Validation of digital pathology imaging for primary histopathological diagnosis.

AIMS: Digital pathology (DP) offers advantages over glass slide microscopy (GS), but data demonstrating a statistically valid equivalent (i.e. non-inferior) performance of DP against GS are required to permit its use in diagnosis. The aim of this study is to provide evidence of non-inferiority. METHODS AND RESULTS: Seventeen pathologists re-reported 3017 cases by DP. Of these, 1009 were re-reported by the same pathologist, and 2008 by a different pathologist. Re-examination of 10 138 scanned slides (2.22 terabytes) produced 72 variances between GS and DP reports, including 21 clinically significant variances. Ground truth lay with GS in 12 cases and with DP in nine cases. These results are within the 95% confidence interval for existing intraobserver and interobserver variability, proving that DP is non-inferior to GS. In three cases, the digital platform was deemed to be responsible for the variance, including a gastric biopsy, where Helicobacter pylori only became visible on slides scanned at the ×60 setting, and a bronchial biopsy and penile biopsy, where dysplasia was reported on DP but was not present on GS. CONCLUSIONS: This is one of the largest studies proving that DP is equivalent to GS for the diagnosis of histopathology specimens. Error rates are similar in both platforms, although some problems e.g. detection of bacteria, are predictable.

Accuracy of clinical diagnosis of benign eyelid lesions: Is a dedicated nurse-led service safe and effective?

This article compares an independent nurse-led benign lesion service with a doctor-led one, and assesses the impact of clinician seniority on diagnostic accuracy rates. Retrospective review of benign lesions referred to a teaching hospital and managed in either a doctor- or nurse-led lid service. All lesions were diagnosed clinically, excised and then sent for histological diagnosis. Lesions were categorized into subtypes. Pre-excision clinical diagnoses were compared with histological diagnoses. Sensitivity, specificity and missed malignancy rates were calculated for each subtype. Accuracy was compared between different grades of doctors and a specialist nurse. 264 and 332 lesions were managed in a doctor-led and nurse-led service, respectively. Rates of accurate sub-typing were 79.6% and 80.4% in the doctor- and nurse-led services, respectively (p > 0.05). Clinician seniority had no bearing. Missed malignancies or pre-malignancies accounted for 1.1% and 1.5% of lesions in the doctor and nurse-led services, respectively (p > 0.05). Overall, the remaining misdiagnoses were benign lesions of another subtype (13.6%) or non-specific histological findings (5.0%) and 98.6% of lesions were confirmed as benign on histology. Overall sensitivity and specificity values were: benign epithelial proliferations 95.6% and 92.2%, epidermal inclusion cysts 92.2% and 88.0%, xanthelasma 97.5% and 100.0%, cysts of Moll 66.7% and 96.6%, naevi 39.4% and 99.8% and molluscum 20.0% and 99.8%, respectively. A dedicated nurse-led service is as effective in managing a range of clinically benign lid lesions as a doctor-led one, and clinician seniority has little impact on the diagnostic accuracy of these lesions.

Full thickness skin grafts in periocular reconstructions: long-term outcomes.

PURPOSE: To evaluate the outcomes of eyelid reconstruction in patients who underwent full thickness skin grafts. METHODS: A retrospective, noncomparative intervention study of patients who underwent periocular reconstruction with full thickness skin grafts between 2005 and 2011. RESULTS: One hundred consecutive Caucasian patients were included in the study, 54 women and 46 men. Mean follow up was 32 months. Indications for full thickness skin grafts were excision of eyelid tumors (98%) and cicatricial ectropion (2%). Site of lid defects were lower lid (60%), medial canthus (32%), upper lid (6%), and lateral canthus (2%). The skin graft donor sites were supraclavicular (44%), upper eyelid (24%), inner brachial (18%), and postauricular (14%).Early postoperative complications included lower eyelid graft contracture (1%) and partial failure (1%). Late sequelae included lower eyelid graft contracture (4%) and hypertrophic scarring (23%). Of the 23 patients with hypertrophic scar, 21 achieved good outcomes following massage with silicone gel and steroid ointment and 2 had persistent moderate lumpiness. No statistically significant association was found between graft hypertrophy and donor site or graft size. As high as 95% of all patients achieved good final eyelid position. Good color match was seen in 94% and graft hypopigmentation in 6%. An association between hypopigmentation and supraclavicular and inner brachial donor site was found to be statistically significant. CONCLUSIONS: Most patients (94%) achieved good eyelid position and color match. Majority (91%) of the early postoperative cicatricial sequelae can be reversed by massage, steroid ointment, and silicone gel application. Full thickness skin grafts have excellent graft survival rates and have minimal donor site morbidity.

Father absence and age at first birth in a Western sample.

OBJECTIVES: Although a large literature has shown links between "father absence" during early childhood, and earlier puberty and sexual behavior in girls in Western populations, there are only a few studies which have looked at timing of reproduction, and only one of these fully incorporated childless respondents to investigate whether father absence is associated with increased hazard of becoming a parent at one time point (early) more than another. Here we sought to clarify exactly when, if at all, father absence increased the likelihood of first birth in a Western sample. METHODS: An online sample of 954 women reported on their childhood living circumstances, their age of menarche, first coitus, first pregnancy, and first birth. RESULTS: Cox regression and Kaplan-Meier plots showed an increased risk of becoming a parent for father absent women in their 20s, but no overall greater likelihood of parenthood. CONCLUSION: These data support the suggestion that father absence is associated with an acceleration of reproductive behavior in Western samples, rather than a simple increase in likelihood of reproduction.

Role of Temporal artery biopsy in a sequential Giant Cell Arteritis fast-track pathway: a 5-year prospective study.

BACKGROUND: Increasing number of centres are establishing sequential fast track pathways (FTP) for management of giant cell arteritis (GCA), with temporal artery ultrasound (US) replacing temporal artery biopsy (TAB) as the first investigational method. Biopsy is performed as second investigation, when US is negative/inconclusive. This study investigates the role of TAB in a sequential GCA-FTP and its utility in those with negative/inconclusive US. METHODS: Prospective study of patients referred for TAB as part of Coventry sequential GCA-FTP May 2014-June 2019. Analysis included sensitivity and specificity of TAB, impact of arterial specimen length and duration of treatment with corticosteroids on sensitivity of TAB and the clinical predictors for a positive biopsy. RESULTS: A total of 1149 patients with suspected GCA were referred to this GCA-FTP, with 109 (9.5%) referred for TAB. Overall sensitivity of TAB was 47% (specificity: 100%) and in patients with negative/inconclusive US sensitivity was 39% (specificity:100%). Post-fixation arterial specimen length <15 mm showed lower sensitivity (14%), which increased to 52% when specimen length was ≥15 mm. Sensitivity of TAB was highest in first 7 (60%) to 10 days (59%) from starting corticosteroids. Predictors of positive biopsy using univariate logistic regression analysis were jaw claudication (OR = 5.40; p = 0.0057), elevated erythrocyte sedimentation rate (OR = 5.50; p = 0.013) and elevated C-reactive protein (OR = 23.7; p = 0.0043). CONCLUSION: This is the first study to look at the role of TAB in a sequential GCA-FTP. Biopsy plays an important role in GCA-FTP, when US is negative/inconclusive. Sensitivity of TAB improved when specimen length was ≥15 mm and performed within 10 days of commencing corticosteroids.

Role of the Adenoplus test in refractory, recurrent and clinically undiagnosed conjunctivitis.

BACKGROUND: In diagnosing adenoviral conjunctivitis, polymerase chain reaction (PCR) is widely adopted as a diagnostic tool. A new antigen-based immunoassay test (AdenoPlus; Rapid Pathogen Screening Inc, Sarasota, Fla.) is commercially available as an alternative diagnostic test. To date, evidence around the role of this test in the clinical setting has been limited and contradictory. OBJECTIVE: To determine the sensitivity and specificity of the AdenoPlus test relative to PCR in detecting the presence of adenovirus in patients with conjunctivitis that is recurrent, refractory to treatment, or clinically of unknown etiology. METHODS: A prospective study of 27 patients presenting to an acute eye clinic with conjunctivitis that is recurrent (Group A), refractory to treatment (Group B), or clinically of unknown etiology (Group C). All patients underwent the AdenoPlus test and PCR analysis. Sensitivity and specificity were calculated for AdenoPlus using PCR as a reference standard. RESULTS: Of 27 patients, 7% were in Group A, 19% in Group B, and 74% in Group C. Relative to PCR, the AdenoPlus test demonstrated a sensitivity of 33.3% (95% CI 4% to 78%) and specificity was 95.2% (95% CI 76% to 100%). Positive predictive value was 66.7% (95% CI 9% to 99%); negative predictive value was 83.3% (95% CI 63% to 95%). CONCLUSIONS: Due to its high specificity, AdenoPlus may be a good diagnostic test, although further study is indicated. Due to its low sensitivity, however, the test should not be used as a screening tool in patients presenting with these features of conjunctivitis.

Anaphylaxis and Clinical Utility of Real-World Measurement of Acute Serum Tryptase in UK Emergency Departments.

BACKGROUND: British guidelines recommend that serial acute serum tryptase measurements be checked in all adults and a subset of children presenting with anaphylaxis. This is the first study reporting the clinical utility of acute serum tryptase in a "real-world" emergency department (ED) setting following the publication of the World Allergy Organization (WAO) criteria for anaphylaxis. OBJECTIVES: To (1) assess sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of acute serum tryptase in anaphylaxis; (b) determine factors associated with higher acute serum tryptase levels; and (c) audit compliance of acute serum tryptase measurement in the ED. METHODS: The methods used were retrospective electronic search for ED admissions to 3 acute care hospitals in Birmingham, UK, with anaphylaxis in 2012 using wide search terms followed by scrutiny of electronic clinical records and application of the WAO diagnostic criteria for anaphylaxis. Patients with an acute serum tryptase measurement were included in the analysis. RESULTS: Acute serum tryptase level was measured in 141 of 426 (33.1%) cases. Mean time from the onset of symptoms to the measurement of acute serum tryptase level was 4 hours 42 minutes (SD ± 05:03 hours) and no patients had serial measurements conforming to British guidelines. Acute serum tryptase level of more than 12.4 ng/mL (75th centile) was associated with a sensitivity, specificity, PPV, and NPV of 28%, 88%, 0.93, and 0.17, respectively. Multiple regression analysis showed that male sex (odds ratio, 2.66; P = .003) and hypotension (odds ratio, 7.08; P = .001) predicted higher acute serum tryptase level. CONCLUSIONS: An acute serum tryptase level of more than 12.4 ng/mL in an ED setting carries high PPV and specificity, but poor sensitivity and NPV.

Active Treatment for Idiopathic Adolescent Scoliosis (ACTIvATeS): a feasibility study.

BACKGROUND: The feasibility of conducting a definitive randomised controlled trial (RCT) evaluating the clinical effectiveness and cost-effectiveness of scoliosis-specific exercises (SSEs) for adolescent idiopathic scoliosis (AIS) is uncertain. OBJECTIVES: The aim of this study was to assess the feasibility of conducting a large, multicentre trial of SSE treatment for patients with AIS, in comparison with standard care, and to refine elements of the study design. The objectives were to (1) update a systematic review of controlled trials evaluating the efficacy of SSE in AIS; (2) survey UK orthopaedic surgeons and physiotherapists to determine current practice, patient populations and equipoise; (3) randomise 50 adolescents to a feasibility trial of either usual care or SSE interventions across a range of sites; (4) develop, document and assess acceptability and adherence of interventions; (5) assess and describe training requirements of physiotherapists; and (6) gain user input in all relevant stages of treatment and protocol design. DESIGN: Multicomponent feasibility study including UK clinician survey, systematic literature review and a randomised feasibility trial. SETTING: The randomised feasibility study involved four secondary care NHS trusts providing specialist care for patients with AIS. PARTICIPANTS: The randomised feasibility study recruited people aged 10-16 years with mild AIS (Cobb angle of < 50°). INTERVENTIONS: The randomised study allocated participants to standard practice of advice and education or a physiotherapy SSE programme supported by a home exercise plan. Our choice of intervention was informed by a systematic review of exercise interventions for AIS. MAIN OUTCOME MEASURES: The main outcome was feasibility of recruitment to the randomised study. Other elements were to inform choice of outcomes for a definitive trial and included curve severity, quality of life, requirement for surgery/brace, adverse events, psychological symptoms, costs and health utilities. RESULTS: A UK survey of orthopaedic consultants and physiotherapists indicated a wide variation in current provision of exercise therapy through physiotherapy services. It also found that clinicians from at least 15 centres would be willing to have their patients involved in a full study. A systematic review update found five new studies that were generally of low quality but showed some promise of effectiveness of SSE. The randomised study recruited 58 patients from four NHS trusts over 11 months and exceeded the pre-specified target recruitment rate of 1.4 participants per centre per month, with acceptable 6-month follow-up (currently 73%). Adherence to treatment was variable (56% of participants completed treatment offered). The qualitative study found the exercise programme to be highly acceptable. We learnt important lessons from patient and public involvement during the study in terms of study and intervention presentation, as well as practical elements such as scheduling of intervention sessions. CONCLUSIONS: A definitive RCT evaluating clinical effectiveness and cost-effectiveness of SSE for idiopathic scoliosis is warranted and feasible. Such a RCT is a priority for future work in the area. There is a sufficiently large patient base, combined with willingness to be randomised within specialist UK centres. Interventions developed during the feasibility study were acceptable to patients, families and physiotherapists and can be given within the affordability envelope of current levels of physiotherapy commissioning. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90480705. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 55. See the NIHR Journals Library website for further project information.

A cluster randomized controlled trial of the effectiveness and cost-effectiveness of intermediate care clinics for diabetes (ICCD): study protocol for a randomized controlled trial.

BACKGROUND: World-wide healthcare systems are faced with an epidemic of type 2 diabetes. In the United Kingdom, clinical care is primarily provided by general practitioners (GPs) rather than hospital specialists. Intermediate care clinics for diabetes (ICCD) potentially provide a model for supporting GPs in their care of people with poorly controlled type 2 diabetes and in their management of cardiovascular risk factors. This study aims to (1) compare patients with type 2 diabetes registered with practices that have access to an ICCD service with those that have access only to usual hospital care; (2) assess the cost-effectiveness of the intervention; and (3) explore the views and experiences of patients, health professionals and other stakeholders. METHODS/DESIGN: This two-arm cluster randomized controlled trial (with integral economic evaluation and qualitative study) is set in general practices in three UK Primary Care Trusts. Practices are randomized to one of two groups with patients referred to either an ICCD (intervention) or to hospital care (control). Intervention group: GP practices in the intervention arm have the opportunity to refer patients to an ICCD - a multidisciplinary team led by a specialist nurse and a diabetologist. Patients are reviewed and managed in the ICCD for a short period with a goal of improving diabetes and cardiovascular risk factor control and are then referred back to practice. or CONTROL GROUP: Standard GP care, with referral to secondary care as required, but no access to ICCD. Participants are adults aged 18 years or older who have type 2 diabetes that is difficult for their GPs to control. The primary outcome is the proportion of participants reaching three risk factor targets: HbA1c (≤7.0%); blood pressure (<140/80); and cholesterol (<4 mmol/l), at the end of the 18-month intervention period. The main secondary outcomes are the proportion of participants reaching individual risk factor targets and the overall 10-year risks for coronary heart disease(CHD) and stroke assessed by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. Other secondary outcomes include body mass index and waist circumference, use of medication, reported smoking, emotional adjustment, patient satisfaction and views on continuity, costs and health related quality of life. We aimed to randomize 50 practices and recruit 2,555 patients. DISCUSSION: Forty-nine practices have been randomized, 1,997 patients have been recruited to the trial, and 20 patients have been recruited to the qualitative study. Results will be available late 2012. TRIAL REGISTRATION: [ClinicalTrials.gov: Identifier NCT00945204].