Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

OBJECTIVE: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and to investigate factors that increase diagnostic yield. DESIGN: Retrospective analysis of data from two prospective cohort studies. SETTING: Fetal medicine centres in the UK and USA. POPULATION: Fetuses with increased NT ≥3.5 mm at 11-14 weeks of gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal whole exome sequencing studies (n = 213). METHODS: We grouped cases based on (1) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (2) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. MAIN OUTCOME MEASURES: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. RESULTS: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. CONCLUSIONS: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis.

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE) study: prospective cohort study and systematic review.

OBJECTIVE: To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD). METHODS: A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup. RESULTS: In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15-27%), 11% (95% CI, 7-15%) and 37% (95% CI, 18-56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17-80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19-63%)), followed by right-sided lesions (26% (95% CI, 9-43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome. CONCLUSIONS: There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Fetal hydrops and the Incremental yield of Next-generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta-analysis.

OBJECTIVE: To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis (NIHF). METHODS: A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound-based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected). RESULTS: In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non-isolated NIHF. In the meta-analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24-34%; P < 0.00001; I2 = 0%) in all NIHF, 21% (95% CI, 13-30%; P < 0.00001; I2 = 0%) in isolated NIHF and 39% (95% CI, 30-49%; P < 0.00001; I2 = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51). CONCLUSIONS: Use of prenatal next-generation sequencing in both isolated and non-isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole-genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

[Recommendations for Performing Bronchoscopy in Times of the COVID-19 Pandemic - Update 12/2020]. / Empfehlungen zur Durchführung einer Bronchoskopie in Zeiten der COVID-19-Pandemie: Update 12/2020.

The SARS-CoV-19 pandemic continues to be globally related with significant morbidity and mortality, making protective measures to prevent transmission of the virus still necessary. Healthcare employees are exposed to a higher risk of infection and this is particularly true when performing aerosol-generating procedures such as bronchoscopy.Since the publication of recommendations for performing a bronchoscopy in the times of COVID-19 more than six months ago, the risk situation has not changed significantly, but due to the considerable gain in knowledge in the meantime, an update of the recommendations was necessary.The updated recommendations include the reduction of aerosol formation, the personal protection of the people involved in the procedure, as well as measures to better organize the processes in the endoscopy suite in order to perform bronchoscopic procedures securely even in times of COVID-19.

[Recommendations for Performing Bronchoscopy in Times of the COVID-19 Pandemic]. / Empfehlungen zur Durchführung einer Bronchoskopie in Zeiten der COVID-19-Pandemie.

COVID-19, caused by coronavirus SARS-CoV-2 is a new and ongoing infectious disease affecting healthcare systems worldwide. Healthcare worker are at high risk for COIVD-19 and many have been infected or even died in countries severely affected by COVID-19 like China or Italy. Bronchoscopy causes cough and aerosol production and has to be considered a significant risk for the staff to get infected. Particular recommendations should guide to prevent spreading COVID-19 and to protect healthcare worker when performing a bronchoscopy.

[Joint Statement of the German Respiratory Society and German Society of Thoracic Surgery in Cooperation with the German Radiological Society: Structural Prerequisites of Centers for Interventional Treatment of Emphysema]. / Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin und der Deutschen Gesellschaft für Thoraxchirurgie in Kooperation mit der Deutschen Röntgengesellschaft: Strukturvoraussetzungen von Zentren für die interventionelle Emphysemtherapie.

Interventional treatment of emphysema offers a wide range of surgical and endoscopic options for patientes with advanced disease. Multidsciplinary collaboration of pulmonology, thoracic surgery and imaging disciplines in patient selection, therapy and follow up ensures treatment quality. The present joint statement describes the required structural and quality prerequsites of treatment centres.

Micro-fluorescence lifetime and spectral imaging of ytterbium doped laser materials.

We present the application of a confocal fluorescence microscope to the analysis of Yb-doped solid-state laser materials, with examples of Yb-doped crystals, photonic crystal fibers and fiber preforms made with different manufacturing processes. Beside the fluorescence lifetime image itself, a microscopic spectral fluorescence emission analysis is presented and spatially resolved emission cross sections are obtained. Doping concentration and its distributions and other laser optical parameters are measured, which help to analyze manufacturing steps. Further properties like photodarkening and saturation are addressed.

[Rebiopsy for Patients with Lung Cancer - Joint Opinion from both the Endoscopic and Thoracic Oncology Sections of the German Society of Pneumology (DGP)]. / Empfehlung der Sektionen 2 und 11 der DGP zur Rebiopsie bei Lungenkarzinomen.

Performing rebiopsies for primary lung cancer and/or their metastases is becoming more and more prominent in daily practice, as the therapeutical spectrum increases and some newer strategies are dependent on immunohistochemical and/or molecular factors. In general, nearly all recurrent lesions or metastases can be reached. However, frequently invasive procedures are necessary with the need to carefully weigh risks and benefits of rebiopsies for the patient in each case. In this review indications for recurrent and progressive disease as well as risks are discussed and alternatives to rebiopsies are shown. This work is the joint opinion from both the endoscopic and thoracic oncology sections of the German Society of Pneumology (DGP).

Modal content measurements (S2) of negative curvature hollow-core photonic crystal fibers.

We present modal content measurements (S2) of two different negative curvature hollow-core photonic crystal fibers: a kagome fiber and an ice cream cone fiber. Their sensitivity towards mode matching, bending and polarization is analyzed. For the kagome fiber, a higher order mode suppression of 17dB under optimal conditions was achieved, and for the ice cream cone fiber there was a suppression of up to 42dB. Polarization turned out to be a critical parameter for good higher order mode suppression in both fibers.

Single mode 4.3 kW output power from a diode-pumped Yb-doped fiber amplifier.

We investigate the average power scaling of two diode-pumped Yb-doped fiber amplifiers emitting a diffraction-limited beam. The first fiber under investigation with a core diameter of 30 µm was able to amplify a 10 W narrow linewidth seed laser up to 2.8 kW average output power before the onset of transverse mode instabilities (TMI). A further power scaling was achieved using a second fiber with a smaller core size (23µm), which allowed for a narrow linewidth output power of 3.5 kW limited by stimulated Brillouin scattering (SBS). We mitigated SBS using a spectral broadening mechanism, which allowed us to further increase the output power to 4.3 kW only limited by the available pump power. Up to this power level, a high slope efficiency of 90% with diffraction-limited beam quality and without any sign of TMI or stimulated Raman scattering for a spectral dynamic range of higher than -80 dB was obtained.

Narrow linewidth, single mode 3 kW average power from a directly diode pumped ytterbium-doped low NA fiber amplifier.

We report on a newly designed and fabricated ytterbium-doped large mode area fiber with an extremely low NA (~0.04) and related systematic investigations on fiber parameters that crucially influence the mode instability threshold. The fiber is used to demonstrate a narrow linewidth, continuous wave, single mode fiber laser amplifier emitting a maximum output power of 3 kW at a wavelength of 1070 nm without reaching the mode-instability threshold. A high slope efficiency of 90 %, excellent beam quality, high temporal stability, and an ASE suppression of 70 dB could be reached with a signal linewidth of only 170 pm.

[Complex control of the source of infection in sepsis : Extracorporeal membrane oxygenation (ECMO) as a bridging concept for tracheal fistula repair in sepsis-associated ARDS]. / Komplexe Fokussanierung in der Sepsis : Extrakorporale Membranoxygenierung (ECMO) als Bridging-Konzept zur trachealen Fistelsanierung bei sepsisassoziiertem ARDS.

Here, we present a case of a tracheal fistula due to an anastomotic insufficiency following abdominothoracic esophageal resection. Despite immediate discontinuity resection, the tracheal fistula could not be surgically closed, resulting in incomplete control of the source of infection and an alternative treatment concept in the form of interventional fistula closure using a Y-tracheal stent. However, owing to existing severe acute respiratory distress syndrome (ARDS), which is associated with a considerable risk of peri-interventional hypoxia, a temporary bridging concept using venovenous extracorporeal membrane oxygenation (ECMO) was implemented successfully.

[Tracheobronchoplasty for Severe Diffuse Tracheomalacia]. / Tracheobronchoplastie bei schwerer diffuser Tracheobronchomalazie.

Patients with diffuse airway instability due to tracheobronchomalacia or excessive dynamic airway collapse are typically highly symptomatic, with marked dyspnoea, recurrent bronchopulmonary infections and excruciating intractable cough. Silicone stents achieve immediate symptom control, but are - due to the typical complications associated with stent treatment - usually not an option for long-term treatment. The aim of surgical intervention is definitive stabilisation of the trachea and of both main bronchi by posterior splinting of the Paries membranaceus with a polypropylene mesh. This operation is an appropriate treatment option for patients with documented severe tracheobronchomalacia or excessive dynamic airway collapse and is ultimately the only therapy that can achieve permanent symptom control. The success of the operation, however, depends on many factors and requires close interdisciplinary collaboration.

Cross-Sectional Survey on Bronchoscopy in Germany--The Current Status of Clinical Practice.

OBJECTIVES: Bronchoscopy is an integral part of pulmonary medicine. In recent years, a series of new technologies have evolved. It is to assume that significant changes have also occurred in clinical practice. We conducted a nationwide survey to evaluate the current status of care and to compare it with earlier reports. METHODS: A standard questionnaire was sent to 1875 institutions to assess the clinical practice of bronchoscopy in Germany with respect to general issues, education, sedation/anaesthesia and technical aspects. RESULTS: The returned questionnaires cover 301,965 bronchoscopies, performed by 2158 physicians over 12 months, making it the largest survey to date. The proportion of rigid bronchoscopies has decreased and amounts to 7.3% at present. Atropine as a premedication is hardly used any more. Sedation is routinely applied in 88% of flexible bronchoscopies, for which a combination of propofol and midazolam is preferred by most institutions (41.3%), followed by propofol monotherapy (28.3%). 74.4% of institutions accept aspirin for transbronchial biopsy, 8.1% dual platelet inhibition. 62.4% of all institutions perform airway recanalisation, favouring cryotherapy and argon plasma coagulation. 9.1% of bronchoscopies are supported by endobronchial ultrasound. CONCLUSION: Compared to preceding surveys, the experience of bronchoscopists, especially regarding interventional procedures, has increased. Endobronchial ultrasound has become a standard of care, as has patient sedation with propofol.

Novel Endoscopic Approaches to Treating Chronic Obstructive Pulmonary Disease and Emphysema.

Chronic obstructive pulmonary disease (COPD) is a widespread disease associated with high morbidity and mortality. The principal aim of therapy is preventing disease progression. Besides rehabilitation and pharmacological treatment, different endoscopic approaches were developed in the past decade extending the therapeutic spectrum. Various endoscopic lung volume reduction (ELVR) techniques are available that differ in the implementation, mechanism of action, complication spectrum, and reversibility. So far, the data on efficacy and safety are variable and still very limited. The most comprehensive data are available for endoscopic valve therapy. This reversible technique leads to lobar atelectasis and thus significant lobar volume reduction in patients with severe emphysema and low collateral ventilation. Implantation of coils leading to parenchymal compression and bronchoscopic thermal vapor ablation inducing an inflammatory reaction are nonblocking ELVR techniques and thus independent of collateral ventilation. Besides ELVR techniques, targeted lung denervation has evolved as the latest development in the field of endoscopic therapy in COPD. The aim of this endoscopic method is sustainable bronchodilation by minimizing the influence of parasympathetic pulmonary nerves on smooth muscles of the airways. This review summarizes the different endoscopic procedures, their mechanism of action, and the results of the clinical trials including efficacy and safety.

1009 nm continuous-wave ytterbium-doped fiber amplifier emitting 146 W.

In this Letter, we demonstrate a single-mode continuous-wave fiber laser amplifier emitting 146 W of average output power at a wavelength of 1009 nm. The wavelength and bandwidth of the seed oscillator are defined by a pair of fiber Bragg gratings. The seed is amplified in a two-stage ytterbium-doped rod-type amplifier to 146 W with a high slope efficiency of 64%, showing excellent beam quality and stability throughout the experiment. The ASE suppression is as high as 63 dB.

[Incidental bronchoscopic findings]. / Der bronchoskopische Zufallsbefund.

Inflexible and flexible bronchoscopy represents a standard diagnostic procedure in pneumology. Besides lung carcinomas, which is the most frequent indication for diagnostic bronchoscopy, a plethora of clinical symptoms such as chronic persistent cough, hoarseness, unexplained dyspnea, hemoptysis, and suspicious findings on auscultation require further endoscopic evaluation. Moreover, bronchoscopy plays a central role in the diagnostic work-up of interstitial lung diseases and persistent lung infiltrates, in particular those of infectious origin (e.g., fungal, viral, tuberculous, and Pneumocystis jiroveci infections). In addition, diagnostic bronchoscopy has more recently been complemented by endobronchial ultrasound (EBUS). EBUS is predominantly employed for the accurate diagnosis and mediastinal staging of lung carcinomas, and the assessment of lympadenopathy-associated diseases such as sarcoidosis.Since endoscopic evaluation is typically preceded by computed tomography (CT) of the chest, genuine incidental findings occur relatively seldom and usually account for pathological findings that have been missed on conventional imaging approaches. For instance, characteristic incidental findings include benign and malignant tumors in the area of the endoscopic access and central airways, anatomical variations and (vascular) malformations, tracheal and bronchial airway alterations, and aspirated objects. This review focuses on bronchoscopic findings that have either been completely missed by conventional imaging or differently interpreted due to its radiologic morphology.

Collateral ventilation.

Although known for more than 80 years, 'collateral ventilation' (CV) became a focus of endoscopic research in the recent decade. Implantation of one-way valves presents an effective treatment option for patients with advanced heterogeneous emphysema optimizing symptoms and quality of life. However, this treatment modality is only successful in case of low interlobar CV. Based on this evidence, attempts to develop different approaches for the quantification of CV have been initiated. In this regard, it is crucial to illuminate the meaning and different aspects of CV.

Endobronchial ultrasound-guided lymph node biopsy with transbronchial needle forceps: a pilot study.

One limitation of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the size of the available needles, frequently yielding only cells for cytological examination. The aim of this pilot study was to evaluate the efficacy and safety of newly developed needle forceps to obtain tissue for the histological diagnosis of enlarged mediastinal lymph nodes. Patients with enlarged, positron emission tomography (PET)-positive lymph nodes were included. The transbronchial needle forceps (TBNF), a sampling instrument combining the characteristics of a needle (bevelled tip for penetrating through the bronchial wall) with forceps (two serrated jaws for grasping tissue) was used through the working channel of the EBUS-TBNA scope. Efficacy and safety was assessed. 50 patients (36 males and 14 females; mean age 51 yrs) with enlarged or PET-positive lymph nodes were included in this pilot study. In 48 (96%) patients penetration of the bronchial wall was possible and in 45 patients tissue for histological diagnosis was obtained. In three patients TBNF provided inadequate material. For patients in whom the material was adequate for a histological examination, a specific diagnosis was established in 43 (86%) out of 50 patients (nonsmall cell lung cancer: n=24; small cell lung cancer: n=7; sarcoidosis: n=4; Hodgkin's lymphoma: n=4; tuberculosis: n=2; and non-Hodgkin's lymphoma: n=2).No clinically significant procedure-related complications were encountered. This study demonstrated that EBUS-TBNF is a safe procedure and provides diagnostic histological specimens of mediastinal lymph nodes.

Cryobiopsy increases the diagnostic yield of endobronchial biopsy: a multicentre trial.

Forceps, brushes or needles are currently the standard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies. The new biopsy technique of cryobiopsy appears to provide better diagnostic samples. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling. A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospective, randomised, single-blinded multicentre study. Patients were randomised to either sampling using forceps or the cryoprobe. After obtaining biopsy samples, a blinded histological evaluation was performed. According to the definitive clinical diagnosis, the diagnostic yield for malignancy was evaluated by a Chi-squared test. A total of 593 patients were randomised, of whom 563 had a final diagnosis of cancer. 281 patients were randomised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe. A definitive diagnosis was achieved in 85.1% of patients randomised to conventional forceps biopsy and 95.0% of patients who underwent cryobiopsy (p<0.001). Importantly, there was no difference in the incidence of significant bleeding. Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy.