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Abstract Background Neonatal Marfan syndrome (nMFS) is a rare condition characterized by severe phenotype and poor prognosis. nMFS is caused by mutations in a specific region of the fibrillin 1 gene (FBN1). Prompt recognition of typical signs of neonatal presentation, such as characteristic facial anomalies with senile appearance, arthrogryposis, and campto-arachnodactyly, is fundamental for performing an early cardiological examination. This usually reveals rapidly progressive cardiovascular disease due to severe atrioventricular valve dysfunction. Case presentation Herein, we report the case of an early-onset cardiac failure in a neonate with Marfan syndrome, with a brief review of the literature of cases with cardiac involvement in neonatal age. Clinical exome sequencing identified the novel heterozygous de novo missense variant c.3152T > G in FBN1 gene (NM_000138.4), causing the aminoacidic change p.Phe1051Cys. Phenotype-genotype correlation led to a multidisciplinary diagnostic and management workflow. Conclusion The prompt recognition of a typical phenotype such as that of Marfan syndrome should lead to a detailed evaluation and close follow-up of cardiac morphology and function. Indeed, multi-disciplinary evaluation based on genotype-phenotype correlations of nMFS cases is essential to finding out the best medical and surgical approach, predicting the relevant impact on patient prognosis, and adequately counseling their families.

Abstract Background Dilated cardiomyopathy (DCM) is an etiologically heterogeneous group of diseases of the myocardium. With the rapid evolution in laboratory investigations, genetic background is increasingly determined including many genes with variable penetrance and expressivity. Biallelic NEXN variants are rare in humans and associated with poor prognosis: fetal and perinatal death or severe DCMs in infants. Case presentation We describe two male infants with prenatal diagnosis of dilated cardiomyopathy with impaired ventricular contractility. One of the patients showed hydrops and polyhydramnios. Postnatally, a DCM with severely reduced systolic function was confirmed and required medical treatment. In patient 1, Whole Exome Sequencing (WES) revealed a homozygous NEXN variant: c.1156dup (p.Met386fs) while in patient 2 a custom Next Generation Sequencing (NGS) panel revealed the homozygous NEXN variant c.1579_1584delp. (Glu527_Glu528del). These NEXN variants have not been previously described. Unlike the unfavorable prognosis described for biallelic NEXN variants, we observed in both our patients a favorable clinical course over time. Conclusion This report might help to broaden the present knowledge regarding NEXN biallelic variants and their clinical expression. It might be worthy to consider the inclusion of the NEXN gene sequencing in the investigation of pediatric patients with DCM.

It's never a good thing when you see an email notification from your union vice president with the subject line 'Heads Up.' Especially on a Saturday. During summer vacation. Teachers' [...]

Abstract Objective Soluble CD27 is a promising cerebrospinal fluid inflammatory biomarker in multiple sclerosis. In this study, we investigate relevant immune and neuro-pathological features of soluble CD27 in multiple sclerosis. Methods Protein levels of soluble CD27 were correlated to inflammatory cell subpopulations and inflammatory cytokines and chemokines detected in cerebrospinal fluid of 137 patients with multiple sclerosis and 47 patients with inflammatory and non-inflammatory neurological disease from three independent cohorts. Production of soluble CD27 was investigated in cell cultures of activated T and B cells and CD27-knockout T cells. In a study including matched cerebrospinal fluid and post-mortem brain tissues of patients with multiple sclerosis and control cases, levels of soluble CD27 were correlated with perivascular and meningeal infiltrates and with neuropathological features. Results We demonstrate that soluble CD27 favours the differentiation of interferon-γ-producing T cells and is released through a secretory mechanism activated by TCR engagement and regulated by neutral sphingomyelinase. We also show that the levels of soluble CD27 correlate with the representation of inflammatory T cell subsets in the CSF of patients with relapsing-remitting multiple sclerosis and with the magnitude of perivascular and meningeal CD27 + CD4 + and CD8 + T cell infiltrates in post-mortem central nervous system tissue, defining a subgroup of patients with extensive active inflammatory lesions. Interpretation Our results demonstrate that soluble CD27 is a biomarker of disease activity, potentially informative for personalized treatment and monitoring of treatment outcomes.

Introduction Poststroke spasticity (PSS) affects up to 40% of patients who had a stroke. Botulinum neurotoxin type A (BoNT-A) has been shown to improve spasticity, but the optimal timing of its application remains unclear. While several predictors of upper limb PSS are known, their utility in clinical practice in relation to BoNT-A treatment has yet to be fully elucidated. The COLOSSEO-BoNT study aims to investigate predictors of PSS and the effects of BoNT-A timing on spasticity-related metrics in a real-world setting.Methods and analysis The recruitment will involve approximately 960 patients who have recently experienced an ischaemic stroke (within 10 days, V0) and will follow them up for 24 months. Parameters will be gathered at specific intervals: (V1) 4, (V2) 8, (V3) 12, (V4) 18 months and (V5) 24 months following enrolment. Patients will be monitored throughout their rehabilitation and outpatient clinic journeys and will be compared based on their BoNT-A treatment status—distinguishing between patients receiving treatment at different timings and those who undergo rehabilitation without treatment. Potential predictors will encompass the Fugl-Meyer assessment, the National Institute of Health Stroke Scale (NIHSS), stroke radiological characteristics, performance status, therapies and access to patient care pathways. Outcomes will evaluate muscle stiffness using the modified Ashworth scale and passive range of motion, along with measures of quality of life, pain, and functionality.Ethics and dissemination This study underwent review and approval by the Ethics Committee of the Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. Regardless of the outcome, the findings will be disseminated through publication in peer-reviewed journals and presentations at national and international conferences.Trial registration number NCT05379413.

BackgroundPrimary ciliary dyskinesia (PCD) is considered a rare cause of chronic rhinosinusitis with nasal polyposis (CRSwNP), which is reported in 6% of children with PCD. The forms of PCD associated with the variants of the GAS8 gene identified so far seem to be linked to recurrent respiratory infections (sinusitis, otitis, and bronchiectasis) without situs inversus.Case presentationWe report a case of an 11-year-old girl with recurrent otitis media, productive cough, and chronic rhinosinusitis with nasal polyposis with homozygosity for a novel nonsense mutation in the GAS8.ConclusionChildren with CRSwNP should be treated in a multidisciplinary manner (ENT, pulmonologist, allergist, pathologist, pediatrician, and geneticist) because nasal polyposis often hides etiologies that must be recognized.

Harper Lee's To Kill a Mockingbird, published sixty years ago, was voted best-loved novel in PBS's The Great American Read poll in 2018 (PBS Publicity). Recently the book has undergone [...]

Abstract Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with metastasis, high recurrence rate, and poor survival. The basic helix-loop-helix transcription factor SHARP1 (Split and Hairy-related Protein 1) has been identified as a suppressor of the metastatic behavior of TNBC. SHARP1 blocks the invasive phenotype of TNBC by inhibiting hypoxia-inducible factors and its loss correlates with poor survival of breast cancer patients. Here, we show that SHARP1 is an unstable protein that is targeted for proteasomal degradation by the E3 ubiquitin ligase complex SCFβTrCP. SHARP1 recruits βTrCP via a phosphodegron encompassing Ser240 and Glu245 which are required for SHARP1 ubiquitylation and degradation. Furthermore, mice injected with TNBC cells expressing the non-degradable SHARP1(S240A/E245A) mutant display reduced tumor growth and increased tumor-free survival. Our study suggests that targeting the βTrCP-dependent degradation of SHARP1 represents a therapeutic strategy in TNBC.

Dropped head syndrome (DHS) is characterized by severe forward flexion of the cervical spine due to an imbalance in neck muscle tone. This condition can be linked to various neuromuscular diseases, including myasthenia gravis (MG). On the other hand, Parkinson’s disease (PD) patients may show a clinically indistinguishable picture named antecollis, which is caused by increased axial tone, but without muscle weakness. Differentiating between DHS and antecollis is crucial due to their distinct treatment requirements. We present the case of a 71-year-old White male with a one-month history of severe neck flexion, mild dysphagia, and dysphonia. His medical history included diabetes mellitus, coronary artery disease, arterial hypertension, and mild cervical spondylosis. Neurological examination revealed features of Parkinsonism, including hypomimia, asymmetric rigidity, and reduced arm swing. There was significant weakness in his neck extensor muscles, with no signs of ptosis or diplopia. Brain/spine MRI scans were unremarkable, but electromyography showed a reduced compound muscle action potentials amplitude in repetitive nerve stimulation, consistent with MG. High-titer acetylcholine receptor antibodies confirmed the diagnosis. Treatment with pyridostigmine (60 to 120 mg/day) and plasma exchange (daily, for five consecutive days) improved the patient’s general condition and neck posture. Concurrently, the patient was diagnosed with PD based on established clinical criteria and improved with carbidopa/levodopa therapy (up to 150/600 mg/daily). This case highlights the rare co-occurrence of MG and PD, emphasizing the need for thorough clinical, neurophysiological, and laboratory evaluations in complex DHS presentations. Managing MG’s life-threatening aspects and addressing PD symptoms requires a tailored approach, showcasing the critical role of neurophysiology in accurate diagnosis and effective treatment.

Abstract Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.

The semantic variant of primary progressive aphasia (svPPA), known also as “semantic dementia (SD),” is a neurodegenerative disorder that pertains to the frontotemporal lobar degeneration clinical syndromes. There is currently no approved pharmacological therapy for all frontotemporal dementia variants. Transcranial direct current stimulation (tDCS) is a promising non-invasive brain stimulation technique capable of modulating cortical excitability through a sub-threshold shift in neuronal resting potential. This technique has previously been applied as adjunct treatment in Alzheimer’s disease, while data for frontotemporal dementia are controversial. In this scoped review, we summarize and critically appraise the currently available evidence regarding the use of tDCS for improving performance in naming and/or matching tasks in patients with svPPA. Clinical trials addressing this topic were identified through MEDLINE (accessed by PubMed) and Web of Science, as of November 2022, week 3. Clinical trials have been unable to show a significant benefit of tDCS in enhancing semantic performance in svPPA patients. The heterogeneity of the studies available in the literature might be a possible explanation. Nevertheless, the results of these studies are promising and may offer valuable insights into methodological differences and overlaps, raising interest among researchers in identifying new non-pharmacological strategies for treating svPPA patients. Further studies are therefore warranted to investigate the potential therapeutic role of tDCS in svPPA.

Purpose: Pre-radiotherapy patient education led by Radiation Therapists (RTT) has been shown to improve patients’ distress and overall experiences. In an effort to offer a remote delivery method while allowing for visual learning and face-to-face communication, this pilot project evaluated the feasibility and acceptability of using virtual videoconferencing for patient education. Methods: This prospective pilot study integrated virtual patient education into standard care. This workflow consisted of a one-on-one, 45-minute tele-education session with an RTT on the day prior to CT-simulation. For this study, patients were offered the option to complete the session using web-based videoconferencing if they had the capability for it. Feasibility was evaluated as the proportion of patients who agreed to and completed virtual education. To evaluate acceptability, patients and RTTs were then emailed post-intervention surveys evaluating their satisfaction with virtual patient education. Results: Over three months 106 of 139 patients (76%) approached consented to virtual education. The median (range) age was 65 (27–93), 69% were male and most had genitourinary (38%) or head-and-neck (29%) cancers. Ninety patients (85%) completed virtual education as planned, with incompletions due to scheduling (8) or patient technical issues (7), or treatment cancellation (1). Sixty-eight patients completed surveys, with the vast majority agreeing virtual education was clear (94%) and helped them prepare (100%), they were comfortable with the technology (96%) and they were satisfied overall (99%). Twelve RTTs responded, suggesting overall that virtual education was higher quality though less feasible than tele-education, and comparable to in-person education. Conclusion: Offering individual, RTT-led virtual education using videoconferencing to patients pre-radiotherapy was feasible and acceptable in this pilot study, and is therefore being recommended as an option for all our patients. Future work will directly compare the effectiveness of in-person versus virtual education, and incorporate individual patient needs and preferences.

BackgroundMonoallelic and biallelic TTN truncating variants (TTNtv) may be responsible for a wide spectrum of musculoskeletal and cardiac disorders with different age at onset. Although the prevalence of heterozygous TTNtv is relatively high in the general population, cardiac phenotyping (mainly cardiomyopathies, CMPs) in biallelic titinopathy has rarely been described in children.MethodsWe reviewed the medical records of pediatric patients with biallelic TTNtv and cardiac involvement. Clinical exome sequencing excluded pathogenic/likely pathogenic variants in major CMP genes.ResultsFive pediatric patients (four male) with biallelic TTNtv were included. Major arthrogryposis multiplex was observed in four patients; no patient showed intellectual disability. At a cardiac level, congenital heart defects (atrial and ventricular septal defects, n = 3) and left ventricular non-compaction (n = 1) were reported. All patients had dilated cardiomyopathy (DCM) diagnosed at birth in one patient and at the age of 10, 13, 14, and 17 years in the other four patients. Heart rhythm monitoring showed tachyarrhythmias (premature ventricular contractions, n = 2; non-sustained ventricular tachycardia, n = 2) and nocturnal first-degree atrio-ventricular block (n = 2). Cardiac magnetic resonance (CMR) imaging was performed in all patients and revealed a peculiar late gadolinium enhancement distribution in three patients. HyperCKemia was present in two patients and end-stage heart failure in four. End-organ damage requiring heart transplantation (HT) was indicated in two patients, who were operated on successfully.ConclusionBiallelic TTNtv should be considered when evaluating children with severe and early-onset DCM, particularly if skeletal and muscular abnormalities are present, e.g., arthrogryposis multiplex and congenital progressive myopathy. End-stage heart failure is common and may require HT.

BackgroundCommercially available health devices are gaining momentum and represent a great opportunity for monitoring patients for prolonged periods. This study aimed at testing the feasibility of a smart device-based secondary prevention program in a cohort of patients with cryptogenic stroke.MethodsIn this proof-of-principle study, patients with non-disabling ischemic stroke and transient ischemic attacks (TIA) in the subacute phase were provided with a smartwatch and smart devices to monitor several parameters – i.e., oxygen saturation, blood pressure, steps a day, heart rate and heart rate variability - for a 4-week period (watch group). This group was compared with a standard-of-care group. Our primary endpoint was the compliance with the use of smart devices that was evaluated as the number of measures performed during the observation period.ResultsIn total, 161 patients were recruited, 87 in the WATCH group and 74 in the control group. In the WATCH group, more than 90% of patients recorded the ECG at least once a day. In total, 5,335 ECGs were recorded during the study. The median blood pressure value was 132/78 mmHg and the median oxygen saturation value was 97%. From a clinical standpoint, although not statistically significant, nine atrial fibrillation episodes (10.3%) in the WATCH group vs. 3 (4%) in the control group were detected.ConclusionOur study suggests that prevention programs for cerebrovascular disease may benefit from the implementation of new technologies.

Drawing on an in-depth case study at a large nonprofit organization, we find, in line with previous scholarship, that women professionals continue to face biased expectations at work and at home. We leverage data from interviews and participant observation to identify a new strategy that women use to navigate professional constraints created by the second shift and workplace double binds: “intentional invisibility.” Intentional invisibility refers to a set of risk-averse, conflict-avoidant strategies that women professionals in our study employ to feel authentic, manage competing expectations in the office, and balance work and familial responsibilities. We find women across the organization reporting intentionally remaining behind the scenes in attempts to avoid backlash and maintain a professional status quo. While intentional invisibility allows women to successfully navigate gender unequal professional and personal landscapes, it could simultaneously present an additional challenge to career advancement.

Measurement(s) bacteria and viruses in Europe and their definition of alien status Technology Type(s) literature review • taxonomic expertise Sample Characteristic - Organism bacteria • viruses Sample Characteristic - Environment terrestrial • marine• freshwater Sample Characteristic - Location Europe

Circadian rhythm impairment may play a role in Parkinson's disease (PD) pathophysiology. Recent literature associated circadian rhythm features to the risk of developing Parkinson and to its progression through stages. The association between the chronotype and the phenotype should be verified on a clinical and biological point of view. Herein we investigate the chronotype of a sample of 50 PD patients with the Morningness Eveningness Questionnaire and monitor their daily activity with a motion sensor embedded in a smartphone. Fibroblasts were collected from PD patients (n = 5) and from sex/age matched controls (n = 3) and tested for the circadian expression of clock genes (CLOCK, BMAL1, PER1, CRY1), and for cell morphology, proliferation, and death. Our results show an association between the chronotype and the PD phenotype. The most representative clinical chronotypes were “moderate morning” (56%), the “intermediate” (24%) and, in a minor part, the “definite morning” (16%). They differed for axial motor impairment, presence of motor fluctuations and quality of life (p

Objectives: neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease mainly affecting optic nerves and the spinal cord. Due to the potentially irreversible tissue damage, prevention of relapses is of utmost importance. Methods: We describe the atypical clinical course and pathology results of a patient with anti-aquaporin-4 antibody (anti-AQP4-Ab)-associated NMOSD who developed aseptic meningitis followed by limbic-encephalitis-like presentation with extensive brain lesions upon treatment with rituximab and tocilizumab. Results: The patient developed subacute cognitive decline with magnetic resonance imaging (MRI) evidence of extensive brain white matter lesions. In the hypothesis of an opportunistic brain infection, she underwent brain biopsy of the temporal pole. Pathology results revealed typical NMOSD findings with complement activation, supporting the hypothesis of an atypical presentation of anti-AQP-Ab-associated NMOSD. Accordingly, treatment with the complement-targeting drug eculizumab was started, leading to a dramatic clinical and MRI improvement. Discussion: aseptic meningitis and limbic encephalitis could represent a rare phenotype of anti-AQP4-Ab-associated NMOSD. [ABSTRACT FROM AUTHOR]

Aymé–Gripp syndrome (AYGRPS) is a multisystemic disorder caused by a subset of pathogenic variants in the MAF gene. Major clinical features include bilateral early cataracts, sensorineural hearing loss (SNHL), and a characteristic facial appearance along with variable neurodevelopmental delay. Pericarditis resulting in pericardial effusion of varying degree has been observed in a subset of affected individuals and could represent a severe feature in neonatal or infantile age. Here, we describe a syndromic infant with massive pericardial effusion and craniofacial features that oriented toward the suspicion of AYGRPS, which was subsequently confirmed by the molecular analysis of MAF. Pericardial effusion was first observed prenatally and documented to be recurrent, progressive, and severe in the first months of life, thus requiring pericardiocentesis and surgical procedures. In this report, we provide further delineation of the minor clinical characteristics, particularly focusing on cardiac features of AYGRPS. A dedicated cardiac surveillance of these findings may help reduce the morbidity and mortality of this rare condition. [ABSTRACT FROM AUTHOR]

BackgroundNon-motor manifestations are the main features of Parkinson's disease (PD). These have been associated with vitamin D abnormalities, but the role of parathormone (PTH) is still obscure. Among the non-motor symptoms of PD, the pathogenesis of restless leg syndrome (RLS) is still debated, but it has been associated with the vitamin D/PTH axis in other disease models. Our study deepens the association between vitamin D and PTH with the prevalence of non-motor symptoms of PD and explores such a relationship in patients reporting leg restlessness.MethodsFifty patients with PD were extensively investigated with motor and non-motor scales. Data on serum levels of vitamin D, PTH, and related metabolites were obtained, and patients were stratified as having vitamin D deficiency or hyperparathyroidism according to standardized criteria.ResultsOverall, 80% of patients with PD exhibited low vitamin D levels, and hyperparathyroidism was diagnosed in 45%. The analysis of the non-motor symptoms profile using the non-motor symptom questionnaire (NMSQ) revealed 36% of leg restlessness, a main feature of RLS. This was significantly associated with worse motor symptoms, quality of sleep, and quality of life. Moreover, it was associated with hyperparathyroidism (OR: 3.48) and with PTH levels, independent of vitamin D, calcium/phosphate levels, and motor status.ConclusionOur results suggest a significant association between the vitamin D/PTH axis and leg restlessness in PD. PTH has a putative role in nociceptive modulation, and previous evidence on hyperparathyroidism has suggested a possible interrelation with RLS. Further investigations are necessary to add PTH to the non-dopaminergic non-motor landscape of PD.

The early differential diagnosis of Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), is challenging because of an overlap of clinical features and the lack of reliable biomarkers. Neural-derived extracellular vesicles (NDEVs) isolated from blood provide a window into the brain's biochemistry and may assist in distinguishing between PD and APS. We verified in a case-control study whether oligomeric α-Synuclein and Tau aggregates isolated from NDEVs could allow the differential diagnosis of these conditions.Blood sampling and clinical data, including disease duration, motor severity, global cognition, and levodopa equivalent daily dose (LEDD), were collected from patients with a diagnosis of either PD (n = 70), PSP (n = 21), or CBD (n = 19). NDEVs were isolated from serum by immunocapture using an antibody against the neuronal surface marker L1CAM; oligomeric α-Synuclein and aggregated Tau were measured by ELISA.NDEVs analyses showed that oligomeric α-Synuclein is significantly augmented in PD compared to APS, whereas Tau aggregates are significantly increased in APS compared to PD (p