Diagnostic Yield Research Articles

Endoscopic resection in subepithelial lesions of the upper gastrointestinal tract; experience of a tertiary referral hospital in The Netherlands.

Objectives Histological confirmation of subepithelial lesions (SELs) in the upper gastrointestinal tract remains challenging. Endoscopic resection of SELs is increasingly used for its excellent diagnostic yield and opportunity to do away with continued surveillance. In this study, we aimed to evaluate the indications, success-rates and complications of different endoscopic resections techniques for SELs in a large, tertiary referral hospital in Rotterdam, The Netherlands. Methods Data between October 2013 and December 2021 were retrospectively collected and analyzed. Main outcomes are R0-resection rate, en bloc resection rate, recurrence rate and procedure-related adverse events (Clavien-Dindo). Secondary outcomes are procedure time, need for surgical intervention and clinical impact on patient management. Results A total of 58 patients were referred for endoscopic resection of upper gastro-intestinal SELs. The median diameter of lesions was 20 mm (range 7-100mm). Median follow-up time was 5 months (range 0.4-75.7). Forty-eight (83%) procedures were completed successfully leading to en bloc resection in 85% and R0-resection in 63%. Procedure-related adverse events occurred in 6 patients (13%). Severe complications (CD grade 3a) were seen in 3 patients. Local recurrence rate for (pre)malignant diagnosis was 2%. Additional surgical intervention was needed in 7 patients (15%). A total of 32 patients (67%) could be discharged from further surveillance after endoscopic resection. Conclusions Endoscopic resection is a safe and effective treatment for SELs and offers valuable information in undetermined SELs in which repeated sampling attempts have failed to provide adequate tissue for diagnosis.

Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease

Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease

Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India

BackgroundCurrent clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India.Results903 smMIPs were designed to target exon and exon–intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood.ConclusionWe developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.

Comparative evaluation of the diagnostic and prognostic performance of CNSide™ versus standard cytology for leptomeningeal disease

Abstract Background This retrospective study compares real-world performance of cerebrospinal fluid (CSF) CNSide™ versus cytology in leptomeningeal disease (LMD). Methods: Consecutive patients with suspected LMD who underwent lumbar punctures for CSF cytology and CNSide™ from January 2020 to December 2022 were reviewed. LMD was classified by EANO criteria. Descriptive statistics, confusion matrix, Kaplan Meier curves, and Cox proportional regression were used. Results Median age for 87 evaluable patients was 63 years (range:23-93); 82 (94%) met EANO criteria for possible/probable/confirmed LMD (EANO/LMD). The commonest primary cancers were breast (36,44.0%) and lung (34,41.5%). Primary lung harbored actionable mutations in 18 (53.0%); primary breast expressed hormone receptors in 27 (75%) and HER2 amplification in 8 (22%). Uncontrolled systemic disease was detected in 35 (40%), while 25 (46%) received systemic therapy with medium/high CNS penetrance at LMD diagnosis. Median time from initial cancer to LMD diagnosis was 31 months (range:13-73). LMD was confirmed by CSF cytology in 23/82 (28%), all identified by CNSide™. CNSide™ identified 13 additional cases (36/82,43.9%), increasing diagnostic yield by 56.5%. Median overall survival (mOS) was 31 weeks (95%CI:21-43), significantly worse for CNSide™ positive versus negative: 4.0 versus 16.0 weeks, respectively (HR=0.50,p=0.010). While survival since LMD diagnosis did not differ by histology, time to LMD diagnosis from initial cancer diagnosis was longer for breast (48.5 months,IQR:30.0-87.5) versus lung (8 months,IQR:0.5-16.0) cohorts. mOS was longer for patients eligible for intrathecal chemotherapy (HR:0.189, 95%CI:0.053-0.672, p=0.010). Conclusions This retrospective, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant molecular CSF analyses.

Mitral Annular Disjunction and Its Progression during Childhood in Marfan Syndrome.

Data on mitral annular disjunction (MAD) in children with Marfan syndrome (MFS) are sparse. To investigate the diagnostic yield of MAD by echocardiography and cardiac magnetic resonance imaging (CMR), its prevalence and progression during childhood. We included patients <21 years old with MFS, defined by 2010 Ghent criteria and a pathogenic FBN1 variant or ectopia lentis. Two readers measured systolic separation between the mitral valve (MV) posterior hinge point and left ventricular (LV) myocardium on initial and subsequent imaging. MAD was defined as MV-LV separation ≥2 mm, MV prolapse (MVP) as atrial displacement ≥2 mm. Kappa coefficients evaluated echocardiogram-CMR agreement. Bland-Altman and intraclass correlation coefficients (ICC) assessed interrater and intermodality reliability. Univariable mixed-effects linear regression was used to evaluate longitudinal changes of MAD. MAD was detected in 60% (110/185) eligible patients. MVP was present in 48% (53/110) of MAD and MAD in 90% (53/59) of MVP. MAD detection by CMR and echocardiography had 96% overall agreement (Kappa = 0.89, p < 0.001) and a 0.32-mm estimate bias (95%CI 0.00, 0.65). ICC by echocardiography, CMR, and between modalities were 0.97 (95%CI 0.93, 0.98), 0.92 (95%CI 0.79, 0.97), and 0.91 (95%CI 0.85, 0.94), respectively. MAD was associated with aortic root dilation (p < 0.001). MAD was found in children of all ages, increased +0.18 mm/year (95%CI +0.14, + 0.22) during a median duration of 5.5 years (IQR 3.1, 7.5 years). MAD indexed by height yielded a constant value +0.0002 mm/m/year (95%CI -0.0002, + 0.0005 mm/m/year). MAD was common in pediatric MFS and was associated with aortic root dilation. MAD detection by echocardiography and CMR was highly reliable, suggesting that routine assessment in MFS is feasible. MAD was present in neonates and progressed over time but remained constant when indexing by height. Further studies are needed to evaluate MAD as a biomarker for clinical outcomes in pediatric MFS.

Diagnostic yield of an inherited retinal disease gene panel in retinopathy of unknown origin

Purpose: Evaluating the presence of class 3, 4 and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO). Methods: Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmological history, complete ophthalmological examination, anti-retinal antibodies and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: non-paraneoplastic autoimmune retinopathy (npAIR), unilateral pigmentary retinopathy (UPR), asymmetrical pigmentary retinopathy (APR) and acute zonal occult outer retinopathy (AZOOR). Results: We included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20 – 68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, 2 also demonstrated class 5 variants in other IRD genes. The remaining 5 patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) npAIR patient in our RUO cohort. When considering the npAIR subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved. Conclusions: Every suspected npAIR patient should benefit from gene panel testing in order not to overlook undiagnosed IRDs. In contrast, UPR, APR and AZOOR subpopulations did not benefit from genetic analysis in this study.

Exploring the clinical utility of exome sequencing/mono, duo, trio in prenatal testing: a retrospective study in a tertiary care centre in south India.

With the availability of Next Generation Sequencing (NGS) diagnosis of genetic disorders has improved significantly. Its use is also applicable to ascertain diagnosis and management in a perinatal setting. The study aims to detect the genetic aetiology of various congenital structural and functional defects using NGS technology in the reproductive cohort at a tertiary centre. The secondary objective is to address challenges in the interpretation of variants. This was a retrospective study of couples who underwent exome sequencing (Mono-testing proband only or Duo-testing parents only or Trio-testing proband and parents) for suspected single gene disorders between years 2020-2022 at a tertiary care perinatal center in the South India. American College of Medical Genetics (ACMG) guidelines were followed to classify the pathogenicity of the variants identified by exome sequencing. The overall diagnostic yield as defined by pathogenic/likely pathogenic variants obtained was (23/43) 53.4 %. The individual subsets have the following diagnostic yield viz., Mono 5/6 (83 %); Carrier 16/32 (50 %); Trio 2/5 (40 %). Diagnostic yield was significantly higher in consanguineous couples. However, miscarriage history, and organ system involvement did not have a significant effect on the diagnostic yield. Prenatal diagnosis was offered for seven patients based on the exome result. One fetus was confirmed with a compound heterozygous pathogenic variant. Diagnostic yield of exome sequencing in our cohort was 53 %. The detection of pathogenic variants was maximum in those cases undergoing mono exome sequencing. In places where there is a high prevalence of consanguinity and endogamy, NGS may be offered as first line test in the context of prenatal diagnosis.

Diagnostic yields and safety of thoracoscopic cryobiopsies in Japan: A single-center retrospective observational study

BackgroundThoracoscopy is useful for diagnosing unexplained pleural effusions. A sufficient specimen volume is often difficult to obtain using forceps biopsies (FBs) but can be obtained with pleural cryobiopsies (CBs). This study aimed to assess the utility and safety of CB during thoracoscopy in the Japanese population. MethodsPatients who underwent thoracoscopic CBs at the Japanese Red Cross Medical Center between January 2017 and August 2023 were included in the study. Data were retrospectively analyzed, including clinical data, thoracoscopic findings, specimen size, diagnostic yield, and complications. The number of collected specimens and the freezing time were left to the discretion of the attending physician. ResultsTwenty-six patients underwent thoracoscopic CB. Specimens obtained by CB were larger than those obtained by FB. Primary lung cancer was the most common cause of pleural effusion, followed by malignant pleural mesothelioma. CB contributed to the diagnosis in 24 of 26 cases (92.3%) and FB contributed to the diagnosis in 11 of 18 cases (61.1%). Severe fibrosis could be diagnosed in all 3 cases by CB, but not by FB. The common complications of CB included bleeding at the biopsy site and atelectasis, but no severe complications occurred. ConclusionsThe utility and safety of thoracoscopic CB for diagnosing pleural effusions in Japan were verified. The diagnostic yield, specimen size, and safety profile of CB support the diagnostic utility of this method.

Diagnostic Yield of Decubitus CT Myelography for Detection of CSF-Venous Fistulas.

Various imaging techniques have been described to detect CSF-Venous Fistulas (CVFs) in the setting of Spontaneous Intracranial Hypotension (SIH), including decubitus CT myelography (dCTM). The expected diagnostic yield of dCTM for CVF detection is not fully established. The purpose of this study was to assess the yield of dCTM among consecutive patients presenting for evaluation of possible SIH, and to examine what impact brain MRI findings of SIH had on diagnostic yield. Single-center, retrospective cohort of consecutive patients presenting over a one-year period who underwent CTM and had no CSF identified in the epidural space. Patients with epidural CSF leaks were included in a secondary cohort. Subjects were grouped according to positioning for the myelogram, either decubitus or prone, and the presence of imaging findings of SIH on pre-procedure brain MRI. Diagnostic yields for each subgroup were calculated, and the yield of dCTM was compared to prone CTM. The study cohort included 302 subjects, including 247 patients with no epidural fluid. Diagnostic yield of dCTM for CVF detection among subjects with positive brain MRI and no epidural fluid was 73%. No CVFs were identified among subjects with negative brain imaging. Among subjects with epidural leak, brain MRI was negative for signs of SIH in 22%. Prone CTM identified a CVF less commonly than dCTM (43% vs. 73%, p=0.19), although the difference was not statistically significant in this small subgroup. We found a diagnostic yield of dCTM to be similar to the yield previously reported for digital subtraction myelography among patients with positive brain imaging. No CVFs were identified in patients with negative brain imaging; epidural CSF leaks accounted for all cases of patients who had SIH with negative brain imaging. This study provides useful data for counseling patients and helps establish a general benchmark for dCTM yield for CVF detection.ABBREVIATIONS: SIH = spontaneous intracranial hypotension; CVF = CSF-Venous Fistula; CTM = CT Myelography; dCTM = decubitus CT myelography; EBP = epidural blood patch.

Contrast-enhanced guided endoscopic ultrasound procedures

Contrast-enhanced endoscopic ultrasound (CH-EUS) can overcome the limitations of endoscopic ultrasound-guided acquisition by identifying microvessels inside inhomogeneous tumours and improving the characterization of these tumours. Despite the initial enthusiasm that oriented needle sampling under CH-EUS guidance could provide better diagnostic yield in pancreatic solid lesions, further studies did not confirm the supplementary values in cases of tissue acquisition guided by CH-EUS. This review details the knowledge based on the available data on contrast-guided procedures. The indications for CH-EUS tissue acquisition include isoechoic EUS lesions with poor visible delineation where CH-EUS can differentiate the lesion vascularisation from the surrounding parenchyma and also the mural nodules within biliopancreatic cystic lesions, which occur in select cases. Additionally, the roles of CH-EUS-guided therapy in patients whose pancreatic fluid collections or bile ducts that have an echogenic content have indications for drainage, and patients who have nonvisualized vessels that need to be highlighted via Doppler EUS are presented. Another indication is represented if there is a need for an immediate assessment of the post-radiofrequency ablation of pancreatic neuroendocrine tumours, in which case CH-EUS can be used to reveal the incomplete tumour destruction.

A Review of Endobronchial-Ultrasound-Guided Transbronchial Intranodal Forceps Biopsy and Cryobiopsy.

Benign and malignant mediastinal lesions are not infrequently encountered in clinical practice. Mediastinoscopy has long been considered the gold standard in evaluating mediastinal pathology. Since its introduction into clinical practice, endobronchial-ultrasonography-guided transbronchial fine needle aspiration (EBUS-TBNA) has replaced mediastinoscopy as the initial procedure of choice to evaluate mediastinal lesions and to stage lung cancer. Its diagnostic yield in benign mediastinal lesions and less common malignancies, however, has remained limited. This has led different proceduralists to investigate additional procedures to improve the diagnostic yield of EBUS-TBNA. In recent years, different published reports concluded that the addition of EBUS-guided intranodal forceps biopsy (IFB) and transbronchial cryobiopsy (TBCB) to EBUS-TBNA increases the diagnostic yield especially in benign mediastinal lesions and uncommon mediastinal malignancies. The purpose of this review is to describe how EBUS-IFB and EBUS-TBCB are performed, to compare their diagnostic yields, and to discuss their limitations and their potential complications. In addition, the review will conclude with a proposed algorithm on how to incorporate EBUS-IFB and EBUS-TBCB into clinical practice.

The Role of Genetic Testing in Adult CKD

The Role of Genetic Testing in Adult CKD

Utility of next generation sequencing in paediatric neurological disorders: experience from South Africa.

Next generation sequencing (NGS)-based tests have become routine first-line investigative modalities in paediatric neurology clinics in many high-income countries (HICs). Studies from these countries show that these tests are both cost-effective and reliable in diagnosing many complex childhood neurological diseases. However, NGS-based testing in low-and middle-income countries (LMICs) is limited due to affordability constraints. The primary objective of this study was to evaluate the diagnostic yield and impact of targeted gene panel sequencing in a selected paediatric cohort attending a tertiary paediatric neurology clinic in the Western Cape Province of South Africa. This retrospective study included 124 consecutive paediatric patients with neurological disease, aged 6 weeks to 17 years, referred for NGS-based multi-gene panel testing over a 41-month period. Twenty-four different disease group-specific panels were utilized. A caregiver experience questionnaire was administered when a pathogenic variant was identified. The overall study diagnostic yield (DY) was 45% (56/124 patients). The diagnostic yield in this study is similar to previously reported paediatric cohorts in HICs. The high yields for neuromuscular disorders (52%) and early epileptic encephalopathies (41%) suggest that NGS-based panels may be more cost-effective as first-line testing in well-defined phenotypes. The latter finding argues for early inclusion of all children with developmental epileptic encephalopathies (DEE), as early diagnosis leads to better treatment and avoidance of unnecessary investigations.

Computed tomography pulmonary angiogram ordering, adherence to decision rules and yield in the emergency department: An observational study.

Pulmonary embolism (PE) frequently requires diagnosis through CT pulmonary angiogram (CTPA). Appropriate application of evidence-based clinical decision tools can reduce unnecessary CTPAs. This study assessed adherence to and the efficacy of various aspects of the Queensland Health suspected PE diagnostic pathway, including Wells score, PE rule out criteria (PERC) and age-adjusted D-dimer interpretation. Retrospective study of CTPAs ordered from 1 January to 30 April 2023 in a tertiary and urban ED in Southeast Queensland. Data on clinical variables, D-dimer and CTPA results were collected through medical record and radiology database review. Descriptive analyses were used to determine adherence to Queensland guidelines and performance of D-dimer interpretation tools (including comparison of age-adjusted PE with a new pre-test probability [PTP]-based model using D-dimer cut-off <1000 ng/mL for Wells score ≤4 and 500 ng/mL for Wells score 4.5-6). A total of 573 CTPAs were available for analysis with a 12.4% (95% confidence interval 10.0-15.4) diagnostic yield. Stratification by Wells score showed yields of 4.0%, 18.5% and 41% for low-, moderate- and high-risk patients, respectively. Twenty-five patients with low-PTP who received CTPA could have been excluded with the PERC rule. Age-adjusted D-dimer interpretation may have prevented 26 CTPAs with no false negatives, whereas PTP approach may have prevented 128 CTPAs with four false negatives. Guideline adherence can be improved, and adherence to existing clinical decision tools may reduce unnecessary CTPA ordering and increase diagnostic yield. The use of the age-adjusted D-dimer had good sensitivity, whereas the new PTP approach will require further prospective research.

Diagnostic yield from symptomatic gastroscopy in the UK: British Society of Gastroenterology analysis using data from the National Endoscopy Database

ObjectiveThis national analysis aimed to calculate the diagnostic yield from gastroscopy for common symptoms, guiding improved resource utilisation.DesignA cross-sectional study was conducted of diagnostic gastroscopies between 1 March 2019 and...

Xpert-Ultra assay on stool and urine to improve tuberculosis diagnosis in children: the Médecins Sans Frontières experience in Guinea-Bissau and South Sudan

Abstract Background Over half of childhood tuberculosis (TB) remains undiagnosed yearly. WHO recommends Xpert-Ultra as a first paediatric diagnosis test, but microbiological confirmation remains low. We aimed to determine the diagnostic performance of Xpert-Ultra on stool and urine in presumptive paediatric TB cases in two high-TB burden settings. Methods This Médecins sans Frontières cross-sectional multicentric study took place at Simão Mendes hospital, Guinea-Bissau (July 2019 to April 2020) and in Malakal hospital, South Sudan (April 2021 to June 2023). Children 6 months to 15 years with presumptive TB underwent clinical and laboratory assessment, with one respiratory and/or extrapulmonary sample (gold standard (GS)), one stool and one urine specimen analysed with Xpert-Ultra. Results A total of 563 children were enrolled in the study, 133 from Bissau, 400 from Malakal; 30 were excluded. Confirmation of TB was achieved in 75 (14.1%) while 248 (46.5%) had unconfirmed TB. Of 553 with GS specimen, the overall diagnostic yield was 12.4% (66/533). A total of 493 and 524 samples were used to evaluate Xpert-Ultra on stool and on urine, respectively. Compared to GS, sensitivity and specificity of Xpert-Ultra on stool were 62.5%(95%CI:49.4-74) and 98.3%(95%CI:96.7-99.2), whereas on urine were 13.9%(95%CI:7.5-24.3) and 99.4%(95%CI:98.1-99.8), respectively. Nine patients were positive on stool and/or urine but negative on GS. Conclusions Xpert-Ultra on stool showed moderate to high sensitivity and high specificity when compared to GS and an added diagnostic yield when GS was negative. Xpert-Ultra on stool was useful in extrapulmonary cases. Xpert-Ultra in urine showed low test performance. Trial registration NCT06239337

Diagnostic yield of dental radiography and digital tomosynthesis for the identification of anatomic structures in cats

IntroductionDigital tomosynthesis (DT) has emerged as a potential imaging modality for evaluating anatomic structures in veterinary medicine. This study aims to validate the diagnostic yield of DT in identifying predefined anatomic structures in feline cadaver heads, comparing it with conventional intraoral dental radiography (DR).MethodsA total of 16 feline cadaver heads were utilized to evaluate 19 predefined clinically relevant anatomic structures using both DR and DT. A semi-quantitative scoring system was employed to characterize the ability of each imaging method to identify these structures.ResultsDT demonstrated a significantly higher diagnostic yield compared to DR for all evaluated anatomic structures. Orthogonal DT imaging identified 13 additional anatomic landmarks compared to a standard 10-view feline set obtained via DR. Moreover, DT achieved statistically significant higher scores for each of these landmarks, indicating improved visualization over DR.DiscussionThese findings validate the utility of DT technology in reliably identifying clinically relevant anatomic structures in the cat skull. This validation serves as a foundation for further exploration of DT imaging in detecting dentoalveolar and other maxillofacial bony lesions and pathologies in cats.

Epidemiology and molecular characterization of adult genetic myopathies in a southeastern region of Spain.

Genetic myopathies constitute a collection of rare diseases that significantly impact patient functionality and quality of life. Early diagnosis of genetic myopathies can prevent future complications and provide families with genetic counselling. Despite the substantial impact of genetic myopathies on the adult population, the global epidemiology of these disorders is inadequately addressed in the literature. To enhance understanding of both the epidemiology and genetics of these disorders within the province of Alicante, situated in southeastern Spain. Between 2020 and 2022, a prospective observational study was conducted at the Alicante Health Area-General Hospital, enrolling patients aged 16 years or older with suspected genetic myopathies. Sociodemographic, clinical, and genetic data were collected. The reference date for prevalence calculation was established as December 31, 2022. Official demographic data of the health area were used to set the population at risk. In total, 83 patients were identified with confirmed genetically related myopathy, resulting in an overall prevalence of 29.59 cases per 100,000 inhabitants. The diagnostic yield for molecular genetic testing was found to be 69.16%. The most prevalent genetic myopathies identified included myotonic dystrophy (27.5%), dystrophinopathies (15.7%), and facioscapulohumeral dystrophy (15.7%). The prevalence of GMs can vary considerably depending on the geographical region and the studied population. The analysis of diagnostic yield suggests that genetic studies should be considered useful in the diagnosis of genetic myopathies.

Genome sequencing reanalysis increases the diagnostic yield in dystonia

PurposeWe investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. MethodsProbands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. ResultsInitial GS analysis in 2019 (n=111) identified a molecular diagnosis in 11.7% (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2% (8/111); 3.6% (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6% (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. ConclusionGS data reanalysis increased the diagnostic yield from 11.7% to 18.9%, with potential extension up to 22.5%. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

Integrating molecular and radiological screening tools during community-based active case-finding for tuberculosis and COVID-19 in southern Africa

ObjectivesTo evaluate diagnostic yield and feasibility of integrating testing for TB and COVID-19 using molecular and radiological screening tools during community-based active case-finding (ACF). MethodsCommunity-based participants with presumed TB and/or COVID-19 were recruited using a mobile clinic. Participants underwent simultaneous point-of-care (POC) testing for TB (sputum; Xpert-Ultra) and COVID-19 (nasopharyngeal swabs; Xpert-SARS-CoV-2). Sputum culture and SARS-CoV-2 RT-PCR served as reference standards. Participants underwent ultra-portable POC chest-radiography with computer-aided detection (CAD). TB infectiousness was evaluated using smear microscopy, cough aerosol sampling studies (CASS), and chest radiographic cavity detection. Feasibility of POC testing was evaluated via user-appraisals. Results601 participants were enrolled, with 144/601 (24.0%) reporting symptoms suggestive of TB and/or COVID-19. 16/144 (11.1%) participants tested positive for TB, while 10/144 (6.9%) tested positive for COVID-19 (2/144 [1.4%] had concurrent TB/COVID-19). 7/16 (43.8%) individuals with TB were probably infectious. Test-specific sensitivity and specificity (95% CI) were: Xpert-Ultra 75.0% (42.8-94.5) and 96.9% (92.4-99.2); Xpert-SARS-CoV-2 66.7% (22.3-95.7) and 97.1% (92.7-99.2). Area-under-the-curve (AUC) for CAD4TB was 0.90 (0.82-0.97). User appraisals indicated POC Xpert to have ‘good’ user-friendliness. ConclusionsIntegrating TB/COVID-19 screening during community-based ACF using POC molecular and radiological tools is feasible, has a high diagnostic yield, and can identity probably infectious persons.