Publications by authors named "Bernhard Haller"

224 Publications

Changes of omentin-1 and chemerin during 4 weeks of lifestyle intervention and 1 year follow-up in children with obesity.

Clin Nutr 2021 Oct 8;40(11):5648-5654. Epub 2021 Oct 8.

Department of Prevention and Sports Medicine, School of Medicine, University Hospital 'rechts der Isar', Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.

Aims: Data about the influence of short-term lifestyle intervention in children with obesity on long-term follow-up body weight, adipokines and cardiometabolic risk parameters is scarce.

Methods: In a subgroup of the LOGIC-trial (Long-term Effects of Lifestyle Intervention in Obesity and Genetic Influence in Children), we assessed anthropometry (BMI, BMI-SDS (Standard Deviation Score), adipokines (omentin-1, chemerin, leptin, adiponectin) and cardiometabolic risk parameters, (e.g. hsCRP) in children with overweight/obesity after 4 weeks of lifestyle intervention (n = 156, 14.0 ± 1.8 yrs) and after one year follow-up (n = 50). Data were compared to normal weight children (JuvenTUM school cohort; n = 152, 13.3 ± 0.7 yrs).

Results: Short-term lifestyle intervention was associated with a significant reduction in BMI and BMI-SDS (p < 0.001), with significant reductions in hsCRP, leptin, and chemerin levels, and an increase in adiponectin and omentin-1 levels (p < 0.001 for all). After one year follow-up a significant reduction in BMI and BMI-SDS was observed in children from the LOGIC-trial (p < 0.001). Improvements in adiponectin (p = 0.025) and chemerin levels (p = 0.027) were seen in children with clear weight loss success (BMI-SDS reduction ≥ 0.2), whereas children with no or only mild weight loss success showed an increase in leptin levels (p < 0.001). An increase in omentin-1 levels was observed after 1 year independent of weight change (p < 0.001).

Conclusion: Effects of short-term weight reduction on mean BMI and BMI-SDS persist over one year. Improvements in omentin-1 levels were independent of short-term or long-term weight loss.

Trial Registration: ClinicalTrials.gov: LOGIC-trial: NCT01067157, JuvenTUM-trial: NCT00988754.
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http://dx.doi.org/10.1016/j.clnu.2021.09.042DOI Listing
October 2021

Partial-brain radiation-induced microvascular cognitive impairment in juvenile murine unilateral hippocampal synaptic plasticity.

Int J Radiat Oncol Biol Phys 2021 Oct 4. Epub 2021 Oct 4.

Department Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Central Institute for Translational Cancer Research, TranslaTUM, Munich, Germany. Electronic address:

Purpose: Radiation-induced cognitive deficits have a severe negative impact on pediatric brain tumor patients. The severity of cognitive symptoms is related to the age of the child when radiation was applied, with the most severe effects seen in the youngest. Previous studies using whole-brain irradiation (WBRT) in mice confirmed these findings. To understand ipsilateral and contralateral changes in the hippocampus after partial-brain irradiation (PBRT) of the left hemisphere we assessed the neuroplasticity and changes in the microvasculature of the irradiated and non-irradiated hippocampus in juvenile mice.

Methods And Materials: The left hemispheres of 5-week old mice were irradiated with 2, 8, 20 Gray (Gy) and a fractionated dose of 8 Gy in 2 fractions (8 Gy/2f) using a Computed Tomography (CT)-image guided Small Animal Radiation Research Platform (SARRP). Long-Term Potentiation (LTP) has been monitored ex vivo in the hippocampal Cornu Ammonis 1 (CA1) region and was assessed 3 days, 5 and 10 weeks after PBRT in both hemispheres and compared to a sham group. Irradiation effects on the hippocampus microvasculature were quantified by Efficient tissue clearing and Multi-Organ Volumetric Imaging (EMOVI).

Results: LTP in irradiated hippocampal slices of juvenile mice declines 3 days after radiation, lasts up to 10 weeks in the irradiated part of the hippocampus and correlates with a significantly reduced microvasculature length. Specifically, LTP inhibition is sustained in the irradiated (20 Gy, 8 Gy/2f, 8 Gy, 2 Gy) hippocampus, whereas the contralateral hippocampus remains unaffected after PBRT. LTP inhibition in the irradiated hemisphere after PBRT might be associated with an impaired microvascular network.

Conclusion: PBRT induces a long-lasting impairment in neuroplasticity and microvessel network of the irradiated hippocampus, whereas the contralateral hippocampus remains unaffected. These findings provide insight into the design of PBRT strategies to better protect the young developing brain from cognitive decline.
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http://dx.doi.org/10.1016/j.ijrobp.2021.09.041DOI Listing
October 2021

Grey and White Matter Volume Changes after Preterm Birth: A Meta-Analytic Approach.

J Pers Med 2021 Aug 30;11(9). Epub 2021 Aug 30.

Department of Neuroradiology, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.

Cross-sectional studies have reported lower brain grey matter volumes (GMV) and white matter volumes (WMV) in preterm (PT) born individuals. While large MRI studies in the normative population have led to a better understanding of brain growth trajectories across the lifespan, such results remain elusive for PT born individuals since large, aggregated datasets of PT born individuals do not exist. To close this gap, we investigated GMV and WMV in PT born individuals as reported in the literature and contrasted it against individual volumetric data and trajectories from the general population. Systematic database search of PubMed and Web of Science in March 2021, and extraction of outcome measures were conducted by two independent reviewers. Individual data on full-term (FT) controls was extracted from freely available databases. Mean GMV, WMV, total intracranial volume (TIV), and mean age at scan were the main outcome measures. Of 532 identified records, nine studies were included with 538 PT born subjects between 1.1 and 28.5 years of age. Reference data was generated from 880 FT controls between 1 and 30 years of age. GMV was consistently lower in PT born individuals from infancy to early adulthood with no evidence for catch-up growth. While GMV changes followed a similar trajectory as FT controls, WMV was particularly low in adolescence after PT birth. Results demonstrate altered brain volumes after PT birth across the first half of lifespan. Future studies should address this issue in large aggregated datasets of PT born individuals.
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http://dx.doi.org/10.3390/jpm11090868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468941PMC
August 2021

Remote monitoring of COVID-19 positive high-risk patients in domestic isolation: A feasibility study.

PLoS One 2021 24;16(9):e0257095. Epub 2021 Sep 24.

Department of Internal Medicine I, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

Background: If a COVID-19 patient develops a so-called severe course, he or she must be taken to hospital as soon as possible. This proves difficult in domestic isolation, as patients are not continuously monitored. The aim of our study was to establish a telemonitoring system in this setting.

Methods: Oxygen saturation, respiratory rate, heart rate and temperature were measured every 15 minutes using an in-ear device. The data was transmitted to the Telecovid Centre via mobile network or internet and monitored 24/7 by a trained team. The data were supplemented by daily telephone calls. The patients´ individual risk was assessed using a modified National Early Warning Score. In case of a deterioration, a physician initiated the appropriate measures. Covid-19 Patients were included if they were older than 60 years or fulfilled at least one of the following conditions: pre-existing disease (cardiovascular, pulmonary, immunologic), obesity (BMI >35), diabetes mellitus, hypertension, active malignancy, or pregnancy.

Findings: 153 patients (median age 59 years, 77 female) were included. Patients were monitored for 9 days (median, IQR 6-13 days) with a daily monitoring time of 13.3 hours (median, IQR 9.4-17.0 hours). 20 patients were referred to the clinic by the Telecovid team. 3 of these required intensive care without invasive ventilation, 4 with invasive ventilation, 1 of the latter died. All patients agreed that the device was easy to use. About 90% of hospitalised patients indicated that they would have delayed hospitalisation further if they had not been part of the study.

Interpretation: Our study demonstrates the successful implementation of a remote monitoring system in a pandemic situation. All clinically necessary information was obtained and adequate measures were derived from it without delay.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257095PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462738PMC
October 2021

Myocardial deformation analysis in late-onset small-for-gestational-age and growth-restricted fetuses using two-dimensional speckle tracking echocardiography: a prospective cohort study.

J Perinat Med 2021 Sep 17. Epub 2021 Sep 17.

Department of Obstetrics and Gynecology, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany.

Objectives: An association between fetal growth restriction (FGR) and increased predisposition to cardiovascular disease (CVD) is suggested. The aim of this study was to evaluate subclinical signs of fetal cardiac remodeling in late-onset small-for-gestational-age (SGA) and growth-restricted fetuses using two-dimensional speckle tracking echocardiography (2D-STE).

Methods: This is a prospective cohort study, including 117 late-onset (≥32 weeks) SGA (birthweight≤10th centile) fetuses and 102 gestational age matched controls. A subgroup analysis was performed: FGR was defined based on either BW (
Results: Global and segmental LPSS and LSR values showed no significant difference between late-onset SGA and control fetuses for both ventricles (p>0.05). Regarding global and segmental LPSS and LSR values of LV/RV, subgroup analysis revealed no significant difference between the FGR (n=81), SGA centile 3-10 (n=36) and control group.

Conclusions: A mild degree of placental dysfunction seems not to influence myocardial deformation properties measured by 2D-STE.
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http://dx.doi.org/10.1515/jpm-2021-0162DOI Listing
September 2021

Omega-3 fatty acid blood levels are inversely associated with cardiometabolic risk factors in HFpEF patients: the Aldo-DHF randomized controlled trial.

Clin Res Cardiol 2021 Aug 28. Epub 2021 Aug 28.

Department of Cardiology, Campus Virchow Klinikum (CVK), Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Objectives: To evaluate associations of omega-3 fatty acid (O3-FA) blood levels with cardiometabolic risk markers, functional capacity and cardiac function/morphology in patients with heart failure with preserved ejection fraction (HFpEF).

Background: O3-FA have been linked to reduced risk for HF and associated phenotypic traits in experimental/clinical studies.

Methods: This is a cross-sectional analysis of data from the Aldo-DHF-RCT. From 422 patients, the omega-3-index (O3I = EPA + DHA) was analyzed at baseline in n = 404 using the HS-Omega-3-Index methodology. Patient characteristics were; 67 ± 8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥ 50%, E/e' 7.1 ± 1.5; median NT-proBNP 158 ng/L (IQR 82-298). Pearson's correlation coefficient and multiple linear regression analyses, using sex and age as covariates, were used to describe associations of the O3I with metabolic phenotype, functional capacity, echocardiographic markers for LVDF, and neurohumoral activation at baseline/12 months.

Results: The O3I was below (< 8%), within (8-11%), and higher (> 11%) than the target range in 374 (93%), 29 (7%), and 1 (0.2%) patients, respectively. Mean O3I was 5.7 ± 1.7%. The O3I was inversely associated with HbA1c (r = - 0.139, p = 0.006), triglycerides-to-HDL-C ratio (r = - 0.12, p = 0.017), triglycerides (r = - 0.117, p = 0.02), non-HDL-C (r = - 0.101, p = 0.044), body-mass-index (r = - 0.149, p = 0.003), waist circumference (r = - 0.121, p = 0.015), waist-to-height ratio (r = - 0.141, p = 0.005), and positively associated with submaximal aerobic capacity (r = 0.113, p = 0.023) and LVEF (r = 0.211, p < 0.001) at baseline. Higher O3I at baseline was predictive of submaximal aerobic capacity (β = 15.614, p < 0,001), maximal aerobic capacity (β = 0.399, p = 0.005) and LVEF (β = 0.698, p = 0.007) at 12 months.

Conclusions: Higher O3I was associated with a more favorable cardiometabolic risk profile and predictive of higher submaximal/maximal aerobic capacity and lower BMI/truncal adiposity in HFpEF patients. Omega-3 fatty acid blood levels are inversely associated with cardiometabolic risk factors in HFpEF patients. Higher O3I was associated with a more favorable cardiometabolic risk profile and aerobic capacity (left) but did not correlate with echocardiographic markers for left ventricular diastolic function or neurohumoral activation (right). An O3I-driven intervention trial might be warranted to answer the question whether O3-FA in therapeutic doses (with the target O3I 8-11%) impact on echocardiographic markers for left ventricular diastolic function and neurohumoral activation in patients with HFpEF. This figure contains modified images from Servier Medical Art ( https://smart.servier.com ) licensed by a Creative Commons Attribution 3.0 Unported License.
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http://dx.doi.org/10.1007/s00392-021-01925-9DOI Listing
August 2021

Intraoperative completion studies in carotid endarterectomy: systematic review and meta-analysis of techniques and outcomes.

Ann Transl Med 2021 Jul;9(14):1201

Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Background: Declining perioperative stroke and death rates over the past 3 decades have been paralleled by an increasing use of intraoperative completion studies (ICS) following carotid endarterectomy (CEA). Techniques applied include angiography, intraoperative duplex ultrasound (IDUS), flowmetry, and angioscopy. This systematic review and meta-analysis is aiming on providing an overview of techniques and corresponding outcomes.

Methods: A PubMed based systematic literature review comprising the years 1980 through 2020 was performed using predefined keywords to identify articles on different ICS techniques. Pooled analyses and meta-analyses estimating risk ratios (RR) and 95% confidence intervals (CI) were performed to compare outcomes of different ICS modes to nonapplication of any ICS. I values were assessed to quantify study heterogeneities.

Results: Identification of 34 studies including patients undergoing CEA with angiography (n=53,218), IDUS (n=20,030), flowmetry (n=16,812), and angioscopy (n=2,291). Corresponding rates of perioperative stroke were 1.5%, 1.8%, 3.6%, and 1.5%, perioperative stroke or death occurred in 1.7%, 1.9%, 2.2%, and 2.0%. Intraoperative surgical revision rates were 6.2%, 5.9%, and 7.9% after CEA with angiography, IDUS, and angioscopy, respectively. Compared to nonapplication of any ICS, the pooled analysis revealed angiography to be significantly associated with lower rates of stroke (RR 0.47; 95% CI, 0.36-0.62; P<0.0001) and stroke or death (RR 0.76; 95% CI, 0.70-0.83; P<0.0001). IDUS was significantly associated with lower rates of stroke (RR 0.56; 95% CI, 0.43-0.73; P<0.0001) and stroke or death (RR 0.83; 95% CI, 0.74-0.93; P=0.0018), whereas angioscopy showed a significant association with a lower stroke rate (RR 0.48; 95% CI, 0.033-0.68; P=0.0001), but no effect on the combined stroke or death rate. Angioscopy was associated with a higher intraoperative revision rate compared to angiography (RR 1.29; 95% CI, 1.07-1.54; P=0.006). The meta-analyses confirmed lower perioperative stroke or death rates for angiography (RR 0.83; 95% CI, 0.76-0.91) and IDUS (RR 0.86; 95% CI, 0.76-0.98) compared to non-application of any ICS, whereas flowmetry showed no significant association.

Conclusions: This study represents the first systematic literature review and meta-analysis on usage of ICSs in CEA. Data strongly indicate a significant beneficial effect of angiography, IDUS, and angioscopy on perioperative CEA outcomes. Any carotid surgeon should consider implementation of ICSs in his routine armamentarium.
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http://dx.doi.org/10.21037/atm-20-2931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350645PMC
July 2021

Effect of Training on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction-Reply.

JAMA 2021 08;326(8):772-773

Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

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http://dx.doi.org/10.1001/jama.2021.10061DOI Listing
August 2021

COVID-19 Vaccination Acceptance and Hesitancy among Healthcare Workers in Germany.

Vaccines (Basel) 2021 Jul 12;9(7). Epub 2021 Jul 12.

Department of Nephrology, School of Medicine, Technical University of Munich, Klinikum Rechts der Isar, 81675 Munich, Germany.

Vaccination hesitancy is a threat to herd immunity. Healthcare workers (HCWs) play a key role in promoting Coronavirus disease 2019 (COVID-19) vaccination in the general population. We therefore aimed to provide data on COVID-19 vaccination acceptance/hesitancy among German HCWs. For this exploratory, cross-sectional study, an online survey was conducted in February 2021. The survey included 54 items on demographics; previous vaccination behavior; trust in vaccines, physicians, the pharmaceutical industry and health politics; fear of adverse effects; assumptions regarding the consequences of COVID-19; knowledge about vaccines; and information seeking behavior. Odds ratios with 95% confidence intervals were calculated and chi-square tests were performed. Four thousand five hundred surveys were analyzed. The overall vaccination acceptance was 91.7%. The age group ≤20 years showed the lowest vaccination acceptance. Factors associated with vaccination hesitancy were lack of trust in authorities and pharmaceutical companies. Attitudes among acquaintances were associated with vaccination hesitancy too. Participants with vaccination hesitancy more often obtained information about COVID-19 vaccines via messenger services or online video platforms and underperformed in the knowledge test. We found high acceptance amongst German HCWs. Several factors associated with vaccination hesitancy were identified which could be targeted in HCW vaccination campaigns.
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http://dx.doi.org/10.3390/vaccines9070777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310090PMC
July 2021

Early Bronchoscopy Improves Extubation Rates after Out-of-Hospital Cardiac Arrest: A Retrospective Cohort Analysis.

J Clin Med 2021 Jul 9;10(14). Epub 2021 Jul 9.

Department of Internal Medicine I, School of Medicine & Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.

Background: Patients suffering from out-of-hospital cardiac arrest (OHCA) frequently receive a bronchoscopy after being admitted to the ICU. We investigated the optimal timing and the outcome in these patients.

Methods: All patients who suffered from OHCA and were treated in our ICU from January 2013 to December 2018 were retrospectively analyzed. The data were collected from the patients' medical files, and included duration of mechanical ventilation, antibiotics, microbiological test results and neurological outcome. The outcome was the effect of early bronchoscopy (≤48 h after administration) on the rate of intubated patients on day five and day seven.

Results: From January 2013 to December 2018, 190 patients were admitted with OHCA. Bronchoscopy was performed in 111 patients out of the 164 patients who survived the first day. Late bronchoscopy >48 h was associated with higher rates of intubation on day five (OR 4.94; 95% CI 1.2-36.72, 86.7% vs. 55.0%, = 0.036) and day seven (OR 4.96; 95% CI 1.38-24.69; 80.0% vs. 43.3%, = 0.019).

Conclusion: This study shows that patients who suffered from OHCA might have a better outcome if they receive a bronchoscopy early after hospital admission. Our data suggests an association of early bronchoscopy with a shorter intubation period.
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http://dx.doi.org/10.3390/jcm10143055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306153PMC
July 2021

Use of monoclonal antibody therapy for nosocomial SARS-CoV-2 infection in patients at high risk for severe COVID-19: experience from a tertiary-care hospital in Germany.

Infection 2021 Jul 9. Epub 2021 Jul 9.

Department of Internal Medicine II, School of Medicine, University Hospital Rechts der Isar, Technical University of Munich, Munich, Germany.

Additional treatment options for coronavirus disease (COVID-19) are urgently needed, particularly for populations at high risk of severe disease. This cross-sectional, retrospective study characterized the outcomes of 43 patients with nosocomial severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection with and without treatment using monoclonal SARS-CoV-2 spike antibodies (bamlanivimab or casirivimab/imdevimab). Our results indicate that treatment with monoclonal antibodies results in a significant decrease in disease progression and mortality when used for asymptomatic patients with early SARS-CoV-2 infection.
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http://dx.doi.org/10.1007/s15010-021-01657-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269399PMC
July 2021

High rate of complete histopathological response in hepatocellular carcinoma patients after combined transarterial chemoembolization and stereotactic body radiation therapy.

World J Gastroenterol 2021 Jun;27(24):3630-3642

Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich 81675, Germany.

Background: Liver transplantation (LT) presents a curative treatment option in patients with early stage hepatocellular carcinoma (HCC) who are not eligible for resection or ablation therapy. Due to a risk of up 30% for waitlist drop-out upon tumor progression, bridging therapies are used to halt tumor growth. Transarterial chemoembolization (TACE) and less commonly stereotactic body radiation therapy (SBRT) or a combination of TACE and SBRT, are used as bridging therapies in LT. However, it remains unclear if one of those treatment options is superior. The analysis of explant livers after transplantation provides the unique opportunity to investigate treatment response by histopathology.

Aim: To analyze histopathological response to a combination of TACE and SBRT in HCC in comparison to TACE or SBRT alone.

Methods: In this multicenter retrospective study, 27 patients who received liver transplantation for HCC were analyzed. Patients received either TACE or SBRT alone, or a combination of TACE and SBRT as bridging therapy to liver transplantation. Liver explants of all patients who received at least one TACE and/or SBRT were analyzed for the presence of residual vital tumor tissue by histopathology to assess differences in treatment response to bridging therapies. Statistical analysis was performed using Fisher-Freeman-Halton exact test, Kruskal-Wallis and Mann-Whitney- tests.

Results: Fourteen patients received TACE only, four patients SBRT only, and nine patients a combination therapy of TACE and SBRT. There were no significant differences between groups regarding age, sex, etiology of underlying liver disease or number and size of tumor lesions. Strikingly, analysis of liver explants revealed that almost all patients in the TACE and SBRT combination group (8/9, 89%) showed no residual vital tumor tissue by histopathology, whereas TACE or SBRT alone resulted in significantly lower rates of complete histopathological response (0/14, 0% and 1/4, 25%, respectively, value < 0.001).

Conclusion: Our data suggests that a combination of TACE and SBRT increases the rate of complete histopathological response compared to TACE or SBRT alone in bridging to liver transplantation.
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http://dx.doi.org/10.3748/wjg.v27.i24.3630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240047PMC
June 2021

Does gestational age at term play a role in the association between cerebroplacental ratio and operative delivery for intrapartum fetal compromise?

Acta Obstet Gynecol Scand 2021 Oct 17;100(10):1910-1916. Epub 2021 Jul 17.

Division of Obstetrics and Perinatal Medicine, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany.

Introduction: To assess the impact of gestational age at term on the association between cerebroplacental ratio (CPR) and operative delivery for intrapartum fetal compromise (IFC) and prognostic performance of CPR to predict operative delivery for IFC.

Material And Methods: This was a retrospective cohort study including 2052 singleton pregnancies delivered between 37 and 41  weeks of gestation in a single tertiary referral center over an 8-year period. CPR was measured within 1 week of delivery. IFC was defined as the presence of persistent pathological cardiotocography pattern or the combination of pathological cardiotocography pattern and fetal scalp pH < 7.20. Operative delivery included instrumental vaginal delivery and cesarean section. Pregnancies were grouped according to birthweight (small for gestational age [SGA, birthweight <10th centile] and appropriate for gestational age [AGA, birthweight 10th-90th centile]) and gestational age by week at delivery. Rates of operative delivery were compared between the subgroups. Prognostic value of CPR was assessed using receiver operating characteristic curve.

Results: Of the study cohort, 308 (15%) had a CPR <10th centile, 374 (18%) operative delivery for IFC, and 298 (15%) were SGA at birth. Overall, the rates of operative delivery for IFC were higher in the low CPR group both in SGA (35% vs. 22%; p = 0.023) and in AGA (23% vs. 16%; p = 0.007). According to gestational age by week at delivery, fetuses with low CPR showed higher rates of operative delivery for IFC with advancing gestational age, mainly in pregnancies delivered at 40 weeks (54% vs. 23%; p = 0.004) and at 41 weeks (60% vs. 19%; p = 0.010) for SGA and at 41 weeks (39% vs. 20%; p = 0.001) for AGA. The predictive value of CPR remained stable throughout term and was poor both in SGA and in AGA.

Conclusions: Both SGA and AGA fetuses with low CPR showed higher rates of operative delivery for IFC at term with advancing gestational age. Prognostic value of CPR throughout term was poor.
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http://dx.doi.org/10.1111/aogs.14222DOI Listing
October 2021

Perinatal Outcome and its Prediction Using Longitudinal Feto-Maternal Doppler Follow-Up in Late Onset Small for Gestational Age Fetuses - A Prospective Cohort Study.

Ultraschall Med 2021 Jun 8. Epub 2021 Jun 8.

Department of Pediatric Cardiology and Congenital Heart Defects, German Heart Centre Munich, München, Germany.

Purpose:  To describe the perinatal outcome of a prospective cohort of late-onset small-for-gestational-age (SGA) fetuses and to test adverse perinatal outcome (APO) prediction using Doppler measurements.

Methods:  Singleton pregnancies from 32 weeks with suspicion of SGA (followed-up each 2 weeks) and randomly selected healthy controls at a university hospital were included. The whole SGA group was divided into the FGR subgroup or SGA percentile 3-10 subgroup. The following Doppler measurements were evaluated prospectively: umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, cerebro-placental ratio (CPR), and mean uterine artery (mUtA) PI. APO was defined as arterial cord blood pH ≤ 7.15 and/or 5-minute Apgar ≤ 7 and/or emergency operative delivery and/or admission to the neonatal unit. Induction of labor was indicated according to a stage-based protocol.

Results:  A total of 149 SGA and 143 control fetuses were included. The number of operative deliveries was similar between both groups (control: 29 %, SGA: 28 %), especially the cesarean delivery rate after the onset of labor (11 % vs. 10 %). Most SGA cases ended up in induction of labor (61 % vs. 31 %, p < 0.001). The areas under the curve (AUC) for APO prediction were similar using the last UA PI, MCA PI, CPR, and mUtA PI and barely reached 0.60. The AUC was best for the FGR subgroup, using the minimal CPR or maximum mUtA PI z-score of all longitudinal measurements (AUC = 0.63).

Conclusion:  SGA fetuses do not have a higher rate of operative delivery if managed according to a risk stratification protocol. Prediction of APO is best for SGA and FGR using the "worst" CPR or mUtA PI but it remains moderate.
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http://dx.doi.org/10.1055/a-1493-2367DOI Listing
June 2021

Effects of Marathon Running on Cognition and Retinal Vascularization: A Longitudinal Observational Study.

Med Sci Sports Exerc 2021 Oct;53(10):2207-2214

Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, GERMANY.

Introduction: Physical activity has beneficial effects on both cardiovascular and neurocognitive parameters, and these two modalities are known to interact at rest. However, findings on their interaction during exercise are inconclusive.

Purpose: Therefore, this longitudinal study aimed to investigate the effects of different forms of exercise (training period, marathon race, and recovery period) on both parameters and their interaction.

Methods: We included 100 marathon runners (MA) (mean ± SD age = 43.6 ± 10.0 yr, 80 males) and 46 age- and sex-matched sedentary controls (SC, for baseline comparison). Over the 6-month study period with six visits (12 and 2 wk before the marathon; immediately, 24 h, 72 h, and 12 wk after the marathon), we assessed cognitive parameters by evaluating the 1- to 3-back d prime, the d2 task, and the Trail Making Tests A (TMT A) and B (TMT B), and the retinal vessel parameters by assessing arteriolar-to-venular ratio (AVR), central retinal arteriolar equivalent (CRAE), and central retinal venular equivalent (CRVE).

Results: In the long-term analysis, 3-back d prime correlated positively with AVR (P = 0.024, B = 1.86, SE = 0.824) and negatively with CRVE (P = 0.05, B = -0.006, SE = 0.003), and TMT B correlated negatively with CRAE (P = 0.025, B = -0.155, SE = 0.069), even after correcting for age and systolic blood pressure as possible confounders. Acute effects were inconsistent with maximal cognitive improvement 24 h after the marathon. AVR was significantly smaller in SC compared with MA.

Conclusion: Chronic exercise seems to prime the central nervous system for acute, intensive bouts of exercise. Our findings indicate a possible relationship between cognitive performance in high-demand tasks and retinal vasculature and support the idea of a neuroplastic effect of exercise.
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http://dx.doi.org/10.1249/MSS.0000000000002699DOI Listing
October 2021

Electrocardiographic parameters of left ventricular hypertrophy and prediction of mortality in hemodialysis patients.

J Nephrol 2021 May 20. Epub 2021 May 20.

Department of Nephrology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

Background: In hemodialysis patients, left ventricular hypertrophy (LVH) contributes to high cardiovascular mortality. We examined cardiovascular mortality prediction by the recently proposed Peguero-Lo Presti voltage since it identifies more patients with electrocardiographic (ECG) LVH than Cornell or Sokolow-Lyon voltages.

Methods: A total of 308 patients on hemodialysis underwent 24 h ECG recordings. LVH parameters were measured before and after dialysis. The primary endpoint of cardiovascular mortality was recorded during a median 3-year follow up. Risk prediction was assessed by Cox regression, both unadjusted and adjusted for the Charlson Comorbidity Index and the Cardiovascular Mortality Risk Score.

Results: The Peguero-Lo Presti voltage identified with 21% the most patients with positive LVH criteria. All voltages significantly increased during dialysis. Factors such as ultrafiltration rate, Kt/V, body mass index, sex, and phosphate were the most relevant for these changes. During follow-up, 26 cardiovascular deaths occurred. Post-dialysis Peguero-Lo Presti cut-off as well as the Peguero-Lo Presti and Cornell voltages were independently associated with cardiovascular mortality in unadjusted and adjusted analysis. The Sokolow-Lyon voltage was not significantly associated with mortality. An optimal cut-off for the prediction of cardiovascular mortality was estimated at 1.38 mV for the Peguero-Lo Presti.

Conclusions: The post-dialysis Peguero-Lo Presti cut-off as well as the Peguero-Lo Presti and Cornell voltages allowed independent risk prediction of cardiovascular mortality in hemodialysis patients. Measuring the ECG LVH parameters after dialysis might allow a standardized interpretation as dialysis-specific factors influence the voltages.
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http://dx.doi.org/10.1007/s40620-021-01068-0DOI Listing
May 2021

Application of regularized regression to identify novel predictors of mortality in a cohort of hemodialysis patients.

Sci Rep 2021 04 29;11(1):9287. Epub 2021 Apr 29.

Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Cohort studies often provide a large array of data on study participants. The techniques of statistical learning can allow an efficient way to analyze large datasets in order to uncover previously unknown, clinically relevant predictors of morbidity or mortality. We applied a combination of elastic net penalized Cox regression and stability selection with the aim of identifying novel predictors of mortality in a cohort of prevalent hemodialysis patients. In our analysis we included 475 patients from the "rISk strAtification in end-stage Renal disease" (ISAR) study, who we split into derivation and confirmation cohorts. A wide array of examinations was available for study participants, resulting in over a hundred potential predictors. In the selection approach many of the well established predictors were retrieved in the derivation cohort. Additionally, the serum levels of IL-12p70 and AST were selected as mortality predictors and confirmed in the withheld subgroup. High IL-12p70 levels were specifically prognostic of infection-related mortality. In summary, we demonstrate an approach how statistical learning can be applied to a cohort study to derive novel hypotheses in a data-driven way. Our results suggest a novel role of IL-12p70 in infection-related mortality, while AST is a promising additional biomarker in patients undergoing hemodialysis.
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http://dx.doi.org/10.1038/s41598-021-88655-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085040PMC
April 2021

Atrophy patterns in isolated subscapularis lesions.

BMC Musculoskelet Disord 2021 Apr 22;22(1):378. Epub 2021 Apr 22.

Department of Orthopedic Sports Medicine, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Background: While supraspinatus atrophy can be described according to the system of Zanetti or Thomazeau there is still a lack of characterization of isolated subscapularis muscle atrophy. The aim of this study was to describe patterns of muscle atrophy following repair of isolated subscapularis (SSC) tendon.

Methods: Forty-nine control shoulder MRI scans, without rotator cuff pathology, atrophy or fatty infiltration, were prospectively evaluated and subscapularis diameters as well as cross sectional areas (complete and upper half) were assessed in a standardized oblique sagittal plane. Calculation of the ratio between the upper half of the cross sectional area (CSA) and the total CSA was performed. Eleven MRI scans of patients with subscapularis atrophy following isolated subscapularis tendon tears were analysed and cross sectional area ratio (upper half /total) determined. To guarantee reliable measurement of the CSA and its ratio, bony landmarks were also defined. All parameters were statistically compared for inter-rater reliability, reproducibility and capacity to quantify subscapularis atrophy.

Results: The mean age in the control group was 49.7 years (± 15.0). The mean cross sectional area (CSA) was 2367.0 mm (± 741.4) for the complete subscapularis muscle and 1048.2 mm (± 313.3) for the upper half, giving a mean ratio of 0.446 (± 0.046). In the subscapularis repair group the mean age was 56.7 years (± 9.3). With a mean cross sectional area of 1554.7 mm (± 419.9) for the complete and of 422.9 mm (± 173.6) for the upper half of the subscapularis muscle, giving a mean CSA ratio of 0.269 (± 0.065) which was seen to be significantly lower than that of the control group (p < 0.05).

Conclusion: Analysis of typical atrophy patterns of the subscapularis muscle demonstrates that the CSA ratio represents a reliable and reproducible assessment tool in quantifying subscapularis atrophy. We propose the classification of subscapularis atrophy as Stage I (mild atrophy) in case of reduction of the cross sectional area ratio < 0.4, Stage II (moderate atrophy) in case of < 0.35 and Stage III (severe atrophy) if < 0.3.
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http://dx.doi.org/10.1186/s12891-021-04241-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063377PMC
April 2021

Prediction of adverse perinatal outcome and the mean time until delivery in twin pregnancies with suspected pre-eclampsia using sFlt-1/PIGF ratio.

Pregnancy Hypertens 2021 Jun 13;24:37-43. Epub 2021 Feb 13.

Department of Obstetrics and Gynecology, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany; Department of Obstetrics and Gynecology, University Hospital RWTH Aachen, RWTH Aachen University, Aachen, Germany.

Purpose: An elevated soluble fms-like tyrosine kinase-1 (sFlt-1) / placental growth factor (PlGF) ratio is associated with adverse perinatal outcome (APO) and the mean time until delivery (MTUD) in singleton pregnancies complicated by pre-eclampsia (PE). Data on APO and MTUD prediction in twin pregnancies using sFlt-1/PlGF ratio are scarce. We evaluated the predictive value of the sFlt-1/PIGF ratio regarding APO and MTUD in twin pregnancies with suspected PE and/or HELLP syndrome.

Methods: This is a single center retrospective cohort study. All twin pregnancies with suspected PE/HELLP and determined sFlt-1/PIGF were included. Composite APO (CAPO) was defined as the presence of at least one of the following outcomes: respiratory distress syndrome (RDS), intubation, admission to neonatal intensive care unit (NICU) and arterial umbilical cord pH value < 7.10. Selective fetal growth restriction (s-FGR) was analyzed separately.

Results: For final analysis, 49 twin pregnancies were included. Median sFlt-1/PIGF ratio was not significantly different in patients with CAPO compared to those without (89.45 vs. 62.00, p = 0.669). MTUD was significantly negative correlated with sFlt-1/PIGF ratio (r = -0.409, p < 0.001). For the whole study cohort, ROC analysis revealed no predictive value for sFlt-1/PIGF and CAPO (AUC = 0.618, 95% CI: 0.387-0.849, p = 0.254). However, sFlt-1/PIGF ratio showed a predictive value for s-FGR (AUC = 0.755, 95% CI: 0.545-0.965, p = 0.032).

Conclusion: In twin pregnancies with PE and/or HELLP, sFlt-1/PIGF ratio may be helpful for s-FGR prediction and decision-making regarding close monitoring of high-risk patients. However, further prospective studies are warranted to define the role of sFlt-1/PlGF ratio as outcome predictor in twin pregnancies.
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http://dx.doi.org/10.1016/j.preghy.2021.02.003DOI Listing
June 2021

Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity Advice on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial.

JAMA 2021 02;325(6):542-551

Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Importance: Endurance exercise is effective in improving peak oxygen consumption (peak V̇o2) in patients with heart failure with preserved ejection fraction (HFpEF). However, it remains unknown whether differing modes of exercise have different effects.

Objective: To determine whether high-intensity interval training, moderate continuous training, and guideline-based advice on physical activity have different effects on change in peak V̇o2 in patients with HFpEF.

Design, Setting, And Participants: Randomized clinical trial at 5 sites (Berlin, Leipzig, and Munich, Germany; Antwerp, Belgium; and Trondheim, Norway) from July 2014 to September 2018. From 532 screened patients, 180 sedentary patients with chronic, stable HFpEF were enrolled. Outcomes were analyzed by core laboratories blinded to treatment groups; however, the patients and staff conducting the evaluations were not blinded.

Interventions: Patients were randomly assigned (1:1:1; n = 60 per group) to high-intensity interval training (3 × 38 minutes/week), moderate continuous training (5 × 40 minutes/week), or guideline control (1-time advice on physical activity according to guidelines) for 12 months (3 months in clinic followed by 9 months telemedically supervised home-based exercise).

Main Outcomes And Measures: Primary end point was change in peak V̇o2 after 3 months, with the minimal clinically important difference set at 2.5 mL/kg/min. Secondary end points included changes in metrics of cardiorespiratory fitness, diastolic function, and natriuretic peptides after 3 and 12 months.

Results: Among 180 patients who were randomized (mean age, 70 years; 120 women [67%]), 166 (92%) and 154 (86%) completed evaluation at 3 and 12 months, respectively. Change in peak V̇o2 over 3 months for high-intensity interval training vs guideline control was 1.1 vs -0.6 mL/kg/min (difference, 1.5 [95% CI, 0.4 to 2.7]); for moderate continuous training vs guideline control, 1.6 vs -0.6 mL/kg/min (difference, 2.0 [95% CI, 0.9 to 3.1]); and for high-intensity interval training vs moderate continuous training, 1.1 vs 1.6 mL/kg/min (difference, -0.4 [95% CI, -1.4 to 0.6]). No comparisons were statistically significant after 12 months. There were no significant changes in diastolic function or natriuretic peptides. Acute coronary syndrome was recorded in 4 high-intensity interval training patients (7%), 3 moderate continuous training patients (5%), and 5 guideline control patients (8%).

Conclusions And Relevance: Among patients with HFpEF, there was no statistically significant difference in change in peak V̇o2 at 3 months between those assigned to high-intensity interval vs moderate continuous training, and neither group met the prespecified minimal clinically important difference compared with the guideline control. These findings do not support either high-intensity interval training or moderate continuous training compared with guideline-based physical activity for patients with HFpEF.

Trial Registration: ClinicalTrials.gov Identifier: NCT02078947.
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http://dx.doi.org/10.1001/jama.2020.26812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873782PMC
February 2021

Quality of Life in Advanced Dementia with Late Onset, Young Onset, and Very Young Onset.

J Alzheimers Dis 2021 ;80(1):283-297

Technical University of Munich, School of Medicine, Department of Psychiatry and Psychotherapy, Munich, Germany.

Background: Advanced stages of dementia are characterized by severe cognitive and physical impairment. It has not yet been investigated whether persons with young onset dementia (YOD) and late onset dementia (LOD) differ in advanced disease stages.

Objectives: To compare quality of life (QoL) between persons with advanced YOD and LOD; to explore the determinants of QoL; to investigate whether YOD and LOD differ with regard to symptoms and care.

Methods: The study was performed in the context of EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of YOD and LOD in Germany). Persons with advanced dementia (PWAD) were assessed and caregivers were interviewed. QoL was measured with the proxy rating Quality of Life in Late Stage Dementia (QUALID) scale.

Results: 93 persons with YOD and 98 with LOD were included. No significant differences in QoL were detected. Determinants of QoL were similar in YOD and LOD. Behavioral and psychological symptoms of dementia (BPSD), suffering and other distressing symptoms were associated with a lower QoL. In YOD but not in LOD antipsychotic treatment was associated with low QoL. The group of persons who were younger than 65 years at the time of the study visit experienced significantly more distressing symptoms than older PWAD.

Conclusion: Overall, persons with advanced YOD do not appear to be disadvantaged compared to old and oldest PWAD. Special attention, however, must be paid to the group of the very young persons who seem to be particularly vulnerable.
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http://dx.doi.org/10.3233/JAD-201302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075393PMC
September 2021

A systematic review of subgroup analyses in randomised clinical trials in cardiovascular disease.

Clin Trials 2021 06 21;18(3):351-360. Epub 2021 Jan 21.

Institute of Medical Informatics, Statistics and Epidemiology, School of Medicine, Technical University of Munich, Munich, Germany.

Background: Subgroup analyses are frequently used to assess heterogeneity of treatment effects in randomised clinical trials. Inconsistent, improper and incomplete implementation, reporting and interpretation have been identified as ongoing challenges. Further, subgroup analyses were frequently criticised because of unreliable or potentially misleading results. More recently, recommendations and guidelines have been provided to improve the reporting of data in this regard.

Methods: This systematic review was based on a literature search within the digital archives of three selected medical journals, and We reviewed articles of randomised clinical trials in the domain of cardiovascular disease which were published in 2015 and 2016. We screened and evaluated the selected articles for the mode of implementation and reporting of subgroup analyses.

Results: We were able to identify a total of 130 eligible publications of randomised clinical trials. In 89/130 (68%) articles, results of at least one subgroup analysis were presented. This was dependent on the considered journal (p < 0.001), the number of included patients (p < 0.001) and the lack of statistical significance of a trial's primary analysis (p < 0.001). The number of reported subgroup analyses ranged from 1 to 101 (median = 13). We were able to comprehend the specification time of reported subgroup analyses for 71/89 (80%) articles, with 55/89 (62%) articles presenting exclusively pre-specified analyses. This information was not always traceable on the basis of provided trial protocols and often did not include the pre-definition of cut-off values for the categorization of subgroups. The use of interaction tests was reported in 84/89 (94%) articles, with 36/89 (40%) articles reporting heterogeneity of the treatment effect for at least one primary or secondary trial outcome. Subgroup analyses were reported more frequently for larger randomised clinical trials, and if primary analyses did not reach statistical significance. Information about the implementation of subgroup analyses was reported most consistently for articles from , since it was also traceable on the basis of provided trial protocols. We were able to comprehend whether subgroup analyses were pre-specified in a majority of the reviewed publications. Even though results of multiple subgroup analyses were reported for most published trials, a corresponding adjustment for multiple testing was rarely considered.

Conclusion: Compared to previous reviews in this context, we observed improvements in the reporting of subgroup analyses of cardiovascular randomised clinical trials. Nonetheless, critical shortcomings, such as inconsistent reporting of the implementation and insufficient pre-specification, persist.
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http://dx.doi.org/10.1177/1740774520984866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174013PMC
June 2021

Endoscopic and percutaneous biliary interventions in patients with altered upper gastrointestinal anatomy-the Munich Multicenter Experience.

Surg Endosc 2021 Jan 4. Epub 2021 Jan 4.

Medizinische Klinik II, Krankenhaus Landshut-Achdorf, Akademisches Lehrkrankenhaus der TU München, Achdorferweg 3, 84036, Landshut, Germany.

Background: In patients with altered upper gastrointestinal anatomy, conventional endoscopic retrograde cholangiography is often not possible and different techniques, like enteroscopy-assisted or percutaneous approaches are required. Aim of this study was to analyze success and complication rates of these techniques in a large collective of patients in the daily clinical practice in a pre-endosonographic biliary drainage era.

Patients And Methods: Patients with altered upper gastrointestinal anatomy with biliary interventions between March 1st, 2006, and June 30th, 2014 in four tertiary endoscopic centers in Munich, Germany were retrospectively analyzed.

Results: At least one endoscopic-assisted biliary intervention was successful in 234/411 patients (56.9%)-in 192 patients in the first, in 34 patients in the second and in 8 patients in the third attempt. Success rates for Billroth-II/Whipple-/Roux-en-Y reconstruction were 70.5%/56.7%/49.5%. Complication rates for these reconstructions were 9.3%/6.5%/6.3%, the overall complication rate was 7.1%. Success rates were highest in patients with Billroth-II reconstruction where use of a duodenoscope was possible, complication rates were also highest in this scenario. Success rates were lowest in longer-limb anatomy like Roux-en-Y reconstruction. Percutaneous biliary drainages (PTBD) were inserted 268 times with substantially higher success (90.7%) as well as complication rates (11.6%) compared to the endoscopic approach. Compared to patients treated endoscopically, patients with PTBD had a lower performance status, more severe cholestasis and a significant higher rate of malignant underlying disease.

Conclusion: In patients with altered upper gastrointestinal anatomy, success rates of endoscopic-assisted biliary interventions are lower compared to PTBD. Still, due to the beneficial complication rates of the endoscopic approach, this technique should be preferred whenever possible and in selected patients who still need to be defined in detail, repeated endoscopic attempts are useful to help achieve the desired result.
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http://dx.doi.org/10.1007/s00464-020-08191-2DOI Listing
January 2021

Coronary calcium scoring assessed on native screening chest CT imaging as predictor for outcome in COVID-19: An analysis of a hospitalized German cohort.

PLoS One 2020 30;15(12):e0244707. Epub 2020 Dec 30.

Department of Diagnostic and Interventional Radiology, School of Medicine & Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Background: Since the outbreak of the COVID-19 pandemic, a number of risk factors for a poor outcome have been identified. Thereby, cardiovascular comorbidity has a major impact on mortality. We investigated whether coronary calcification as a marker for coronary artery disease (CAD) is appropriate for risk prediction in COVID-19.

Methods: Hospitalized patients with COVID-19 (n = 109) were analyzed regarding clinical outcome after native computed tomography (CT) imaging for COVID-19 screening. CAC (coronary calcium score) and clinical outcome (need for intensive care treatment or death) data were calculated following a standardized protocol. We defined three endpoints: critical COVID-19 and transfer to ICU, fatal COVID-19 and death, composite endpoint critical and fatal COVID-19, a composite of ICU treatment and death. We evaluated the association of clinical outcome with the CAC. Patients were dichotomized by the median of CAC. Hazard ratios and odds ratios were calculated for the events death or ICU or a composite of death and ICU.

Results: We observed significantly more events for patients with CAC above the group's median of 31 for critical outcome (HR: 1.97[1.09,3.57], p = 0.026), for fatal outcome (HR: 4.95[1.07,22.9], p = 0.041) and the composite endpoint (HR: 2.31[1.28,4.17], p = 0.0056. Also, odds ratio was significantly increased for critical outcome (OR: 3.01 [1.37, 6.61], p = 0.01) and for fatal outcome (OR: 5.3 [1.09, 25.8], p = 0.02).

Conclusion: The results indicate a significant association between CAC and clinical outcome in COVID-19. Our data therefore suggest that CAC might be useful in risk prediction in patients with COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244707PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773182PMC
January 2021

The immunologic tumor microenvironment in endometrioid endometrial cancer in the morphomolecular context: mutual correlations and prognostic impact depending on molecular alterations.

Cancer Immunol Immunother 2021 Jun 19;70(6):1679-1689. Epub 2020 Dec 19.

Institute of Pathology, Technical University Munich, Trogerstrasse 18, 81675, Munich, Germany.

Objective: POLE-mutant, microsatellite-instable (MSI), p53-mutant and non-specific molecular profile (NSMP) are TCGA-defined molecular subgroups of endometrial cancer (EC). Hypothesizing that morphology and tumor immunology might differ depending on molecular background concerning composition and prognostic impact, we aimed to comprehensively interconnect morphologic, immunologic and molecular data.

Methods: TCGA-defined molecular groups were determined by immunohistochemistry and sequencing in n = 142 endometrioid EC. WHO-defined histopathological grading was performed. The immunologic microenvironment (iTME) was characterised by the quantification of intraepithelial and stromal populations of tumor-infiltrating lymphocytes (TIL: overall T-cells; T-Killer cells; regulatory T-cells (Treg)). Immunologic parameters were correlated with WHO-grading, TCGA-subgroups and prognosis.

Results: High density TIL were significantly more frequent in high-grade (G3) compared to low-grade (G1/2) EC in the whole cohort and in the subgroup of POLE-wildtype-/microsatellite-stable-EC. MSI was associated with high-level TIL-infiltration when taking into account the type of mismatch repair defect (MLH1/PMS2; MSH2/MSH6). Prognostic impact of biomarkers depended on molecular subgroups: In p53-mutant EC, Treg were independently prognostic, in NSMP, the unique independently prognostic biomarker was WHO-grading.

Conclusions: EC morphology and immunology differ depending on genetics. Our study delineated two molecularly distinct subgroups of immunogenic EC characterized by high-density TIL-infiltration: MSI EC and high-grade POLE-wildtype/microsatellite-stable-EC. Prognostic impact of TIL-populations relied on TCGA-subgroups indicating specific roles for TIL depending on molecular background. In NSMP, histopathological grading was the only prognostic biomarker demonstrating the relevance of WHO-grading in an era of molecular subtyping.
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http://dx.doi.org/10.1007/s00262-020-02813-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139910PMC
June 2021

The Effect of Orthognathic Surgery on Temporomandibular Joint Function and Symptoms: What are the Risk Factors? A Longitudinal Analysis of 375 Patients.

J Oral Maxillofac Surg 2021 04 17;79(4):763-773. Epub 2020 Nov 17.

Head, Department of Oral and Maxillofacial Surgery, Medical University Innsbruck, Innsbruck, Austria. Electronic address:

Purpose: The effects of orthognathic surgery (OGS) on the temporomandibular joint (TMJ) are still controversial. Based on a high-volume uniform collective, the function and clinical symptoms of the TMJ and the dysfunction index (Di) by Helkimo were evaluated prior and up to 2 years after OGS.

Methods: A longitudinal cohort study was performed between 2006 and 2016. A comprehensive examination focusing on TMJ function, temporomandibular disorder (TMD) symptoms, and the Di had been performed preopertaively (T0) and postoperatively at 6 weeks (T1), 6 months (T2), 1 year (T3), and 2 years (T4). The predictor variables used were sex, age, skeletal class, type of surgery, and amount of dysfunction or number of TMD complaints before treatment. The outcome of this study was TMD symptoms and the Di. Descriptive and bivariate statistics were computed, and the significance level was set at P < .05.

Results: The sample consisted of 375 patients (247 women, 128 men, mean age 28.1 ± 9.4 years), 269 with skeletal Class II (71.7%) and 106 with skeletal Class III (28.3%) treated with sagittal split osteotomy bilateral sagittal split osteotomy (n = 173) or Le Fort I and bilateral sagittal split osteotomy (n = 202). Severe signs of dysfunction (Di 2/3) were seen in 5.9% of the patients before OGS and in 2.1% of the patients 2 years after OGS. The difference in Di (Di0/1 and Di2/3) between T0 and T1/T2 was statistically significant (P = .028; P = .011, respectively). TMD symptoms were significantly reduced 2 years after OGS (P = .028). Female gender (P = .013), skeletal Class II (P < .001), and counterclockwise rotation (P < .001) were the only risk factors significantly associated with the occurrence of TMD at T1.

Conclusions: The results of this study suggest that in most cases TMD symptoms can be significantly reduced and only a few can be induced with OGS. No risk factors were found for long-term effects on the TMJ.
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http://dx.doi.org/10.1016/j.joms.2020.11.010DOI Listing
April 2021

Role of Brain Biomarkers S-100-Beta and Neuron-Specific Enolase for Detection and Follow-Up of Hepatic Encephalopathy in Cirrhosis before, during and after Treatment with L-Ornithine-L-Aspartate.

GE Port J Gastroenterol 2020 Nov 21;27(6):391-403. Epub 2020 Apr 21.

Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Bogenhausen Academic Teaching Hospital, Technical University of Munich, Munich, Germany.

Introduction: Hepatic encephalopathy (HE), in the context of liver cirrhosis, seems to result from low-grade cerebral edema of the astrocytes. Serum brain biomarkers S-100-beta und neuron-specific enolase (NSE) are often elevated in brain injury. We hypothesized that neuromarkers S-100-beta and NSE can be used in the diagnosis of HE, compared with standardized diagnostic tools.

Material And Methods: A prospective non-randomized intervention study was performed using L-ornithine-L-aspartate (LOLA) for HE treatment. Primary endpoint was the evaluation of neuromarkers S-100-beta and NSE for detection and diagnosis of follow-up of HE. As secondary endpoints, the efficacy of LOLA on the course of HE and the diagnostic role of Portosystemic-Encephalopathy-Syndrome score (PHES) and critical flicker frequency (CFF) were analyzed. For diagnosis of covert (CHE) and overt (OHE) HE, West-Haven criteria (WHC), PHES and CFF were assessed at study entry. LOLA was applied (20 g i.v.) for 6 days. At the end of the study, HE evaluation was repeated. S-100-beta, NSE and ammonia were assessed in each patient before, during and after therapy with LOLA.

Results: 30 patients were included. At study entry, CHE was diagnosed in 50% and OHE in 50% of all subjects. A total of 25 participants completed the study. After LOLA therapy, deterioration of HE occurred in <11%, while most patients showed improvement (e.g. improved CFF in 79%). No significant correlation with HE severity (as diagnosed by WHC, PHES and CFF) could be demonstrated for any biochemical parameter. In addition, there were no significant changes in brain biomarkers during the treatment period.

Discussion: While CFF as well as PHES showed good correlation with treatment response, S-100-beta and NSE did not significantly correlate with HE severity compared to proven diagnostic methods, and do not seem reliable biochemical markers for the follow-up under therapy.
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http://dx.doi.org/10.1159/000507225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670347PMC
November 2020

The Effect of Exercise Intensity and Volume on Metabolic Phenotype in Patients with Metabolic Syndrome: A Randomized Controlled Trial.

Metab Syndr Relat Disord 2021 03 24;19(2):107-114. Epub 2020 Nov 24.

Department of Prevention and Sports Medicine, School of Medicine, Technical University of Munich, Munich, Germany.

Moderate intensity continuous training (MICT) ameliorates dysmetabolism in patients with metabolic syndrome (MetS). The impact of low- (1HIIT) versus high-volume high-intensity interval training (4HIIT) versus MICT on central adiposity, insulin resistance, and atherogenic dyslipidemia in patients with MetS has not yet been reported. Twenty-nine patients with MetS according to International Diabetes Federation criteria (nine females, age 61 ± 5 years, body mass index 31.1 ± 3.7 kg/m, waist circumference (WC) ♀ 102.2 ± 10.6 cm, ♂ 108.5 ± 8.6 cm) were randomized (1:1:1) to 16 weeks of (1) MICT (5 × 30 min/week, 35%-50% heart rate reserve (HRR), (2) 1HIIT (3 × 17 min/week incl. 4 min @80%-90% HRR), and (3) 4HIIT (3 × 38 min/week incl. 4 × 4 min @80%-90% HRR). Peak oxygen uptake (O), WC and anthropometric/metabolic indices indicative of MetS, fasting glucose/insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), dyslipidemia, and respiratory exchange ratio (RER) at warm-up were quantified at baseline and study completion. Analysis of variance and paired t tests were used for statistical analysis. Analyses were performed after checking for parametric distribution. There were no significant differences between groups in waist-to-height ratio (♀: Δ -0.10 ± -0.05, ♂: Δ -0.08 ± -0.06,  = 0.916), WC (♀: Δ -1.4 ± -0.1 cm, ♂: Δ 0.1 ± 0.9 cm,  = 0.590), fasting glucose (Δ -1.18 ± 16.7 μU/mL,  = 0.773), fasting insulin (Δ 0.76 ± 13.4 μU/mL,  = 0.509), HOMA-IR (Δ 0.55 ± 4.1,  = 0.158), atherogenic dyslipidemia [triglycerides (TAG) Δ -10.1 ± 46.9 mg/dL,  = 0.468, high-density lipoprotein cholesterol (HDL-C) Δ 1.5 ± 5.4,  = 0.665, TAG/HDL-C -0.19 ± 1.3,  = 0.502], O ( = 0.999), or RER ( = 0.842). In the entire group, waist-to-height-ratio and O significantly improved by a clinically meaningful amount (Δ 2.7 ± 0.9 mL/min/kg;  < 0.001) and RER at warm-up significantly decreased (Δ -0.03 ± 0.06,  = 0.039). In patients with MetS, there was no significant difference between HIIT, irrespective of volume, to MICT for improving exercise capacity or metabolic health.
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http://dx.doi.org/10.1089/met.2020.0105DOI Listing
March 2021

Colon diverticulosis is not a risk factor for the detection of adenomatous polyps - results of a prospective study.

Z Gastroenterol 2021 Feb 4;59(2):135-142. Epub 2020 Nov 4.

Klinik für Innere Medizin II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.

Background And Aims:  Colon diverticula (CD) and adenomatous polyps are frequently found during colonoscopy. Data from the literature contains inconsistent information about whether patients with CD have a higher risk for colon adenomas. A positive correlation might influence the current guidelines for screening colonoscopies. The aim of this study was to examine whether presence of CD is associated with endoscopic adenoma detection.

Materials And Methods:  This was a prospective study at 2 centers in Germany. Patients with an indication for colonoscopy were included. The number and localization of diverticula were recorded. Detected polyps were resected, and histopathological results were captured. Logistic regression models were fitted to the data to evaluate the association between CD and adenoma detection.

Results:  A total of 938 colonoscopies was included. CD occurred in 49.1 % of the colonoscopies. The polyp and adenoma detection rates (PDR, ADR) were 50.3 % and 32.3 %. In 37.5 % of the patients with diverticula, at least 1 adenoma was detected, whereas this was the case in 27.3 % in the absence of diverticula. The presence of diverticula was positively correlated with the detection of adenomas in univariate analysis (p = 0.001), but no significant association could be found in multivariable analysis (p = 0.775). Increasing age (p < 0.001), male sex (p = 0.005), and longer withdrawal time (p < 0.001) were significant predictors for adenoma detection in the multivariable analysis. Similar results were also observed for both the distal and the proximal colon.

Discussion:  Diverticula and adenomas are frequently found during colonoscopies. However, diverticula disease was not significantly associated with adenoma detection after adjustment for relevant prognostic factors. Older age, male sex, and duration of withdrawal time are predictors for the detection of adenomatous polyps.
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http://dx.doi.org/10.1055/a-1246-3295DOI Listing
February 2021

Opportunistic osteoporosis screening: contrast-enhanced dual-layer spectral CT provides accurate measurements of vertebral bone mineral density.

Eur Radiol 2021 May 14;31(5):3147-3155. Epub 2020 Oct 14.

Department of Radiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Objectives: Osteoporosis remains under-diagnosed, which may be improved by opportunistic bone mineral density (BMD) measurements on CT. However, correcting for the influence of intravenous iodine-based contrast agent is challenging. The purpose of this study was to assess the diagnostic accuracy of iodine-corrected vertebral BMD measurements derived from non-dedicated contrast-enhanced phantomless dual-layer spectral CT (DLCT) examinations.

Methods: Vertebral volumetric DLCT-BMD was measured in native, arterial, and portal-venous scans of 132 patients (63 ± 16 years; 32% women) using virtual monoenergetic images (50 and 200 keV). For comparison, conventional BMD was determined using an asynchronous QCT calibration. Additionally, iodine densities were measured in the abdominal aorta (AA), inferior vena cava, and vena portae (VP) on each CT phase to adjust for iodine-related measurement errors in multivariable linear regressions and a generalized estimated equation, and conversion equations were calculated.

Results: BMD values derived from contrast-enhanced phases using conversion equations adjusted for individual vessel iodine concentrations of VP and/or AA showed a high agreement with those from non-enhanced scans in Bland-Altman plots. Mean absolute errors (MAE) of DLCT-BMD were 3.57 mg/ml for the arterial (R = 0.989) and 3.69 mg/ml for the portal-venous phase (R = 0.987) (conventional BMD: 4.70 [R = 0.983] and 5.15 mg/ml [R = 0.981]). In the phase-independent analysis, MAE was 4.49 mg/ml for DLCT (R = 0.989) (conventional BMD: 4.82 mg/ml [R = 0.981]).

Conclusions: Converted BMD derived from contrast-enhanced DLCT examinations and adjusted for individual vessel iodine concentrations showed a high agreement with non-enhanced DLCT-BMD, suggesting that opportunistic BMD measurements are feasible even in non-dedicated contrast-enhanced DLCT examinations.

Key Points: • Accurate BMD values can be converted from contrast-enhanced DLCT scans, independent from the used scan phase. • DLCT-BMD measurements from contrast-enhanced scans should be adjusted with iodine concentrations of portal vein and/or abdominal aorta, which significantly improves the goodness-of-fit of conversion models.
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http://dx.doi.org/10.1007/s00330-020-07319-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043862PMC
May 2021
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