Epilepsy in Duchenne and Becker muscular dystrophies.

OBJECTIVE: Duchenne and Becker muscular dystrophies (DMD and BMD) are dystrophinopathies caused by variants in DMD gene, resulting in reduced or absent dystrophin. These conditions, characterized by muscle weakness, also manifest central nervous system (CNS) comorbidities due to dystrophin expression in the CNS. Prior studies have indicated a higher prevalence of epilepsy in individuals with dystrophinopathy compared to the general population. Our research aimed to investigate epilepsy prevalence in dystrophinopathies and characterize associated electroencephalograms (EEGs) and seizures. METHODS: We reviewed 416 individuals with dystrophinopathy, followed up at three centers between 2010 and 2023, to investigate the lifetime epilepsy prevalence and characterize EEGs and seizures in those individuals diagnosed with epilepsy. Associations between epilepsy and type of dystrophinopathy, genotype, and cognitive involvement were studied. RESULTS: Our study revealed a higher epilepsy prevalence than the general population (1.4%; 95% confidence interval: 0.7-3.2%), but notably lower than previously reported in smaller dystrophinopathy cohorts. No significant differences were found in epilepsy prevalence between DMD and BMD or based on underlying genotypes. Cognitive impairment was not found to be linked to higher epilepsy rates. The most prevalent epilepsy types in dystrophinopathies resembled those observed in the broader pediatric population, with most individuals effectively controlled through monotherapy. INTERPRETATION: The actual epilepsy prevalence in dystrophinopathies may be markedly lower than previously estimated, possibly half or even less. Our study provides valuable insights into the epilepsy landscape in individuals with dystrophinopathy, impacting medical care, especially for those with concurrent epilepsy.

The relationships between fear of missing out and psychological and sociocultural factors in Latinx emerging adult college students.

OBJECTIVES: The proliferation of social media has resulted in negative consequences such as fear of missing out (FoMO), the anxious feelings one has when others are having rewarding experiences. Few studies have assessed FoMO in Latinx emerging adult college students, none utilizing the socioecological framework. This study assessed the relationships between FoMO and psychological and sociocultural risk and protective factors. METHOD: Latinx college students (n = 452; Mage = 19.97 years, SD = 1.89; 77.2% female) completed an online survey assessing demographics, FoMO, social media addiction, depression, anxiety, stress, Machiavellianism, narcissism, psychopathy, familism, and acculturation. Two multiple linear regressions assessed the associations between FoMO and psychological and sociocultural factors. RESULTS: Both regressions were statistically significant. First, FoMO was positively associated with social media addiction, depression, and Machiavellianism. Second, FoMO was positively associated with familial honor and negatively associated with familial interconnectedness and ethnic social relations. CONCLUSIONS: Associations between FoMO and psychological factors are consistent with past literature, yet they highlight the need for prospective studies to assess temporality. The fact that FoMO was related uniquely to familistic attitudes suggests the importance of family in FoMO perceptions and the need to assess these associations in a more nuanced manner. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Relative Age Effect Analysis in the History of the Ballon d'Or (1956-2023).

Ballon d'Or is the most important individual award in football, and is a significant measure of excellence. From our knowledge, this is the first study that explored the relative age effect (RAE) throughout the history of the Ballon d'Or. A total of 1899 football players nominated for the award from the first edition in 1956 to the most recent edition (2023) were analyzed. To assess the RAE, the birthdate distributions were categorized into four trimesters. The comparison involved correcting for the uniform distribution using chi-square analysis, with Cramer's V serving as a measure of effect size. Standardized residuals were computed to identify quarters that exhibited significant deviation from the expected values. Odds Ratio and 95% confidence intervals were used to identify discrepancies between trimesters. The results indicated a pronounced presence of an RAE at the global level. However, the longitudinal analysis revealed variations in the behavior of the RAE over time. In the initial decades, there is an overrepresentation of players born in the last months of the year. Subsequently, there is no discernible RAE. In the most recent decades, there has been a clear resurgence of RAE, with an overrepresentation of players born in the first quarters of the year.

Coherent Electron-Vibron Interactions in Surface-Enhanced Raman Scattering (SERS).

In this Letter we identify coherent electron-vibron interactions between near-resonant and nonresonant electronic levels that contribute beyond standard optomechanical models for off-resonant or resonance surface-enhanced Raman scattering (SERS). By developing an open-system quantum model using first molecular interaction principles, we show how the Raman interference of both resonant and nonresonant contributions can provide several orders of magnitude modifications of the SERS peaks with respect to former optomechanical models and over the fluorescence backgrounds. This cooperative optomechanical mechanism allows for generating an enhancement of nonclassical photon pair correlations between Stokes and anti-Stokes photons, which can be detected by photon-counting measurements. Our results demonstrate Raman enhancements and suppressions of coherent nature that significantly impact the standard estimations of the optomechanical contribution from SERS spectra and their quantum mechanical observable effects.

SRF transcriptionally regulates the oligodendrocyte cytoskeleton during CNS myelination.

Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)-a transcription factor known to regulate expression of actin and actin regulators in other cell types-as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the mechanistic role of SRF in oligodendrocyte lineage cells. Here, we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in oligodendrocyte precursor cells and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Surprisingly, oligodendrocyte-restricted loss of SRF results in upregulation of gene signatures associated with aging and neurodegenerative diseases. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies an essential pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.

Increased Proteolytic Activity of Serratia marcescens Clinical Isolate HU1848 Is Associated with Higher eepR Expression.

Serratia marcescens is a global opportunistic pathogen. In vitro cytotoxicity of this bacterium is mainly related to metalloprotease serralysin (PrtS) activity. Proteolytic capability varies among the different isolates. Here, we characterized protease production and transcriptional regulators at 37°C of two S. marcescens isolates from bronchial expectorations, HU1848 and SmUNAM836. As a reference strain the insect pathogen S. marcescens Db10 was included. Zymography of supernatant cultures revealed a single (SmUNAM836) or double proteolytic zones (HU1848 and Db10). Mass spectrometry confirmed the identity of PrtS and the serralysin-like protease SlpB from supernatant samples. Elevated proteolytic activity and prtS expression were evidenced in the HU1848 strain through azocasein degradation and qRT-PCR, respectively. Evaluation of transcriptional regulators revealed higher eepR expression in HU1848, whereas cpxR and hexS transcriptional levels were similar between studied strains. Higher eepR expression in HU1848 was further confirmed through an in vivo transcriptional assay. Moreover, two putative CpxR binding motifs were identified within the eepR regulatory region. EMSA validated the interaction of CpxR with both motifs. The evaluation of eepR transcription in a cpxR deletion strain indicated that CpxR negatively regulates eepR. Sequence conservation suggests that regulation of eepR by CpxR is common along S. marcescens species. Overall, our data incorporates CpxR to the complex regulatory mechanisms governing eepR expression and associates the increased proteolytic activity of the HU1848 strain with higher eepR transcription. Based on the global impact of EepR in secondary metabolites production, our work contributes to understanding virulence factors variances across S. marcescens isolates.

Effectiveness of a Peer Mentoring on University Dropout and Academic Performance / La eficacia de un programa de mentoría en el abandono y el rendimiento académico

Mentoring programs have been proposed to reduce dropout and increase academic performance. We analyzed the effect of peer mentoring on university dropout and academic performance in the context of Spain. We applied a quasi-experimental posttest-only control group design with 3,774 students (mentees, n = 1,887; control, n = 1,887). Mentees had participated in a peer mentoring program. We apply the student’s t-test, Cohen’s d, phi statistic, and chi-square statistic. Mentees exhibited lower dropout than controls and showed higher academic performance regardless of the area of knowledge. Results support the implementation of mentoring programs in Spanish universities with the goal of reducing student dropout and increasing academic performance. The research provides empirical evidence for theory building in higher education studies, developmental relationships, and integration programs. (AU)

Se ha propuesto la aplicación de programas de mentoría para reducir la deserción universitaria y aumentar el rendimiento académico. En el artículo analizamos el efecto de la mentoría entre pares sobre el abandono universitario y el rendimiento académico en España. Aplicamos un diseño de grupo de control cuasiexperimental con medida post en una muestra de 3.774 estudiantes (mentorados, n = 1,887; control, n = 1,887). Los mentorados habían participado en un programa de mentoría entre pares. Aplicamos la prueba t de Student, la d de Cohen, el estadístico phi y el chi-cuadrado. Los mentorados presentaban un menor abandono que los controles y un mayor rendimiento académico independientemente del área de conocimiento. Los resultados avalan la implementación de programas de mentoría en las universidades españolas con el objetivo de reducir el abandono universitario y aumentar el rendimiento académico. La investigación proporciona evidencia empírica para la elaboración de teorías en estudios de educación superior, relaciones de desarrollo y programas de integración. (AU)

Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom.

Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services.

Recurrent atraumatic compartment syndrome as a manifestation of genetic neuromuscular disease.

Compartment syndrome (CS) is a medical emergency that occurs secondary to excessively high pressures within a confined fibro-osseous space, resulting in reduced perfusion and subsequent tissue injury. CS can be divided into acute forms, most commonly due to trauma and considered an orthopaedic emergency, and chronic forms, most commonly presenting in athletes with recurrent exercise-induced pain. Downstream pathophysiological mechanisms are complex but do share commonalities with mechanisms implicated in genetic neuromuscular disorders. Here we present 3 patients with recurrent CS in the context of a RYR1-related disorder (n = 1) and PYGM-related McArdle disease (n = 2), two of whom presented many years before the diagnosis of an underlying neuromuscular disorder was suspected. We also summarize the literature on previously published cases with CS in the context of a genetically confirmed neuromuscular disorder and outline how the calcium signalling alterations in RYR1-related disorders and the metabolic abnormalities in McArdle disease may feed into CS-causative mechanisms. These findings expand the phenotypical spectrum of RYR1-related disorders and McArdle disease; whilst most forms of recurrent CS will be sporadic, above and other genetic backgrounds ought to be considered in particular in patients where other suggestive clinical features are present.

Los Músculos Isquiosurales y su Capacidad Profiláctica sobre la Translación Tibial Anterior en Lesión de Ligamento Cruzado Anterior: Una Revisión Sistemática / The Hamstrings Muscles and their Prophylactic Capacity on Anterior Tibial Translation in Anterior Cruciate Ligament Injury: A Systematic Review

La ruptura de ligamento cruzado anterior (LCA) es la lesión de rodilla más común que se trata de una reconstruc- ción quirúrgica. El objetivo principal de esta revisión fue analizar la importancia de la función de los músculos isquiosurales como factor de riesgo de posibles lesiones de LCA. Se llevó a cabo siguiendo las normas Preferred Reported Item for Systematic Reviews and Meta- analyses (PRISMA). La fuente de la recopilación de datos fue la consulta directa de las bases de datos Pubmed, Sportdiscus, Web of Science y Scopus. Para la recuperación documental, se utilizaron varias palabras clave y se evaluó la calidad de los estudios que fueron seleccionados mediante la escala PEDro. Los déficits de la función muscular en los músculos isquiosurales se han relacionado con una mayor translación tibial anterior y, como consecuencia, un incremento del estrés tensional sobre el LCA entre los 10° y 45° de flexión de rodilla. Una co-activación de los músculos isquiosurales con el músculo cuádriceps femoral puede ser de gran ayuda para reducir los factores de riesgo de la lesión LCA.

SUMMARY: Anterior cruciate ligament (ACL) rupture is the most common knee injury to undergo surgery in the sports setting. The main objective of this review was to analyze the importance of hamstring function as a risk factor for potential ACL injury. It was conducted following the Preferred Reported Item for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The source of data collection was direct consultation of the Pubmed, Sportdiscus, Web of Science and Scopus databases. For documentary retrieval, several key words were used and the quality of the studies that were selected was assessed using the PEDro scale. Muscle function deficits in the hamstrings have been related to increased anterior tibial translation and, as a consequence, increased tensional stress on the ACL between 10° and 45° of knee flexion. A co-activation of the hamstrings with the quadriceps may be helpful in reducing the risk factors for ACL injury.

Parent Experiences with the Process of Sharing Inpatient Safety Concerns for Children with Medical Complexity: A Qualitative Analysis.

OBJECTIVE: To describe the process of identifying and reporting inpatient safety concerns from the perspective of parents of children with medical complexity (CMC). METHODS: We conducted a secondary analysis of qualitative data from semi-structured interviews with 31 English and Spanish-speaking parents of CMC at two tertiary children's hospitals. Interviews lasted 45-60 minutes and were audio-recorded, translated, and transcribed. Three researchers inductively and deductively coded transcripts using an iteratively refined codebook with validation by a fourth researcher. Thematic analysis was used to develop a conceptual model of the process of inpatient parent safety reporting. RESULTS: We identified four steps illustrating the process of inpatient parent safety concern reporting 1) parent recognizing concern, 2) parent reporting concern, 3) staff/hospital response continuum, and 4) parent feelings of validation/invalidation. Many parents endorsed that they were the first to catch a safety concern and were identified as unique reporters of safety information. Parents typically described reporting their concerns verbally and in real-time to the person they felt could quickly remedy the situation. There was a spectrum of validation. Some parents reported their concerns were not acknowledged and addressed, which led them to feel overlooked, disregarded, or judged. Others reported their concerns were acknowledged and addressed, resulting in parents feeling heard and seen and often leading to changes in clinical care. CONCLUSIONS: Parents described a multi-step process of reporting safety concerns during hospitalization and a spectrum of staff response and validation. These findings can inform family-centered interventions that support safety concern reporting in the inpatient setting.

Psychosocial and personality trait associates of phubbing and being phubbed in hispanic emerging adult college students.

Phubbing is when one uses their smartphone in a social interaction instead of interacting with the other individual(s) in their presence. Phubbing and being phubbed are growing concerns as the number of smartphones and frequency of smartphone use increases. This study assessed the relationships between phubbing, being phubbed, psychosocial constructs, and socially adverse personality traits among Hispanic emerging adult college students. Hispanic college students (n = 452) completed a survey assessing: sociodemographics, phubbing, being phubbed, depression, anxiety, stress, Machiavellianism, narcissism, psychopathy, and need for drama (interpersonal manipulation, impulsive outspokenness, persistent perceived victimhood). Hispanic emerging adult college students reported low-to-moderate levels of phubbing and being phubbed. Regarding phubbing findings, nomophobia (fear of separation from one's phone), interpersonal conflict, and problem acknowledgement were positively associated with negative affect. Moreover, interpersonal conflict, self-isolation, and problem acknowledgement were positively associated with interpersonal manipulation. Regarding being phubbed findings, perceived norms, feeling ignored, and interpersonal conflict were positively associated with persistent perceived victimhood. Findings indicate that Hispanic college students may use their smartphones in social settings to alleviate negative affect. Moreover, a virtual environment on a smartphone may be easier to manipulate and can be used to continue garnering attention and portraying oneself as the victim, fulfilling one's need for drama. Regarding exploratory mediations, phubbing and being phubbed mediated the relationships between multiple socially adverse personality traits and negative affect. The clinical implications of these results are discussed. Prospective studies are warranted to determine temporality. Supplementary information: The online version contains supplementary material available at 10.1007/s12144-023-04767-y.

Muscle Ultrasound Abnormalities in Individuals with RYR1-Related Malignant Hyperthermia Susceptibility.

BACKGROUND: Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility. OBJECTIVE: To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients. METHODS: We performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders. RESULTS: A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy. CONCLUSIONS: Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity.

The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD).

In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.

Interaction with single-stranded DNA-binding protein modulates Escherichia coli RadD DNA repair activities.

The bacterial RadD enzyme is important for multiple genome maintenance pathways, including RecA DNA strand exchange and RecA-independent suppression of DNA crossover template switching. However, much remains unknown about the precise roles of RadD. One potential clue into RadD mechanisms is its direct interaction with the single-stranded DNA binding protein (SSB), which coats single-stranded DNA exposed during genome maintenance reactions in cells. Interaction with SSB stimulates the ATPase activity of RadD. To probe the mechanism and importance of RadD-SSB complex formation, we identified a pocket on RadD that is essential for binding SSB. In a mechanism shared with many other SSB-interacting proteins, RadD uses a hydrophobic pocket framed by basic residues to bind the C-terminal end of SSB. We found that RadD variants that substitute acidic residues for basic residues in the SSB binding site impair RadD:SSB complex formation and eliminate SSB stimulation of RadD ATPase activity in vitro. Additionally, mutant Escherichia coli strains carrying charge reversal radD changes display increased sensitivity to DNA damaging agents synergistically with deletions of radA and recG, although the phenotypes of the SSB-binding radD mutants are not as severe as a full radD deletion. This suggests that cellular RadD requires an intact interaction with SSB for full RadD function.

Candida albicans causes brain regional invasion and necrosis, and activation of microglia during lethal neonatal neurocandidiasis.

Neurocandidiasis is a fungal infection that primarily affects neonates, which is associated with 70% case fatality rates, while pediatric patients who survive infection often have long-term neurological sequelae, making it a clinical requirement to understand the pathogenesis of neonatal neurocandidiasis. Currently, the brain regions to Candida albicans invasion during the neonatal period are not characterized. In this study, 0-day-old mice were infected with C. albicans intravenously to determine dissemination and invasion into the brain at different times post-infection by fungal burden assay and histopathological analysis, additionally cellular death and microglial activation were evaluated by flow cytometry. The results evidenced the dissemination of C. albicans within the first hour of infection in the brain. The meninges were the initial site of invasion during the first 6 hours post infection and then filamentous structures into the brain parenchyma increases during infection, the anatomic regions most susceptible to invasion being the cerebral cortex, thalamus, hypothalamus, midbrain, pons, and medulla oblongata. Furthermore, C. albicans invasion of brain tissue results in cell necrosis and activation of microglia as a consequence of fungal invasion.

Hypoxic Burden in Obstructive Sleep Apnea: Present and Future

Conventional measures of obstructive sleep apnea (OSA) severity, such as the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) are commonly used to quantify OSA severity and guide therapeutical decision-making processes. However, it is widely recognized that both AHI and ODI have important limitations and novel physiologically-informed metrics are needed to better capture the severity of OSA and characterize its physiological consequences, particularly the severity of recurrent nocturnal hypoxemia, ensuing the respiratory events. According to recent studies, the sleep apnea-specific “hypoxic burden (HB)”, defined as the sum of individual areas under the oxygen desaturation curve, has shown some promise in identifying high risk individuals with OSA. In addition to the frequency of respiratory events, HB capture the depth and duration of OSA-related hypoxemia that may prove to be important disease characterizing features, not captured by the conventional “frequency-based” metrics, such as AHI and ODI. In this “perspective” paper the methods to quantify the HB, its characteristics, associations with health outcomes, and its limitations will be discussed. (AU)

New treatments in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a severe neurodegenerative condition due to recessive mutations in the SMN1 gene resulting in insufficiency of survival motor neuron (SMN) protein. Lack of SMN protein results in irreversible degeneration of lower motor neurons and consequential muscle atrophy and weakness. SMN2, a SMN1 homologue, produces low levels of functional SMN protein with the potential to partially compensate SMN1 loss. Several compounds have been shown to successfully restore SMN protein production in motor neurons, either by enhancing SMN2 gene function or by direct replacement of the SMN1 gene. Clinical trials of these compounds have demonstrated the potential to substantially alter the natural history of SMA and have led to their implementation into clinical practice. To date, 3 novel drugs, nusinersen, onasemnogene aberparvovec and risdiplam, have received marketing authorisation for SMA treatment by several authorities including Food and Drug Administration and European Medicines Agency. While implementing these drugs into daily clinical practice, clinicians face a number of new challenges, including identifying the most advantageous treatment for any individual, optimisation of outcomes and management of a modified SMA phenotype. Considering that treatment initiation at the pre-symptomatic or paucisymptomatic stage appears to be associated with better outcomes, health services need to support early diagnosis for this now treatable condition. This review aims to give an overview of the current therapeutic landscape of SMA, to provide an understanding of current practice of SMA management and to help increase awareness of the imminent need for urgent early diagnosis at the pre-symptomatic stage.