Identifying the real-world challenges of dysplasia surveillance in inflammatory bowel disease: a retrospective cohort study in a tertiary health network.

BACKGROUND: Dysplasia surveillance in inflammatory bowel disease (IBD) is often suboptimal and deviates from guidelines. AIMS: To assess dysplasia surveillance behaviours and adherence to guidelines amongst a large tertiary teaching health network with a specialised IBD unit to identify areas where dysplasia surveillance could be improved. METHODS: A retrospective audit of IBD surveillance colonoscopy practice over an 18-month period was performed using the Provation Endoscopy Database and the hospital's primary sclerosing cholangitis database. RESULTS: The audit identified 115 dysplasia surveillance colonoscopies. A total of 37% of index dysplasia colonoscopies were outside recommended guidelines. A total of 10% had inadequate bowel preparation and only 40% had excellent bowel preparation. A total of 28% of patients underwent dye-based chromoendoscopy and 69% underwent high-definition white-light endoscopy. Dye chromoendoscopy was more likely to be used by IBD specialists than interventional endoscopists (P = 0.008) and other endoscopists (P = 0.004). Only IBD specialists and interventional endoscopists used dye chromoendoscopy. Dysplasia or colorectal cancer was detected in 3.4% of the colonoscopies. Overall, the several dysplasia examinations were lower than expected. CONCLUSIONS: Dysplasia surveillance in the IBD population remains an area of improvement given the current national guidelines. IBD specialists are more likely to perform dye chromoendoscopy than other endoscopists/gastroenterologists. Dysplasia rates in this real-world contemporary setting are less than expected in historical studies and may represent improvements in IBD management principles and medications.

Usability Testing of a Digital Assessment Routing Tool for Musculoskeletal Disorders: Iterative, Convergent Mixed Methods Study.

BACKGROUND: Musculoskeletal disorders negatively affect millions of patients worldwide, placing significant demand on health care systems. Digital technologies that improve clinical outcomes and efficiency across the care pathway are development priorities. We developed the musculoskeletal Digital Assessment Routing Tool (DART) to enable self-assessment and immediate direction to the right care. OBJECTIVE: We aimed to assess and resolve all serious DART usability issues to create a positive user experience and enhance system adoption before conducting randomized controlled trials for the integration of DART into musculoskeletal management pathways. METHODS: An iterative, convergent mixed methods design was used, with 22 adult participants assessing 50 different clinical presentations over 5 testing rounds across 4 DART iterations. Participants were recruited using purposive sampling, with quotas for age, habitual internet use, and English-language ability. Quantitative data collection was defined by the constructs within the International Organization for Standardization 9241-210-2019 standard, with user satisfaction measured by the System Usability Scale. Study end points were resolution of all grade 1 and 2 usability problems and a mean System Usability Scale score of ≥80 across a minimum of 3 user group sessions. RESULTS: All participants (mean age 48.6, SD 15.2; range 20-77 years) completed the study. Every assessment resulted in a recommendation with no DART system errors and a mean completion time of 5.2 (SD 4.44, range 1-18) minutes. Usability problems were reduced from 12 to 0, with trust and intention to act improving during the study. The relationship between eHealth literacy and age, as explored with a scatter plot and calculation of the Pearson correlation coefficient, was performed for all participants (r=-0.2; 20/22, 91%) and repeated with a potential outlier removed (r=-0.23), with no meaningful relationships observed or found for either. The mean satisfaction for daily internet users was highest (19/22, 86%; mean 86.5, SD 4.48; 90% confidence level [CL] 1.78 or -1.78), with nonnative English speakers (6/22, 27%; mean 78.1, SD 4.60; 90% CL 3.79 or -3.79) and infrequent internet users scoring the lowest (3/22, 14%; mean 70.8, SD 5.44; 90% CL 9.17 or -9.17), although the CIs overlap. The mean score across all groups was 84.3 (SD 4.67), corresponding to an excellent system, with qualitative data from all participants confirming that DART was simple to use. CONCLUSIONS: All serious DART usability issues were resolved, and a good level of satisfaction, trust, and willingness to act on the DART recommendation was demonstrated, thus allowing progression to randomized controlled trials that assess safety and effectiveness against usual care comparators. The iterative, convergent mixed methods design proved highly effective in fully evaluating DART from a user perspective and could provide a blueprint for other researchers of mobile health systems. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/27205.

Usability Testing of a Digital Assessment Routing Tool: Protocol for an Iterative Convergent Mixed Methods Study.

BACKGROUND: Musculoskeletal conditions account for 16% of global disability, resulting in a negative effect on millions of patients and an increasing burden on health care utilization. Digital technologies that improve health care outcomes and efficiency are considered a priority; however, innovations are often inadequately developed and poorly adopted. Further, they are rarely tested with sufficient rigor in clinical trials-the gold standard for clinical proof of efficacy. We have developed a new musculoskeletal Digital Assessment Routing Tool (DART) that allows users to self-assess and be directed to the right care. DART requires usability testing in preparation for clinical trials. OBJECTIVE: This study will use the iterative convergent mixed methods design to assess and mitigate all serious usability issues to optimize user experience and adoption. Using this methodology, we will provide justifiable confidence to progress to full-scale randomized controlled trials when DART is integrated into clinical management pathways. This study protocol will provide a blueprint for future usability studies of mobile health solutions. METHODS: We will collect qualitative and quantitative data from 20-30 participants aged 18 years and older for 4 months. The exact number of participants recruited will be dependent on the number of iterative cycles required to reach the study end points. Building on previous internal testing and stakeholder involvement, quantitative data collection is defined by the constructs within the ISO 9241-210-2019 standard and the system usability scale, providing a usability score for DART. Guided by the participant responses to quantitative questioning, the researcher will focus the qualitative data collection on specific usability problems. These will then be graded to provide the rationale for further DART system improvements throughout the iterative cycles. RESULTS: This study received approval from the Queen Mary University of London Ethics of Research Committee (QMREC2018/48/048) on June 4, 2020. At manuscript submission, study recruitment was on-going, with data collection to be completed and results published in 2021. CONCLUSIONS: This study will provide evidence concerning mobile health DART system usability and acceptance determining system improvements required to support user adoption and minimize suboptimal system usability as a potential confounder within subsequent noninferiority clinical trials. Success should produce a safe effective system with excellent usability, facilitating quicker and easier patient access to appropriate care while reducing the burden on primary and secondary care musculoskeletal services. This deliberately rigorous approach to mobile health innovation could be used as a guide for other developers of similar apps. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/27205.

Association of Gabapentin or Pregabalin Use and Incidence of Acute Angle-closure Glaucoma.

PRECIS: Gabapentin and its derivatives have numerous indications and are commonly prescribed medications. In this article, we provide evidence of a link between gabapentinoid use and incidence of acute angle-closure glaucoma. PURPOSE: Gabapentinoids, such as gabapentin and pregabalin, are commonly prescribed classes of drugs in North America. We sought to determine the association of gabapentin or pregabalin use and the incidence of acute angle-closure glaucoma. MATERIALS AND METHODS: This was a nested case-control study. All adult patients who developed acute angle-closure glaucoma between January 1, 2006 and December 31, 2016, and enrolled in the PharMetrics Plus database were eligible for inclusion. A conditional logistic regression model was constructed to assess the association between gabapentin or pregabalin use and the incidence of acute angle-closure glaucoma. RESULTS: Incidence of acute angle-closure glaucoma was found to be statistically significantly associated with the use of gabapentin in the year before diagnosis [relative risk (RR), 1.42; 95% confidence interval (CI), 1.00-2.00]. This association was not observed to be statistically significant with the current use of gabapentin (RR, 1.28; 95% CI, 0.77-2.12). Incidence of acute angle-closure glaucoma (AAG) was not found to be statistically significantly associated with either use of pregabalin in the year before diagnosis or current use (RR, 1.00; 95% CI, 0.51-1.93 and RR, 1.50; 95% CI, 0.66-3.38, respectively). CONCLUSIONS: To the best of our knowledge this is the first study to investigate the association between gabapentin or pregabalin use and the incidence of AAG. Gabapentin use in the year before diagnosis was found to be associated with the incidence of AAG.

Structure-function relationships in histidine-rich antimicrobial peptides from Atlantic cod.

Gad-1 and Gad-2 are antimicrobial peptide (AMP) sequences encoded by paralogous genes. They are rich in histidine, which suggests that their activity might be pH-dependent. We examined their structure-function relationships with a view to learning how to improve AMP therapeutic ratios. Activity assays with Gram-negative bacteria and cancer cell lines demonstrate that Gad-2 is substantially more active at slightly acidic pH than it is at neutral pH. By contrast, the activity of Gad-1 at lower pH is similar to its activity at pH7. Circular dichroism spectra indicate that the greater functional plasticity of Gad-2 correlates with a greater structural plasticity; Gad-2's percent helicity varies dramatically with altered pH and lipid environment. Interestingly, Gad-2's highest levels of helicity do not correspond to the conditions where it is most active. High resolution solution NMR structures were determined in SDS micelles at pH5, conditions that induce an intermediate level of helicity in the peptides. Gad-1 is more helical than Gad-2, with both peptides exhibiting the greatest helical tendencies in their central region and lowest helicity in their N-termini. The high resolution structures suggest that maximum activity relies on the appropriate balance between an N-terminal region with mixed hydrophobic/hydrophilic structure features and an amphipathic central and C-terminal region. Taken together with previous studies, our results suggest that to improve the therapeutic ratio of AMPs, consideration should be given to including sequential histidine-pairs, keeping the overall charge of the peptide modest, and retaining a degree of structural plasticity and imperfect amphipathicity.

Characterization and expression studies of Gaduscidin-1 and Gaduscidin-2; paralogous antimicrobial peptide-like transcripts from Atlantic cod (Gadus morhua).

Piscidins are a family of antimicrobial peptides (AMPs) from fish that constitute an important component of their innate immune system. Based on previously generated Atlantic cod (Gadus morhua) expressed sequence tags (ESTs), we identified sequences representing two paralogous AMP-like transcripts. These Atlantic cod paralogues were termed gaduscidins (GAD-1 and GAD-2), derived from the genus name Gadus. We obtained full-length cDNA sequences for these putative AMP-encoding transcripts using bi-directional rapid amplification of cDNA ends (RACE). GAD-1 and GAD-2 putative peptides exhibit sequence similarity with members of the piscidin family from teleost fish. Quantitative reverse transcription - polymerase chain reaction (QPCR) was utilized in transcript expression studies of GAD-1 and GAD-2. We examined the constitutive expression of these transcripts in six tissues (head kidney, blood, brain, gill, pyloric caecum, and spleen) of non-stressed juvenile cod; GAD-1 and GAD-2 transcripts were detected in all six tissues, with the highest expression of both transcripts being in spleen, head kidney, and gill. Transcript expression of GAD-1 and GAD-2 was also examined in immune tissues (spleen and head kidney) following intraperitoneal (IP) injection of formalin-killed, atypical Aeromonas salmonicida (ASAL) or phosphate-buffered saline (PBS control). Both transcripts were weakly (less than 4-fold) up-regulated by ASAL in spleen but non-responsive to ASAL in head kidney. Since GAD-1 and GAD-2 transcripts are highly expressed constitutively in immune-relevant tissues (e.g. spleen and head kidney), and are weakly induced in spleen following IP injection with bacterial antigens, they may represent important components of innate immunity in Atlantic cod.

Impact of asymptomatic nodavirus carrier state and intraperitoneal viral mimic injection on brain transcript expression in Atlantic cod (Gadus morhua).

Nodaviruses and other RNA viruses have a profoundly negative impact on the global aquaculture industry. Nodaviruses target nervous tissue causing viral nervous necrosis, a disease characterized by neurological damage, swimming abnormalities, and morbidity. This study used functional genomic techniques to study the Atlantic cod (Gadus morhua) brain transcript expression responses to asymptomatic high nodavirus carrier state and intraperitoneal injection of polyriboinosinic polyribocytidylic acid (pIC). Reciprocal suppression subtractive hybridization (SSH) cDNA libraries enriched for virus-responsive brain transcripts were constructed and characterized. We generated 1,938 expressed sequence tags (ESTs) from a forward brain SSH library (enriched for transcripts upregulated by nodavirus and/or pIC) and 1,980 ESTs from a reverse brain SSH library (enriched for transcripts downregulated by nodavirus and/or pIC). To examine the effect of nodavirus carrier state on individual brain gene expression in asymptomatic cod, 27 transcripts of interest were selected for quantitative reverse transcription-polymerase chain reaction (QPCR) studies. Transcripts found to be >10-fold upregulated in individuals with a high nodavirus carrier state relative to those in a no/low nodavirus carrier state were identified as ISG15, IL8, DHX58 (alias LGP2), ZNFX1, RSAD2 (alias viperin), and SACS (sacsin, alias spastic ataxia of Charlevoix-Saguenay). These and other SSH-identified transcripts were also found by QPCR to be significantly (P < 0.05) upregulated by pIC compared with saline-injected controls within 72 h of injection. Several transcripts identified in the reverse SSH library, including two putative ubiquitination pathway members (HERC4 and SUMO2), were found to be significantly (P < 0.05) downregulated in individuals with a high nodavirus carrier state. Our data shows that Atlantic cod brains have a strong interferon pathway response to asymptomatic high nodavirus carrier state and that many interferon pathway and other immune relevant transcripts are significantly induced in brain by both nodavirus and pIC.