The diagnostic and prognostic role of cerebrospinal fluid biomarkers in glucose transporter 1 deficiency: a systematic review.

The purpose of this study is to investigate the diagnostic and prognostic role of cerebrospinal fluid (CSF) biomarkers in the diagnostic work-up of glucose transporter 1 (GLUT1) deficiency. Reported here is a systematic review according to PRISMA guidelines collecting clinical and biochemical data about all published patients who underwent CSF analysis. Clinical phenotypes were compared between groups defined by the levels of CSF glucose (≤ 2.2 mmol/L versus > 2.2 mmol/L), CSF/blood glucose ratio (≤ 0.45 versus > 0.45), and CSF lactate (≤ 1 mmol/L versus > 1 mmol/L). Five hundred sixty-two patients fulfilled the inclusion criteria with a mean age at the diagnosis of 8.6 ± 6.7 years. Patients with CSF glucose ≤ 2.2 mmol/L and CSF/blood glucose ratio ≤ 0.45 presented with an earlier onset of symptoms (16.4 ± 22.0 versus 54.4 ± 45.9 months, p < 0.01; 15.7 ± 23.8 versus 40.9 ± 38.0 months, p < 0.01) and received an earlier molecular genetic confirmation (92.1 ± 72.8 versus 157.1 ± 106.2 months, p < 0.01). CSF glucose ≤ 2.2 mmol/L was consistently associated with response to ketogenic diet (p = 0.018) and antiseizure medications (p = 0.025). CSF/blood glucose ratio ≤ 0.45 was significantly associated with absence seizures (p = 0.048), paroxysmal exercise-induced dyskinesia (p = 0.046), and intellectual disability (p = 0.016) while CSF lactate > 1 mmol/L was associated with a response to antiseizure medications (p = 0.026) but not to ketogenic diet.Conclusions:This systematic review supported the diagnostic usefulness of lumbar puncture for the early identification of patients with GLUT1 deficiency responsive to treatments especially if they present with co-occurring epilepsy, movement, and neurodevelopmental disorders. What is Known: • Phenotypes of GLUT1 deficiency syndrome range between early epileptic and developmental encephalopathy to paroxysmal movement disorders and developmental impairment What is New: • CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with early onset absences • CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with paroxysmal exercise induced dyskinesia and intellectual disability. • CSF glucose may predict better than CSF blood/glucose and lactate the response to ketogenic diet and antiseizure medications.

Autosomal Recessive Guanosine Triphosphate Cyclohydrolase I Deficiency: Redefining the Phenotypic Spectrum and Outcomes.

BACKGROUND: The GCH1 gene encodes the enzyme guanosine triphosphate cyclohydrolase I (GTPCH), which catalyzes the rate-limiting step in the biosynthesis of tetrahydrobiopterin (BH4), a critical cofactor in the production of monoamine neurotransmitters. Autosomal dominant GTPCH (adGTPCH) deficiency is the most common cause of dopa-responsive dystonia (DRD), whereas the recessive form (arGTPCH) is an ultrarare and poorly characterized disorder with earlier and more complex presentation that may disrupt neurodevelopmental processes. Here, we delineated the phenotypic spectrum of ARGTPCHD and investigated the predictive value of biochemical and genetic correlates for disease outcome. OBJECTIVES: The aim was to study 4 new cases of arGTPCH deficiency and systematically review patients reported in the literature. METHODS: Clinical, biochemical, and genetic data and treatment response of 45 patients are presented. RESULTS: Three phenotypes were outlined: (1) early-infantile encephalopathic phenotype with profound disability (24 of 45 patients), (2) dystonia-parkinsonism phenotype with infantile/early-childhood onset of developmental stagnation/regression preceding the emergence of movement disorder (7 of 45), and (3) late-onset DRD phenotype (14 of 45). All 3 phenotypes were responsive to pharmacological treatment, which for the first 2 must be initiated early to prevent disabling neurodevelopmental outcomes. A gradient of BH4 defect and genetic variant severity characterizes the 3 clinical subgroups. Hyperphenylalaninemia was not observed in the second and third groups and was associated with a higher likelihood of intellectual disability. CONCLUSIONS: The clinical spectrum of arGTPCH deficiency is a continuum from early-onset encephalopathies to classical DRD. Genotype and biochemical alterations may allow early diagnosis and predict clinical severity. Early treatment remains critical, especially for the most severe patients.

RhoB plays a central role in hyperosmolarity-induced cell shrinkage in renal cells.

The small Rho GTP-binding proteins are important cell morphology, function, and apoptosis regulators. Unlike other Rho proteins, RhoB can be subjected to either geranylgeranylation (RhoB-GG) or farnesylation (RhoB-F), making that the only target of the farnesyltransferase inhibitor (FTI). Fluorescence resonance energy transfer experiments revealed that RhoB is activated by hyperosmolarity. By contrast, hyposmolarity did not affect RhoB activity. Interestingly, treatment with farnesyltransferase inhibitor-277 (FTI-277) decreased the cell size. To evaluate whether RhoB plays a role in volume reduction, renal collecting duct MCD4 cells and Human Kidney, HK-2 were transiently transfected with RhoB-wildtype-Enhance Green Fluorescence Protein (RhoB-wt-EGFP) and RhoB-CLLL-EGFP which cannot undergo farnesylation. A calcein-based fluorescent assay revealed that hyperosmolarity caused a significant reduction of cell volume in mock and RhoB-wt-EGFP-expressing cells. By contrast, cells treated with FTI-277 or expressing the RhoB-CLLL-EGFP mutant did not properly respond to hyperosmolarity with respect to mock and RhoB-wt-EGFP expressing cells. These findings were further confirmed by 3D-LSCM showing that RhoB-CLLL-EGFP cells displayed a significant reduction in cell size compared to cells expressing RhoB-wt-EGFP. Moreover, flow cytometry analysis revealed that RhoB-CLLL-EGFP expressing cells as well as FTI-277-treated cells showed a significant increase in cell apoptosis. Together, these data suggested that: (i) RhoB is sensitive to hyperosmolarity and not to hyposmolarity; (ii) inhibition of RhoB farnesylation associates with an increase in cell apoptosis, likely suggesting that RhoB might be a paramount player controlling apoptosis by interfering with responses to cell volume change.

Expiratory braking defines the breathing patterns of asphyxiated neonates during therapeutic hypothermia.

Introduction: Although neonatal breathing patterns vary after perinatal asphyxia, whether they change during therapeutic hypothermia (TH) remains unclear. We characterized breathing patterns in infants during TH for hypoxic-ischemic encephalopathy (HIE) and normothermia after rewarming. Methods: In seventeen spontaneously breathing infants receiving TH for HIE and in three who did not receive TH, we analyzed respiratory flow and esophageal pressure tracings for respiratory timing variables, pulmonary mechanics and respiratory effort. Breaths were classified as braked (inspiratory:expiratory ratio ≥1.5) and unbraked (<1.5). Results: According to the expiratory flow shape braked breaths were chategorized into early peak expiratory flow, late peak expiratory flow, slow flow, and post-inspiratory hold flow (PiHF). The most braked breaths had lower rates, larger tidal volume but lower minute ventilation, inspiratory airway resistance and respiratory effort, except for the PiHF, which had higher resistance and respiratory effort. The braked pattern predominated during TH, but not during normothermia or in the uncooled infants. Conclusions: We speculate that during TH for HIE low respiratory rates favor neonatal braked breathing to preserve lung volume. Given the generally low respiratory effort, it seems reasonable to leave spontaneous breathing unassisted. However, if the PiHF pattern predominates, ventilatory support may be required.

Additional copies of 1q negatively impact the outcome of multiple myeloma patients and induce transcriptomic deregulation in malignant plasma cells.

Additional copies of chromosome 1 long arm (1q) are frequently found in multiple myeloma (MM) and predict high-risk disease. Available data suggest a different outcome and biology of patients with amplification (Amp1q, ≥4 copies of 1q) vs. gain (Gain1q, 3 copies of 1q) of 1q. We evaluated the impact of Amp1q/Gain1q on the outcome of newly diagnosed MM patients enrolled in the FORTE trial (NCT02203643). Among 400 patients with available 1q data, 52 (13%) had Amp1q and 129 (32%) Gain1q. After a median follow-up of 62 months, median progression-free survival (PFS) was 21.2 months in the Amp1q group, 54.9 months in Gain1q, and not reached (NR) in Normal 1q. PFS was significantly hampered by the presence of Amp1q (HR 3.34 vs. Normal 1q, P < 0.0001; HR 1.99 vs. Gain1q, P = 0.0008). Patients with Gain1q had also a significantly shorter PFS compared with Normal 1q (HR 1.68, P = 0.0031). Concomitant poor prognostic factors or the failure to achieve MRD negativity predicted a median PFS < 12 months in Amp1q patients. Carfilzomib-lenalidomide-dexamethasone plus autologous stem cell transplantation treatment improved the adverse effect of Gain1q but not Amp1q. Transcriptomic data showed that additional 1q copies were associated with deregulation in apoptosis signaling, p38 MAPK signaling, and Myc-related genes.

Epilepsy phenotypes across the different age-ranges in IQSEC2-related encephalopathy: An Italian multicentre retrospective cohort study.

BACKGROUND: Epilepsy is a hallmark of IQSEC2-related encephalopathy within a phenotypic variability ranging between early onset epileptic and developmental encephalopathy and X-linked intellectual disability with epilepsy. PATIENTS AND METHODS: Data including demographic aspects, gene variants, seizure semiology and timing, EEG features, neuroimaging and response to therapy were retrospectively collected in patients with IQSEC2-related epilepsy referring to 8 Italian tertiary centres. RESULTS: The reported cohort included 11 patients (8 males and 3 females). Mean age at the onset of epilepsy was 3.90±2.80 years. No cases were reported in the first year of life. No specific epileptic syndromes were recognized. Predominant seizure-types in the age range 12-36 months included focal onset tonic seizures with impaired awareness, myoclonic seizures, and late onset spasms. Generalized motor seizures were predominant in patients between 3 and 6 years and between 12 and 18 years while focal motor seizures with impaired awareness were the most represented types between 6 and 12 years. No patients experienced status epilepticus. EEG patterns included a delayed maturation of EEG organization, irregular focal or diffuse slow activity, multifocal or diffuse epileptiform abnormalities. No structural epileptogenic lesions were detected at MRI. Valproate, lamotrigine, clobazam, topiramate and levetiracetam were the most used antiseizure medication. Complete seizure freedom was achieved only in 2 patients. CONCLUSIONS: Onset of epilepsy after the first year of age, predominance of focal seizures with impaired awareness and generalized motor seizures, no pathognomonic underlying epileptic syndrome and infrequent occurrence of status epilepticus emerged as the main features of IQSEC2-related epilepsy phenotype.

Psychiatric Manifestations in Children and Adolescents with Inherited Metabolic Diseases.

Background: Inherited metabolic disorders (IEMs) can be represented in children and adolescents by psychiatric disorders. The early diagnosis of IEMs is crucial for clinical outcome and treatment. The aim of this review is to analyze the most recurrent and specific psychiatric features related to IEMs in pediatrics, based on the onset type and psychiatric phenotypes. Methods: Following the PRISMA Statement, a systematic literature review was performed using a predefined algorithm to find suitable publications in scientific databases of interest. After removing duplicates and screening titles and abstracts, suitable papers were analyzed and screened for inclusion and exclusion criteria. Finally, the data of interest were retrieved from the remaining articles. Results: The results of this study are reported by type of symptoms onset (acute and chronic) and by possible psychiatric features related to IEMs. Psychiatric phenomenology has been grouped into five main clinical manifestations: mood and anxiety disorders; schizophrenia-spectrum disorders; catatonia; eating disorders; and self-injurious behaviors. Conclusions: The inclusion of a variety of psychiatric manifestations in children and adolescents with different IEMs is a key strength of this study, which allowed us to explore the facets of seemingly different disorders in depth, avoiding possible misdiagnoses, with the related delay of early and appropriate treatments.

Mast cell signaling and its role in urticaria.

Chronic urticaria is a mast cell (MC)-driven disease characterized by the development of itching wheals and/or angioedema. In the last decades, outstanding progress has been made in defining the mechanisms involved in MC activation, and novel activating and inhibitory receptors expressed in MC surface were identified and characterized. Besides an IgE-mediated activation through high-affinity IgE receptor cross-linking, other activating receptors, including Mas-related G-protein-coupled receptor-X2, C5a receptor, and protease-activated receptors 1 and 2 are responsible for MC activation. This would partly explain the reason some subgroups of chronic spontaneous urticaria (CSU), the most frequent form of urticaria in the general population, do not respond to IgE target therapies, requiring other therapeutic approaches for improving the management of the disease. In this review, we shed some light on the current knowledge of the immunologic and nonimmunologic mechanisms regulating MC activation in CSU, considering the complex inflammatory scenario underlying CSU pathogenesis, and novel potential MC-targeted therapies, including surface receptors and cytoplasmic signaling proteins.

Misdiagnosis of functional neurological symptom disorders in paediatrics: Narrative review and relevant case report.

Functional neurological symptom disorders (FNSD) pose a common challenge in clinical practice, particularly in pediatric cases where the clinical phenotypes can be intricate and easily confused with structural disturbances. The frequent coexistence of FNSDs with other medical disorders often results in misdiagnosis. In this review, we highlight the distinctions between FNSD and various psychiatric and neurological conditions. Contrary to the misconception that FNSD is a diagnosis of exclusion, we underscore its nature as a diagnosis of inclusion, contingent upon recognizing specific clinical features. However, our focus is on a critical learning point illustrated by the case of a 14-year-old male initially diagnosed with FNSD, but subsequently found to have a rare primary monogenic movement disorder (paroxysmal kinesigenic dyskinesia, PKD). The crucial takeaway from this case is the importance of avoiding an FNSD diagnosis based solely on psychiatric comorbidity and suppressible symptoms. Instead, clinicians should diligently assess for specific features indicative of FNSD, which were absent in this case. This emphasizes the importance of making a diagnosis of inclusion. Extended follow-up and clinical-oriented genetic testing might help identify comorbidities, prevent misdiagnosis, and guide interventions in complex cases, which cannot be simply classified as "functional" solely because other conditions can be excluded.

Understanding and Avoiding Mistakes in Diagnosing Children with Functional Neurological Symptom Disorders: A Review and Case Report: This article discusses Functional Neurological Symptom Disorders (FNSDs), focusing on misdiagnosis, differential diagnosis, and other diagnostic challenges, particularly in pediatric cases. FNSDs involve motor or sensory symptoms that are inconsistent over time and unexplained by neurological disease, often associated with psychosocial factors. The article highlights the complexity of distinguishing FNSDs from other neurological and psychiatric conditions, emphasizing the importance of careful evaluation. The authors review various conditions that can mimic FNSDs, such as epileptic seizures, syncope, and different motor disorders. They emphasize the need to consider psychiatric conditions in the differential diagnosis, including factitious disorders, and malingering. The article presents a case study of a 14-year-old with involuntary movements, initially diagnosed as having a Functional Movement Disorder. After careful evaluation, the patient was diagnosed with a genetic dystonia (PRRT2 mutation). The case shows the importance of not rely solely on psychological problems, bizarre presentations or suppressible symptoms when diagnosing FNSDs.

Biallelic variants in GTPBP3: New patients, phenotypic spectrum, and outcome.

INTRODUCTION: COXPD23 is a rare mitochondrial disease caused by biallelic pathogenic variants in GTPBP3. We report on two siblings with a mild phenotype. CASE REPORTS: The young boy presented with global developmental delay, ataxic gait and upper limbs tremor, and the older sister with absence seizures and hypertrophic cardiomyopathy. Respiratory chain impairment was confirmed in muscle. DISCUSSION: Reviewed cases point toward clustering around two prevalent phenotypes: an early-onset presentation with severe fatal encephalopathy and a late milder presentation with global developmental delay/ID and cardiopathy, with the latter as, is the main feature. Our patients showed an intermediate phenotype with intrafamilial variability.

The burden of epilepsy on long-term outcome of genetic developmental and epileptic encephalopathies: A single tertiary center longitudinal retrospective cohort study.

BACKGROUND: This retrospective cohort analysis highlighted neurodevelopmental outcome predictors of genetic developmental and epileptic encephalopathies (DEE). PATIENTS AND METHODS: Patients' demographic, clinical and molecular genetics data were collected. All patients underwent clinical, developmental, and neuropsychological assessments. RESULTS: We recruited 100 participants (53 males, 47 females) with a mean follow-up lasting 10.46 ± 8.37 years. Age at epilepsy-onset was predictive of poor adaptive and cognitive functions (VABS-II score, r = 0.350, p = 0.001; BRIEF control subscale, r = -0.253; p = 0.031). Duration of epilepsy correlated negatively with IQ (r = -0.234, p = 0.019) and VABS-II score (r = -0.367, p = 0.001). Correlations were found between delayed/lacking EEG maturation/organization and IQ (r = 0.587, p = 0.001), VABS-II score (r = 0.658, p = 0.001), BRIEF-MI and BRIEF-GEC scores (r = -0.375, p = 0.001; r = -0.236, p = 0.033), ASEBA anxiety (r = -0.220, p = 0.047) and ADHD (r = -0.233, p = 0.035) scores. The number of antiseizure medications (ASMs) correlated with IQ (r = -0.414, p = 0.001), VABS-II (r = -0.496, p = 0.001), and BRIEF-MI (r = 0.294, p = 0.012) scores; while age at the beginning of therapy with ASEBA anxiety score (r = 0.272, p = 0.013). The occurrence of status epilepticus was associated with worse adaptive performances. The linear regression analysis model showed that delayed/lacking EEG maturation/organization had a significant influence on the IQ (R2 = 0.252, p < 0.001) and the BRIEF-GEC variability (R2 = 0.042, p = 0.036). The delayed/lacking EEG maturation/organization and the duration of epilepsy also had a significant influence on the VABS-II score (R2 = 0.455, p = 0.005). CONCLUSIONS: Age at seizure-onset, EEG maturation/organization, duration of epilepsy, occurrence of status epilepticus, age at the introduction and number of ASMs used are reliable predictors of long-term outcomes in patients with genetic DEE.

IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma.

ABSTRACT: Primary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724.

Thermodynamics and S-Palmitoylation Dependence of Interactions between Human Aquaporin-4 M1 Tetramers in Model Membranes.

Aquaporin-4 (AQP4) is a water channel protein found primarily in the central nervous system (CNS) that helps to regulate water-ion homeostasis. AQP4 exists in two major isoforms: M1 and M23. While both isoforms have a homotetrameric quaternary structure and are functionally identical when transporting water, the M23 isoform forms large protein aggregates known as orthogonal arrays of particles (OAPs). In contrast, the M1 isoform creates a peripheral layer around the outside of these OAPs, suggesting a thermodynamically stable interaction between the two. Structurally, the M1 isoform has an N-terminal tail that is 22 amino acids longer than the M23 isoform and contains two solvent-accessible cysteines available for S-palmitoylation at cysteine-13 (Cys-13) and cysteine-17 (Cys-17) in the amino acid sequence. Earlier work suggests that the palmitoylation of these cysteines might aid in regulating AQP4 assemblies. This work discusses the thermodynamic driving forces for M1 protein-protein interactions and how the palmitoylation state of M1 affects them. Using temperature-dependent single-particle tracking, the standard state free energies, enthalpies, and entropies were measured for these interactions. Furthermore, we present a binding model based on measured thermodynamics and a structural modeling study. The results of this study demonstrate that the M1 isoform will associate with itself according to the following expressions: 2[AQP4-M1]4 ↔ [[AQP4-M1]4]2 when palmitoylated and 3[AQP4-M1]4 ↔ [AQP4-M1]4 + [[AQP4-M1]4]2 ↔ [[AQP4-M1]4]3 when depalmitoylated. This is primarily due to a conformational change induced by adding the palmitic acid groups at Cys-13 and Cys-17 in the N-terminal tails of the homotetramers. In addition, a statistical mechanical model was developed to estimate the Gibbs free energy, enthalpy, and entropy for forming dimers and trimers. These results were in good agreement with experimental values.

Efficacy and safety of biosimilar Peg-filgrastim after autologous stem cell transplant in myeloma and lymphoma patients: a comparative study with biosimilar Filgrastim, Lenograstim, and originator Peg-filgrastim.

Data about biosimilar Peg-filgrastim (bioPEG) in autologous stem cell transplant (ASCT) are still scarce. The aim of this study has been to assess efficacy and safety of bioPEG among lymphoma and myeloma patients undergoing ASCT, comparing these data with historical controls receiving other G-CSFs. Furthermore, an economic evaluation has been included to estimate the savings by using bioPEG. This is a prospective cohort study comparing lymphoma and myeloma patients undergoing ASCT and receiving bioPEG (n = 73) with three historical consecutive cohorts collected retrospectively who received other G-CSFs (Lenograstim - Leno - n = 101, biosimilar Filgrastim - bioFIL n = 392, and originator Peg-filgrastim - oriPEG n = 60). We observed a significantly shorter time to neutrophils and platelet engraftment (p < 0.001) in patients treated with bioPEG and oriPEG. Moreover, patients who received bioPEG showed a shorter hospitalization time (p < 0.001) and a lower transfusion need (p < 0.001). We did not observe any significant difference in terms of transplant-related mortality, mucositis, and diarrhea among the four groups. No serious adverse events were associated with bioPEG. Similar data were obtained after running a stratified analysis for lymphomas and myeloma separately conducted by using a propensity score matching. The average total cost per patient of bioPEG was € 18218.9 compared to € 23707.8, € 20677.3 and € 19754.9 of Leno, oriPEG, and bioFIL, respectively. In conclusion, bioPEG seems to be as effective as the originator and more effective than short-acting G-CSFs in terms of post-transplant engraftment in myeloma and lymphoma patients undergoing ASCT. Moreover, bioPEG was cost-effective when compared with the other G-CSFs.

The multifaceted role of mast cells in the pathogenesis of rheumatoid arthritis.

Mast cells (MC) are tissue duelling cells playing an active role in both innate and adaptive immune system. They act as first players in different microbial infections and exert a crucial role in allergy, chronic inflammation, fibrosis, and rheumatic diseases (RD), including rheumatoid arthritis (RA). MC are normally present in human synovia and they increase in the joints of RA patients, contributing to inflammatory and remodelling processes. Due to their great plasticity and multifunctionality, MC exert a wide range of roles in different stages of the disease. To date, the results obtained by in-vitro and in-vivo studies have contributed to better clarify the dynamic role of MC in local arthritis of RA and have improved our knowledge on different aspect of the disease. Although different mice models have been extensively used to investigate the contribution of MC in different stages of RA, those models often fail to reproduce the complexity and the heterogeneity of the human disease. Here, we provide an overview on different roles of MC in RA pathogenesis and how these cells might influence some clinical features of the disease.

Cancer mortality after kidney transplantation: A multicenter cohort study in Italy.

Kidney transplant (KT) recipients are known to be at risk of developing several cancer types; however, cancer mortality in this population is underinvestigated. Our study aimed to assess the risk of cancer death among Italian KT recipients compared to the corresponding general population. A cohort study was conducted among 7373 individuals who underwent KT between 2003 and 2020 in 17 Italian centers. Date and cause of death were retrieved until 31 December 2020. Indirect standardization was used to estimate standardized mortality ratios (SMRs) and corresponding 95% confidence intervals (CIs). Cancer was the most common cause of death among the 7373 KT recipients, constituting 32.4% of all deaths. A 1.8-fold excess mortality (95% CI: 1.59-2.09) was observed for all cancers combined. Lymphomas (SMR = 6.17, 95% CI: 3.81-9.25), kidney cancer (SMR = 5.44, 95% CI: 2.97-8.88) and skin melanoma (SMR = 3.19, 95% CI: 1.03-6.98) showed the highest excess death risks. In addition, SMRs were increased about 1.6 to 3.0 times for cancers of lung, breast, bladder and other hematopoietic and lymphoid tissues. As compared to the general population, relative cancer mortality risk remained significantly elevated in all age groups though it decreased with increasing age. A linear temporal increase in SMR over time was documented for all cancers combined (P < .01). Our study documented significantly higher risks of cancer death in KT recipients than in the corresponding general population. Such results support further investigation into the prevention and early detection of cancer in KT recipients.

'A novel TRIP4 Variant Associated with Peripheral Neuropathy: Expanding the Clinical and Genetic Spectrum of ASC1-Related Myopathy'.

Activating Signal Cointegrator 1 complex (ASC-1 complex) is a ribonucleoprotein tetramer participating in transcriptional coactivation and RNA processing, consisting of four subunits: ASCC1-ASCC3 and ASC-1. Pathogenic variants in the TRIP4 and ASCC1 genes, encoding the ASC-1 and ASCC1 subunits, were recently described in congenital myopathic conditions without signs of motor neuron involvement, and Spinal Muscular Atrophy-like (SMA-like) phenotype with prenatal bone fractures. We present a novel pathogenic TRIP4 variant in two siblings with severe phenotype and mixed sensory-motor polyneuropathy. The reviewed phenotypic spectrum is broad, but sensory-motor polyneuropathy is so-far unreported. We thus expand ASC-1 related myopathy phenotype.

What are the considerations when initiating treatment for epilepsy in children?

INTRODUCTION: There is a very wide spectrum of epilepsies and developmental and epileptic encephalopathies that affect children, from self-limited forms, not necessarily requiring treatment, to severe drug-resistant ones. AREAS COVERED: In this perspective, the authors discuss the main factors to consider before drug prescription in children, considering the most recent clinical research, including age, seizure type, epilepsy syndrome, etiology, efficacy and safety profile, comorbidities, gender, available formulations, costs and drug coverage, and regulatory issues. The literature search was conducted through a PubMed search on antiseizure medications for patients aged 0-18, with respect to each of the aforementioned factors, and by checking the reference lists of relevant papers. EXPERT OPINION: The most expanding field of research and innovation for clinical practice is precision medicine, which addresses the holistic treatment of genetic epilepsies and developmental and epileptic encephalopathies. It achieves this by addressing their detrimental effects on synapses, neurotransmission, and cellular signaling pathways with the double aim to treat seizures and to rescue neurodevelopmental trajectories, but also the issue of adverse events and drug resistance through pharmacogenomics.

Scalp high-frequency oscillations differentiate neonates with seizures from healthy neonates.

OBJECTIVE: We aimed to investigate (1) whether an automated detector can capture scalp high-frequency oscillations (HFO) in neonates and (2) whether scalp HFO rates can differentiate neonates with seizures from healthy neonates. METHODS: We considered 20 neonates with EEG-confirmed seizures and four healthy neonates. We applied a previously validated automated HFO detector to determine scalp HFO rates in quiet sleep. RESULTS: Etiology in neonates with seizures included hypoxic-ischemic encephalopathy in 11 cases, structural vascular lesions in 6, and genetic causes in 3. The HFO rates were significantly higher in neonates with seizures (0.098 ± 0.091 HFO/min) than in healthy neonates (0.038 ± 0.025 HFO/min; P = 0.02) with a Hedge's g value of 0.68 indicating a medium effect size. The HFO rate of 0.1 HFO/min/ch yielded the highest Youden index in discriminating neonates with seizures from healthy neonates. In neonates with seizures, etiology, status epilepticus, EEG background activity, and seizure patterns did not significantly impact HFO rates. SIGNIFICANCE: Neonatal scalp HFO can be detected automatically and differentiate neonates with seizures from healthy neonates. Our observations have significant implications for neuromonitoring in neonates. This is the first step in establishing neonatal HFO as a biomarker for neonatal seizures.