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Background: Studies in separate cohorts suggest possible discrepancies between inhaled medicines supplied (median 50-60%) and medicines used (median 30-40%). We performed the first study that directly compares CF medicine supply against use to identify the cost of excess medicines supply., Methods: This cross-sectional study included participants from 12 UK adult centres with ≥1 year of continuous adherence data from data-logging nebulisers. Medicine supply was measured as medication possession ratio (MPR) for a 1-year period from the first suitable supply date. Medicine use was measured as electronic data capture (EDC) adherence over the same period. The cost of excess medicines was calculated as whole excess box(es) supplied after accounting for the discrepancy between EDC adherence and MPR with 20% contingency., Results: Among 275 participants, 133 (48.4%) were females and mean age was 30 years (95% CI 29-31 years). Median EDC adherence was 57% (IQR 23-86%), median MPR was 74% (IQR 46-96%) and the discrepancy between measures was median 14% (IQR 2-29%). Even with 20% contingency, mean potential cost of excess medicines was £1,124 (95% CI £855-1,394), ranging from £183 (95% CI £29-338) for EDC adherence ≥80% to £2,017 (95% CI £1,507-2,526) for EDC adherence <50%., Conclusions: This study provides a conservative estimate of excess inhaled medicines supply cost among adults with CF in the UK. The excess supply cost was highest among those with lowest EDC adherence, highlighting the importance of adherence support and supplying medicine according to actual use. MPR provides information about medicine supply but over-estimates actual medicine use., (Copyright © 2021. Published by Elsevier B.V.)

Background: Pseudomonas aeruginosa (PA) status influences management decisions in cystic fibrosis (CF) but diagnostic approaches vary. We evaluated the ability of the CFHealthHub (CFHH) criteria, which consist of two major and four minor statements, in diagnosing chronic PA infection among adults with CF., Methods: In this retrospective cross-sectional analysis, we compared the CFHH criteria against the Leeds criteria. Data were collected between 1st January and 31 st December 2016 from all adults with CF receiving care at Sheffield, excluding those with lung transplantation (n = 7) or on ivacaftor (n = 13). The CFHH criteria PA status were cross-tabulated against the Leeds criteria, and clinical outcomes between chronic PA vs non chronic PA for both criteria were compared., Results: This analysis included 186 adults with CF (90 females, median age 27 years, median baseline FEV 1 78.5%). The CFHH criteria diagnosed more cases of chronic PA (116/186, 62.4% vs 79/186, 42.5%), and 37/107 cases of non-chronic PA according to the Leeds criteria were deemed chronic PA by the CFHH criteria. The magnitude of difference in %FEV 1 decline between chronic PA vs non chronic PA was slightly greater for the CFHH criteria (-0.6%, 95% CI -1.8 to 0.6%) compared to the Leeds criteria (-0.2%, 95% CI -1.3 to 1.0%)., Conclusions: The CFHH criteria detected more chronic PA cases yet still retained similar levels of discrimination for health outcomes in comparison to the Leeds criteria. These findings provide preliminary evidence for the validity of the CFHH criteria among adults with CF., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Patterned films are essential to the commonplace technologies of modern life. However, they come at high cost to the planet, being produced from non-renewable, petrochemical-derived polymers and utilising substrates that require harsh, top-down etching techniques. Biopolymers offer a cheap, sustainable and viable alternative easily integrated into existing production techniques. We describe a simple method for the production of patterned biopolymer surfaces and the assignment of each biopolymer domain, which allows for selective metal incorporation used in many patterning applications. Protein and polysaccharide domains were identified by selective etching and metal incorporation; a first for biopolymer blends. Morphologies akin to those observed with synthetic polymer blends and block-copolymers were realised across a large range of feature diameter (200 nm to - 20 μm) and types (salami structure, continuous, porous and droplet-matrix). The morphologies of the films were tuneable with simple recipe changes, highlighting that these biopolymer blends are a feasible alternative to traditional polymers when patterning surfaces. The protein to polysaccharide ratio, viscosity, casting method and spin speed were found to influence the final film morphology. High protein concentrations generally resulted in porous structures whereas higher polysaccharide concentrations resulted in spherical discontinuous domains. Low spin speed conditions resulted in growth of protuberances ranging from 200 nm to 22 μm in diameter, while higher spin speeds resulted in more monodisperse features, with smaller maximal diameter structures ranging from 300 nm to 12.5 μm., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Accurate centre-level medication adherence measurement allows identification of highly performing CF centres, drives shared learning and informs quality improvement. Self-reported adherence is unreliable but data-logging nebulisers can capture objective data. However, adherence levels in current literature are limited by the use of agreed prescriptions and convenience sampling. In this single-centre retrospective study, we quantified the differences in centre-level adherence with different methods of calculating adherence (unadjusted vs normative adherence) and different data sampling frames (convenience sampling vs including difficult to obtain data)., Methods: Adherence data were objectively captured using I-neb® from 2013-2016 in Sheffield Adult CF Centre. Adults on non data-logging devices, on ivacaftor or with previous lung transplantation were excluded. Adherence was calculated based on agreed regimen ('unadjusted adherence') or minimum required regimen ('normative adherence'). I-nebs® not brought to clinic were downloaded during home visits. Adults not on any inhaled therapy but with chronic Pseudomonas aeruginosa infection were included by counting their adherence as "0"., Results: Of the 131 included adults, 126 provided I-neb® data. Calculating unadjusted adherence from I-nebs® brought to clinics resulted in the highest centre-level adherence (median 41.8% in 2013). Median adherence reduced after sequentially accounting for minimum required regimen (40.0% in 2013), I-nebs® not brought to clinics (32.9% in 2013) and adults not on any inhaled therapy (31.0% in 2013)., Conclusions: Different approaches of calculating adherence produced different adherence levels. Adherence levels based only on agreed regimen among adults who readily brought their nebulisers to clinics can over-estimate the effective adherence of CF centres., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: In CF, people with higher FEV 1 are less aggressively treated with intravenous (IV) antibiotics, with resultant negative impact on their health outcomes. This could be entirely clinician-driven, but patient choice may also influence IV use. In this prospective observational study, we explored IV recommendations by clinicians and IV acceptance by adults with CF to understand how clinical presentations consistent with exacerbations resulted in IV use., Methods: Clinical presentations consistent with exacerbations, IV recommendation by clinicians and IV acceptance by patients were prospectively identified for every adult with CF in Sheffield throughout 2016, excluding those who had lung transplantation (n = 7) or on ivacaftor (n = 13). Relevant demographic data, e.g. %FEV 1 , were extracted from medical records. Multi-level mixed-effects logistic regression models were used to compare IV recommendations vs non-recommendations for all clinical encounters, and IV acceptance vs non-acceptance for all IV recommendations., Results: Among 186 adults (median age 27 years, median FEV 1 78.5%), there were 434 exacerbation events and 318 IV use episodes following 1010 clinical encounters. Only 254 (58.5%) of exacerbations were IV treated. A diagnosis of exacerbation, higher number of symptoms and lower %FEV 1 were independent predictors for IV recommendation by clinicians. Higher number of symptoms and lower %FEV 1 were also independent predictors for IV acceptance by adults with CF., Conclusions: Lower IV use among adults with higher %FEV 1 was influenced by both clinicians' and patients' decisions. Using IV antibiotics as an exacerbation surrogate could under-estimate exacerbation rates and conceal differential treatment decisions according to varying clinical characteristics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The Epidemiologic Study of Cystic Fibrosis using 1995-1996 and 2003-2005 data found that CF centres with lowest FEV 1 tended to use fewer intravenous antibiotics. We repeated the analyses using 2013-2014 UK CF registry data to determine if this was still the case., Methods: Analysing data for 2013 and 2014 separately, 28 adult CF centres were ranked according to median % age-adjusted FEV 1 . The top 7 centres were placed in the 'upper quarter' (best FEV 1 ), the bottom 7 centres in 'lower quarter' (lowest FEV 1 ), and the rest in 'middle half'. IV use was stratified according to %FEV 1 , then compared between the three groups., Results: Centres in the 'upper quarter' and 'middle half' used significantly more IV antibiotics compared to centres in the 'lower quarter' (van Elteren test P-value<0.001). Regression analyses showed that people with CF attending centres in the 'upper quarter' or 'middle half' are 30-50% more likely to receive at least one IV course per year compared to people attending centres in the 'lower quarter'., Conclusions: CF centres with lowest FEV 1 are still distinguished by lower use of intravenous antibiotics., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The data coordinating center (DCC) of the Asthma Clinical Research Network (ACRN) is responsible for the support of 11 pulmonary-function testing systems and two quality control systems. Pulmonary-function data from these systems are used as outcome indicators in studies conducted by the ACRN. Each of these systems is composed of a spirometer, a personal computer for data acquisition from the spirometer, a modem, and a printer. These systems are located at six clinical centers nationwide. An analysis conducted at the beginning of the first ACRN protocol identified the following requirements: (1) standard pulmonary-function testing, (2) standard methacholine-challenge testing, (3) the ability to handle simultaneous multiple protocols as well as have data from non-ACRN subjects, (4) the ability to separate data from different protocols as well as separate ACRN and non-ACRN data, (5) the ability to transmit data from the remote clinical centers to the DCC, (6) the ability to ensure quality data and to report on those results, and (7) the ability to provide remote support.

Data management system development for the first Asthma Clinical Research Network (ACRN) study began at the data coordinating center (DCC) in May 1995 with the requirement for delivery of a production system by November 1995. Special methods had to be used to establish an internet local area network (LAN), place clinical client systems, and achieve an accelerated software development cycle. The development of a fully integrated data management system prior to the start of the study was not possible. Therefore an early analysis focused on identifying discrete groupings of data management functions that would allow development of distinct database modules to provide specific functionality such as subject randomization, subject registration, and data entry. The modules were categorized as either being associated with clinical centers or the DCC so that the clinical center modules could be developed and delivered to meet the start date of the study. In the second phase of development during the relatively slow patient-enrollment period, the DCC functional modules were delivered discretely over time. While at the time this development model was a necessity due to limited DCC resources, it continues to be used today as it permits the DCC to implement studies more rapidly and efficiently for the ACRN. This paper describes the methodologies used to develop an internet-based LAN, establish clinical center client systems, establish DCC client and server operations, and develop a data management system. It describes the circumstances that contributed to the development of these systems and the special methodologies developed. The technical aspects of the data management system and LAN are presented as well as a description of the requirements and constraints analysis used to develop the hardware and software systems.

D-Glucarate has shown modest chemopreventive and synergistic chemopreventive effects with retinoids in a number of tumor models as well as a similar antiproliferative effect in MCF-7 human tumor cells in culture. It has been postulated that D-glucarate exerts some of its effects by equilibrium conversion to D-glucarolactone, a potent beta-glucuronidase inhibitor. In the present study, D-glucarate and a number of its analogues, including D-glucarolactone, were evaluated as antiproliferatives in the MCF-7 model with and without added retinoid. Results suggest that the effects of glucarate are reasonably specific for its structure and may not require conversion to glucarolactone.

The biological activity of a series of cyclopropyl analogs of all-trans- and 13-cis-retinoic acid has been evaluated in the vaginal smear assay carried out in vitamin A-deficient rats. These analogs were designed to probe the role of the 13-cis isomer in the actions of the parent all-trans-retinoic acid by blocking the interconversion of these two compounds. Although relatively less active, the potency of some of the cyclopropyl analogs suggests that 13-cis-retinoic acid is a fully active metabolite of all-trans-retinoic acid. Since 13-cis-retinoic acid represents a small percentage of the retinoic acid metabolites, the physiological significance of this activity is still unclear. Possible reasons for the reduced activity of the cyclopropyl analogs, as well as an aromatic analog of retinoic acid, are discussed.