Patient-specific responses to splice-modifying treatments in spinal muscular atrophy fibroblasts.

The availability of three therapies for the neuromuscular disease spinal muscular atrophy (SMA) highlights the need to match patients to the optimal treatment. Two of these treatments (nusinersen and risdiplam) target splicing of , but treatment outcomes vary from patient to patient. An incomplete understanding of the complex interactions among SMA genetics, SMN protein and mRNA levels, and gene-targeting treatments, limits our ability to explain this variability and identify optimal treatment strategies for individual patients.

Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.

A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls.

Tactile breathing guidance increases oxygen saturation but not alertness or hypoxia symptoms.

We investigated the effect of tactile guided slow deep breathing compared with that of spontaneous breathing on blood oxygen saturation (SpO2), alertness, and hypoxia symptoms during acute hypobaric hypoxia. We also evaluated the usability of this tactile breathing guidance. Twelve male military pilots were exposed to a simulated altitude of 4,572 m (15,000 ft) in a repeated measures study while breathing spontaneously and during tactile guided slow deep breathing.

Three-dimensional cardiac models: a pre-clinical testing platform.

Major advancements in human pluripotent stem cell (hPSC) technology over recent years have yielded valuable tools for cardiovascular research. Multi-cell type 3-dimensional (3D) cardiac models in particular, are providing complementary approaches to animal studies that are better representatives than simple 2-dimensional (2D) cultures of differentiated hPSCs. These human 3D cardiac models can be broadly divided into two categories; namely those generated through aggregating pre-differentiated cells and those that form self-organizing structures during their in vitro differentiation from hPSCs.

Altered mitochondrial function in fibroblast cell lines derived from disease carriers of spinal muscular atrophy.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive childhood-onset neuromuscular disease with a carrier frequency of ~1:50. Mitochondrial abnormalities are widespread in patients with SMA. Disease carriers for SMA (i.

IgM anti-GM2 antibodies in patients with multifocal motor neuropathy target Schwann cells and are associated with early onset.

Background: Multifocal motor neuropathy (MMN) is a rare, chronic immune-mediated polyneuropathy characterized by asymmetric distal limb weakness. An important feature of MMN is the presence of IgM antibodies against gangliosides, in particular GM1 and less often GM2. Antibodies against GM1 bind to motor neurons (MNs) and cause damage through complement activation.

Application of deep learning on mammographies to discriminate between low and high-risk DCIS for patient participation in active surveillance trials.

Background: Ductal Carcinoma In Situ (DCIS) can progress to invasive breast cancer, but most DCIS lesions never will. Therefore, four clinical trials (COMET, LORIS, LORETTA, AND LORD) test whether active surveillance for women with low-risk Ductal carcinoma In Situ is safe (E. S.

A 21-bp deletion in the complement regulator CD55 promotor region is associated with multifocal motor neuropathy and its disease course.

Background And Aims: To further substantiate the role of antibody-mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane-bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course.

Methods: We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters.

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

Background: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported.

Attentional Tunneling in Pilots During a Visual Tracking Task With a Head Mounted Display.

Objective: We examined whether active head aiming with a Helmet Mounted Display (HMD) can draw the pilot's attention away from a primary flight task. Furthermore, we examined whether visual clutter increases this effect.

Background: Head up display symbology can result in attentional tunneling, and clutter makes it difficult to identify objects.

Promoting expression in gene therapy: more is not always better.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by loss-of-function of . SMA is characterized by degeneration of motor neurons in the spinal cord, leading to progressive muscle weakness and atrophy. One of three currently available treatments is onasemnogene abeparvovec, an AAV9-based gene replacement therapy.

Using Galvanic Vestibular Stimulation to Induce Post-Roll Illusion in a Fixed-Base Flight Simulator.

The illusions of head motion induced by galvanic vestibular stimulation (GVS) can be used to compromise flight performance of pilots in fixed-base simulators. However, the stimuli used in the majority of studies fail to mimic disorientation in realistic flight because they are independent from the simulated aircraft motion. This study investigated the potential of bilateral-bipolar GVS coupled to aircraft roll in a fixed-base simulator to mimic vestibular spatial disorientation illusions, specifically the "post-roll illusion" observed during flight.

Neurofilament light protein as a biomarker for spinal muscular atrophy: a review and reference ranges.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron () gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration.

Helicopter Pilot Performance and Workload in a Following Task in a Degraded Visual Environment.

In this study, we investigated the impact of a loss of horizon due to atmospheric conditions on flight performance and workload of helicopter pilots during a low-altitude, dynamic flight task in windy conditions at sea. We also examined the potential benefits of a helmet-mounted display (HMD) for this specific task. In a fixed-based helicopter simulator, 16 military helicopter pilots were asked to follow a maneuvering go-fast vessel in a good visual environment (GVE) and in a degraded visual environment (DVE).

Understanding the combined effects of sleep deprivation and acute social stress on cognitive performance using a comprehensive approach.

Background: Sleep deprivation (SD) and acute social stress are common, often unavoidable, and frequently co-occurring stressors in high-risk professions. Both stressors are known to acutely induce inflammatory responses and an increasing body of literature suggests this may lead to cognitive impairment. This study examined the combined effects of total SD and acute social stress on cognitive performance and took a comprehensive approach to explore their (shared) underlying mechanism leading to cognitive decline.

Virtual reality as a countermeasure for astronaut motion sickness during simulated post-flight water landings.

Entry motion sickness (EMS) affects crewmembers upon return to Earth following extended adaptation to microgravity. Anticholinergic pharmaceuticals (e.g.

Innovating spinal muscular atrophy models in the therapeutic era.

Spinal muscular atrophy (SMA) is a severe, monogenetic, neuromuscular disease. A thorough understanding of its genetic cause and the availability of robust models has led to the development and approval of three gene-targeting therapies. This is a unique and exciting development for the field of neuromuscular diseases, many of which remain untreatable.

Multifocal motor neuropathy is not associated with altered innate immune responses to endotoxin.

Objective: Antibody- and complement-mediated peripheral nerve inflammation are central in the pathogenesis of MMN. Here, we studied innate immune responses to endotoxin in patients with MMN and controls to further our understanding of MMN risk factors and disease modifiers.

Methods: We stimulated whole blood of 52 patients with MMN and 24 controls with endotoxin and collected plasma.

Hypoxia impairs reaction time but not response accuracy in a visual choice reaction task.

We investigated the effect of hypoxia on the reaction time (RT) and response accuracy of pilots performing a visual choice reaction task that corresponded to the scanning of helmet mounted display (HMD) symbology. Eighteen male military pilots performed the task in a hypobaric chamber at two simulated altitudes (92 m and 4572 m) in a single-blinded repeated measures and counter-balanced design. The visual stimuli were displayed in low and high contrast and at a 30- and 50-degree field of view (FoV).

Biopsy-Guided Pathological Response Assessment in Breast Cancer is Insufficient: Additional Pathology Findings of the MICRA Trial.

Background: Neoadjuvant systemic treatment (NST) leads to pathologic complete response (pCR) in 10-89% of breast cancer patients depending on subtype. The added value of surgery is uncertain in patients who reach pCR; however, current imaging and biopsy techniques aiming to predict pCR are not accurate enough. This study aims to quantify the residual disease remaining after NST in patients with a favorable response on MRI and residual disease missed with biopsies.

Effects of heat load and hypobaric hypoxia on cognitive performance: a combined stressor approach.

This study investigates how cognitive performance is affected by the combination of two stressors that are operationally relevant for helicopter pilots: heat load and hypobaric hypoxia. Fifteen participants were exposed to (1) no stressors, (2) heat load, (3) hypobaric hypoxia, and (4) combined heat load and hypobaric hypoxia. Hypobaric hypoxia (13,000 ft) was achieved in a hypobaric chamber.

Psammomatoid Ossifying Fibroma Is Defined by SATB2 Rearrangement.

Psammomatoid ossifying fibroma (PsOF), also known as juvenile PsOF, is a benign fibro-osseous neoplasm predominantly affecting the extragnathic bones, particularly the frontal and ethmoid bones, with a preference for adolescents and young adults. The clinical and morphologic features of PsOF may overlap with those of other fibro-osseous lesions, and additional molecular markers would help increase diagnostic accuracy. Because identical chromosomal breakpoints at bands Xq26 and 2q33 have been described in 3 cases of PsOF located in the orbita, we aimed to identify the exact genes involved in these chromosomal breakpoints and determine their frequency in PsOF using transcriptome sequencing and fluorescence in situ hybridization (FISH).

Inflammatory markers in cerebrospinal fluid of paediatric spinal muscular atrophy patients receiving nusinersen treatment.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease with onset during infancy or early childhood. Recent therapeutic advances targeting the genetic defect that underlies SMA improved survival in patients with infantile onset SMA (type 1) and improved motor function in SMA type 1-3. The most commonly used therapy for SMA, the antisense oligonucleotide nusinersen, is delivered by repeated intrathecal injections.