Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health-related quality of life and productivity.

OBJECTIVES: To describe real-world use/effectiveness of pegcetacoplan (PEG) in paroxysmal nocturnal haemoglobinuria (PNH). METHODS: Data were drawn from the Adelphi PNH Disease Specific Programme™, a cross-sectional survey conducted in France, Italy, Germany, Spain and the United States from January to November 2022. Patients had a confirmed PNH diagnosis and received PEG for ≥1 month. Physicians reported patient characteristics, treatment use/satisfaction and their perception of patients' fatigue and health-related quality of life (HRQoL). Patients reported treatment satisfaction and completed questionnaires assessing fatigue, HRQoL and productivity. Descriptive statistics were reported. RESULTS: Overall, 14 physicians provided data for 61 patients who had received 1080 mg/dose PEG for 1.3-14.8 months. At data collection compared to PEG initiation: haemoglobin was 2.5 g/dL higher on average; proportion of patients with lactate dehydrogenase (LDH) ≥1.5 × upper limit of normal was reduced by 27.4%; physician-perceived fatigue was lower and HRQoL better. Physician- and patient-reported treatment satisfaction was high for >90% of patients. Physicians and patients were more satisfied with PEG than previously prescribed C5 complement inhibitors. Mean work impairment and activity impairment in the 7 days prior to data collection were 32.9% and 22.4%, respectively. CONCLUSIONS: These real-world data support the effectiveness of PEG through positive effects on haemoglobin, LDH, fatigue and HRQoL.

The disease burden of paroxysmal nocturnal hemoglobinuria in Denmark: Epidemiology, survival, healthcare resource utilization, costs, treatment gaps, and labor market attachment.

OBJECTIVES: To establish epidemiology, healthcare costs, and labor market attachment in patients with paroxysmal nocturnal hemoglobinuria (Pt-PNH) in Denmark. METHODS: Data were from Statistics Denmark and the Danish Health Data Authority national population registers (2005-2021). Descriptive baseline statistics characterized the Pt-PNH analytic population; ordinary least squares and adjusted Cox proportional hazards regressions measured outcomes in the Pt-PNH versus Danish general population matched comparators. RESULTS: Overall PNH incidence in Denmark was n = 11 during 2007-2009, n = 25 during 2016-2018 and n = 7 during 2019-2020; prevalence increased from n = 13 in 2006 to n = 62 in 2021. Of the overall n = 85 Pt-PNH; n = 24 were treated with complement-5 inhibitors (Pt-C5i) and n = 61 not treated with C5i (Pt-nC5i). Versus respective comparators, all patients had significantly greater annual per-patient costs (from inpatient hospital admissions, outpatient contacts, PNH treatments; indirect costs from lost earnings + transfer payments; post-diagnosis for Pt-PNH and Pt-nC5i, post-treatment initiation for Pt-C5i). The Pt-C5i incurred the greatest healthcare and indirect cost differences (€709 119; €152 832, respectively) followed by the Pt-PNH (€189 323; €29 159, respectively) and Pt-nC5i (€95 548; €4713, respectively). The Pt-PNH versus comparators also had an increased hazard of death (2.71 [95% CI, 1.63 - 4.51]). CONCLUSION: Although a rare disease, PNH is associated with significant patient, healthcare system, and societal burdens in Denmark.

Real-World Effectiveness of rFIXFc Prophylaxis in Patients with Haemophilia B Switched from Standard Half-Life Therapy in Three European Countries.

INTRODUCTION: The current study describes real-world clinical outcomes and factor usage among patients with haemophilia B switching from standard half-life factor IX (SHL FIX) treatment to recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis in European treatment centres. METHODS: This non-interventional, retrospective, multicentre chart review evaluated medical records from adult and paediatric patients with haemophilia B in Denmark, Germany and the UK. Patients had documented SHL FIX treatment, on-demand or prophylaxis, for ≥ 6 months before starting rFIXFc prophylaxis, and subsequent data for ≥ 6 months afterwards (up to 24 months). Primary endpoints included annualised bleeding rates (ABRs), prophylactic factor consumption and injection frequency. RESULTS: Data from 30 patients (24/30 [80.0%] with severe disease) showed overall mean (standard deviation, SD) ABRs of 4.7 (6.3) on SHL FIX treatment and 1.7 (2.3) after switching to rFIXFc prophylaxis. The reduction in mean (SD) ABRs was greater when switching from SHL FIX on-demand treatment (n = 6), with a decrease from 10.5 (9.9) to 2.6 (4.5), than when switching from SHL FIX prophylaxis (n = 24), with a decrease from 3.3 (4.3) to 1.5 (1.4). Among prior SHL FIX prophylaxis patients, switching to rFIXFc prophylaxis increased the proportion of those with zero bleeds from 21.7% to 45.8% during the 6 months before and after switching, respectively. In the total population, five of six target joints (83.3%) present when patients started rFIXFc prophylaxis subsequently resolved. In patients switching from SHL FIX prophylaxis to rFIXFc prophylaxis, mean (SD) weekly injection frequency was reduced by 1.0 (0.7) and mean (SD) factor consumption was reduced by 27.7 (49.6) IU/kg/week. CONCLUSION: This study demonstrates the effectiveness of rFIXFc prophylaxis in real-world clinical practice. Improvements in both clinical effectiveness and factor usage associated with rFIXFc prophylaxis may potentially reduce patient burden and improve quality of life.

Patients diagnosed with COVID-19 and treated with anakinra: a real-world study in the USA.

Anakinra, a recombinant, non-glycosylated human interleukin (IL)-1 receptor antagonist, has been used in real-world clinical practice to manage hyperinflammation in coronavirus disease 2019 (COVID-19). This retrospective, observational study analyses US hospital inpatient data of patients diagnosed with moderate/severe COVID-19 and treated with anakinra between 1 April and 31 August 2020. Of the 119 patients included in the analysis, 63.9% were male, 48.6% were of black ethnicity, and the mean (standard deviation [SD]) age was 64.7 (12.5) years. Mean (SD) time from hospital admission to anakinra initiation was 7.3 (6.1) days. Following anakinra initiation, 73.1% of patients received antibiotics, 55.5% received antithrombotics, and 91.0% received corticosteroids. Overall, 64.7% of patients required intensive care unit (ICU) admittance, and 28.6% received mechanical ventilation following admission. Patients who did not require ICU admittance or who were discharged alive experienced a significantly shorter time between hospital admission and receiving anakinra treatment compared with those admitted to the ICU (5 vs. 8 days; P = 0.002) or those who died in hospital (6 vs. 9 days; P = 0.01). Patients with myocardial infarction or renal conditions were six times (P < 0.01) and three times (P = 0.01), respectively, more likely to die in hospital than be discharged alive. A longer time from hospital admission until anakinra treatment was associated with significantly higher mortality (P = 0.01). Findings from this real-world study suggest that a shorter time from hospital admission to anakinra treatment is associated with significantly lower ICU admissions and mortality among patients with moderate/severe COVID-19.

Quality control methods in accelerometer data processing: identifying extreme counts.

BACKGROUND: Accelerometers are designed to measure plausible human activity, however extremely high count values (EHCV) have been recorded in large-scale studies. Using population data, we develop methodological principles for establishing an EHCV threshold, propose a threshold to define EHCV in the ActiGraph GT1M, determine occurrences of EHCV in a large-scale study, identify device-specific error values, and investigate the influence of varying EHCV thresholds on daily vigorous PA (VPA). METHODS: We estimated quantiles to analyse the distribution of all accelerometer positive count values obtained from 9005 seven-year old children participating in the UK Millennium Cohort Study. A threshold to identify EHCV was derived by differentiating the quantile function. Data were screened for device-specific error count values and EHCV, and a sensitivity analysis conducted to compare daily VPA estimates using three approaches to accounting for EHCV. RESULTS: Using our proposed threshold of ≥ 11,715 counts/minute to identify EHCV, we found that only 0.7% of all non-zero counts measured in MCS children were EHCV; in 99.7% of these children, EHCV comprised < 1% of total non-zero counts. Only 11 MCS children (0.12% of sample) returned accelerometers that contained negative counts; out of 237 such values, 211 counts were equal to -32,768 in one child. The medians of daily minutes spent in VPA obtained without excluding EHCV, and when using a higher threshold (≥19,442 counts/minute) were, respectively, 6.2% and 4.6% higher than when using our threshold (6.5 minutes; p<0.0001). CONCLUSIONS: Quality control processes should be undertaken during accelerometer fieldwork and prior to analysing data to identify monitors recording error values and EHCV. The proposed threshold will improve the validity of VPA estimates in children's studies using the ActiGraph GT1M by ensuring only plausible data are analysed. These methods can be applied to define appropriate EHCV thresholds for different accelerometer models.

How active are our children? Findings from the Millennium Cohort Study.

OBJECTIVE: To describe levels of physical activity, sedentary time and adherence to Chief Medical Officers (CMO) physical activity guidelines among primary school-aged children across the UK using objective accelerometer-based measurements. DESIGN: Nationally representative prospective cohort study. SETTING: Children born across the UK, between 2000 and 2002. PARTICIPANTS: 6497 7-year-old to 8-year-old singleton children for whom reliable accelerometer data were available for at least 10 h a day for at least 2 days. MAIN OUTCOME MEASURES: Physical activity in counts per minute (cpm); time spent in sedentary and moderate-to-vigorous intensity physical activity (MVPA); proportion of children meeting CMO guidelines (≥60 min/day MVPA); average daily steps. EXPLANATORY MEASURES: Gender, ethnicity, maternal current/most recent occupation, lone parenthood status, number of children in the household and country/region of residence. RESULTS: The median daily physical activity level was 595 cpm (IQR 507, 697). Children spent a median of 60 min (IQR 47-76) in MVPA/day and were sedentary for a median of 6.4 h/day (IQR 6-7). Only 51% met CMO guidelines, with girls (38%) less active than boys (63%). Children took an average of 10 229 (95% CI (8777 to 11 775)) steps each day. Children of Indian ethnicity were significantly less active overall than all other ethnic groups. Children of Bangladeshi origin and those living in Northern Ireland were least likely to meet CMO guidelines. CONCLUSIONS: Only half of 7-year-old children in the UK achieve recommended levels of physical activity, with significant gender, ethnic and geographic variations. Longitudinal studies are needed to better understand the relevance of these (in)activity patterns for long-term health and well-being. In the meantime population-wide efforts to boost physical activity among young people are needed which are likely to require a broad range of policy interventions.

Quality control methods in accelerometer data processing: defining minimum wear time.

BACKGROUND: When using accelerometers to measure physical activity, researchers need to determine whether subjects have worn their device for a sufficient period to be included in analyses. We propose a minimum wear criterion using population-based accelerometer data, and explore the influence of gender and the purposeful inclusion of children with weekend data on reliability. METHODS: Accelerometer data obtained during the age seven sweep of the UK Millennium Cohort Study were analysed. Children were asked to wear an ActiGraph GT1M accelerometer for seven days. Reliability coefficients(r) of mean daily counts/minute were calculated using the Spearman-Brown formula based on the intraclass correlation coefficient. An r of 1.0 indicates that all the variation is between- rather than within-children and that measurement is 100% reliable. An r of 0.8 is often regarded as acceptable reliability. Analyses were repeated on data from children who met different minimum daily wear times (one to 10 hours) and wear days (one to seven days). Analyses were conducted for all children, separately for boys and girls, and separately for children with and without weekend data. RESULTS: At least one hour of wear time data was obtained from 7,704 singletons. Reliability increased as the minimum number of days and the daily wear time increased. A high reliability (r = 0.86) and sample size (n = 6,528) was achieved when children with ≥ two days lasting ≥10 hours/day were included in analyses. Reliability coefficients were similar for both genders. Purposeful sampling of children with weekend data resulted in comparable reliabilities to those calculated independent of weekend wear. CONCLUSION: Quality control procedures should be undertaken before analysing accelerometer data in large-scale studies. Using data from children with ≥ two days lasting ≥10 hours/day should provide reliable estimates of physical activity. It's unnecessary to include only children with accelerometer data collected during weekends in analyses.

Predictors of non-response in a UK-wide cohort study of children's accelerometer-determined physical activity using postal methods.

OBJECTIVES: To investigate the biological, social, behavioural and environmental factors associated with non-consent, and non-return of reliable accelerometer data (≥2 days lasting ≥10 h/day), in a UK-wide postal study of children's activity. DESIGN: Nationally representative prospective cohort study. SETTING: Children born across the UK, between 2000 and 2002. PARTICIPANTS: 13 681 7 to 8-year-old singleton children who were invited to wear an accelerometer on their right hip for 7 consecutive days. Consenting families were posted an Actigraph GT1M accelerometer and asked to return it by post. PRIMARY OUTCOME MEASURES: Study consent and reliable accelerometer data acquisition. RESULTS: Consent was obtained for 12 872 (94.5%) interviewed singletons, of whom 6497 (50.5%) returned reliable accelerometer data. Consent was less likely for children with a limiting illness or disability, children who did not have people smoking near them, children who had access to a garden, and those who lived in Northern Ireland. From those who consented, reliable accelerometer data were less likely to be acquired from children who: were boys; overweight/obese; of white, mixed or 'other' ethnicity; had an illness or disability limiting daily activity; whose mothers did not have a degree; who lived in rented accommodation; who exercised once a week or less; who had been breastfed; were from disadvantaged wards; had younger mothers or lone mothers; or were from households with just one, or more than three children. CONCLUSIONS: Studies need to encourage consent and reliable data return in the wide range of groups we have identified to improve response and reduce non-response bias. Additional efforts targeted at such children should increase study consent and data acquisition while also reducing non-response bias. Adjustment must be made for missing data that account for missing data as a non-random event.

Seasonal variation in accelerometer-determined sedentary behaviour and physical activity in children: a review.

AIM: To undertake a review of the methods and findings of published research evaluating the influence of season on accelerometer-determined sedentary behaviour (SB) and physical activity (PA) in children. METHODS: A literature search was carried out using PubMed, Embase, Medline and Web of Science up to, and including, June 2011. The search strategy focused on four key elements: children, SB or PA, season and accelerometer. Articles were eligible for inclusion if they were published in English, included healthy study participants aged ≤ 18 years, reported at least one outcome variable derived from accelerometer-determined measurements, and compared SB or PA between two or more seasons, or controlled for season of measurement. Eligible papers were reviewed and evidence tables compiled reporting on publication year, country studied, study recruitment, consent rate, sample descriptives, study design, accelerometer protocol, valid accelerometer data receipt, season definition, statistical methods and key findings. RESULTS: Sixteen of 819 articles were eligible for inclusion: children aged two to five years, six to twelve, or six to 18 years were included in five, six and five articles respectively. Six articles were from the UK, six from other European countries, three from the USA and one from New Zealand. Study sample sizes ranged from 64 to 5595. PA was reported in all articles but SB in only three. Only four studies were longitudinal and none of these reported SB. Seasonal variation in PA was reported in all UK studies, being highest in summer and lowest in winter. In four non-UK studies seasonal variation in PA was not found. Findings were inconclusive for SB. CONCLUSION: There is sufficient evidence to support public health interventions aimed at increasing PA during winter in UK children. No conclusions can be drawn regarding the effect of season on children's SB reflecting few studies of small sample size, lack of repeat measures, incomparable definitions of season and inconsistent accelerometer protocols. Future research should determine factors that drive seasonal patterns in PA and SB in children such as age, sex, and geographic and climatic setting to inform interventions and target populations.

Actigraph accelerometer-defined boundaries for sedentary behaviour and physical activity intensities in 7 year old children.

BACKGROUND: Accurate objective assessment of sedentary and physical activity behaviours during childhood is integral to the understanding of their relation to later health outcomes, as well as to documenting the frequency and distribution of physical activity within a population. PURPOSE: To calibrate the Actigraph GT1M accelerometer, using energy expenditure (EE) as the criterion measure, to define thresholds for sedentary behaviour and physical activity categories suitable for use in a large scale epidemiological study in young children. METHODS: Accelerometer-based assessments of physical activity (counts per minute) were calibrated against EE measures (kcal x kg(-1) x hr(-1)) obtained over a range of exercise intensities using a COSMED K4b(2) portable metabolic unit in 53 seven-year-old children. Children performed seven activities: lying down viewing television, sitting upright playing a computer game, slow walking, brisk walking, jogging, hopscotch and basketball. Threshold count values were established to identify sedentary behaviour and light, moderate and vigorous physical activity using linear discriminant analysis (LDA) and evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: EE was significantly associated with counts for all non-sedentary activities with the exception of jogging. Threshold values for accelerometer counts (counts x minute(-1)) were <100 for sedentary behaviour and ≤2240, ≤3840 and ≥3841 for light, moderate and vigorous physical activity respectively. The area under the ROC curves for discrimination of sedentary behaviour and vigorous activity were 0.98. Boundaries for light and moderate physical activity were less well defined (0.61 and 0.60 respectively). Sensitivity and specificity were higher for sedentary (99% and 97%) and vigorous (95% and 91%) than for light (60% and 83%) and moderate (61% and 76%) thresholds. CONCLUSION: The accelerometer cut points established in this study can be used to classify sedentary behaviour and to distinguish between light, moderate and vigorous physical activity in children of this age.