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Background: Pseudoxanthoma elasticum (PXE) is a rare, inherited disease characterised by specific skin lesions, progressive loss of vision and early onset atherosclerosis. Atherosclerosis in PXE leads to an increased rate of vascular occlusion and severe intermittent claudication. Although genetically determined, the individual course of PXE is highly variable. Up to now, there is no sufficient parameter to identify individuals at risk of rapid disease progression. This present study focused the lipid profile of patients with PXE and its possible influence on the clinical severity of peripheral artery disease (PAD). Patients and methods: 112 patients with PXE were retrospectively screened. Patients without a complete lipid profile consisting of total cholesterol (TC), triglycerides (TGC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and Lipoprotein(a) (Lp[a]) where excluded as well as patients with already initiated lipid-lowering therapy. 52 patients met the inclusion criteria. An age-adjusted ordinal regression model was applied to determine the association of each lipid fraction with the severity of PAD assessed as Fontaine classification. Results: The lipid profile of patients with PXE was unremarkable (TGC: 135.8±105.8 mg/dl; TC: 172.5±44.4 mg/dl; HDL: 63.0±18.2 mg/dl; Lp[a]: 64.7±93.5 nmol/l). Ordinal regression showed a significant association of Lp(a) with the severity of PAD with an odds ratio of 1.01 (1.00-1.02; p = 0.004), whereas the other fractions of the lipid profile had no significant influence. Conclusions: This study provides the largest evaluation of blood lipids up to now and the first characterization of Lp(a) levels in patients with PXE. We were able to provide first evidence of a correlation between elevated levels of Lp(a) and the severity of PAD. The present results suggest that determination of Lp(a) in early stages of PXE could help to identify patients at risk of rapid disease progression and with the need of intensified walking exercise training.

Non-syndromic cleft lip with/without cleft palate (nsCL/P) is a highly heritable facial disorder. To date, systematic investigations of the contribution of rare variants in non-coding regions to nsCL/P etiology are sparse. Here, we re-analyzed available whole-genome sequence (WGS) data from 211 European case-parent trios with nsCL/P and identified 13,522 de novo mutations (DNMs) in nsCL/P cases, 13,055 of which mapped to non-coding regions. We integrated these data with DNMs from a reference cohort, with results of previous genome-wide association studies (GWASs), and functional and epigenetic datasets of relevance to embryonic facial development. A significant enrichment of nsCL/P DNMs was observed at two GWAS risk loci (4q28.1 (p = 8 × 10 -4 ) and 2p21 (p = 0.02)), suggesting a convergence of both common and rare variants at these loci. We also mapped the DNMs to 810 position weight matrices indicative of transcription factor (TF) binding, and quantified the effect of the allelic changes in silico . This revealed a nominally significant overrepresentation of DNMs (p = 0.037), and a stronger effect on binding strength, for DNMs located in the sequence of the core binding region of the TF Musculin (MSC). Notably, MSC is involved in facial muscle development, together with a set of nsCL/P genes located at GWAS loci. Supported by additional results from single-cell transcriptomic data and molecular binding assays, this suggests that variation in MSC binding sites contributes to nsCL/P etiology. Our study describes a set of approaches that can be applied to increase the added value of WGS data., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

We present a new procedure for enhanced variable selection for component-wise gradient boosting. Statistical boosting is a computational approach that emerged from machine learning, which allows to fit regression models in the presence of high-dimensional data. Furthermore, the algorithm can lead to data-driven variable selection. In practice, however, the final models typically tend to include too many variables in some situations. This occurs particularly for low-dimensional data ( p < n ), where we observe a slow overfitting behavior of boosting. As a result, more variables get included into the final model without altering the prediction accuracy. Many of these false positives are incorporated with a small coefficient and therefore have a small impact, but lead to a larger model. We try to overcome this issue by giving the algorithm the chance to deselect base-learners with minor importance. We analyze the impact of the new approach on variable selection and prediction performance in comparison to alternative methods including boosting with earlier stopping as well as twin boosting. We illustrate our approach with data of an ongoing cohort study for chronic kidney disease patients, where the most influential predictors for the health-related quality of life measure are selected in a distributional regression approach based on beta regression.

Purpose:  To evaluate the longitudinal pattern of fetal heart rate short term variation (STV) and Doppler indices and their correlation to each other in severe growth restricted (IUGR) fetuses., Materials and Methods:  In this retrospective study, pregnancies with a birth weight below the 10th percentile, born between 24 and 34 gestational weeks with serial Doppler measurements in combination with a computerized CTG (cCTG) with calculated STV were included. Longitudinal changes of both Doppler indices and STV values were evaluated with generalized additive models, adjusted for gestational age and the individual. For all measurements the frequency of abnormal values with regard to the time interval before delivery and Pearson correlations between Doppler indices and STV values were calculated., Results:  41 fetuses with a total of 1413 observations were included. Over the course of the whole study period, regression analyses showed no significant change of STV values (p = 0.38). Only on the day of delivery, a prominent decrease was observed (mean STV d28-22: 7.97 vs. mean STV on day 0: 6.8). Doppler indices of UA and MCA showed a continuous, significant deterioration starting about three weeks prior to delivery (p = 0.007; UA and p < 0.001, MCA). Correlation between any Doppler index and STV values was poor., Conclusion:  Fetal heart rate STV does not deteriorate continuously. Therefore, cCTG monitoring should be performed at least daily in these high-risk fetuses. Doppler indices of umbilical artery (UA) and middle cerebral artery (MCA), however, showed continuous deterioration starting about 3 weeks prior to delivery., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau 181 , total tau, and Aβ 1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau 181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau 181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ 1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Background: Isolation precautions used in methicillin-resistant Staph ylo coc cus aureus (MRSA) infection control are effective in inhibiting pathogen transmission, but may cause unintended consequences in medical care. In addition, while costs attributed to MRSA are known to be substantial, little is known about their reimbursement in the German Diagnosis Related Groups (G-DRG) payment system. The aim of our study was to examine the effect of isolation precautions used in MRSA infection control on care processes, patient outcomes and deliver reliable data on MRSA-attributed reimbursement. Methods: A retrospective, matched cohort study of inpatients admitted to a general care teaching hospital in Bad Neuenahr, Germany, between January 1 st , 2016, and December 31 st , 2017 was performed. Patients isolated for MRSA colonization were matched to non-isolated controls based on age, gender, MRSA-adjusted Patient Clinical Complexity Level (Ma-PCCL) and Major Diagnostic Category (MDC). Main outcome measures on care processes and patient outcomes included adverse events, patient complaints, 30-day readmission rates, length of stay, type of discharge, and performance of instrument-based diagnostics. MRSA-attributed reimbursement was measured by conducting two separate G-DRG groupings, one with inclusion of MRSA-related codes and one without. Results: A total of 26,059 patients were admitted to Maria Hilf Hospital in Bad Neuenahr, Germany, during the study period. We identified 304 patients isolated for MRSA colonization. Compared to non-isolated matched controls, those on isolation precautions for MRSA colonization acquired about 45% more pressure ulcers and experienced significant delays in the performance of radiological diagnostics and echocardiographs. Patients isolated for MRSA colonization received about 49% fewer echocardiographs and had about 38% fewer abdominal ultrasound exams performed compared to non-isolated matched controls. A non-significant tendency towards fewer discharges to rehabilitation clinics and higher mortality rates were observed in patients isolated for MRSA colonization. Reimbursements were negligibly affected when MRSA-related codes were integrated by the grouper. Conclusion: Isolation precautions are associated with adverse consequences for care processes. These consequences need to be mitigated in order to justify placing patients at risk., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2019 Labus et al.)

Objective: Olecranon fractures are common injuries in patients of any age. The vast majority are treated with two operation techniques: a plate fixation (PF) or tension band wiring (TBW). The objective of this study is to compare the outcomes of surgically treated olecranon fractures with plate fixation or tension band wiring. We hypothesise that PF patients would show significantly inferior outcomes due to more complex injuries., Patients and Methods: Between 2010 and 2017, a total of 108 patients were treated with plate fixation and or tension band wiring. Clinical data of 40 surgically treated olecranon fractures were collected and analysed. Clinical and functional evaluations were performed using Mayo-Score, DASH-Score, Weseley -Score and subject elbow value (SEV). Furthermore, complication rates, time to return to work and operation duration were documented., Results: The mean follow-up was 70.5 ± 45.6 months. Time of return to work was 6.5 ± 2.2 weeks in the TBW group and 10.9 ± 6,6 in the PF group (p = 0.372). The mean duration of surgery was 95.2 ± 47.0 min in the TBW group and 192.5 ± 113.0 min in the PF group (p = 0.001). In the TBW group, the mean hospitalisation period was 7.9 ± 10.1 days and 11.2 ± 9.8 days in the PF group. Revisions were required in 0.3 ± 0.6 of cases (0.2 ± 0.5 in TBE and 0.4 ± 0.7 in PF). The median DASH Score was 7.0 (3.6-13.7) in the TBW group and 12.1 (5.5-24.8) in the PF group (p = 0.948)., Conclusion: Tension band wiring and plate fixation are both practical treatment options with mostly positive outcomes, even though high complication rates can occur. There were no significant differences in either group concerning functional outcome or time back to work. The duration of surgery was significantly higher in the PF group, whereas the incidence of metalwork-associated complications was higher in the TBW group., (© 2019 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)