Association Between Visual Acuity and Prospective Fall Risk in Generally Healthy and Active Older Adults: The 3-Year DO-HEALTH Study.

OBJECTIVE: Although aging has a strong impact on visual acuity (VA) and falls, their interaction is understudied in generally healthy older adults. This study aimed to examine if and to what extent baseline VA is associated with an increased risk of all and injurious falls over 3 years in generally healthy community-dwelling older adults. DESIGN: Observational analysis of DO-HEALTH, a double-blind, randomized controlled trial. SETTING AND PARTICIPANTS: Multicenter trial with 7 European centers: Zurich, Basel, Geneva (Switzerland), Berlin (Germany), Innsbruck (Austria), Toulouse (France), and Coimbra (Portugal), including 2157 community-dwelling adults aged 70 years and older without any major health events in the 5 years prior to enrollment, sufficient mobility, and good cognitive status. METHODS: The numbers of all and injurious falls were recorded prospectively by diary and in-person assessment every 3 months. Decreased VA at baseline was defined as better-eye VA lower than 1.0. We applied negative binomial regression models for all and injurious falls, adjusted for age, sex, prior falls, treatment allocation, study site, baseline body mass index, and use of walking aids. RESULTS: Among the 2131 participants included in this analysis (mean age: 74.9 years, 61.7% were women, 82.6% at least moderately physically active), 1464 (68.7%) had decreased VA. Overall, 3290 falls including 2116 injurious falls were recorded over 3 years. Decreased VA at baseline was associated with a 22% increased incidence rate of all falls [adjusted incidence rate ratio (aIRR) = 1.22, 95% CI 1.07, 1.38, P = .003] and 20% increased incidence rate of injurious falls (aIRR = 1.20, 95% CI 1.05, 1.37, P = .007). CONCLUSIONS AND IMPLICATIONS: Our findings suggest that decreased VA is an independent predictor of an about 20% increased risk of all and injurious falls, highlighting the importance of regular eye examinations and VA measurements for fall prevention, even in generally healthy and active older adults.

Small molecule autoencoders: architecture engineering to optimize latent space utility and sustainability.

Autoencoders are frequently used to embed molecules for training of downstream deep learning models. However, evaluation of the chemical information quality in the latent spaces is lacking and the model architectures are often arbitrarily chosen. Unoptimized architectures may not only negatively affect latent space quality but also increase energy consumption during training, making the models unsustainable. We conducted systematic experiments to better understand how the autoencoder architecture affects the reconstruction and latent space quality and how it can be optimized towards the encoding task as well as energy consumption. We can show that optimizing the architecture allows us to maintain the quality of a generic architecture but using 97% less data and reducing energy consumption by around 36%. We additionally observed that representing the molecules as SELFIES reduced the reconstruction performance compared to SMILES and that training with enumerated SMILES drastically improved latent space quality. Scientific Contribution: This work provides the first comprehensive systematic analysis of how choosing the autoencoder architecture affects the reconstruction performance of small molecules, the chemical information content of the latent space as well as the energy required for training. Demonstrated on the MOSES benchmarking dataset it provides first valuable insights into how autoencoders for the embedding of small molecules can be designed to optimize their utility and simultaneously become more sustainable, both in terms of energy consumption as well as the required amount of training data. All code, data and model checkpoints are made available on Zenodo (Oestreich et al. Small molecule autoencoders: architecture engineering to optimize latent space utility and sustainability. Zenodo, 2024). Furthermore, the top models can be found on GitHub with scripts to encode custom molecules: https://github.com/MarieOestreich/small-molecule-autoencoders .

Characteristics Associated with COVID-19 Breakthrough Infections after Booster Vaccinations in Healthcare Workers: Insights from the TüSeRe:exact Study.

Background: The prevalence of COVID-19 breakthrough infections in healthcare workers (HCWs) remains an issue of concern. This study examines the different characteristics associated with breakthrough infections in HCWs. Methods: From the total participants in the TüSeRe:exact study (n = 1046), we specifically included study participants who had received three vaccinations and were not infected prior to the third vaccination. Participants were invited to complete an online questionnaire, which included inquiries about any breakthrough infections they might have experienced. Univariate Cox regression analysis was used to investigate the association between participant characteristics and breakthrough infections. Results: Among 629 HCWs (497 female and 132 male), 241 (38%) experienced breakthrough infections during the follow-up period. The frequency of breakthrough infections was 39.2% (195/497) among female participants and 34.8% (46/132) among male participants (p = 0.357). The Cox regression model adjusted for age and sex showed that participants with cardiovascular disease (hazard ratio (95%CI) = 0.621 (0.392-0.985); p = 0.043) and those taking antihypertensives (hazard ratio (95%CI) = 0.551 (0.331-0.915); p = 0.021) had a significantly lower hazard ratio for breakthrough infections. The use of analgesics after the first vaccine (hazard ratio (95%CI) = 1.343 (1.025-1.759); p = 0.032) was associated with an increased risk of breakthrough infections. Conclusions: These findings can inform targeted preventive measures and risk management strategies to protect frontline workers and maintain a resilient healthcare system during the ongoing pandemic.

Smart hospital: achieving interoperability and raw data collection from medical devices in clinical routine.

Introduction: Today, modern technology is used to diagnose and treat cardiovascular disease. These medical devices provide exact measures and raw data such as imaging data or biosignals. So far, the Broad Integration of These Health Data into Hospital Information Technology Structures-Especially in Germany-is Lacking, and if data integration takes place, only non-Evaluable Findings are Usually Integrated into the Hospital Information Technology Structures. A Comprehensive Integration of raw Data and Structured Medical Information has not yet Been Established. The aim of this project was to design and implement an interoperable database (cardio-vascular-information-system, CVIS) for the automated integration of al medical device data (parameters and raw data) in cardio-vascular medicine. Methods: The CVIS serves as a data integration and preparation system at the interface between the various devices and the hospital IT infrastructure. In our project, we were able to establish a database with integration of proprietary device interfaces, which could be integrated into the electronic health record (EHR) with various HL7 and web interfaces. Results: In the period between 1.7.2020 and 30.6.2022, the data integrated into this database were evaluated. During this time, 114,858 patients were automatically included in the database and medical data of 50,295 of them were entered. For technical examinations, more than 4.5 million readings (an average of 28.5 per examination) and 684,696 image data and raw signals (28,935 ECG files, 655,761 structured reports, 91,113 x-ray objects, 559,648 ultrasound objects in 54 different examination types, 5,000 endoscopy objects) were integrated into the database. Over 10.2 million bidirectional HL7 messages (approximately 14,000/day) were successfully processed. 98,458 documents were transferred to the central document management system, 55,154 materials (average 7.77 per order) were recorded and stored in the database, 21,196 diagnoses and 50,353 services/OPS were recorded and transferred. On average, 3.3 examinations per patient were recorded; in addition, there are an average of 13 laboratory examinations. Discussion: Fully automated data integration from medical devices including the raw data is feasible and already creates a comprehensive database for multimodal modern analysis approaches in a short time. This is the basis for national and international projects by extracting research data using FHIR.

hCoCena: A toolbox for network-based co-expression analysis and horizontal integration of transcriptomic datasets.

As the number and complexity of transcriptomic datasets increase, there is a rising demand for accessible and user-friendly analysis tools. Here, we present hCoCena (horizontal construction of co-expression networks and analysis), a toolbox facilitating the analysis of a single dataset, as well as the joint analysis of multiple datasets. We describe steps for workspace setup, formatting tables, data processing, and network integration. We then detail procedures for gene clustering, gene set enrichment analysis, and transcription factor enrichment analysis. For complete details on the use and execution of this protocol, please refer to Oestreich et al.1.

TGF-ß specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf.

T follicular helper (TFH) cells are essential for effective antibody responses, but deciphering the intrinsic wiring of mouse TFH cells has long been hampered by the lack of a reliable protocol for their generation in vitro. We report that transforming growth factor-ß (TGF-ß) induces robust expression of TFH hallmark molecules CXCR5 and Bcl6 in activated mouse CD4+ T cells in vitro. TGF-ß-induced mouse CXCR5+ TFH cells are phenotypically, transcriptionally, and functionally similar to in vivo-generated TFH cells and provide critical help to B cells. The study further reveals that TGF-ß-induced CXCR5 expression is independent of Bcl6 but requires the transcription factor c-Maf. Classical TGF-ß-containing T helper 17 (TH17)-inducing conditions also yield separate CXCR5+ and IL-17A-producing cells, highlighting shared and distinct cell fate trajectories of TFH and TH17 cells. We demonstrate that excess IL-2 in high-density T cell cultures interferes with the TGF-ß-induced TFH cell program, that TFH and TH17 cells share a common developmental stage, and that c-Maf acts as a switch factor for TFH versus TH17 cell fates in TGF-ß-rich environments in vitro and in vivo.

Two regulatory T cell populations in the visceral adipose tissue shape systemic metabolism.

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.

DWT-CNNTRN: a Convolutional Transformer for ECG Classification with Discrete Wavelet Transform.

Cardiovascular diseases are the leading cause of death worldwide. The diagnoses of cardiovascular diseases are usually carried out by cardiologists utilizing Electrocardiograms (ECGs). To assist these physicians in making an accurate diagnosis, there is a growing need for reliable and automatic ECG classifiers.In this study, a new method is proposed to classify 12-lead ECG recordings. The proposed model is composed of four components: the CNN(Convolutional Neural Network) module, the transformer module, the global hybrid pooling layer, and a classification layer. To improve the classification performance, the model takes the discrete wavelet transform of ECG signals as the model inputs and utilizes a hybrid pooling layer to condense the most important features over each period.The proposed model is evaluated using the test set of the China Physiological Signal Challenge 2018 dataset with 12-lead ECGs. It performs with an average accuracy of 0.86 and an average F1-scores of 0.83. The scores are particularly good for the block conditions (LBBB, RBBB, I-AVB). The main advantage of the proposed model is that, it obtains good results with a significantly smaller number of parameters compared to other individual and ensemble models.Clinical relevance- This work establishes a new ECG classifier model with high performance and low model size. It can make automatic ECG analysis more accessible, efficient, and accurate, especially in remote or underserved areas.

Identification of drug candidates targeting monocyte reprogramming in people living with HIV.

Introduction: People living with HIV (PLHIV) are characterized by functional reprogramming of innate immune cells even after long-term antiretroviral therapy (ART). In order to assess technical feasibility of omics technologies for application to larger cohorts, we compared multiple omics data layers. Methods: Bulk and single-cell transcriptomics, flow cytometry, proteomics, chromatin landscape analysis by ATAC-seq as well as ex vivo drug stimulation were performed in a small number of blood samples derived from PLHIV and healthy controls from the 200-HIV cohort study. Results: Single-cell RNA-seq analysis revealed that most immune cells in peripheral blood of PLHIV are altered in their transcriptomes and that a specific functional monocyte state previously described in acute HIV infection is still existing in PLHIV while other monocyte cell states are only occurring acute infection. Further, a reverse transcriptome approach on a rather small number of PLHIV was sufficient to identify drug candidates for reversing the transcriptional phenotype of monocytes in PLHIV. Discussion: These scientific findings and technological advancements for clinical application of single-cell transcriptomics form the basis for the larger 2000-HIV multicenter cohort study on PLHIV, for which a combination of bulk and single-cell transcriptomics will be included as the leading technology to determine disease endotypes in PLHIV and to predict disease trajectories and outcomes.

Cardiomyocyte precursors generated by direct reprogramming and molecular beacon selection attenuate ventricular remodeling after experimental myocardial infarction.

BACKGROUND: Direct cardiac reprogramming is currently being investigated for the generation of cells with a true cardiomyocyte (CM) phenotype. Based on the original approach of cardiac transcription factor-induced reprogramming of fibroblasts into CM-like cells, various modifications of that strategy have been developed. However, they uniformly suffer from poor reprogramming efficacy and a lack of translational tools for target cell expansion and purification. Therefore, our group has developed a unique approach to generate proliferative cells with a pre-CM phenotype that can be expanded in vitro to yield substantial cell doses. METHODS: Cardiac fibroblasts were reprogrammed toward CM fate using lentiviral transduction of cardiac transcriptions factors (GATA4, MEF2C, TBX5, and MYOCD). The resulting cellular phenotype was analyzed by RNA sequencing and immunocytology. Live target cells were purified based on intracellular CM marker expression using molecular beacon technology and fluorescence-activated cell sorting. CM commitment was assessed using 5-azacytidine-based differentiation assays and the therapeutic effect was evaluated in a mouse model of acute myocardial infarction using echocardiography and histology. The cellular secretome was analyzed using mass spectrometry. RESULTS: We found that proliferative CM precursor-like cells were part of the phenotype spectrum arising during direct reprogramming of fibroblasts toward CMs. These induced CM precursors (iCMPs) expressed CPC- and CM-specific proteins and were selectable via hairpin-shaped oligonucleotide hybridization probes targeting Myh6/7-mRNA-expressing cells. After purification, iCMPs were capable of extensive expansion, with preserved phenotype when under ascorbic acid supplementation, and gave rise to CM-like cells with organized sarcomeres in differentiation assays. When transplanted into infarcted mouse hearts, iCMPs prevented CM loss, attenuated fibrotic scarring, and preserved ventricular function, which can in part be attributed to their substantial secretion of factors with documented beneficial effect on cardiac repair. CONCLUSIONS: Fibroblast reprogramming combined with molecular beacon-based cell selection yields an iCMP-like cell population with cardioprotective potential. Further studies are needed to elucidate mechanism-of-action and translational potential.

Simultaneous Detection of Different Antibody Classes in a Multiplexed Serological Test.

To monitor the progression of infectious diseases, it is useful to assess immunoreactivity against various antigenic determinants, and measure different antibody isotypes because they appear at different stages of the host immune response. With Lyme borreliosis, the pathogenic agent can be one of the multiple members of the Borrelia species. Therefore, correct sample classification requires evaluating the immunoreactivity against different antigens of different Borrelia species. Additionally, anti-pathogen IgG and IgM responses can have different elicitation time courses during disease progression. Here we demonstrate the development of a two-reporter multiplex immunoassay that has utility in identifying Borrelia-specific immune response in human serum samples by simultaneously evaluating both IgG and IgM immunoreactivity against different bacterial antigens in the same reaction well. This dual-reporter approach retains the analytical performance of single-reporter methods while conserving time and resources and reducing sample size requirements. This assay allows essentially double the serological information to be generated from a blood sample in half the time.

Correlation between Clinical Characteristics and Antibody Levels in COVID-19 Convalescent Plasma Donor Candidates.

COVID-19 convalescent plasma (CCP) with high neutralizing antibodies has been suggested in preventing disease progression in COVID-19. In this study, we investigated the relationship between clinical donor characteristics and neutralizing anti-SARS-CoV-2 antibodies in CCP donors. COVID-19 convalescent plasma donors were included into the study. Clinical parameters were recorded and anti-SARS-CoV-2 antibody levels (Spike Trimer, Receptor Binding Domain (RBD), S1, S2 and nucleocapsid protein) as well as ACE2 binding inhibition were measured. An ACE2 binding inhibition < 20% was defined as an inadequate neutralization capacity. Univariate and multivariable logistic regression analysis was used to detect the predictors of inadequate neutralization capacity. Ninety-one CCP donors (56 female; 61%) were analyzed. A robust correlation between all SARS-CoV-2 IgG antibodies and ACE2 binding inhibition, as well as a positive correlation between donor age, body mass index, and a negative correlation between time since symptom onset and antibody levels were found. We identified time since symptom onset, normal body mass index (BMI), and the absence of high fever as independent predictors of inadequate neutralization capacity. Gender, duration of symptoms, and number of symptoms were not associated with SARS-CoV-2 IgG antibody levels or neutralization. Neutralizing capacity was correlated with SARS-CoV-2 IgG antibodies and associated with time since symptom onset, BMI, and fever. These clinical parameters can be easily incorporated into the preselection of CCP donors.

Indications, Complications, and Early Postoperative Course of Recovery of Intraocular Lens Exchange Surgery: a Single-Center Retrospective Study.

PURPOSE: To analyze the indications, complications, and early course of recovery of intraocular lens (IOL) exchange surgery. MATERIAL AND METHODS: Records of patients who underwent IOL exchange during a 6-year period at a tertiary referral center were reviewed and the indications and complications after surgical intervention were analyzed. Their effects on postoperative corrected distance visual acuity (CDVA), intraocular pressure (IOP), use of IOP-lowering medications, and refractive cylindrical power were assessed. RESULTS: One hundred and seventy-one eyes (165 patients) were investigated. The most frequent indication for IOL exchange was lens dislocation in 163 eyes (95.32%). The main causes of IOL dislocation were pseudoexfoliation syndrome (PEX) in 98 eyes (57.31%) and complications during cataract surgery in 40 eyes (23.39%). During IOL exchange, an anterior iris-claw fixation was performed in 159 eyes (92.98%). After significant initial deterioration to 1.59 ± 1.08 logMAR on postoperative day 1 (p ≤ 0.001), the CDVA recovered to preoperative levels within 28 days. A significant decrease in IOP was observed on postoperative day 1 (p = 0.04). The most common postoperative complications were corneal edema in 114 eyes (66.67%) and vitreous hemorrhage in 67 eyes (39.18%). CONCLUSION: The high early postoperative prevalence of corneal edema and intraocular hemorrhage was found to affect visual recovery after IOL exchange, causing a significant initial deterioration of CDVA and a delay of full visual recovery. These findings suggest that surgical approaches minimizing the risk of this type of complications should be favored.

Systemic alterations in neutrophils and their precursors in early-stage chronic obstructive pulmonary disease.

Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification.

Robot-Assisted Epiretinal Membrane Peeling: A Prospective Assessment of Pre- and Intra-Operative Times and of Surgeons' Subjective Perceptions.

PURPOSE: The Preceyes Surgical System (PSS) is a robotic assistive device that may enhance surgical precision. This study assessed pre- and intra-operative times and surgeons' perceptions of robot-assisted epiretinal membrane peeling (RA-MP). METHODS: We analyzed the time requirement of three main tasks: the preparation of the PSS (I), patient preparation (II), and surgery (III). Following surgery, the surgeons were asked questions about their experience. RESULTS: RA-MP was performed in nine eyes of nine patients. Task I required an average time of 12.3 min, initially taking 15 min but decreasing to 6 min in the last surgery. Task II showed a mean time of 47.2 (range of 36-65) min. Task III had a mean time of 72.4 (range of 57-100) min. A mean time of 27.9 (range of 9-46) min was necessary for RA-MP. The responses to the questionnaire revealed a trend towards increasing ease and reduced stress as familiarity with the PSS increased. CONCLUSIONS: A substantial reduction in pre- and intra-operative times, decreasing to a total of 115 min, was demonstrated. RA-MP was positively anticipated by the surgeons and led to no hand or arm strain while being more complex than manual MP.

[Diagnostic and Therapeutic Management of Episcleritis and Scleritis]. / Diagnostisches und therapeutisches Management der Episkleritis und Skleritis.

While episcleritis is a benign disease only affecting the episclera, scleritis is an ocular inflammation with typically severe pain and not rarely affecting adjacent tissue.Scleritis is classified into anterior and posterior forms. Anterior scleritis is further subdivided into diffuse, nodular, necrotizing with inflammation, and necrotizing scleritis without inflammation (scleromalacia perforans). A systemic disease such as rheumatoid arthritis or granulomatosis with polyangiitis is associated with up to 50% of all patients with scleritis or episcleritis, consequently a systemic work-up with blood sampling and imaging as well as collaboration with internists are necessary.Differentiating these two entities is of high importance for planning the treatment: episcleritis has a self-limited course, whereas treatment of scleritis is obligatory to protect patients from irreversible visual loss, organ damage, and furthermore reduce the risk of mortality.Treatment depending of subtype and associated systemic disease may involve non-steroidal anti-inflammatory drugs, corticosteroids, and disease-modifying anti-rheumatic drugs.

Antibody Binding and Angiotensin-Converting Enzyme 2 Binding Inhibition Is Significantly Reduced for Both the BA.1 and BA.2 Omicron Variants.

BACKGROUND: The rapid emergence of the Omicron variant and its large number of mutations led to its classification as a variant of concern (VOC) by the World Health Organization. Subsequently, Omicron evolved into distinct sublineages (eg, BA.1 and BA.2), which currently represent the majority of global infections. Initial studies of the neutralizing response toward BA.1 in convalescent and vaccinated individuals showed a substantial reduction. METHODS: We assessed antibody (immunoglobulin G [IgG]) binding, ACE2 (angiotensin-converting enzyme 2) binding inhibition, and IgG binding dynamics for the Omicron BA.1 and BA.2 variants compared to a panel of VOCs/variants of interest, in a large cohort (N = 352) of convalescent, vaccinated, and infected and subsequently vaccinated individuals. RESULTS: While Omicron was capable of efficiently binding to ACE2, antibodies elicited by infection or immunization showed reduced binding capacities and ACE2 binding inhibition compared to wild type. Whereas BA.1 exhibited less IgG binding compared to BA.2, BA.2 showed reduced inhibition of ACE2 binding. Among vaccinated samples, antibody binding to Omicron only improved after administration of a third dose. CONCLUSIONS: Omicron BA.1 and BA.2 can still efficiently bind to ACE2, while vaccine/infection-derived antibodies can bind to Omicron. The extent of the mutations within both variants prevents a strong inhibitory binding response. As a result, both Omicron variants are able to evade control by preexisting antibodies.

A Modification of the Inverted Internal Limiting Membrane Flap Technique without Heavy Liquids and Prone Posturing. / Eine Modifikation der inversen Membrana-limitans-interna-Lappentechnik ohne Einsatz schwerer Flüssigkeiten und Bauchlagerung.

Primary closure of large macular holes remains challenging, and variations of inverted inner limiting membrane (ILM) flap surgery have been described. In the present retrospective, interventional, single-centre case series, we propose a superior flap design with minimal posturing. Eight eyes of eight patients (four women and four men) in the period between July 2020 and March 2022 underwent 23 G three-port vitrectomy with a superior inverted ILM flap and 20% SF6 endotamponade for a full thickness macular hole (MH) by the same experienced surgeon (F. M. H.). Seven MHs were classified as large (> 400 µm) and one as medium (250 - 400 µm). The mean MLD was 638.0 ± 166.4 µm (range: 353 - 851 µm). MH closure was achieved in all (8/8, 100%) patients with a single surgery. The median best-corrected visual acuity (BCVA) improved from 6/120 (Snellen) (range: finger counting [FC] to 6/19) preoperatively to 6/19 (range: FC to 6/9.5) after surgery, without any intra- or postoperative complications. The superior inverted ILM flap technique seems to be a safe and successful approach for the primary closure of large MHs. Further studies should investigate our proposed surgical technique on a larger population, potentially without air or gas endotamponade.