Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy

Two populations of X-ray pulsars produced by two types of supernovae

Two types of supernova are thought to produce the overwhelming majority of neutron stars in the Universe. The first type, iron-core collapse supernovae, occurs when a high-mass star develops a degenerate iron core that exceeds the Chandrasekhar limit. The second type, electron-capture supernovae, is associated with the collapse of a lower-mass oxygen-neon-magnesium core as it loses pressure support owing to the sudden capture of electrons by neon and/or magnesium nuclei. It has hitherto been impossible to identify the two distinct families of neutron stars produced in these formation channels. Here we report that a large, well-known class of neutron-star-hosting X-ray pulsars is actually composed of two distinct sub-populations with different characteristic spin periods, orbital periods and orbital eccentricities. This class, the Be/X-ray binaries, contains neutron stars that accrete material from a more massive companion star. The two sub-populations are most probably associated with the two distinct types of neutron-star-forming supernovae, with electron-capture supernovae preferentially producing system with short spin period, short orbital periods and low eccentricity. Intriguingly, the split between the two sub-populations is clearest in the distribution of the logarithm of spin period, a result that had not been predicted and which still remains to be explaine

Dose dense 1 week on/1 week off temozolomide in recurrent glioma: a retrospective study

Alternative temozolomide regimens have been proposed to overcome O6-methylguanine-DNA methyltransferase mediated resistance. We investigated the efficacy and tolerability of 1 week on/1 week off temozolomide (ddTMZ) regimen in a cohort of patients treated with ddTMZ between 2005 and 2011 for the progression of a glioblastoma during or after chemo-radiation with temozolomide or a recurrence of another type of glioma after radiotherapy and at least one line of chemotherapy. Patients received ddTMZ at 100–150 mg/m2/d (days 1–7 and 15–21 in cycles of 28-days). All patients had a contrast enhancing lesion on MRI and the response was assessed by MRI using the RANO criteria; complete and partial responses were considered objective responses. Fifty-three patients were included. The median number of cycles of ddTMZ was 4 (range 1–12). Eight patients discontinued chemotherapy because of toxicity. Two of 24 patients with a progressive glioblastoma had an objective response; progression free survival at 6 months (PFS-6) in glioblastoma was 29%. Three of the 16 patients with a recurrent WHO grade 2 or 3 astrocytoma or oligodendroglioma or oligo-astrocytoma without combined 1p and 19q loss had an objective response and PFS-6 in these patients was 38%. Four out of the 12 evaluable patients with a recurrent WHO grade 2 or 3 oligodendroglioma or oligo-astrocytoma with combined 1p and 19q loss had an objective response; PFS-6 in these patients was 62%. This study indicates that ddTMZ is safe and effective in recurrent glioma, despite previous temozolomide and/or nitrosourea chemotherapy. Our data do not suggest superior efficacy of this schedule as compared to the standard day 1–5 every 4 weeks schedule

The Connectome Visualization Utility: Software for Visualization of Human Brain Networks

In analysis of the human connectome, the connectivity of the human brain is collected from multiple imaging modalities and analyzed using graph theoretical techniques. The dimensionality of human connectivity data is high, and making sense of the complex networks in connectomics requires sophisticated visualization and analysis software. The current availability of software packages to analyze the human connectome is limited. The Connectome Visualization Utility (CVU) is a new software package designed for the visualization and network analysis of human brain networks. CVU complements existing software packages by offering expanded interactive analysis and advanced visualization features, including the automated visualization of networks in three different complementary styles and features the special visualization of scalar graph theoretical properties and modular structure. By decoupling the process of network creation from network visualization and analysis, we ensure that CVU can visualize networks from any imaging modality. CVU offers a graphical user interface, interactive scripting, and represents data uses transparent neuroimaging and matrix-based file types rather than opaque application-specific file formats

Entangled-State Cycles of Atomic Collective-Spin States

We study quantum trajectories of collective atomic spin states of $N$ effective two-level atoms driven with laser and cavity fields. We show that interesting ``entangled-state cycles'' arise probabilistically when the (Raman) transition rates between the two atomic levels are set equal. For odd (even) $N$, there are $(N+1)/2$ ($N/2$) possible cycles. During each cycle the $N$-qubit state switches, with each cavity photon emission, between the states $(|N/2,m>\pm |N/2,-m>)/\sqrt{2}$, where $|N/2,m>$ is a Dicke state in a rotated collective basis. The quantum number $m$ ($>0$), which distinguishes the particular cycle, is determined by the photon counting record and varies randomly from one trajectory to the next. For even $N$ it is also possible, under the same conditions, to prepare probabilistically (but in steady state) the Dicke state $|N/2,0>$, i.e., an $N$-qubit state with $N/2$ excitations, which is of particular interest in the context of multipartite entanglement.Comment: 10 pages, 9 figure

Insights into adherence to medication and lifestyle recommendations in an international cohort of patients with catecholaminergic polymorphic ventricular tachycardia.

AIMS: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT. METHODS AND RESULTS: An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22-50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3-12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6-31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1-1.3, P < 0.001) were independently associated with non-adherence. CONCLUSION: The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education

Structural basis for CRISPR RNA-guided DNA recognition by Cascade

The CRISPR (clustered regularly interspaced short palindromic repeats) immune system in prokaryotes uses small guide RNAs to neutralize invading viruses and plasmids. In Escherichia coli, immunity depends on a ribonucleoprotein complex called Cascade. Here we present the composition and low-resolution structure of Cascade and show how it recognizes double-stranded DNA (dsDNA) targets in a sequence-specific manner. Cascade is a 405-kDa complex comprising five functionally essential CRISPR-associated (Cas) proteins (CasA1B2C6D1E1) and a 61-nucleotide CRISPR RNA (crRNA) with 5′-hydroxyl and 2′,3′-cyclic phosphate termini. The crRNA guides Cascade to dsDNA target sequences by forming base pairs with the complementary DNA strand while displacing the noncomplementary strand to form an R-loop. Cascade recognizes target DNA without consuming ATP, which suggests that continuous invader DNA surveillance takes place without energy investment. The structure of Cascade shows an unusual seahorse shape that undergoes conformational changes when it binds target DNA.

Cost-effectiveness of postural exercise therapy versus physiotherapy in computer screen-workers with early non-specific work-related upper limb disorders (WRULD); a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Exercise therapies generate substantial costs in computer workers with non-specific work-related upper limb disorders (WRULD).</p> <p>Aims</p> <p>To study if postural exercise therapy is cost-effective compared to regular physiotherapy in screen-workers with early complaints, both from health care and societal perspective.</p> <p>Methods</p> <p>Prospective randomized trial including cost-effectiveness analysis; one year follow-up. Participants: Eighty-eight screen-workers with early non-specific WRULD; six drop-outs. Interventions: A ten week postural exercise program versus regular physiotherapy. Outcome measures: Effectiveness measures: Pain: visual analogous scale (VAS), self-perceived WRULD (yes/no). Functional outcome: Disabilities of Arm, Shoulder and Hand- Dutch Language Version (DASH-DLV). Quality of life outcome: EQ-5D.</p> <p>Economic measures: health care costs including patient and family costs and productivity costs resulting in societal costs. Cost-effectiveness measures: health care costs and societal costs related to the effectiveness measures. Outcome measures were assessed at baseline; three, six and twelve months after baseline.</p> <p>Results</p> <p>At baseline both groups were comparable for baseline characteristics except scores on the Pain Catastrophizing Scale and comparable for costs. No significant differences between the groups concerning effectiveness at one year follow-up were found. Effectiveness scores slightly improved over time. After one year 55% of participants were free of complaints. After one year the postural exercise group had higher mean total health care costs, but lower productivity costs compared to the physiotherapy group. Mean societal costs after one year (therefore) were in favor of postural exercise therapy [- €622; 95% CI -2087; +590)]. After one year, only self- perceived WRULD seemed to result in acceptable cost-effectiveness of the postural exercise strategy over physiotherapy; however the probability of acceptable cost-effectiveness did not exceed 60%.</p> <p>Considering societal costs related to QALYs, postural exercise therapy had a probability of over 80% to be cost-effective over a wide range of cost-effectiveness ceiling ratios; however based on a marginal QALY-difference of 0.1 over a 12 month time frame.</p> <p>Conclusion</p> <p>Although our trial failed to find significant differences in VAS, QALYs and ICERs based on VAS and QALYs at one-year follow-up, CEACs suggest that postural exercise therapy according to Mensendieck/Cesar has a higher probability of being cost-effective compared to regular physiotherapy; however further research is required.</p> <p>Trial registration</p> <p>ISRCTN 15872455</p

Interventions to prevent disability in frail community-dwelling elderly: a systematic review

<p>Abstract</p> <p>Background</p> <p>There is an interest for intervention studies aiming at the prevention of disability in community-dwelling physically frail older persons, though an overview on their content, methodological quality and effectiveness is lacking.</p> <p>Methods</p> <p>A search for clinical trials involved databases PubMed, CINAHL and Cochrane Central Register of Controlled Trials and manually hand searching. Trials that included community-dwelling frail older persons based on physical frailty indicators and used disability measures for outcome evaluation were included. The selection of papers and data-extraction was performed by two independent reviewers. Out of 4602 titles, 10 papers remained that met the inclusion criteria. Of these, 9 were of sufficient methodological quality and concerned 2 nutritional interventions and 8 physical exercise interventions.</p> <p>Results</p> <p>No evidence was found for the effect of nutritional interventions on disability measures. The physical exercise interventions involved 2 single-component programs focusing on lower extremity strength and 6 multi-component programs addressing a variety of physical parameters. Out of 8 physical exercise interventions, three reported positive outcomes for disability. There was no evidence for the effect of single lower extremity strength training on disability. Differences between the multi-component interventions in e.g. individualization, duration, intensity and setting hamper the interpretation of the elements that consistently produced successful outcomes.</p> <p>Conclusion</p> <p>There is an indication that relatively long-lasting and high-intensive multicomponent exercise programs have a positive effect on ADL and IADL disability for community-living moderate physically frail older persons. Future research into disability prevention in physical frail older persons could be directed to more individualized and comprehensive programs.</p

A New Method for Morphometric Analysis of Tissue Distribution of Mobile Cells in Relation to Immobile Tissue Structures

The distribution of cells in stained tissue sections provides information that may be analyzed by means of morphometric computation. We developed an algorithm for automated analysis for the purpose of answering questions pertaining to the relative densities of wandering cells in the vicinity of comparatively immobile tissue structures such as vessels or tumors. As an example, we present the analysis of distribution of CD56-positive cells and of CXCR3-positive cells (relative densities of peri-vascular versus non-vascular cell populations) in relation to the endothelium of capillaries and venules of human parietal decidua tissue of first trimester pregnancy. In addition, the distibution of CD56-positive cells (mostly uterine NK cells) in relation to spiral arteries is analyzed. The image analysis is based on microphotographs of two-color immunohistological stainings. Discrete distances (10–50 µm) from the fixed structures were chosen for the purpose of definining the extent of neighborhood areas. For the sake of better comparison of cell distributions at different overall cell densities a model of random distribution of “cells” in relation to neighborhood areas and rest decidua of a specific sample was built. In the chosen instances, we found increased perivascular density of CD56-positive cells and of CXCR3-positive cells. In contrast, no accumulation of CD56-positive cells was found in the neighborhood of spiral arteries