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Background Conditional logistic regression trees have been proposed as a flexible alternative to the standard method of conditional logistic regression for the analysis of matched case–control studies. While they allow to avoid the strict assumption of linearity and automatically incorporate interactions, conditional logistic regression trees may suffer from a relatively high variability. Further machine learning methods for the analysis of matched case–control studies are missing because conventional machine learning methods cannot handle the matched structure of the data. Results A random forest method for the analysis of matched case–control studies based on conditional logistic regression trees is proposed, which overcomes the issue of high variability. It provides an accurate estimation of exposure effects while being more flexible in the functional form of covariate effects. The efficacy of the method is illustrated in a simulation study and within an application to real-world data from a matched case–control study on the effect of regular participation in cervical cancer screening on the development of cervical cancer. Conclusions The proposed random forest method is a promising add-on to the toolbox for the analysis of matched case–control studies and addresses the need for machine-learning methods in this field. It provides a more flexible approach compared to the standard method of conditional logistic regression, but also compared to conditional logistic regression trees. It allows for non-linearity and the automatic inclusion of interaction effects and is suitable both for exploratory and explanatory analyses.

A SARS-CoV2 super-spreading event occurred during carnival in a small town in Germany. Due to the rapidly imposed lockdown and its relatively closed community, this town was seen as an ideal model to investigate the infection fatality rate (IFR). Here, a 7-day seroepidemiological observational study was performed to collect information and biomaterials from a random, household-based study population. The number of infections was determined by IgG analyses and PCR testing. We found that of the 919 individuals with evaluable infection status, 15.5% (95% CI:[12.3%; 19.0%]) were infected. This is a fivefold higher rate than the reported cases for this community (3.1%). 22.2% of all infected individuals were asymptomatic. The estimated IFR was 0.36% (95% CI:[0.29%; 0.45%]) for the community and 0.35% [0.28%; 0.45%] when age-standardized to the population of the community. Participation in carnival increased both infection rate (21.3% versus 9.5%, p  < 0.001) and number of symptoms (estimated relative mean increase 1.6, p  = 0.007). While the infection rate here is not representative for Germany, the IFR is useful to estimate the consequences of the pandemic in places with similar healthcare systems and population characteristics. Whether the super-spreading event not only increases the infection rate but also affects the IFR requires further investigation. Here the authors present a SARS-CoV2 seroepidemiological observational study from a random, household-based study population in a small town in Germany, showing the effect of a super-spreading event on infection rate, severity, and potentially infection fatality rate.

The presentational flow chart \"unwell adult\" of the Manchester Triage System (MTS) occupies a special role in this triage system, defined as the nonspecific presentation of an emergency patient. Current scientific studies show that a considerable proportion of emergency room patients present with so-called \"nonspecific complaints\". The aim of the present study is to investigate in detail the initial assessment of emergency patients triaged according to the presentational flow chart \"unwell adult\". Monocentric, retrospective observational study. Data on 14,636 emergency department visits between March 12.sup.th and August 12.sup.th, 2019 were included. During the observation period, the presentational flow chart \"unwell adult\" was used 1,143 times and it was the third most frequently used presentational flow chart. Patients triaged with this flow chart often had unspecific complaints upon admission to the emergency department. Patients triaged with the \"unwell adult\" chart were often classified with a lower triage level. Notably, patients who died in hospital during the observation period frequently received low triage levels. The AUC for the MTS flow chart \"unwell adult\" and hospitalization in general for older patients (age [greater than or equal to] 65 years) was 0.639 (95% CI 0.578-0.701), and 0.730 (95% CI 0.714-0.746) in patients triaged with more specific charts. The AUC for the MTS flow chart \"unwell adult\" and admission to ICU for older patients (age [greater than or equal to]65 years) was 0.631 (95% CI 0.547-0.715) and 0.807 (95% CI 0.790-0.824) for patients triaged with more specific flow charts. Comparison of the predictive ability of the MTS for in-hospital mortality in the group triaged with the presentational flow chart \"unwell adult\" revealed an AUC of 0.682 (95% CI 0.595-0.769) vs. 0.834 (95% CI 0.799-0.869) in the other presentational flow charts. The presentational flow chart \"unwell adult\" is frequently used by triage nurses for initial assessment of patients. Patient characteristics assessed with the presentational flow chart \"unwell adult\" differ significantly from those assessed with MTS presentational flow charts for more specific symptoms. The quality of the initial assessment in terms of a well-functioning triage priority assessment tool is less accurate than the performance of the MTS described in the literature.

Risk assessment before interventions in elderly patients becomes more and more vital due to an increasing number of elderly patients requiring surgery. Existing risk scores are often not tailored to marginalized groups such as patients aged 80 years or older. We aimed to develop an easy-to-use and readily applicable risk assessment tool that implements pre-interventional predictors of 30-day mortality in elderly patients (≥80 years) undergoing interventions under anesthesia. Using Cox regression analysis, we compared different sets of predictors by taking into account their ease of availability and by evaluating predictive accuracy. Coefficient estimates were utilized to set up a scoring system that was internally validated. Model building and evaluation were based on data from the Peri-Interventional Outcome Study in the Elderly (POSE), which was conducted as a European multicenter, observational prospective cohort study. Our risk assessment tool, named PIRATE, contains three predictors assessable at admission (urgency , severity and living conditions ). Discriminatory power, as measured by the concordance index, was 0.75. The estimated prediction error, as measured by the Brier score, was 0.036 (covariate-free reference model: 0.043). PIRATE is an easy-to-use risk assessment tool that helps stratifying elderly patients undergoing interventions with anesthesia at increased risk of mortality. PIRATE is readily available and applies to a wide variety of settings. In particular, it covers patients needing elective or emergency surgery and undergoing in-hospital or day-case surgery. Also, it applies to all types of interventions, from minor to major. It may serve as a basis for multidisciplinary and informed shared decision-making.

For quantification of Optical Coherence Tomography Angiography (OCTA) images, Vessel Density (VD) and Vessel Skeleton Density (VSD) are well established parameters and different algorithms are in use for their calculation. However, comparability, reliability and ability to discriminate healthy and impaired macular perfusion of different algorithms are unclear, yet, of potential high clinical relevance. Hence, we assessed comparability and test-retest reliability of the most common approaches. Two consecutive 3×3mm OCTA en face images of the superficial and deep retinal layer were acquired with swept-source OCTA. VD and VSD were calculated with manual thresholding and six automated thresholding algorithms (Huang, Li, Otsu, Moments, Mean, Percentile) using ImageJ and compared in terms of intra-class correlation coefficients, measurement differences and repeatability coefficients. Receiver operating characteristic analyses (healthy vs. macular pathology) were performed and Area Under the Curve (AUC) values were calculated. Twenty-six eyes (8 female, mean age: 47 years) of 15 patients were included (thereof 15 eyes with macular pathology). Binarization thresholds, VD and VSD differed significantly between the algorithms and compared to manual thresholding (p < 0.0001). Inter-measurement differences did not differ significantly between patients with healthy versus pathologic maculae (p ≥ 0.685). Reproducibility was higher for the automated algorithms compared to manual thresholding on all measures of reproducibility assessed. AUC was significantly higher for the Mean algorithm compared to the manual approach with respect to the superficial retinal layer. Automated thresholding algorithms yield a higher reproducibility of OCTA parameters and allow for a more sensitive diagnosis of macular pathology. However, different algorithms are not interchangeable nor results readily comparable. Especially the Mean algorithm should be investigated in further detail. Automated thresholding algorithms are preferable but more standardization is needed for clinical use.

The concentration of sodium is a functional cell parameter and absolute quantification can be interesting for diagnostical purposes. The accuracy of sodium magnetic resonance imaging ((23)Na-MRI) is strongly biased by partial volume effects (PVEs). Hence our purpose was to establish a partial volume correction (PVC) method for (23)Na-MRI. The existing geometric transfer matrix (GTM) correction method was transferred from positron emission tomography (PET) to (23)Na-MRI and tested in a phantom study. Different parameters, as well as accuracy of registration and segmentation were evaluated prior to first in vivo measurements. In vivo sodium data-sets of the human brain were obtained at B0=7T with a nominal spatial resolution of (3mm)(3) using a density adapted radial pulse sequence. A volunteer study with four healthy subjects was performed to measure partial volume (PV) corrected tissue sodium concentration (TSC) which was verified by means of an intrinsic correction control. In the phantom study the PVC algorithm yielded a good correction performance and reduced the discrepancy between the measured sodium concentration value and the expected value in the smallest compartments of the phantom by 11% to a mean PVE induced discrepancy of 5.7% after correction. The corrected in vivo data showed a reduction of PVE bias for the investigated compartments for all volunteers, resulting in a mean reduction of discrepancy between two separate CSF compartments from 36% to 7.6%. The absolute TSC for two separate CSF compartments (sulci, lateral ventricles), gray and white brain matter after correction were 129±8mmol/L, 138±4mmol/L, 48±1mmol/L and 43±3mmol/L, respectively. The applied PVC algorithm reduces the PV-bias in quantitative (23)Na-MRI. Accurate, high-resolution anatomical data is required to enable appropriate PVC. The algorithm and segmentation approach is robust and leads to reproducible results.

The concentration of sodium is a functional cell parameter and absolute quantification can be interesting for diagnostical purposes. The accuracy of sodium magnetic resonance imaging (23Na-MRI) is strongly biased by partial volume effects (PVEs). Hence our purpose was to establish a partial volume correction (PVC) method for 23Na-MRI. The existing geometric transfer matrix (GTM) correction method was transferred from positron emission tomography (PET) to 23Na-MRI and tested in a phantom study. Different parameters, as well as accuracy of registration and segmentation were evaluated prior to first in vivo measurements. In vivo sodium data-sets of the human brain were obtained at B0=7T with a nominal spatial resolution of (3mm)3 using a density adapted radial pulse sequence. A volunteer study with four healthy subjects was performed to measure partial volume (PV) corrected tissue sodium concentration (TSC) which was verified by means of an intrinsic correction control. In the phantom study the PVC algorithm yielded a good correction performance and reduced the discrepancy between the measured sodium concentration value and the expected value in the smallest compartments of the phantom by 11% to a mean PVE induced discrepancy of 5.7% after correction. The corrected in vivo data showed a reduction of PVE bias for the investigated compartments for all volunteers, resulting in a mean reduction of discrepancy between two separate CSF compartments from 36% to 7.6%. The absolute TSC for two separate CSF compartments (sulci, lateral ventricles), gray and white brain matter after correction were 129±8mmol/L, 138±4mmol/L, 48±1mmol/L and 43±3mmol/L, respectively. The applied PVC algorithm reduces the PV-bias in quantitative 23Na-MRI. Accurate, high-resolution anatomical data is required to enable appropriate PVC. The algorithm and segmentation approach is robust and leads to reproducible results. •Partial volume correction introduced to 23Na-MRI.•Markedly reduced bias of partial volume effects for determination of sodium levels.•High resolution morphological data enhances quantification accuracy of 23Na-MRI.

Purpose Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect. Methods This retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥ 10 6 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥ 10 6 copies/ml. Therapeutic strategies and risk groups were compared using odds ratios and Fisher’s tests or Kaplan−Meier analysis and long-rank tests. Multivariable regression analysis was performed. Results 144 patients were included with a median duration of SARS-CoV-2 viral load ≥ 10 6 copies/ml of 8.0 days (IQR 6.0–15.3). Underlying haematological malignancies (HM) ( p  = 0.03) and treatment initiation later than five days after diagnosis ( p  < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% ( n  = 21/144), particularly in patients with underlying HM (OR 3.5; 95% CI 1.2–9.9; p  = 0.02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially related to combination treatment. Conclusion Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients.

Macular Telangiectasia Type 2 (MacTel) is a chronic, progressive disease of the central retina characterized by vascular and neurodegenerative changes. As there is currently no treatment for non-neovascular MacTel, there is a dearth for biomarkers identifying eyes with an increased risk for disease progression for patient counseling and clinical trial recruitment. Eyes were classified to be stable or progressive, defined by the fundus photography-based grading system by Gass and Blodi. First, structural differences between these two groups were assessed, employing optical coherence tomography (OCT) and OCT-angiography. Univariate regression analyses revealed evidence towards a lower superficial retinal layer (SRL) vessel density (VD), skeleton density (SD) and deep retinal layer (DRL) SD in progressing compared to stable eyes (p = 0.05, p = 0.05, p = 0.07). Second, a multivariable predictive model was employed to examine the predictive value of structural and functional parameters for disease progression. Baseline best corrected visual acuity (BCVA) and SRL SD are prognostic for disease progression (p < 0.001, p = 0.05). The presence of ellipsoid zone (EZ) loss is prognostic for future central retinal thickness (p < 0.01). We propose SRL SD, BCVA, and EZ loss as prognostic biomarkers and as possible outcome measures in future interventional studies in MacTel.

As most rare diseases, intermediate uveitis lacks reliable endpoints necessary for randomized clinical trials. Therefore, we investigated longitudinal changes of retinal and choriocapillaris perfusion on optical coherence tomography angiography (OCT-A) in intermediate uveitis and their prognostic value for future best corrected visual acuity (BCVA) and central retinal thickness (CRT). In this retrospective, longitudinal cohort study eyes of patients with intermediate uveitis were imaged by swept-source OCT-A (macula-centered 3 × 3 mm; PLEX Elite 9000, Zeiss) and stratified into clinically stable, worsened and improved based on changes in clinical parameters. Superficial (SRL) and deep retinal layers (DRL) were automatically analyzed for vessel density (VD) and choriocapillaris layer for non-perfused area (CCNPA) using ImageJ. Mixed-effects regression analysis controlling for age, sex, and OCT-A signal strength index (SSI) was used to evaluate the prognostic value of OCT-A parameters. 91 eyes (62 stable, 12 worsened, and 17 improved) were included in the analysis and mean follow-up time was 296 days. Longitudinal changes of VD were different between all three groups ( p  = 0.002 for SRL and p  = 0.017 for DRL). Clinically worsened eyes showed a decrease in VD (− 0.032 ± 0.055 for SRL and − 0.027 ± 0.025 for DRL), whereas clinically improved eyes showed an increase in VD (0.037 ± 0.039 for SRL and 0.001 ± 0.023 for DRL). No difference was found for CCNPA. When controlling for age, sex, and SSI, observed differences held true in clinically worsened eyes for DRL ( p  = 0.011) and in clinically improved eyes for SRL ( p  = 0.002). An increase of CCNPA in clinically worsened eyes ( p  = 0.03) compared to clinically stable and improved eyes was evident. Predictive analysis revealed an association of VD in SRL and DRL at baseline with BCVA at follow-up ( p  = 0.039 and p  = 0.047, respectively) and of VD in SRL at baseline with CRT at follow-up ( p  = 0.046). Alterations in retinal perfusion on OCT-A in intermediate uveitis are partly reversible and OCT-A VD may serve to predict future BCVA and CRT. Thus, perfusion parameters on OCT-A might aid monitoring and serve as prognostic imaging-biomarker.