Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome

Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%-53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential

Biopsychosocial Predictors of Quality of Life in Paediatric Patients With Sickle Cell Disease

Sickle cell disease (SCD) refers to a group of inherited blood disorders with considerable morbidity that causes severe pain, reduces life expectancy, and requires significant self-management. Acute painful episodes are the hallmark of SCD, but persistent daily pain is also highly prevalent in this population. Characterising the impact and experience of SCD-related morbidity (i.e., sleep disruption, frequent emergency department visits, cognitive dysfunction) on health-related quality of life (HRQOL) requires multiple assessment methods to best capture the underlying mechanisms. To gain a greater understanding of the effect of common symptom categories on HRQOL and to determine potential pain coping targets, the present study investigated whether demographic, socioeconomic, sleepiness, pain burden, frequency of emergency department (ED) visits, and cognition predicted HRQOL in a paediatric sample of patients with SCD. Our study was a secondary analysis of baseline assessment data of children with SCD aged 8-15 years (n = 30) in the Prevention of Morbidity in Sickle Cell Anaemia Phase 2b (POMSb2) randomised controlled clinical trial of auto-adjusting continuous positive airways pressure. Patients completed cognitive testing (IQ, Processing Speed Index, Delis-Kaplan Executive Function Scale (DKEFS) Tower, Conner's Continuous Performance Test), sleepiness (Epworth Sleepiness Scale), and HRQOL (PedsQL Sickle Cell Module) at baseline. Patients reported pain burden (Sickle Cell Pain Burden Inventory-Youth) each month over 8 visits. Caregivers provided demographic information and reported their child's executive function (Behavioural Rating Inventory of Executive Function) at baseline. Data from our analysis demonstrated that demographic factors (i.e., age, gender, level of neighbourhood deprivation) and treatment variables (i.e., hydroxyurea use) did not independently predict HRQOL, and laboratory values (i.e., haemoglobin, haematocrit, mean oxygen saturation) were not significantly correlated with HRQOL (ps > 0.05). However, sleepiness, pain burden, ED visits, and executive dysfunction independently predicted HRQOL (R 2 = 0.66) with large effects (η2 = 0.16 to 0.32). These findings identify specific, measurable symptom categories that may serve as targets to improve HRQOL that are responsive to change. This knowledge will be useful for multimodal interventions for paediatric patients with SCD that include sleep management, pain coping strategies, and executive function training

A Comparison of MRI Quantitative Susceptibility Mapping and TRUST-Based Measures of Brain Venous Oxygen Saturation in Sickle Cell Anaemia

In recent years, interest has grown in the potential for magnetic resonance imaging (MRI) measures of venous oxygen saturation (Yv) to improve neurological risk prediction. T2-relaxation-under-spin-tagging (TRUST) is an MRI technique which has revealed changes in Yv in patients with sickle cell anemia (SCA). However, prior studies comparing Yv in patients with SCA relative to healthy controls have reported opposing results depending on whether the calibration model, developed to convert blood T2 to Yv, is based on healthy human hemoglobin (HbA), bovine hemoglobin (HbBV) or sickle hemoglobin (HbS). MRI Quantitative Susceptibility Mapping (QSM) is an alternative technique that may hold promise for estimating Yv in SCA as blood magnetic susceptibility is linearly dependent upon Yv, and no significant difference has been found between the magnetic susceptibility of HbA and HbS. Therefore, the aim of this study was to compare estimates of Yv using QSM and TRUST with five published calibration models in healthy controls and patients with SCA. 17 patients with SCA and 13 healthy controls underwent MRI. Susceptibility maps were calculated from a multi-parametric mapping acquisition and Yv was calculated from the mean susceptibility in a region of interest in the superior sagittal sinus. TRUST estimates of T2, within a similar but much smaller region, were converted to Yv using five different calibration models. Correlation and Bland-Altman analyses were performed to compare estimates of Yv between TRUST and QSM methods. For each method, t-tests were also used to explore group-wise differences between patients with SCA and healthy controls. In healthy controls, significant correlations were observed between QSM and TRUST measures of Yv, while in SCA, there were no such correlations. The magnitude and direction of group-wise differences in Yv varied with method. The TRUST-HbBV and QSM methods suggested decreased Yv in SCA relative to healthy controls, while the TRUST-HbS (p < 0.01) and TRUST-HbA models suggested increased Yv in SCA as in previous studies. Further validation of all MRI measures of Yv, relative to ground truth measures such as O15 PET and jugular vein catheterization, is required in SCA before QSM or TRUST methods can be considered for neurological risk prediction

The open future, bivalence and assertion

It is highly intuitive that the future is open and the past is closed—whereas it is unsettled whether there will be a fourth world war, it is settled that there was a first. Recently, it has become increasingly popular to claim that the intuitive openness of the future implies that contingent statements about the future, such as ‘there will be a sea battle tomorrow,’ are non-bivalent (neither true nor false). In this paper, we argue that the non-bivalence of future contingents is at odds with our pre-theoretic intuitions about the openness of the future. These are revealed by our pragmatic judgments concerning the correctness and incorrectness of assertions of future contingents. We argue that the pragmatic data together with a plausible account of assertion shows that in many cases we take future contingents to be true (or to be false), though we take the future to be open in relevant respects. It follows that appeals to intuition to support the non-bivalence of future contingents is untenable. Intuition favours bivalence

A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism

BACKGROUND: As genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting, and life-threatening heart conduction disturbances with wide intra- and inter-familial clinical variability. Roughly half of EDMD patients are linked to six genes encoding nuclear envelope proteins, but the disease mechanism remains unclear because the affected proteins function in both cell mechanics and genome regulation. METHODS: A primer library was generated to test for mutations in 301 genes from four categories: (I) all known EDMD-linked genes; (II) genes mutated in related muscular dystrophies; (III) candidates generated by exome sequencing in five families; (IV) functional candidates - other muscle nuclear envelope proteins functioning in mechanical/genome processes affected in EDMD. This was used to sequence 56 unlinked patients with EDMD-like phenotype. FINDINGS: Twenty-one patients could be clearly assigned: 18 with mutations in genes of similar muscular dystrophies; 3 with previously missed mutations in EDMD-linked genes. The other categories yielded novel candidate genes, most encoding nuclear envelope proteins with functions in gene regulation. INTERPRETATION: Our multi-pronged approach identified new disease alleles and many new candidate EDMD genes. Their known functions strongly argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction due to connectivity of candidates from the nuclear envelope to the plasma membrane. This approach highlights the value of testing for related diseases using primer libraries and may be applied for other genetically heterogeneous orphan diseases. FUNDING: The Wellcome Trust, Muscular Dystrophy UK, Medical Research Council, European Community's Seventh Framework Programme "Integrated European -omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)"

Attitudes About COVID-19 and Health (ATTACH): Online Survey and Mixed Methods Study

Background: Behavioral mitigation strategies to slow the spread of COVID-19 have resulted in sweeping lifestyle changes, with short- and long-term psychological, well-being, and quality of life implications. The Attitudes About COVID-19 and Health (ATTACH) study focuses on understanding attitudes and beliefs while considering the impact on mental and physical health and the influence of broader demographic and geographic factors on attitudes, beliefs, and mental health burden. / Objective: In this assessment of our first wave of data collection, we provide baseline cohort description of the ATTACH study participants in the United Kingdom, the United States, and Mexico. Additionally, we assess responses to daily poll questions related to COVID-19 and conduct a cross-sectional analysis of baseline assessments collected in the UK between June 26 and October 31, 2020. / Methods: The ATTACH study uses smartphone app technology and online survey data collection. Participants completed poll questions related to COVID-19 2 times daily and a monthly survey assessing mental health, social isolation, physical health, and quality of life. Poll question responses were graphed using 95% Clopper–Pearson (exact) tests with 95% CIs. Pearson correlations, hierarchical linear regression analyses, and generalized linear models assessed relationships, predictors of self-reported outcomes, and group differences, respectively. / Results: By October 31, 2020, 1405, 80, and 90 participants had consented to participate in the UK, United States, and Mexico, respectively. Descriptive data for the UK daily poll questions indicated that participants generally followed social distancing measures, but worry and negative impacts on families increased as the pandemic progressed. Although participants generally reported feeling that the reasons for current measures had been made clear, there was low trust that the government was doing everything in its power to meet public needs. In the UK, 1282 participants also completed a monthly survey (94.99% [1326/1396] White, 72.22% [1014/1404] female, and 20.12% [277/1377] key or essential workers); 18.88% (242/1282) of UK participants reported a preexisting mental health disorder, 31.36% (402/1282) reported a preexisting chronic medical illness, and 35.11% (493/1404) were aged over 65; 57.72% (740/1282) of participants reported being more sedentary since the pandemic began, and 41.89% (537/1282) reported reduced access to medical care. Those with poorer mental health outcomes lived in more deprived neighborhoods, in larger households (Ps<.05), had more preexisting mental health disorders and medical conditions, and were younger than 65 years (all Ps<.001). / Conclusions: Communities who have been exposed to additional harm during the COVID-19 pandemic were experiencing worse mental outcomes. Factors including having a medical condition, or living in a deprived neighborhood or larger household were associated with heightened risk. Future longitudinal studies should investigate the link between COVID-19 exposure, mental health, and sociodemographic and residential characteristics

Dialetheism in Action: A New Strategy for Solving the Equal Validity Paradox

This paper starts from the Equal Validity Paradox, a paradoxical argument connected to the so-called phenomenon of faultless disagreement. It is argued that there are at least six strategies for solving the paradox. After presenting the first five strategies and their main problems, the paper focuses on the sixth strategy which rejects the assumption that every proposition cannot be both true a false. Dialetheism is the natural candidate for developing strategy six. After presenting strategy six in detail, we formulate a normative problem for the dialetheist and offer a tentative solution to it. We then elaborate further considerations connecting strategy six to pluralism about truth and logic. Even if strategy six is a hard path to take, its scrutiny highlights some important points on truth, logic and the norms for acceptance and rejection

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial

BACKGROUND: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. METHODS: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. DISCUSSION: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020

Further insights from structural mass spectrometry into endocytosis adaptor protein assemblies

As a fundament in many biologically relevant processes, endocytosis in its different guises has been arousing interest for decades and still does so. This is true for the actual transport and its initiation alike. In clathrin-mediated endocytosis, a comparatively well understood endocytic pathway, a set of adaptor proteins bind specific lipids in the plasma membrane, subsequently assemble and thus form a crucial bridge from clathrin to actin for the ongoing process. These adaptor proteins are highly interesting themselves and the subject of this manuscript. Using many of the instruments that are available now in the mass spectrometry toolbox, we added some facets to the picture of how these minimal assemblies may look, how they form, and what influences the structure. Especially, lipids in the adaptor protein complexes result in reduced charging of a normal sized complex due to their specific binding position. The results further support our structural model of a double ring structure with interfacial lipids

a controlled multicenter study with assessment of echocardiographic reference values, and the frequency of dilatation and aneurysm in Marfan syndrome

Background Echocardiographic upper normal limits of both main pulmonary artery (MPA) diameters (MPA-d) and ratio of MPA to aortic root diameter (MPA-r) are not defined in healthy adults. Accordingly, frequency of MPA dilatation based on echocardiography remains to be assessed in adults with Marfan syndrome (MFS). Methods We enrolled 123 normal adults (72 men, 52 women aged 42 ± 14 years) and 98 patients with MFS (42 men, 56 women aged 39 ± 14 years) in a retrospective cross-sectional observational controlled study in four tertiary care centers. We defined outcome measures including upper normal limits of MPA-d and MPA-r as 95 quantile of normal persons, MPA dilatation as diameters > upper normal limits, MPA aneurysm as diameters >4 cm, and indication for surgery as MPA diameters >6 cm. Results MPA diameters revealed normal distribution without correlation to age, sex, body weight, body height, body mass index and body surface area. The upper normal limit was 2.6 cm (95% confidence interval (CI) =2.44-2.76 cm) for MPA-d, and 1.05 (95% CI = .86–1.24) for MPA-r. MPA dilatation presented in 6 normal persons (4.9%) and in 68 MFS patients (69.4%; P < .001), MPA aneurysm presented only in MFS (15 patients; 15.3%; P < .001), and no patient required surgery. Mean MPA-r were increased in MFS (P 1.05 were equally frequent in 7 normal persons (5%) and in 8 MFS patients (10.5%; P = .161). MPA-r related to aortic root diameters (P = .042), reduced left ventricular ejection fraction (P = .006), and increased pulmonary artery systolic pressures (P = .040). No clinical manifestations of MFS and no FBN1 mutation characteristics related to MPA diameters. Conclusions We established 2.6 cm for MPA-d and 1.05 for MPA-r as upper normal limits. MFS exhibits a high prevalence of MPA dilatation and aneurysm. However, patients may require MPA surgery only in scarce circumstances, most likely because formation of marked MPA aneurysm may require LV dysfunction and increased PASP