Nationally Automated Colonoscopy Performance Feedback Increases Polyp Detection: The NED APRIQOT Randomized Controlled Trial.

BACKGROUND & AIMS: Postcolonoscopy colorectal cancer incidence and mortality rates are higher for endoscopists with low polyp detection rates. Using the UK's National Endoscopy Database (NED), which automatically captures real-time data, we assessed if providing feedback of case-mix-adjusted mean number of polyps (aMNP), as a key performance indicator, improved endoscopists' performance. Feedback was delivered via a theory-informed, evidence-based audit and feedback intervention. METHODS: This multicenter, prospective, NED Automated Performance Reports to Improve Quality Outcomes Trial randomized National Health Service endoscopy centers to intervention or control. Intervention-arm endoscopists were e-mailed tailored monthly reports automatically generated within NED, informed by qualitative interviews and behavior change theory. The primary outcome was endoscopists' aMNP during the 9-month intervention. RESULTS: From November 2020 to July 2021, 541 endoscopists across 36 centers (19 intervention; 17 control) performed 54,770 procedures during the intervention, and 15,960 procedures during the 3-month postintervention period. Comparing the intervention arm with the control arm, endoscopists during the intervention period: aMNP was nonsignificantly higher (7%; 95% CI, -1% to 14%; P = .08). The unadjusted MNP (10%; 95% CI, 1%-20%) and polyp detection rate (10%; 95% CI, 4%-16%) were significantly higher. Differences were not maintained in the postintervention period. In the intervention arm, endoscopists accessing NED Automated Performance Reports to Improve Quality Outcomes Trial webpages had a higher aMNP than those who did not (aMNP, 118 vs 102; P = .03). CONCLUSIONS: Although our automated feedback intervention did not increase aMNP significantly in the intervention period, MNP and polyp detection rate did improve significantly. Engaged endoscopists benefited most and improvements were not maintained postintervention; future work should address engagement in feedback and consider the effectiveness of continuous feedback. CLINICAL TRIALS REGISTRY:  www.isrctn.org ISRCTN11126923 .

Unintentional pediatric poisonings before and during the COVID-19 pandemic: A population-based study.

OBJECTIVES: The impact of coronavirus disease 2019 (COVID-19) on unintentional pediatric poisonings is unclear. We examined changes in emergency department (ED) visits and hospitalizations for poisonings before and during the COVID-19 pandemic. We compared changes in cannabis vs non-cannabis poisoning events given the recent legalization of cannabis in October 2018 and cannabis edibles in January 2020. STUDY DESIGN: Interrupted time-series (ITS) analyses of changes in population-level ED visits and hospitalizations for poisonings in children aged 0-9 years in Ontario, Canada (annual population of 1.4 million children), over two time periods: pre-pandemic (January 2010-March 2020) and pandemic (April 2020-December 2021). RESULTS: Overall, there were 28,292 ED visits and 2641 hospitalizations for unintentional poisonings. During the pandemic, poisonings per 100,000 person-years decreased by 14.6% for ED visits (40.15 pre- vs. 34.29 during) and increased by 35.9% for hospitalizations (3.48 pre- vs. 4.73 during). ED visits dropped immediately (Incidence Rate Ratio [IRR], 0.76; 95% CI, 0.70-0.82) at the onset of the pandemic, followed by a gradual return to baseline (quarterly change, IRR 1.04, 95%CI 1.03-1.06), while hospitalizations had an immediate increase (IRR 1.34; 95% CI, 1.08-1.66) and no gradual change. The only increase in poisonings was for cannabis which had a 10.7-fold for ED visits (0.45 to 4.83 per 100,000 person-years) and a 12.1-fold increase for hospitalizations (0.16 to 1.91 per 100,000 person-years). Excluding cannabis, there was no overall increase in poisoning hospitalizations. CONCLUSIONS: The COVID-19 pandemic was not associated with increases in any type of unintentional pediatric poisonings, with the exception of cannabis poisonings. Increased cannabis poisonings may be explained by the legalization of non-medical cannabis edibles in Canada in January 2020.

The effect of hospital-physician integration on hospital costs.

This study evaluates whether hospital costs are lower when hospitals integrate with physician practices. It addresses a common element in policy attempts to contain healthcare costs, which is to encourage greater coordination in healthcare delivery. Despite a clear trend toward greater hospital-physician integration, there is little direct evidence about whether integration lowers hospital costs. The results in this paper show that hospital costs increase by one to three percent after hospital-physician integration. We also do not find consistent evidence that hospital-physician integration is associated with higher quality but potentially more costly hospital care. The modest increase in hospital costs appears to derive from an increase in outpatient visits, rather than from higher costs of inpatient care. These findings do not support the hypothesis that increased coordination between hospitals and physicians has led to lower hospital costs.

The impact of a digital joint school educational programme on post-operative outcomes following lower limb arthroplasty: a retrospective comparative cohort study.

BACKGROUND: As part of an ongoing service improvement project, a digital 'joint school' (DJS) was developed to provide education and support to patients undergoing total hip (THR) and total knee (TKR) replacement surgery. The DJS allowed patients to access personalised care plans and educational resources using web-enabled devices, from being listed for surgery until 12 months post-operation. The aim of this study was to compare a cohort of patients enrolled into the DJS with a cohort of patients from the same NHS trust who received a standard 'non-digital' package of education and support in terms of Health-Related Quality of Life (HRQoL), functional outcomes and hospital length of stay (LoS). METHODS: A retrospective comparative cohort study of all patients undergoing primary TKR/THR at a single NHS trust between 1st Jan 2018 and 31st Dec 2019 (n = 2406) was undertaken. The DJS was offered to all patients attending the clinics of early adopting surgeons and the remaining surgeons offered their patient's standard written and verbal information. This allowed comparison between patients that received the DJS (n = 595) and those that received standard care (n = 1811). For each patient, demographic data, LoS and patient reported outcome measures (EQ-5D-3L, Oxford hip/knee scores (OKS/OHS)) were obtained. Polynomial regressions, adjusting for age, sex, Charlson Comorbidity Index (CCI) and pre-operative OKS/OHS or EQ-5D, were used to compare the outcomes for patients receiving DJS and those receiving standard care. FINDINGS: Patients that used the DJS had greater improvements in their EQ-5D, and OKS/OHS compared to patients receiving standard care for both TKR and THR (EQ-5D difference: TKR coefficient estimate (est) = 0.070 (95%CI 0.004 to 0.135); THR est = 0.114 (95%CI 0.061 to 0.166)) and OKS/OHS difference: TKR est = 5.016 (95%CI 2.211 to 7.820); THR est = 4.106 (95%CI 2.257 to 5.955)). The DJS had a statistically significant reduction on LoS for patients who underwent THR but not TKR. CONCLUSION: The use of a DJS was associated with improved functional outcomes when compared to a standard 'non-digital' method. The improvements between pre-operative and post-operative outcomes in EQ-5D and OKS/OHS were higher for patients using the DJS. Furthermore, THR patients also had a shorter LoS.

Payment Discrepancies and Access to Primary Care Physicians for Dual-eligible Medicare-Medicaid Beneficiaries.

BACKGROUND: Physicians often receive lower payments for dual-eligible Medicare-Medicaid beneficiaries versus nondual Medicare beneficiaries because of state reimbursement caps. The Affordable Care Act (ACA) primary care fee bump temporarily eliminated this differential in 2013-2014. OBJECTIVE: To examine how dual payment policy impacts primary care physicians' (PCP) acceptance of duals. RESEARCH DESIGN: We assessed differences in the likelihood that PCPs had dual caseloads of ≥10% or 20% in states with lower versus full dual reimbursement using linear probability models adjusted for physician and area-level traits. Using a triple-difference approach, we examined changes in dual caseloads for PCPs versus a control group of specialists in states with fee bumps versus no change during years postbump versus prebump. SUBJECTS: PCPs and specialists (cardiologists, orthopedic surgeons, general surgeons) that billed fee-for-service Medicare. MEASURES: State dual payment policies and physicians' dual caseloads as a percentage of their Medicare patients. RESULTS: In 2012, 81% of PCPs had dual caseloads of ≥10% and this was less likely among PCPs in states with lower versus full dual reimbursement (eg, difference=-4.52 percentage points; 95% confidence interval, -6.80 to -2.25). The proportion of PCPs with dual caseloads of ≥10% or 20% decreased significantly between 2012 and 2017 and the fee bump was not consistently associated with increases in dual caseloads. CONCLUSIONS: Pre-ACA, PCPs' participation in the dual program appeared to be lower in states with lower reimbursement for duals. Despite the ACA fee bump, dual caseloads declined over time, raising concerns of worsening access to care.

Impact of emergency care centralisation on mortality and efficiency: a retrospective service evaluation.

OBJECTIVE: Evidence favours centralisation of emergency care for specific conditions, but it remains unclear whether broader implementation improves outcomes and efficiency. Routine healthcare data examined consolidation of three district general hospitals with mixed medical admission units (MAU) into a single high-volume site directing patients from the ED to specialty wards with consultant presence from 08:00 to 20:00. METHODS: Consecutive unscheduled adult index admissions from matching postcode areas were identified retrospectively in Hospital Episode Statistics over a 3-year period: precentralisation baseline (from 16 June 2014 to 15 June 2015; n=18 586), year 1 postcentralisation (from 16 June 2015 to 15 June 2016; n=16 126) and year 2 postcentralisation (from 16 June 2016 to 15 June 2017; n=17 727). Logistic regression including key demographic covariates compared baseline with year 1 and year 2 probabilities of mortality and daily discharge until day 60 after admission and readmission within 60 days of discharge. RESULTS: Relative to baseline, admission postcentralisation was associated with favourable OR (95% CI) for day 60 mortality (year 1: 0.95 (0.88 to 1.02), p=0.18; year 2: 0.94 (0.91 to 0.97), p<0.01), mainly among patients aged 80+ years (year 1: 0.88 (0.79 to 0.97); year 2: 0.91 (0.87 to 0.96)). The probability of being discharged alive on any day since admission increased (year 1: 1.07 (1.04 to 1.10), p<0.01; year 2: 1.04 (1.02 to 1.05), p<0.01) and the risk of readmission decreased (year 1: 0.90 (0.87 to 0.94), p<0.01; year 2: 0.92 (0.90 to 0.94), p<0.01). CONCLUSION: A centralised site providing early specialist care was associated with improved short-term outcomes and efficiency relative to lower volume ED admitting to MAU, particularly for older patients.

The Role of Disulfide Bond Replacements in Analogues of the Tarantula Toxin ProTx-II and Their Effects on Inhibition of the Voltage-Gated Sodium Ion Channel Nav1.7.

Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate.

Engineered protease-resistant antibodies with selectable cell-killing functions.

Molecularly engineered antibodies with fit-for-purpose properties will differentiate next generation antibody therapeutics from traditional IgG1 scaffolds. One requirement for engineering the most appropriate properties for a particular therapeutic area is an understanding of the intricacies of the target microenvironment in which the antibody is expected to function. Our group and others have demonstrated that proteases secreted by invasive tumors and pathological microorganisms are capable of cleaving human IgG1, the most commonly adopted isotype among monoclonal antibody therapeutics. Specific cleavage in the lower hinge of IgG1 results in a loss of Fc-mediated cell-killing functions without a concomitant loss of antigen binding capability or circulating antibody half-life. Proteolytic cleavage in the hinge region by tumor-associated or microbial proteases is postulated as a means of evading host immune responses, and antibodies engineered with potent cell-killing functions that are also resistant to hinge proteolysis are of interest. Mutation of the lower hinge region of an IgG1 resulted in protease resistance but also resulted in a profound loss of Fc-mediated cell-killing functions. In the present study, we demonstrate that specific mutations of the CH2 domain in conjunction with lower hinge mutations can restore and sometimes enhance cell-killing functions while still retaining protease resistance. By identifying mutations that can restore either complement- or Fcγ receptor-mediated functions on a protease-resistant scaffold, we were able to generate a novel protease-resistant platform with selective cell-killing functionality.

Delta-Conotoxin Structure Prediction and Analysis through Large-scale Comparative and Deep Learning Modeling Approaches.

The delta-conotoxins, a class of peptide produced in the venom of cone snails, are of interest due to their ability to inhibit the inactivation of voltage-gated sodium channels causing paralysis and other neurological responses, but difficulties in their isolation and synthesis have made structural characterization challenging. Taking advantage of recent breakthroughs in computational algorithms for structure prediction that have made modeling especially useful when experimental data is sparse, this work uses both the deep-learning based algorithm AlphaFold and comparative modeling method RosettaCM to model and analyze 18 previously uncharacterized delta-conotoxins derived from piscivorous, vermivorous, and molluscivorous cone snails. The models provide useful insights into structural aspects of these peptides and suggest features likely to be significant in influencing their binding and different pharmacological activities against their targets, with implications for drug development. Additionally, the described protocol provides a roadmap for the modeling of similar disulfide-rich peptides by these complementary methods.

Changes in cannabis involvement in emergency department visits for anxiety disorders after cannabis legalization: a repeated cross-sectional study.

Background: An increasing number of countries have or are considering legalizing cannabis. One concern is that legalization of cannabis will result in increased cannabis use and in turn a higher prevalence of anxiety disorders. We examined changes in emergency department (ED) visits for anxiety disorders with cannabis involvement in Ontario, over a period that involved medical and non-medical cannabis legalization. Methods: This repeated cross-sectional population-based study identified all ED visits for anxiety disorders from residents of Ontario, Canada aged 10-105 between 2008 and 2022 (n = 15.7 million individuals). We used interrupted time series analyses to examine immediate and gradual changes in cannabis-involvement and alcohol-involvement (control condition) over four policy periods: medical cannabis legalization (January 2008-November 2015), expanded medical access (December 2015-September 2018), non-medical cannabis legalization with restrictions (October 2018-February 2020), and commercialization which overlapped with the COVID-19 pandemic (March 2020-December 2022). Poisson models were used to generate incidence rate ratios with 95% confidence intervals. Findings: Over the 14-year study, there were 438,700 individuals with one or more ED visits for anxiety disorders of which 3880 (0.89%) individuals had cannabis involvement and 6329 (1.45%) individuals had alcohol involvement. During the commercialization/COVID-19 period monthly rates of anxiety disorders with cannabis-involvement were 156% higher (0.11 vs 0.29 per 100,000 individuals) relative to the pre-legalization period, compared to a 27% increase for alcohol-involvement (0.27 vs 0.35 per 1100,000 individuals). Rates of anxiety ED visits with cannabis involvement per 100,000 individuals increased gradually over the study period with no immediate or gradual changes after expanded medical access, legalization with restrictions or commercialization/COVID-19. However, during the commercialization/COVID-19 period there were large declines in total anxiety disorder ED visits and anxiety disorder ED visits with alcohol-involvement. Consequently, during this period there was an immediate 31.4% relative increase in the proportion of anxiety visits with cannabis-involvement (incidence rate ratio [IRR], 1.31; 95% CI 1.05-1.65). Interpretation: We found large relative increases in anxiety disorder ED visits with cannabis involvement over a 14-year period involving medical and non-medical cannabis legalization. These findings may reflect increasing anxiety disorder problems from cannabis use, increasing self-medication of anxiety disorders with cannabis use, or both. The proportion of anxiety ED visits with cannabis involvement increased during the final period of the study but could have been the results of the market commercialization, COVID-19 or both and ongoing monitoring is indicated. Funding: Canadian Institutes of Health Research (grant #452360).

Quantifying the cost savings and health impacts of improving colonoscopy quality: an economic evaluation.

OBJECTIVE: To estimate and quantify the cost implications and health impacts of improving the performance of English endoscopy services to the optimum quality as defined by postcolonoscopy colorectal cancer (PCCRC) rates. DESIGN: A semi-Markov state-transition model was constructed, following the logical treatment pathway of individuals who could potentially undergo a diagnostic colonoscopy. The model consisted of three identical arms, each representing a high, middle or low-performing trust's endoscopy service, defined by PCCRC rates. A cohort of 40-year-old individuals was simulated in each arm of the model. The model's time horizon was when the cohort reached 90 years of age and the total costs and quality-adjusted life-years (QALYs) were calculated for all trusts. Scenario and sensitivity analyses were also conducted. RESULTS: A 40-year-old individual gains 0.0006 QALYs and savings of £6.75 over the model lifetime by attending a high-performing trust compared with attending a middle-performing trust and gains 0.0012 QALYs and savings of £14.64 compared with attending a low-performing trust. For the population of England aged between 40 and 86, if all low and middle-performing trusts were improved to the level of a high-performing trust, QALY gains of 14 044 and cost savings of £249 311 295 are possible. Higher quality trusts dominated lower quality trusts; any improvement in the PCCRC rate was cost-effective. CONCLUSION: Improving the quality of endoscopy services would lead to QALY gains among the population, in addition to cost savings to the healthcare provider. If all middle and low-performing trusts were improved to the level of a high-performing trust, our results estimate that the English National Health Service would save approximately £5 million per year.

Robotic and laparoscopic gynaecological surgery: a prospective multicentre observational cohort study and economic evaluation in England.

OBJECTIVE: To compare the health-related quality of life and cost-effectiveness of robot-assisted laparoscopic surgery (RALS) versus conventional 'straight stick' laparoscopic surgery (CLS) in women undergoing hysterectomy as part of their treatment for either suspected or proven gynaecological malignancy. DESIGN: Multicentre prospective observational cohort study. SETTING: Patients aged 16+ undergoing hysterectomy as part of their treatment for gynaecological malignancy at 12 National Health Service (NHS) cancer units and centres in England between August 2017 and February 2020. PARTICIPANTS: 275 patients recruited with 159 RALS, 73 CLS eligible for analysis. OUTCOME MEASURES: Primary outcome was the European Organisation for Research and Treatment of Cancer Quality of Life measure (EORTC). Secondary outcomes included EuroQol-5 Dimension (EQ-5D-5L) utility, 6-minute walk test (6MWT), NHS costs using pounds sterling (£) 2018-2019 prices and cost-effectiveness. The cost-effectiveness evaluation compared EQ-5D-5L quality adjusted life years and costs between RALS and CLS. RESULTS: No difference identified between RALS and CLS for EORTC, EQ-5D-5L utility and 6MWT. RALS had unadjusted mean cost difference of £556 (95% CI -£314 to £1315) versus CLS and mean quality adjusted life year (QALY) difference of 0.0024 (95% CI -0.00051 to 0.0057), non-parametric incremental cost-effectiveness ratio of £231 667per QALY. For the adjusted cost-effectiveness analysis, RALS dominated CLS with a mean cost difference of -£188 (95% CI -£1321 to £827) and QALY difference of 0.0024 (95% CI -0.0008 to 0.0057). CONCLUSIONS: Findings suggest that RALS versus CLS in women undergoing hysterectomy (after adjusting for differences in morbidity) is cost-effective with lower costs and QALYs. Results are highly sensitive to the usage of robotic hardware with higher usage increasing the probability of cost-effectiveness. Non-inferiority randomised controlled trial would be of benefit to decision-makers to provide further evidence on the cost-effectiveness of RALS versus CLS but may not be practical due to surgical preferences of surgeons and the extensive roll out of RALS.

Digital health coaching to improve patient preparedness for elective lower limb arthroplasty: a quality improvement project.

Major surgery carries high risks with comorbidities, frailty and health risk behaviours meaning patients are often unprepared for the physiological insult. Since 2018, the Prepwell programme at South Tees Hospitals NHS Foundation Trust has supported patients to improve their preoperative health and fitness. In April 2020, the face-to-face service was suspended due to the pandemic, leading to the team implementing a three-tiered remote digital support pathway, including digital health coaching via a mobile phone application. METHODS: Patients scheduled for elective lower limb arthroplasty were offered 8 weeks of digital health coaching preoperatively. Following consent, participants were assigned a personal health coach to set individual behaviour change goals supported by online resources, alongside a digitally delivered exercise programme. Participants completed self-assessment questionnaires at Entry to, and Exit from, the programme, with outcome data collected 21 days postoperatively. The primary outcome was the change in Patient Activation Measure (PAM). RESULTS: Fifty-seven of 189 patients (30.2%) consented to referral for digital health coaching. Forty participants completed the 8-week programme. Median PAM increased from 58.1 to 67.8 (p=0.002). Thirty-five per cent of participants were in a non-activated PAM level at Entry, reducing to 15% at Exit with no participants in PAM level 1 at completion. Seventy-one percent of non-activated participants improved their PAM by one level or more, compared with 45% for the whole cohort. Median LOS was 2 days, 1 day less than the Trust's arthroplasty patient population during the study period (unadjusted comparison). CONCLUSIONS: Digital health coaching was successfully implemented for patients awaiting elective lower limb arthroplasty. We observed significant improvements in participants' PAM scores after the programme, with the largest increase in participants with lower activation scores at Entry. Further study is needed to confirm the effects of digital health coaching in this and other perioperative groups.

Improved interface packing and design opportunities revealed by CryoEM analysis of a designed protein nanocage.

Symmetric protein assemblies play important roles in nature which makes them an attractive target for engineering. De novo symmetric protein complexes can be created through computational protein design to tailor their properties from first principles, and recently several protein nanocages have been created by bringing together protein components through hydrophobic interactions. Accurate experimental structures of newly-developed proteins are essential to validate their design, improve assembly stability, and tailor downstream applications. We describe the CryoEM structure of the nanocage I3-01, at an overall resolution of 3.5 Å. I3-01, comprising 60 aldolase subunits arranged with icosahedral symmetry, has resisted high-resolution characterization. Some key differences between the refined structure and the original design are identified, such as improved packing of hydrophobic sidechains, providing insight to the resistance of I3-01 to high-resolution averaging. Based on our analysis, we suggest factors important in the design and structural processing of new assemblies.

Patient-held health IT adoption across the primary-secondary care interface: a Normalisation Process Theory perspective.

Patient-held Health Information Technologies (HIT) can reduce medical error by improving communication between patients and the healthcare team. Despite the proposed benefits, the roll-out of patient-held HIT solutions remains nascent, leaving considerable gaps in our understanding of the adoption challenges inherent. This paper adopts Normalisation Process Theory to study the factors which support or impede the adoption and "normalisation" of patient-held HIT, particularly across the primary-secondary care interface. The authors conducted an in-depth case study of HIT adoption across four GP practices, and the wards of a 350 bed hospital. 35 semi-structured interviews were completed. Findings point towards both user-specific and network-specific factors as significant challenges to normalisation across primary-secondary care. This includes factors related to interactional workability, skill set workability, relational integration, and contextual integration. We also discuss challenges specific to patient-held HIT adoption e.g., understanding the patient/clinician experience, supporting informal clinician networks, and spanning across IT boundaries.

Trans-iliac rat aorta stenting: a novel high throughput preclinical stent model for restenosis and thrombosis.

BACKGROUND: Currently, preclinical stent development requires elaborate large animal models, which are time consuming and expensive. We herein report a high throughput rat aorta stenting model which could provide a rapid and low-cost platform for preclinical stent development. METHODS: A total of 86 metal stents (316L stainless steel 13 mm, VasoTech, Inc.) coated with poly (D, L-lactide-co-glycolide)/amorphous calcium phosphate (PLGA/ACP) copolymer were pre-mounted on 1.5 mm × 15 mm balloon catheters and were implanted into aspirin treated Sprague-Dawley rats (500-700 g) initially using either direct placement in the abdominal aorta (group A, n = 7) or a trans-iliac approach (cut-down, group B, n = 79). The surviving rats were sacrificed at 1, 2, 4, and 12 wk post-implantation and the stented arteries were analyzed histopathologically. RESULTS: Four rats died in group A and nine rats died in group B within 48 h post-stent implantation (mortality: 57% versus 11%, P < 0.05). All animals that died had stent thrombosis/paralysis with visible thrombus on necropsy. Histologically, neointimal growth peaked at approximately 4 wk post-implantation. CONCLUSION: This result suggests that human-sized stents can be successfully implanted into the rat aorta via iliac artery insertion with a significantly higher survival rate than trans-aorta implantation. The model system allows rapid (4-12 wk) assessment of stent biocompatibility with mortality/paralysis used as an indicator of stent thrombosis.

Effect of ß-sheet crystalline content on mass transfer in silk films.

The material properties of silk are favorable for drug delivery due to the ability to control material structure and morphology under ambient, aqueous processing conditions. Mass transport of compounds with varying physical-chemical characteristics was studied in silk fibroin films with control of ß-sheet crystalline content. Two compounds, vitamin B12 and fluorescein isothiocynate (FITC) labeled lysozyme were studied in a diffusion apparatus to determine transport through silk films. The films exhibited size exclusion phenomenon with permeability coefficients with contrasting trends with increases in ß-sheet crystallinity. The size exclusion phenomenon observed with the two model compounds was characterized by contrasting trends in permeability coefficients of the films as a function of ß-sheet crystallinity. The diffusivity of the compounds was examined in the context of free volume theory. Apart from the ß-sheet crystallinity, size of the compound and its interactions with silk influenced mass transfer. Diffusivity of vitamin B12 was modeled to define a power law relationship with ß-sheet crystallinity. The results of the study demonstrate that diffusion of therapeutic agents though silk fibroin films can be directed to match a desired rate by modulating secondary structure of the silk proteins.

A Chemical Biology Approach to Probing the Folding Pathways of the Inhibitory Cystine Knot (ICK) Peptide ProTx-II.

Peptide toxins that adopt the inhibitory cystine knot (ICK) scaffold have very stable three-dimensional structures as a result of the conformational constraints imposed by the configuration of the three disulfide bonds that are the hallmark of this fold. Understanding the oxidative folding pathways of these complex peptides, many of which are important therapeutic leads, is important in order to devise reliable synthetic routes to correctly folded, biologically active peptides. Previous research on the ICK peptide ProTx-II has shown that in the absence of an equilibrating redox buffer, misfolded intermediates form that prevent the formation of the native disulfide bond configuration. In this paper, we used tandem mass spectrometry to examine these misfolded peptides, and identified two non-native singly bridged peptides, one with a Cys(III)-Cys(IV) linkage and one with a Cys(V)-Cys(VI) linkage. Based on these results, we propose that the C-terminus of ProTx-II has an important role in initiating the folding of this peptide. To test this hypothesis, we have also studied the folding pathways of analogs of ProTx-II containing the disulfide-bond directing group penicillamine (Pen) under the same conditions. We find that placing Pen residues at the C-terminus of the ProTx-II analogs directs the folding pathway away from the singly bridged misfolded intermediates that represent a kinetic trap for the native sequence, and allows a fully oxidized final product to be formed with three disulfide bridges. However, multiple two-disulfide peptides were also produced, indicating that further study is required to fully control the folding pathways of this modified scaffold.

World Café approach: exploring the future vision of oral anticoagulants for patients with atrial fibrillation (AF) in Ireland.

OBJECTIVES: To explore and reflect on the current anticoagulation therapy offered to patients with atrial fibrillation (AF), potential challenges and the future vision for oral anticoagulants for patients with AF and healthcare professionals in Ireland. DESIGN: A multistakeholder focus group using a World Café approach. PARTICIPANTS: Nine participants from academic, clinical and health backgrounds attended the focus group together with a facilitator. RESULTS: Enhanced patient empowerment; more effective use of technology and developing system-based medical care pathways would provide improved supports for AF management. The challenges in providing these include cost and access issues, the doctor-patient relationship and the provision of education. While consensus for developing evidence-based pathways to maximise efficiency and effectiveness of AF treatment was evident, it would require a shared vision between stakeholders of integrated care. The benefits of embracing technological advances for clinicians and patients were evident; however, clinicians indicate this can increase pressure on already stretched resources; coupled with institutional barriers (including scarce resources) arising from the complex nature of anticoagulation for patients with AF, which emerged strongly. Including the unpredictable nature of warfarin, hidden costs associated with monitoring, adverse clinical effects, different patient cohorts (including those prescribed anticoagulant for the first time vs those switching from warfarin to a new oral anticoagulant (NOAC)), non-adherence concerns and undesirable impacts on patients' daily lives. CONCLUSIONS: While anticoagulation therapy for patients with AF using NOACs has been widely adopted and is diffusing into routine practice, significant operationalisation issues and barriers to effective treatment/management persist. The reflections reported in this study are a catalyst for future discussion and research.

Embedding the Pillars of Quality in Health Information Technology Solutions Using "Integrated Patient Journey Mapping" (IPJM): Case Study.

BACKGROUND: Health information technology (HIT) and associated data analytics offer significant opportunities for tackling some of the more complex challenges currently facing the health care sector. However, to deliver robust health care service improvements, it is essential that HIT solutions be designed by parallelly considering the 3 core pillars of health care quality: clinical effectiveness, patient safety, and patient experience. This requires multidisciplinary teams to design interventions that both adhere to medical protocols and achieve the tripartite goals of effectiveness, safety, and experience. OBJECTIVE: In this paper, we present a design tool called Integrated Patient Journey Mapping (IPJM) that was developed to assist multidisciplinary teams in designing effective HIT solutions to address the 3 core pillars of health care quality. IPJM is intended to support the analysis of requirements as well as to promote empathy and the emergence of shared commitment and understanding among multidisciplinary teams. METHODS: A 6-month, in-depth case study was conducted to derive findings on the use of IPJM during Learning to Evaluate Blood Pressure at Home (LEANBH), a connected health project that developed an HIT solution for the perinatal health context. Data were collected from over 700 hours of participant observations and 10 semistructured interviews. RESULTS: The findings indicate that IPJM offered a constructive tool for multidisciplinary teams to work together in designing an HIT solution, through mapping the physical and emotional journey of patients for both the current service and the proposed connected health service. This allowed team members to consider the goals, tasks, constraints, and actors involved in the delivery of this journey and to capture requirements for the digital touchpoints of the connected health service. CONCLUSIONS: Overall, IPJM facilitates the design and implementation of complex HITs that require multidisciplinary participation.