No Radiographic Evidence of Medial Collateral Ligament Elongation in Valgus Osteoarthritic Knees Enables Treatment with Kinematically Aligned Total Knee Arthroplasty.

PURPOSE: When performing caliper-verified kinematically aligned total knee arthroplasty (KA TKA) in the osteoarthritic (OA) knee with valgus deformity, an elongated medial collateral ligament (MCL) could result in a valgus setting of the tibial component. The present study analyzed KA TKA in patients with valgus deformities (i.e., tibiofemoral angle > 10° valgus) and determined 1) the occurrence of radiograph-ic MCL elongation, 2) the incidence of lateral collateral ligament (LCL) and posterior cruciate ligament (PCL) release and the use of constrained components, and 3) whether the one-year Forgotten Joint Score (FJS), Oxford Knee Score (OKS), Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR), and Likert satisfaction score were comparable to KA TKAs for OA deformities ≤ 10° val-gus. METHODS: One hundred and two consecutive patients who underwent KA TKA by a single surgeon were analyzed radiographically and clinically at a minimum follow-up of 1 year. Radiographic MCL elongation was identified by a > 1° valgus orientation of the tibial component relative to the OA tibial joint line. RESULTS: Twenty-six patients had a radiographic anatomic tibiofemoral angle > 10° valgus (range of OA deformity 11° to 23° valgus). Seventy-six had an OA deformity ≤ 10° valgus (10° valgus to -14° varus). No patient had MCL elongation, a ligament release, or required constrained components. The median 78 FJS, 42 OKS, and 76 KOOS JR, and the 85% satisfaction rate of the patients with a > 10° OA valgus deformity were not significantly different from those with a ≤ 10° OA valgus deformity (p ≥ 0.17). CONCLUSIONS: Because MCL elongation was not detected in OA deformities up to 23° valgus, the risk of under-correcting the valgus deformity leading to instability and poor outcome scores is low when per-forming KA TKA using primary components without releasing the LCL and/or PCL.

Introducing Attribute Association Graphs to Facilitate Medical Data Exploration: Development and Evaluation Using Epidemiological Study Data.

BACKGROUND: Interpretability and intuitive visualization facilitate medical knowledge generation through big data. In addition, robustness to high-dimensional and missing data is a requirement for statistical approaches in the medical domain. A method tailored to the needs of physicians must meet all the abovementioned criteria. OBJECTIVE: This study aims to develop an accessible tool for visual data exploration without the need for programming knowledge, adjusting complex parameterizations, or handling missing data. We sought to use statistical analysis using the setting of disease and control cohorts familiar to clinical researchers. We aimed to guide the user by identifying and highlighting data patterns associated with disease and reveal relations between attributes within the data set. METHODS: We introduce the attribute association graph, a novel graph structure designed for visual data exploration using robust statistical metrics. The nodes capture frequencies of participant attributes in disease and control cohorts as well as deviations between groups. The edges represent conditional relations between attributes. The graph is visualized using the Neo4j (Neo4j, Inc) data platform and can be interactively explored without the need for technical knowledge. Nodes with high deviations between cohorts and edges of noticeable conditional relationship are highlighted to guide the user during the exploration. The graph is accompanied by a dashboard visualizing variable distributions. For evaluation, we applied the graph and dashboard to the Hamburg City Health Study data set, a large cohort study conducted in the city of Hamburg, Germany. All data structures can be accessed freely by researchers, physicians, and patients. In addition, we developed a user test conducted with physicians incorporating the System Usability Scale, individual questions, and user tasks. RESULTS: We evaluated the attribute association graph and dashboard through an exemplary data analysis of participants with a general cardiovascular disease in the Hamburg City Health Study data set. All results extracted from the graph structure and dashboard are in accordance with findings from the literature, except for unusually low cholesterol levels in participants with cardiovascular disease, which could be induced by medication. In addition, 95% CIs of Pearson correlation coefficients were calculated for all associations identified during the data analysis, confirming the results. In addition, a user test with 10 physicians assessing the usability of the proposed methods was conducted. A System Usability Scale score of 70.5% and average successful task completion of 81.4% were reported. CONCLUSIONS: The proposed attribute association graph and dashboard enable intuitive visual data exploration. They are robust to high-dimensional as well as missing data and require no parameterization. The usability for clinicians was confirmed via a user test, and the validity of the statistical results was confirmed by associations known from literature and standard statistical inference.

Learning debiased graph representations from the OMOP common data model for synthetic data generation.

BACKGROUND: Generating synthetic patient data is crucial for medical research, but common approaches build up on black-box models which do not allow for expert verification or intervention. We propose a highly available method which enables synthetic data generation from real patient records in a privacy preserving and compliant fashion, is interpretable and allows for expert intervention. METHODS: Our approach ties together two established tools in medical informatics, namely OMOP as a data standard for electronic health records and Synthea as a data synthetization method. For this study, data pipelines were built which extract data from OMOP, convert them into time series format, learn temporal rules by 2 statistical algorithms (Markov chain, TARM) and 3 algorithms of causal discovery (DYNOTEARS, J-PCMCI+, LiNGAM) and map the outputs into Synthea graphs. The graphs are evaluated quantitatively by their individual and relative complexity and qualitatively by medical experts. RESULTS: The algorithms were found to learn qualitatively and quantitatively different graph representations. Whereas the Markov chain results in extremely large graphs, TARM, DYNOTEARS, and J-PCMCI+ were found to reduce the data dimension during learning. The MultiGroupDirect LiNGAM algorithm was found to not be applicable to the problem statement at hand. CONCLUSION: Only TARM and DYNOTEARS are practical algorithms for real-world data in this use case. As causal discovery is a method to debias purely statistical relationships, the gradient-based causal discovery algorithm DYNOTEARS was found to be most suitable.

Bilateral Acute Macular Neuroretinopathy (AMN) after COVID-19 and its Clinical Course. / Bilaterale akute makuläre Neuroretinopathie (AMN) nach COVID-19 und Verlauf.

Acute macular neuroretinopathy (AMN) is a rare disease entity. It is mainly observed in young women with a history of influenza-like infection or who have been taking oral contraceptives for several years. Patients typically describe subjective visual deterioration and mono- or bilateral paracentral relative scotomas. In some cases, funduscopic ophthalmic examination may reveal subtle sharply demarcated flat lesions of reddish-brown or orange colour in the macular region. Diagnosis is usually made by near-infrared fundus imaging which shows hyporeflective areas, and SD-OCT imaging which manifests changes in the outer retinal layers. In the following, three patient cases with bilateral AMN are described which occurred in direct temporal relationship to a recent SARS-CoV-2 infection.

Bispecific antibody CD73xEGFR more selectively inhibits the CD73/adenosine immune checkpoint on cancer cells and concurrently counteracts pro-oncogenic activities of CD73 and EGFR.

BACKGROUND: CD73 is an ecto-enzyme that is involved in the conversion of pro-inflammatory extracellular ATP (eATP) excreted by cancer cells under stress to anti-inflammatory adenosine (ADO). A broad variety of solid cancer types was shown to exploit CD73 overexpression as a suppressive immune checkpoint. Consequently, CD73-antagonistic antibodies, most notably oleclumab, are currently evaluated in several multicenter trials for clinical applicability. However, the efficacy of conventional monospecific CD73-inhibiting antibodies may be limited due to on-target/off-tumor binding to CD73 on normal cells. Therefore, a novel approach that more selectively directs CD73 immune checkpoint inhibition towards cancer cells is warranted. METHODS: To address this issue, we constructed a novel tetravalent bispecific antibody (bsAb), designated bsAb CD73xEGFR. Subsequently, the anticancer activities of bsAb CD73xEGFR were evaluated using in vitro and in vivo tumor models. RESULTS: In vitro treatment of various carcinoma cell types with bsAb CD73xEGFR potently inhibited the enzyme activity of CD73 (~71%) in an EGFR-directed manner. In this process, bsAb CD73xEGFR induced rapid internalization of antigen/antibody complexes, which resulted in a prolonged concurrent displacement of both CD73 and EGFR from the cancer cell surface. In addition, bsAb CD73xEGFR sensitized cancer to the cytotoxic activity of various chemotherapeutic agents and potently inhibited the proliferative/migratory capacity (~40%) of cancer cells. Unexpectedly, we uncovered that treatment of carcinoma cells with oleclumab appeared to enhance several pro-oncogenic features, including upregulation and phosphorylation of EGFR, tumor cell proliferation (~20%), and resistance towards cytotoxic agents and ionizing radiation (~39%). Importantly, in a tumor model using immunocompetent BALB/c mice inoculated with syngeneic CD73pos/EGFRpos CT26 cancer cells, treatment with bsAb CD73xEGFR outperformed oleclumab (65% vs 31% tumor volume reduction). Compared with oleclumab, treatment with bsAb CD73xEGFR enhanced the intratumoral presence of CD8pos T cells and M1 macrophages. CONCLUSIONS: BsAb CD73xEGFR outperforms oleclumab as it inhibits the CD73/ADO immune checkpoint in an EGFR-directed manner and concurrently counteracts several oncogenic activities of EGFR and CD73. Therefore, bsAb CD73xEGFR may be of significant clinical potential for various forms of difficult-to-treat solid cancer types.

Impact of COVID-19 on Fracture Incidence in Germany: A Comparative Age and Gender Analysis of Pre- and Post-Outbreak Periods.

In March 2020, Germany imposed a nationwide lockdown to curb the spread of COVID-19, prompting questions about the impact on the incidence of common fractures. This study examined 15 fracture types in pre-outbreak (2010-2019) and post-outbreak (2020-2021) periods, using data categorized by age (18-64 years, >65 years) and sex (male, female). Linear regression assessed annual growth rates, and mean fracture numbers were compared across periods for significant differences. Results indicated a positive correlation between fracture incidence rates and time for various types, such as cervical, thoracic, lumbar, and pelvic spine fractures, rib fractures, femoral neck, pertrochanteric femur, femoral shaft, and ankle fractures. Frequencies of proximal humerus, distal radius, femoral neck, pertrochanteric femur, femoral shaft, and ankle fractures in 2020 and 2021 were within predicted ranges from previous years. However, rib fractures and spinal fractures (cervical, thoracic, lumbar, and pelvic spine) occurred less frequently during this time. Notably, this study found a consistent decline in most fracture types for individuals aged 18-64 after the pandemic's onset, while the fracture incidence of hip fractures, often referred to as fragility fractures, for those over 65 remained unchanged. Fibula fractures showed the most considerable decrease in both age groups. In conclusion, the COVID-19 pandemic substantially impacted fracture incidence, with lower rates among individuals under 65 and unchanged fragility fractures in the elderly population.

A Novel Bispecific Antibody for EpCAM-Directed Inhibition of the CD73/Adenosine Immune Checkpoint in Ovarian Cancer.

PD-1/PD-L1-inhibiting antibodies have shown disappointing efficacy in patients with refractory ovarian cancer (OC). Apparently, OC cells exploit nonoverlapping immunosuppressive mechanisms to evade the immune system. In this respect, the CD73-adenosine inhibitory immune checkpoint is of particular interest, as it rapidly converts pro-inflammatory ATP released from cancer cells to immunosuppressive adenosine (ADO). Moreover, cancer-cell-produced ADO is known to form a highly immunosuppressive extra-tumoral 'halo' that chronically inhibits the anticancer activity of various immune effector cells. Thus far, conventional CD73-blocking antibodies such as oleclumab show limited clinical efficacy, probably due to the fact that it indiscriminately binds to and blocks CD73 on a massive surplus of normal cells. To address this issue, we constructed a novel bispecific antibody (bsAb) CD73xEpCAM that inhibits CD73 expressed on the OC cell surface in an EpCAM-directed manner. Importantly, bsAb CD73xEpCAM showed potent capacity to inhibit the CD73 enzyme activity in an EpCAM-directed manner and restore the cytotoxic activity of ADO-suppressed anticancer T cells. Additionally, treatment with bsAb CD73xEpCAM potently inhibited the proliferative capacity of OC cells and enhanced their sensitivity to cisplatin, doxorubicin, 5FU, and ionizing radiation. BsAb CD73xEpCAM may be useful in the development of tumor-directed immunotherapeutic approaches to overcome the CD73-mediated immunosuppression in patients with refractory OC.

Isolated non-immune hydrops fetalis: an observational study on complete spontaneous resolution, perinatal outcome, and long-term follow-up.

PURPOSE: The aim of our study was to investigate spontaneous resolution and postnatal outcome in non-immune hydrops fetalis (NIHF). We specifically studied NIHF cases that occurred without any other anomalies in the prenatal diagnostic workup, defined as isolated NIHF (iNIHF). METHODS: To identify iNIHF we retrospectively classified prenatal findings of 700 NIHF singletons, diagnosed in our prenatal referral center between 1997 and 2016. We studied the occurrence of prenatal resolution in iNIHF and linked it to the perinatal outcome. We obtained long-term outcome by contacting the parents, children, and the pediatricians and listed all functional and structural anomalies and temporary logopedic, psychosocial and motoric impairments. RESULTS: Among 70 iNIHF cases, 54 (77.1%) resolved completely prenatally. The baby-take-home rate was 98.1% in these cases. In contrast, the baby-take-home rate in the subgroup without complete resolution was 25.0%. We achieved pediatric long-term outcome in 27 of 57 survivors (47.4%) of iNIHF with a mean follow-up period of 10.9 years. Among these 27 children, fetal hydrops had completely resolved prenatally in 26 cases and had regressed to a mild effusion in one case. In the pediatric development, two children had significant functional impairment and two children showed recurrent skin edema. CONCLUSION: Complete spontaneous resolution was the most common intrauterine course of iNIHF in our collective. Completely resolved iNIHF had a favorable perinatal outcome in our study. Our data on the long-term outcomes are consistent with the assumption of an increased rate of functional impairments. TRIAL REGISTRY: Internal study number of Heinrich-Heine-University, Duesseldorf: 6177R. Date of registration: December 2017.

Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue

Post-COVID-19 syndrome (PCS) summarizes persisting sequelae after infection with the severe-acute-respiratory-syndrome-Coronavirus-2 (SARS-CoV-2). PCS can affect patients of all covid-19 disease severities. As previous studies revealed impaired blood flow as a provoking factor for triggering PCS, it was the aim of the present study to investigate a potential association of self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT-Angiography (OCT-A) and quantified by the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic Fatigue (CF) was assessed with the variables Bell score, age and gender. The VD in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed considering the repetitions (12 times). Taking in account of such repetitions a mixed model was performed to detect possible differences in the least square means between different groups of analysis. An age effect on VD was observed between patients and controls (p<0.0001). Gender analysis yielded that women with PCS showed lower VD levels in SVP compared to male patients (p=0.0015). The PCS patients showed significantly lower VD of ICP as compared to the controls (p=0.0001, [CI: 0.32; 1]). Moreover, considering PCS patients, the mixed model reveals a significant difference between chronic fatigue (CF) and without CF in VD of SVP (p=0.0033, [CI: -4.5; -0.92]). The model included age, gender and the variable Bell score, representing a subjective marker for CF. Consequently, the retinal microcirculation might be an objective biomarker in subjective-reported chronic fatigue of patients with PCS.

Identification of critical control points for antibiotic resistance discharge in sewers.

Disrupting the spread of clinically relevant antibiotic resistance genes (ARGs) is one of the key components for the success of the One Health strategy. While waste water treatment plants (WWTPs) represent a final control point for daily discharges of antibiotic resistance genes (ARGs) to the aquatic environment, a decentralized upstream monitoring of wastewater feeds of selected urban drainage areas for blaCTX-M32, blaCTX-M15, blaOXA48, blaCMY-2, mecA, blaNDM-1, blaKPC3, vanA, and mcr-1 representing clinically relevant ARGs has been performed. Besides hospitals, also retirement homes were found to be responsible for high levels of ARG discharges compared to housing area sewer systems. The monitoring combines qPCR-based quantifications, flow volume-based analyses, and multiple antibiotic resistance analyses of isolates. As result of the study, local actions at identified critical control points could help to prevent contaminations of larger volumes of wastewaters. This strategy will support a more cost-effective treatment compared to central actions at WWTPs, only. A polluter-pays principle should be applied by this monitoring strategy.

Detection of therapeutically relevant and concomitant rare somatic variants in colorectal cancer.

In colorectal cancer (CRC), clinically relevant biomarkers are known for genome-guided therapy that can be detected by both first and next generation methods. The aim of our work was to introduce a robust NGS assay that will be able to detect, in addition to standard predictive single nucleotide-based biomarkers, even rare and concomitant clinically relevant variants. Another aim was to identify truncating mutations in APC and pathogenic variants in TP53 to divide patients into potentially prognostic groups. A multigene panel with hotspots in 50 cancer-critical genes was used. Finally, 86 patients diagnosed with primary or metastatic colorectal cancer were enrolled. In total, there were identified 163 pathogenic variants, among them in the genes most recurrent mutated in CRC such as TP53 (49%), the RAS family genes KRAS and NRAS (47%), APC (43%), and PIK3CA (15%). In 30 samples, two driver mutations were present in one sample, 11 patients were without any mutations covered by this panel. In one patient, a novel variant in BRAF p.D594E was found, not previously seen in CRC, and was concomitant with KRAS p.G12A. In KRAS, a potentially sensitive mutation to anti-EGFR therapy p.A59T was found along with the PIK3CA missense variant p.E545K. It was possible to divide patients into groups based on the occurrence of truncating APC variant alone or concomitant with TP53 or KRAS. Our results demonstrate the potential of small multigene panels that can be used in diagnostics for the detection of rare therapeutically relevant variants. Moreover, the division of patients into groups based on the presence of APC and TP53 mutations enables this panel to be used in retrospective studies on the effectiveness of treatment with anti-EGFR inhibitors.

Antibiotic-resistant bacteria, antibiotic resistance genes, and antibiotic residues in wastewater from a poultry slaughterhouse after conventional and advanced treatments.

Slaughterhouse wastewater is considered a reservoir for antibiotic-resistant bacteria and antibiotic residues, which are not sufficiently removed by conventional treatment processes. This study focuses on the occurrence of ESKAPE bacteria (Enterococcus spp., S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, Enterobacter spp.), ESBL (extended-spectrum ß-lactamase)-producing E. coli, antibiotic resistance genes (ARGs) and antibiotic residues in wastewater from a poultry slaughterhouse. The efficacy of conventional and advanced treatments (i.e., ozonation) of the in-house wastewater treatment plant regarding their removal was also evaluated. Target culturable bacteria were detected only in the influent and effluent after conventional treatment. High abundances of genes (e.g., blaTEM, blaCTX-M-15, blaCTX-M-32, blaOXA-48, blaCMY and mcr-1) of up to 1.48 × 106 copies/100 mL were detected in raw influent. All of them were already significantly reduced by 1-4.2 log units after conventional treatment. Following ozonation, mcr-1 and blaCTX-M-32 were further reduced below the limit of detection. Antibiotic residues were detected in 55.6% (n = 10/18) of the wastewater samples. Despite the significant reduction through conventional and advanced treatments, effluents still exhibited high concentrations of some ARGs (e.g., sul1, ermB and blaOXA-48), ranging from 1.75 × 102 to 3.44 × 103 copies/100 mL. Thus, a combination of oxidative, adsorptive and membrane-based technologies should be considered.

Determination of antibiotic resistance genes in a WWTP-impacted river in surface water, sediment, and biofilm: Influence of seasonality and water quality.

Many pathogenic bacteria are adapted to live in aquatic habitats, which makes rivers possible sources and spread pathways of antibiotic resistance, since they usually receive effluents from wastewater treatment plants (WWTP), possibly containing antibiotic residues and also antibiotic-resistant bacteria. This study investigates different monitoring strategies to identify the occurrence of antibiotic-resistant bacteria in rivers. We analyzed the presence of 13 antibiotic resistance genes (ARGs) and seven gene markers for facultative pathogenic bacteria (FPB) with qPCR in sampling sites upstream and downstream of a small WWTP in Southern Germany. Five sampling campaigns were conducted from February to June 2019. Surface water, sediment, and biofilm samples were analyzed. The biofilm was collected from an artificial sampler placed in the river. blaTEM, ermB, tetM, and sul1 genes were detected in all samples analyzed. The results showed there was a previous background in the river, but the WWTP and the water quality of the river influenced the concentration and occurrence of ARGs and FPB. Genes representing resistance against strong or last-resort antibiotics, such as mecA, blaCMY-2, blaKPC-3, and mcr-1, and multidrug resistance were also detected, mainly in samples collected downstream of the WWTP. Downstream of the WWTP, the occurrence of ARG and FPB correlated with ammoniacal nitrogen, while upstream of the WWTP correlated with turbidity, suspended solids, and seasonal factors such as UVA radiation and the presence of macrophytes. Biofilm samples presented higher abundances of ARGs and FPB. The biofilm sampler was efficient and allowed to collect biofilms from specific periods, which helped to identify seasonal patterns.

Evaluation of antibiotic resistance dissemination by wastewater treatment plant effluents with different catchment areas in Germany.

The study quantified the abundances of antibiotic resistance genes (ARGs) and facultative pathogenic bacteria (FPB) as well as one mobile genetic element in genomic DNA via qPCR from 23 different wastewater treatment plant (WWTP) effluents in Germany. 12 clinically relevant ARGs were categorized into frequently, intermediately, and rarely occurring genetic parameters of communal wastewaters. Taxonomic PCR quantifications of five FPB targeting Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, and enterococci were performed. The WWTPs differed in their catchment areas being impacted by hospitals, food processing companies, or housing areas only. The total discharges of the analyzed ARGs and FPB were found to cluster independently of the sizes of the WWTPs with a maximum difference of two log units within one cluster. Initially, quantitative data evaluations revealed no significant difference between ARG categories and WWTP catchment areas. More distinct correlations became obvious with a Pearson correlation approach, where each single taxonomic marker is compared to each ARG target. Here, increased correlation of FPB (i.e. E. coli, K. pneumoniae, P. aeruginosa, and enterococci) with clinically relevant ARGs of the category of rarely occurring resistance genes (blaNDM-1, vanA) was found in WWTP effluents being influenced by hospital wastewaters.

Concordance-analysis and evaluation of different diagnostic algorithms used in first trimester screening for late-onset preeclampsia.

Objective: Concordance-analysis and evaluation of existing algorithms detecting late-onset preeclampsia during first trimester screeningMethods: Retrospective cohort study investigating risk algorithms of late-onset preeclampsia during first trimester screening in a German prenatal center. Three previously developed algorithms including anamnestic factors (Apriori) and biophysical markers (BioM) were investigated by using detection rates (DR) with fixed FPR 10% and fixed cutoff >1:100. Furthermore, we set up a concordance-analysis of test results in late-onset preeclampsia cases to examine the effect of influencing factors and to detect potential weaknesses of the algorithms. Therefore, we modeled the probability of discordances as a function of the influencing factors based on a logistic regression, that was fitted using a Bayesian approach.Results: 6,113 pregnancies were considered, whereof 700 have been excluded and 5,413 pregnancies were analyzed. 98 (1.8%) patients developed preeclampsia (79 late-onsets, 19 early-onsets). The Apriori-algorithm reaches a DR of 34.2%, by adding BioM (MAP and UtA-PI) the DR improves to 57.0% (FPR of 10%). In concordance-analysis of Apriori algorithm and Apriori+BioM algorithms, influencing factor BMI<25 increases the chance of discordances sigificantly. Additional, in the subgroup of late-onset preeclampsias with BMI<25 the DR is higher in Apriori+BioM algorithms than in Apriori algorithm alone. If both compared algorithms include BioM, influencing factor MAP decreases the chance of discordances significantly. All other tested influencing factors do not have a statistically significant effect on discordancesConclusion: Normal-weight patients benefit more from the integration of MAP and UtA-PI compared to overweight/obese patients.

Markers of liver regeneration-the role of growth factors and cytokines: a systematic review.

BACKGROUND: Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. METHODS: MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. RESULTS: Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. CONCLUSION: High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.

Dissemination prevention of antibiotic resistant and facultative pathogenic bacteria by ultrafiltration and ozone treatment at an urban wastewater treatment plant.

Conventional wastewater treatment is not sufficient for the removal of hygienically relevant bacteria and achieves only limited reductions. This study focuses on the reduction efficiencies of two semi-industrial ultrafiltration units operating at a large scale municipal wastewater treatment plant. In total, 7 clinically relevant antibiotic resistance genes, together with 3 taxonomic gene markers targeting specific facultative pathogenic bacteria were analysed via qPCR analyses before and after advanced treatment. In parallel with membrane technologies, an ozone treatment (1 g ozone/g DOC) was performed for comparison of the different reduction efficiencies. Both ultrafiltration units showed increased reduction efficiencies for facultative pathogenic bacteria and antibiotic resistance genes of up to 6 log units, resulting mostly in a strong reduction of the bacterial targets. In comparison, the ozone treatment showed some reduction efficiency, but was less effective compared with ultrafiltration due to low ozone dosages frequently used for micro-pollutant removal at municipal wastewater treatment plants. Additionally, metagenome analyses demonstrated the accumulation of facultative pathogenic bacteria, antibiotic resistance genes, virulence factor genes, and metabolic gene targets in the back flush retentate of the membranes, which opens further questions about retentate fluid material handling at urban wastewater treatment plants.

Antibiotic resistance genes in treated wastewater and in the receiving water bodies: A pan-European survey of urban settings.

There is increasing public concern regarding the fate of antibiotic resistance genes (ARGs) during wastewater treatment, their persistence during the treatment process and their potential impacts on the receiving water bodies. In this study, we used quantitative PCR (qPCR) to determine the abundance of nine ARGs and a class 1 integron associated integrase gene in 16 wastewater treatment plant (WWTP) effluents from ten different European countries. In order to assess the impact on the receiving water bodies, gene abundances in the latter were also analysed. Six out of the nine ARGs analysed were detected in all effluent and river water samples. Among the quantified genes, intI1 and sul1 were the most abundant. Our results demonstrate that European WWTP contribute to the enrichment of the resistome in the receiving water bodies with the particular impact being dependent on the effluent load and local hydrological conditions. The ARGs concentrations in WWTP effluents were found to be inversely correlated to the number of implemented biological treatment steps, indicating a possible option for WWTP management. Furthermore, this study has identified blaOXA-58 as a possible resistance gene for future studies investigating the impact of WWTPs on their receiving water.

Technical Aspects of Stapled Hepatectomy in Liver Surgery: How We Do It.

There are diverse approaches to parenchymal transection and the preferred approach remains controversial among liver surgeons. Stapling devices, which were initially established for vascular control, have been the standard parenchymal transection technique in many departments for more than 15 years. This article describes the technical aspects, tips, and tricks of stapled hepatectomy using right hemihepatectomy as an example. The existing literature on this topic is also reviewed.

Urinary Outcomes in Patients with Down's Syndrome and Hirschsprung's Disease.

INTRODUCTION: Previous research in children with Hirschsprung's disease (HD) and Down's syndrome (DS) has focused on colorectal outcomes. We set out to review urinary outcomes in this patient group. MATERIALS AND METHODS: The medical records of all patients aged five years and older with HD were reviewed, and patients and caregivers filled out the Vancouver Symptom Score at intake, which is designed and validated to diagnose dysfunctional elimination syndrome. RESULTS: A total of 104 patients with HD were included in this study. Of these, 16 (15%) patients had DS. There were no significant differences in the prevalence of enterocolitis or colorectal symptoms between patients with or without DS. Five of 88 (6%) patients without DS and 7 of 16 (44%) (p = 0.00001) with DS reported having urinary accidents. Patients with HD and DS scored higher on the Vancouver score (9 vs. 17.5; p = 0.007), indicating more severe urinary symptoms. Patients who also reported fecal accidents scored significantly higher on the Vancouver (12 vs. 9; n = 61; p = 0.016), indicating more problems. CONCLUSION: Patients with DS appear to be a unique subset of HD patients who have a higher prevalence of urinary symptoms after surgery. In the postoperative care of patients with HD and DS, a strong focus should be placed on postoperative urinary care in addition to their bowel care. This could significantly ease care and contribute to the quality of life of the parents and the patient.