An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.

INTRODUCTION: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization. METHODS: We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling. RESULTS: ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways. DISCUSSION: This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity. HIGHLIGHTS: ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.

Snuffbox distal transradial access (dTRA) for arteriovenous fistuloplasty in Singapore: Going distal is safe.

AIM: Arteriovenous fistula (AVF) dysfunction resulting from stenosis or occlusion, is a prevalent issue in end-stage renal failure patients reliant on autogenous AVFs for dialysis. Recently, a distal transradial approach (dTRA) has emerged, offering advantages such as diminished access site complications, better patient comfort and reduced risk of radial artery occlusion. Our study seeks to assess the effectiveness, outcomes and complication rates of employing dTRA for arteriovenous fistuloplasty in Singaporean patients. METHODS: A retrospective review of all dTRA fistuloplasties performed on dysfunctional or slow to mature AVFs from 2017 to 2023 in our institution was performed. Patients with a distal radial artery measuring 2 mm or more with no evidence of occlusion or thrombosis were included. Patients who required central venoplasty or cutting balloon angioplasty were excluded. Outcome measures included technical success, mean procedure duration, complications and post-intervention primary patency at 1, 3 and 6 months. Patients were followed up for 12 months post-intervention. RESULTS: A total of 37 patients were included. 97.3% of patients undergoing dTRA fistuloplasty had radiocephalic fistulas while 2.7% had brachiobasilic fistulas. There was 100% technical success (defined as success in radial artery cannulation, sheath insertion and crossing of stenotic lesions) in our study as all patients successfully underwent fistuloplasty via dTRA approach. One-month patency rate was 97.4%, 3-month patency rate was 92.1% and 6-month patency rate was 86.8%. There were no immediate complications (haematoma, infection, bleeding, pseudoaneurysm, occlusion) of the radial artery post-intervention. CONCLUSION: Our paper illustrates the safety and efficacy of utilising dTRA for arteriovenous fistuloplasty. This approach offers distinct benefits in addressing non-mature or dysfunctional distal forearm arteriovenous fistulas and should be taken into account in anatomically suitable cases.

Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.

Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.

As genetic testing has become more accessible and affordable, variants of uncertain significance (VUS) are increasingly identified, and determining whether these variants play causal roles in disease is a major challenge. The known disease-associated Annexin A11 (ANXA11) mutations result in ANXA11 aggregation, alterations in lysosomal-RNA granule co-trafficking, and TDP-43 mis-localization and present as amyotrophic lateral sclerosis or frontotemporal dementia. We identified a novel VUS in ANXA11 (P93S) in a kindred with corticobasal syndrome and unique radiographic features that segregated with disease. We then queried neurodegenerative disorder clinic databases to identify the phenotypic spread of ANXA11 mutations. Multi-modal computational analysis of this variant was performed and the effect of this VUS on ANXA11 function and TDP-43 biology was characterized in iPSC-derived neurons. Single-cell sequencing and proteomic analysis of iPSC-derived neurons and microglia were used to determine the multiomic signature of this VUS. Mutations in ANXA11 were found in association with clinically diagnosed corticobasal syndrome, thereby establishing corticobasal syndrome as part of ANXA11 clinical spectrum. In iPSC-derived neurons expressing mutant ANXA11, we found decreased colocalization of lysosomes and decreased neuritic RNA as well as decreased nuclear TDP-43 and increased formation of cryptic exons compared to controls. Multiomic assessment of the P93S variant in iPSC-derived neurons and microglia indicates that the pathogenic omic signature in neurons is modest compared to microglia. Additionally, omic studies reveal that immune dysregulation and interferon signaling pathways in microglia are central to disease. Collectively, these findings identify a new pathogenic variant in ANXA11, expand the range of clinical syndromes caused by ANXA11 mutations, and implicate both neuronal and microglia dysfunction in ANXA11 pathophysiology. This work illustrates the potential for iPSC-derived cellular models to revolutionize the variant annotation process and provides a generalizable approach to determining causality of novel variants across genes.

Scrotal Wall Metastasis from Adenocarcinoma of Unknown Origin, with Concurrent Extramammary Paget's Disease - a Case Report.

INTRODUCTION: Scrotal cancer is a very rare disease, with the most common subtype being squamous cell carcinoma. Metastatic carcinoma to the scrotal wall is very rare. A histological finding of adenocarcinoma in a scrotal malignancy invariably suggests a metastasis from another primary cancer. We describe an enigmatic case of metastatic adenocarcinoma to the scrotum managed as metastatic adenocarcinoma of unknown origin. Attempts to identify a primary cancer were complicated by ambiguous diagnostic results. This is the first case in literature of metastatic cancer to the scrotum from an adenocarcinoma of unknown origin, and this was complicated by concurrent extramammary Paget's disease. CASE PRESENTATION: A 70-year-old male presented with painless progressive scrotal skin swelling, which was shown on histology to be adenocarcinoma. Immunohistochemistry showed prostatic lineage markers. However, the argument for a prostatic primary was weakened by negative prostate transrectal ultrasound biopsy findings and negative radiological findings. The scrotal metastatic adenocarcinoma was managed as metastatic adenocarcinoma of unknown origin. A differential of occult poorly differentiated prostatic primary was considered in view of the clinical phenotype of an elderly male patient with extensive sclerotic bony metastases, immunohistochemistry results and relatively low PSA level in relation to systemic burden of disease. The patient was managed with palliative systemic chemotherapy (carboplatin/paclitaxel) with initial disease response, but eventually developed progressive disease. DISCUSSION AND CONCLUSION: Finding of adenocarcinoma in scrotal skin malignancy indicates a metastasis and should prompt further work-up to identify a primary cancer, particularly of other genitourinary or lower gastrointestinal origin, so that treatment can be targeted at the underlying primary malignancy. However, attempts to identify a primary cancer might be complicated by ambiguous diagnostic results.

Cognitive determinants of decisional capacity in neurodegenerative disorders.

OBJECTIVE: Cognitive contributions to decisional capacity are complex and not well understood. Capacity to consent for research has been linked to executive function, but executive function assessment tools are imperfect. In this study, we examine the relationship between decisional capacity and a newly developed executive function composite score and determine whether cognitive performance can predict impaired decisional capacity. METHODS: This is a cross sectional study of participants at the National Institutes of Health with frontotemporal dementia-amyotrophic lateral sclerosis spectrum disorders enrolled between 2017 and 2022. A structured interview tool was used to ascertain research decisional capacity. Study participant Uniform Data Set (v3.0) executive function (UDS3-EF) composite score, Clinical Dementia Rating Scale©, and Neuropsychiatric Inventory was determined. RESULTS: A decrease in UDS3-EF composite score significantly increased the odds of impaired decisional capacity (OR = 2.92, 95% CI [1.66-5.13], p = 0.0002). Executive function was most impaired in frontotemporal dementia (-2.86, SD = 1.26) and least impaired in amyotrophic lateral sclerosis (-0.52, SD = 1.25) participants. The UDS3-EF composite score was also strongly correlated to the Clinical Dementia Rating Scale©. INTERPRETATION: Decisional capacity is intrinsically related to executive function in neurodegenerative disorders, and executive dysfunction may predict a lack of decisional capacity alerting investigators of the need for additional scrutiny during the informed consent process.

The Utility of Ultrasound Guidance to Improve the Safety of Closure of Antegrade Common Femoral Artery Access after Lower Limb Revascularization.

This study aimed to investigate the feasibility of ultrasound (US)-guidance in reducing adverse event (AE) rates when using Angioseal device during antegrade lower limb angioplasty via common femoral artery access. From December 2016 to November 2022, 1,322 patients were identified, including 1,131 (85.6%) patients who underwent US-guided closure and 191 (14.4%) who underwent non-US-guided closure. Moderate AEs were encountered in 10 (5.2%) patients in the non-US-guided closure group compared to 38 (3.4%) patients in the US-guided closure group (P = .208). Severe AEs were encountered in 4 (2.1%) patients in the non-US-guided closure group compared to 3 (0.3%) patients in the US-guided closure group (P = .010). Overall AEs occurred in 14 (7.3%) patients in the non-US-guided closure group compared to 41 (3.6%) patients in the US-guided closure group (P = .029). Binary logistic regression showed that only non-US guidance was an independent risk factor for the occurrence of severe AEs (P = .008).

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to ALS and FTD, leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. However, the possibility of de novo protein synthesis from cryptic exon transcripts has not been explored. Here, we show that mRNA transcripts harboring cryptic exons generate de novo proteins both in TDP-43 deficient cellular models and in disease. Using coordinated transcriptomic and proteomic studies of TDP-43 depleted iPSC-derived neurons, we identified numerous peptides that mapped to cryptic exons. Cryptic exons identified in iPSC models were highly predictive of cryptic exons expressed in brains of patients with TDP-43 proteinopathy, including cryptic transcripts that generated de novo proteins. We discovered that inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Finally, we showed that these de novo peptides were present in CSF from patients with ALS. The demonstration of cryptic exon translation suggests new mechanisms for ALS pathophysiology downstream of TDP-43 dysfunction and may provide a strategy for novel biomarker development.

Single-centre experience with endovascular rotational thrombectomy for single session salvage of thrombosed arteriovenous fistulas and grafts.

OBJECTIVES: This paper documents our experience and outcomes of using a relatively new endovascular rotational thrombectomy device for salvage of thrombosed vascular access. METHODOLOGY: A retrospective study reviewing patients with thrombosed native AVF or AVG who underwent endovascular declotting using a rotational thrombectomy device between November 2018 and May 2020 at a tertiary university hospital in Southeast Asia. We evaluated demographics, procedural data, technical and procedural success, patency rates and complications. RESULTS: A total of 40 patients underwent single session endovascular declotting of thrombosed vascular access. The mean follow-up period was 21.6 months (range 13.4-31 months). The technical success was 92.5% and clinical success was 80%. About 50% of patients had concomitant thrombolysis for pharmacomechanical thrombectomy. One patient had a myocardial infarction during the post-operative period. There were no other major complications within 30 days. The primary patency was 45.5% at 6 months and 22.7% at 12 months. Assisted primary patency was 68.1% at 6 months and 61.6% at 12 months, which was maintained up to 2 years. The secondary patency was 84.1% at 6 and 12 months. CONCLUSION: Our study shows that rotational thrombectomy device for single session thrombectomy of thrombosed arteriovenous fistulas and grafts is safe and effective. A high technical and clinical success rate was achieved, with low complication rates and specific advantages compared to other techniques, including reduced length of hospital stay. Our reported mid-term outcomes are reasonable with an assisted primary patency of 62% at 12 and 24 months. The use of newer techniques and novel dedicated thrombectomy devices show promise.

Amyotrophic lateral sclerosis mimics.

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disorder characterized by progressive degeneration of cortical, bulbar, and spinal motor neurons. When a patient presents with a progressive upper and/or lower motor syndrome, clinicians must pay particular attention to any atypical features in the history and/or clinical examination suggesting an alternate diagnosis, as up to 10% percent of patients initially diagnosed with ALS have a mimic of ALS. ALS is a clinical diagnosis and requires the exclusion of other disorders that may have similar presentations but a more favorable prognosis or an effective therapy. Because there is currently no specific diagnostic biomarker that is sensitive or specific for ALS, understanding the spectrum of clinical presentations of ALS and its mimics is paramount. While true mimics of ALS are rare, the clinician must correctly identify these disorders to avoid the misdiagnosis of ALS and to initiate effective treatment where available.

The Efficacy of Clinical Tests to Diagnose Evaporative Dry Eye Disease Related to Meibomian Gland Dysfunction.

OBJECTIVES: To determine the efficacy of widely available subtype clinical tests to characterize evaporative dry eye disease (EDED) related to meibomian gland dysfunction (MGD) compared to normal and to validate those clinical cut points in an independent sample. METHODS: A diagnostic accuracy study (52 subjects), an investigator-masked study, was followed by a larger independent sample (364 subjects) analysis to confirm efficacy in normal and EDED subjects. All subjects were 18 years of age and older and were classified using a battery of clinical tests for dry eye that included symptoms, tear meniscus height, tear stability, ocular staining, evaporative-specific tests, and the Schirmer I test. RESULTS: Normal (nondry eye; n = 26) and EDED (n = 26) subjects completed the efficacy study. The global tests of tear breakup time, staining, and symptoms all produced AUCs ≥ 0.70, representing acceptable discrimination. EDED-specific tests of eyelid marginal signs, gland secretion quality, and gland loss did not demonstrate acceptable test efficacy or differences between normal and EDED subjects. In a larger, independent sample of normal and EDED subjects, gland secretion quality and eyelid marginal score achieved acceptable diagnostic levels: AUCs of 0.789 (CI: 0.734-0.844) and 0.729 (CI: 0.648-0.810), respectively, but not lipid interferometry grade or lower eyelid gland dropout estimated using meiboscopy. CONCLUSIONS: Meibomian gland secretion quality is an efficient and useful functional indicator in EDED and should be incorporated into core outcome sets for this dry eye subtype.

Morphological characteristics of Meibomian Glands and their Influence on Dry Eye disease in contact lens wearers.

PURPOSE: Meibomian glands (MG) are now easily imaged via clinical meibography machines. The purpose of this work was to explore the utility of the known MG morphology metrics for predicting dry eye disease (DED) in contact lens (CL) wearers. METHODS: Successful and previous CL wearers were recruited. DED was diagnosed if the participant's worst eye had a reduced tear meniscus height (TMH) of <0.2 mm or non-invasive tear break-up time (NITBUT) of <10 s and a Standardized Patient Evaluation of Eye Dryness (SPEED) score >5.0. Meibography was performed and images were subjectively graded by two examiners for the following MG characteristics: distorted, tortuous, hooked, abnormal gap, overlapping, fluffy areas, tadpoling, thinned, thickened, ghost, no extension to lid margin, shortened and dropout (atrophy). DED diagnostic ability of each metric was determined with receiver operating characteristic (ROC) analysis. RESULTS: A total of 112 participants were recruited, with 18.8% having DED and 60.7% being female. The only MG morphology metrics that were marginally predictive of DED were thickened upper eyelid MGs (p = 0.046), thickened mean upper plus lower eyelid MGs (p = 0.007), and atrophy of upper eyelid MGs (p = 0.043); however, none of these metrics reached a meaningful area under the curve in ROC analysis (all <0.70). CONCLUSION: While abnormal MG morphology is likely suggestive of DED in CL wearers, none of the MG morphology metrics evaluated alone in this study had clinically meaningful predictive value for detecting DED in this group of current and previous CL wearers.

Validation of the Modified Schein Dry Eye Symptom Questionnaire and Comparison With the Ocular Surface Disease Index.

PURPOSE: This study evaluated the validity and diagnostic efficacy of a modified Schein dry eye questionnaire and compared it to the Ocular Surface Disease Index (OSDI). METHODS: The original Schein survey was modified to allow numerical scoring on a 0 to 24 scale and evaluated in prospective studies in normal and dry eye subjects. Receiver operating characteristic (ROC) analysis for test efficacy in aqueous deficient dry eye (ADDE) and evaporative dry eye (EDE) related to meibomian gland dysfunction was determined. RESULTS: Dry eye subtype, age and gender were statistically significant in explaining variation in modified Schein scores (n = 377; general linear model; all P values < 0.006) whereas for Ocular Surface Disease Index (OSDI) only age and gender were significant, but not dry eye subtype. The modified Schein ROC curve had an area under the curve (AUC) of 0.693 (95% confidence interval [CI], 0.635-0.753), with cutpoint of 7.5 (sensitivity of 0.75, specificity of 0.55). Similarly, the OSDI had an AUC of 0.685 (95% CI, 0.610-0.760), at a cutpoint of 10.4 (sensitivity of 0.75, specificity of 0.55). Modified Schein and OSDI correlated well (Pearson r = 0.81; P < 0.001). Symptom change for the modified Schein with artificial tear treatment was significant in EDE subjects (Dunnet's tests, P value < 0.001). CONCLUSIONS: The modified Schein questionnaire is rapid to administer and score and compares well with the OSDI for test efficacy. Moreover, it differentiates normals from ADDE and EDE subtypes and is responsive to dry eye treatment. These attributes make the modified Schein survey an attractive dry eye symptom characterization instrument. TRANSLATIONAL RELEVANCE: The modified Schein symptom survey, validated against clinical diagnosis and an existing survey, provides a new, efficacious diagnostic and treatment monitoring instrument in dry eye disease.

Randomized Controlled Trial Comparing Drug-coated Balloon Angioplasty versus Conventional Balloon Angioplasty for Treating Below-the-Knee Arteries in Critical Limb Ischemia: The SINGA-PACLI Trial.

Background There is a paucity of randomized trials demonstrating superior efficacy of drug-coated balloon angioplasty (DCBA) compared with conventional percutaneous transluminal angioplasty (PTA) for below-the-knee arterial disease in patients with -critical limb ischemia. Purpose To compare DCBA versus PTA for below-the-knee lesions in participants with critical limb ischemia through 12 months. Materials and Methods In this prospective, randomized, two-center, double-blind superiority study, participants with critical limb ischemia with rest pain or tissue loss with atherosclerotic disease in the native below-the-knee arteries were randomly assigned (in a one-to-one ratio) to DCBA or PTA after stratification for diabetes and renal failure between November 2013 and October 2017. The primary efficacy end point was angiographic primary patency at 6 months analyzed on an intention-to-treat basis. Secondary end points through 12 months were composed of major adverse events including death and major amputations, wound healing, limb salvage, clinically driven target-lesion revascularization, and amputation-free survival. Primary and binary secondary end points, analyzed by using generalized-linear model and time-to-event analyses, were estimated with Kaplan-Meier survival curves and hazard ratios (Cox regression). Results Seventy participants (mean age, 61 years ± 10 [standard deviation]; 43 men) in the DCBA group and 68 (mean age, 64 years ± 10; 50 men) in the PTA group were evaluated. The percentage of patients with angiographic primary patency at 6 months was 43% (30 of 70) in the DCBA group and 38% (26 of 68) in the PTA group (P = .48). Through 12 months, the percentage of deaths was similar: 21% in the DCBA group and 16% in the PTA group (P = .43). Amputation-free survival rate assessed with Kaplan-Meier curves differed through 12 months: 59% (41 of 70) in the DCBA group compared with 78% (53 of 68) in the PTA group (P = .01). Conclusion In participants with critical limb ischemia, the drug-coated balloon angioplasty group and the conventional percutaneous transluminal angioplasty group had similar primary patency rates at 6 months after treatment of below-the-knee arteries. Amputation-free survival rates through 12 months were higher in the percutaneous transluminal angioplasty group. © RSNA, 2021 Online supplemental material is available for this article.

Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases.

BACKGROUND: We used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres. METHODS: WES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays. RESULTS: Molecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in FBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2 and SPTLC1. Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients. CONCLUSIONS: Integrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.

Combined Biopsy and Imaging-Guided Microwave Ablation by Using a Coaxial Guiding Needle.

This article demonstrates the technique of using a coaxial guiding needle to perform combined percutaneous biopsy and microwave ablation via a single tract. From May 2019 to July 2020, 14 patients underwent combined biopsy and microwave ablation by using a coaxial guiding cannula. Tumors were in the kidney of six patients (43%), the liver of six patients (43%), and the lung in two patients (14%). The diagnostic yield of biopsy was 86% (12/14). Ablation technical success rate was 100%. In conclusion, using a coaxial guiding needle in microwave ablation and biopsy is safe and effective.

Advanced Techniques in the Percutaneous Ablation of Liver Tumours.

Percutaneous ablation is an accepted treatment modality for primary hepatocellular carcinoma (HCC) and liver metastases. The goal of curative ablation is to cause the necrosis of all tumour cells with an adequate margin, akin to surgical resection, while minimising local damage to non-target tissue. Aside from the ablative modality, the proceduralist must decide the most appropriate imaging modality for visualising the tumour and monitoring the ablation zone. The proceduralist may also employ protective measures to minimise injury to non-target organs. This review article discusses the important considerations an interventionalist needs to consider when performing the percutaneous ablation of liver tumours. It covers the different ablative modalities, image guidance, and protective techniques, with an emphasis on new and advanced ablative modalities and adjunctive techniques to optimise results and achieve satisfactory ablation margins.