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"Weber, Susanne"
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Altered Expression of Antimicrobial Peptides in the Upper Gastrointestinal Tract of Patients with Diabetes Mellitus
Antimicrobial peptides (AMP) are essential components of innate immunity with a broad range of antimicrobial activities against bacteria, viruses, and fungi. The aim of this study was to investigate AMP expression in the upper gastrointestinal tract in normal and pathological metabolic states in humans. Furthermore, we examined the correlation between vitamin D levels and AMP expression in the same cohort. Serum concentrations of 25-hydroxyvitamin D3 were measured, and mRNA expression of β-defensins HBD-1, -2, -3, -4, α-defensins HD-5 and -6 and cathelicidin in the upper gastrointestinal tract epithelia were determined by quantitative RT-PCR in 31 individuals (10 with type 2 diabetes, 10 with insulin resistance, and 11 healthy controls). The majority of the cohort showed low vitamin D concentrations, which were negatively correlated with mRNA expression levels of HBD-3 in corpus mucosa. HBD-1 and HBD-3 mRNA were expressed in corpus mucosa, with the former significantly decreased in patients with diabetes. Hence, we conclude that type 2 diabetes is associated with reduced AMP expression in the upper gastrointestinal tract, which might contribute towards epithelial barrier dysfunction and increased bacterial translocation in these patients.
Journal Article
Stacked probability plots of the extended illness-death model using constant transition hazards – an easy to use shiny app
Background
Extended illness-death models (a specific class of multistate models) are a useful tool to analyse situations like hospital-acquired infections, ventilation-associated pneumonia, and transfers between hospitals. The main components of these models are hazard rates and transition probabilities. Calculation of different measures and their interpretation can be challenging due to their complexity.
Methods
By assuming time-constant hazards, the complexity of these models becomes manageable and closed mathematical forms for transition probabilities can be derived. Using these forms, we created a tool in R to visualize transition probabilities via stacked probability plots.
Results
In this article, we present this tool and give some insights into its theoretical background. Using published examples, we give guidelines on how this tool can be used. Our goal is to provide an instrument that helps obtain a deeper understanding of a complex multistate setting.
Conclusion
While multistate models (in particular extended illness-death models), can be highly complex, this tool can be used in studies to both understand assumptions, which have been made during planning and as a first step in analysing complex data structures. An online version of this tool can be found at
https://eidm.imbi.uni-freiburg.de/
.
Journal Article
Evaluating hypothetical interventions effects on hospital-acquired infection outcomes with stacked probability visualization: R Shiny apps based on a multistate modelling approach
Hospital-acquired infections (HAIs), contribute to increased morbidity, prolonged hospital stays, and higher healthcare costs. Evaluating intervention effects in dynamic clinical settings requires advanced modeling techniques. This study presents HAISim and StaViC, two interactive R Shiny apps designed to support decision-making in Infection Prevention and Control.
A six-state extended illness-death multistate model was built with a time-constant transition hazard assumption. The multistate model maps patient trajectories involving healthcare-associated infections as an intermediate event, and mortality and discharge as absorbing events in order to describe the time-dependent dynamics within hospitals. Using two settings, we simulated the implementation of hypothetical treatments by modifying hazard rates: Setting 1 (improved treatment intervention only) and Setting 2 (combined enhanced treatment and infection prevention). These were used to create the interactive and user-friendly R Shiny Apps HAISim (HAIs Interventions Simulator) and StaViC (Stacked probAbility Visualization & Comparison). The Shiny Apps use inputs from literature or user data, such as transition-specific hazard rates and intervention-related parameters.
HAISim models the effects of hypothetically improved treatment and infection prevention on outcomes such as the number of lives saved and the number of patient days decreased by simulating a hypothetical scenario based on actual clinical data. StaViC makes it possible to compare potential interventions and their impacts before and after implementation by visualizing the stacked probabilities of patients across various health conditions.
These tools bridge methodological rigor and practical implementation, offering hospitals a flexible framework to prioritize cost-effective IPC strategies.
Journal Article
The stability of the MOC as diagnosed from model projections for pre-industrial, present and future climates
The stability of the Atlantic meridional overturning circulation (MOC) is investigated for various climate scenario runs, using data from the CMIP3 archive of coupled atmosphere-ocean models. Apart from atmospheric feedbacks, the sign of the salt flux into the Atlantic basin that is carried by the MOC determines whether the MOC is in the single or multiple equilibria regime. This salt advection feedback is analyzed by diagnosing the freshwater and salt budgets for the combined Atlantic and Arctic basins. Consistent with the finding that almost all coupled climate models recover from hosing experiments, it is found that most models feature a negative salt advection feedback in their pre-industrial climate: freshwater perturbations are damped by this feedback, excluding the existence of a stable off-state for the MOC. All models feature enhanced evaporation over the Atlantic basin in future climates, but for a moderate increase in radiative forcing (
B
1 and 2 CO
2
scenarios), there is a decrease of the fresh water flux carried by the MOC into the Atlantic (the deficit is made up by increased fresh water transport by the gyre circulation). In this forcing regime the salt advection feedback becomes less negative: for three models from an ensemble of eight it is positive in a 2 CO
2
climate, while two models feature a positive feedback in the pre-industrial climate. For even warmer climates (
A
1
B
-equilibrium and 4 CO
2
) the salt feedback becomes more negative (damping) again. It is shown that the decrease in northward fresh water transport at 34°S by the MOC (in
B
1-equilibrium and 2 CO
2
) is due to a reduction of the inflow of intermediate waters relative to thermocline waters, associated with a robust shoaling of the MOC in future, warmer climates. In
A
1
B
and 4 CO
2
climates northward freshwater transport increases again. The MOC keeps shoaling, but both intermediate and thermocline water masses freshen.
Journal Article
A family with gallstone disease: defining inherited risk in the era of clinical genetic testing
Gallstones are among the most frequent hepatobiliary conditions. Although in most cases, they remain asymptomatic, they can cause complications and, in such cases, invasive treatments like endoscopic retrograde cholangiography (ERC) or cholecystectomy are required. Here, we present the results of genetic testing of a single family with a high incidence of symptomatic gallstones and cholestatic liver phenotypes. Gallstone disease was detected among seven family members spanning three generations, and DNA samples were available from five of them. Genotyping was performed using TaqMan assays for known, selected genetic risk factors for gallstones and cholestasis, as well as next generation sequencing (NGS) of three genes involved in hepatobiliary transport. In all genotyped patients, we detected at least one copy of the gallstone-predisposing p.D19H variant in the hepatobiliary sterol transporter
ABCG5/8
, and in three cases, this variant was found in the rare homozygous state. In addition, the patients were all homozygous carriers of two intronic variants (c.2211+16C >T and c.3508-16T>C) and two common polymorphisms (c.504C>T and c.711A>T) in the
ABCB4
gene, as well as the
ATP8B1
gene variant c.696T>C. All genotyped patients also carried the predisposing variants c.1331C>T and c.3084A>G of the hepatobiliary bile salt export pump
ABCB11
in either heterozygous or homozygous form. Hence, we propose that these variants taken together may have contributed to the high frequency of gallstone disease in this family, although functional studies for some variants are still lacking. In this report, we present these findings and discuss the challenges associated with interpreting sequencing data.
Journal Article
Transcription Factor TFAP2C Regulates Major Programs Required for Murine Fetal Germ Cell Maintenance and Haploinsufficiency Predisposes to Teratomas in Male Mice
Maintenance and maturation of primordial germ cells is controlled by complex genetic and epigenetic cascades, and disturbances in this network lead to either infertility or malignant aberration. Transcription factor TFAP2C has been described to be essential for primordial germ cell maintenance and to be upregulated in several human germ cell cancers. Using global gene expression profiling, we identified genes deregulated upon loss of Tfap2c in embryonic stem cells and primordial germ cell-like cells. We show that loss of Tfap2c affects many aspects of the genetic network regulating germ cell biology, such as downregulation of maturation markers and induction of markers indicative for somatic differentiation, cell cycle, epigenetic remodeling and pluripotency. Chromatin-immunoprecipitation analyses demonstrated binding of TFAP2C to regulatory regions of deregulated genes (Sfrp1, Dmrt1, Nanos3, c-Kit, Cdk6, Cdkn1a, Fgf4, Klf4, Dnmt3b and Dnmt3l) suggesting that these genes are direct transcriptional targets of TFAP2C in primordial germ cells. Since Tfap2c deficient primordial germ cell-like cells display cancer related deregulations in epigenetic remodeling, cell cycle and pluripotency control, the Tfap2c-knockout allele was bred onto 129S2/Sv genetic background. There, mice heterozygous for Tfap2c develop with high incidence germ cell cancer resembling human pediatric germ cell tumors. Precursor lesions can be observed as early as E16.5 in developing testes displaying persisting expression of pluripotency markers. We further demonstrate that mice with a heterozygous deletion of the TFAP2C target gene Nanos3 are also prone to develop teratomas. These data highlight TFAP2C as a critical and dose-sensitive regulator of germ cell fate.
Journal Article
Skin advanced glycation end-products as indicators of the metabolic profile in diabetes mellitus: correlations with glycemic control, liver phenotypes and metabolic biomarkers
Introduction
The production of advanced glycation end-products (AGEs) is a key pathomechanism related to the complications of diabetes mellitus. The measurement of HbA1c as one of the AGEs is widely used in the clinic, but also other proteins undergo glycation in the course of diabetes. Here, we measure skin AGEs (SAGEs) in patients with diabetes type 1 (DM1) and type 2 (DM2) and correlate them with metabolic markers as well as non-invasively measured liver fibrosis and steatosis.
Patients and methods
In this cross-sectional study, a total of 64 patients with either DM1 or DM2 and 28 healthy controls were recruited. SAGEs were measured using autofluorescence (AGE Reader). Liver fibrosis and steatosis were quantified using transient elastography, which determines liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). FGF19, FGF21 and GDF-15 were measured in blood samples using ELISA.
Results
SAGEs were elevated in both groups of patients with diabetes as compared to healthy controls (both
p
< 0.001) and were higher in patients with DM2 in comparison to DM1 (
p
= 0.006). SAGEs correlated positively with HbA1c (
r
= 0.404,
p
< 0.001), CAP (
r
= 0.260,
p
= 0.016) and LSM (
r
= 0.356,
p
< 0.001), and negatively with insulin growth factor binding protein 3 (
p
< 0.001). We also detected a positive correlation between GDF15 and SAGEs (
r
= 0.469,
p
< 0.001).
Conclusions
SAGEs are significantly elevated in patients with both DM types 1 and 2 and correlate with metabolic markers, including HbA1c and GDF15. They might also help to detect patients with advanced liver injury in the setting of diabetes.
Journal Article
Delayed graft function is associated with an increased rate of renal allograft rejection: A retrospective single center analysis
The association of delayed graft function (DGF) and biopsy proven acute rejection (BPAR) of renal allografts is controversial. Borderline rejections comprise a major portion of biopsy results but the significance of such histologic changes is debated. The present study explores the impact of DGF on BPAR with a special emphasis on discriminating the effects of borderline rejection.
Single center analysis of 417 deceased donor kidney recipients (age>18; transplantation date 1/2008-2/2015). Patients with primary non-function were excluded. DGF was defined as the need for dialysis within the first week after transplantation. Acute rejection was defined according to Banff criteria. Cox proportional hazards models were used to examine the relationship of DGF with BPAR within the first year.
No graft loss was observed during the first year after transplantation. DGF significantly associated with BPAR in the first year, irrespective of whether borderline rejections were included (HR 1.71, 95%CI 1.16,2.53) or excluded (HR 1.79, 95%CI 1.13,2.84).
DGF is significantly associated with rejection-with or without borderline changes-within the first year.
Journal Article
Exploring the potential of large language models for integration into an academic statistical consulting service–the EXPOLS study protocol
The advancement of Artificial Intelligence, particularly Large Language Models (LLMs), is rapidly progressing. LLMs, such as OpenAI's GPT, are becoming vital in scientific and medical processes, including text production, knowledge synthesis, translation, patient communication and data analysis. However, the outcome quality needs to be evaluated to assess the full potential for usage in statistical applications. LLMs show potential for all research areas, including teaching. Integrating LLMs in research, education and medical care poses opportunities and challenges, depending on user competence, experience and attitudes.
This project aims at exploring the use of LLMs in supporting statistical consulting by evaluating the utility, efficiency and satisfaction related to the use of LLMs in statistical consulting from both advisee and consultant perspective. Within this project, we will develop, execute and evaluate a training module for the use of LLMs in statistical consulting. In this context, we aim to identify the strengths, limitations and areas for potential improvement. Furthermore, we will explore experiences, attitudes, fears and current practices regarding the use of LLMs of the staff at the Medical Center and the University of Freiburg.
This multimodal study includes four study parts using qualitative and quantitative methods to gather data. Study part (I) is designed as mixed mode study to explore the use of LLMs in supporting statistical consulting and to evaluate the utility, efficiency and satisfaction related to the use of LLMs. Study part (II) uses a standardized online questionnaire to evaluate the training module. Study part (III) evaluates the consulting sessions using LLMs from advisee perspective. Study part (IV) explores experiences, attitudes, fears and current practices regarding the use of LLMs of the staff at the Medical Center and the University of Freiburg. This study is registered at the Freiburg Registry of Clinical Studies under the ID: FRKS004971.
Journal Article