Beyond the surface: Imaging of (sub)clinical joint changes in haemophilia

Haemophilia is an X-linked inherited coagulation disorder that results in an increased bleeding tendency. Most bleeding occurs in the large synovial joints (elbows, knees, ankles). Recurrent joint bleeding eventually leads to irreversible haemophilic arthropathy, which causes pain and reduces functionality and quality of life. Prophylactic treatment prevents most bleeding episodes. However, (subclinical) joint bleeding and inflammation still occur. Surprisingly, even in the absence of clinically overt joint bleeding, long-term progression to arthropathy is observed. Subclinical bleeding and inflammation are therefore thought to contribute to the development of arthropathy. Early detection of these subclinical processes is becoming increasingly important in the prevention of arthropathy as overt joint bleeding becomes rare with new replacement therapies. This thesis focused on the detection of subclinical bleeding, the screening for subclinical joint inflammation, and the use of ultrasound in the management of acute joint episodes. The first part of this thesis discussed the detection of subclinical bleeding. Chapter 2 demonstrated that quantitative MRI T1 and T2 relaxometry can differentiate between haemorrhagic joint effusion with low blood concentration and synovial fluid in vitro. Chapter 3 demonstrated good feasibility and reproducibility of the T2-relaxometry method at 3 Tesla in vivo. Chapter 4 describes evidence for subclinical joint bleeding in people with severe haemophilia on long-term prophylaxis. Conventional MRI of joints without a history of bleeding showed evidence of previous subclinical bleeding in 16% of people with severe haemophilia A on prophylaxis. The second part of this thesis focused on screening for subclinical joint inflammation. Chapters 5 and 6 are devoted to screening for (subclinical) synovial proliferation as a proxy for joint inflammation. The literature review in Chapter 5 showed that physical examination underestimates the prevalence of ultrasound-detected synovial proliferation. Therefore, ultrasound appears to have added value in screening for subclinical synovial hypertrophy. The findings in Chapter 6 support the value of ultrasound screening for subclinical synovial proliferation. The role of ultrasound is further emphasized by the failure of biochemical markers to identify ultrasound-detected subclinical synovial proliferation. The third part of this thesis discusses the use of ultrasound in management of acute joint episodes. Although subclinical joint disease can be detected by imaging, its impact on patient management remained unclear. The cross-sectional study in Chapter 7 described that ultrasound, when added to clinical assessment, often changed the diagnosis and treatment of acute musculoskeletal complaints in people with haemophilia and von Willebrand disease (VWD). In Chapter 8, ultrasound and physical examination were used to monitor the recovery of joint bleeding in people with haemophilia and VWD. Ultrasound and physical examination provided complementary information in monitoring joint bleed recovery. In conclusion, ultrasound should be used in haemophilia care as a screening tool for (subclinical) joint damage, as a diagnostic tool for acute joint episodes, and as a monitoring tool for recovery from joint bleeding. MRI remains the reference standard for imaging early joint changes in haemophilia and is therefore best used as a troubleshooter in difficult clinical cases and as a sensitive outcome measure in research

Exceptions to the rule of informed consent for research with an intervention

Background In specific situations it may be necessary to make an exception to the general rule of informed consent for scientific research with an intervention. Earlier reviews only described subsets of arguments for exceptions to waive consent. Methods Here, we provide a more extensive literature review of possible exceptions to the rule of informed consent and the accompanying arguments based on literature from 1997 onwards, using both Pubmed and PsycINFO in our search strategy. Results We identified three main categories of arguments for the acceptability of a consent waiver: data validity and quality, major practical problems, and distress or confusion of participants. Approval by a medical ethical review board always needs to be obtained. Further, we provide examples of specific conditions under which consent waiving might be allowed, such as additional privacy protection measures. Conclusions The reasons legitimized by the authors of the papers in this overview can be used by researchers to form their own opinion about requesting an exception to the rule of informed consent for their own study. Importantly, rules and guidelines applicable in their country, institute and research field should be followed. Moreover, researchers should also take the conditions under which they feel an exception is legitimized under consideration. After discussions with relevant stakeholders, a formal request should be sent to an IRB

The method of detection of ductal carcinoma in situ has no therapeutic implications: results of a population-based cohort study

Multivariable-adjusted Cox regression analysis of ipsilateral and contralateral invasive breast cancer in women aged 49–75 years at DCIS diagnosis (DCIS diagnostic period 1989–2004). Age was the primary time scale, time since DCIS diagnosis (0–5, 5–10, and ≥10 years) the secondary time scale, and DCIS treatment a time-varying covariable (DOCX 22 kb

Toward the optimal strategy for sustained weight loss in overweight cancer survivors:A systematic review of the literature

Purpose: To gain more insight into the optimal strategy to achieve weight loss and weight loss maintenance in overweight and obese cancer survivors after completion of initial treatment, this systematic review aimed to provide an overview of the literature on intervention effects on weight, to describe intervention components used in effective interventions, to identify and synthesize behaviour change techniques (BCTs) and to assess the frequency with which these BCTs were used in effective interventions. Methods: Six databases were searched for original research articles describing weight changes in adult overweight cancer survivors after participation in a lifestyle intervention initiated after completion of initial treatment. Two researchers independently screened the retrieved papers and extracted BCTs using the BCT Taxonomy version 1. Results: Thirty-two papers describing 27 interventions were included. Interventions that were evaluated with a robust study design (n = 8) generally showe

Agreement between oral contraceptive users and prescribers: implications for case-control studies

Case-control studies examining the effects of oral contraceptives (OC) are prone to misclassification bias due to errors in assessment of OC use. Concern about inaccurate exposure histories has increased since current studies require women to recall OC use over prolonged periods of time. In preparation for a case-control study of breast cancer and OC use, an investigation was carried out to assess agreement between women's lifetime histories of OC use (covering a period of up to 20 years) and prescribers' records. OC histories were obtained during personal interview with 218 women who had used OC at some point in their lives (127 breast cancer patients, 91 controls). Recall was aided by an album with color photographs of all OC marketed in the Netherlands from 1962 onwards (n = 65), and a calendar that covered the women's life span from date of birth to menopause. The participants were asked for the names of all physicians who prescribed OC for them. The rate of response from the prescribers was high (94%), but only half of the forms provided useful information. Patient-prescriber agreement on brand names (including dosage) was 70%. About half of the women agreed with their prescribers on starting dates to within less than a year's difference. Approximately the same percentage of agreement was found for stopping dates. Multiple linear regression indicated that agreement on brand names and dates of usage was lower for women of low socioeconomic status, for healthy women (as compared to breast cancer patients) and for periods of pill use that had to be recalled from the more distant past. Agreement on total duration of use was high enough to permit testing of a moderately strong duration-response relationship in a case-control study

Women's adjustment trajectories during IVF and impact on mental health 11–17 years later

STUDY QUESTION Do patients present different adjustment trajectories during and after IVF treatment? SUMMARY ANSWER Most women show resilient trajectories during and after IVF treatment but 37% show temporary or chronic maladjustment during IVF and 10% are maladjusted 11–17 years after treatment. WHAT IS KNOWN ALREADY Research on patient psychosocial adjustment during treatment has contributed to identifying the most distressful stages of IVF treatment and profiling patients at risk for emotional maladjustment at these specific stages. This knowledge is currently driving the deliverance of psychosocial care at fertility clinics by tailoring it to patients' risk profiles and specific treatment stages. However, current care does not take into consideration how individuals adjust across the entire treatment pathway. This can be assessed by profiling individual adjustment trajectories. STUDY DESIGN, SIZE, DURATION A longitudinal cohort study with five assessment moments that combines data from two different studies, the STRESSIVF and OMEGA projects. Participants enrolled in the STRESSIVF study (started IVF in 1998–2000) were assessed before and after the first IVF treatment cycle and 6 months and 2.5 years after the last IVF cycle. A subset participated in the OMEGA project (started IVF in 1995–2000) and reported on their mental health 11–17 years after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS Three hundred and forty-eight women participated in the STRESSIVF project and 108 of these in the OMEGA. Anxiety was measured with the State and Trait Anxiety Inventory, depression with the Beck Depression Inventory and mental health with the Mental Health Inventory. Latent class growth mixed modelling was carried out to identify distinct anxiety and depression trajectories over the four STRESSIVF study assessment moments. Multinominal logistic regressions were conducted to investigate predictors of trajectory membership, and stepwise linear regressions were performed to investigate if adjustment trajectories predicted mental health 11–17 years after IVF treatment. MAIN RESULTS AND THE ROLE OF CHANCE A total of 67 and 86% of women showed normal levels of anxiety and depression, respectively, throughout treatment (resilient trajectories), 24 and 33% experienced anxiety and depression only during treatment (recovery trajectories), 4.6 and 4.9% experienced anxiety and depression only after treatment (delayed trajectories), and 4.3% showed chronic anxiety (chronic trajectory, not identified for depression). Non-resilient trajectories were associated with unsuccessful treatment, marital dissatisfaction, lack of social support and negative infertility cognitions. One in 10 women had a delayed or chronic trajectory and these trajectories predicted serious mental health impairment 11–17 years after treatment. LIMITATIONS, REASONS FOR CAUTION The study only focuses on women. In the OMEGA project adjustment was assessed using a mental health measure. Although we could investigate how trajectories predicted mental health, it would have been preferable to map anxiety and depression trajectories up to 11–17 years after treatment. Missing analysis showed selective dropout from the study but this was accounted for by using mixed models and imputation procedures. Finally, data on other life stressors were not collected; therefore any contribution from these events cannot be assessed. WIDER IMPLICATIONS OF THE FINDINGS Fertility health-care providers have been called upon considering their responsibility in supporting patients in the aftermath of treatment. Results show it is possible to profile different groups of at-risk women at the start of the treatment and tailor psychosocial support to risk profile to promote health adjustment during treatment and thereafter

Screening for subclinical synovial proliferation in haemophilia: A systematic review and meta-analysis comparing physical examination and ultrasound

Introduction: Ultrasound is increasingly used as addition to physical examination for detection of subclinical joint changes in haemophilia. However, the added value of ultrasound to physical examination for detecting synovial proliferation is not fully established. Aim: To determine the diagnostic accuracy of swelling at physical examination for ultrasound-detected synovial proliferation in haemophilia. Methods: PubMed and EMBASE were searched up to 2 August 2022. Studies reporting original data on occurrence of swelling at physical examination and synovial proliferation on ultrasound of index joints in persons with haemophilia were included. Risk of bias and applicability were assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Diagnostic accuracy parameters of swelling at physical examination for ultrasound-detected synovial proliferation were determined. Summary sensitivity and specificity were calculated using a bivariate random-effects model. Results: Fifteen studies reporting on swelling at physical examination and synovial proliferation on ultrasound in 2890 joints of 627 patients were included. Prevalence of subclinical synovial proliferation ranged between 0% and 55%. Sensitivity of swelling was low [summary estimate.34; 95% confidence interval (CI).24-.46], while specificity was high (summary estimate.97; CI.92-.99). Predictive values varied widely due to inter-study differences in prevalence of synovial proliferation. Conclusion: Joint swelling has low sensitivity for presence of ultrasound-detected synovial proliferation in haemophilia, suggesting underestimation of synovial proliferation by physical examination alone. Consequently, ultrasound screening may generate important information on synovial changes which would otherwise remain undetected

Monitoring recovery of joints after bleeding: Physical examination and ultrasound are complementary

AIM: Traditionally, recovery after a joint bleed in people with bleeding disorders is evaluated by clinical symptoms. Following a bleed, however, asymptomatic joints may still show synovial hypertrophy and effusion on ultrasound. We evaluated the duration of full recovery from a joint bleed. Additionally, we determined how recovery differed when assessed by physical examination and ultrasound. METHODS: In this retrospective cohort study, we investigated joint bleeds in elbows, knees and ankles of people with haemophilia or Von Willebrand disease who attended the Van Creveldkliniek between 2016 and 2021. Physical examination (warmth, swelling, range of motion and gait) and ultrasound (effusion and synovial hypertrophy) were performed within 7 days after the onset of the bleed, 1 week after the first examination and monthly thereafter until patients had recovered fully. Joint bleeds were treated in line with the current international treatment guidelines. RESULTS: We evaluated 30 joint bleeds in 26 patients. The median recovery time was 1 month (range 0.3-5 months). In 47% of the joint bleeds, the recovery took longer than 1 month. The moment of recovery based on physical examination and ultrasound differed in 27% of bleeds. Both persistent abnormalities at physical examination in joints with normalized ultrasounds and persistent ultrasound findings in clinically recovered joints occurred. CONCLUSION: Joint bleed recovery can take long and recovery times differed per bleed. Recovery differed when assessed by physical examination or ultrasound. Therefore, both should be used to closely monitor recovery of joint bleeds and offer personalized care