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Becker muscular dystrophy (BMD) is due to DMD mutations allowing partial expression of dystrophin. A detailed description of disease trajectories in different mutational subgroups, and the identification of factors predicting progressive vs. stable disease, are indispensable for the design and interpretation current and future clinical trials. We recruited male patients with a molecularly confirmed diagnosis of BMD at our Institution and followed them up with longitudinal functional evaluations including North Star Ambulatory Assessment (NSAA), 6-minute walk test (6MWT), and timed function measures (TFTs). Linear mixed models were applied to describing functional trajectories in the overall cohort and in mutational subgroups. We recruited 107 patients, with an average age of 31.4 ± 17.3 years at baseline. Eight-six patients (84%) had single- or multi-exon deletions, the most common being del 45-47 (15.9%) and del 45-48 (15.9%), followed by del x-51 (14.0%), del 48 (11.2%), del 45-55 (4.7%), and del 48-49 (3.7%). Dystrophin quantification via immunoblot was available for 62 patients (57.9%) and showed a "trimodal" pattern: 20 patients (32%) 90-100% relative to controls, in 10 (16%) 50%, and in 7 patients (11.3%) below 10% compared to controls. Mutational groups with higher dystrophin levels include del x-51, del 48, del 45-55, proximal rod deletions, del 3-9, and some del 45-48 patients. Conversely, groups with lower dystrophin levels encompass del 45-47, most del 45-48, and nonsense mutations. Mean dystrophin quantity was 60% ± 34%, with a minimum of 3% and a maximum of 100%. Time-to-event analyses of age at loss of ambulation estimated that only 25% of BMD patients lose ambulation by 60 years of age. Ninety-four patients were tested for 6MWT, 93 for time to run/walk 10m, 86 for time to climb 4 standard steps, 78 for time to rise from the floor, and 100 for NSAA at baseline. The mean follow-up duration was 6.1 years (± 3.6), ranging from 0 to a maximum of 11.5 years, with an average of 6.4 ± 3.5 clinical evaluations per patient, up to a maximum of 13. In the overall cohort, a statistically significant yearly decrease of -0.64 NSAA points was estimated. del 45-47 and del 45-48, showed a steady decrease, estimated respectively at -0.99 and -0.78 points per year. In del 48, a statistically significant but not clinically relevant decrease of -0.03 was observed, most patients starting from 34/34 at baseline. In the del x-51 group, there was no significant decrease of NSAA. Baseline NSAA value appeared to be a strong predictor of disease progression, with patient scoring between 10 and 32 at baseline showing the fastest decrease of functional measures. 6MWT and TFTs showed similar trends to NSAA in the longitudinal follow-up. These data confirm and refine genotype-phenotype correlations in BMD; quantify the decline in several practical and reliable motor outcome measures, which can be directly applied to power calculations for upcoming trials; and point to inclusion/exclusion criteria for trials aiming to demonstrate efficacy in motor outcomes in BMD, e.g. inclusion of patients with NSAA ≥ 32. [ABSTRACT FROM AUTHOR]

This retrospective, cross-sectional study aimed to characterise Becker muscular dystrophy (BMD) using information from a large patient cohort at the John Walton Muscular Dystrophy Research Centre, Newcastle, UK. The analysis included data from 163 male patients with genetically confirmed BMD, defined by in-frame DMD gene variations. A subset of patients with mutations predicted to induce reading frameshift was also included if they expressed dystrophin in muscle biopsy samples. Large deletions in the DMD-gene were commonest (78% of cases), followed by large duplications and small mutations, each accounting for 11% of cases. Genetic testing was prompted by a positive family history in 28% of cases, skeletal muscle symptoms in 51%, neurocognitive issues in 10%, incidental detection of high serum CK levels (7%), or cardiomyopathy (4%). The mean age at last neuromuscular assessment was 33.2 years (range 1.4-86.3). Twenty-three percent of patients were non-ambulant, with mean age at loss of ambulation (LoA) of 42.2 years (range 11.2-77.6 years). LoA was significantly related to age of symptom onset but not with specific mutation types. Cardiac involvement was observed in 52.3% of patients. Severe respiratory impairment (Forced Vital Capacity <60%) was rare (13.6%) and was more prevalent in non-ambulatory patients. The longitudinal trajectory of respiratory function will be presented. Behavioural and learning difficulties were frequently reported (44.1%); 18.4% of patients had a formal neuropsychiatric diagnosis. 'Real world' data from retrospective analyses of clinical case records, such as presented here, contribute to improved understanding of the variability of phenotypes of BMD. Combining the findings of this with those from other large centres is an important step in the process of developing standards of care guidance for BMD. Detailed natural history data is also a prerequisite for the design of clinical trials of novel therapies. [ABSTRACT FROM AUTHOR]

In end-of-life cancer care, 10–20% of bereaved family members experience adverse mental health effects, including prolonged grief disorder. Despite great efforts, evidence-based recommendations to support their grieving process and well-being are often not successfully adopted into routine clinical care. This study identified facilitators and barriers using implementation science methodology. 81 registered nurses working in cancer care from four hospitals and three home care services in Switzerland assessed their current family support practices in end-of-life care and bereavement care. They then assessed organisational attributes of their institution and their own individual characteristics and skills regarding literature-based factors of potential relevance. Facilitators and barriers to guideline-based family support were determined using fractional logistic regression. Service specialisation in palliative care, a culture that supports change, the availability of family support guidelines, billing/reimbursement of bereavement support services, and individual knowledge of family support and skill were systematically associated with higher adoption of guideline-based family support practices. Lack of privacy with families and insufficient training acted as significant barriers. While several potentially relevant factors have emerged in the literature, certain organisational and individual determinants actually empirically predict guideline-based family support according to nurses in end-of-life cancer care, with some determinants having much stronger implications than others. This provides crucial guidance for focussing quality improvement and implementation efforts through tailored strategies, especially with scarce resources. Furthermore, adoption is lower in bereavement care than in end-of-life care, suggesting a particular need for supportive organisational cultures including specific training and billing/reimbursement options. • 10%–20% of bereaved family members of cancer patients suffer psychologically. • Guideline-based recommendations for family support are not consistently implemented. • It is unclear, which factors actually empirically predict successful implementation. • In this study, implementation science methods identify the strongest factors. • This enables implementation efforts to be effective and sustainable. [ABSTRACT FROM AUTHOR]

The aim of this study was to verify the presence of BRAF mutations in a series of six patients affected by drug-resistant focal epilepsy associated with neocortical posterior temporal gangliogliomas (GG) who were subjected to lesionectomy between June 2008 and November 2013. GG are an increasingly recognized cause of epilepsy and represent the most common tumor in young patients undergoing surgery for intractable focal epilepsy. BRAF mutations have been identified in up to 50% of GG. Interestingly, these six patients shared a specific anatomical posterior temporal site. In all patients, histological examination confirmed the diagnosis of GG, and two were also associated with a focal cortical dysplasia (FCD) type IIa. BRAF mutations were found in four out of six GG (66.6%). Furthermore, dysplastic tissue of Patient 2 showed a concomitant BRAF V600E mutation. All patients but one (83.3%) achieved Engel Class Ia seizure control. The patient carrying a concomitant BRAF mutation in GG and FCD fell into Engel Class II. Further analyses will be required in order to better understand the meaning of BRAF mutations in epilepsy-associated tumors and FCD and their possible role as a prognostic seizure outcome and tumor behavior marker. [ABSTRACT FROM AUTHOR]

The possibility of a net rotation of the lithosphere with respect to the mantle is generally overlooked since it depends on the adopted mantle reference frames, which are arbitrary. We review the geological and geophysical signatures of plate boundaries, and show that they are markedly asymmetric worldwide. Then we compare available reference frames of plate motions relative to the mantle and discuss which is at best able to fit global tectonic data. Different assumptions about the depths of hotspot sources (below or within the asthenosphere, which decouples the lithosphere from the deep mantle) predict different rates of net rotation of the lithosphere relative to the mantle. The widely used no-net-rotation (NNR) reference frame, and low (<0.2°–0.4°/Ma) net rotation rates (deep hotspots source) predict an average net rotation in which some plates move eastward relative to the mantle (e.g., Nazca). With fast (>1°/Ma) net rotation (shallow hotspots source), all plates, albeit at different velocity, move westerly along a curved trajectory, with a tectonic equator tilted about 30° relative to the geographic equator. This is consistent with the observed global tectonic asymmetries. [ABSTRACT FROM AUTHOR]

We propose that the brittle-ductile transition (BDT) controls the seismic cycle. In particular, the movements detected by space geodesy record the steady state deformation in the ductile lower crust, whereas the stick-slip behavior of the brittle upper crust is constrained by its larger friction. GPS data allow analyzing the strain rate along active plate boundaries. In all tectonic settings, we propose that earthquakes primarily occur along active fault segments characterized by relative minima of strain rate, segments which are locked or slowly creeping. We discuss regional examples where large earthquakes happened in areas of relative low strain rate. Regardless the tectonic style, the interseismic stress and strain pattern inverts during the coseismic stage. Where a dilated band formed during the interseismic stage, this will be shortened at the coseismic stage, and vice-versa what was previously shortened, it will be dilated. The interseismic energy accumulation and the coseismic expenditure rather depend on the tectonic setting (extensional, contractional, or strike-slip). The gravitational potential energy dominates along normal faults, whereas the elastic energy prevails for thrust earthquakes and performs work against the gravity force. The energy budget in strike-slip tectonic setting is also primarily due elastic energy. Therefore, precursors may be different as a function of the tectonic setting. In this model, with a given displacement, the magnitude of an earthquake results from the coseismic slip of the deformed volume above the BDT rather than only on the fault length, and it also depends on the fault kinematics. [ABSTRACT FROM AUTHOR]

The fault activation (fault on) interrupts the enduring fault locking (fault off) and marks the end of a seismic cycle in which the brittle-ductile transition (BDT) acts as a sort of switch. We suggest that the fluid flow rates differ during the different periods of the seismic cycle (interseismic, pre-seismic, coseismic and post-seismic) and in particular as a function of the tectonic style. Regional examples indicate that tectonic-related fluids anomalies depend on the stage of the tectonic cycle and the tectonic style. Although it is difficult to model an increasing permeability with depth and several BDT transitions plus independent acquicludes may occur in the crust, we devised the simplest numerical model of a fault constantly shearing in the ductile deeper crust while being locked in the brittle shallow layer, with variable homogeneous permeabilities. The results indicate different behaviors in the three main tectonic settings. In tensional tectonics, a stretched band antithetic to the normal fault forms above the BDT during the interseismic period. Fractures close and fluids are expelled during the coseismic stage. The mechanism reverses in compressional tectonics. During the interseismic stage, an over-compressed band forms above the BDT. The band dilates while rebounding in the coseismic stage and attracts fluids locally. At the tip lines along strike-slip faults, two couples of subvertical bands show different behavior, one in dilation/compression and one in compression/dilation. This deformation pattern inverts during the coseismic stage. Sometimes a pre-seismic stage in which fluids start moving may be observed and could potentially become a precursor. [ABSTRACT FROM AUTHOR]

Takotsubo cardiomyopathy (TC) is a rare but increasingly recognized mimic of acute coronary syndrome. Patients present with angina, ST-segment changes on electrocardiogram (both elevations and depressions), and rapid rises in cardiac biomarkers. Many kinds of stressful events have been associated with TC, but only a handful of drug-related cases have previously been reported. We describe the case of a 58-year-old woman who developed TC 2 days after crack cocaine use, a diagnosis first suggested as bedside echocardiography in the emergency department. Recognition of the classic echocardiographic appearance of TC—apical hypokinesis causing “ballooning” of the left ventricle during systole—may greatly assist providers in the early identification of this condition. [ABSTRACT FROM AUTHOR]

Stratifying risk of patients with acute coronary syndrome (ACS) in the emergency department (ED) remains a frequent challenge. When ST-elevation criteria are absent, current recommendations rely upon insensitive and time-intensive methods such as the electrocardiogram and cardiac enzyme testing. Here, we report on a series of cases, where emergency physicians used a simplified model for identifying regional wall motion abnormalities by point-of-care echocardiography in patients presenting with chest pain to the ED. With the use of a simplified model described herein, high-risk patients with ACS were identified rapidly in a cohort usually difficult to risk stratify. [ABSTRACT FROM AUTHOR]

Abstract: Cavernomas and cortical dysplasia are well-known causes of partial epilepsy. The association between cavernoma and cortical dysplasia in an epileptic patient has not yet been sufficiently documented. We report a case of long-term, drug-resistant, partial left temporal epilepsy associated with a cavernoma. According to the neurophysiological non-invasive presurgical study, the patient was submitted to a tailored left temporal resection. The histopathological study showed the coexistence of cavernoma and cortical dysplasia. This is an interesting combination of epilepsy-related pathologies that have so far not been documented. [Copyright &y& Elsevier]

Historically, cardiologist and neurologist have been required in the diagnosis of loss of consciousness. Convulsive syncopes related to vaso-vagal asystole are counted in differential diagnosis of epileptic seizures because of the several clinical similarities. Moreover, during epileptic seizures, heart is often involved showing many patterns of alteration ranging from brief tachycardia to prolonged ictal asystole. Sometimes these episodes imply also respiratory changes suggesting a probable vegetative alteration during or immediately after the seizure. Prolonged video-EEG monitoring allowed us to record many of these phenomena. Despite the frequent long-life benign history, our practical approach was frequently aggressive and the patient underwent to pace-maker implant, at least in case of prolonged ictal asystole. In fact, during the last years, the ghost of SUDEP (Sudden Unexspected Death in Epilepsy) has modified our overtures on this field. Notwithstanding, reviewing our cases, we found different type of possible ictal arrhythmias according with familial and personal history of the patient, cardiological evaluation, drug response, patient’s social life and patient’s expectations. We suggest that all these variables might be considered when evaluating these cases because of a possible tailored therapeutical approach. [ABSTRACT FROM AUTHOR]

Takotsubo cardiomyopathy (TC) is a rare but increasingly recognized mimic of acute coronary syndrome. Patients present with angina,ST-segment changes on electrocardiogram (both elevations and depressions),and rapid rises in cardiac biomarkers. Many kinds of stressful events have been associated with TC, but only a handful of drug-related cases have previously been reported. We describe the case of a 58-year-old woman who developed TC 2 days after crack cocaine use, a diagnosis first suggested as bedside echocardiography in the emergency department.Recognition of the classic echocardiographic appearance of TC-apical hypokinesis causing 'ballooning' of the left ventricle during systole-may greatly assist providers in the early identification of this condition. [ABSTRACT FROM AUTHOR]

Sudden unexpected death in epilepsy (SUDEP) represents the main cause of death in patients with refractory epilepsy. A number of mechanisms have been proposed, including seizure-induced asystolia. We report two new patients with ictal asystolia revealed by long-term video-EEG monitoring. Case 1. A 76year-old male with 1year history of sudden falls to the ground associated with loss of consciousness, pallor and sweating, sometimes preceded by an olfactory hallucination. EEG: left temporal spikes. MRI: cerebral vascular changes. Case 2. A 55year-old male with a 10year history of focal seizures characterized by epigastric aura and loss of contact, more recently followed by sudden falls to the ground with pallor and stiffening. EEG: left temporal spikes. MRI: left temporal dysplasia. The video-EEG monitoring allowed to capture a number of seizures originating from the left temporal lobe and associated with ictal asystolia lasting for 10–20s, with a corresponding syncope-like EEG picture. Focal seizures complicated by ictal asystolia may be suspected on clinical grounds by the appearance of syncope-like events preceded by typical epileptic auras. Long-term video-EEG recording is the gold standard to detect these events which may require pacemaker implantation. [Copyright &y& Elsevier]

The DMD Hub, a collaboration between Duchenne UK and the John Walton Muscular Dystrophy Research Centre at Newcastle University, has successfully established a UK clinical trial accelerator network (CTAN) able and ready to deliver trials in DMD (www.dmdhub.org). Here we present the DMD Hub CTAN model which includes building workforce capacity, establishing an effective communication infrastructure, harmonising costings and trial set up, enabling fair and equitable recruitment, providing training and education opportunities to staff, adapting to new challenges and evolving to ensure utility and sustainability. The DMD Hub has developed a suite of tools and services for patients, clinical trial and clinical sites, contract research organisations and industry, spanning the clinical trial landscape. We are now delivering these services to industry taking a national, central coordinating role in the set-up and delivery of DMD trials using the established site network and infrastructure. The offer to industry covers early engagement with sites, study and site feasibility, support with study set up including costing and reviewing documentation for the national ethic approval, and recruitment to clinical research studies. The aim is to provide a collaborative, harmonised and streamlined approach to clinical trial set up and delivery that benefits all stakeholders. For sponsors this means quicker set up and delivery timelines, enabled through site engagement, patient insight into trial implementation and recruitment, and robust site feasibility; for sites, it will lead to improved processes, less duplication of effort and increased number of clinical trials; for patients, it will ensure effective recruitment and increased opportunity to access clinical trials. The DMD Hub network model has been successfully replicated in other neuromuscular diseases; the Becker Muscular Dystrophy Hub (www.bmd-hub.org) was launched in early 2024 and several of the DMD Hub tools have also been used as models for other rare disease areas in recent successful grant applications. A nationally coordinated, inclusive approach based on specific needs of the different stakeholders can successfully improve clinical trial delivery and increase capacity. [ABSTRACT FROM AUTHOR]