Effect of Corneal Cross-linking versus Standard Care on Keratoconus Progression in Young Patients: The KERALINK Randomized Controlled Trial

PURPOSE: To examine the efficacy and safety of corneal cross-linking (CXL) for stabilization of progressive keratoconus. DESIGN: Observer-masked, randomized, controlled, parallel-group superiority trial. PARTICIPANTS: Sixty participants 10 to 16 years of age with progressive keratoconus, one eye of each deemed the study eye. METHODS: The study eye was randomized to either CXL plus standard care or standard care alone, with spectacle or contact lens correction as necessary for vision. MAIN OUTCOME MEASURES: The primary outcome was steep keratometry (K2) in the study eye as a measure of the steepness of the cornea at 18 months. Secondary outcomes included keratoconus progression defined as a 1.5-diopter (D) increase in K2, visual acuity, keratoconus apex corneal thickness, and quality of life. RESULTS: Of 60 participants, 30 were randomized to CXL and standard care groups. Of these, 30 patients in the CXL group and 28 patients in the standard care group were analyzed. Mean K2 in the study eye 18 months after randomization was 49.7 D (standard deviation [SD], 3.8 D) in the CXL group and 53.4 D (SD, 5.8 D) in the standard care group. The adjusted mean difference in K2 in the study eye was -3.0 D (95% confidence interval [CI], -4.9 to -1.1 D; P = 0.002), favoring CXL. Adjusted differences between groups in uncorrected and corrected vision favored eyes receiving CXL: -0.31 logarithm of the minimum angle of resolution (logMAR; 95% CI, -0.50 to -0.11 logMAR; P = 0.002) and -0.51 logMAR (95% CI, -1.37 to 0.35 logMAR; P = 0.002). Keratoconus progression in the study eye occurred in 2 patients (7%) randomized to CXL compared with 12 patients (43%) randomized to standard care. The unadjusted odds ratio suggests that on average, patients in the CXL arm had 90% (odds ratio, 0.1; 95% CI, 0.02-0.48; P = 0.004) lower odds of experiencing progression compared with those receiving standard care. CONCLUSIONS: CXL arrests progression of keratoconus in the majority of young patients. CXL should be considered as a first-line treatment in progressive disease. If the arrest of keratoconus progression induced by CXL is sustained in longer follow-up, particular benefit may be derived from avoiding a later requirement for contact lens wear or corneal transplantation

Epithelium-off corneal cross-linking surgery compared with standard care in 10- to 16-year-olds with progressive keratoconus: the KERALINK RCT

Background: Keratoconus is a disease of the cornea affecting vision that is usually first diagnosed in the first three decades. The abnormality of corneal shape and thickness tends to progress until the patient reaches approximately 30 years of age. Epithelium-off corneal cross-linking is a procedure that has been demonstrated to be effective in randomised trials in adults and observational studies in young patients. // Objectives: The KERALINK trial examined the efficacy and safety of epithelium-off corneal cross-linking, compared with standard care by spectacle or contact lens correction, for stabilisation of progressive keratoconus. // Design: In this observer-masked, randomised, controlled, parallel-group superiority trial, 60 participants aged 10–16 years with progressive keratoconus were randomised; 58 participants completed the study. Progression was defined as a 1.5 D increase in corneal power measured by maximum or mean power (K2) in the steepest corneal meridian in the study eye, measured by corneal tomography. // Setting: Referral clinics in four UK hospitals. // Interventions: Participants were randomised to corneal cross-linking plus standard care or standard care alone, with spectacle or contact lens correction as necessary for vision, and were monitored for 18 months. // Main outcome measures: The primary outcome was K2 in the study eye as a measure of the steepness of the cornea at 18 months post randomisation. Secondary outcomes included keratoconus progression, visual acuity, keratoconus apex corneal thickness and quality of life. // Results: Of 60 participants, 30 were randomised to the corneal cross-linking and standard-care groups. Of these, 30 patients in the corneal cross-linking group and 28 patients in the standard-care group were analysed. The mean (standard deviation) K2 in the study eye at 18 months post randomisation was 49.7 D (3.8 D) in the corneal cross-linking group and 53.4 D (5.8 D) in the standard-care group. The adjusted mean difference in K2 in the study eye was –3.0 D (95% confidence interval –4.93 D to –1.08 D; p = 0.002), favouring corneal cross-linking. Uncorrected and corrected differences in logMAR vision at 18 months were better in eyes receiving corneal cross-linking: –0.31 (95% confidence interval –0.50 to –0.11; p = 0.002) and –0.30 (95% confidence interval –0.48 to –0.11; p = 0.002). Keratoconus progression in the study eye occurred in two patients (7%) randomised to corneal cross-linking compared with 12 (43%) patients randomised to standard care. The unadjusted odds ratio suggests that, on average, patients in the corneal cross-linking group had 90% (odds ratio 0.1, 95% confidence interval 0.02 to 0.48; p = 0.004) lower odds of experiencing progression than those receiving standard care. Quality-of-life outcomes were similar in both groups. No adverse events were attributable to corneal cross-linking. // Limitations: Measurements of K2 in those eyes with the most significant progression were in some cases indicated as suspect by corneal topography device software. // Conclusions: Corneal cross-linking arrests progression of keratoconus in the great majority of young patients. These data support a consideration of a change in practice, such that corneal cross-linking could be considered as first-line treatment in progressive disease. If the arrest of keratoconus progression induced by corneal cross-linking is sustained in longer follow-up, there may be particular benefit in avoiding the later requirement for contact lens wear or corneal transplantation. However, keratoconus does not continue to progress in all patients receiving standard care. For future work, the most important questions to be answered are whether or not (1) the arrest of keratoconus progression induced by corneal cross-linking is maintained in the long term and (2) the proportion of those receiving standard care who show significant progression increases with time

New quick method for isolating RNA from laser captured cells stained by immunofluorescent immunohistochemistry; RNA suitable for direct use in fluorogenic TaqMan one-step real-time RT-PCR

We describe a new approach for reliably isolating one-step real-time quantitative RT-PCR-quality RNA from laser captured cells retrieved from frozen sections previously subjected to immunofluorescent immunohistochemistry (IF-IHC) and subsequently subjected to fluorogenic one-step real-time RT-PCR analysis without the need for costly, time-consuming linear amplification. One cell’s worth of RNA can now be interrogated with confidence. This approach represents an amalgam of technologies already offered commercially by Applied Biosystems, Arcturus and Invitrogen. It is the primary focus of this communication to expose the details and execution of an important new LCM RNA isolation technique, but also provide a detailed account of the IF-IHC procedure preceding RNA isolation, and provide information regarding our approach to fluorogenic one-step real-time RT-PCR in general. Experimental results shown here are meant to supplement the primary aim and are not intended to represent a complete scientific study. It is important to mention, that since LCM-RT-PCR is still far less expensive than micro-array analysis, we feel this approach to isolating RNA from LCM samples will be of continuing use to many researchers with limited budgets in the years ahead

Addressing fluorogenic real-time qPCR inhibition using the novel custom Excel file system 'FocusField2-6GallupqPCRSet-upTool-001' to attain consistently high fidelity qPCR reactions

The purpose of this manuscript is to discuss fluorogenic real-time quantitative polymerase chain reaction (qPCR) inhibition and to introduce/define a novel Microsoft Excel-based file system which provides a way to detect and avoid inhibition, and enables investigators to consistently design dynamically-sound, truly LOG-linear qPCR reactions very quickly. The qPCR problems this invention solves are universal to all qPCR reactions, and it performs all necessary qPCR set-up calculations in about 52 seconds (using a pentium 4 processor) for up to seven qPCR targets and seventy-two samples at a time – calculations that commonly take capable investigators days to finish. We have named this custom Excel-based file system "FocusField2-6GallupqPCRSet-upTool-001" (FF2-6-001 qPCR set-up tool), and are in the process of transforming it into professional qPCR set-up software to be made available in 2007. The current prototype is already fully functional

What works for whom in the management of diabetes in people living with dementia: a realist review

Background Dementia and diabetes mellitus are common long-term conditions and co-exist in a large number of older people. People living with dementia (PLWD) may be less able to manage their diabetes, putting them at increased risk of complications such as hypoglycaemia. The aim of this review was to identify key mechanisms within different interventions that are likely to improve diabetes outcomes in PLWD. Methods This is a realist review involving scoping of the literature and stakeholder interviews to develop theoretical explanations of how interventions might work, systematic searches of the evidence to test and develop the theories and their validation with a purposive sample of stakeholders. Twenty-six stakeholders — user/patient representatives, dementia care providers, clinicians specialising in diabetes or dementia and researchers — took part in interviews, and 24 participated in a consensus conference. Results We included 89 papers. Ten focused on PLWD and diabetes, and the remainder related to people with either dementia, diabetes or other long-term conditions. We identified six context-mechanism-outcome configurations which provide an explanatory account of how interventions might work to improve the management of diabetes in PLWD. This includes embedding positive attitudes towards PLWD, person-centred approaches to care planning, developing skills to provide tailored and flexible care, regular contact, family engagement and usability of assistive devices. An overarching contingency emerged concerning the synergy between an intervention strategy, the dementia trajectory and social and environmental factors, especially family involvement. Conclusions Evidence highlighted the need for personalised care, continuity and family-centred approaches, although there was limited evidence that this happens routinely. This review suggests there is a need for a flexible service model that prioritises quality of life, independence and patient and carer priorities. Future research on the management of diabetes in older people with complex health needs, including those with dementia, needs to look at how organisational structures and workforce development can be better aligned to their needs. Trial registration PROSPERO, CRD42015020625. Registered on 18 May 2015