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Abnormal expression of the cell cycle inhibitor and p53 target CDKN1A/p21 has been associated with paradoxical outcomes, such as hyperproliferation in p53-deficient cancer cells or hypoproliferation that affects hematopoietic stem cell behavior, leading to bone marrow failure (BMF). Notably, p21 is known to be overexpressed in Fanconi anemia (FA), which is a rare syndrome that predisposes patients to BMF and cancer. However, why p21 is overexpressed in FA and how it contributes to the FA phenotype(s) are still poorly understood. Here, we revealed that while the upregulation of p21 is largely dependent on p53, it also depends on the transcription factor microphthalmia (MITF) as well as on its interaction with the nucleolar protein NPM1. Upregulation of p21 expression in FA cells leads to p21 accumulation in the chromatin fraction, p21 immunoprecipitation with PCNA, S-phase lengthening and genetic instability. p21 depletion in FA cells rescues the S-phase abnormalities and reduces their genetic instability. In addition, we observed that reactive oxygen species (ROS) accumulation, another key feature of FA cells, is required to trigger an increase in PCNA/chromatin-associated p21 and to impact replication progression. Therefore, we propose a mechanism by which p21 and ROS cooperate to induce replication abnormalities that fuel genetic instability.

Objectives: To describe adherence to a 12-week web-based aerobic exercise programme, to compare characteristics between those who adhere or not, and to identify barriers for exercising in patients with hip or knee osteoarthritis. Design: Single-arm feasibility study. Subjects: Patients with hip or knee osteoarthritis in specialist healthcare, age 40–80 years, and not candidates for joint surgery. Methods: Adherence to a 12-week exercise programme was defined as having completed ≥ 2 exercise sessions a week for at least 8 weeks. Baseline differences between adherent and non-adherent groups in demographics, symptoms, disability, physical activity and fitness were assessed using Mann–Whitney U or χ2 tests. Reasons for not completing exercise sessions were reported in weekly diaries. Results: A total of 29 patients (median age 64 years, 72% female) were included. Median baseline pain (numerical rating scale 0–10) was 5. Fifteen patients adhered to the exercise programme, 14 did not. Non-adherent patients were less active (p = 0.032) and had lower cardiorespiratory fitness (p = 0.031). The most frequently reported barrier to exercising was sickness. Less than 10% reported pain as a barrier. Conclusion: Half of the patients with hip or knee osteoarthritis adhered to the digitally delivered exercise programme and the most frequently reported barrier for adherence was sickness, while less than 10% reported pain as a reason for not exercising. Trial registration: ClinicalTrials.gov, NCT04084834. The Regional Committee for Medical and Health Research Ethics South-East, 2018/2198.

Abstract Background Patient organisations may be an under-utilised resource in follow-up of patients requiring long-term exercise as part of their disease management. The purpose of this study was to explore the feasibility of a web-based exercise program delivered by a patient organisation to patients with hip and/or knee osteoarthritis (OA). Methods In this pre–post feasibility study, patients aged 40–80 years with hip and/or knee OA were recruited from Diakonhjemmet Hospital. The 12-week intervention was delivered through a patient organisation’s digital platform. Feasibility was evaluated by proportion of eligible patients enrolled, proportion of enrolled patients who provided valid accelerometer data at baseline, and proportion completing the cardiorespiratory exercise test according to protocol at baseline and completed follow-up assessments. Patient acceptability was evaluated for website usability, satisfaction with the initial exercise level and comprehensibility of the exercise program. Change in clinical outcomes were assessed for physical activity, cardiorespiratory fitness and patient-reported variables. Results In total, 49 eligible patients were identified and 35 were enrolled. Thirty (86%) of these attended baseline assessments and provided valid accelerometer data and 18 (51%) completed the maximal cardiorespiratory exercise test according to protocol. Twenty-two (63%) patients completed the follow-up questionnaire, and they rated the website usability as ‘acceptable’ [median 77.5 out of 100 (IQR 56.9, 85.6)], 19 (86%) reported that the initial exercise level was ‘just right’ and 18 (82%) that the exercise program was ‘very easy’ or ’quite easy’ to comprehend. Improvement in both moderate to vigorous physical activity (mean change 16.4 min/day; 95% CI 6.9 to 25.9) and cardiorespiratory fitness, VO2peak (mean change 1.83 ml/kg/min; 95% CI 0.29 to 3.36) were found in a subgroup of 8 patients completing these tests. Across all patient-reported outcomes 24–52% of the patients had a meaningful improvement (n = 22). Conclusion A web-based exercise program delivered by a patient organisation was found to be feasible and acceptable in patients with hip and/or knee OA. Trial registration ClinicalTrials.gov, NCT04084834 (registered 10 September 2019). The Regional Committee for Medical and Health Research Ethics south-east, 2018/2198. URL: Prosjekt #632074 - Aktiv med web-basert støtte. - Cristin (registered 7 June 2019).

Abnormal expression of the cell cycle inhibitor and p53 target CDKN1A/p21 has been associated with paradoxical outcomes, such as hyperproliferation in p53-deficient cancer cells or hypoproliferation that affects hematopoietic stem cell behavior, leading to bone marrow failure (BMF). Notably, p21 is known to be overexpressed in Fanconi anemia (FA), which is a rare syndrome that predisposes patients to BMF and cancer. However, why p21 is overexpressed in FA and how it contributes to the FA phenotype(s) are still poorly understood. Here, we revealed that while the upregulation of p21 is largely dependent on p53, it also depends on the transcription factor microphthalmia (MITF) as well as on its interaction with the nucleolar protein NPM1. Upregulation of p21 expression in FA cells leads to p21 accumulation in the chromatin fraction, p21 immunoprecipitation with PCNA, S-phase lengthening and genetic instability. p21 depletion in FA cells rescues the S-phase abnormalities and reduces their genetic instability. In addition, we observed that reactive oxygen species (ROS) accumulation, another key feature of FA cells, is required to trigger an increase in PCNA/chromatin-associated p21 and to impact replication progression. Therefore, we propose a mechanism by which p21 and ROS cooperate to induce replication abnormalities that fuel genetic instability. Author summary: Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and a predisposition to cancer caused by biallelic mutations in genes encoding proteins involved in the FANC/BRCA DNA repair pathway. Bone marrow failure has been attributed to the abnormal overexpression of the p53/p21 axis in response to the inherent DNA damage accompanying the loss of the FANC/BRCA pathway, leading to cell cycle arrest and subsequent hematopoietic stem cell exhaustion. Here, we revealed an alternative pathway that contributes to p21 overexpression independent of p53. Indeed, we found that in TP53-null cells, the loss of the FANC pathway still leads to p21 overexpression. We demonstrated that this overexpression is dependent on the transcription factor MITF, which increases CDKN1A mRNA (which encodes p21), and on the NPM1 protein, which directly stabilizes p21. Both mechanisms are independent of DNA damage and/or DNA damage signaling, and therefore, this study provides a shift in the paradigm explaining the bone marrow failure observed in Fanconi anemia. Notably, we demonstrated that, in association with the known higher level of ROS in FA cells, the overexpression of p21 contributes to generating replication stress, which contributes to their genetic instability. [ABSTRACT FROM AUTHOR]

Abstract Background Randomization is the foundation of any clinical trial involving treatment comparison. It helps mitigate selection bias, promotes similarity of treatment groups with respect to important known and unknown confounders, and contributes to the validity of statistical tests. Various restricted randomization procedures with different probabilistic structures and different statistical properties are available. The goal of this paper is to present a systematic roadmap for the choice and application of a restricted randomization procedure in a clinical trial. Methods We survey available restricted randomization procedures for sequential allocation of subjects in a randomized, comparative, parallel group clinical trial with equal (1:1) allocation. We explore statistical properties of these procedures, including balance/randomness tradeoff, type I error rate and power. We perform head-to-head comparisons of different procedures through simulation under various experimental scenarios, including cases when common model assumptions are violated. We also provide some real-life clinical trial examples to illustrate the thinking process for selecting a randomization procedure for implementation in practice. Results Restricted randomization procedures targeting 1:1 allocation vary in the degree of balance/randomness they induce, and more importantly, they vary in terms of validity and efficiency of statistical inference when common model assumptions are violated (e.g. when outcomes are affected by a linear time trend; measurement error distribution is misspecified; or selection bias is introduced in the experiment). Some procedures are more robust than others. Covariate-adjusted analysis may be essential to ensure validity of the results. Special considerations are required when selecting a randomization procedure for a clinical trial with very small sample size. Conclusions The choice of randomization design, data analytic technique (parametric or nonparametric), and analysis strategy (randomization-based or population model-based) are all very important considerations. Randomization-based tests are robust and valid alternatives to likelihood-based tests and should be considered more frequently by clinical investigators.

Abstract Background To tailor physical activity treatment programs for patients with osteoarthritis, clinicians need valid and feasible measurement tools to evaluate habitual physical activity. The widely used International Physical Activity Questionnaire-Short Form (IPAQ-SF) is not previously validated in patients with osteoarthritis. Purpose To assess the concurrent criterion validity of the IPAQ-SF in patients with osteoarthritis, using an accelerometer as a criterion-method. Method Patients with osteoarthritis (n = 115) were recruited at The Division of Rheumatology and Research at Diakonhjemmet Hospital (Oslo, Norway). Physical activity was measured by patients wearing an accelerometer (ActiGraph wGT3X-BT) for seven consecutive days, followed by reporting their physical activity for the past 7 days using the IPAQ-SF. Comparison of proportions that fulfilled physical activity recommendations as measured by the two methods were tested by Pearson Chi-Square analysis. Differences in physical activity levels between the IPAQ-SF and the accelerometer were analyzed with Wilcoxon Signed-Rank Test and Spearman rank correlation test. Bland-Altman plots were used to visualize the concurrent criterion validity for total- and intensity-specific physical activity levels. Results In total, 93 patients provided complete physical activity data, mean (SD) age was 65 (8.7) years, 87% were women. According to the IPAQ-SF, 57% of the patients fulfilled the minimum physical activity recommendations compared to 31% according to the accelerometer (p = 0.043). When comparing the IPAQ-SF to the accelerometer we found significant under-reporting of total physical activity MET-minutes (p =