Difficulties in prediction and early identification of (acute kidney injury) AKI have hindered the ability to develop preventive and therapeutic measures for this syndrome. We tested the hypothesis ...that a urine test measuring insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in acute kidney injury (AKI), could predict AKI in cardiac surgery patients.
We studied 50 patients at high risk for AKI undergoing cardiac surgery with cardiopulmonary bypass (CPB). Serial urine samples were analyzed for TIMP-2*IGFBP7 concentrations. The primary outcome measure was AKI as defined by international consensus criteria following surgery. Furthermore, we investigated whether urine TIMP-2*IGFBP7 could predict renal recovery from AKI prior to hospital discharge.
26 patients (52%) developed AKI. Diagnosis based on serum creatinine and/or oliguria did not occur until 1-3 days after CPB. In contrast, urine concentration of TIMP-2*IGFBP7 rose from a mean of 0.49 (SE 0.24) at baseline to 1.51 (SE 0.57) 4 h after CPB in patients who developed AKI. The maximum urinary TIMP-2*IGFBP7 concentration achieved in the first 24 hours following surgery (composite time point) demonstrated an area under the receiver-operating characteristic curve of 0.84. Sensitivity was 0.92, and specificity was 0.81 for a cutoff value of 0.50. The decline in urinary TIMP-2*IGFBP7 values was the strongest predictor for renal recovery.
Urinary TIMP-2*IGFBP7 serves as a sensitive and specific biomarker to predict AKI early after cardiac surgery and to predict renal recovery.
www.germanctr.de/, DRKS-ID: DRKS00005062.
The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 ...recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.
•We present comprehensive information on genetic driver events in a uniformly treated cohort of 664 adult AML patients aged 18 to 86 years.•Mutations in NPM1, FLT3, CEBPA, TP53, and, in patients <60 years, DNMT3A and RUNX1, are the most important molecular risk factors in AML.
Immunotherapy can become a crucial therapeutic option to improve prognosis for lung cancer patients. First clinical trials with therapies targeting the programmed cell death receptor PD-1 and its ...ligand PD-L1 have shown promising results in several solid tumors. However, in lung cancer the diagnostic, prognostic and predictive value of these immunologic factors remains unclear.
The impact of both factors was evaluated in a study collective of 321 clinically well-annotated patients with non-small lung cancer (NSCLC) using immunohistochemistry.
PD-1 expression by tumor infiltrating lymphocytes (TILs) was found in 22%, whereas tumor cell associated PD-L1 expression was observed in 24% of the NSCLC tumors. In Fisher's exact test a positive correlation was found for PD-L1 and Bcl-xl protein expression (p = 0.013). Interestingly, PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas (SCC, p = 0.042, log rank test), with adjuvant therapy (p = 0.017), with increased tumor size (pT2-4, p = 0.039) and with positive lymph node status (pN1-3, p = 0.010). These observations were confirmed by multivariate cox regression models.
One major finding of our study is the identification of a prognostic implication of PD-L1 in subsets of NSCLC patients with pulmonary SCC, with increased tumor size, with a positive lymph node status and NSCLC patients who received adjuvant therapies. This study provides first data for immune-context related risk stratification of NSCLC patients. Further studies are necessary both to confirm this observation and to evaluate the predictive value of PD-1 and PD-L1 in NSCLC in the context of PD-1 inhibition.
Escherichia coli bovine mastitis is a disease of significant economic importance in the dairy industry. Molecular characterization of mastitis-associated E. coli (MAEC) did not result in the ...identification of common traits. Nevertheless, a mammary pathogenic E. coli (MPEC) pathotype has been proposed suggesting virulence traits that differentiate MAEC from commensal E. coli. The present study was designed to investigate the MPEC pathotype hypothesis by comparing the genomes of MAEC and commensal bovine E. coli.
We sequenced the genomes of eight E. coli isolated from bovine mastitis cases and six fecal commensal isolates from udder-healthy cows. We analyzed the phylogenetic history of bovine E. coli genomes by supplementing this strain panel with eleven bovine-associated E. coli from public databases. The majority of the isolates originate from phylogroups A and B1, but neither MAEC nor commensal strains could be unambiguously distinguished by phylogenetic lineage. The gene content of both MAEC and commensal strains is highly diverse and dominated by their phylogenetic background. Although individual strains carry some typical E. coli virulence-associated genes, no traits important for pathogenicity could be specifically attributed to MAEC. Instead, both commensal strains and MAEC have very few gene families enriched in either pathotype. Only the aerobactin siderophore gene cluster was enriched in commensal E. coli within our strain panel.
This is the first characterization of a phylogenetically diverse strain panel including several MAEC and commensal isolates. With our comparative genomics approach we could not confirm previous studies that argue for a positive selection of specific traits enabling MAEC to elicit bovine mastitis. Instead, MAEC are facultative and opportunistic pathogens recruited from the highly diverse bovine gastrointestinal microbiota. Virulence-associated genes implicated in mastitis are a by-product of commensalism with the primary function to enhance fitness in the bovine gastrointestinal tract. Therefore, we put the definition of the MPEC pathotype into question and suggest to designate corresponding isolates as MAEC.
The lack of early biomarkers for acute kidney injury (AKI) seriously inhibits the initiation of preventive and therapeutic measures for this syndrome in a timely manner. We tested the hypothesis that ...insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, function as early biomarkers for AKI after congenital heart surgery with cardiopulmonary bypass (CPB).
We prospectively studied 51 children undergoing cardiac surgery with CPB. Serial urine samples were analyzed for TIMP-2•IGFBP7. The primary outcome measure was AKI defined by the pRIFLE criteria within 72 hours after surgery.
12 children (24%) developed AKI within 1.67 (SE 0.3) days after surgery. Children who developed AKI after cardiac surgery had a significant higher urinary TIMP-2•IGFBP7 as early as 4 h after the procedure, compared to children who did not develop AKI (mean of 1.93 ((ng/ml)²/1000) (SE 0.4) vs 0.47 ((ng/ml)²/1000) (SE 0.1), respectively; p<0.05). Urinary TIMP-2•IGFBP7 4 hours following surgery demonstrated an area under the receiver-operating characteristic curve of 0.85. Sensitivity was 0.83, and specificity was 0.77 for a cutoff value of 0.70 ((ng/ml)²/1000).
Urinary TIMP-2•IGFBP7 represent sensitive, specific, and highly predictive early biomarkers for AKI after surgery for congenital heart disease.
www.germanctr.de/, DRKS00005062.
Background: Smart devices that are able to measure blood pressure (BP) are valuable for hypertension or heart failure management using digital technology. Data regarding their diagnostic accuracy in ...comparison to standard noninvasive measurement in accordance to Riva-Rocci are sparse. This study compared a wearable watch-type oscillometric BP monitor (Omron HeartGuide), a wearable watch-type infrared BP monitor (Smart Wear), a conventional ambulatory BP monitor, and auscultatory sphygmomanometry. Methods: Therefore, 159 consecutive patients (84 male, 75 female, mean age 64.33 ± 16.14 years) performed observed single measurements with the smart device compared to auscultatory sphygmomanometry (n = 109) or multiple measurements during 24 h compared to a conventional ambulatory BP monitor on the upper arm (n = 50). The two BP monitoring devices were simultaneously worn on the same arm throughout the monitoring period. In a subgroup of 50 patients, single measurements were also performed with an additional infrared smart device. Results: The intraclass correlation coefficient (ICC) between the difference and the mean of the oscillometric Omron HeartGuide and the conventional method for the single measurement was calculated for both systole (0.765) and diastole (0.732). This is exactly how the ICC was calculated for the individual mean values calculated over the 24 h long-term measurement of the individual patients for both systole (0.880) and diastole (0.829). The ICC between the infrared device and the conventional method was “bad” for SBP (0.329) and DBP (0.025). Therefore, no further long-term measurements were performed with the infrared device. Conclusion: The Omron HeartGuide device provided comparable BP values to the standard devices for single and long-term measurements. The infrared smart device failed to acquire valid measurement data.
Medical education research focuses on the development of efficient learning methods promoting the acquisition of student's knowledge and competencies. Evaluation of any modification of educational ...approaches needs to be evaluated accordingly and a reliable effect size needs to be reached. Our aim is to provide a methodological basis to calculate effect sizes from longitudinal progress test data that can be used as reference values in further research. We used longitudinally collected progress test data and evaluated the increasing knowledge of medical students from the first to the fifth academic year. Students were asked to participate in the progress test, which consists of 200 multiple-choice questions in single best answer format with an additional 'don't know' option. All available individual test scores of all progress tests (n = 10) administered between April 2012 and October 2017 were analyzed. Due to the large amount of missing test results, e.g., from students at the beginning of their studies, a linear mixed model was fitted to include all collected data. In total, we analyzed 6324 test scores provided by 2587 medical students. Mean score for medical knowledge (% correct answers) increases from 16.6% (SD: 10.8%) to 51.0% (SD: 15.7%, overall effects size using linear mixed models d = 1.55). Medical students showed a learning effect of d = 0.54 (total gain: 6.9%) between the 1
st
and 2
nd
, d = 0.88 (total gain: 12.0%) between the 2
nd
and 3
rd
, d = 0.60 (total gain: 7.9%) between the 3
rd
and 4
th
and d = 0.58 (total gain: 7.9%) between the 4
th
and 5
th
study year. We demonstrated that incomplete data from longitudinally collected progress tests can be used to acquire reliable effect size estimates. The demonstrated effects size between d = 0.53-0.9 by study year may help researchers to design studies in medical education.
PSMA (prostate-specific membrane antigen) is overexpressed in prostate cancer cells and is reported to be a promising target for antibody-based radioligand therapy in patients with metastasized ...prostate cancer. Since PSMA expression is not restricted to prostate cancer, the underlying study investigates PSMA expression in non-small cell lung cancer (NSCLC).
Immunohistochemistry was used to identify PSMA expression in n = 275 samples of NSCLC tissue specimens. By means of CD34 co-expression, the level of PSMA expression in tumor associated neovasculature was investigated. The impact of PSMA expression on clinicopathologic parameters and prognosis was evaluated.
PSMA tumor cell expression in NSCLC is as low as 6% and was predominantly found in squamous cell carcinoma (p = 0.002). Neovascular PSMA expression was found in 49% of NSCLC. High neovascular PSMA expression was associated with higher tumor grading (G3/G4) (p < 0.001). Neither for PSMA tumor cell expression, nor for PSMA neovascular cell expression prognostic effects were found for the investigated NSCLC cases.
Here, we report on the expression of PSMA in NSCLC tissue samples. Against the background of a potential treatment with radiolabeled PSMA ligands, our data might serve for the future identification of patients who could benefit from this therapeutic option.
Rasmussen encephalitis (RE) is a rare paediatric epilepsy with uni-hemispheric inflammation and progressive neurological deficits. To elucidate RE immunopathology, we applied T-cell receptor (TCR) ...sequencing to blood (n=23), cerebrospinal fluid (n=2) and brain biopsies (n=5) of RE patients, and paediatric controls. RE patients present with peripheral CD8(+) T-cell expansion and its strength correlates with disease severity. In addition, RE is the only paediatric epilepsy with prominent T-cell expansions in the CNS. Consistently, common clones are shared between RE patients, who also share MHC-I alleles. Public RE clones share Vβ genes and length of the CDR3. Rituximab/natalizumab/basiliximab treatment does not change TCR diversity, stem cell transplantation replaces the TCR repertoire with minimal overlap between donor and recipient, as observed in individual cases. Our study supports the hypothesis of an antigen-specific attack of peripherally expanded CD8(+) lymphocytes against CNS structures in RE, which might be ameliorated by restricting access to the CNS.
Although preventive interventions for eating disorders in general have shown promise, interventions specifically targeting individuals at risk for anorexia nervosa (AN) are lacking.
The aim of this ...study was to determine the efficacy of a guided, indicated web-based prevention program for women at risk for AN.
We conducted a randomized controlled efficacy trial for women at risk for AN. Assessments were carried out at baseline (before the intervention), after the intervention (10 weeks after baseline), and at 6- and 12-month follow-ups (FUs). A total of 168 women with low body weight (17.5 kg/m
≤BMI≤19 kg/m
) and high weight concerns or with normal body weight (19 kg/m
<BMI≤25 kg/m
), high weight concerns, and high restrained eating were recruited from 3 German universities as well as on the web and randomized to Student Bodies-AN (SB-AN; intervention group IG) or a wait-list control group (CG). The exclusion criteria were current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-based full-syndrome eating disorders and serious medical or mental problems. The interventions were a cognitive-behavioral guided web-based prevention program (SB-AN) over 10 weeks (IG) and a wait-list CG. The primary outcomes were clinically significant changes in disordered eating attitudes and behaviors and change in BMI at 12-month FU in the group of participants who were underweight. The secondary outcomes were new onset of eating disorders, symptoms of disordered eating, and associated psychopathology.
Data were available for 81.5% (137/168) of the women after the intervention and for 69% (116/168) of the women at 12-month FU. At 12-month FU, the IG participants showed larger decreases in Eating Disorder Examination total scores (38/48, 79% vs 33/58, 57%) than the CG participants and the IG participants who were underweight also showed larger clinically relevant increases in BMI (15/31, 49% vs 10/32, 32%) than the CG participants, but these differences were not significant. In addition, after the intervention and at 12-month FU, we found a significant increase in continuously measured BMI for the participants who were underweight and significant improvements in disordered eating attitudes and behaviors (eg, restrained eating as well as weight and shape concerns). At all time points, the rates of new-onset eating disorder cases were (nonsignificantly) lower in the IG than in the CG and the reductions in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-based eating disorder syndromes were (nonsignificantly) higher in the IG than in the CG.
SB-AN is the first preventive intervention shown to significantly reduce specific risk factors for, and symptoms of, AN and shows promise for reducing full-syndrome AN onset.
ISRCTN Registry ISRCTN70380261; https://www.isrctn.com/ISRCTN70380261.
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