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Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases. Aberrant changes in DNA methylation have been implicated in various neurodevelopmental disorders but remain under studied in developmental and epileptic encephalopathies. Here, the authors demonstrate the diagnostic utility of genome-wide DNA methylation analyses toward identifying molecular etiologies in developmental and epileptic encephalopathies.

Introduction Pathogenic variants in STXBP1 cause a spectrum of disorders mainly consisting of developmental and epileptic encephalopathy (DEE), often featuring drug-resistant epilepsy. An increased mortality risk occurs in individuals with drug-resistant epilepsy and DEE, with sudden unexpected death in epilepsy (SUDEP) often the major cause of death. This study aimed to identify the rate and causes of mortality in STXBP1 -related disorders. Methods Through an international call, we analyzed data on individuals with STXBP1 pathogenic variants, who passed away from causes related to their disease. Results We estimated a mortality rate of 3.2% (31/966), based on the STXBP1 Foundation and the STXBP1 Global Connect registry. In total, we analyzed data on 40 individuals (23 males) harboring pathogenic STXBP1 variants, collected from different centers worldwide. They died at a median age of 13 years (range: 11 months—46 years). The most common cause of death was SUDEP (36%), followed by pulmonary infections and respiratory complications (33%). The incidence of SUDEP peaked in mid-childhood, while non-SUDEP causes were more frequent in early childhood or adulthood (p = 0.006). In the most severe phenotypes, death was related to non-SUDEP causes ( p  = 0.018). Conclusion We found a mortality rate in STXBP1 -related disorders similar to other DEEs, with an early age at death and SUDEP as well as pulmonary infections as the main cause of death. These findings assist in prognostic evaluation and genetic counseling for the families. They help to define the mortality risk of STXBP1 -related disorders and implement preventative strategies.

Background The coronavirus disease 19 (COVID-19) has had a profound impact on our healthcare system. Surgery in particular faced significant challenges related to allocation of resources and equitable patient selection, resulting in a delay in non-emergent procedures. We sought to study the impact of the COVID-19 pandemic on patient outcomes after thyroidectomy. Methods This was a cross-sectional study using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database that included all thyroidectomies from 2018 to 2020. The primary outcome evaluated was surgical outcomes during 2020, the first year of the pandemic, compared to years preceding the pandemic. Factors associated with adverse postoperative outcomes during the study period were included in a multivariate analysis. Results The volume of thyroidectomy procedures in 2020 decreased 16.4% when compared to the preceding years. During 2020, there was a significant increase in mortality (0.14% vs. 0.07%, p  = 0.03), unplanned intubation (0.45% vs. 0.27%, p  < 0.01) and cardiac arrest (0.11% vs. 0.03%, p  < 0.01), while other complications remained stable. Undergoing surgery in 2020 remained as a risk factor for mortality in a multivariate analysis (OR 2.4 95% CI 1.3–4.4). Conclusion The first year of the COVID-19 pandemic had a significant impact on outcomes after thyroidectomy resulting in increased mortality. As the world recovers, there will likely be an increase number of patients seeking care who were unable to obtain it during the pandemic. Close attention should be placed on the outcomes which were altered during the pandemic.

Patient-reported outcome measures for parathyroid and thyroid disease (PROMPT) is a 30-question, previously validated, survey assessing symptoms on a scale from 0 to 100. Using PROMPT, we aimed to assess symptom improvement for patients undergoing thyroidectomy and parathyroidectomy. Single-center prospective study in which PROMPT was used to assess symptom improvement in patients undergoing parathyroidectomy or thyroidectomy. A postoperative assessment was performed approximately 6 months after surgery and compared to its baseline preoperative assessment. A total of 144 patients completed both assessments (71 parathyroidectomy, 73 thyroidectomy). Parathyroidectomy patients demonstrated significant improvements in all hyperparathyroidism domains (38.2–28.3, p < 0.001) regardless of preoperative calcium and parathyroid hormone levels. Thyroidectomy patients experienced improvement in their compressive symptoms (25.6–16.5, p < 0.001). PROMPT objectively demonstrates the clinical effectiveness of parathyroidectomy and thyroidectomy in alleviating subjective patient symptoms. PROMPT offers promising use as a standardized metric to assess quality of life improvement within endocrine surgery. •PROMPT can objectively demonstrate the clinical effectiveness of parathyroidectomy and thyroidectomy.•PROMPT can objectively demonstrate the clinical effectiveness of parathyroidectomy regardless of the biochemical profile.•PROMPT can help evaluate patients in a high-volume clinic with mixed thyroid and parathyroid disease states.

Background T2-weighted fast spin-echo imaging (T2-W FSE) is frequently degraded by motion in pediatric patients. MR imaging with periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) employs alternate sampling of k-space to achieve motion reduction. Objective To compare T2-W PROPELLER FSE (T2-W PROP) with conventional T2-W FSE for: (1) image quality; (2) presence of artefacts; and (3) ability to detect lesions. Materials and methods Ninety-five pediatric patients undergoing brain MRI (1.5 T) were evaluated with T2-W FSE and T2-W PROP. Three independent radiologists rated T2-W FSE and T2-W PROP, assessing image quality, presence of artefacts, and diagnostic confidence. Chi-square analysis and Wilcoxon signed rank test were used to assess the radiologists’ responses. Results Compared with T2-W FSE, T2-W PROP demonstrated better image quality and reduced motion artefacts, with the greatest benefit in children younger than 6 months. Although detection rates were comparable for the two sequences, blood products were more conspicuous on T2-W FSE. Diagnostic confidence was higher using T2-W PROP in children younger than 6 months. Average inter-rater agreement was 87%. Conclusion T2-W PROP showed reduced motion artefacts and improved diagnostic confidence in children younger than 6 months. Thus, use of T2-W PROP rather than T2-W FSE should be considered in routine imaging of this age group, with caution required in identifying blood products.

To report our results for the placement of central venous stents in patients undergoing hemodialysis. Ten Wallstents (Schneider, Bülach, Switzerland) were placed in 10 patients with shunt thrombosis, shunt dysfunction or arm swelling associated with central vein stenosis or occlusion. Technical success, patency and complications were evaluated. Stent deployment was successful in all cases. In seven cases (70%) there was significant delayed stent shortening. In two of these cases there was also stent migration. All these cases required additional stents. Primary patency rates at 6, 12 and 24 months were 66%, 25% and 0. Twenty-three additional procedures (percutaneous transluminal angioplasty or stenting) were required to achieve secondary patency rates at 6, 12 and 24 months of 100%, 75% and 57%. Stent placement in the central veins of dialysis patients has a high technical success rate resulting in symptomatic relief and preservation of access. Repeat interventions are required to maintain patency. Significant delayed shortening of the Wallstent occurred in 70% of patients which may have affected the patency rates. Strategies are suggested to avoid this problem.

Background: Hepatic grafr-versus-host disease (GVHD) is associated with significant morbidity and mortality. Standard therapy includes systemically administered immunosuppressive drugs. More recent reports have described catheter-directed intrahepatic arterial (IHA) delivery of low-dose methotrexate (MTX) and methylprednisolone in the treatment of corticosteroid-resistant severe hepatic GVHD. Objective: This article reports on MTX toxicity and the variability in plasma drug concentrations after IHA administration of low-dose MTX in patients with severe hepatic GVHD. Methods: In this open-label, uncontrolled pilot study, MTX and methylprednisolone were administered via the hepatic artery in patients with corticosteroid-resistant grade III or IV GVHD of the liver. Patients also received standard therapy. MTX concentrations were measured in the hepatic artery 5 and 10 minutes after injection and in peripheral venous blood at 1, 2, and 24 hours. Results: Six patients (5 males [83.3%], I female [16.7%]; median age, 32 years; range, 8–42 years) were enrolled in the study. No hepatotoxicity was observed after IHA administration of MTX. In 5 patients with normal renal function, plasma drug concentrations 24 hours after administration of MTX ranged from 0.01 to 0.12 μmol/L (mean [SD], 0.043 [0.042] μmol/L). In 1 patient with renal failure, plasma MTX concentrations were 1.0 μmol/L 24 hours after administration and 0.07 μmol/L 5 days after administration. The severe hematologic and renal toxicity observed in this patient may have contributed to his death. Adverse events in patients with GVHD and normal renal function, who had normal plasma MTX concentrations, were comparable to those that have been reported after administration of an intravenous infusion. Conclusions: In patients with GVHD and normal renal function, IHA administration of low-dose MTX was not associated with liver or bone marrow toxicity. Further study is needed to determine the optimal protocols for treating corticosteroid-resistant hepatic GVHD.