Impact of a VA-ECMO in Combination with an Extracorporeal Cytokine Hemadsorption System in Critically Ill Patients with Cardiogenic Shock-Design and Rationale of the ECMOsorb Trial.

BACKGROUND: Cardiogenic shock and arrest present as critical, life-threatening emergencies characterized by severely compromised tissue perfusion and inadequate oxygen supply. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) serves as a mechanical support system for patients suffering shock refractory to conventional resuscitation. Despite the utilization of VA-ECMO, clinical deterioration due to systemic inflammatory response syndrome (SIRS) resulting from the underlying shock and exposure of blood cells to the artificial surfaces of the ECMO circuit may occur. To address this issue, cytokine adsorbers offer a valuable solution by eliminating blood proteins, thereby controlling SIRS and potentially improving hemodynamics. Consequently, a prospective, randomized, blinded clinical trial will be carried out with ECMOsorb. METHODS AND STUDY DESIGN: ECMOsorb is a single-center, controlled, randomized, triple-blinded trial that will compare the hemodynamic effects of treatment with a VA-ECMO in combination with a cytokine adsorber (CytoSorb®, intervention) to treatment with VA-ECMO only (control) in patients with cardiogenic shock (with or without prior cardiopulmonary resuscitation (CPR)) requiring extracorporeal, hemodynamic support. Fifty-four patients will be randomized in a 1:1 fashion to the intervention or control group over a 36-month period. The primary endpoint of ECMOsorb is the improvement of the Inotropic Score (IS) 72 h after the intervention. Prognostic indicators, including mortality rates, hemodynamic parameters, laboratory findings, echocardiographic assessments, quality of life measurements, and clinical parameters, will serve as secondary outcome measures. The safety evaluation encompasses endpoints such as air embolisms, allergic reactions, peripheral ischemic complications, vascular complications, bleeding incidents, and stroke occurrences. CONCLUSIONS: The ECMOsorb trial seeks to assess the efficacy of a cytokine adsorber (CytoSorb®; CytoSorbents Europe GmbH, Berlin, Germany) in reducing SIRS and improving hemodynamics in patients with cardiogenic shock who are receiving VA-ECMO. We hypothesize that a reduction in cytokine levels can lead to faster weaning from inotropic and mechanical circulatory support, and ultimately to improved recovery.

Evaluation of CIN2/3 Lesion Regression in GynTect® DNA Methylation-Marker-Negative Patients in a Longitudinal Study.

Cervical intraepithelial neoplasia (CIN) grade 2/3 has a high spontaneous regression rate, especially among women ≤29 years of age. To reduce overtreatment, reliable prognostic biomarkers would be helpful. The main aim of this study was to analyze the negative predictive value of the methylation marker panel GynTect® for lesion regression. In this prospective, multicenter, longitudinal observational proof-of-concept study, women aged ≤29 years with histologically confirmed CIN2 (n = 24) or CIN3 (n = 36) were closely monitored without treatment for up to 24 or 12 months, respectively. The outcome was either regression, persistence, or progression of the lesion. For each patient, a single baseline sample (V0) for cytology, hrHPV detection and methylation analysis was taken. In a primary analysis, the negative predictive value (NPV) of a GynTect®-negative test result at V0 for regression was determined. We tested the null hypothesis NPV ≤ 70% against the alternative hypothesis NPV ≥ 90%. Twelve of the eighteen GynTect®-negative CIN2 patients showed regression (NPV = 67%, 90% CI 44-85%, p = 0.53). Of the 27 GynTect®-negative CIN3 lesions, 15 regressed (NPV = 56%, 90% CI 38-72%, p = 0.92). Although the majority of GynTect®-negative lesions regressed, the postulated NPV of ≥90% was not observed. Thus, the clinical relevance for an implementation of the GynTect® assay for patients undergoing watchful waiting remains questionable. Further studies with longer observation periods should be undertaken.

Transfer of FRozen Encapsulated multi-donor Stool filtrate for active ulcerative Colitis (FRESCO): study protocol for a prospective, multicenter, double-blind, randomized, controlled trial.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with significant morbidity and mortality. Although the precise cause remains unknown, disturbances in the intestinal microbial community have been linked to its pathogenesis. Randomized controlled trials in UC and relapsing Clostridioides difficile infection (CDI) have established fecal microbiota (FM) transfer (FMT) as an effective therapy. In this context, preliminary results indicated that the transfer of sterile fecal microbiota filtrates (<0.2 µm; FMF, FMFT) of donor stool also drives gastrointestinal microbiota changes and eliminates symptoms in CDI patients. However, along with the success of FMT, regulatory agencies issued safety alerts following reports of serious adverse events due to transmission of enteric pathogens through FMT. To reduce this risk, we established an extensive test protocol for our donors and quarantine regulations for the produced capsules, but alternative concepts are desirable. METHODS: Our project is a randomized, controlled, longitudinal, prospective, three-arm, multicenter, double-blind study to determine the safety and efficacy of repeated long-term, multi-donor FM or FMF transfers compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active UC. The primary outcome will be clinical remission at week 12. DISCUSSION: This proposal aims to examine (a) the efficacy of encapsulated transfer of FM and FMF as a therapy for mild to moderate UC, (b) the short- and long-term safety of FMT and FMFT in patients with UC, and (c) the microbial and immunologic changes that occur after FMT and FMFT to help understand how and why it affects inflammatory bowel disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03843385 . DRKS (Deutsches Register für Klinische Studien) DRKS00020471.

Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance.

PURPOSE: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. METHODS: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients' individual HPV-integration sites (vcj-PCR on the basis of NGS). RESULTS: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6-34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8-27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7-20.7%) and predicted ten of fourteen recurrences at six months. CONCLUSIONS: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.

Complementary and alternative medicine is positively associated with religiousness/spirituality.

BACKGROUND: Complementary and alternative medicine (CAM) is used often by patients with different diseases. While some authors subsume religiousness and spirituality to CAM, others do not. The objective of the present study was to assess the prevalence and types of CAM usage as well as the participants' spirituality/religiousness in an outpatient department for endocrinology and metabolic diseases. METHODS: All individuals visiting the outpatient department at a German university hospital from April to June 2009 were offered a standardized questionnaire on the use of dietary supplements and alternative therapies as well as their religiousness/spirituality. Demographic and clinical data of 428 respondents were taken from the electronic health record. RESULTS: Of the respondents, 16.4% (n = 66) classified themselves to be religious/spiritual and 67.9% (n = 273) as not religious/spiritual. Women were more religious/spiritual than men (p = 0.02). 41.4% of the respondents used supplements and 27.4% additional therapies. The use of supplements and additional therapies was more frequent in people with higher religiousness/spirituality (p = 0.005 and p = 0.01,resp.) but there were no associations between religiousness/spirituality and the number of consultations, costs for drugs, appraisal of the physicians treatment methods, the perceived effectiveness of prescribed drugs, fear of late complications or of side effects. CONCLUSIONS: A higher religiousness/spirituality is associated with a more frequent use of supplements or additional therapies in individuals with endocrinopathies or metabolic diseases. As CAM has been shown to be associated with worse outcome, addressing religiousness/spirituality which stresses the responsibility of the person for his life might offer an additional resource and should be further studied.

Snacking is Common in People with Diabetes Type 1 and Type 2 with Insulin Therapy and Is Not Associated With Metabolic Control or Quality of Life.

OBJECTIVE: The aim of this observational study was to analyse snacking pattern and satisfaction with snacking, and to associate snacking patterns with metabolic control and quality of life in people with diabetes type 1 and 2 on insulin therapy. METHODS: In 2017, 390 people with diabetes were interviewed in a university outpatient department: 132 diabetes type 1 (56.1y, diabetes duration 24.2y, HbA1c 7.0%), 89 diabetes type 2/biphasic insulin (72.8y, diabetes duration 22.0y, HbA1c 7.1%) and 169 diabetes type 2/prandial insulin (66.7y, diabetes duration 20.5y, HbA1c 7.0%). Standardised questionnaires were used to assess eating patterns, satisfaction with snacking, treatment satisfaction and quality of life. RESULTS: The far majority snacked regardless of diabetes type and type of insulin therapy (70.5% type 1, 80.9% type 2/biphasic insulin, 74.6% type 2/prandial insulin) and liked to do so or did not mind (type 1 diabetes 79.5%, type 2 diabetes/biphasic insulin 84.8%, type 2 diabetes/prandial insulin 83.5%). Snacking because of recommendations of healthcare professionals was rare (10.8% type 1 diabetes, 8.2% type 2 diabetes/biphasic insulin, 9.4% type 2 diabetes/prandial insulin). Snacking and not snacking participants did not differ in respect to HbA1c, quality of life or treatment satisfaction. CONCLUSIONS: Snacking seems to be a common habit in individuals with diabetes and most of them like to snack. Snacking is not associated with better or worse metabolic control or quality of life. The decision to snack or not to snack can be left to the individual and integrated into the therapy without danger for the glycaemic control.

Mortality and its Causes in a German Cohort with Diabetes Mellitus Type 1 after 20 Years of Follow-Up: The JEVIN Trial.

BACKGROUND: The JEVIN trial started as a cross-sectional study in 1989/90 in Jena. After a follow-up of more than 20 years, the mortality incidence of JEVIN participants with type 1 diabetes was surveyed. METHODS: 103 (78.6%) of the 131 JEVIN patients participating at baseline could be examined. 38 persons (36.9%) had deceased. All JEVIN survey data and routine examinations documented in the electronic patient record EMIL® of surviving and deceased participants were used for analyses. We compared the data of the surviving with the deceased participants (follow-up time: 2,166 person-years). RESULTS: The incidence rate of death was 1.75/100 person-years. Median observation time for all patients was 23.1 years (range 0.61-26.6 years). Mean age at death was 58.5 years (34.2-78.4 years), and diabetes duration 35 years (3.5-68.5 years). Most frequent causes of death were: cardiovascular diseases (48.2%, n=13) and infections (25.9%, n=7). There were no differences in age (p=0.302), diabetes duration (p=0.371), BMI (p=0.535), blood pressure (p=0.622/0.820), gender (p=0.566), and smoking status (p=0.709) between surviving and deceased persons. The mean HbA1c of the last year before death or last visit was higher in the deceased than surviving persons (7.5% vs. 7.0%; p=0.010). 57.4% of the surviving and 87.0% of the deceased participants had nephropathy (p=0.012), 79.7% vs. 89.7% retinopathy (p=0.241) and 61.4% vs. 63.3% neuropathy (p=0.860), but only nephropathy was significantly associated with increased mortality risk (HR=4.208, CI:1.226-14.440; HR=2.360, CI:0.696-8.004; HR=0.944, CI:0.436-2.043). CONCLUSIONS: In the JEVIN population with diabetes mellitus type 1 only, diabetic nephropathy was associated with higher mortality risk.

Informed shared decision-making programme on the prevention of myocardial infarction in type 2 diabetes: a randomised controlled trial.

OBJECTIVE: To evaluate an informed shared decision-making programme (ISDM-P) for people with type 2 diabetes under high fidelity conditions. DESIGN: Randomised, single-blinded trial with sham control intervention and follow-up of 6 months. SETTING: Single-centre diabetes clinic providing care according to the national disease management programme in Germany. PARTICIPANTS: 154 people with type 2 diabetes without diagnosis of ischaemic heart disease or stroke. INTERVENTIONS: The ISDM-P is executed by diabetes educators. Core component is a patient decision aid on the prevention of myocardial infarction supplemented by a 90 min group teaching session. The structurally equivalent control intervention addresses stress issues. MAIN OUTCOME MEASURES: Primary outcome was risk comprehension, including realistic expectations about benefits and harms of interventions. It was assessed by a 12-item questionnaire after the teaching session when patients set and prioritise their treatment goals. Key secondary outcome was adherence to treatment goals, operationalised as achievement of individual goals and medication uptake. ISDM-P teaching sessions were video-taped to monitor intervention fidelity. RESULTS: 72 of 77 ISDM-P and 71 of 77 control patients completed the questionnaire (score 0-12). ISDM-P patients achieved higher levels of risk comprehension, mean score 8.25 vs 2.62, difference 5.63 (95% CI 4.82 to 6.44), and realistic expectations (score 0-6), 4.51 vs 0.85, 3.67 (3.23 to 4.11). More ISDM-P patients wished to take statins, 59.2% vs 30.4%, 28.7% (12.9% to 44.5%); more prioritised blood pressure control, 51.4% vs 25.7%, and fewer intensive glucose control, 33.3% vs 60%, p=0.002. More ISDM-P patients achieved their glycated haemoglobin goals, 95.8% vs 85.7%, 10.1% (0.6% to 19.5%). Achievement of prioritised goals and medication uptake were comparable between groups. CONCLUSIONS: The ISDM-P on preventive measures in type 2 diabetes was effective under high fidelity conditions. Involvement of diabetes educators may facilitate implementation of the informed shared decision-making. TRIAL REGISTRATION NUMBER: ISRCTN84636255.

An evidence-based shared decision making programme on the prevention of myocardial infarction in type 2 diabetes: protocol of a randomised-controlled trial.

BACKGROUND: Lack of patient involvement in decision making has been suggested as one reason for limited treatment success. Concepts such as shared decision making may contribute to high quality healthcare by supporting patients to make informed decisions together with their physicians.A multi-component shared decision making programme on the prevention of heart attack in type 2 diabetes has been developed. It aims at improving the quality of decision-making by providing evidence-based patient information, enhancing patients' knowledge, and supporting them to actively participate in decision-making. In this study the efficacy of the programme is evaluated in the setting of a diabetes clinic. METHODS/DESIGN: A single blinded randomised-controlled trial is conducted to compare the shared decision making programme with a control-intervention. The intervention consists of an evidence-based patient decision aid on the prevention of myocardial infarction and a corresponding counselling module provided by diabetes educators. Similar in duration and structure, the control-intervention targets nutrition, sports, and stress coping. A total of 154 patients between 40 and 69 years of age with type 2 diabetes and no previous diagnosis of ischaemic heart disease or stroke are enrolled and allocated either to the intervention or the control-intervention. Primary outcome measure is the patients' knowledge on benefits and harms of heart attack prevention captured by a standardised knowledge test. Key secondary outcome measure is the achievement of treatment goals prioritised by the individual patient. Treatment goals refer to statin taking, HbA1c-, blood pressure levels and smoking status. Outcomes are assessed directly after the counselling and at 6 months follow-up. Analyses will be carried out on intention-to-treat basis. Concurrent qualitative methods are used to explore intervention fidelity and to gain insight into implementation processes. DISCUSSION: Interventions to facilitate evidence-based shared decision making represent an innovative approach in diabetes care. The results of this study will provide information on the efficacy of such a concept in the setting of a diabetes clinic in Germany. TRIAL REGISTRATION: ISRCTN84636255.

A retrospective study on the incidence and risk factors of severe hypoglycemia in primary care.

AIMS: To investigate the incidence and risk factors of severe hypoglycemia (SH) in primary care. SH was defined as hypoglycemia with coma, or the need of glucose or glucagon injection. METHODS: We performed a cross-sectional retrospective study in patients with diabetes treated in primary care in Germany. We analyzed an unselected sample of participants with type 1 (n = 373) and type 2 diabetes (n = 4481) who participated in an insurance plan from the health care insurer Deutsche BKK. Data of participants with type 1 diabetes are as follows: women, n = 155 (42%); age, 49±16 years; diabetes duration, 20+13 years; BMI, 28±6 kg/m2; GHb, 7.1+1.5%; GHb≤7%, n = 263 (71%); GHb≥8.5%, n = 48 (13%). Data of participants with type 2 diabetes: women, n = 1979 (44%); age, 66±10 years; diabetes duration, 8±7 years; BMI, 30±5 kg/m2; GHb, 6.6±1.3%; GHb≤7%, n = 3747 (84%); GHb≥8.5%, n = 360 (8%); insulin therapy, n = 1175 (26%). RESULTS: The incidence of SH in type 1 diabetes: 1.3% (CI: 0.4%, 3.1%) per year; type 2 diabetes with insulin therapy: 0.9% (CI: 0.5%, 1.7%); without insulin therapy: 0.3% (CI: 0.1%, 0.6%). The event rate was 0.02 SH per patient/year in type 1 diabetes and 0.01 in type 2 diabetes, respectively. Low BMI, GHb, insulin therapy and female gender were associated with an increased risk of SH. CONCLUSIONS: In primary care, patients with diabetes can achieve good glycemic control with very rare events of SH. Due to low incidence, SH would have been an inappropriate parameter to evaluate the outcome quality of diabetes therapy in primary care.

Retinal vessel oxygen saturation under flicker light stimulation in patients with nonproliferative diabetic retinopathy.

PURPOSE: We investigated the response of retinal vessel diameters and oxygen saturation to flicker light stimulation of neuronal activity in patients with diabetic retinopathy. METHODS: We included 18 patients with nonproliferative diabetic retinopathy (mean age 62.2 ± 8.3 years, diabetes type 1 in 4 patients and type 2 in 14, hemoglobin A1c 7.7 ± 0.9%, duration of diabetes 24.1 ± 9.3 years) and 20 age-matched healthy controls (age 66.7 ± 10.3 years). Dual wavelength (548 and 610 nm) fundus images were taken before and during luminance flicker stimulation (12.5 Hz, modulation depth > 1:25) for 90 seconds. Diameters (central retinal arterial [CRAE] and venous [CRVE] equivalents) and oxygen saturation (SO(2)) were determined, and averaged for all arterioles and venules in an annular area centered at the optic disk. RESULTS: Flicker light increased CRAE, CRVE, and venous SO(2) by 0.6 ± 6.6%, 2.7 ± 6.1%, and 2.0 ± 2.4% (P < 0.05), respectively, in the patients as well as 4.7 ± 8.4% (P < 0.05), 8.7 ± 5.2% (P < 0.05), and 4.2 ± 3.5% (P < 0.05), respectively, in the controls. The arterial SO(2) remained unchanged in both groups. The increase of the venous SO2 correlated significantly (P = 0.027) with that of the CRAE. There was a trend (P = 0.06) for lower increase of the venous SO(2) with higher body mass index. CONCLUSIONS: Our results support the thesis of an impaired regulation of oxygen supply to the diabetic retina. Whereas in healthy subjects the stimulation of neuronal activity increases the vascular diameters and, subsequently, the oxygen supply, this increase is reduced in diabetic retinopathy. This may hint at the role of endothelial dysfunction in the etiology of the disease.