COVID-19 Outcomes in Kidney Transplant Recipients in a German Transplant Center.

Kidney transplant recipients (KTRs) show higher morbidity and mortality from COVID-19 than the general population and have an impaired response to vaccination. We analyzed COVID-19 incidence and clinical outcomes in a single-center cohort of approximately 2500 KTRs. Between 1 February 2020 and 1 July 2022, 578 KTRs were infected with SARS-CoV-2, with 25 (4%) recurrent infections. In total, 208 KTRs (36%) were hospitalized, and 39 (7%) died. Among vaccinated patients, infection with the Omicron variant had a mortality of 2%. Unvaccinated patients infected with the Omicron variant showed mortality (9% vs. 11%) and morbidity (hospitalization 52% vs. 54%, ICU admission 12% vs. 18%) comparable to the pre-Omicron era. Multivariable analysis revealed that being unvaccinated (OR = 2.15, 95% CI [1.38, 3.35]), infection in the pre-Omicron era (OR = 3.06, 95% CI [1.92, 4.87]), and higher patient age (OR = 1.04, 95% CI [1.03, 1.06]) are independent risk factors for COVID-19 hospitalization, whereas a steroid-free immunosuppressive regimen was found to reduce the risk of COVID-19 hospitalization (OR = 0.51, 95% CI [0.33, 0.79]). This suggests that both virological changes in the Omicron variant and vaccination reduce the risk for morbidity and mortality from COVID-19 in KTRs. Our data extend the knowledge from the general population to KTRs and provide important insights into outcomes during the Omicron era.

Risk Factors for Hepatitis E Virus Infection and Eating Habits in Kidney Transplant Recipients.

There is a significant risk for ongoing and treatment-resistant courses of hepatitis E virus (HEV) infection in patients after solid organ transplantation. The aim of this study was to identify risk factors for the development of hepatitis E, including the dietary habits of patients. We conducted a retrospective single-center study with 59 adult kidney and combined kidney transplant recipients who were diagnosed with HEV infection between 2013 and 2020. The outcomes of HEV infections were analyzed during a median follow-up of 4.3 years. Patients were compared with a control cohort of 251 transplant patients with elevated liver enzymes but without evidence of an HEV infection. Patients' alimentary exposures during the time before disease onset or diagnosis were assessed. Previous intense immunosuppression, especially treatment with high-dose steroids and rituximab, was a significant risk factor to acquire hepatitis E after solid organ transplantation. Only 11 out of 59 (18.6%) patients reached remission without further ribavirin (RBV) treatment. A total of 48 patients were treated with RBV, of which 19 patients (39.6%) had either viral rebounds after the end of treatment or did not reach viral clearance at all. Higher age (>60 years) and a BMI ≤ 20 kg/m2 were risk factors for RBV treatment failure. Deterioration in kidney function with a drop in eGFR (p = 0.046) and a rise in proteinuria was more common in patients with persistent hepatitis E viremia. HEV infection was associated with the consumption of undercooked pork or pork products prior to infection. Patients also reported processing raw meat with bare hands at home more frequently than the controls. Overall, we showed that the intensity of immunosuppression, higher age, a low BMI and the consumption of undercooked pork meat correlated with the development of hepatitis E.

Declining Course of Humoral Immune Response in Initially Responding Kidney Transplant Recipients after Repeated SARS-CoV-2 Vaccination.

The immunogenicity of SARS-CoV-2 vaccines in kidney transplant recipients is limited, resulting in inadequately low serological response rates and low immunoglobulin (Ig) levels, correlating with reduced protection against death and hospitalization from COVID-19. We retrospectively examined the time course of anti-SARS-CoV-2 Ig antibody levels after up to five repeated vaccinations in 644 previously nonresponding kidney transplant recipients. Using anti SARS-CoV-2 IgG/IgA ELISA and the total Ig ECLIA assays, we compared antibody levels at 1 month with levels at 2 and 4 months, respectively. Additionally, we correlated the measurements of the used assays. Between 1 and 2 months, and between 1 and 4 months, mean anti-SARS-CoV-2 Ig levels in responders decreased by 14% and 25%, respectively, depending on the assay. Absolute Ig values and time course of antibody levels showed high interindividual variability. Ig levels decreased by at least 20% in 77 of 148 paired samples with loss of sufficient serological protection over time occurring in 18 out of 148 (12.2%). IgG ELISA and total Ig ECLIA assays showed a strong positive correlation (Kendall's tau = 0.78), yet the two assays determined divergent results in 99 of 751 (13.2%) measurements. IgG and IgA assays showed overall strong correlation but divergent results in 270 of 1.173 (23.0%) cases and only weak correlation of antibody levels in positive samples. Large interindividual variability and significant loss of serological response after 4 months supports repeated serological sampling and consideration of shorter vaccination intervals in kidney transplant recipients.

Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients.

Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired. We retrospectively analyzed the serological response of up to five doses of the SARS-CoV-2 vaccine in KTR from 27 December 2020 until 31 December 2021. Particularly, the influence of the different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. In total, 4277 vaccinations against SARS-CoV-2 in 1478 patients were analyzed. Serological response was 19.5% after 1203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth, and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%. In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased the serological response rate to 75% in comparison to the no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations. Except for belatacept-treated patients, repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination.

Initial Experience With SARS-CoV-2-Neutralizing Monoclonal Antibodies in Kidney or Combined Kidney-Pancreas Transplant Recipients.

Background: Antiviral drugs have shown little impact in patient infected with acute respiratory coronavirus 2 (SARS-CoV-2). Especially for immunocompromised persons positive for SARS-CoV-2, novel treatments are warranted. Recently, the U.S. FDA has granted an emergency use authorization (EUA) to two monoclonal antibodies (mAb) targeting the viral spike protein: bamlanivimab and casivirimab and imdevimab. As per the EUA, all SARS-CoV-2 positive organ transplant recipients can receive mAb treatment. Patients and methods: We queried our center's transplant registry to identify SARS-CoV-2 infected recipients treated with single doses of either Bamlanivimab or casivirimab/imdevimab up to May 31, 2021. We analyzed clinical outcomes, renal function and virus-specific antibodies. The co-primary endpoints were hospitalization due to COVID-19 and SARS-CoV-2 RT-PCR negativity. Results: Thirteen patients at a median interval of 55 (IQR, 26-110) months from transplant were treated: 8 with bamlanivimab and 5 with casivirimab/imdevimab. In all, 4/13 (31%) patients were hospitalized at some time, while 11/13 (85%) achieved PCR negativity. 2/4 hospitalized patients received mAb as rescue treatment. Overall mortality was 23%, with one death attributable to transplant-associated lymphoma. All six patients infected with the B 1.1.7 variant were alive at last contact. Conclusion: mAb treatment appears effective when administered early to SARS-CoV-2-infected transplant recipients.

Predictors of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Patients: Baseline Characteristics, Immunosuppression, and the Role of IMPDH Monitoring.

Immunosuppression increases the risk of severe coronavirus disease 2019 (COVID-19). Morbidity and mortality of this disease in kidney transplant patients are higher than in the general population. As the vaccination response of transplant patients is weak, serological monitoring was performed. In this cohort study, we analyzed the determinants of vaccination response. All patients had no history of COVID-19. With anti-spike IgG monitoring, 148 responders and 415 non-responders were identified. We compared both groups using multivariate analyses of the cohort and a sub-cohort of mycophenolic-acid-treated patients. We investigated the influence of patient characteristics, immunosuppression, and erythrocyte inosine monophosphate dehydrogenase (IMPDH) activity. In responders, the time after transplantation was longer (13.5 vs. 8.5 years), the glomerular filtration rate was higher (56.9 vs. 47.8 mL/min/1.73 m2), and responders were younger (53.0 vs. 57.4 years). Heterologous vaccination was more effective than homologous vaccination. Calcineurin inhibitors plus mycophenolate reduced the seroconversion rate. No seroconversion was observed in belatacept patients. In mycophenolate-treated patients, IMPDH activity was a significantly better predictor of response than mycophenolate dose (AUC 0.84 vs. 0.62, p < 0.001). Immunosuppression strongly affects vaccine response. Modifications to immunosuppression should be considered in order to facilitate this response. Erythrocyte IMPDH activity can be used to guide mycophenolate treatment.

Estimation of pulmonary artery pressure with transesophageal echocardiography: An observer-blinded test accuracy study.

ABSTRACT: With the declining use of the pulmonary artery catheter (PAC), transesophageal echocardiography (TEE) has become an appealing alternative to obtain pulmonary artery pressure non-invasively using the simplified Bernoulli equation. The validation of this method in the perioperative setting has been scarce with no clear recommendations about which view is the most accurate to estimate right ventricular systolic pressure (RVSP).Therefore, we performed a prospective, observer-blinded, diagnostic test accuracy study to assess the difference in systolic pulmonary artery pressure (sysPAP) measuring both, invasively sysPAP and estimated RVSP with TEE in 3 different views: the mid-esophageal (ME) 4Chamber, the ME right ventricular (RV) inflow-outflow and the ME modified bicaval view.To show a clinically significant difference of at least 10% in RVSP, we included 40 cardiac surgical patients divided into 3 subgroups: Patients with mild to moderate tricuspid regurgitation (TR) and mean PAP <25 mm Hg, patients with mild to moderate TR and mean PAP≥ 25 mm Hg, and patients with severe TR.For the whole cohort, bias of estimated RVSP compared to measured sysPAP was 5.27 mm Hg, precision was 7.96 mm Hg, limits of agreement were -10.66 to 21.19 mm Hg. The best agreement between the 2 methods was found in patients with severe TR and in the ME RV inflow-outflow and the modified bicaval view. Good Doppler signals were available in 35% and 46% in these views, and in 20% in the ME 4 chamber view.The estimation of the sysPAP by TEE cannot be considered reliable in the clinical perioperative setting. Only measurements that provide a full Doppler envelope show sufficient precision to provide accurate estimations.

Immunogenicity of COVID-19 Tozinameran Vaccination in Patients on Chronic Dialysis.

Patients with kidney failure have notoriously weak responses to common vaccines. Thus, immunogenicity of novel SARS-CoV-2 vaccines might be impaired in this group. To determine immunogenicity of SARS-CoV-2 vaccination in patients with chronic dialysis, we analyzed the humoral and T-cell response after two doses of mRNA vaccine Tozinameran (BNT162b2 BioNTech/Pfizer). This observational study included 43 patients on dialysis before vaccination with two doses of Tozinameran 21 days apart. Overall, 36 patients completed the observation period until three weeks after the second dose and 32 patients were further analyzed at week 10. Serum samples were analyzed by SARS-CoV-2 specific IgG and IgA antibodies ~1, ~3-4 and ~10 weeks after the second vaccination. In addition, SARS-CoV-2-specific T-cell responses were assessed at ~3-4 weeks by an interferon-gamma release assay (IGRA). Antibody and T cell outcomes at this timepoint were compared to a group of 44 elderly patients not on dialysis, after immunization with Tozinameran. Median age of patients on chronic dialysis was 74.0 years (IQR 66.0, 82.0). The proportion of males was higher (69.4%) than females. Only 20/36 patients (55.6%, 95%CI: 38.29-71.67) developed SARS-CoV-2-IgG antibodies at the first sampling, whereas 32/36 patients (88.9%, 95%CI: 73.00-96.38) demonstrated IgG detection at the second sampling. In a longitudinal follow-up at ~10 weeks after the second dose, the proportion of dialysis patients reactive for anti-SARS-CoV-2-IgG decreased to 27/32 (84.37%, 95%CI: 66.46-94.10) The proportion of anti-SARS-CoV-2 S1 IgA decreased from 33/36 (91.67%; 95%CI: 76.41-97.82) at weeks 3-4 down to 19/32 (59.38; 95%CI: 40.79-75.78). Compared to a cohort of vaccinees with similar age but not on chronic dialysis seroconversion rates and antibody titers were significantly lower. SARS-CoV-2-specific T-cell responses 3 weeks after second vaccination were detected in 21/31 vaccinated dialysis patients (67.7%, 95%CI: 48.53-82.68) compared to 42/44 (93.3%, 95%CI: 76.49-98.84) in controls of similar age. Patients on dialysis demonstrate a delayed, but robust immune response three to four weeks after the second dose, which indicates effective vaccination of this vulnerable group. However, the lower immunogenicity of Tozinameran in these patients needs further attention to develop potential countermeasures such as an additional booster vaccination.

Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients.

Patients with kidney failure are at increased risk for SARS-CoV-2 infection making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 35 HC, 44 DP and 40 KTR. Markedly impaired anti-BNT162b2 responses were identified among KTR and DP compared to HC. In DP, the response was delayed (3-4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5% and 68.2%, respectively. In contrast, KTR did not develop IgG responses except one patient who had a prior unrecognized infection and developed anti-S1 IgG. The majority of antigen-specific B cells (RBD+) were identified in the plasmablast or post-switch memory B cell compartments in HC, whereas RBD+ B cells were enriched among pre-switch and naïve B cells from DP and KTR. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.

Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients.

Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2, with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine-induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after the standard second vaccination dose. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4 of 39 and 1 of 39 transplanted individuals showed IgA and IgG seroconversion at day 8 ± 1 after booster immunization, with minor changes until day 23 ± 5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared with those in controls and dialysis patients and this was accompanied by a broad impairment in effector cytokine production, memory differentiation, and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Promotion of anti-HLA antibodies or acute rejection was not detected after vaccination. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk of developing severe COVID-19.

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation.

PURPOSE: Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder. METHODS: In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders. RESULTS: In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected. CONCLUSION: Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD.

Carotid artery blood flow velocities during open-heart surgery and its association with delirium: A prospective, observational pilot study.

The aim of this prospective observational single-centre pilot study was to evaluate the association between alterations in carotid artery blood flow velocities during cardiac surgery and postoperative delirium.Carotid artery blood flow velocity was determined perioperatively at 5 different timepoints by duplex sonography in 36 adult cardiac surgical patients. Delirium was assessed using the Confusion Assessment Method for the ICU and the Intensive Care Delirium Screening Checklist. Additionally, blood flow velocities in the middle cerebral arteries, differences in regional cerebral tissue oxygenation and quantity and quality of microemboli were measured.Delirium was detected in 7 of 36 patients. After cardiopulmonary bypass carotid artery blood flow velocities increased by +23 cm/second (95% confidence interval (CI) 9-36 cm/second) in non-delirious patients compared to preoperative values (P = .002), but not in delirious patients (+3 cm/second [95% CI -25 to 32 cm/second], P = .5781). Middle cerebral artery blood flow velocities were higher at aortic de-cannulation in non-delirious patients (29 cm/second [inter-quartile range (IQR), 24-36 cm/second] vs 12 cm/second [IQR, 10-19 cm/second]; P = .017). Furthermore, brain tissue oxygenation was higher in non-delirious patients during surgery.Our results suggest that higher cerebral blood flow velocities after aortic de-clamping and probably also improved brain oxygenation might be beneficial to prevent postoperative delirium.

Resident performance in basic perioperative transesophageal echocardiography: Comparing 3 teaching methods in a randomized controlled trial.

BACKGROUND: Training in transesophageal echocardiography (TEE) is based on hands-on training in the operating room, which is time consuming and therefore limits its experience among anesthesiologists. Medical simulations have been successfully used for training of invasive procedures in many areas.This paper compares the difference in effectiveness of teaching the 11 basic TEE views using either e-learning, simulation based training or hands-on training in the operating room in 3 groups of residents. METHODS: We included 51 anesthesia and intensive care residents of all training levels but no prior training in echocardiography in this prospective randomized single-center study.Residents received a tutorial about theoretical knowledge followed by 2 practical study sessions either by e-learning using an online simulator (www.pie.med.utoronto.ca/TEE), with the simulation mannequin (CAE Vimedix Simulator) or in the operating room. Both, a theoretical multiple choice test (0-50 points) and a practical exam test (0-110 points) on the simulation mannequin had to be completed.The primary endpoint was the post-training scores in the practical and theoretical exams after all training sessions. RESULTS: Residents received significantly higher test scores in both practical and theoretical examinations after training with the simulation mannequin (108.41 ±â€Š2.09, 40.6 ±â€Š5.23, n = 17) compared with e-learning (106.88 ±â€Š4.53, 36 ±â€Š4.76, n = 17) or hands-on training (106.82 ±â€Š2.01, 34.94 ±â€Š4.72, n = 17). CONCLUSIONS: Simulation based TEE training provides more effective training than other teaching methods. It is therefore especially suitable for the initial stages of TEE training to acquire psychomotor skills and knowledge of echo-anatomy.

Hemoadsorption does not Have Influence on Hemolysis During Cardiopulmonary Bypass.

Cardiopulmonary bypass (CPB) induces hemolysis, which manifests as plasma free hemoglobin. We investigated in a post hoc analysis of a single-center, blinded, controlled study whether the use of a novel hemoadsorption device (CytoSorb, CytoSorbents Europe GmbH, Berlin, Germany) affects hemolysis during CPB. A total of 35 patients undergoing elective CPB surgery with an expected CPB duration of more than 120 min were included in the analysis. The hemoadsorption device was used in 17 patients (intervention group) and not used in 18 patients (control group). The primary outcome was differences of postoperative free hemoglobin and haptoglobin levels. As secondary outcomes, we investigated differences in postoperative lactate dehydrogenase and bilirubin levels. Postoperative free hemoglobin levels were not significantly different between the groups. However, there were statistically significant differences between the treatment and control groups in the median levels of haptoglobin (58.4 vs. 17.9 mg/dL, respectively; P < 0.01) and lactate dehydrogenase (353.0 vs. 432.0 U/L, respectively; P < 0.05) on postoperative day 1. Thus, in this study, we did not find an effect on hemolysis in patients treated with hemoadsorption, though lower haptoglobin level and higher secondary hemolysis markers on postoperative day 1 in patients not treated with the hemoadsorber may be an indication of some moderate effect of the device. Studies with larger samples are needed to clarify the significance of the small differences detected in this study.

High altitude trekking after lung transplantation: a prospective study using lung ultrasound to detect comets tails for interstitial pulmonary edema in lung transplant recipients and healthy volunteers.

The intensity of physical activity which can be tolerated after lung transplantation and the tolerance to prolonged exercise at high altitude are poorly investigated. Lung ultrasound comet tails have been used in the diagnosis of interstitial pulmonary edema and high pulmonary altitude edema. The aim was to assess the number of lung ultrasound comet tails and to monitor changes in the optic nerve sheath diameter (ONSD) during a climb to the top of Mount Kilimanjaro in 10 lung transplant recipients and 10 healthy controls at three different altitude levels: 1360, 3505, 4900 m. Lung transplant recipients showed a constant increase in comet tail scores with altitude, whereas control subjects only showed an increase at the highest measurement point. Differences between groups (transplant versus control) reached significance only after the first ascend: 0.9 (95% CI: -0.41; 2.21) vs. 0.1 (95% CI: -0.12; 0.32) (P = 0.2; 1360 m), 2.33 (95% CI: 0.64; 4.02) vs. 0.3 (95% CI: -0.18; 0.78) (P = 0.04; 3505 m), and 4.11 (95% CI: 0.13; 0.34) vs. 2.9 (95% CI: 0.49; 5.31) (P = 0.15; 4900 m); ONSD increased significantly in both groups from 3.53 (95% CI: 0.34; 0.66) at 1360 m to 4.11 (95% CI: 0.36; 0.71) at 4900 m (P < 0.05). Lungs of transplant recipients are able to adapt to altitude and capable of performing prolonged exercise at high altitude after slow ascend.

Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.

The exceptionally large SYNE1 (spectrin repeat-containing nuclear envelope protein 1) gene encodes different nesprin-1 isoforms, which are differentially expressed in striated muscle and in cerebellar and cerebral neurons. Nesprin-1 isoforms can function in cytoskeletal, nuclear, and vesicle anchoring. SYNE1 variants have been associated with a spectrum of neurological and neuromuscular disease. Homozygosity mapping combined with exome sequencing identified a disease-causing nonsense mutation in the ultimate exon of full-length SYNE1 transcript in an 8-year-old boy with distal arthrogryposis and muscular hypotonia. mRNA analysis showed that the mutant transcript is expressed at wild-type levels. The variant truncates nesprin-1 isoforms for the C-terminal KASH (Klarsicht-ANC-Syne homology) domain. This is the third family with recessive arthrogryposis caused by homozygous distal-truncating SYNE1 variants. There is a SYNE1 genotype-phenotype correlation emerging, with more proximal homozygous SYNE1 variants causing recessive cerebellar ataxia of variable onset (SCAR8; ARCA-1).

The native cardiac output in human sepsis: a systematic review.

BACKGROUND: The cardiac output (CO) response to sepsis is typically measured in the intensive care unit after modification by fluid and/or vasoactive drug resuscitation and found to be hyperdynamic. In contrast, the native (preresuscitation) CO in human sepsis is poorly defined. DESIGN AND DATA SOURCES: Systematic literature review of studies reporting the cardiac index (CI) of patients with sepsis before resuscitation, using searches of PubMed, MEDLINE and Embase. RESULTS: We identified 5667 citations from 1929 to 2014. Of 179 articles meeting inclusion criteria, only four studies reported CO measurements before any treatment, in a total of 181 patients. Only two of the four studies reported age distribution (mean age, 72 years) for a total of 159 patients. We calculated the mean CI in these four studies to be 2.68 L/ min/m(2) (SD, 0.42 L/min/m(2); median, 2.52 L/min/m(2); range, 2.36-3.3 L/min/m(2)). Only one study presented mixed venous oxygen saturation data as an estimate of the adequacy of perfusion, and in three studies there was evidence of reduced cardiac performance. CONCLUSION: Data about the native CO in human sepsis are scant because therapeutic intervention usually precedes measurement. From the limited data available, it appears that most patients are in a normodynamic haemodynamic state at presentation, and cardiac performance also seems to be impaired at the earliest stage of sepsis. As initial resuscitation is partly predicated on assumptions about the underlying cardiovascular physiology, our findings suggest the need to address this knowledge deficit in the management of patients with severe sepsis.

Modeling Requirements for Cohort and Register IT.

BACKGROUND: The project KoRegIT (funded by TMF e.V.) aimed to develop a generic catalog of requirements for research networks like cohort studies and registers (KoReg). The catalog supports such kind of research networks to build up and to manage their organizational and IT infrastructure. OBJECTIVES: To make transparent the complex relationships between requirements, which are described in use cases from a given text catalog. By analyzing and modeling the requirements a better understanding and optimizations of the catalog are intended. There are two subgoals: a) to investigate one cohort study and two registers and to model the current state of their IT infrastructure; b) to analyze the current state models and to find simplifications within the generic catalog. METHODS: Processing the generic catalog was performed by means of text extraction, conceptualization and concept mapping. Then methods of enterprise architecture planning (EAP) are used to model the extracted information. To work on objective a) questionnaires are developed by utilizing the model. They are used for semi-structured interviews, whose results are evaluated via qualitative content analysis. Afterwards the current state was modeled. Objective b) was done by model analysis. RESULTS: A given generic text catalog of requirements was transferred into a model. As result of objective a) current state models of one existing cohort study and two registers are created and analyzed. An optimized model called KoReg-reference-model is the result of objective b). CONCLUSION: It is possible to use methods of EAP to model requirements. This enables a better overview of the partly connected requirements by means of visualization. The model based approach also enables the analysis and comparison of the empirical data from the current state models. Information managers could reduce the effort of planning the IT infrastructure utilizing the KoReg-reference-model. Modeling the current state and the generation of reports from the model, which could be used as requirements specification for bids, is supported, too.