High Diagnostic Yield Research Articles

Cardiac hereditary diseases: genetic insights from a single center 15-year experience

Abstract Funding Acknowledgements Type of funding sources: None. Background In the last decades, the implementation of high-throughput next-generation (NGS) technologies has profoundly changed the landscape of human genome sequencing. However, the molecular diagnosis in cardiac hereditary diseases is still hampered by the incomplete penetrance, variable expressivity, and genetic heterogeneity of the diseases. Objective We report our 15-year experience on a cohort of consecutive patients (pts) with suspicion of cardiac hereditary disease referred to the specialized cardiogenetic outpatient clinic of our center. Methods We retrospectively reviewed DNA sequencing results of pts referred to our center from July 1st 2007 through December 31st 2021, who were tested with NGS technologies for suspected cardiac hereditary diseases including channelopathies, inherited cardiomyopathies and unexplained sudden cardiac death. Results Among the 488 tested pts, the most frequent clinical indication were presymptomatic screening (37.3%) for a known familial variant, followed by suspected arrhythmic syndrome (28.3%) and hereditary cardiomyopathy (26.8%). A likely pathogenic/pathogenic variant was found in 198 pts for an overall diagnostic yield of 40.6% and of 23.6% considering only index cases. The rate of identified mutation-carriers was higher among pts with cardiomyopathy (45.8%) than among pts with inherited arrhythmic syndromes (37%). Panel A and B display variant distribution in arrhythmic syndromes and cardiomyopathies respectively. In particular, the highest diagnostic yield was observed among pts with suspected hypertrophic cardiomyopathy (60.7%) and catecholaminergic polymorphic ventricular tachycardia (50%), followed by congenital long QT syndrome (48.6%). The pathogenic variants were mainly identified in genes with definitive scientific evidence of causal association with the disease. Conclusions The 15-year experience of our specialized cardiogenetic outpatient clinic has demonstrated the pivotal role of genetic analysis for the diagnostic confirmation and, hence for the therapeutic management of pts with suspected cardiac hereditary disease.

Diagnostic yield in national team football players

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Malta Football Association. Introduction Sudden cardiac death (SCD) is an important cause of morbidity in competitive athletes. Pre-participation evaluation (PPE) is mandatory for most sporting organisations. The ECG plays a very important diagnostic role and is included in most screening algorithms. PPE for athletes ≥14 years registered with the National Football Association is now mandatory. Study objectives: The objective of this study was to assess the diagnostic yield of PPE in a group of elite Maltese football players competing at national level. Methodology Players selected at national level (years 2020-2022) underwent PPE (history, physical examination, and resting ECG). Senior team players also underwent echocardiography (biannually) as per regulations. Data was tabulated and analyzed in Microsoft Excel. Results 300 athletes (69% male) were selected in this timeframe. 10.6% (n=32) required referral for secondary evaluation, equating to 1 in 11 athletes screened. Referrals were more frequent in male vs female athletes (22.1% vs 10.2%, p=0.005). Most referrals were from the men’s senior’s squad (22.5%), followed by the men’s U17 squad (21.7%) and 20% of the men’s U15 team. The ECG was the commonest reason for referral to a sports cardiologist (n=23, 71.8%). The commonest abnormal ECG patterns included anterior TWI (n=9, 3.0%), inferior/lateral TWI (n=6, 2.0%) and WPW (n=2, 0.7%). 108 (36.0%) had echocardiography as a first line screening modality. This was abnormal in a fifth of those referred (n=7, 21.9%), 4 of these had a normal ECG. 3 (1.0%) athletes were diagnosed with a condition linked to SCD (n=2 WPW, n=1 HCM). Another 5 (1.7%) athletes were diagnosed with a cardiac disorder (n=1 left ventricular outflow tract ectopy, n=1 dilated aortic root, n=1 aortic regurgitation, n=1 atrial septal defect, n=1 mitral regurgitation). Echocardiography doubled the diagnostic yield (1.3% vs 2.7%), with 3 athletes having otherwise a normal history, physical examination and ECG. 1 in 38 athletes (2.7%) were given a cardiac diagnosis, 1 in 100 athletes (1.0%) were labelled with a condition linked to SCD. Conclusion The referral rate is comparable to that reported in international screening programs, higher in males. The ECG was the commonest reason for referral. The overall diagnostic yield equates to 2.7%, while 1.0% were given a diagnosis linked to SCD. The higher diagnostic yield in this population highlights the importance of raising awareness about heart disease and PPE in young athletes.

Genetic landscape in Russian patients with familial left ventricular noncompaction.

Left ventricular noncompaction (LVNC) cardiomyopathy is a disorder that can be complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. The aim of this study is to clarify the genetic landscape of LVNC in a large cohort of well-phenotyped Russian patients with LVNC, including 48 families (n=214). All index patients underwent clinical examination and genetic analysis, as well as family members who agreed to participate in the clinical study and/or in the genetic testing. The genetic testing included next generation sequencing and genetic classification according to ACMG guidelines. A total of 55 alleles of 54 pathogenic and likely pathogenic variants in 24 genes were identified, with the largest number in the MYH7 and TTN genes. A significant proportion of variants -8 of 54 (14.8%) -have not been described earlier in other populations and may be specific to LVNC patients in Russia. In LVNC patients, the presence of each subsequent variant is associated with increased odds of having more severe LVNC subtypes than isolated LVNC with preserved ejection fraction. The corresponding odds ratio is 2.77 (1.37 -7.37; p <0.001) per variant after adjustment for sex, age, and family. Overall, the genetic analysis of LVNC patients, accompanied by cardiomyopathy-related family history analysis, resulted in a high diagnostic yield of 89.6%. These results suggest that genetic screening should be applied to the diagnosis and prognosis of LVNC patients.

A holistic approach to maximise diagnostic output in trio exome sequencing.

Rare genetic diseases are a major cause for severe illness in children. Whole exome sequencing (WES) is a powerful tool for identifying genetic causes of rare diseases. For a better and faster assessment of the vast number of variants that are identified in the index patient in WES, parental sequencing can be applied ("trio WES"). We assessed the diagnostic rate of routine trio WES including analysis of copy number variants in 224 pediatric patients during an evaluation period of three years. Trio WES provided a diagnosis in 67 (30%) of all 224 analysed children. The turnaround time of trio WES analysis has been reduced significantly from 41 days in 2019 to 23 days in 2021. Copy number variants could be identified to be causative in 10 cases (4.5%), underlying the importance of copy number variant analysis. Variants in three genes which were previously not associated with a clinical condition (GAD1, TMEM222 and ZNFX1) were identified using the matching tool GeneMatcher and were part of the first description of a new syndrome. Trio WES has proven to have a high diagnostic yield and to shorten the process of identifying the correct diagnosis in paediatric patients. Re-evaluation of all 224 trio WES 1-3 years after initial analysis did not establish new diagnoses. Initiating (trio) WES as a first-tier diagnostics including copy number variant detection should be considered as early as possible, especially for children treated in ICU, if a monogenetic disease is suspected.

Informing a value care model: lessons from an integrated adult neurogenomics clinic.

Advances in genomics provide improved opportunities for diagnosis of complex neurogenetic disorders, yet the optimal approach to translate these benefits to the outpatient clinic is unclear. We retrospectively reviewed referral indications and outcomes of an integrated multidisciplinary team (MDT) clinic pathway for adults with suspected neurogenetic disorders. The associated cost implications were estimated. Consecutive patients who attended the neurogenomics clinic from January 2017 to April 2020 were included. The clinic comprised neurologists, clinical geneticists and genetic counsellors, who assessed each patient concurrently. Ninety-nine new patients were referred spanning 45 different clinical diagnoses. Following MDT clinical assessment, 23% (23/99) of referral diagnoses were revised prior to molecular testing. Eighty-one patients (82%) underwent genetic testing, including 43 exome-based panels, 15 whole-genome sequencing, 14 single gene tests, 27 repeat-primed polymerase chain reaction testing and two chromosomal microarrays. Overall, 33/99patients (33%) received a diagnosis, either a molecular diagnosis (n = 24, of which 22 were diagnostic and two were predictive) or a clinical diagnosis (n = 9). Of the clinical diagnosis cohort, five patients received a diagnosis without molecular testing and four patients whose negative testing (one diagnostic and three predictive) allowed exclusion of genetic differentials and, hence, confirmation of clinical diagnoses. The diagnostic rate following MDT and diagnostic testing was 30% (28/94), excluding the five predictive testing cases. MDT assessment aligned with eventual molecular diagnoses in 96% of cases. The estimated average costs were AU$1386 per patient undergoing MDT assessment and AU$4159 per diagnosis achieved. We present an integrated multidisciplinary neurogenomics clinic pathway providing a diagnostic yield of 33% (30% excluding predictive testing cases), with costing implications. The relatively high diagnostic yield may be attributed to multidisciplinary input integrating accurate phenotyping of complex disorders and interpretation of genomic findings.

Análisis de las técnicas invasivas diagnósticas para la confirmación anatomopatológica del mesotelioma pleural

Background and objectiveMesothelioma is an infrequent neoplasm with a poor prognosis that is related to exposure to asbestos and whose peak incidence in Europe is estimated from 2020. Its diagnosis is complex, imaging techniques and the performance of invasive pleural techniques being essential for pathological confirmation. The different diagnostic yields of these invasive techniques are collected in the medical literature. The present work consisted of reviewing how the definitive diagnosis of mesothelioma cases in our center was reached to check if there was concordance with the data in the bibliography. Materials and methodsRetrospective review of patients with a diagnosis of pleural mesothelioma in the period 2019-2021, analyzing demographic data and exposure to asbestos, the semiology of the radiological findings and the invasive techniques performed to reach the diagnosis. ResultsTwenty-six mesothelioma cases were reviewed (22 men and 4 women). Median age 74years. Nine patients had a history of asbestos exposure. Moderate-severe pleural effusion was the most frequent radiological finding (23/26). The sensitivity of the invasive techniques was as follows: cytology 13%, biopsy without image guidance 11%, image-guided biopsy 93%, surgical biopsy 67%. ConclusionsIn our review, pleural biopsy performed with image guidance was the test that had the highest diagnostic yield, so it should be considered as the initial invasive test for the study of mesothelioma.

Post-mortem genetic testing in sudden cardiac death and genetic screening of relatives at risk: lessons learned from a Czech pilot multidisciplinary study

Sudden cardiac death (SCD) might have an inherited cardiac condition background. Genetic testing supports post-mortem diagnosis and screening of relatives at risk. Our aim is to determine the feasibility of a Czech national collaboration group and to establish the clinical importance of molecular autopsy and family screening. From 2016 to 2021, we have evaluated 100 unrelated SCD cases (71.0% males, age: 33.3 (12.8) years). Genetic testing was performed by next-generation sequencing utilizing a panel of 100 genes related to inherited cardiac/aortic conditions and/or whole exome sequencing. According to autopsy, cases were divided into cardiomyopathies, sudden arrhythmic death syndrome, sudden unexplained death syndrome, and sudden aortic death. We identified pathogenic/likely pathogenic variants following ACMG/AMP recommendations in 22/100 (22.0%) of cases. Since poor DNA quality, we have performed indirect DNA testing in affected relatives or in healthy parents reaching a diagnostic genetic yield of 11/24 (45.8%) and 1/10 (10.0%), respectively. Cardiological and genetic screening disclose 83/301 (27.6%) relatives at risk of SCD. Genetic testing in affected relatives as starting material leads to a high diagnostic yield offering a valuable alternative when suitable material is not available. This is the first multidisciplinary/multicenter molecular autopsy study in the Czech Republic which supports the establishment of this type of diagnostic tests. A central coordinator and proper communication among centers are crucial for the success of a collaboration at a national level.

Motorized spiral enteroscopy – a prospective analysis of 82 procedures at a single tertiary center

Introduction Motorized spiral enteroscopy (MSE) is a promising novel deep enteroscopy technique. The purpose of our study was to evaluate efficiency and safety of MSE in a single tertiary endoscopy center. Methods We prospectively evaluated all consecutive patients undergoing MSE in our endoscopy unit from June 2019 through June 2022. Main outcomes were technical success rate, proportion of procedures with sufficient depth of insertion, success rate of total enteroscopy, diagnostic yield and complication rate. Results A total of 82 examinations in 62 patients (56% males, mean age 58 ± 18 years) were performed, 56 from antegrade and 26 from retrograde approach. Technical success rate was 94% (77/82) and in 89% (72/82) of cases, depth of insertion was considered sufficient. Total enteroscopy was indicated in 19 patients and it was achieved in 16 of them (84%), either by antegrade in 4 or by combined approach in 12 cases. Diagnostic yield was 81%. Lesion of the small bowel was found in 43 of patients. Mean insertion time was 40 for antegrade and 44 min for retrograde procedures, respectively. Complications occurred in 3% (2/62) of patients. One patient suffered from mild acute pancreatitis after total enteroscopy and there was one intussusception of the sigmoid during endoscope withdrawal resolved by parallel colonoscope insertion. Conclusion In our series of 82 procedures in 62 patients examined by MSE during a three-year period, we show high technical success rate (94%), diagnostic yield (81%) and low complication rate (3%).

Comparison between percutaneous transthoracic co-axial needle CT-guided biopsy and transbronchial lung biopsy for the diagnosis of persistent pulmonary consolidation

BackgroundDiagnosing persistent pulmonary consolidation still faces challenges. The purpose of this study is to compare the diagnostic yield and the complication rate between percutaneous transthoracic CT-guided coaxial needle biopsy (PTCNB) and transbronchial lung biopsy (TBLB) of persistent pulmonary consolidation.MaterialsFrom January 1, 2016, to December 31, 2020, we have retrospectively enrolled a total of 155 consecutive patients (95 males, 60 females) with persistent pulmonary consolidation who underwent both TBLB and PTCNB. According to the standard reference, the diagnostic yield, accuracy, sensitivity and specificity of PTCNB and TBLB were assessed and compared.ResultsAccording to the standard reference, the final biopsy diagnoses of 11 cases were confirmed true malignant based on the surgical resections, the remaining were confirmed by clinical and imaging follow-up for at least 12 months. The overall diagnostic accuracy, sensitivity and specificity of PTCNB for malignant diagnosis were 91.61%, 72.34% and 100%, whereas of TBLB were 87.74%, 59.57% and 100%. The diagnostic yield of PTCNB and TBLB were 50.32% and 25.16%, respectively. For the TBLB-based negative cases, PTCNB provided a definite diagnostic yield of 37.93%. There were 45 (29.03%), 22 (14.19%) and 13 (8.39%) patients who experienced pneumothorax, intrapulmonary hemorrhage and hemoptysis, respectively, in PTCNB, while there were only 5 (3.22%) cases of mild intraprocedural bleeding occurring in TBLB.ConclusionsCT-guided co-axial needle biopsy is an effective and safe modality, associated with higher diagnostic yield and better diagnostic accuracy compared to transbronchial lung biopsy for malignancy presenting as persistent consolidation, especially as the complementary method for TBLB-based negative lung lesions.Key PointsBoth PTCNB and TBLB showed high diagnostic accuracy for malignancy.PTCNB had a higher diagnostic yield than TBLB for persistent pulmonary consolidation.PTCNB could provide a complementary diagnosis for TBLB-based negative lung consolidation.

Diagnostic outcomes of robotic-assisted bronchoscopy for pulmonary lesions in a real-world multicenter community setting

BackgroundRobot-assisted bronchoscopy (RAB) is among the newest bronchoscopic technologies, allowing improved visualization and access for small and hard-to-reach nodules. RAB studies have primarily been conducted at academic centers, limiting the generalizability of results to the broader real-world setting, while variability in diagnostic yield definitions has impaired the validity of cross-study comparisons. The objective of this study was to determine the diagnostic yield and sensitivity for malignancy of RAB in patients with pulmonary lesions in a community setting and explore the impact of different definitions on diagnostic yield estimates.MethodsData were collected retrospectively from medical records of patients ≥ 21 years who underwent bronchoscopy with the Monarch® Platform (Auris Health, Inc., Redwood City, CA) for biopsy of pulmonary lesions at three US community hospitals between January 2019 and March 2020. Diagnostic yield was calculated at the index RAB and using 12-month follow-up data. At index, all malignant and benign (specific and non-specific) diagnoses were considered diagnostic. After 12 months, benign non-specific cases were considered diagnostic only when follow-up data corroborated the benign result. An alternative definition at index classified benign non-specific results as non-diagnostic, while an alternative 12-month definition categorized index non-diagnostic cases as diagnostic if no malignancy was diagnosed during follow-up.ResultsThe study included 264 patients. Median lesion size was 19.3 mm, 58.9% were peripherally located, and 30.1% had a bronchus sign. Samples were obtained via Monarch in 99.6% of patients. Pathology led to a malignant diagnosis in 115 patients (43.6%), a benign diagnosis in 110 (41.7%), and 39 (14.8%) non-diagnostic cases. Index diagnostic yield was 85.2% (95% CI: [80.9%, 89.5%]) and the 12-month diagnostic yield was 79.4% (95% CI: [74.4%, 84.3%]). Alternative definitions resulted in diagnostic yield estimates of 58.7% (95% CI: [52.8%, 64.7%]) at index and 89.0% (95% CI: [85.1%, 92.8%]) at 12 months. Sensitivity for malignancy was 79.3% (95% CI: [72.7%, 85.9%]) and cancer prevalence was 58.0% after 12 months.ConclusionsRAB demonstrated a high diagnostic yield in the largest study to date, despite representing a real-world community population with a relatively low prevalence of cancer. Alternative definitions had a considerable impact on diagnostic yield estimates.

Comparison of electromagnetic navigation bronchoscopy and transthoracic needle biopsy for diagnosing bronchus sign-positive pulmonary lesions

ObjectivesElectromagnetic navigation bronchoscopy (ENB) is an advanced technique for diagnosing peripheral pulmonary lesions, and the bronchus sign is a well-established factor for improving the diagnostic performance. However, ENB is a novel technology compared to the commonly adopted transthoracic needle biopsy (TTNB). There are limited data on the comparison of these techniques for diagnosing bronchus sign-positive lesions. Therefore, we aimed to compare the diagnostic yield and complication rates of ENB and TTNB for diagnosing lung cancer in bronchus sign-positive pulmonary lesions. Materials and methodsWe assessed 2,258 individuals who underwent either of the techniques for initial biopsy between September 2016 and May 2022 at a tertiary center in South Korea and analyzed 1,248 participants (153 ENB and 1,095 TTNB cases) with a positive bronchus sign. We performed multivariable logistic regression analyses to evaluate the factors associated with the diagnostic yield, sensitivity for malignancy, and procedure-related complications. In addition, the outcomes were compared between the two techniques after a 1:2 propensity score-matching to control for pre-procedural factors. ResultsAfter adjustments for clinical/radiological factors, performing TTNB over ENB was not significantly associated with a higher diagnostic yield but with a higher risk of pneumothorax (OR = 9.69, 95% CI = 4.15–22.59). Propensity score-matching resulted in 459 participants (153 ENB and 306 TTNB cases) with balanced pre-procedural characteristics. The overall diagnostic yield did not differ significantly between ENB and TTNB (85.0% vs. 89.9%, p = 0.124). The diagnostic yield (86.7% vs. 90.3%, p = 0.280) and sensitivity for malignancy (85.3% vs. 88.8%, p = 0.361) were comparable among patients with a class 2 bronchus sign. However, TTNB demonstrated a significantly higher complication rate of pneumothorax (28.8% vs. 3.9%, p < 0.001) and pneumothorax requiring tube drainage (6.5% vs. 2.0%, p = 0.034) than ENB. ConclusionENB demonstrated a diagnostic yield comparable with that of TTNB for diagnosing bronchus sign-positive peripheral pulmonary lesions with significantly lower complication rates.

High diagnostic yield of multigene panel testing in patients with endocrine tumors

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Routine immediate postoperative radiographs rarely identify unknown complications after shoulder arthroplasty.

Intraoperative complications after shoulder arthroplasty (SA) are uncommon, yet surgeons continue to obtain immediate postoperative radiographs despite prior literature questioning the efficacy of these images. There is a paucity of literature describing the role of immediate postoperative radiographs in revision SA. This study aimed to evaluate the utility of immediate postoperative radiographs in identifying intraoperative complications leading to a change in care after primary or revision SA. We hypothesized that routine postoperative ("survey") radiographs would not provide a high diagnostic yield in identifying early complications requiring a change in postoperative management. A retrospective review of 4063 SAs (1298 primary anatomic total shoulder arthroplasties [aTSAs], 2162 primary reverse shoulder arthroplasties [RSAs], 129 revision aTSAs, and 474 revision RSAs) was performed from a multi-institutional arthroplasty database. All shoulders were evaluated with a single immediate postoperative (survey) radiograph that was read by a musculoskeletal radiologist and by the treating orthopedic surgery team. The radiology reports of all 4063 immediate postoperative radiographs were reviewed to determine whether complications had been identified. For patients in whom complications were identified, the medical record was then reviewed to determine whether the survey radiograph resulted in a return to the operating room or a change in management between the surgical procedure and the first postoperative clinic visit with radiographic evaluation. Complications were reported by a radiologist on the basis of immediate postoperative radiographs in 10 of 4063 shoulders (0.2%, or 1 of every 500 arthroplasties). Complications were reported after 4 primary RSAs, 4 revision aTSAs, and 2 revision RSAs; no complication was reported after any of the primary aTSAs. Of the 10 complications, only 3 were unknown to the treating surgeon following the operation and none altered immediate postoperative management. Early complications were reported at a rate of 1% after revision arthroplasty vs. 0.1% after primary arthroplasty (P=.001). Additionally, revision aTSA was found to have a higher rate of complications reported on radiographs, with a rate of 3.1%, compared with revision RSA, at 0.4% (P=.021). The radiology reports of routine immediate postoperative radiographs rarely identified postoperative complications (0.2%). In all cases, postoperative management remained unaltered until the time of the first postoperative visit. The value and medicolegal implications of immediate postoperative radiographs may inform the decision to abandon obtaining these studies routinely.

The role of single positron emission computed tomography imaging in the diagnosis of brain death whenever Trans-cranial Doppler fails to support it: A retrospective cohort study.

Although there is widespread acceptance of the concept of brain death/death by neurologic criteria (BD/DNC), there is marked variability in the use of ancillary tests worldwide. Transcranial Doppler (TCD) is a useful ancillary test for brain death confirmation because it is safe, noninvasive, and done at the bedside. However, it is considered less sensitive than Single Photon Emission Computed Tomography (SPECT) Tc-HMPAO (99m). This study aims to test the yield of brain perfusion SPECT testing after a TCD has demonstrated some level of intracranial blood flow among patients fulfilling clinical criteria for BD/DNC. This was a single-center retrospective cohort study of all the patients fulfilling clinical criteria for BD/DNC who underwent brain perfusion SPECT after an intracerebral circulatory arrest was not confirmed by TCD between July 2016 and January 2022. TCD was an initial ancillary test performed in 252 patients (99.6%) fulfilling clinical criteria for BD/DNC. A complete circulatory arrest was demonstrated in 228 (90.5%) patients. Brain perfusion SPECT was performed in the remaining 24 patients. The absence of cerebral perfusion consistent with BD/DNC was found in 21 cases (87.5%). BD/DN could not be confirmed in three patients (12.5%). SPECT testing has a high diagnostic yield when TCD fails to confirm a suspected diagnosis of BD/DNC. Combining these two modalities may be an optimal strategy for BD/DNC diagnosis when this is required by local regulations or when confounding factors interfere with the performance of a complete clinical assessment.

SARS-CoV-2 Detection by Digital Polymerase Chain Reaction and Immunohistochemistry in Skin Biopsies from 52 Patients with Different COVID-19-Associated Cutaneous Phenotypes

Background: COronaVIrus Disease 19 (COVID-19) is associated with a wide spectrum of skin manifestations, but SARS-CoV-2 RNA in lesional skin has been demonstrated only in few cases. Objective: The objective of this study was to demonstrate SARS-CoV-2 presence in skin samples from patients with different COVID-19-related cutaneous phenotypes. Methods: Demographic and clinical data from 52 patients with COVID-19-associated cutaneous manifestations were collected. Immunohistochemistry and digital PCR (dPCR) were performed in all skin samples. RNA in situ hybridization (ISH) was used to confirm the presence of SARS-CoV-2 RNA. Results: Twenty out of 52 (38%) patients presented SARS-CoV-2 positivity in the skin. Among these, 10/52 (19%) patients tested positive for spike protein on immunohistochemistry, five of whom had also positive testing on dPCR. Of the latter, one tested positive both for ISH and ACE-2 on immunohistochemistry while another one tested positive for nucleocapsid protein. Twelve patients showed positivity only for nucleocapsid protein on immunohistochemistry. Conclusions: SARS-CoV-2 was detected only in 38% of patients, without any association with a specific cutaneous phenotype, suggesting that the pathophysiology of cutaneous lesions mostly depends on the activation of the immune system. The combination of spike and nucleocapsid immunohistochemistry has higher diagnostic yield than dPCR. Skin persistence of SARS-CoV-2 may depend on timing of skin lesions, viral load, and immune response.

Diagnostic yield and safety of navigation bronchoscopy: A systematic review and meta-analysis

BackgroundNavigation bronchoscopy has seen rapid development in the past decade in terms of new navigation techniques and multi-modality approaches utilizing different techniques and tools. This systematic review analyses the diagnostic yield and safety of navigation bronchoscopy for the diagnosis of peripheral pulmonary nodules suspected of lung cancer. MethodsAn extensive search was performed in Embase, Medline and Cochrane CENTRAL in May 2022. Eligible studies used cone-beam CT-guided navigation (CBCT), electromagnetic navigation (EMN), robotic navigation (RB) or virtual bronchoscopy (VB) as the primary navigation technique. Primary outcomes were diagnostic yield and adverse events. Quality of studies was assessed using QUADAS-2. Random effects meta-analysis was performed, with subgroup analyses for different navigation techniques, newer versus older techniques, nodule size, publication year, and strictness of diagnostic yield definition. Explorative analyses of subgroups reported by studies was performed for nodule size and bronchus sign. ResultsA total of 95 studies (n = 10,381 patients; n = 10,682 nodules) were included. The majority (n = 63; 66.3%) had high risk of bias or applicability concerns in at least one QUADAS-2 domain. Summary diagnostic yield was 70.9% (95%-CI 68.4%-73.2%). Overall pneumothorax rate was 2.5%. Newer navigation techniques using advanced imaging and/or robotics(CBCT, RB, tomosynthesis guided EMN; n = 24 studies) had a statistically significant higher diagnostic yield compared to longer established techniques (EMN, VB; n = 82 studies): 77.5% (95%-CI 74.7%-80.1%) vs 68.8% (95%-CI 65.9%-71.6%) (p < 0.001).Explorative subgroup analyses showed that larger nodule size and bronchus sign presence were associated with a statistically significant higher diagnostic yield. Other subgroup analyses showed no significant differences. ConclusionNavigation bronchoscopy is a safe procedure, with the potential for high diagnostic yield, in particular using newer techniques such as RB, CBCT and tomosynthesis-guided EMN. Studies showed a large amount of heterogeneity, making comparisons difficult. Standardized definitions for outcomes with relevant clinical context will improve future comparability.

Diagnostic yield and safety of ultrasound-guided percutaneous testicular biopsies in children.

Traditionally, testicular biopsy is performed using an open surgical approach. Ultrasound-guided percutaneous biopsy is a less invasive alternative and can be performed in children. The aim of this study is to report our technique and to assess the diagnostic accuracy and safety of ultrasound-guided percutaneous biopsy of testicular masses in children. This is a 16-year retrospective review of ultrasound-guided percutaneous testicular biopsies at a single pediatric hospital. We performednine ultrasound-guided testicular biopsies in 9 patients (median age: 3years, range: 4months-11years; median weight: 20.9kg, range: 8.4-35kg; median volume of testicular lesion biopsied: 4.4mL, range: 1.2-17mL). A percutaneous co-axial technique was used for 5/9 biopsies with absorbable gelatin sponge tract embolization performed in 4 of those biopsies. A non-co-axial technique was used in 4/9 biopsies. A median of three cores, range 2-6, were obtained. The diagnostic yield was 89% with one biopsy yielding material suggestive of, but insufficient for, a definitive diagnosis. The most common histological diagnosis was leukemic infiltration, occurring in 6/9 biopsies. Of the remaining three biopsies, one biopsy was suggestive of, but not confirmatory for, juvenile granulosa cell tumor and two biopsies confirmed normal testicular tissue; the long-term follow-up of which demonstrated normal growth and no lasting damage. There was one (clinically insignificant) complication out of nine biopsies (11%, 95% confidence interval 0-44%): a mild, self-resolving scrotal hematoma. Ultrasound-guided testicular biopsy can be performed safely in children as an alternative to open surgical biopsy, with a high diagnostic yield and low complication rate.

The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature

Introduction: Among children born small for gestational age, 10–15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. Methods: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <−2 SD for gestational age and life-minimum height <−2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. Results: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. Conclusions: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.

The contribution of competing mechanisms in stroke despite anticoagulation in patients with atrial fibrillation.

For reasons poorly understood, strokes frequently occur in patients with atrial fibrillation (AF) despite oral anticoagulation. Better data are needed to inform randomised trials (RCTs) of new strategies to prevent recurrence in these patients. We investigate the relative contribution of competing stroke mechanisms in patients with AF who have stroke despite anticoagulation (OAC+) compared with those who are anticoagulant naïve (OAC-) at the time of their event. We performed a cross-sectional study leveraging data from a prospective stroke registry (2015-2022). Eligible patients had ischemic stroke and AF. Stroke classification was performed by a single stroke-specialist blinded to OAC status using TOAST criteria. The presence of atherosclerotic plaque was determined using duplex ultrasonography, computerised tomography (CT) or magnetic resonance (MR) angiography. Imaging was reviewed by a single reader. Logistic regression was used to identify independent predictors of stroke despite anticoagulation. Of 596 patients included, 198 (33.2%) were in the OAC+ group. A competing cause for stroke was more frequent in patients with OAC+ versus OAC- (69/198 (34.8%)) versus 77/398 (19.3%), p < 0.001). After adjustment, both small vessel occlusion (odds ratio (OR): 2.46, 95% CI: 1.20-5.06) and arterial atheroma (⩾50% stenosis) (OR: 1.78, 95% CI: 1.07-2.94) were independently associated with stroke despite anticoagulation. Patients with AF-associated stroke despite OAC are much more likely than patients who are OAC-naïve to have competing stroke mechanisms. Rigorous investigation for alternative stroke causes in stroke despite OAC has a high diagnostic yield. These data should be used to guide patient selection for future RCTs in this population.

Scope of medical rigid thoracoscopy in patients with pleural effusion of unknown etiology: A prospective single center study

Background: Pleural diseases commonly encountered are pleural effusion, pneumothorax, pleural wall thickening, and pleural mass. Medical thoracoscopy is a minimally invasive procedure that allows diagnostic and therapeutic intervention. The medical diagnostic thoracoscopy in local anesthesia is a simple, low-cost investigation with relatively high diagnostic accuracy, no mortality, and low morbidity. A diagnosis of pleural tuberculosis (TB) could be achieved in 99% of patients as against 51% using closed pleural biopsy. Aims and Objectives: Assessment of the role of medical rigid thoracoscopy in patients with pleural effusion of unknown etiology in a tertiary health care setup. The primary objectives of the study were to evaluate the diagnostic yield of medical thoracoscopy in pleural effusion of unknown etiology. Materials and Methods: The study duration/time frame to address the study: November 2017–February 2019 sample size with Justification Sample size: Minimum 31 patients. It was a prospective observational study. All patients admitted in hospital/daycare at LHRC presenting with pleural effusion with unknown etiology. All patients had a medical thoracoscopy, and samples were sent for microbiological and histological analysis. Clinical, thoracoscopic results and histopathological data of the patients were collected prospectively and analyzed. Results: In this study, 28 patients out of 31 patients were diagnosed. The diagnostic yield of thoracoscopic pleural biopsy was 90.3% Out of 31 patients, the most common complication found was chest pain 48.4% (15/31), followed by 09.7% (03/31) of the cases had complications such as surgical emphysema, postoperative fever, and bleeding. There were no complications in 32.2% (10/31) patients. Conclusion: Medical thoracoscopy is a noble procedure that helps the pulmonologist/surgeon to inspect the pleural cavity. It is a safe and effective diagnostic as well as a therapeutic tool with a high diagnostic yield. The most common differentials of undiagnosed pleural effusion cases are TB and malignancy.