Explore the vast range of titles available.

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3–7 ng/mL (low exposure) and 9–15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex. In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2–65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01713946. Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2–22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3–37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5–49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1–21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8–41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0–48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group. Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures. Novartis Pharmaceuticals Corporation.

Background Recently, natural tissue repair has become popular in the treatment of pelvic organ prolapsed. In this study, we compared patients who underwent cystocele repair with the rug-weaving plication technique, a natural tissue repair method implemented since 2022 for anterior prolapse, with those treated using conventional colporrhaphy. Methods We retrospectively reviewed the data of 65 patients who underwent anterior vaginal wall repair with the rug-weaving plication technique ( n  = 33, Group 1) or conventional colporrhaphy ( n  = 32, Group 2). We recorded the patients’ clinicodemographic and surgical data. At the 6-month postoperative follow-up, we assessed patients’ complaints, degree of prolapse (using the simplified Pelvic Organ Prolapse Quantification system), and pelvic floor muscle strength (using the Modified Oxford Score). Anterior vaginal wall thickness was measured using transvaginal ultrasonography. We compared clinicodemographic and surgical data and postoperative outcomes between the two groups. Results The two groups were comparable in terms of age ( p  = 0.326), number of pregnancies ( p  = 0.307), number of parities ( p  = 0.555), preoperative anterior wall simplified Pelvic Organ Prolapse Quantification grade ( p  = 0.380), preoperative apical prolapse simplified Pelvic Organ Prolapse Quantification grade ( p  = 0.518), postoperative Modified Oxford Score ( p  = 0.857), operation time ( p  = 0.809), postoperative haemoglobin ( p  = 0.674), and amount of bleeding ( p  = 0.951). Compared with Group 2, Group 1 had significantly higher postoperative anterior vaginal wall thickness ( p  < 0.001) and significantly lower postoperative anterior wall simplified Pelvic Organ Prolapse Quantification grade ( p  < 0.001). Conclusions The rug-weaving plication technique may offer a viable alternative for cystocele repair without mesh, using natural tissue and potentially reducing mesh-related complications and recurrence rates. Clinical trial number NCT06410469 (03/05/2024).

Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health. Ataxia is a rare disease that affects balance and co-ordination, leading to difficulties in walking and other movements. The disease mostly affects adults, but some children are born with it and they often have additional cognitive and developmental problems. Mutations in at least 60 genes are known to be able to cause ataxia, but it is thought that there are still more to be found. Kim, Sandford et al. studied two siblings with the childhood form of ataxia and found that they both had a mutation in a gene called ATG5. The protein produced by the mutant ATG5 gene was less able to interact with another protein called ATG12. Furthermore, the cells of both children had defects in a process called autophagy – which destroys old and faulty proteins to prevent them accumulating and causing damage to the cell. Next, Kim, Sandford et al. examined the effect of this mutation in baker’s yeast cells. Cells with a mutation in the yeast equivalent of human ATG5 had lower levels of autophagy than normal cells. Further experiments used fruit flies that lacked fly Atg5, which were unable to fly or walk properly. Inserting the normal form of human ATG5 into the flies restored normal movement, but the mutant form of the gene had less of an effect. These findings suggest that a mutation in ATG5 can be responsible for the symptoms of childhood ataxia. Kim, Sandford et al. think that other people with severe ataxia may have mutations in genes involved in autophagy. Therefore, the next step is to study autophagy in cells from many other ataxia patients.

Breaking bad news is a difficult but unavoidable responsibility of physicians. It constitutes a set of stressfull duties, which become more critical during uncertain medical situations such as the COVID-19 pandemic. The purpose of the current study; To determine the factors that affect physicians’ attitudes and approaches in giving bad news about, life-threatening medical conditions. All staff working in the COVID-19 wards as physicians were invited to complete a standardized questionnaire evaluating the descriptive properties and attitude and approach to breaking bad news in this cross-sectional study. A total of 120 physicians were included in the study. An approximately equal number of physicians working in internal medicine and surgical branches were included in the study ( p  = 0.540). Internal medicine specialists encountered breaking bad news more commonly than surgeons ( p  = 0.002). Only 14.2% of them stated that they “always” felt competent. Approximately, 68.3% ( n  = 82) of the physicians did not receive any kind of training on breaking bad news. More than half of the physicians stated feeling anxious about breaking bad news, particularly when announcing death. Announcement of death due to COVID-19 (5.8%) followed announcing fatal diseases (13.3%) and limb loss with function loss (8.3%). The COVID-19 pandemic revealed the physicians’ need for education on “breaking bad news.” Physicians with a shorter work experience had a higher rate of receiving undergraduate education about breaking bad news than those with more work experience. As the length of service increased, there was a significant increase in the rate of receiving education regarding breaking bad news after graduation ( p  = 0.037). Additionally, it helped to convey the optimal approach in extraordinary and uncertain medical situations. Our study findings support this statement.The most common reason for breaking bad news is the announcement of death, which should be conveyed to the patient’s relatives in accordance with communication principles, taking into account their current situation. This approach can effectively reduce the anxiety experienced by the physician breaking the news and mitigate reactions from the patient’s relatives such as refusal and incomprehension in the face of the patient’s loss.

In subacute sclerosing panencephalitis (SSPE) the persistence of measles virus (MeV) may be related to the altered immune response. In this study, cytokine responses of lymphocytes and monocytes were evaluated in SSPE compared to controls with non-inflammatory (NICON) and inflammatory (ICON) diseases. Patients with SSPE (n = 120), 78 patients with ICON and 63 patients with NICON were included in this study. Phenotypes of peripheral blood mononuclear cells (PBMC) have been analyzed by flow cytometry. CD3 and CD28, and S . aureus Cowan strain I (SAC) stimulated and unstimulated cells were cultured and IL-2, IL-10, IFN-γ, IL-12p40, IL-12p70 and IL-23 were detected in supernatants by ELISA. MeV peptides were used for MeV-specific stimulation and IFN-γ secretion of PBMC was measured by ELISPOT. Spontaneous and stimulated secretions of IL-10 were lower in SSPE compared to both control groups. T cell stimulation induced lower IFN-γ production than ICON group, but higher IL-2 than NICON group in SSPE. Stimulated PBMC produced lower IL-12p70 in SSPE and had decreased CD46 on the cell surface, suggesting the interaction with the virus. IFN-γ responses against MeV peptides were not prominent and similar to NICON patients. The immune response did not reveal an inflammatory activity to eliminate the virus in SSPE patients. Even IL-10 production was diminished implicating that the response is self-limited in controlling the disease.

Panthothenate kinase-associated neurodegeneration (PKAN) belongs to a group of hereditary neurodegenerative disorders known as neuroacanthocytosis (NA). This genetically heterogeneous group of diseases is characterized by degeneration of neurons in the basal ganglia and by the presence of deformed red blood cells with thorny protrusions, acanthocytes, in the circulation. The goal of our study is to elucidate the molecular mechanisms underlying this aberrant red cell morphology and the corresponding functional consequences. This could shed light on the etiology of the neurodegeneration. We performed a qualitative and semi-quantitative morphological, immunofluorescent, biochemical and functional analysis of the red cells of several patients with PKAN and, for the first time, of the red cells of their family members. We show that the blood of patients with PKAN contains not only variable numbers of acanthocytes, but also a wide range of other misshapen red cells. Immunofluorescent and immunoblot analyses suggest an altered membrane organization, rather than quantitative changes in protein expression. Strikingly, these changes are not limited to the red blood cells of PKAN patients, but are also present in the red cells of heterozygous carriers without neurological problems. Furthermore, changes are not only present in acanthocytes, but also in other red cells, including discocytes. The patients' cells, however, are more fragile, as observed in a spleen-mimicking device. These morphological, molecular and functional characteristics of red cells in patients with PKAN and their family members offer new tools for diagnosis and present a window into the pathophysiology of neuroacanthocytosis.

Background Syndromic intellectual disability (ID) with accompanying primary microcephaly is a group of rare neurodevelopmental disorders exhibiting extreme genetic and clinical heterogeneity. This layered heterogeneity can partially be resolved by unbiased genetic approaches targeting the genome with next generation sequencing (NGS) technologies, including exome sequencing (ES). Objective This study was performed to dissect the clinical and genetic features in five distinct IDM cases. Methods Singleton or trio ES approach followed by in-depth variant analysis using alternative inheritance models was performed. Results We have identified biallelic loss of function variants in genes WDR62 and AP4M1 in three families, together with de novo missense variants in genes SOX11 and TRIO in two families. ES based haplotype analysis in two cases upon identification of an identical WDR62 variant in the homozygous state in two cases was suggestive of a small shared haplotype of 0.1 Mb. Additionally, we have shown a paternal origin for the de novo variant in TRIO via a polymorphic tag SNP, which enlightens the mutational mechanism for this variant. Conclusion In populations with high parental consanguinity, an autosomal recessive inheritance pattern for data analysis is usually the most obvious choice. Therefore, heterozygous variants may be overlooked in standard NGS analyses in consanguineous families. Our findings underlie the importance of using multiple inheritance models in NGS data analysis.

Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2 - a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1 knockout cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global knockout of Spns1 caused embryonic lethality between E12.5-E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC) and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1 knockout (Spns1-KO) mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K-AKT signaling pathway. Furthermore, we identified three human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and exhibiting cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.

Objective: Among the hypomyelinating diseases of childhood, Pelizaeus Merzbacher disease (PMD) is caused by X-linked proteolipid protein (PLP) gene mutations, whereas patients without mutations of PLP gene-called Pelizaues Merzbacher-like disease (PMLD) have recessive gap junction protein α12 (gap junction alpha-12/gap junction gamma-2) gene mutations. The aim of this study was to evaluate clinical severity and progression in time in patients with PMD and PMLD. Methods: The motor developmental stages of the patients were reviewed; disease severity was classified according to the walking ability they were able to achieve. Progression pattern was determined according to comparison of neurological findings at the time of the study and at follow-up visits. Patients with PMD and PMLD were compared in terms of disease severity and progression rates as well as patient groups with a unique causative mutation were analyzed individually. Results: There were 9 patients with PMD (mean age 15.2±3.1) and 11 patients with PMLD (mean age 12.4±1.9). The presence of severe disease was more common in patients with PMD when compared to PMLD. In X-linked PMD, missense mutations were associated with the most severe disease and rapid progression, while deletion mutations were associated with mild disease severity and slow progression. Disease severity and progression patterns seemed to be heterogenous in different causative mutations of PMLD. Conclusion: Although PMLD might have milder disease phenotype when compared to PMD, certain causative mutations in different genetic traits may cause different disease severity and progression patterns.

Objective: Motor development is at the forefront of evaluation of neurodevelopmental functions in the first 6 months of life. Significant spontaneous movement patterns of infants are called general movements. General movements are rough and complex movements involving the entire body. Prechtl qualitative assesment of general movements (GMA) can be performed in the first 20 weeks. It has been reported that GMA can identify motor problems with 98% sensitivity. Our aim is to investigate the specificity and sensitivity of GMA in our series by comparing the results of GMA and neurological evaluation. Materials and Methods: Eighty infants who were less than 20 weeks old were included into the study. All infants were assessed with both neurological evaluation and video recording for the GMA at the Spastic Childrens Foundation of Turkey. As a standard technique; video recording was obtained in the GMA room of comfortably dressed infants when they were not sleepy or restless in the GMA room for 3-5 minutes in the supine position. The assessments were based on the corrected age for the preterm infants. Results: The GMA and neurological evaluation results were found to be incompatible with each other in only 8 of 80 infants. A total of 90 video recordings were made of the 80 infants. Our study revealed that GMA can identify the motor problems with 95.8% sensitivity and 87.5% specificity. Conclusion: Our study demonstrates that GHA may be an independent method that can identify motor problems during infancy. This study has an importance because it is one of the few independent studies that was completed by a differentiated cerebral palsy center, where GMA is applied as a standard method.