Arrhythmias and cardiac MRI associations in patients with established cardiac dystrophinopathy.

AIMS: Some patients with cardiac dystrophinopathy die suddenly. Whether such deaths are preventable by specific antiarrhythmic management or simply indicate heart failure overwhelming medical therapies is uncertain. The aim of this prospective, cohort study was to describe the occurrence and nature of cardiac arrhythmias recorded during prolonged continuous ECG rhythm surveillance in patients with established cardiac dystrophinopathy and relate them to abnormalities on cardiac MRI. METHODS AND RESULTS: A cohort of 10 patients (36.3 years; 3 female) with LVEF<40% due to Duchenne (3) or Becker muscular (4) dystrophy or Duchenne muscular dystrophy-gene carrying effects in females (3) were recruited, had cardiac MRI, ECG signal-averaging and ECG loop-recorder implants. All were on standard of care heart medications and none had prior history of arrhythmias.No deaths or brady arrhythmias occurred during median follow-up 30 months (range 13-35). Self-limiting episodes of asymptomatic tachyarrhythmia (range 1-29) were confirmed in 8 (80%) patients (ventricular only 2; ventricular and atrial 6). Higher ventricular arrhythmia burden correlated with extent of myocardial fibrosis (extracellular volume%, p=0.029; native T1, p=0.49; late gadolinium enhancement, p=0.49), but not with LVEF% (p=1.0) on MRI and atrial arrhythmias with left atrial dilatation. Features of VT episodes suggested various underlying arrhythmia mechanisms. CONCLUSIONS: The overall prevalence of arrhythmias was low. Even in such a small sample size, higher arrhythmia counts occurred in those with larger scar burden and greater ventricular volume, suggesting key roles for myocardial stretch as well as disease progression in arrhythmogenesis. These features overlap with the stage of left ventricular dysfunction when heart failure also becomes overt. The findings of this pilot study should help inform the design of a definitive study of specific antiarrhythmic management in dystrophinopathy. TRIAL REGISTRATION NUMBER: ISRCTN15622536.

Managing multiple sclerosis in individuals aged 55 and above: a comprehensive review.

Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic.

Salt-rich versus salt-poor structural scenarios in the central Northern Calcareous Alps: implications for the Hallstatt facies and early Alpine tectonic evolution (Eastern Alps, Austria).

One of the most remarkable features of the central Northern Calcareous Alps (Eastern Alps, Austria) is the widespread presence of Upper Triassic deep-water carbonates (the Hallstatt facies) and Permo-Triassic evaporites resting on deep-water Middle Jurassic strata and their underlying Upper Triassic shallow-water carbonate platform successions. The Hallstatt facies and accompanying evaporites have been classically interpreted to originate either from a location south of the time-equivalent carbonate platforms, or to have been deposited in deeper water seaways within the broad platform domain. To date, this dispute has been addressed mostly through the analysis of Triassic and Jurassic facies distribution in map view, which, however, is subject to some degree of ambiguity and subjectivity. In this contribution we present, for the first time, sequentially restored regional cross-sections through the central Northern Calcareous Alps to understand the implications of the contrasting paleogeographic models. We present (a) an interpretation based on a highly allochthonous origin of the Triassic deep-water units and (b) an interpretation based on their relative autochthony in which we incorporate the potential influence of salt tectonics in the central NCA. The restored cross-sections provide a framework within which the alternative scenarios and their paleogeographic implications can be better understood. Through this analysis we propose that salt tectonics in the central NCA can provide a valid explanation for apparent inconsistencies in the relative autochthony scenario and thus constitutes a reasonable alternative to the currently accepted allochthony scenario.

Identification of a Potential Entry-Fusion Complex Based on Sequence Homology of African Swine Fever and Vaccinia Virus.

African swine fever virus (ASFV) belongs to the family of Asfarviridae, part of the group of nucleocytoplasmic large DNA viruses (NCLDV). Little is known about the internalization of ASFV in the host cell and the fusion membrane events that take place at early stages of the infection. Poxviruses, also members of the NCLDV and represented by vaccinia virus (VACV), are large, enveloped, double-stranded DNA viruses. Poxviruses were considered unique in having an elaborate entry-fusion complex (EFC) composed of 11 highly conserved proteins integrated into the membrane of mature virions. Recent advances in methodological techniques have again revealed several connections between VACV EFC proteins. In this study, we explored the possibility of an analogous ASFV EFC by identifying ten candidate proteins exhibiting structural similarities with VACV EFC proteins. This could reveal key functions of these ASFV proteins, drawing attention to shared features between the two virus families, suggesting the potential existence of an ASFV entry-fusion complex.

Preventive interventions for children and adolescents of parents with mental illness: A systematic review.

BACKGROUND: Children of parents with mental disorders have a relatively high risk of developing a mental illness or behavioural disorder. OBJECTIVE: The aim of this systematic review was to evaluate the efficacy of preventive psychotherapeutic interventions in children of parents with mental illness. In particular, the development of mental illness and/or psychological symptomatology in this population was assessed. METHOD: This qualitative systematic review looked at interventions targeting children aged 4-18 years without a diagnosed mental disorder, alone or with their families, with a parent with a diagnosed mental disorder. The protocol was pre-registered in Open Science Framework. A total of 1255 references were retrieved from MEDLINE, PsychArticles, PsycINFO, Springer Link, Science Direct, Scopus and WOS databases, and 12 references from grey literature. This search was replicated by an external reviewer. RESULTS: Fifteen studies involving 1941 children and 1328 parents were included. Interventions were based on cognitive-behavioural and/or psychoeducational components, including six randomized controlled trials. Internalizing symptomatology was assessed in 80% of the studies, externalizing and prosocial behaviour in 47%, and coping style in 33%. Only two studies measured the future risk of developing a mental disorder (ORs of 2.37 and 6.6). There was variability in the format of the intervention (group; family) as well as in the type of intervention and its duration (from one session to 12 sessions). CONCLUSIONS: Interventions for children of parents with mental disorder were clinically and statistically significant, especially in preventing internalizing symptomatology at one-year follow-up, with effect sizes ranging from d = -0.28 to 0.57 (95% CI).

Durable ventricular assist device in Spain (2007-2020). First report of the REGALAD registry.

INTRODUCTION AND OBJECTIVES: This report presents the clinical characteristics, outcomes and complications of all consecutive patients implanted with a long-term mechanical circulatory support device in Spain between 2007 and 2020. METHODS: Analysis of the Spanish Registry of durable ventricular assist devices (REGALAD) including data form Spanish centers with a mechanical circulatory support program. RESULTS: During the study period, 263 ventricular assist devices were implanted in 22 hospitals. The implanted device was an isolated continuous-flow left ventricular assist device in 182 patients (69%), a pulsatile-flow device (58 isolated left ventricular and 21 biventricular) in 79 (30%), and a total artificial heart in 2 patients (1%). The strategy of the implant was as bridge to heart transplant in 78 patients (30%), bridge to candidacy in 110 (42%), bridge to recovery in 3 (1%) and destination therapy in 72 patients (27%). Overall survival at 6, 12 and 24 months was 79%, 74% and 69%, respectively, and was better in continuous-flow left ventricular assist devices (84%, 80%, and 75%). The main adverse events related to this therapy were infections (37% of patients), bleeding (35%), neurological (29%), and device malfunction (17%). CONCLUSIONS: Durable ventricular assist devices have emerged in Spain in the last few years as a useful therapy for patients with advanced heart failure. As in other international registries, the current trend is to use continuous-flow intracorporeal left ventricular devices, which are associated with better results. Adverse events continue to be frequent and severe.

Risk of complications after a non-ST segment elevation acute myocardial infarction in a Latin-American cohort: An application of the ACTION ICU score.

BACKGROUND: European Society of Cardiology (ESC) guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation (NSTEMI) recommend Intensive Care Unit (ICU) surveillance during the first 24-48 h. Interestingly, the in-hospital mortality of NSTEMI patients has consistently decreased, giving some patients the option to be managed in general hospital wards. The ACTION ICU score has been proposed to identify high-risk patients with NSTEMI and guide the selective risk-based need for ICU care. OBJECTIVE: To evaluate the usefulness of the ACTION ICU score to predict patients' risk of developing complications requiring ICU care in a Latin-American cohort with NSTEMI. METHODS: We applied the ACTION ICU score in a retrospective cohort. A composite primary outcome included: cardiorespiratory arrest, shock, high-grade atrio-ventricular block, respiratory failure, stroke, or death. The predictive performance of this model was estimated with a conditional multivariable logistic regression analysis. RESULTS: Of 1,062 patients with NSTEMI, the primary outcome was present in 75 patients (7.1%), and 1,019 (96%) were admitted to ICU. The most common event was respiratory failure (4.0%), followed by cardiogenic shock (3.7%), and cardiac arrest (1.7%). The presence of heart failure signs or symptoms had the highest association with the primary outcome (OR:2.16; 95%CI:1.61-2.92). The best cut-off point for this population was 3 (complications risk: 4.0%, SEN:96%, SP:15.4%, NPV:98.1%, PPV:7.9%). CONCLUSION: The ACTION ICU score may be a promising tool to identify the need for ICU care in Latin-American patients with NSTEMI. Furthermore, additional research is needed to evaluate the cost-effectiveness of this strategy.

Emplacement and associated sedimentary record of the Jurassic submarine salt allochthon of the Wurzeralm (Eastern Alps, Austria).

A fossil salt sheet emplaced in the Jurassic in submarine conditions is described in the Eastern Alps of Austria, providing unique insights into the emplacement of similar submarine structures and their potential control on depositional systems. The salt sheet is a plug-fed extrusion emplaced due to squeezing of a salt diapir under compression. The preserved mylonitic shear fabric in the evaporites indicates radial, south-directed emplacement of the salt sheet. Tectono-sedimentary relationships record the evolution of the salt structure, from initial diapiric growth, to salt sheet extrusion and posterior collapse. Syn-extrusion sediments record the variable bathymetry of the extruding salt sheet, with reefal carbonates building up on the crestal bulge while their deeper water equivalents accumulated on the extruding salt lobe. This is the first description of a salt allochthon still linked to its source diapir in the Eastern Alps.

On the emergence of the correlation between life expectancy and the variance in the age at death.

Recent empirical studies have found various patterns in the correlations between lifespan inequality and life expectancy in modern human populations. However, it is unclear how general these regularities are. Here we establish three theorems that provide theoretical foundations for such regularities. We show that for populations with a finite maximum lifespan ω, and under certain continuity assumptions, the variance in the age at death is bounded by a function of lifespan that has a maximum and tends to zero as life expectancy tends to zero and ω. We show how the change in said variance is determined by a particular interplay between the coefficient of variation and the mean age in the population. These results lead to three hypotheses-a three-phased pattern of change for the correlation between the variance and life expectancy, a particular shape of the associated variance function, and that survival curve Type is one driver of the pattern. We illustrate those hypotheses empirically via a study of the 10 countries in the Human Mortality Database with the oldest available data. Our results elucidate the emergence of the aforementioned correlation patterns and provide demographically meaningful conditions under which those correlations reverse.

A new Algorithm for Detecting Clinical High Risk of Psychosis in Adolescents.

BACKGROUND: The delimitation of the clinical high risk of psychosis (CHRp) is characterized by the wide variety of symptoms assessed from different approaches from the onset of psychosis. This study aimed to create a systematic procedure for an effective and accurate earlydetection of CHRp in educational settings. METHOD: A representative sample of 1,824 adolescents (average age, 15.79; 53.8%, women) was used to develop an online assessment system and a new 3-track, 3-level algorithm that combines symptoms of the main risk approaches: ultra-high risk (UHR), basic symptoms (BS), and anomalies in the subjective self-experience (ASE) with functional deficit. RESULTS: The acceptability and feasibility of the online screening system were confirmed by the data. Of the total participants, 68 (3.7%) were identified as high-risk and 417 (22.9%) were identified as moderate, which also supports the functionality of the proposed algorithm. CONCLUSIONS: The system indicates a dynamic model of progression of the different symptoms in the early stages of psychosis, and it may constitute a first line of identification for severe mental disorders in young people in the earliest stages, allowing application of initial preventive measures.

Advancing Key Gaps in the Knowledge of Plasmodium vivax Cryptic Infections Using Humanized Mouse Models and Organs-on-Chips.

Plasmodium vivax is the most widely distributed human malaria parasite representing 36.3% of disease burden in the South-East Asia region and the most predominant species in the region of the Americas. Recent estimates indicate that 3.3 billion of people are under risk of infection with circa 7 million clinical cases reported each year. This burden is certainly underestimated as the vast majority of chronic infections are asymptomatic. For centuries, it has been widely accepted that the only source of cryptic parasites is the liver dormant stages known as hypnozoites. However, recent evidence indicates that niches outside the liver, in particular in the spleen and the bone marrow, can represent a major source of cryptic chronic erythrocytic infections. The origin of such chronic infections is highly controversial as many key knowledge gaps remain unanswered. Yet, as parasites in these niches seem to be sheltered from immune response and antimalarial drugs, research on this area should be reinforced if elimination of malaria is to be achieved. Due to ethical and technical considerations, working with the liver, bone marrow and spleen from natural infections is very difficult. Recent advances in the development of humanized mouse models and organs-on-a-chip models, offer novel technological frontiers to study human diseases, vaccine validation and drug discovery. Here, we review current data of these frontier technologies in malaria, highlighting major challenges ahead to study P. vivax cryptic niches, which perpetuate transmission and burden.

Quantizing Chaplygin Hamiltonizable nonholonomic systems.

In this article we develop a quantization procedure for Chaplygin Hamiltonizable nonholonomic systems-mechanical systems subject to non-integrable velocity constraints whose reduced mechanics is Hamiltonian after a suitable time reparametrization-using Poincaré transformations and geometric quantization. We illustrate the theory developed through examples and discuss potential applications to the study of the quantum mechanics of nanovehicles.

How to Get Away with Gradients.

Biomolecular gradients are widely present in multiple biological processes. Historically they were reproduced in vitro by using micropipettes, Boyden and Zigmond chambers, or hydrogels. Despite the great utility of these setups in the study of gradient-related problems such as chemotaxis, they face limitations when trying to translate more complex in vivo-like scenarios to in vitro systems. In the last 20 years, the advances in manufacturing of micromechanical systems (MEMS) had opened the possibility of applying this technology to biology (BioMEMS). In particular, microfluidics has proven extremely efficient in setting-up biomolecular gradients which are stable, controllable, reproducible and at length scales that are relevant to cells. In this chapter, we give an overview of different methods to generate molecular gradients using microfluidics, then we discuss the different steps of the pipeline to fabricate a gradient generator microfluidic device, and at the end, we show an application example of the fabrication of a microfluidic device that can be used to generate a surface-bound biomolecular gradient.

A real-world evidence study of nabiximols in multiple sclerosis patients with resistant spasticity: Analysis in relation to the newly described 'spasticity-plus syndrome'.

BACKGROUND AND PURPOSE: Nabiximols is a therapeutic option for patients with multiple sclerosis (MS) spasticity whose symptoms are poorly controlled by conventional oral first-line medications. This study aimed to assess the relationship between changes in spasticity severity (measured on the 0-10 numeric rating scale [NRS]) and the presence of associated symptoms in patients treated with nabiximols, and to investigate the presence of the newly described 'spasticity-plus syndrome'. METHODS: We analyzed real-world data from the Italian Medicines Agency e-Registry on 1138 patients with MS spasticity who began treatment with nabiximols. Evaluation time points were baseline, 4 weeks, and 3, 6, 12 and 18 months after treatment start. RESULTS: Common symptoms associated with MS spasticity in this cohort were pain (38.4% at baseline), sleep disturbances (32.7%), and spasms/cramps (28.5%). Pain was frequently clustered with sleep disturbances (57.2% of pain cases) and spasms/cramps (43.9%). Approximately one-third of patients with data at all evaluation time points maintained treatment at 18 months. Nabiximols reduced the baseline mean spasticity 0-10 NRS score by 24.6% at Week 4, and by 33.9% at 18 months in treatment continuers. Nabiximols resolved a range of MS spasticity-associated symptoms at Week 4, and after 18 months in treatment continuers. CONCLUSION: This real-world analysis supports the concept of a spasticity-plus syndrome and suggests that nabiximols can favorably impact a range of spasticity-associated symptoms.

Under-graduate nursing students working during the first outbreak of the COVID-19 pandemic: A qualitative study of psychosocial effects and coping strategies.

BACKGROUND: The first wave of the COVID-19 pandemic caused a shortage of health care staff, forcing the hiring of senior nursing students. AIMS: To describe the psychosocial impact and coping strategies used by nursing students during the first outbreak of the COVID-19 pandemic and to understand the coping strategies they employed. METHOD: A qualitative exploratory study was conducted, based on Sandelowski's proposal. Purposive sampling was carried out to recruit 18 students hired during the pandemic. The students were interviewed between 18 March and 15 June 2020. Semi-structured interviews were conducted using a digital platform. An inductive thematic analysis was performed. FINDINGS: The students lived alone and isolated during their contract to protect their cohabitants from possible contagion. The impact of working during the pandemic leads to experiences of stress, insomnia, nightmares and anxiety. Nursing students coped with the emotional burden through mental disconnection and the support of co-workers and family members. CONCLUSION: Psychological support and tutoring should be provided by health centres. In addition, in these special circumstances, universities should adapt the training provided.

Streambed microbial communities in the transition zone between groundwater and a first-order stream as impacted by bidirectional water exchange.

The input of nitrate and other agricultural pollutants in higher-order streams largely derives from first-order streams. The streambed as the transition zone between groundwater and stream water has a decisive impact on the attenuation of such pollutants. This reactivity is not yet well understood for lower-order agricultural streams, which are often anthropogenically altered and lack the streambed complexity allowing for extensive hyporheic exchange. Reactive hot spots in such streambeds have been hypothesized as a function of hydrology, which controls the local gaining (groundwater exfiltration) or losing (infiltration) of stream water. However, streambed microbial communities and activities associated with such reactive zones remain mostly uncharted. In this study, sediments of a first-order agriculturally impacted stream in southern Germany were investigated. Along with a hydraulic dissection of distinct gaining and losing reaches of the stream, community composition and the abundance of bacterial communities in the streambed were investigated using PacBio long-read sequencing of bacterial 16S rRNA gene amplicons, and qPCR of bacterial 16S rRNA and denitrification genes (nirK and nirS). We show that bidirectional water exchange between groundwater and the stream represents an important control for sediment microbiota, especially for nitrate-reducing populations. Typical heterotrophic denitrifiers were most abundant in a midstream net losing section, while up- and downstream net gaining sections were associated with an enrichment of sulfur-oxidizing potential nitrate reducers affiliated with Sulfuricurvum and Thiobacillus spp. Dispersal-based community assembly was found to dominate such spots of groundwater exfiltration. Our results indicate a coupling of N- and S-cycling processes in the streambed of an agricultural first-order stream, and a prominent control of microbiology by hydrology and hydrochemistry in situ. Such detailed local heterogeneities in exchange fluxes and streambed microbiomes have not been reported to date, but seem relevant for understanding the reactivity of lower-order streams.

Ventricular assist devices in transposition and failing systemic right ventricle: role of tricuspid valve replacement.

OBJECTIVES: Ventricular assist device (VAD) for systemic right ventricular (RV) failure patients post-atrial switch, for transposition of the great arteries (TGA), and those with congenitally corrected TGA has proven useful to reduce transpulmonary gradient and bridge-to-transplantation. The purpose of this study is to describe our experience of VAD in systemic RV failure and our move towards concomitant tricuspid valve replacement (TVR). METHODS: This is a single-centre retrospective study of consecutive adult patients receiving HeartWare VAD for systemic RV failure between 2010 and 2019. From 2017, concomitant TVR was performed routinely. Demographic, clinical variables and echocardiographic and haemodynamic measurements pre- and post-VAD implantation were recorded. Complications on support, heart transplantation and survival rates were described. RESULTS: Eighteen patients underwent VAD implantation. Moderate or severe systemic tricuspid regurgitation was present in 83.3% of patients, and subpulmonic left ventricular impairment in 88.9%. One-year survival was 72.2%. VAD implantation was technically feasible and successful in all but one. Post-VAD, transpulmonary gradient fell from 16 (15-22) to 10 (7-13) mmHg (P = 0.01). Patients with TVR (n = 6) also demonstrated a reduction in mean pulmonary and wedge pressures. Furthermore, subpulmonic left ventricular end-diastolic dimension (44.3 vs 39.6 mm; P = 0.03) and function improved in this group. After 1 year of support, 72.2% of patients were suitable for transplantation. CONCLUSIONS: VAD is an effective strategy as bridge-to-candidacy and bridge-to-transplantation in patients with end-stage systemic RV failure. Concomitant TVR at the time of implant is associated with better early haemodynamic and echocardiographic results post-VAD.

Hippocampal infarction: redefining transient global amnesia.

BACKGROUND AND AIMS: Transient global amnesia (TGA) is a clinical syndrome characterized by sudden anterograde amnesia not accompanied by other neurological symptoms. There is no consensus on the underlying pathophysiological mechanism. However, diffusion-weighted imaging (DWI) of the magnetic resonance imaging (MRI) has demonstrated hippocampal lesions in as many as 50% of cases. This paper describes a series of patients with TGA and hippocampal lesions. METHODS: This study assessed vascular risk factors in patients older than age 18 admitted to the Hospital Universitario San Ignacio, Bogota, Colombia, from May 2017 to June 2020 with a diagnosis of TGA and evidence of hippocampal ischemic lesion on 3 Tesla brain MRI. RESULTS: The authors identified 36 patients, 72.2% female, with mean age 62 years. Cardiovascular risk factors, most frequently high blood pressure, carotid disease, and dyslipidemia, were present in 75% of these patients. Hippocampal lesions were unilateral in 80% of cases, with median size 2.5 mm, most frequently located at the hippocampal body. Approximately 14% of patients also presented acute ischemic lesions in locations other than the hippocampus. CONCLUSIONS: TGA is a clinical entity previously considered to have undetermined etiology. The present study used brain MRI to identify a group of patients with hippocampal ischemic lesions, finding associated vascular risk factors in a high proportion of them.