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Introduction: The aim of the study was to evaluate the effectiveness of cerclage in women with previous late miscarriages or premature births. The primary aim was to prolong pregnancy and achieve a term delivery. Secondarily, it was investigated whether an intervention after an early pathological 75-g-oGTT result influences these endpoints., Methods: A total of 133 cases were analyzed retrospectively. 80 women underwent primary cerclage between the 14th and 16th week of pregnancy; 53 women underwent secondary cerclage after cervical shortening of less than 25 mm. This group was further subdivided into therapeutic and emergency cerclage groups. Women with early pathologic 75-g-oGTT were treated diabetologically., Results: Primary cerclage prolonged pregnancy by 20.6 weeks and led to a term delivery in 51 women (63.8%). In the group with secondary cerclage, 25 women (47.2%) had a term delivery with a prolongation of 20.1 weeks. For amniotic sac prolapse, the prolongation was 7.9 weeks. Pathological 75-g-oGTT results were found in 63 women. Early intervention had no significant effect on prolongation and term delivery., Conclusion: Primary cerclage was more effective in achieving term delivery. Women with therapeutic cerclage without amniotic sac prolapse also benefited. With cervical shortening without prolapse, the prolongation was the same in both groups. The worst outcome was observed in emergency cerclage with amniotic sac prolapse. An early 75-g-oGTT is important in order to recognize and treat gestational diabetes in time., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Purpose: While the optimal delivery method of twin pregnancies is debated, the rate of cesarean deliveries is increasing. This retrospective study evaluates delivery methods and neonatal outcome of twin pregnancies during two time periods and aims to identify predictive factors for the delivery outcome., Methods: 553 twin pregnancies were identified in the institutional database of the University Women's Hospital Freiburg, Germany. 230 and 323 deliveries occurred in period I (2009-2014) and period II (2015-2021), respectively. Cesarean births due to non-vertex position of the first fetus were excluded. In period II, the management of twin pregnancies was reviewed; adjusted and systematic training with standardized procedures was implemented., Results: Period II showed significantly lower rates of planned cesarean deliveries (44.0% vs. 63.5%, p < 0.0001) and higher rates of vaginal deliveries (68% vs. 52.4%, p = 0.02). Independent risk factors for primary cesarean delivery were period I, maternal age > 40 years, nulliparity, a history with a previous cesarean, gestational age < 37 completed weeks, monochorionicity and increasing birth weight difference (per 100 g or > 20%). Predictive factors for successful vaginal delivery were previous vaginal delivery gestational age between 34 and 36 weeks and vertex/vertex presentation of the fetuses. The neonatal outcomes of period I and II were not significantly different, but planned cesareans in general were associated with increased admission rates to the neonatal intensive care units. Inter-twin interval had no significant impact on neonatal outcome., Conclusion: Structured regular training of obstetrical procedures may significantly reduce high cesarean rates and increase the benefit-risk ratio of vaginal deliveries., (© 2023. The Author(s).)

Purpose: Timely and accurate data on the epidemiology of sepsis are essential to inform policy decisions and research priorities. We aimed to investigate the validity of inpatient administrative health data (IAHD) for surveillance and quality assurance of sepsis care., Methods: We conducted a retrospective validation study in a disproportional stratified random sample of 10,334 inpatient cases of age ≥ 15 years treated in 2015-2017 in ten German hospitals. The accuracy of coding of sepsis and risk factors for mortality in IAHD was assessed compared to reference standard diagnoses obtained by a chart review. Hospital-level risk-adjusted mortality of sepsis as calculated from IAHD information was compared to mortality calculated from chart review information., Results: ICD-coding of sepsis in IAHD showed high positive predictive value (76.9-85.7% depending on sepsis definition), but low sensitivity (26.8-38%), which led to an underestimation of sepsis incidence (1.4% vs. 3.3% for severe sepsis-1). Not naming sepsis in the chart was strongly associated with under-coding of sepsis. The frequency of correctly naming sepsis and ICD-coding of sepsis varied strongly between hospitals (range of sensitivity of naming: 29-71.7%, of ICD-diagnosis: 10.7-58.5%). Risk-adjusted mortality of sepsis per hospital calculated from coding in IAHD showed no substantial correlation to reference standard risk-adjusted mortality (r = 0.09)., Conclusion: Due to the under-coding of sepsis in IAHD, previous epidemiological studies underestimated the burden of sepsis in Germany. There is a large variability between hospitals in accuracy of diagnosing and coding of sepsis. Therefore, IAHD alone is not suited to assess quality of sepsis care., (© 2023. The Author(s).)

Mitochondria are increasingly recognized as cellular hubs to orchestrate signaling pathways that regulate metabolism, redox homeostasis, and cell fate decisions. Recent research revealed a role of mitochondria also in innate immune signaling; however, the mechanisms of how mitochondria affect signal transduction are poorly understood. Here, we show that the NF-κB pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF-κB to the nucleus. TNF treatment induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1- and K63-linked ubiquitin chains are generated. NF-κB is locally activated and transported to the nucleus by mitochondria, leading to an increase in mitochondria-nucleus contact sites in a HOIP-dependent manner. Notably, TNF-induced stabilization of the mitochondrial kinase PINK1 furthermore contributes to signal amplification by antagonizing the M1-ubiquitin-specific deubiquitinase OTULIN. Overall, our study reveals a role for mitochondria in amplifying TNF-mediated NF-κB activation, both serving as a signaling platform, as well as a transport mode for activated NF-κB to the nuclear., (© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background: Soft-tissue sarcomas (STS) are rare malignancies of the soft tissue., Purpose: To assess whether the magnetic resonance imaging (MRI) configuration of primary STS can predict the configuration of a recurring tumor and whether the MRI configuration of multiple recurrences differs in one and the same patient., Material and Methods: Thirty-nine patients with histologically proven recurrent STS were included in this retrospective study and underwent pre- and post-treatment MRI. Three main configurations of primary and recurrent tumors were identified: polycyclic/multilobulated; ovoid/nodular; and streaky., Results: Sixty recurrent lesions were detected: 34 ovoid/nodular; 15 polycyclic/multilobulated; and 11 streaky. Five recurrences were multifocal and eight were bifocal. Of 39 patients, 28 (71.8%) presented one recurrence within the MRI follow-up period ( P  = 0.006); in 10 patients (25.6%), up to three different configurations of recurring STS were identified in one patient. Recurrences of polycyclic/multilobulated primaries were mostly ovoid/nodular (48%; P  = 0.003) or polycyclic/multilobulated (37%; P  = 0.014), and recurring ovoid/nodular STS significantly most often showed the same configuration as the primary tumor (85%; P  < 0.001). Primary STS with a streaky configuration recurred in all three configurations in roughly equal proportions. Homogeneity/heterogeneity and tumor borders are significantly associated with the configuration of recurrences., Conclusion: Primary STS configuration may help predict recurrent tumor configuration when the primary STS had a polycyclic/multilobulated or ovoid/nodular configuration. However, recurrent STS configuration can also differ from primary STS configuration, especially when the primary STS had a streaky configuration, rendering recurrent STS difficult to predict. Different configurations of recurrent STS in one and the same patient are common.

Background: Soft-tissue sarcomas (STS) are rare tumors of the soft tissue. Recent diagnostic studies on STS mainly dealt with only few cases of STS and did not investigate the post-therapeutic performance of MRI in a routine clinical setting. Therefore, we assessed the long-term diagnostic accuracy of MRI for detecting recurrent STS at a multidisciplinary sarcoma center., Methods: In all, 1055 postoperative follow-up MRIs of 204 patients were included in the study. MRI follow-up scans were systematically reviewed for diagnostic values (true-positive/-negative and false-positive/-negative results) in detecting recurrences. Pathological reports and follow-up MRIs were set as baseline references., Results: The median age of the patients was 55.3 ± 18.2 years. Of the patients, 34.8% presented with recurrences. Here, 65 follow-up scans were true positive, 23 false positive, 6 false negative, and 961 true negative. The overall sensitivity and specificity of MRI for detecting recurrences were 92 and 98%, respectively, with an accuracy of 97%. For intramuscular lesions and after surgery alone the sensitivity was higher (95 and 97%, respectively) than for subcutaneous lesions and surgery with additional radiation therapy (83 and 86%, respectively), at similarly high specificities (96-98%). The 6 false-negative results were found in streaky (n = 2) and small ovoid/nodular (n = 4) recurring lesions. The false-positive lesions imitated streaky (n = 14), ovoid/nodular (n = 8), and polycyclic/multilobulated recurring tumors (n = 1). All false-positive results were found in patients in whom the primary tumors were polycyclic/multilobulated in appearance., Conclusion: MRI shows a high diagnostic accuracy for detecting recurrent STS, with a high sensitivity and specificity. The diagnostic accuracy decreases in subcutaneous lesions and after surgery with radiation therapy, compared to intramuscular lesions and surgery alone. Radiologists should pay particular attention to streaky and small ovoid/nodular recurring lesions and patients with polycyclic/multilobulated primary tumors.

Purpose: To assess post-treatment subcutaneous edema, muscle edema, and seroma in MRI after soft-tissue sarcoma (STS) resection with regard to muscle involvement of STS and therapy., Methods: In all, 177 patients were included and received 1.5-T MRI follow-up examinations after treatment. Post-treatment changes were classified according to type of therapy (therapy 1-surgery; therapy 2-surgery with radiation therapy) and primary tumor localization in soft tissue (localization 1, subcutaneous tissue; localization 2, muscle involvement). Subcutaneous and muscle edema were divided into three grades: grade 0, absence of edema; grade 1, low-to-moderate edema; and grade 2, high-grade edema., Results: The mean age of the patients was 55.7 ± 18.2 years and the mean volume of the resected primary STS was 321.5 cm 3 . After therapy 1 of a sarcoma in localization 1, patients significantly more often showed low-grade subcutaneous tissue edema and an absence of muscle edema (p < 0.001) than high-grade edema. The risk for grade 2 subcutaneous tissue and muscle edema significantly increased with a tumor in localization 2 (RR = 2.58, p = 0.016 and RR = 15, p = 0.0065/RR = 2.05 , p = 0.021, respectively) and after therapy 2 (RR = 15, p = 0.0087 and RR = 2.05, p < 0.0001, respectively). Of the patients with sarcoma in localization 2, 88% developed grade 2 muscle edema after therapy 2; 40% of the patients developed post-treatment seroma. The risk for seroma is significantly higher after surgery and radiation therapy than after surgery alone (p < 0.001)., Conclusion: High-grade postoperative subcutaneous and muscle edema are significantly associated with muscle involvement of primary STS both in patients with and without radiation therapy. The risk for seroma is significantly higher after surgery with additional radiation therapy than after surgery alone., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The Parkin-coregulated gene ( PACRG ), which encodes a protein of unknown function, shares a bidirectional promoter with Parkin ( PRKN ), which encodes an E3 ubiquitin ligase. Because PRKN is important in mitochondrial quality control and protection against stress, we tested whether PACRG also affected these pathways in various cultured human cell lines and in mouse embryonic fibroblasts. PACRG did not play a role in mitophagy but did play a role in tumor necrosis factor (TNF) signaling. Similarly to Parkin, PACRG promoted nuclear factor κB (NF-κB) activation in response to TNF. TNF-induced nuclear translocation of the NF-κB subunit p65 and NF-κB-dependent transcription were decreased in PACRG-deficient cells. Defective canonical NF-κB activation in the absence of PACRG was accompanied by a decrease in linear ubiquitylation mediated by the linear ubiquitin chain assembly complex (LUBAC), which is composed of the two E3 ubiquitin ligases HOIP and HOIL-1L and the adaptor protein SHARPIN. Upon TNF stimulation, PACRG was recruited to the activated TNF receptor complex and interacted with LUBAC components. PACRG functionally replaced SHARPIN in this context. In SHARPIN-deficient cells, PACRG prevented LUBAC destabilization, restored HOIP-dependent linear ubiquitylation, and protected cells from TNF-induced apoptosis. This function of PACRG in positively regulating TNF signaling may help to explain the association of PACRG and PRKN polymorphisms with an increased susceptibility to intracellular pathogens., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies., (© 2019 The Authors.)

Elevated matrix metalloproteinase-7 (MMP-7) tissue expression and serum concentration have been shown to be associated with cancer progression and metastasis. The aim of our study was to assess the prognostic value of preoperative circulating MMP-7 levels in serum samples of patients with clinically localized prostate cancer. Furthermore, we compared the serum MMP-7 levels between patients with organ confined and metastatic prostate cancer. MMP-7 levels were measured in 93 patients with localized prostate cancer, 13 patients with distant bone metastasis and in sera of 19 controls using enzyme-linked immunosorbent assay. The results were compared to the clinical follow-up data. We did not find any significant difference in MMP-7 serum levels between patients and controls (p = 0.268). Circulating MMP-7 serum concentration was significantly elevated in patients with distant metastasis (p < 0.001). For the detection of distant prostate cancer metastasis, using a cut-off value of 3.7 ng/ml, a specificity of 69% and a sensitivity of 92% were observed. Multivariate analysis identified high MMP-7 serum concentration as an independent risk factor for prostate cancer-related death both in a preoperative and a postoperative model (p = 0.003 and 0.018, respectively). Furthermore, the evaluation of predictive models revealed that addition of serum MMP-7 levels to the preoperatively available predictors improves prognostic accuracy (the concordance index increased from 0.631 to 0.734 when MMP-7 was included). Based on these, we concluded that MMP-7 is a potential marker to identify patients with metastatic prostate cancer. In clinically localized prostate cancer, MMP-7 may provide independent prognostic information, thereby helping to optimize therapy decisions., (Copyright © 2010 UICC.)