BACKGROUND/AIMS:To describe the relationship between the novel biomarker retinal nerve fibre layer thickness slope (RNFL-S), and visual field sensitivity (VFS) in healthy and early glaucoma eyes. METHODS:This prospective cross-sectional study of 50 early glaucoma and 139 healthy eyes analysed RNFL-S locally along retinal nerve fibre trajectories that were automatically traced and centred on 24-2 and 10-2 visual field (VF) test points. Corresponding virtual B-scans were extracted from stitched wide-field polarisation-sensitive optical coherence tomography images. A linear mixed-effects model (LMM) assessed the association between VFS and the factors RNFL-S, glaucoma status and age. RESULTS:The average VF mean deviation was -3.11±1.51 dB in glaucoma (mean age: 63.0±9.3 years) and -0.36±1.10 dB in healthy eyes (mean age: 47.9±16.3 years). In healthy subjects, VFS and the corresponding RNFL-S were 31.8±2.4 dB (12.5±2.9 µm/mm) in the upper hemisphere and 32.4±2.2 dB (12.5±2.5 µm/mm) in the lower hemisphere. In glaucoma patients, these values were significantly lower: 27.5±7.0 dB (8.6 ± 3.9 µm/mm, p<0.001) in the upper hemisphere and 30.1±4.3 dB (10.5±3.3 µm/mm, p<0.001) in the lower hemisphere. Significant point-wise Spearman correlation coefficients (up to r=0.61) were observed, particularly in the upper VF hemisphere within the central 10° and close to the optic nerve head. The LMM showed a positive association between VFS and RNFL-S (β=0.0415, SE=0.0023, p<0.001, R²=0.1885). Glaucoma was significantly associated with lower VFS (β=-2.468, SE=0.069, p<0.001). Age negatively correlated with VFS (β=-0.048, SE=0.002, p<0.001). CONCLUSION:Local RNFL-S is significantly correlated with VFS, highlighting its potential as a biomarker for focal glaucoma damage.

Objectives: To assess the association of structural biomarkers derived from optical coherence tomography (OCT) and choriocapillaris (CC) flow information with point-wise retinal sensitivity (PWS) measured by microperimetry (MP) in intermediate age-related macular degeneration (iAMD). Methods: Patients with iAMD received imaging with spectral-domain (SD)-OCT (Spectralis, Heidelberg Engineering) and OCT-angiography (OCT-A) (PLEX Elite 9000, ZEISS). In addition, MP examinations in photopic setting (MP-3, NIDEK) and mesopic background illumination (MAIA2, ICare) were performed. The thickness of the ellipsoid-zone (EZ) and the outer nuclear layer (ONL), as well as the volume of drusen and HRF, were segmented using deep-learning (DL)-based approaches. CC flow deficit percentage (FD%) was extracted from OCT-A slabs using a novel binarization method. Semiautomatic co-registration of MP examinations, OCT-A slabs, and OCT volumes was performed. Three exploratory models were calculated using multivariable mixed-effects models: (1) structure-function (SF) using structural OCT biomarkers, (2) flow-function (FF) utilizing OCT-A derived flow information, and (3) structure-flow-function (SFF) incorporating both OCT and OCT-A data. Model performance was evaluated using AIC and BIC criterion. Results: 19 eyes of 19 patients were evaluated, totalling 3297 MP-stimuli, 1873 B-scans, and 19 OCT-A slabs. Mean (SD) age was 76 (7) years, and sensitivity was 26.0 (3.36) dB in the MP-3 and 22.42 (3.64) dB in the MAIA2. Mesopic MAIA2 examinations showed significantly lower PWS values (-3.56 to -3.63 dB; p < 0.001). Drusen and HRF volume decreased PWS (-0.6 [95% CI: -1.04; -0.16] dB/nL; p = 0.007 and -9.56 [95% CI: -12.86; -6.26] dB/nL; p < 0.001), while ONL was positively associated with PWS (0.06 [0.05; 0.07] at an eccentricity of 5.2°; p < 0.001) in the SF model. CC FD% was not significantly associated with PWS in the FF and the SFF model (p > 0.05 in both cases). In the SFF model drusen volume (-1.69 [95% CI: -2.09; -1.29] dB/nL; p < 0.001), EZ (0.04 [95% CI: 0.02; 0.06] dB/µm; p < 0.001), and ONL thickness (0.03 [95% CI: 0.02; 0.04] dB/µm; p < 0.001) were significant predictors for PWS. The SF model exhibited the lowest AIC and BIC indicating best model performance. Conclusions: Structural parameters derived from SD-OCT such as HRF, drusen volume, and outer retinal layer thickness may be more closely associated with PWS, with CC FD% as an OCT-A-derived metric contributing limited additional explanatory benefit in cross-sectional analyses.

The FBMS R package provides a unified interface for Bayesian model selection and model averaging across a broad class of regression models, including Gaussian regression, generalized linear models, and models with nonlinear functional relationships, with possible extensions to mixed-effects and survival models. Users specify candidate predictors together with transformation and interaction rules, and FBMS automatically explores the corresponding model spaces, estimates marginal likelihoods, and returns posterior model and inclusion probabilities, best and median probability models, posterior modes of parameters, and predictions with associated uncertainty. The core machinery combines mode-jumping Markov chain Monte Carlo with a genetically modified extension that iteratively generates and evaluates nonlinear features in the framework of Bayesian generalized nonlinear regression, while supporting flexible prior specification (including g-priors, Jeffreys priors, and empirical Bayes constructions), subsampling for large datasets, parallel computation, and the option to supply custom likelihoods for specialized applications. As special cases, the framework covers models based on fractional polynomials, logic regression, neural networks, symbolic regression, and classical linear regression.

The FBMS R package facilitates Bayesian model selection and model averaging in complex regression settings by employing a variety of Monte Carlo model exploration methods. At its core, the package implements an efficient Mode Jumping Markov Chain Monte Carlo (MJMCMC) algorithm, designed to improve mixing in multi-modal posterior landscapes within Bayesian generalized linear models. In addition, it provides a genetically modified MJMCMC (GMJMCMC) algorithm that introduces nonlinear feature generation, thereby enabling the estimation of Bayesian generalized nonlinear models (BGNLMs). Within this framework, the algorithm maintains and updates populations of transformed features, computes their posterior probabilities, and evaluates the posteriors of models constructed from them. We demonstrate the effective use of FBMS for both inferential and predictive modeling in Gaussian regression, focusing on different instances of the BGNLM class of models. Furthermore, through a broad set of applications, we illustrate how the methodology can be extended to increasingly complex modeling scenarios, extending to other response distributions and mixed effect models.

BACKGROUND:Patients with suspicious pulmonary lesions are traditionally rejected or delisted for lung transplantation (LTx). Data on the overall prevalence of suspicious lung lesions in candidates for LTx, their characteristics, and the proportion of malignancy among these lesions are lacking. METHODS:We performed a retrospective analysis of all patients with suspicious lung nodules who underwent LTx between January 2012 and October 2022. We compared characteristics of lesions, assessed definitive histology reports, analyzed postoperative outcomes, and calculated overall survival at 1-, 3-, and 5-years. RESULTS:Out of 1070 transplanted patients, 79 (7.4%) had suspicious lung lesions prior to LTx. In this group, COPD was the most frequent indication for LTx (83.5% of patients). Pathology reports confirmed lung cancer in explanted native lungs in only 12 of the 79 patients (15.1%). The most common lung cancer entity was adenocarcinoma in 8 patients (66.7%). Ten of the 12 (83.3%) patients were in stage I, II and 2 (16.6%) patients were in stage-IIIA disease based on final histological work-up after LTx. Overall survival did not differ between 'malignant nodules' subgroup, 'non-malignant nodules' subgroup and their respective matched controls at 1 year (87.5% vs 89.7% vs 88.2%), 3 years (87.5% vs 78.6% vs 77.5%) or 5 years (87.5% vs 70.1% vs 68.6%) (cox proportional-hazards model, p=0.541). CONCLUSIONS:Patients with unverified suspicious lung lesions should not be excluded from LTx, as only a small proportion of these nodules are malignant. Long-term survival is unaffected even in cases the explanted lung harbors an early-stage lung cancer.

To investigate the impact of retinal fluid dynamics on visual outcomes in patients with treatment-naïve neovascular age-related macular degeneration (nAMD) treated in the real world over 5 years using approved AI-based fluid monitoring. Real-world data comprising OCT scans and electronic medical records from 148 patients (187 eyes) were extracted from the Fight Retinal Blindness! (FRB! ) Zürich database. OCT scans were analysed using an approved AI algorithm (RetInSight, Vienna, Austria) to quantify fluid volumes by compartements. The impact of fluid persistence and fluctuations on BCVA change was assessed using forward stepwise regression and mixed models. Fluid compartments were further categorized into quartiles (SD-Qs), and the effect of fluid fluctuations on BCVA analysed (SD-Q1 least and SD-Q4 greatest variability of fluctuations). The greatest PED fluctuations in the central 1-mm showed an accentuated BCVA decrease after 2 and 4 years (estimate: -0.07, P = 0.019; estimate: -0.15, P < 0.01). After 4 years, eyes in SD-Q4 compared with SD-Q1 with greater PED fluctuations in the central 1-mm and 6-mm area were affected by a significant mean reduction in BCVA (-5.7 letters (P = 0.013); -6.1 letters (P = 0.015)). Greater intraretinal fluid (IRF) fluctuations (central 1-mm) (SD-Q4 compared with SD-Q1) were associated with a significantly worse mean BCVA by -6.8 letters (P = 0.018) after 5 years. Fluid persistence was not associated with statistically significant BCVA changes. In routine clinical management of nAMD, greater fluctuations of PED and IRF correlate with worse BCVA outcomes over long-term follow-up. A well-suited treatment regimen is required in the real world which can be utilized with AI-based fluid monitoring.

Background: A decrease in governmental vaccination initiatives and diminishing public enthusiasm for vaccines could jeopardize vaccine uptake, potentially endangering those who are most at risk. In this survey study, we evaluated the current acceptance rates of the newly developed monovalent XBB1.5-adapted COVID-19 vaccine among kidney transplant recipients and dialysis patients in Austria and Israel and identified factors influencing vaccine acceptance. Methods: The survey involved a total of 656 patients aged 18 and older and was carried out from 20 November to 21 December 2023, at the Medical University of Vienna, Austria and the Rabin Medical Center in Petah Tikva, Israel. Logistic regression analysis was used to explore the relationships between vaccine acceptance and variables such as age, gender, country, past COVID-19 infection status and severity, renal replacement therapy, education level, and willingness to receive the annual flu vaccine. Results: The survey showed that 54% of patients in Austria and 63% in Israel expressed acceptance of the modified XBB1.5-adapted COVID-19 vaccine. The main hesitancy was due to concerns about potential side effects, with 44% in Austria and 53% in Israel expressing apprehension. A willingness to receive the influenza vaccine, older age in Austria, and kidney transplant status in Israel were key predictors of greater COVID-19 vaccine acceptance. Conclusions: This study showed that more than 50% of our kidney transplant recipients and dialysis patients were willing to receive the adapted COVID-19 vaccine. Yet, vaccine hesitancy remained a significant barrier even among these high-risk groups, despite the availability of an updated COVID-19 vaccine targeting the Omicron subvariant XBB1.5.

BACKGROUND:Chronic rhinosinusitis (CRS) is a common, heterogeneous upper airway inflammatory disorder, affecting approximately 12% of the general population. The disease is clinically stratified into CRS without nasal polyps and CRS with nasal polyps, including the most severe subtype of nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD). OBJECTIVE:To identify molecular signatures and biomarkers allowing for the distinction between different disease endotypes and controls, we used targeted proteomics combined with bioinformatics and machine learning analyses. METHODS:Nasal secretions and serum from 80 patients (20 each of CRS without nasal polyps, CRS with nasal polyps, N-ERD, and disease controls) were subjected to high-throughput targeted proteomics (Olink). The expression patterns of 161 and 2677 proteins, for nasal secretions and serum, respectively, were analyzed alongside clinical evaluations of nasal polyp and smell test scores. RESULTS:Two distinct expression patterns were identified in nasal secretions: proteins associated with macrophage recruitment and type 2 inflammation were increased in CRS with nasal polyps and N-ERD, whereas proteins associated with innate immunity, particularly Toll-like receptor 4 signaling, were gradually downregulated from disease control to N-ERD. Furthermore, using machine learning, we confirmed 2 potential biomarkers for nasal polyposis: the glial cell line-derived neurotrophic factor in nasal secretions and Charcot-Leyden crystal protein in serum. CONCLUSIONS:Our findings provide unique insights into CRS pathophysiology and highlight potential biomarkers for precision diagnosis and treatment, particularly in severe cases such as N-ERD.

Rationale: Passenger lymphocyte syndrome (PLS) may complicate minor ABO mismatched lung transplantation (LuTX) via donor-derived red cell antibody-induced hemolysis. Objectives: To ascertain the incidence and specificity of PLS-relevant antibodies among the study population as well as the dynamics of hemolysis parameters and the transfusion requirement of patients with or without PLS. Methods: In this cohort study, 1,011 patients who received LuTX between January 2010 and June 2019 were studied retrospectively. Prospectively, 87 LuTX (July 2019 to June 2021) were analyzed. Postoperative ABO antibody and hemolytic marker determinations, transfusion requirement, and duration of postoperative hospital care were analyzed. Retrospectively, blood group A recipients of O grafts with PLS were compared with those without. Measurements and Main Results: PLS affected 18.18% (retrospective) and 30.77% (prospective) of A recipients receiving O grafts, 5.13% of B recipients of O grafts, and 20% of AB patients receiving O transplants. Anti-A and anti-A1 were the predominant PLS-inducing antibodies, followed by anti-B and anti-A,B. Significantly lower hemoglobin values (median, 7.4 vs. 8.3 g/dl; P = 0.0063) and an approximately twice as high percentage of patients requiring blood transfusions were seen in PLS. No significant differences in other laboratory markers, duration of hospital stay, or other complications after LuTX were registered. Conclusions: Minor ABO incompatible LuTX recipients are at considerable risk of developing clinically significant PLS. Post-transplant monitoring combining red cell serology and hemolysis marker determination appears advisable so as not to overlook hemolytic episodes that necessitate antigen-negative transfusion therapy.

BackgroundAnti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance.MethodsIgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method.ResultsThe median age at onset was 66 years (range: 54–75), disease duration 10 years (range: 15–156 months), and follow-up 25 months (range: 0–83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab.ConclusionOur findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.

Purpose: A high rate of lost to follow-up (LTFU) in patients with phenylketonuria (PKU) represents a main challenge. In this study, we investigated potential risk factors for becoming LTFU related to adolescence as a critical period of life. Methods: We retrospectively analyzed longitudinal data collected from 1993 to 2019 of patients diagnosed with classic PKU that were followed at our center during adolescence (14-18 y) and at least once in adulthood (>18 y). Patients who interrupted their contact with our center after the 18th birthday for at least 2 years were classified as LTFU. We performed a multivariate regression analysis to investigate following potential risk factors for becoming LTFU in adult life: sex, dietary compliance during adolescence assessed through the mean of the annual medians of phenylalanine plasma values, average number of contacts with the center during adolescence and age at first visit after the 18th birthday. Results: 93 patients (52 males, 41 females) were included in the study. 58% became LTFU during adulthood. The mean age at the last visit before becoming LTFU was 26.2 +/- 5.1 years. In the multivariate Cox regression analysis we found that poor dietary compliance during adolescence was significantly associated with a higher risk of becoming LTFU during adulthood (p-value = 0.028). Discussion: Adult patients who displayed poor treatment adherence during adolescence should be identified and carefully monitored to prevent loss of contact.

Animal research often involves experiments in which the effect of several factors on a particular outcome is of scientific interest. Many researchers approach such experiments by varying just one factor at a time. As a consequence, they design and analyze the experiments based on a pairwise comparison between two groups. However, this approach uses unreasonably large numbers of animals and leads to severe limitations in terms of the research questions that can be answered. Factorial designs and analyses offer a more efficient way to perform and assess experiments with multiple factors of interest. We will illustrate the basic principles behind these designs, discussing a simple example with only two factors before suggesting how to design and analyze more complex experiments involving larger numbers of factors based on multiway analysis of variance.

BACKGROUND Prone positioning has become a standard therapy in acute respiratory distress syndrome to improve oxygenation and decrease mortality. However, little is known about prone positioning in lung transplant recipients. This large, singe-center analysis investigated whether prone positioning improves gas exchange after lung transplantation. METHODS Clinical data of 583 patients were analyzed. Prone position was considered in case of impaired gas exchange Pa O2 /fraction of oxygen in inhaled air (<250), signs of edema after lung transplantation, and/or evidence of reperfusion injury. Patients with hemodynamic instability or active bleeding were not proned. Impact of prone positioning (n = 165) on gas exchange, early outcome and survival were determined and compared with patients in supine positioning (n = 418). RESULTS Patients in prone position were younger, more likely to have interstitial lung disease, and had a higher lung allocation score. Patients were proned fora median of 19 hours (interquartile range,15-26) hours). They had significantly lower Pa O2 /fraction of oxygen in inhaled air (227 +/- 96 vs 303 +/- 127 mm Hg, P = .004), and lower lung compliance (24.8 +/- 9.1 mL/mbar vs 29.8 +/- 9.7 mL/mbar, P < .001) immediately after lung transplantation. Both values significantly improved after prone positioning for 24 hours (Pa O2 /fraction of oxygen ratio: 331 +/- 91 mm Hg; lung compliance: 31.7 +/- 20.2 mL/ mbar). Survival at 90 days was similar between the 2 groups (93% vs 96%, P = .105). CONCLUSIONS Prone positioning led to a significant improvement in lung compliance and oxygenation after lung transplantation. Prospective studies are needed to confirm the benefit of prone positioning in lung transplantation. (Ann Thorac Surg 2024;117:1045-52) (c) 2024 The Authors. Published by Elsevier Inc. on behalf of The Society of Thoracic Surgeons. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Purpose: We conducted an outcome analysis on surgically treated laryngeal squamous cell carcinoma (LSCC) patients. Methods: A multicenter retrospective study with 352 patients was analyzed. A new nomogram that incorporates age, T- and N-classification, and treatment was created. Results: Recurrence was observed in 65 (18.5%) patients after a mean time of 16.5 months. After 60 months, 91 (25.9%) of patients developed secondary primary tumors (SPT), most commonly in the lungs (n = 29; 8.2%) followed by other head and neck cancers (n = 21; 6.0%). Notably, the mean time to occurrence of secondary head and neck cancers was twice that of lung cancer (101.1 vs. 47.5 months). Conclusion: Recurrent disease is less common in LSCC patients and appears much earlier than SPT. Because one in every four laryngeal cancer patients develops SPTs within 5–10 years, long-term care and follow-up, including imaging studies, are highly recommended. The nomogram was useful for estimating survival.

Anti-SARS-CoV-2 vaccination of dialysis patients has been proven to be safe and effective to reduce COVID-19-related morbidity and mortality. However, data on the durability of anti-SARS-CoV-2 antibodies post-vaccination in peritoneal dialysis (PD) patients are scarce. In this prospective single-center cohort study we measured anti-SARS-CoV-2 RBD antibodies 3 and 6 months after the 3rd dose of the mRNA-1273 vaccine in 27 adult PD patients and recorded breakthrough infections. Furthermore, in a mixed model analysis, we analyzed potential factors influencing the humoral response following vaccination. Anti-SARS-CoV-2 RBD antibody levels declined from 21,424 BAU/mL at 1 month to 8397 BAU/mL at 3 months and to 5120 BAU/mL at 6 months after the 3rd dose, but remained higher than pre-3rd dose levels (212 BAU/mL). Eight patients (29.6%) were infected with SARS-CoV-2 within six months from the 3rd dose during the Omicron wave. Previous high antibody levels, high glomerular filtration rate (GFR) and low Davies Comorbidity Score were associated with higher anti-SARS-CoV-2 antibody levels after the booster. In conclusion, PD patients exhibited a robust and durable humoral response after a third dose of the mRNA-1273 vaccine. A high GFR and low comorbidity as well as previous high antibody levels predicted a better humoral response to vaccination.

Variable selection methods based on L0 penalties have excellent theoretical properties to select sparse models in a high-dimensional setting. There exist modifications of the Bayesian Information Criterion (BIC) which either control the familywise error rate (mBIC) or the false discovery rate (mBIC2) in terms of which regressors are selected to enter a model. However, the minimization of L0 penalties comprises a mixed-integer problem which is known to be NP-hard and therefore becomes computationally challenging with increasing numbers of regressor variables. This is one reason why alternatives like the LASSO have become so popular, which involve convex optimization problems that are easier to solve. The last few years have seen some real progress in developing new algorithms to minimize L0 penalties. The aim of this article is to compare the performance of these algorithms in terms of minimizing L0 -based selection criteria. Simulation studies covering a wide range of scenarios that are inspired by genetic association studies are used to compare the values of selection criteria obtained with different algorithms. In addition, some statistical characteristics of the selected models and the runtime of algorithms are compared. Finally, the performance of the algorithms is illustrated in a real data example concerned with expression quantitative trait loci (eQTL) mapping.