The Dutch registry for facioscapulohumeral muscular dystrophy: Cohort profile and longitudinal patient reported outcomes.

Facioscapulohumeral dystrophy (FSHD) is the second most prevalent inherited muscular disorder and currently lacks a pharmaceutical treatment. The Dutch FSHD Registry was initiated in 2015 as a result of an international collaboration on trial readiness. This paper presents the cohort profile and six years of follow-up data of the registered FSHD patients. At the time of self-registration and every six months thereafter, participants were invited to complete a digital survey of patient and disease characteristics and the Dutch versions of the Checklist Individual Strength (CIS20R), the Individualised Neuromuscular Quality of Life Questionnaire (INQoL), the Beck Depression Index - Primary Care and the McGill Pain Questionnaire. From March 2015 to March 2021, 373 participants completed at least one survey. At baseline, fatigue and muscle weakness were the most frequently reported symptoms (median CIS20R sumscore 77 [IQR 60-92], median INQoL Fatigue score 58 [IQR 42-68] and median INQoL weakness score 58 [IQR 42-68]). Pain was experienced most often in the head and shoulder region (193, 52%). Nineteen of the 23 (sub)sections of questionnaires showed no significant changes over time. We conclude that the Dutch FSHD Registry was successfully set up, enabling collection of longitudinal data and facilitating recruitment in several studies.

ECG criteria for the detection of high-risk cardiovascular conditions in master athletes.

OBJECTIVE: Structured electrocardiography (ECG) analysis is used to screen athletes for high-risk cardiovascular conditions (HRCC) to prevent sudden cardiac death. ECG criteria have been specified and recommended for use in young athletes ≤ 35 years. However, it is unclear whether these ECG criteria can also be applied to master athletes >35 years. AIM: The purpose of this study was to test whether the existing ECG criteria for detecting HRCC in young athletes can be applied to master athletes. METHODS: We conducted a cross-sectional study among athletes >35 years screened for HRCC between 2006 and 2010. We performed a blinded retrospective analysis of master athletes' ECGs, separately applying European Society of Cardiology (ESC)-2005, Seattle, and International criteria. HRCC were defined using recommendations from the international cardiac societies American Heart Association and American College of Cardiology, and ESC, based on ECG screening and cardiovascular evaluation (CVE). RESULTS: We included 2578 master athletes in the study, of whom 494 had initial screening abnormalities mandating CVE. Atrial enlargement (109, 4.1%) and left ventricular hypertrophy (98, 3.8%) were the most common ECG abnormalities found using the ESC-2005 or Seattle criteria. Applying the International criteria, ST-segment deviation (66, 2.6%), and T-wave inversion (58, 2.2%) were most frequent. The ESC-2005 criteria detected more HRCC (46, 1.8%) compared with the Seattle (36, 1.4%) and International criteria (33, 1.3%). The most frequently detected HRCC was coronary artery disease (24, 0.9%). CONCLUSION: ECG criteria recommended for use in young athletes can be applied to master athletes' ECGs to detect HRCC. The ESC-2005 criteria had the highest sensitivity for detecting HRCC among master athletes.

Growth rate of invasive ductal carcinomas from a screened 50-74-year-old population.

Objective As breast cancer growth rate is associated with menopause, most screening programmes target mainly women aged 50-74. We studied the association between age at diagnosis and growth rate in this screening-specific age range. Methods We used data from breast cancer patients diagnosed in the screening programme in Nijmegen, the Netherlands. The data were restricted to the screening rounds when analogue mammography was used in both the screening and clinical setting. Growth rate expressed as tumour volume doubling time was based on increasing tumour size in longitudinal series of mammograms. Estimates were based on (a) tumours showing at least two measurable shadows, (b) tumours showing a shadow at detection only (left censored), and (c) tumours showing no growth (right-censored observation). All 293 tumours were consecutively diagnosed invasive ductal breast cancers in participants of the Nijmegen screening programme in the period 2000-2007. Results Depending on the assumptions made on tumour margins and mammographic density, the relation of volume doubling time with age non-significantly varies from a decrease of 3.3% to an increase of 1.4% for each year increase in age at diagnosis (all P-values ≥ 0.18). Applying left censoring on indistinct tumours, the geometric mean volume doubling time was 191 days (95% confidence interval 158-230). Conclusion We found no significant change in growth rate with age in women diagnosed with invasive ductal breast cancer in the screening age range 50-74. This outcome does not support differential screening intervals by age based solely on breast cancer growth rate for this particular group.

Overdiagnosis in cancer screening: the need for a standardized denominator.

It is widely accepted that overdiagnosis is a major harm of screening, but its extent is still topic of controversy. This is partly the result of incomparable overdiagnosis estimates in scientific literature, as a variety of denominators are used to calculate the percentage of overdiagnosis in cancer screening. We propose to use the following denominator to calculate the percentage of overdiagnosis: 'all cancers detected during the screening period, both interval and screen-detected, in participants of a screening programme'. This denominator is more appropriate than existing denominators because it presents overdiagnosis as a real percentage, is unaffected by attendance percentages, is applicable to all observational study designs, and can be easily recalculated to absolute numbers. This denominator can be widely applied and increases comparability between overdiagnosis estimates, which is needed to correctly present the balance between the benefits and harms of screening.

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy.

Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C --> T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance.