Chronic Airways Assessment Test: psychometric properties in patients with asthma and/or COPD.

BACKGROUND: No short patient-reported outcome (PRO) instruments assess overall health status across different obstructive lung diseases. Thus, the wording of the introduction to the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) was modified to permit use in asthma and/or COPD. This tool is called the Chronic Airways Assessment Test (CAAT). METHODS: The psychometric properties of the CAAT were evaluated using baseline data from the NOVELTY study (NCT02760329) in patients with physician-assigned asthma, asthma + COPD or COPD. Analyses included exploratory/confirmatory factor analyses, differential item functioning and analysis of construct validity. Responses to the CAAT and CAT were compared in patients with asthma + COPD and those with COPD. RESULTS: CAAT items were internally consistent (Cronbach's alpha: > 0.7) within each diagnostic group (n = 510). Models for structural and measurement invariance were strong. Tests of differential item functioning showed small differences between asthma and COPD in individual items, but these were not consistent in direction and had minimal overall impact on the total score. The CAAT and CAT were highly consistent when assessed in all NOVELTY patients who completed both (N = 277, Pearson's correlation coefficient: 0.90). Like the CAT itself, CAAT scores correlated moderately (0.4-0.7) to strongly (> 0.7) with other PRO measures and weakly (< 0.4) with spirometry measures. CONCLUSIONS: CAAT scores appear to reflect the same health impairment across asthma and COPD, making the CAAT an appropriate PRO instrument for patients with asthma and/or COPD. Its brevity makes it suitable for use in clinical studies and routine clinical practice. TRIAL REGISTRATION: NCT02760329.

Muscle mass and quality as predictors for complications, recurrence and length of hospital stay in acute uncomplicated diverticulitis: a retrospective cohort study.

OBJECTIVES: The aim of this study was to investigate the potential correlation between muscle mass/muscle quality and risk of complications or recurrence in patients presenting with acute uncomplicated diverticulitis. It was also to study if low muscle mass/quality correlated to prolonged hospital stay. MATERIALS AND METHODS: The study population comprised 501 patients admitted to Helsingborg Hospital or Skåne University Hospital between 1 January 2015 and 31 December 2017, who had been diagnosed with acute uncomplicated diverticulitis and undergone computed tomography upon admission. The scans were used to estimate skeletal muscle mass and muscle radiation attenuation (an indicator for muscle quality). Skeletal muscle index was obtained by adjusting skeletal muscle mass to the patients' height. Values of below the fifth percentile of a normal population were considered low. RESULTS: There were no differences between the patients with normal versus those with low skeletal muscle mass, skeletal muscle index or muscle radiation attenuation regarding risk of complications or recurrence of diverticular disease. However, as only 11 patients had complications, no conclusion as to a potential correlation can be made. Low muscle quality correlated to longer hospital stay, also when adjusting for other potential confounders. CONCLUSIONS: Muscle mass/quality do not seem to serve as predictor of risk for recurrent disease in patients with acute uncomplicated diverticulitis. However, low muscle radiation attenuation was associated with prolonged hospital stay. This indicates that muscle quality, assessed by computed tomography scan, might be used in clinical practise to identify patients at risk of longer hospitalisation.

Validity and responsiveness of the Daily- and Clinical visit-PROactive Physical Activity in COPD (D-PPAC and C-PPAC) instruments.

BACKGROUND: The Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients' experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation. OBJECTIVE: To test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries. METHODS: We used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID. RESULTS: We included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score. CONCLUSIONS: The D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables.

Heterogeneity within and between physician-diagnosed asthma and/or COPD: NOVELTY cohort.

BACKGROUND: Studies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options. NOVELTY is a global, 3-year, prospective observational study of patients with asthma and/or COPD from real-world clinical practice. We investigated heterogeneity and overlap by diagnosis and severity in this cohort. METHODS: Patients with physician-assigned asthma, COPD or both (asthma+COPD) were enrolled, and stratified by diagnosis and severity. Baseline characteristics were reported descriptively by physician-assigned diagnosis and/or severity. Factors associated with physician-assessed severity were evaluated using ordinal logistic regression analysis. RESULTS: Of 11 243 patients, 5940 (52.8%) had physician-assigned asthma, 1396 (12.4%) had asthma+COPD and 3907 (34.8%) had COPD; almost half were from primary care. Symptoms, health-related quality of life and spirometry showed substantial heterogeneity and overlap between asthma, asthma+COPD and COPD, with 23%, 62% and 64% of patients, respectively, having a ratio of post-bronchodilator forced expiratory volume in 1 s to forced vital capacity below the lower limit of normal. Symptoms and exacerbations increased with greater physician-assessed severity and were higher in asthma+COPD. However, 24.3% with mild asthma and 20.4% with mild COPD had experienced ≥1 exacerbation in the past 12 months. Medication records suggested both under-treatment and over-treatment relative to severity. Blood eosinophil counts varied little across diagnosis and severity groups, but blood neutrophil counts increased with severity across all diagnoses. CONCLUSION: This analysis demonstrates marked heterogeneity within, and overlap between, physician-assigned diagnosis and severity groups in patients with asthma and/or COPD. Current diagnostic and severity classifications in clinical practice poorly differentiate between clinical phenotypes that may have specific risks and treatment implications.

Development of a preliminary conceptual model of the patient experience of chronic kidney disease: a targeted literature review and analysis.

BACKGROUND: Patient-reported outcome (PRO) instruments should capture the experiences of disease and treatment that patients consider most important in order to inform patient-centred care and product development. The aim of this study was to develop a preliminary conceptual model of patient experience in chronic kidney disease (CKD) based on a targeted literature review and to characterize existing PRO instruments used in CKD. METHODS: PubMed, EMBASE and Cochrane databases and recent society meetings were searched for publications reporting signs/symptoms and life impacts of CKD. Concepts identified in the literature review were used to develop a preliminary conceptual model of patient experience of CKD, overall, and within patient subpopulations of differing CKD causes, severities and complications. PRO instruments, identified from PRO databases, CKD literature and CKD clinical trials, were assessed for content validity, psychometric strength and coverage of concepts in the literature review. RESULTS: In total, 100 publications met criteria for analysis; 56 signs/symptoms and 37 life impacts of CKD were identified from these sources. The most frequently mentioned signs/symptoms were pain/discomfort (57% of publications) and tiredness/low energy/lethargy/fatigue (42%); the most commonly reported life impacts were anxiety/depression (49%) and decrements in physical functioning (43%). Signs/symptoms and life impacts varied across the subpopulations and were more frequent at advanced CKD stages. The preliminary conceptual model grouped signs/symptoms into seven domains (pain/discomfort; energy/fatigue; sleep-related; gastrointestinal-related; urinary-related; skin-/hair-/nails-related; and other) and life impacts into six domains (psychological/emotional strain; cognitive impairment; dietary habit disruption; physical function decrements; interference with social relationships; and other). Eleven PRO instruments were considered to be promising for use in CKD; all had limitations. CONCLUSIONS: Although preliminary, the proposed conceptual model highlights key PROs for people with CKD and is intended to spur development of more tailored PRO instruments to assess these concepts.

The greenhouse gas emission effects of rewetting drained peatlands and growing wetland plants for biogas fuel production.

Efforts to mitigate greenhouse gas (GHG) emissions are receiving increased attention among governmental and commercial actors. In recent years, the interest in paludiculture, i.e. the use of rewetted peatlands, has grown because of its potential to reduce GHG emissions by stopping soil decomposition. Moreover, cultivating wetland plants on rewetted peatlands for bioenergy production that replaces fossil fuels in the transport sector, can contribute to additional GHG emission reductions. In this study, an analysis of literature data was conducted to obtain data on GHG emissions (CO2 and CH4) and biomass production from rewetted peatlands cultivated with two different wetland plant species: Phragmites australis (Pa) and Typha latifolia (Tl). In addition, a biogas experiment was carried out to investigate the biomethane yield of Pa and Tl biomass, and the reduction of global warming potential (GWP) by using biomethane as vehicle fuel. The results show that peatland rewetting can be an important measure to mitigate the GWP as it reduces GHG emissions from the soil, particularly on a 100-year timescale but also to some extent on a 20-year timescale. More specifically, rewetting of 1 km2 of peatland can result in a GWP reduction corresponding to the emissions from ±2600 average sized petrol cars annually. Growing Pa on rewetted peatlands reduces soil GHG emissions more than growing Tl, but Pa and Tl produced similar amounts of biomass and biomethane per land area. Our study concludes that Pa, because of a more pronounced GWP reduction, is the most suitable wetland plant to cultivate after peatland rewetting.

A qualitative study of facilitators and barriers to participate in a needle exchange program for women who inject drugs.

BACKGROUND: Women who inject drugs (WWID) show higher levels of injecting risk behaviour compared to men, putting them at risk of contracting HIV and hepatitis C (HCV). Compared to men, WWID are also less present in harm reduction programs such as needle exchange programs (NEP). The aim of this study is to investigate reasons for, and barriers to, participation in NEP among WWID in Sweden, and to identify measures that could be taken to strengthen the program and increase participation among WWID. METHOD: In-depth interviews (IDIs) were conducted with 20 WWID who had participated in the Stockholm NEP for at least six months and was over 18 years old. IDIs were audio recorded and transcribed et verbatim. Qualitative content analysis was used to identify themes. RESULTS: The need for sterile injection equipment was identified as the main driver to join and remain in the NEP program. Continuous participation in the NEP was further driven by easy access to a multitude of health-related services. The most valued service was the sexual and reproductive health services (SRHR), allowing participants to access contraceptives, cervical cancer screening and sexually transmitted infections testing (STI-testing). NEP staffs' respectful treatment of participants further contributed to program participation. However, participants also expressed a number of concerns around NEP participation, which created barriers to joining. These included losing custody or visitation rights to children, male partner jealousy and violence, unwillingness to spend time in the waiting area and fear of receiving positive HIV/HCV test results. Practical barriers included limited opening hours and travel distance to the NEP. To strengthen the program, most participants requested additional SRHR services. Most participants also proposed some form of "women only" access to the NEP, to strengthen the feeling of the NEP as a safe space. CONCLUSION: This study identified factors that may increase uptake of NEP among WWID. Additional SRHR services and "women only" access are recommended to be implemented and evaluated as part of NEP. These findings may inform and improve the current scale-up of NEPs in Sweden to ensure equal access to services.

Using interviews and observations in clinical practice to enhance authenticity in virtual patients for interprofessional education.

BACKGROUND: Interprofessional collaboration is increasingly important in healthcare, but interprofessional education (IPE) faces challenges, such as different study programmes with varied schedules and campuses. These challenges can be met, in part, by using web-based virtual patients (VPs) as a tool in IPE. However, demands for relevant patient presentations and clinical practice increase when VPs are used by students from different programmes. The aim of this study was to improve the presentation of professional perspectives regarding nurses and physicians and their collaboration in order to increase the clinical authenticity of existing VPs. METHODS: Clinical observations were conducted to gain familiarity with the context. Semi-structured interviews were performed with individual nurses and physicians with experience of patients with leg ulcers. The interviews were recorded, transcribed and analysed using thematic analysis. RESULTS: The clinical observations exposed a lack of interprofessional collaboration in practice with regard to patients with leg ulcers. The interview analysis resulted in two themes: Clinical care and Organizational structure. The theme Clinical care included nursing with a holistic approach to the patient and awareness of the patient's well-being, including nutrition and home situation. The theme Organizational structure revealed a lack of teamwork in primary care. The interviewees stressed learning together and sharing responsibility, and they emphasised the importance of implementing interprofessional learning in the education of nurses and physicians in order to stimulate future teamwork. The VP should offer a broad medical history so that healthcare students are made aware of how a disease can affect the patient's social situation, and thereby illustrate the importance of interprofessional collaboration. The information should also be comprehensive and clear, leading to a diagnosis, so the student can gain clinical knowledge and build a foundation for discussion of treatment. CONCLUSIONS: Interviews and observations in clinical practice can be used to enhance authenticity in VPs for interprofessional learning. A thorough look at authentic clinical environments can enrich and improve educational settings using VPs, and it can highlight the challenges students can encounter in clinical care of the patient and in an organisation with regard to interprofessional collaboration.

A cross-sectional assessment of the prevalence and burden of mild asthma in urban China using the 2010, 2012, and 2013 China National Health and Wellness Surveys.

OBJECTIVE: To estimate the prevalence of mild asthma in urban China and to measure the association between asthma severity and quality of life (QOL), work productivity, and healthcare resource use. METHODS: Data were from the China National Health and Wellness Surveys (NHWS) conducted between 2010 and 2013 (N = 59,935), Internet-based surveys of adults in urban China. Patients were categorized by asthma severity according to self-report and Global Initiative for Asthma (GINA2014) guidelines via self-reported medication use (mild [GINA 1-2] vs moderate/severe [GINA 3-4]). Propensity scores were used to identify matched controls without asthma. These three groups (mild vs. moderate/severe vs. matched control) were compared with respect to QOL (revised Short Form-12/36), work productivity (WPAI questionnaire), and healthcare use using generalized linear models. RESULTS: 1,191 respondents reported an asthma diagnosis (1.99%). Then 455 (0.77% and 76.86% of the total sample and asthma sample which could be categorized based on GINA2014 guidelines, respectively) and 897 (1.50% and 75.31% of the total and asthma sample, respectively) had mild asthma based on GINA2014 guidelines and self-report, respectively. Compared with matched controls, mild patients based on GINA2014 guidelines reported worse QOL (Physical Component Summary = 44.67 vs. 48.97), more overall work impairment (54.51% vs. 34.35%), and more all-cause emergency room visits in the past 6 months (1.95 vs. 0.63 visits) (all p <.05). Similar results were observed using self-reported severity. CONCLUSIONS: Most patients with asthma in the China NHWS are mild according to either definition. Asthma patients experience significant burden to QOL, work productivity, activity impairment, and healthcare resource use.

Risk behaviour determinants among people who inject drugs in Stockholm, Sweden over a 10-year period, from 2002 to 2012.

BACKGROUND: People who inject drugs (PWID) frequently engage in injection risk behaviours exposing them to blood-borne infections. Understanding the underlying causes that drive various types and levels of risk behaviours is important to better target preventive interventions. METHODS: A total of 2150 PWID in Swedish remand prisons were interviewed between 2002 and 2012. Questions on socio-demographic and drug-related variables were asked in relation to the following outcomes: Having shared injection drug solution and having lent out or having received already used drug injection equipment within a 12 month recall period. RESULTS: Women shared solutions more than men (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.03; 2.21). Those who had begun to inject drugs before age 17 had a higher risk (OR 1.43, 95% CI 0.99; 2.08) of having received used equipment compared to 17-19 year olds. Amphetamine-injectors shared solutions more than those injecting heroin (OR 2.43, 95% CI 1.64; 3.62). A housing contract lowered the risk of unsafe injection by 37-59% compared to being homeless. CONCLUSIONS: Women, early drug debut, amphetamine users and homeless people had a significantly higher level of injection risk behaviour and need special attention and tailored prevention to successfully combat hepatitis C and HIV transmission among PWID. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT02234167.

Development of the chronic obstructive pulmonary disease morning symptom diary (COPD-MSD).

BACKGROUND: The morning tends to be the most difficult time of day for many patients with chronic obstructive pulmonary disease (COPD) when symptoms can limit one's ability to perform even simple activities. Morning symptoms have been linked to higher levels of work absenteeism, thereby increasing the already substantial economic burden associated with COPD. A validated patient-reported outcome (PRO) instrument designed to capture morning symptoms will allow for a more comprehensive approach to the evaluation of treatment benefit in COPD clinical trials. METHODS: A qualitative interview study was conducted among a sample of symptomatic adults with COPD. Concept elicitation interviews (n = 35) were conducted to identify COPD morning symptoms, followed by cognitive interviews (n = 21) to ensure patient comprehension of the items, instructions and response options of the draft COPD Morning Symptom Diary (COPD-MSD). All interview transcript data were coded using ATLAS.ti software for content analysis. RESULTS: Mean age of the concept elicitation and cognitive interview sample was 65.0 years (±7.5) and 62.3 years (±8.3), respectively. The study sample represented the full range of COPD severity (Global Initiative for Chronic Lung Disease [GOLD] classifications I-IV) and included a mix of racial backgrounds, employment status and educational achievement. During the concept elicitation interviews, the three most frequently reported morning symptoms were shortness of breath (n = 35/35; 100 %), phlegm/mucus (n = 31/35; 88.6 %), and cough (n = 30/35; 85.7 %). A group of clinical and instrument development experts convened to review the concept elicitation data and develop the initial 32-item draft COPD-MSD. Cognitive interviews indicated subjects found the draft COPD-MSD to be comprehensive, clear, and easy to understand. The COPD-MSD underwent minor editorial revisions and streamlining based on cognitive interviews and input from the experts to yield the final 19-item daily diary. CONCLUSIONS: This study supports the content validity of the new COPD-MSD and positions the diary for quantitative psychometric testing.

The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease.

No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD). Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors. Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.236 COPD patients from five European centres were included. Results indicated the concept of physical activity in COPD had two domains, labelled "amount" and "difficulty". After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14. Both demonstrated good model fit (person separation index >0.7). Confirmatory factor analysis supported the bidimensional structure. Both instruments had good internal consistency (Cronbach's α>0.8), test-retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.Daily and clinical visit "PROactive physical activity in COPD" instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.

Determinants and outcomes of physical activity in patients with COPD: a systematic review.

BACKGROUND: The relationship between physical activity, disease severity, health status and prognosis in patients with COPD has not been systematically assessed. Our aim was to identify and summarise studies assessing associations between physical activity and its determinants and/or outcomes in patients with COPD and to develop a conceptual model for physical activity in COPD. METHODS: We conducted a systematic search of four databases (Medline, Embase, CINAHL and Psychinfo) prior to November 2012. Teams of two reviewers independently selected articles, extracted data and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess quality of evidence. RESULTS: 86 studies were included: 59 were focused on determinants, 23 on outcomes and 4 on both. Hyperinflation, exercise capacity, dyspnoea, previous exacerbations, gas exchange, systemic inflammation, quality of life and self-efficacy were consistently related to physical activity, but often based on cross-sectional studies and low-quality evidence. Results from studies of pharmacological and non-pharmacological treatments were inconsistent and the quality of evidence was low to very low. As outcomes, COPD exacerbations and mortality were consistently associated with low levels of physical activity based on moderate quality evidence. Physical activity was associated with other outcomes such as dyspnoea, health-related quality of life, exercise capacity and FEV1 but based on cross-sectional studies and low to very low quality evidence. CONCLUSIONS: Physical activity level in COPD is consistently associated with mortality and exacerbations, but there is poor evidence about determinants of physical activity, including the impact of treatment.

The PROactive innovative conceptual framework on physical activity.

Although physical activity is considered an important therapeutic target in chronic obstructive pulmonary disease (COPD), what "physical activity" means to COPD patients and how their perspective is best measured is poorly understood. We designed a conceptual framework, guiding the development and content validation of two patient reported outcome (PRO) instruments on physical activity (PROactive PRO instruments). 116 patients from four European countries with diverse demographics and COPD phenotypes participated in three consecutive qualitative studies (63% male, age mean±sd 66±9 years, 35% Global Initiative for Chronic Obstructive Lung Disease stage III-IV). 23 interviews and eight focus groups (n = 54) identified the main themes and candidate items of the framework. 39 cognitive debriefings allowed the clarity of the items and instructions to be optimised. Three themes emerged, i.e. impact of COPD on amount of physical activity, symptoms experienced during physical activity, and adaptations made to facilitate physical activity. The themes were similar irrespective of country, demographic or disease characteristics. Iterative rounds of appraisal and refinement of candidate items resulted in 30 items with a daily recall period and 34 items with a 7-day recall period. For the first time, our approach provides comprehensive insight on physical activity from the COPD patients' perspective. The PROactive PRO instruments' content validity represents the pivotal basis for empirically based item reduction and validation.

Development of a Conceptual Model of Physical Functioning Limitations Experienced by Patients with Late-Stage Chronic Kidney Disease: A Qualitative Interview Study.

INTRODUCTION: Limitations in physical functioning are common in patients with late-stage chronic kidney disease (CKD) and can greatly affect their lives. Using patient interviews, this study reports experiences associated with physical functioning limitations for patients with late-stage CKD. METHODS: A preliminary conceptual model on concepts relevant to physical functioning limitations in patients with CKD was developed using data from a targeted literature review (patients with CKD stages IV-V) and previous interviews (patients with CKD stages IIIa-IIIb). The preliminary conceptual model informed a semi-structured interview guide designed to capture experiences of physical functioning limitations in patients with CKD. Patients with CKD stages IV-V who were not receiving dialysis were interviewed; their responses were used to develop a comprehensive conceptual model summarizing their experiences associated with physical functioning limitations. RESULTS: A total of 25 patients with CKD stage IV (n = 19) or V (n = 6) were interviewed. Based on patient responses, the reported concepts were grouped into one of six categories: physical functioning limitations/difficulties, behavioural impacts, activity participation restrictions, symptoms attributed to physical functioning limitations, impacts on sleep and emotional functioning impacts related to physical functioning limitations. Twenty-three patients reported concepts associated with physical functioning limitations, most frequently 'walking up and down stairs' (83%) and 'walking distances' (74%). All 23 patients also reported behavioural impacts, including 'need to rest/subsequent periods of rest' (100%) and 'participation in fewer activities' (91%). As well as summarizing the reported concepts, the comprehensive conceptual model shows how concepts may relate to one another; for example, challenging symptoms or difficulty completing tasks can lead to changes in patient behaviour such as purposely reducing or avoiding activities. CONCLUSIONS: This study found that patients with late-stage CKD not receiving dialysis who experience physical functioning limitations report a range of impacts on their daily lives. The comprehensive conceptual model summarizes the concepts reported and the relationships between them, providing a holistic understanding of how patients with late-stage CKD are affected by physical functioning limitations. Infographic available for this article. INFOGRAPHIC.

Real-world walking cadence in people with COPD.

Introduction: The clinical validity of real-world walking cadence in people with COPD is unsettled. Our objective was to assess the levels, variability and association with clinically relevant COPD characteristics and outcomes of real-world walking cadence. Methods: We assessed walking cadence (steps per minute during walking bouts longer than 10 s) from 7 days' accelerometer data in 593 individuals with COPD from five European countries, and clinical and functional characteristics from validated questionnaires and standardised tests. Severe exacerbations during a 12-month follow-up were recorded from patient reports and medical registries. Results: Participants were mostly male (80%) and had mean±sd age of 68±8 years, post-bronchodilator forced expiratory volume in 1 s (FEV1) of 57±19% predicted and walked 6880±3926 steps·day-1. Mean walking cadence was 88±9 steps·min-1, followed a normal distribution and was highly stable within-person (intraclass correlation coefficient 0.92, 95% CI 0.90-0.93). After adjusting for age, sex, height and number of walking bouts in fractional polynomial or linear regressions, walking cadence was positively associated with FEV1, 6-min walk distance, physical activity (steps·day-1, time in moderate-to-vigorous physical activity, vector magnitude units, walking time, intensity during locomotion), physical activity experience and health-related quality of life and negatively associated with breathlessness and depression (all p<0.05). These associations remained after further adjustment for daily steps. In negative binomial regression adjusted for multiple confounders, walking cadence related to lower number of severe exacerbations during follow-up (incidence rate ratio 0.94 per step·min-1, 95% CI 0.91-0.99, p=0.009). Conclusions: Higher real-world walking cadence is associated with better COPD status and lower severe exacerbations risk, which makes it attractive as a future prognostic marker and clinical outcome.

Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain.

Lithium was recently shown to inhibit apoptosis and promote survival of neural progenitor cells after hypoxia-ischemia in the immature rat brain. Our aim was to evaluate the effects of lithium on cell death and proliferation in the hippocampus after irradiation (IR) to the immature brain. Male mice were injected with 2 mmol/kg lithium chloride i.p. on postnatal day 9 (P9) and additional lithium injections, 1 mmol/kg, were administered at 24 h intervals for up to 7 days. BrdU was injected 4 h after lithium injections on P9 and P10. The left hemisphere received a single dose of 8 Gy (MV photons) on P11. The animals were euthanized 6 h or 7 weeks after IR. The number of BrdU-labeled cells in the subgranular zone (SGZ) of the granule cell layer (GCL) 6h after IR was 24% higher in the lithium-treated mice. The number of proliferating, phospho-histone H3-positive cells in the SGZ 7 weeks after IR was 59% higher in the lithium group, so the effect was long-lasting. The number of apoptotic cells in the SGZ 6 h after IR was lower in the lithium group, as judged by 3 different parameters, pyknosis, staining for active caspase-3 and TUNEL. Newly formed cells (BrdU-labeled 1 or 2 days before IR) showed the greatest degree of protection, as judged by 50% fewer TUNEL-positive cells, whereas non-BrdU-labeled cells showed 38% fewer TUNEL-positive cells 6 h after IR. Consequently, the growth retardation of the GCL was less pronounced in the lithium group. The number and size of microglia in the DG were also lower in the lithium group, indicating reduced inflammation. Learning was facilitated after lithium treatment, as judged by improved context-dependent fear conditioning, and improved place learning, as judged by assessment in the IntelliCage platform. In summary, lithium administration could decrease IR-induced neural progenitor cell apoptosis in the GCL of the hippocampus and ameliorate learning impairments. It remains to be shown if lithium can be used to prevent the debilitating cognitive late effects seen in children treated with cranial radiotherapy.

From Meaningful Outcomes to Meaningful Change Thresholds: A Path to Progress for Establishing Digital Endpoints.

This paper examines the use of digital endpoints (DEs) derived from digital health technologies (DHTs), focusing primarily on the specific considerations regarding the determination of meaningful change thresholds (MCT). Using DHTs in drug development is becoming more commonplace. There is general acceptance of the value of DHTs supporting patient-centric trial design, capturing data outside the traditional clinical trial setting, and generating DEs with the potential to be more sensitive to change than conventional assessments. However, the transition from exploratory endpoints to primary and secondary endpoints capable of supporting labeling claims requires these endpoints to be substantive with reproducible population-specific values. Meaningful change represents the amount of change in an endpoint measure perceived as important to patients and should be determined for each digital endpoint and given population under consideration. This paper examines existing approaches to determine meaningful change thresholds and explores examples of these methodologies and their use as part of DE development: emphasizing the importance of determining what aspects of health are important to patients and ensuring the DE captures these concepts of interest and aligns with the overarching endpoint strategy. Examples are drawn from published DE qualification documentation and responses to qualification submissions under review by the various regulatory authorities. It is the hope that these insights will inform and strengthen the development and validation of DEs as drug development tools, particularly for those new to the approaches to determine MCTs.