Development and international validation of custom-engineered and code-free deep-learning models for detection of plus disease in retinopathy of prematurity: a retrospective study.

BACKGROUND: Retinopathy of prematurity (ROP), a leading cause of childhood blindness, is diagnosed through interval screening by paediatric ophthalmologists. However, improved survival of premature neonates coupled with a scarcity of available experts has raised concerns about the sustainability of this approach. We aimed to develop bespoke and code-free deep learning-based classifiers for plus disease, a hallmark of ROP, in an ethnically diverse population in London, UK, and externally validate them in ethnically, geographically, and socioeconomically diverse populations in four countries and three continents. Code-free deep learning is not reliant on the availability of expertly trained data scientists, thus being of particular potential benefit for low resource health-care settings. METHODS: This retrospective cohort study used retinal images from 1370 neonates admitted to a neonatal unit at Homerton University Hospital NHS Foundation Trust, London, UK, between 2008 and 2018. Images were acquired using a Retcam Version 2 device (Natus Medical, Pleasanton, CA, USA) on all babies who were either born at less than 32 weeks gestational age or had a birthweight of less than 1501 g. Each images was graded by two junior ophthalmologists with disagreements adjudicated by a senior paediatric ophthalmologist. Bespoke and code-free deep learning models (CFDL) were developed for the discrimination of healthy, pre-plus disease, and plus disease. Performance was assessed internally on 200 images with the majority vote of three senior paediatric ophthalmologists as the reference standard. External validation was on 338 retinal images from four separate datasets from the USA, Brazil, and Egypt with images derived from Retcam and the 3nethra neo device (Forus Health, Bengaluru, India). FINDINGS: Of the 7414 retinal images in the original dataset, 6141 images were used in the final development dataset. For the discrimination of healthy versus pre-plus or plus disease, the bespoke model had an area under the curve (AUC) of 0·986 (95% CI 0·973-0·996) and the CFDL model had an AUC of 0·989 (0·979-0·997) on the internal test set. Both models generalised well to external validation test sets acquired using the Retcam for discriminating healthy from pre-plus or plus disease (bespoke range was 0·975-1·000 and CFDL range was 0·969-0·995). The CFDL model was inferior to the bespoke model on discriminating pre-plus disease from healthy or plus disease in the USA dataset (CFDL 0·808 [95% CI 0·671-0·909, bespoke 0·942 [0·892-0·982]], p=0·0070). Performance also reduced when tested on the 3nethra neo imaging device (CFDL 0·865 [0·742-0·965] and bespoke 0·891 [0·783-0·977]). INTERPRETATION: Both bespoke and CFDL models conferred similar performance to senior paediatric ophthalmologists for discriminating healthy retinal images from ones with features of pre-plus or plus disease; however, CFDL models might generalise less well when considering minority classes. Care should be taken when testing on data acquired using alternative imaging devices from that used for the development dataset. Our study justifies further validation of plus disease classifiers in ROP screening and supports a potential role for code-free approaches to help prevent blindness in vulnerable neonates. FUNDING: National Institute for Health Research Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and the University College London Institute of Ophthalmology. TRANSLATIONS: For the Portuguese and Arabic translations of the abstract see Supplementary Materials section

Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication

Funding Information: We thank Thorsten Wolff, Daniel Bourquain, Jessica Schulz, and Christian Mache from the Robert-Koch Institute and Martin Beer from the Friedrich Loeffler Institute (FLI) for providing isolates of SARS-CoV-2 variants. We thank Anna Kraft and Gabriele Czerwinski (both FLI) for support in the preparation of samples for pathology, and Catherine Hambly (University of Aberdeen) for help with daily energy expenditure measurements. We would like to thank Cathrin Bierwirth (University Medical Center Göttingen), Isabell Schulz, Anne-Kathrin Donner, and Frank-Thorben Peters for excellent technician assistance and Jasmin Fertey and Alexandra Rockstroh for providing the virus stocks for the mice experiment (Fraunhofer Institute IZI Leipzig). We acknowledge support by the Open Access Publication Funds of the Göttingen University. KMS was a member of the Göttingen Graduate School GGNB during this work. This work was funded by the COVID-19 Forschungsnetzwerk Niedersachsen (COFONI) to MD, by the Federal Ministry of Education and Research Germany ( Bundesministerium für Bildung und Forschung; BMBF ; OrganSARS , 01KI2058 ) to SP and TM, and by a grant of the Max Planck Foundation to DG. Declaration of interests AS, HK, EP, and DV are employees of Immunic AG and own shares and/or stock-options of the parent company of Immunic AG, Immunic Inc. Some of the Immunic AG employees also hold patents for the Immunic compounds described in this manuscript (WO2012/001,148, WO03006425). KMS, AD, and MD are employees of University Medical Center Göttingen, which has signed a License Agreement with Immunic AG covering the combination of DHODH inhibitors and nucleoside analogs to treat viral infections, including COVID-19 (inventors: MD, KMS, and AD). The other authors declare no conflict of interest.Peer reviewedPublisher PD

Population Genetic Diversity and Structure of a Naturally Isolated Plant Species, Rhodiola dumulosa (Crassulaceae)

Aims: Rhodiola dumulosa (Crassulaceae) is a perennial diploid species found in high-montane areas. It is distributed in fragmented populations across northern, central and northwestern China. In this study, we aimed to (i) measure the genetic diversity of this species and that of its populations; (ii) describe the genetic structure of these populations across the entire distribution range in China; and (iii) evaluate the extent of gene flow among the naturally fragmented populations. Methods: Samples from 1089 individuals within 35 populations of R. dumulosa were collected, covering as much of the entire distribution range of this species within China as possible. Population genetic diversity and structure were analyzed using AFLP molecular markers. Gene flow among populations was estimated according to the level of population differentiation. Important Findings: The total genetic diversity of R. dumulosa was high but decreased with increasing altitude. Populationstructure analysis indicated that the most closely related populations were geographically restricted and occurred in close proximity to each other. A significant isolation-by-distance pattern, caused by the naturally fragmented population distribution, was observed. At least two distinct gene pools were found in the 35 sampled populations, one composed of populations in northern China and the other composed of populations in central and northwestern China. The calculation of Nei’s gene diversity index revealed that the genetic diversity in the northern China pool (0.1972) was lower than that in th

Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson\u27s disease study

\ua9 The Author(s) 2024. Estimates of the spectrum and frequency of pathogenic variants in Parkinson’s disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson’s disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 7 10−34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 7 10−35). Female patients were 22% more likely to have a positive PDGT (P = 3 7 10−4), and for individuals with FH+ this likelihood was 55% higher (P = 1 7 10−14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD

Relationship between peripheral-central blood pressure and cardiac-renal damage in kidney transplant recipients

PubMedID: 30777552Objectives: Hypertension is a common and important problem in kidney transplant recipients, directly affecting graft and patient survival. Here, we evaluated the relationship between renal-cardiac damage and peripheral and central aortic blood pressure levels in renal transplant recipients. Materials and Methods: We measured peripheral blood pressure (office, daytime ambulatory, and central aortic) in 46 kidney transplant recipients. Biochemical parameters were simultaneously measured. Electro - cardiography and echocardiography were performed. Patients with office blood pressure > 140/90 mm Hg or who were treated with antihypertensive drugs were accepted as hypertensive. Results: Ambulatory blood pressure measurements were higher than office blood pressure measurements (at 135.6/85.6 mm Hg vs 121.8/77.5 mm Hg in hypertensive and at 118.8/77.6 mm Hg vs 101.6/62.5 mm Hg in normotensive patients) (P .05). Left ventricle hyper - trophy was found to be less common in patients using angiotensin-converting enzyme, although not significantly (P >.05). Conclusions: In kidney transplant recipients, blood pressure should be monitored with ambulatory blood pressure measurements, even when normal office pressure levels are shown. The aim of antihypertensive therapy is not only to decrease brachial artery pressure but also to keep central aortic systolic blood pressure in the proper interval, adjusted according to age. This may more effectively prevent the development of renal cardiac damage versus peripheral blood pressure measurement monitoring. © Başkent University 2019 Printed in Turkey. All Rights Reserved

Comamonas testosteroni peritonitis secondary to dislocated intrauterine device and laparoscopic intervention in a continuous ambulatory peritoneal dialysis patient

PubMedID: 24133084[No abstract available