Understanding FEV1 for the purpose of cystic fibrosis registry comparisons: Does bias in annual review FEV1 affect between-centre comparison within the UK? An analysis of registry data

Rationale, aims and objective: We previously demonstrated that annual review %FEV1 under-estimates lung health of adults with CF compared to %FEV1 captured during periods of clinical stability. This has implications in the comparisons against registries with encounter-based FEV1, such as the US. It is uncertain whether this bias affects between-centre comparison within the UK. Previous funnel plot analyses have identified variation in annual review %FEV1 according to centre size, hence we investigated whether paired differences between annual review and best %FEV1 also vary according to centre size. Methods: This registry analysis included 18 adult CF centres in the UK with ≥80% completeness for best FEV1 data in 2014. Mean discrepancy between annual review and best %FEV1 is a surrogate for the extent by which annual review %FEV1 underestimates lung health; and was plotted against centre size. A Local Polynomial Regression (LOESS) curve was used to explore the relationship between the two variables. An appropriate model is fitted based on the LOESS curve to determine the strength of relationship between discrepancies in %FEV1 and centre size. Results: There is an inverted U-shaped relationship between mean discrepancies in %FEV1 and centre size. A regression of the paired mean difference in %FEV1 against centre size showed a significant improvement in the goodness of fit for a quadratic model (R2 = 23.8% for a quadratic model compared with 0.4% for a linear one; p = 0.048 for the quadratic term). Conclusions: Annual review %FEV1 under-estimated lung health of adults from small and large centres in the UK to a greater extent compared to medium-sized centres. A plot of %FEV1 against centre size (e.g. funnel plot comparison) would be affected by systematic bias in annual review %FEV1. Therefore, annual review %FEV1 is an unreliable metric to compare health outcomes of adult CF centres within the UK

Rescue therapy within the UK Cystic Fibrosis registry: an exploration of the predictors of intravenous antibiotic use amongst adults with CF

Background and objective: Intravenous (i.v.) antibiotics are needed for rescue when preventative therapy fails to achieve stability among adults with cystic fibrosis (CF). Understanding the distribution of i.v. days can provide insight into the care that adults with CF need. We aim to determine the baseline characteristics that are associated with higher i.v. use, in particular to test the hypothesis that prior-year i.v. use is associated with future-year i.v. use. Methods: This is a cross-sectional analysis of the 2013–2014 UK CF registry data. Stepwise logistic regression was performed using current-year i.v. days as the dependent variable, and demographic variables including prior-year i.v. days as the covariates. Based on these results, study sample was divided into clinically meaningful subgroups using analysis similar to tree-based method. Results: Data were available for 4269 adults in 2013 and 4644 adults in 2014. Prior-year i.v. use was the strongest predictor for current-year i.v. use followed by forced expiratory volume in 1 s (FEV1). Adults with high prioryear i.v. use (>14 days) continued to require high levels of i.v., regardless of FEV1. Those with high prior-year i. v. use and FEV1 ≥70% had higher current-year i.v. days compared to adults with low prior-year i.v. use and FEV1 <40% (28 days, interquartile range (IQR): 11–41 days vs 14 days, IQR: 0–28 days; Mann–Whitney P-value <0.001 in 2013). Conclusion: CF people with prior high levels of rescue often continue to need high levels of rescue even if they have good FEV1. The reasons for this require further investigations

Exploring the implications of different approaches to estimate centre-level adherence using objective adherence data in an adult cystic fibrosis centre - a retrospective observational study

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

Accurate reporting of adherence to inhaled therapies in adults with cystic fibrosis: methods to calculate “normative adherence”

Background: Preventative inhaled treatments in cystic fibrosis will only be effective in maintaining lung health if used appropriately. An accurate adherence index should therefore reflect treatment effectiveness, but the standard method of reporting adherence, that is, as a percentage of the agreed regimen between clinicians and people with cystic fibrosis, does not account for the appropriateness of the treatment regimen. We describe two different indices of inhaled therapy adherence for adults with cystic fibrosis which take into account effectiveness, that is, “simple” and “sophisticated” normative adherence. Methods to calculate normative adherence: Denominator adjustment involves fixing a minimum appropriate value based on the recommended therapy given a person’s characteristics. For simple normative adherence, the denominator is determined by the person’s Pseudomonas status. For sophisticated normative adherence, the denominator is determined by the person’s Pseudomonas status and history of pulmonary exacerbations over the previous year. Numerator adjustment involves capping the daily maximum inhaled therapy use at 100% so that medication overuse does not artificially inflate the adherence level. Three illustrative cases: Case A is an example of inhaled therapy under prescription based on Pseudomonas status resulting in lower simple normative adherence compared to unadjusted adherence. Case B is an example of inhaled therapy under-prescription based on previous exacerbation history resulting in lower sophisticated normative adherence compared to unadjusted adherence and simple normative adherence. Case C is an example of nebulizer overuse exaggerating the magnitude of unadjusted adherence. Conclusion: Different methods of reporting adherence can result in different magnitudes of adherence. We have proposed two methods of standardizing the calculation of adherence which should better reflect treatment effectiveness. The value of these indices can be tested empirically in clinical trials in which there is careful definition of treatment regimens related to key patient characteristics, alongside accurate measurement of health outcomes

Do cystic fibrosis centres with the lowest FEV1 still use the least amount of intravenous antibiotics? A registry-based comparison of intravenous antibiotic use among adult CF centres in the UK

BACKGROUND: The Epidemiologic Study of Cystic Fibrosis using 1995-1996 and 2003-2005 data found that CF centres with lowest FEV1 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 FEV1. The top 7 centres were placed in the 'upper quarter' (best FEV1), the bottom 7 centres in 'lower quarter' (lowest FEV1), and the rest in 'middle half'. IV use was stratified according to %FEV1, 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 FEV1 are still distinguished by lower use of intravenous antibiotics

A pragmatic behavior-based habit index for adherence to nebulized treatments among adults with cystic fibrosis

Background: Habit, a psychological process that automatically generates urges to perform a behavior in associated settings, is potentially an important determinant of medication adherence. Habit is challenging to measure because, as a psychological construct, it cannot be directly observed. We describe a method of using routinely available objective adherence data from electronic data capture (EDC) to generate a behavior-based index of adherence habit and demonstrate how this index can be applied. Methods to generate the habit index: Our proposed habit index is a “frequency in context” measure. It estimates habit as a multiplicative product of behavior frequency (generated from weekly percentage adherence) and context stability (inferred from time of nebulizer use). Although different timescales can be used, we chose to generate weekly habit scores since we believe that this is the most granular level at which context stability can be reasonably calculated. An application of the habit index: A hallmark of habit is to predict future behavior, hence we used time series method to cross-correlate the habit index with nebulizer adherence in the subsequent week among 123 adults with cystic fibrosis (52, 42.3% female; median age 25 years) over a median duration of 153 weeks (IQR 74–198 weeks). The mean cross-correlation coefficient (R) between the habit index and subsequent adherence was 0.40 (95% CI 0.36–0.44). Adjusting for current adherence, the unstandardized regression coefficient (B) for the habit index was 0.30 (95% CI -1.04 to 1.65). Conclusion: We have described a pragmatic method to infer “habit” from adherence data routinely captured with EDC and provided proof-of-principle evidence regarding the feasibility of this concept. The continuous stream of data from EDC allows the habit index to unobtrusively assess “habit” at various time points over prolonged periods, and hence the habit index may be applicable in habit formation studies

Comparison of case note review methods for evaluating quality and safety in health care

Objectives: To determine which of two methods of case note review – holistic (implicit) and criterion-based (explicit) – provides the most useful and reliable information for quality and safety of care, and the level of agreement within and between groups of health-care professionals when they use the two methods to review the same record. To explore the process–outcome relationship between holistic and criterion-based quality-of-care measures and hospital-level outcome indicators. © 2010 Crown Copyrigh

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS

BACKGROUND: Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire. OBJECTIVE: The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT. METHODS: Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT. RESULTS: CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years. CONCLUSION: This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients

Autologous stem cell transplantation in multiple sclerosis: Results from a single centre

Background: In the last 2 decades, intensive immunosuppression followed by autologous stem cell transplantation (ASCT) has been proposed as a possible strategy for treatment of severe immune-mediated disorders, including multiple sclerosis (MS). Objective: To review the outcome of ASCT for MS in Western Australia. Methods: Eligibility criteria for ASCT were (1) progression of sustained disability with expanded disability status scale (EDSS) score increase of more than 1/10 over a 12 month period, (2) advanced MS with threatened loss of ambulation and (3) rapidly progressive disease not adequately assessed by EDSS. Stem cell mobilization was with cyclophosphamide (CY) 2g/m 2 and granu - locyte-colony stimulating factor 5ug/kg bd. conditioning chemo - therapy was with CY 50mg/kg and rabbit antithymocyte globulin 1mg/kg days -5 to -2. Patients were assessed at 3, 6, 12 and 24 months post-transplant. Results: Fourteen patients underwent ASCT. Median age was 47 years; median time from diagnosis to transplant was 12 years. Diagnosis at transplant was secondary progressive MS (12), pri - mary progressive MS (1) and neuromyelitis optica (1). About half the cohorts were neurologically stable at 24 months while the remainder had clinically relevant neurological deterioration. Two patients had meaningful improvement in bladder function. Follow-up MRI showed no Gd-enhancing lesions, but two patients developed new cerebral lesions on T2 weighted imaging. Conclusion: In this group of patients with advanced MS, neuro - logical function 24 months post-ASCT was essentially stable in half the cohort while the remainder experienced clinical progres - sion. It is not possible to conclude whether ASCT altered the natu - ral history of the disease

Pathogenesis of reproductive and metabolic PCOS traits in a mouse model

Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder; however, the etiology and pathogenesis of PCOS are poorly understood and current management is symptom-based. Defining the pathogenesis of PCOS traits is important for developing early PCOS detection markers and new treatment strategies. Hyperandrogenism is a defining characteristic of PCOS, and studies support a role for androgen-driven actions in the development of PCOS. Therefore, we aimed to determine the temporal pattern of development of PCOS features in a well-characterized dihydrotestosterone (DHT)-induced PCOS mouse model after 2, 4, and 8 weeks of DHT exposure. Following 2 weeks of treatment, DHT induced the key PCOS reproductive features of acyclicity, anovulation, and multifollicular ovaries as well as a decrease in large antral follicle health. DHT-treated mice displayed the metabolic PCOS characteristics of increased body weight and exhibited increased visceral adiposity after 8 weeks of DHT treatment. DHT treatment also led to an increase in circulating cholesterol after 2 weeks of exposure and had an overall effect on fasting glucose levels, but not triglycerides, aspartate transaminase (AST) and alanine transaminase (ALT) levels, or hepatic steatosis. These data reveal that in this experimental PCOS mouse model, acyclicity, anovulation, and increased body weight are early features of a developing PCOS phenotype whereas adiposity, impaired glucose tolerance, dyslipidemia, and hepatic steatosis are later developing features of PCOS. These findings provide insights into the likely sequence of PCOS trait development and support the addition of body weight criteria to the early diagnosis of PCOS.Valentina Rodriguez Paris, Melissa C. Edwards, Ali Aflatounian, Michael J. Bertoldo, William L. Ledger, David J. Handelsman, Robert B. Gilchrist, and Kirsty A. Walter