BACKGROUND:Clostridioides difficile infection (CDI) is a major cause of healthcare-associated diarrhoea with significant morbidity and mortality worldwide. In Germany, CDI incidence has declined in recent years. However, prospective multi-centre data on all-cause in-hospital mortality among CDI patients and on risk factors for death remain scarce. METHODS:We conducted a prospective multi-centre surveillance study in six German university hospitals between 2016 and 2020 to assess all-cause in-hospital mortality among CDI patients. Additionally, multi-variable logistic regression was used to identify risk factors for death. RESULTS:A total of 3592 CDI cases were recorded, of whom 46.7% were female. Overall all-cause in-hospital mortality was 11.7%, whereas CDI-attributable mortality was 0.4% (N = 16). Independent risk factors for death in CDI patients included increasing age (3% per year, adjusted odds ratio [aOR]: 1.03, 95% confidence interval [CI]: 1.02-1.04), longer hospital stay (1% per day, aOR: 1.01, 95% CI: 1.00-1.01), admission to internal medicine (aOR: 1.60, 95% CI: 1.32-1.94) or haematology-oncology (aOR: 2.38, 95% CI: 1.75-3.24) as proxies for patient complexity, and elevated creatinine levels within ± 2 days of sampling (6% per mg/dL, aOR: 1.06, 95% CI: 0.99-1.13). In contrast, diagnosis on a general ward (vs intensive care unit or intermediate care, irrespective of speciality) was associated with a lower risk of death (aOR: 0.34, 95% CI: 0.28-0.42). CONCLUSIONS:Our study provides a comprehensive assessment of all-cause in-hospital mortality among CDI patients in Germany. By identifying robust and easily accessible risk factors for death, our findings support improved risk stratification and may inform targeted management strategies for high-risk patient populations.

OBJECTIVE:Antibiotic de-escalation (ADE) is a key antimicrobial stewardship quality indicator. We aimed to evaluate the rate and patterns of ADE among clinically stable patients with bloodstream infection. METHODS:We analysed secondary data from two prospective multicentre cohort studies, BLOOMY and BLOOMY-PREDICT. ADE was assessed among patients eligible for safe ADE on day 5 after index blood culture. Narrowing of antibiotic spectrum was determined by a ranking based on WHO AWaRe-classification. Risk factors for not performing ADE (non-ADE) were studied using multivariable logistic regression. RESULTS:In total, 937 of 3824 study patients (24.50%) were eligible, of which 218 (23.27%) did not have an option for de-escalation based on antimicrobial susceptibility testing. Of 719 patients in which ADE was feasible, only 406 (56.47%) received ADE. Empiric monotherapy (OR [95% CI] = 5.68 [3.77-8.56], P < 0.001), Gram-negative pathogen (OR 2.27 [1.60-3.24], P < 0.001), healthcare-associated infection (OR 1.55 [1.01-2.39], P = 0.046), and hospital-acquisition (OR 1.63 [1.02-2.61], P = 0.042) were identified as independent factors associated with non-ADE. Conversely, ICU treatment on day 0 (OR 0.60 [0.38-0.95], P = 0.029) was independently associated with de-escalation, alongside a strong study centre effect (OR 0.26 [0.15-0.44], P < 0.001). Further, in-hospital mortality was not associated with ADE (46/406, 11.33% vs. 29/313, 9.27%, P = 0.369). Low ADE rates in patients with urogenital focus and unnecessary carbapenem use were issues of particular concern in our cohort. CONCLUSIONS:Available opportunities for ADE were frequently missed in our setting, especially in Gram-negative bloodstream infection. Antimicrobial stewardship efforts should therefore be strengthened to promote ADE.

Mortality in Staphylococcus aureus bloodstream infections (BSI) is high. While clinical scores and host risk factors have been evaluated in large clinical cohorts, the relevance of the plethora of virulence factors produced by S. aureus for BSI mortality has remained elusive. By combining a comprehensive, standardized clinical data set with whole genome sequencing analysis of 643 S. aureus isolates from a multicentric BSI study and applying logistic regression analyses, we identified proteins associated with both increased and decreased in-hospital mortality. Adjustment with two clinical severity scores and sex revealed a diverse set of 116 staphylococcal proteins involved in immune modulation, metal homeostasis, adhesion, transcription, and translation (among other functions) as prognostic markers for in-hospital mortality. But also several uncharacterized proteins were associated with in-hospital mortality. Nine predictive proteins were confirmed with an orthogonal statistical approach. Most of the identified proteins have not previously been linked to infection outcomes and represent promising candidates for predictive biomarkers.

OBJECTIVES:Infection prevention and control (IPC) and antimicrobial stewardship (AMS) measures are critical to reducing transmission and infection by Clostridioides difficile (CDI) and other enteric pathogens. This study evaluated the impact of enhanced IPC and AMS on CDI and bloodstream infections (BSIs) caused by vancomycin-resistant enterococci (VRE) and third-generation cephalosporin-resistant Enterobacterales (3GCREB). METHODS:The study was conducted in five German university hospitals from January 2016 to July 2019. IPC and AMS interventions were sequentially enhanced in three departments with high-incidence CDI at baseline using a stepped-wedge cluster intervention approach. Main outcome measures were incidence densities of CDI and BSI caused by VRE and 3GCREB. An interrupted time series analysis was performed to assess the intervention effects during a normalized study period. RESULTS:Across 15 departments, >384,000 patient days were included. Incidence density of target infections was low (CDI, 0.77; VRE BSI, 0.07; and 3GCREB BSI, 0.09 per 1000 patient days). Pooled interrupted time series analysis results showed a significant reduction in CDI incidence density following the enhancement of AMS measures (AMS period regression slopes difference, -0.089; F[p] = 5.400 [0.037]). Regarding the incidence density of VRE/3GCREB BSI, no relevant changes could be observed (regression slopes difference, -0.19; F[p] = 0.667 [0.429]). A subgroup analysis focusing on haematological and oncological departments showed that AMS influenced prescription behaviour according to implemented AMS strategies, but not clinical outcomes. DISCUSSION:Combined with IPC enhanced short-term AMS measures led to a significant reduction in the incidence of CDI, whereas the incidence of BSI by VRE and 3GCREB remained unchanged in sites with well-established baseline IPC and AMS programmes and low incidence of hospital-associated infections.

Objectives To analyse recent epidemiological trends of bloodstream infections (BSI) caused by Enterococcus spp. In adult patients admitted to tertiary care centres in Germany. Methods Epidemiological data from the multicentre R-NET study was analysed. Patients presenting with E. faecium or E. faecalis in blood cultures in six German tertiary care university hospitals between October 2016 and June 2020 were prospectively evaluated. In vancomycin-resistant enterococci (VRE), the presence of vanA / vanB was confirmed via molecular methods. Results In the 4-year study period, 3001 patients with BSI due to Enterococcus spp. were identified. E. faecium was detected in 1830 patients (61%) and E. faecalis in 1229 patients (41%). Most BSI occurred in (sub-) specialties of internal medicine. The pooled incidence density of enterococcal BSI increased significantly (4.0 to 4.5 cases per 10,000 patient days), which was primarily driven by VRE BSI (0.5 to 1.0 cases per 10,000 patient days). In 2020, the proportion of VRE BSI was > 12% in all study sites (range, 12.8–32.2%). Molecular detection of resistance in 363 VRE isolates showed a predominance of the vanB gene (77.1%). Conclusion This large multicentre study highlights an increase of BSI due to E. faecium , which was primarily driven by VRE. The high rates of hospital- and ICU-acquired VRE BSI point towards an important role of prior antibiotic exposure and invasive procedures as risk factors. Due to limited treatment options and high mortality rates of VRE BSI, the increasing incidence of VRE BSI is of major concern.

Background: For Clostridioides difficile infections (CDIs) in Germany no longitudinal multi-centre studies with standardized protocols for diagnosing CDI are available. Recent evaluations of general surveillance databases in Germany indicate a downward trend in CDI rates. We aimed to describe the actual burden and trends of CDI in German university hospitals from 2016 to 2020. Methods: Our study was a prospective multi-centre study covering six German university hospitals. We report the data in total, stratified by year, by medical specialty as well as by CDI severity. Multi-variable regression analyses were performed to assess risk factors for severe CDI. Results: We registered 3780 CDI cases among 1,436,352 patients. The median length of stay (LOS) of CDI cases was 20 days (interquartile range 11-37) compared with a general LOS of 4.2 days. In-hospital all-cause mortality in CDI patients was 11.7% (N = 444/3780), while mortality attributed to CDI was 0.4% (N = 16/3761). CDI recurrence rate was comparatively low at 7.2%. The incidence density of severe healthcare-associated healthcare onset (HAHO)-CDI showed a significant decrease from 2.25/10,000 patient days (pd) in 2016 to 1.49/10,000 pd in 2020 (trend calculation P=0.032). Conclusions: Compared with a European point-prevalence study in 2013/2014, where overall CDI incidence density was 11.2 cases/10,000 pd in Germany (EUCLID), we see in our study halved overall CDI rates of 5.6 cases/10,000 pd in 2020. Our study shows current data on the distribution of CDI cases in German university hospitals and thus provides international comparative data on the key indicators of CDI. under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Objectives: Assessment of vancomycin-resistant Enterococcus faecium (VREfm) prevalence upon hospital admission and analysis of risk factors for colonization. Methods: From 2014 to 2018, patients were recruited within 72 hours of admission to seven participating German university hospitals, screened for VREfm and questioned for potential risk factors (prior multidrug-resistant organism detection, current/prior antibiotic consumption, prior hospital, rehabilitation or long-term care facility stay, international travel, animal contact and proton pump inhibitor [PPI]/antacid therapy). Genotype analysis was done using cgMLST typing. Multivariable analysis was performed. Results: In 5 years, 265 of 17,349 included patients were colonized with VREfm (a prevalence of 1.5%). Risk factors for VREfm colonization were age (adjusted OR [aOR], 1.02; 95% CI, 1.01-1.03), previous (aOR, 2.71; 95% CI, 1.87-3.92) or current (aOR, 2.91; 95% CI, 2.60-3.24) antibiotic treatment, prior multidrugresistant organism detection (aOR, 2.83; 95% CI, 2.21-3.63), prior stay in a long-term care facility (aOR, 2.19; 95% CI, 1.62-2.97), prior stay in a hospital (aOR, 2.91; 95% CI, 2.05-4.13) and prior consumption of PPI/antacids (aOR, 1.29; 95% CI, 1.18-1.41). Overall, the VREfm admission prevalence increased by 33% each year and 2% each year of life. 250 of 265 isolates were genotyped and 141 (53.2%) of the VREfm were the emerging ST117. Multivariable analysis showed that ST117 and non-ST117 VREfm colonized patients differed with respect to admission year and prior multidrug-resistant organism detection. Discussion: Age, healthcare contacts and antibiotic and PPI/antacid consumption increase the individual risk of VREfm colonization. The VREfm admission prevalence increase in Germany is mainly driven by the emergence of ST117. Anna M. Rohde, Clin Microbiol Infect 2023;29:515 (c) 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Objectives To analyse the influence of antibiotic consumption on healthcare-associated healthcare onset (HAHO) Clostridioides difficile infection (CDI) in a German university hospital setting. Methods Monthly ward-level antibiotic consumption measured in DDD/100 patient days (pd) and CDI surveillance data from five university hospitals in the period 2017 through 2019 were analysed. Uni- and multivariable analyses were performed with generalized estimating equation models. Results A total of 225 wards with 7347 surveillance months and 4 036 602 pd participated. With 1184 HAHO-CDI cases, there was a median incidence density of 0.17/1000 pd (IQR 0.03-0.43) across all specialties, with substantial differences among specialties. Haematology-oncology wards showed the highest median incidence density (0.67/1000 pd, IQR 0.44-1.01), followed by medical ICUs (0.45/1000 pd, IQR 0.27-0.73) and medical general wards (0.32/1000 pd, IQR 0.18-0.53). Multivariable analysis revealed carbapenem (mostly meropenem) consumption to be the only antibiotic class associated with increased HAHO-CDI incidence density. Each carbapenem DDD/100 pd administered increased the HAHO-CDI incidence density by 1.3% [incidence rate ratio (IRR) 1.013; 95% CI 1.006-1.019]. Specialty-specific analyses showed this influence only to be valid for haematological-oncological wards. Overall, factors like ward specialty (e.g. haematology-oncology ward IRR 2.961, 95% CI 2.203-3.980) or other CDI cases on ward had a stronger influence on HAHO-CDI incidence density (e.g. community-associated CDI or unknown association case in same month IRR 1.476, 95% CI 1.242-1.755) than antibiotic consumption. Conclusions In the German university hospital setting, monthly ward-level carbapenem consumption seems to increase the HAHO-CDI incidence density predominantly on haematological-oncological wards. Furthermore, other patient-specific factors seem to be equally important to control HAHO-CDI.

Objectives: Staphylococcus aureus bloodstream infection (SAB) is a common and severe infection. This study aims to describe temporal trends in numbers, epidemiological characteristics, clinical manifesta-tions, and outcomes of SAB. Methods: We performed a post-hoc analysis of three prospective SAB cohorts at the University Medical Centre Freiburg between 2006 and 2019. We validated our findings in a large German multi-centre cohort of five tertiary care centres (R-Net consortium, 2017-2019). Time-dependent trends were esti-mated using Poisson or beta regression models. Results: We included 1797 patients in the mono-centric and 2336 patients in the multi-centric analysis. Overall, we observed an increasing number of SAB cases over 14 years (6.4%/year and 1000 patient days, 95% CI: 5.1% to 7.7%), paralleled by an increase in the proportion of community-acquired SAB (4.9%/year [95% CI: 2.1% to 7.8%]) anda decrease in the rate of methicillin-resistant-SAB (-8.5%/year [95% CI:-11.2% to-5.6%]). All of these findings were confirmed in the multi-centre validation cohort (6.2% cases per 1000 patient cases/year [95% CI:-0.6% to 12.6%], community-acquired-SAB 8.7% [95% CI:-1.2% to 19.6%], methicillin-resistant S. aureus-SAB-18.6% [95% CI:-30.6 to-5.8%]). Moreover, we found an increasing proportion of patients with multiple risk factors for complicated/difficult-to-treat SAB (8.5%/year, 95% CI: 3.6% to 13.5%, p < 0.001), alongside an overall higher level of comorbidities (Charlson comorbidity score 0.23 points/year, 95% CI: 0.09 to 0.37, p 0.005). At the same time, the rate of deep-seated foci such as osteomyelitis or deep-seated abscesses significantly increased (6.7%, 95% CI: 3.9% to 9.6%, p < 0.001). A reduction of in-hospital mortality by 0.6% per year (95% CI: 0.08% to 1%) was observed in the subgroup of patients with infectious diseases consultations. Discussion: We found an increasing number of SAB combined with a significant increase in comorbidities and complicating factors in tertiary care centres. The resulting challenges in securing adequate SAB management in the face of high patient turnover will become an important task for physicians. Philipp Math?e, Clin Microbiol Infect 2023;29:1197.e9-1197.e15 (c) 2023 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

Species within the Enterobacter cloacae complex (ECC) include globally important nosocomial pathogens. A three-year study of ECC in Germany identified Enterobacter xiangfangensis as the most common species (65.5%) detected, a result replicated by examining a global pool of 3246 isolates. Antibiotic resistance profiling revealed widespread resistance and heteroresistance to the antibiotic colistin and detected the mobile colistin resistance (mcr)-9 gene in 19.2% of all isolates. We show that resistance and heteroresistance properties depend on the chromosomal arnBCADTEF gene cassette whose products catalyze transfer of L-Ara4N to lipid A. Using comparative genomics, mutational analysis, and quantitative lipid A profiling we demonstrate that intrinsic lipid A modification levels are genospecies-dependent and governed by allelic variations in phoPQ and mgrB, that encode a two-component sensor-activator system and specific inhibitor peptide. By generating phoPQ chimeras and combining them with mgrB alleles, we show that interactions at the pH-sensing interface of the sensory histidine kinase phoQ dictate arnBCADTEF expression levels. To minimize therapeutic failures, we developed an assay that accurately detects colistin resistance levels for any ECC isolate.

To analyse the epidemiology and population structure of third-generation cephalosporin-resistant (3GCR) and carbapenem-resistant (CR) Klebsiella pneumoniae complex isolates, patients were screened for rectal colonisation with 3GCR/CR K. pneumoniae complex on admission to six German university hospitals (2016–2019). Also collected were 3GCR/CR and susceptible K. pneumoniae isolates from patients with bloodstream infections (2016–2018). Whole-genome sequencing was performed followed by multilocus sequencing typing (MLST), core-genome MLST, and resistome and virulome analysis. The admission prevalence of 3GCR K. pneumoniae complex isolates during the 4-year study period was 0.8%, and 1.0 bloodstream infection per 1000 patient admissions was caused by K. pneumoniae complex (3GCR prevalence, 15.1%). A total of seven K. pneumoniae complex bloodstream isolates were CR (0.8%). The majority of colonising and bloodstream 3GCR isolates were identified as K. pneumoniae, 96.7% and 98.8%, respectively; the remainder were K. variicola and K. quasipneumoniae. cgMLST showed a polyclonal population of colonising and bloodstream isolates, which was also reflected by MLST and virulome analysis. CTX-M-15 was the most prevalent extended-spectrum beta-lactamase, and 29.7% of the colonising and 48.8% of the bloodstream isolates were high-risk clones. The present study provides an insight into the polyclonal 3GCR K. pneumoniae population in German hospitals.

Background The burden of bloodstream infections remains high worldwide and cannot be confined to short-term in-hospital mortality. We aimed to develop scores to predict short-term and long-term mortality in patients with bloodstream infections. Methods The Bloodstream Infection due to Multidrug-resistant Organisms: Multicenter Study on Risk Factors and Clinical Outcomes (BLOOMY) study is a prospective, multicentre cohort study at six German tertiary care university hospitals to develop and validate two scores assessing 14-day and 6-month mortality in patients with bloodstream infections. We excluded patients younger than 18 years or who were admitted to an ophthalmology or psychiatry ward. Microbiological, clinical, laboratory, treatment, and survival data were prospectively collected on day 0 and day 3 and then from day 7 onwards, weekly. Participants were followed up for 6 months. All patients in the derivation cohort who were alive on day 3 were included in the analysis. Predictive scores were developed using logistic regression and Cox proportional hazards models with a machine-learning approach. Validation was completed using the C statistic and predictive accuracy was assessed using sensitivity, specificity, and predictive values. Findings Between Feb 1,2017, and Jan 31,2019,2568 (61.5%) of 4179 eligible patients were recruited into the derivation cohort. The in-hospital mortality rate was 23.75% (95% CI 22.15-25.44; 610 of 2568 patients) and the 6-month mortality rate was 41.55% (39.54-43-59; 949 of 2284). The model predictors for 14-day mortality (C statistic 0.873, 95% CI 0.849-0-896) and 6-month mortality (0.807, 0.784-0-831) included age, body-mass index, platelet and leukocyte counts, C-reactive protein concentrations, malignancy (ie, comorbidity), in-hospital acquisition, and pathogen. Additional predictors were, for 14-day mortality, mental status, hypotension, and the need for mechanical ventilation on day 3 and, for 6-month mortality, focus of infection, in-hospital complications, and glomerular filtration rate at the end of treatment. The scores were validated in a cohort of 1023 patients with bloodstream infections, recruited between Oct 9,2019, and Dec 31, 2020. The BLOOMY 14-day score showed a sensitivity of 61.32% (95% CI 51.81-70.04), a specificity of 86.36% (83.80-88.58), a positive predictive value (PPV) of 37.57% (30.70-44.99), and a negative predictive value (NPV) of 94.35% (92.42-95.80). The BLOOMY 6-month score showed a sensitivity of 69.93% (61.97-76.84), a specificity of 66.44% (61.86-70-73), a PPV of 40.82% (34.85-47-07), and a NPV of 86.97% (82.91-90.18). Interpretation The BLOOMY scores showed good discrimination and predictive values and could support the development of protocols to manage bloodstream infections and also help to estimate the short-term and long-term burdens of bloodstream infections. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Objectives To analyse the rectal carriage rate and the molecular epidemiology of vancomycin-resistant Enterococcus faecium (VREfm) recovered from patients upon hospital admission. Methods Adult patients were screened at six German university hospitals from five different federal states upon hospital admission for rectal colonization with VREfm between 2014 and 2018. Molecular characterization of VREfm was performed by WGS followed by MLST and core-genome MLST analysis. Results Of 16350 patients recruited, 263 were colonized with VREfm, with increasing prevalence rates during the 5 year study period (from 0.8% to 2.6%). In total, 78.5% of the VREfm were vanB positive and 20.2% vanA positive, while 1.2% harboured both vanA and vanB. The predominant ST was ST117 (56.7%) followed by ST80 (15%), ST203 (10.9%), ST78 (5.7%) and ST17 (3.2%). ST117/vanB VREfm isolates formed a large cluster of 96 closely related isolates extending across all six study centres and four smaller clusters comprising 13, 5, 4 and 3 isolates each. In contrast, among the other STs inter-regional clonal relatedness was rarely observed. Conclusions To our knowledge, this is the largest admission prevalence and molecular epidemiology study of VREfm. These data provide insight into the epidemiology of VREfm at six German university hospitals and demonstrate the remarkable inter-regional clonal expansion of the ST117/vanB VREfm clone.

Antibiotic resistance is increasing worldwide. The implementation of antibiotic stewardship programmes (ASPs) is of utmost importance to optimize antibiotic use in order to prevent resistance development without harming patients. The emergency department (ED), cornerstone between hospital and community, represents a crucial setting for addressing ASP implementation; however, evidence data on ASP in ED are poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was implemented in a general ED with the aim to evaluate its impact on antibiotic use and costs. Secondly, the study focused on assessing the impact on length of hospital stay (LOS), Clostridioides difficile infection (CDI) incidence rate, and mortality in the patients' group admitted from ED to medical wards. The ASP implementation was associated with a reduction of antibiotic use and costs. A mild but sustained LOS decrease in all medical wards and a significant downward trend of CDI incidence rate were observed, while mortality did not significantly change. In conclusion, the implementation of our ED-based ASP has demonstrated to be feasible and safe and might clinically benefit the hospital admitted patients' group. Further research is needed to identify the most suitable ASP design for ED and the key outcome measures to reliably assess its effectiveness.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus and the upper two-thirds of the vagina in otherwise phenotypically normal females. It is found isolated or associated with renal, skeletal and other malformations. Despite ongoing research, the etiology is mainly unknown. For a long time, the hypothesis of deficient hormone receptors as the cause for MRKHS has existed, supported by previous findings of our group. The aim of the present study was to identify unknown genetic causes for MRKHS and to compare them with data banks including a review of the literature. DNA sequence analysis of the oxytocin receptor ( OXTR) and estrogen receptor-1 gene ( ESR1) was performed in a group of 93 clinically well-defined patients with uterovaginal aplasia (68 with the isolated form and 25 with associated malformations). In total, we detected three OXTR variants in 18 MRKHS patients with one leading to a missense mutation, and six ESR1 variants in 21 MRKHS patients, two of these causing amino acid changes and therefore potentially disease. The identified variants on DNA level might impair receptor function through different molecular mechanisms. Mutations of ESR1 and OXTR are associated with MRKHS. Thus, we consider these genes potential candidates associated with the manifestation of MRKHS.

INTRODUCTION:Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus and the upper two-thirds of the vagina in otherwise phenotypically normal females. It is found isolated or associated with renal, skeletal and other malformations. Despite ongoing research, the etiology is mainly unknown. For a long time, the hypothesis of deficient hormone receptors as the cause for MRKHS has existed, supported by previous findings of our group. The aim of the present study was to identify unknown genetic causes for MRKHS and to compare them with data banks including a review of the literature. MATERIAL AND METHODS:DNA sequence analysis of the oxytocin receptor (OXTR) and estrogen receptor-1 gene (ESR1) was performed in a group of 93 clinically well-defined patients with uterovaginal aplasia (68 with the isolated form and 25 with associated malformations). RESULTS:In total, we detected three OXTR variants in 18 MRKHS patients with one leading to a missense mutation, and six ESR1 variants in 21 MRKHS patients, two of these causing amino acid changes and therefore potentially disease. CONCLUSIONS:The identified variants on DNA level might impair receptor function through different molecular mechanisms. Mutations of ESR1 and OXTR are associated with MRKHS. Thus, we consider these genes potential candidates associated with the manifestation of MRKHS.

BACKGROUND/AIMS:Uterine rudiments from patients with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) contain all tissues typically found in the uterus. Endometrium from the rudiments predominantly exhibits basalis-like features, and endometrial proliferative capacity in patients' epithelium and stroma is significantly lower.METHODS:This single-center, prospective study conducted at a major German university hospital compared in-vitro decidualization in cultured ESCs from MRKHS patients and hysterectomy controls. Primary ESC cultures were established from both sources. Hormone-induced prolactin and IGFBP-1 secretion served as a measure of their ability to undergo decidualization in response to hormonal stimulation. Expression levels of 8 key marker genes of decidualization were also determined.RESULTS:At day 9, mean secretion of prolactin and IGFBP-1 was significantly reduced by 89.0% and 99.5%, respectively, in MRKHS ESCs vs. hysterectomy controls, both indicating impaired decidualization of MRKHS ESCs. Key decidual markers confirmed impaired decidualization in MRKHS patients.CONCLUSION:Our results indicate that the ESCs from MRKHS patients lack hormone responsiveness as a potential sign of dysfunctional hormone receptor function, which may also play a role in the onset of MRKHS. Further studies are needed to corroborate our findings, directly address receptor function, and elucidate the role of other potential determinants of uterine development and adult function.

Objective: To find a potential underlying cause for Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) discordance-in monozygotic twins.Design: Prospective comparative study.Setting: University hospital. Patient(s): Our study genetically analyzed 5 MRKHS-discordant monozygotic twin pairs with the unique opportunity to include saliva and rudimentary uterine tissue.Intervention(s): Blood, saliva, or rudimentary uterine tissue from five MRKHS-discordant twins was analyzed and compared between twin pairs as well as within the same individual where applicable. We used copy number variations (CNVs) to identify differences.Main Outcome Measure(s): CNVs in blood, rudimentary uterine tissue, and saliva, network analysis, and review of the literature.Result(s): One duplication found in the affected twin included two genes, matrix metalloproteinase 14 (MMIP14) and low-density lipoprotein receptor-related protein 10 (LRP 1 0), which have known functions in the embryonic development of the uterus and endometrium. The duplicated region was detected in rudimentary uterine tissue from the same individual but not in saliva, making a tissue-specific mosaicism a possible explanation for twin discordance. Additional network analysis revealed important connections to differentially expressed genes from previous studies. These genes encode several molecules involved in extracellular matrix (ECM) remodeling and neoangiogenesis.Conclusion(s): MMP-14, LRP-10, ECM, and neoangiogenesis genes are identified as candidate genes in a tissue-specific mosaicisin. The detected clusters provide evidence of deficient vascularization during uterine development and/or disturbed reorganization of ECM components, potentially during mullerian duct elongation signaled by the embryologically relevant phosphatidylinositol 3-kinase/protein kinase B pathway. Therefore, we consider these genes to be new candidates in the manifestation of MRKHS. (C) 2015 by American Society for Reproductive Medicine.

Hintergrund: Eine familiäre Häufung bei Mayer-Rokitansky-Küster-Hauser-Syndrom (MRKHS) macht eine genetische Ursache wahrscheinlich. Versuche einen genetischen Lokus zu definieren blieben jedoch bislang ohne Erfolg und Fälle von diskordanten monozygoten Zwillingen stellen eine rein genetische Ursache in Frage.