016 to 04/2018. Mean age was 57 years; 80% were male; 97% had OPC; 90% had AJCC stage 3&4 disease; 86% had concomitant chemotherapy only, 4% induction&concomitant and 10% no chemotherapy. 111/112 had RT doses as prescribed (1 patient died before RT). Median of the mean inferior PCM dose was S-IMRT 49.8Gy (IQR 47.1-52.4) vs. Do-IMRT 28.4Gy (21.3-37.4), p < 0.0001; superior∣dle PCM dose was S-IMRT 57.2Gy (56.3-58.3) vs. Do-IMRT 49.7Gy (49.4-49.9), p < 0.0001. Do-IMRT had significantly higher MDADI scores: S-IMRT 70.3 (SD 17.3) vs. Do-IMRT 77.7 (16.1), p = 0.016. 3 local recurrences (1 S-IMRT, 2 Do-IMRT) have been reported. Conclusion(s): Do-IMRT reduced RT dose to the DARS and improved patient reported swallowing function compared with S-IMRT. This is the first randomised study to demonstrate functional benefit of swallow-sparing IMRT in OPC.

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Management of mid-urethral tape complications: a retrospective study (2020)

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Type of publication:
Journal article

Author(s):
Offiah I.; *Rachaneni S.; Dua A.

Citation:
Journal of Obstetrics and Gynecology of India; Apr 2020; vol. 70 (no. 2); p. 152-157

Abstract:
Background/purpose of the study: Following mid-urethral tape insertion, for stress urinary incontinence (SUI), a proportion of women experience complications such as voiding dysfunction or tape erosion which fail to respond to conservative management approaches. These women thus require further surgical treatment. Our objective was to describe the outcomes of the surgical management of complications in these women. Method(s): This retrospective study describes the results obtained following the surgical management of mid-urethral tape complications. Twenty-nine consecutive women who required mid-urethral tape lysis, loosening or excision for tape-related complications in the period 2007-2017 were included. Primary outcomes were improvement in voiding dysfunction and resolution of pain, while secondary outcomes were evaluation of the recurrence of stress urinary incontinence and patient satisfaction. Patient outcomes were measured using the Patient Global Impression of Improvement questionnaire. Result(s): There were 1459 mid-urethral tape procedures performed in the study period. Twenty-nine women (1.99%) who had revision surgery for tape complication were identified. Interventions included tape loosening or lysis in 19 women and tape excision in ten women. Twenty-three of the 29 patients reported a significant improvement in their symptoms postoperatively. Two women had a recurrence of SUI in the tape excision cohort; all patients following tape loosening or lysis remained continent. Conclusion(s): Tape revision surgery is a safe and effective treatment for mid-urethral tape complications with the majority of women maintaining continence following revision. Early intervention and proactive management of complications, by the appropriate specialist, will improve outcomes.

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The Cortical Basal ganglia Functional Scale (CBFS): Development and preliminary validation (2020)

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Type of publication:
Journal article

Author(s):
Lang A.E.; Stebbins G.T.; Wang P.; Boxer A.L.; Jabbari E.; Morris H.; Lamb R.; Boxer (PI) A.; Boeve B.; Dickerson B.; Grossman M.; Litvan I.; Ljubenkov P.; Rojas-Martinez J.; Pantelyat A.; Tartaglia M.-C.; Wills A.-M.; Morris (PI) H.; Amar K.; *Capps E.; Carey G.; Church A.; Critchley P.; Ghosh B.; Houlden H.; Hu M.; Kobylecki C.; Massey L.; Molloy S.; Nath U.; Pavese N.; Rowe J.B.

Citation:
Parkinsonism and Related Disorders; Oct 2020; vol. 79 ; p. 121-126

Abstract:
Objective: To develop a patient/care-giver reported scale capable of easily and reliably assessing functional disability in 4 repeat tauopathies (4RTs). Background(s): 4R tauopathies including progressive supranuclear palsy, corticobasal degeneration and a subset of frontotemporal dementias manifest a range of overlapping clinical phenotypes. No available rating scale is capable of evaluating the functional impact of these complex disorders. Method(s): A multi-staged modified Delphi process was used to propose, evaluate and rank potential scale items providing content validity ratios. Staged cognitive pretesting involving input from examiners, patients and caregivers was followed by validation testing in patients participating in the 4R Tauopathy Neuroimaging Initiative or the PROgressive Supranuclear Palsy CorTico-Basal Syndrome MSA Longitudinal Study. Clinimetric properties were examined using classical test theory and item response methods, assessing data quality, reliability, construct validity, convergent validity and known-group validity. Result(s): The resultant Cortical Basal ganglia Functional Scale (CBFS) included questions on Motor Experiences in Daily Living (14 items) and Non-Motor Experiences of Daily Living (17 items). Reliability was acceptable for internal consistency, test-retest stability, item discrimination, item-scaling thresholds and item-fit. Examination of construct validity revealed a parsimonious two-factor solution, and concurrent validity demonstrated significant correlations between the CBFS and other measures of disease severity and functional impairment. The CBFS significantly discriminated between all diagnostic groups and controls (all AUCs>90). The CBFS scores demonstrated sensitivity to change over a 12 month follow-up in patients with probable 4RTs. Conclusion(s): The CBFS is a patient/care-giver reported outcome measure with excellent clinimetric properties that captures disability correlated with motor, cognitive and psychiatric impairments.

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Expansile Endocervical Crypt Involvement by CIN2-3 as a Risk Factor for High Grade Cytology Recurrence after Cold Coagulation Cervical Treatment (2020)

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Type of publication:
Journal article

Author(s):
*Papoutsis D.; *Underwood M.; *Parry-Smith W.; *Panikkar J.; *Williams J.

Citation:
Geburtshilfe und Frauenheilkunde; Sep 2020; vol. 80 (no. 9); p. 891-895

Abstract:
Introduction: To determine whether expansile endocervical crypt involvement (ECI) on pretreatment cervical punch biopsies is a risk factor for high grade cytology recurrence in women following cold coagulation for cervical intraepithelial neoplasia (CIN).Materials and Methods: This was a secondary analysis on the results of an observational study of women who had a single cold coagulation cervical treatment between 2001–2011 and who were followed up for cytology recurrence. Women with a previous cervical treatment were excluded.
Results: 559 women were identified with a mean age of 28.7 ± 6.2 years. Expansile and non-expansile ECI were identified in 5.4 and 4.3% of women, respectively. The proportion of women with high grade cytology recurrence was 10% for those with expansile ECI and 2.3% for those without. Multivariate analysis showed that women with expansile ECI when compared to those without, had a four-fold greater risk for high grade cytology recurrence (HR = 4.22; 95% CI: 1.10–16.29, p = 0.036). There was no significant association found between non-expansile ECI and overall or high grade cytology recurrence. The increased biopsy depth and the CIN3 grade of pretreatment cervical punch biopsies were significantly associated with greater odds for the detection of expansile ECI. We calculated that the optimal-cut off of pretreatment cervical punch biopsy depth for the detection of expansile ECI was 4 mm (sensitivity: 73.3%; specificity: 55.1%).
Conclusions: Expansile ECI is a risk factor that increases the likelihood of high grade cytology recurrence following cold coagulation. Deeper pretreatment cervical punch biopsies need to be taken so as not to miss expansile ECI prior to ablative treatment.

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Effective echo screening and inter modality agreement in the assessment of ascending thoracic aorta dimension (2020)

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Type of publication:
Conference abstract

Author(s):
*Botley S.; *Challinor E.; *Ingram T.; *Lee E.; *Pakala V.

Citation:
Heart; Jul 2020; vol. 106

Abstract:
Introduction: Accurate measurement and interval monitoring of the ascending aorta for at risk individuals are crucial for prevention of life-threatening complications. Echocardiography (echo) is the first line screening test. Positive results are referred for computed tomography (CT) or magnetic resonance imaging (MRI), both are considered gold standard methods for imaging the whole aorta. These tests involve radiation (CT) and contrast (CT & MRI) exposure. An effective screening echo streamlines subsequent referrals to CT and MRI. Several published references (1,2,3) are in clinical use. Measurements are normalised to body surface area (1,3), height (2), gender (2,3) and age (3). The aims of this study were: Assess the inter-modality agreement of ascending aorta measurements between echo and CT. Compare the rate of 'dilated aorta' using the existing references (1,2,3). Methods Between Sep 2018 and Sep 2019, 107 patients underwent gated CT thoracic aorta at our institute as per clinically indicated. We retrospectively examined these records. We used Bland Altman plot to assess inter-modality agreement (echo & CT) of ascending aorta measurements. We reported inter and intra-observer variability for echo measurements as coefficient of variation. Echo aorta measurements were coded into 'dilated' or 'normal' after normalising for age, sex, height and weight as per the existing references (1,2,3). The rates of 'dilated aorta' using the three reference methods (1,2,3) were compared using Chi-squared test with Bonferroni adjustment. Statistical analysis was performed using SPSS 25 (IBM). Results Data were excluded from analysis due to incomplete biometrics (9), poor echo images (27). 71 subjects were included for analysis (age 68 +/- 14 years, BSA 1.9 +/- 0.2 m2, 52.1% male). 16 had bicuspid aortic valves. Intra- and interobserver variability for echo measurements were 1.2% and 1.4% respectively. Figure 1 shows the inter-modality agreement of ascending aorta measurements. Echo underestimated ascending aorta dimensions by a mean of 1.4 +/- 2.7 mm (95% CI 0.7-2.0 mm). There was a significant difference in the rates of 'dilated aorta' using the existing reference ranges (1,2,3): 59% (1), 27% (3) and 59% (2) of subjects had 'dilated aorta', c2 = 15.3, p=0.00. Conclusion Echo is an effective screening test for detecting ascending aorta dilatation. In our department, it has excellent intra- and inter- observer variability and good measurement agreement with CT. Normalising aortic dimension (3) resulted in the fewest 'positive test' requiring further imaging; potentially improving clinical efficacy of the service and avoiding contrast and radiation exposure for the patients.

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The Incidence of and Predictors for Severe Perineal Trauma and Intact Perineum in Women Having a Waterbirth in England: A Hospital-Based Study (2021)

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Type of publication:
Journal article

Author(s):
*Dimitrios Papoutsis, Angeliki Antonakou, *Adam Gornall, and Chara Tzavara

Citation:
Journal of Women's Health; May 2021; vol. 30 (no. 5); p. 681-688

Abstract:
Background: To determine the incidence of and predictors for obstetric anal sphincter injuries (OASIS) and intact perineum in women giving birth in the water and compare with the general obstetric population.
Materials and Methods: Data were retrospectively collected for women who had singleton cephalic presentation vaginal births in the water and the general obstetric population between August 2007 and December 2017.
Results: We identified 1,007 women who had a waterbirth and 36,924 women from the general obstetric population. There was no significant difference in the incidence of OASIS between waterbirths and the general obstetric population (2.3% vs. 2.0%). Having a waterbirth was associated with a lower probability for an intact perineum (odds ratio [OR] = 0.83; confidence interval [95% CI]: 0.73–0.94) when compared with the general obstetric population (44.7% vs. 51.3%). Nulliparous women with a waterbirth when compared with multiparous women had an eightfold higher likelihood for the occurrence of OASIS (OR = 8.28; 95% CI: 2.64–25.86). The risk for a higher degree of OASIS was associated with increased maternal age in the total sample (OR = 1.08; 95% CI: 1.06–1.11) and with a lower body mass index (BMI) at booking in multiparous women (OR = 0.96; 95% CI: 0.92–0.99). The risk for any type of perineal trauma was associated with increased maternal age in the total sample (OR = 1.10; 95% CI: 1.07–1.13) and with a lower BMI at booking in multiparous women (OR = 0.95; 95% CI: 0.91–0.99).
Conclusions: We found that giving birth in the water reduced the chance of having an intact perineum. We have also shown that nulliparity, increased maternal age in all women, and a lower BMI at booking in multiparous were associated with OASIS and lower rates of intact perineum in waterbirths.

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Can adjuncts to bowel preparation for colonoscopy improve patient experience and result in superior bowel cleanliness? A systematic review and meta-analysis (2020)

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Type of publication:
Systematic Review

Author(s):
Kamran, Umair; *Abbasi, Abdullah; Tahir, Imran; Hodson, James; Siau, Keith

Citation:
United European gastroenterology journal; Aug 2020 [epub ahead of print]

Abstract:
BACKGROUND Bowel preparation for colonoscopy is often poorly tolerated due to poor palatability and adverse effects. This can negatively impact on the patient experience and on the quality of bowel preparation. This systematic review and meta-analysis was carried out to assess whether adjuncts to bowel preparation affected palatability, tolerability and quality of bowel preparation (bowel cleanliness).METHODS A systematic search strategy was conducted on PubMed, MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews to identify studies evaluating adjunct use for colonoscopic bowel preparation. Studies comparing different regimens and volumes were excluded. Specific outcomes studied included palatability (taste), willingness to repeat bowel preparation, gastrointestinal adverse events and the quality of bowel preparation. Data across studies were pooled using a random-effects model and heterogeneity assessed using I2-statistics.RESULTS Of 467 studies screened, six were included for analysis (all single-blind randomised trials; n = 1187 patients). Adjuncts comprised citrus reticulata peel, orange juice, menthol candy drops, simethicone, Coke Zero and sugar-free chewing gum. Overall, adjunct use was associated with improved palatability (mean difference 0.62, 95% confidence interval 0.29-0.96, p < 0.001) on a scale of 0-5, acceptability of taste (odds ratio 2.75, 95% confidence interval: 1.52-4.95, p < 0.001) and willingness to repeat bowel preparation (odds ratio 2.92, 95% confidence interval: 1.97-4.35, p < 0.001). Patients in the adjunct group reported lower rates of bloating (odds ratio 0.48, 95% confidence interval: 0.29-0.77, p = 0.003) and vomiting (odds ratio 0.47, 95% confidence interval 0.27-0.81, p = 0.007), but no difference in nausea (p = 0.10) or abdominal pain (p = 0.62). Adjunct use resulted in superior bowel cleanliness (odds ratio 2.52, 95% confidence interval: 1.31-4.85, p = 0.006). Heterogeneity varied across outcomes, ranging from 0% (vomiting) to 81% (palatability), without evidence of publication bias. The overall quality of evidence was rated moderate.CONCLUSION In this meta-analysis, the use of adjuncts was associated with better palatability, less vomiting and bloating, willingness to repeat bowel preparation and superior quality of bowel preparation. The addition of adjuncts to bowel preparation may improve outcomes of colonoscopy and the overall patient experience.

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A minimum dataset for a level 1 echocardiogram: A guideline protocol from the british society of echocardiography (2020)

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Type of publication:
Journal article

Author(s):
Hindocha R.; Garry D.; Short N.; *Ingram T.E.; Steeds R.P.; Colebourn C.L.; Pearce K.; Sharma V.

Citation:
Echo Research and Practice; Jun 2020; vol. 7 (no. 2)

Abstract:
The British Society of Echocardiography has previously outlined a minimum dataset for a standard transthoracic echocardiogram, and this remains the basis on which an echocardiographic study should be performed. The importance of ultrasound in excluding critical conditions that may require urgent treatment is well known. Several point-of-care echo protocols have been developed for use by non-echocardiography specialists. However, these protocols are often only used in specific circumstances and are usually limited to 2D echocardiography. Furthermore, although the uptake in training for these protocols has been reasonable, there is little in the way of structured support available from accredited sonographers in the ongoing training and reaccreditation of those undertaking these point-of-care scans. In addition, it is well recognised that the provision of echocardiography on a 24/7 basis is extremely challenging, particularly outside of tertiary cardiac centres. Consequently, following discussions with NHS England, the British Society of Echocardiography has developed the Level 1 echocardiogram in order to support the rapid identification of critical cardiac pathology that may require emergency treatment. It is intended that these scans will be performed by non-specialists in echocardiography and crucially are not designed to replace a full standard transthoracic echocardiogram. Indeed, it is expected that a significant number of patients, in whom a Level 1 echocardiogram is required, will need to have a full echocardiogram performed as soon as is practically possible. This document outlines the minimum dataset for a Level 1 echocardiogram. The accreditation process for Level 1 echo is described separately.

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Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): providing resuscitative care (2020)

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Type of publication:
Journal article

Author(s):
*Kempsell-Smith M.; *Meenan S.

Citation:
Nursing children and young people; 2020 Sep 10;32(5):13-16

Abstract:
Little is understood about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic. Furthermore, there is limited literature available and few case studies exploring the observations of colleagues involved in managing patients with COVID-19. Children represent a small sample of the confirmed cases of COVID-19 in the UK but the reasons for this are relatively unknown. Most children are asymptomatic or exhibit mild symptoms from COVID-19 infection. However, a small number have been identified who develop a significant systemic inflammatory response, referred to as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). PIMS-TS involvespersistent fever and organ dysfunction. PIMS-TS can also share clinical features with other conditions including toxic shock syndrome, septic shock and Kawasaki disease. This article presents a case study to explore the resuscitative care provided to a ten-year-old child with suspected PIMS-TS.

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