Morphological changes of macular neovascularization during long-term anti-VEGF-therapy in neovascular age-related macular degeneration.

PURPOSE: To analyze the morphological changes of macular neovascularization (MNV) in exudative neovascular age-related macular degeneration under long-term intravitreal anti-vascular endothelial growth factor (VEGF) therapy in a retrospective cohort study. METHODS AND PATIENTS: We evaluated 143 nAMD eyes of 94 patients (31 male, 63 female; initial age 55-97 y, mean age 75.9 ± 7.5 y), who started anti-VEGF therapy (IVAN pro re nata (PRN) protocol) between 2009-2018 and received ongoing therapy until the last recorded visit (mean follow-up 5.3 ± 2.9 y, range 1-14 y). The mean total number of injections was 33.3 ± 19.8 with 7.0 ± 2.3 injections/year. MNV size and, if present, associated complete retinal pigment epithelium (RPE) and outer retina atrophy (cRORA) size were measured on optical coherence tomography (OCT) volume scans at the initial visit and for each year of follow-up. MNV and cRORA were identified on B-scans and their respective borders were manually transposed onto the en-face near infrared image and measured in mm2. RESULTS: MNV enlarged through follow-up, with a mean growth rate of 1.24 mm2 / year. The mean growth in MNV size was independent of initial MNV size, age, gender, MNV subtypes or number of injections per year. Nevertheless, a great interindividual variation in size and growth was observed. cRORA developed in association with increasing MNV size and its incidence increased linearly over follow-up. cRORA lesions also showed continuous growth by a rate of 1.22 mm2 / year. CONCLUSIONS: Despite frequent long-term anti-VEGF therapy, we observed ongoing MNV growth. This is consistent with the concept that the development of MNV may be a physiological biological repair mechanism to preserve RPE and photoreceptor function, provided hyperpermeability and fluid exudation are controlled. Whether recurring low VEGF levels or other factors are responsible for MNV growth remains controversial.

Graft-versus-host disease following liver transplantation: A systematic review of literature.

BACKGROUND: Graft-versus-host disease following liver transplantation is a serious and usually fatal complication. Data identifying the risk factors and specifying the diagnosis and treatment options of the disease are scarce and contentious. Moreover, recommendations for therapeutic approaches are similarly sparse. METHODS: A systematic review of the literature from 1988 to 2020 on graft-versus-host disease following liver transplantation was performed using the PubMed and MEDLINE databases. Medical subject headings, such as graft-versus-host disease and GvHD were used in combination with solid organ transplant, transplantation, or liver transplant. Following duplicate removal, 9298 articles were screened for suitability. A total of 238 full-text articles were analyzed for eligibility, resulting in 130 eligible articles for meta-analysis. Two hundred twenty-five patients developing graft-versus-host disease following liver transplantation reported herein were mainly published in case reports and case series. RESULTS: Graft-versus-host disease occurred with an incidence of 1.2%. 85% developed following deceased donor liver transplant and 15% following living-related donor liver transplantation. The median follow-up period following liver transplantation was 84 days (interquartile range, 45-180). The median time from liver transplantation to graft-versus-host disease onset was 30 days (interquartile range, 21-42). The main clinical features included skin rash (59%), fever (43%), diarrhea (36%), and pancytopenia (30%). The overall mortality rate was 71%. Neither univariate (HR = 0.999; 95% CI, 0.493-2.023; p = 1.0) nor multivariate Cox regression analysis revealed a significant correlation between adaptation of immunosuppression and survival probability (HR = 1.475; 95% CI, 0.659-3.303; p = 0.3). CONCLUSIONS: This systematic review suggests that an increase in immunosuppressive regimen does not yield any survival benefit in patients suffering from graft-versus-host disease following liver transplantation.

Submacular Hemorrhages Show No Significant Seasonal Variations in a European Cohort.

The aim of the article is to investigate the seasonality of acute submacular hemorrhages (SMHs) in a European population and analyze the influence of the seasons, arterial hypertension, and intake of anticoagulatory/antiplatelet (AC/AP) medication on hemorrhage size. This retrospective, monocentric study included 164 eyes of 164 patients treated for acute SMH at the University Hospital Münster, Germany, between 1 January 2016 and 31 December 2021. Data on the day of occurrence, hemorrhage size, and general patient characteristics were recorded. "Test for cyclic trends in incidence data" and the Chi-Square Test were applied to investigate seasonal variations in SMH incidence. Fisher's exact test was used to investigate the influence of the seasons, arterial hypertension, and intake of AC/AP medication on hemorrhage size. A statistical analysis did not reveal significant seasonal variations in the occurrence of SMHs (p = 0.81). While the seasons and the presence of systemic arterial hypertension did not exert a significant influence, the intake of AC/AP medication significantly affected the size of SMH (p = 0.03). In this European cohort, no significant seasonal variations of SMHs were observed. However, in patients with risk factors, such as neovascular age-related macular degeneration (nAMD), the chance of an increase in hemorrhage size should be considered when initiating AC/AP therapy.

Immunodeficiency is prevalent in congenital heart disease and associated with increased risk of emergency admissions and death.

AIMS: To provide population-based data on the prevalence and clinical significance of immune deficiency syndromes (IDS) associated with congenital heart disease (CHD). METHODS AND RESULTS: Utilizing administrative German Health System data the prevalence of increased susceptibility to infection (ISI) or confirmed IDS was assessed in CHD patients and compared with an age-matched non-congenital control group. Furthermore, the prognostic significance of IDS was assessed using all-cause mortality and freedom from emergency hospital admission. A total of 54 449 CHD patients were included. Of these 14 998 (27.5%) had ISI and 3034 (5.6%) had a documented IDS (compared with 2.9% of the age-matched general population). During an observation period of 394 289 patient-years, 3824 CHD patients died, and 31 017 patients experienced a combined event of all-cause mortality or emergency admission. On multivariable Cox proportional-hazard analysis, the presence of ISI [hazard ratio (HR): 2.14, P < 0.001] or documented IDS (HR: 1.77, P = 0.035) emerged as independent predictors of all-cause mortality. In addition, ISI and confirmed IDS were associated with a significantly higher risk of emergency hospital admission (P = 0.01 for both on competing risk analysis) during follow-up. CONCLUSION: Limited immune competence is common in CHD patients and associated with an increased risk of morbidity and mortality. This highlights the need for structured IDS screening and collaboration with immunology specialists as immunodeficiency may be amenable to specific therapy. Furthermore, studies are required to assess whether IDS patients might benefit from intensified antibiotic shielding or tailored prophylaxis.

Fetal adrenal gland size and umbilical artery Doppler in growth-restricted fetuses.

OBJECTIVES: In fetal growth restriction (FGR), Doppler ultrasound is the most important method for the detection and management. However, additional parameters are needed to improve the distinction between constitutionally small fetuses and fetuses affected by FGR. METHODS: A total of 445 singleton pregnancies between 23 and 40 weeks of gestation were included in our retrospective study, of which 67 with FGR and 378 normal fetuses. A 2D-plane of the fetal adrenal gland was obtained and the adrenal gland ratio was measured. Spearman's correlation coefficient was calculated to assess the association of fetal Doppler and adrenal gland ratio with outcome parameters. Logistic regression analysis was performed to assess the statistical significance of "PI of the umbilical artery" and "adrenal gland ratio" as prognostic factors for intrauterine growth restriction (IUGR). RESULTS: PI of the umbilical artery was shown to correlate with outcome parameters (WG_Delivery: r=-0.125, p=0.008; birth weight: r=-0.268, p<0.001; birth weight centile: r=-0.248, p<0.001; APGAR at 5 min: r=-0.117, p=0.014). Adrenal gland ratio showed no correlation with any of the outcome parameters. In logistic regression however, both PI of the umbilical artery and the adrenal ratio were shown to be significantly associated with fetal IUGR. When combining the two parameters, predictive value was superior to the predictive value of each individual parameter (AUC 0.738 [95% CI 0.670; 0.806]). CONCLUSIONS: The adrenal gland ratio can be a useful addition to Doppler ultrasound when it comes to the detection of fetal FGR. Prospective studies are needed to establish references ranges and cut-off values for clinical decision-making.

Update Reference Charts: Fetal Biometry between the 15th and 42nd Week of Gestation.

OBJECTIVES: This study was designed to establish new reference charts for BPD (biparietal diameter), OFD (occipitofrontal diameter), HC (head circumference), CM (cisterna magna), TCD (transverse cerebellar diameter), PCV (posterior cerebral ventricle), AC (abdominal circumference), FL (femur length), and HL (humerus length) and extend known charts to 42 weeks of gestation. These new charts were compared to studies carried out by Snijders and Nicolaides, the INTERGROWTH 21st Project, and the WHO Fetal Growth Charts. METHODS: In this retrospective cross-sectional single-center study of 12,972 low-risk pregnancies, biometric data between the 15th and 42nd weeks of gestation were evaluated. Only one examination per pregnancy was selected for statistical analysis. Descriptive analysis for the 5th, 50th, and 95th quantile was performed for each parameter as listed above. Regression models were used to fit the mean and the SD at each gestational age. RESULTS: Initially the reference curves for BPD, OFD, HC, AC, FL, and HL show a linear increase, which changes into a cubic increase towards the end of pregnancy. The results of this study show statistically noticeable differences from the percentile curves of the studies listed above. CONCLUSIONS: The percentile curves in this study differ from the commonly used ones. The presented standard curves can be used as a reference in prenatal diagnostics.

How Old Is Old? An Age-Stratified Analysis of Elderly Liver Donors above 65.

In liver transplantation, older donor age is a well-known risk factor for dismal outcomes, especially due to the high susceptibility of older grafts to ischemia-reperfusion injury. However, whether the factors correlating with impaired graft and patient survival following the transplantation of older grafts follow a linear trend among elderly donors remains elusive. In this study, liver transplantations between January 2006 and May 2018 were analyzed retrospectively. Ninety-two recipients of grafts from donors ≥65 years were identified and divided into two groups: (1) ≥65-69 and (2) ≥ 70 years. One-year patient survival was comparable between recipients of grafts from donors ≥65-69 and ≥70 years (78.9% and 70.0%). One-year graft survival was 73.1% (donor ≥65-69) and 62.5% (donor ≥ 70), while multivariate analysis revealed superior one-year graft survival to be associated with a donor age of ≥65-69. No statistically significant differences were found for rates of primary non-function. The influence of donor age on graft and patient survival appears not to have a distinct impact on dismal outcomes in the range of 65-70 years. The impact of old donor age needs to be balanced with other risk factors, as these donors provide grafts that offer a lifesaving graft function.

Effect of Intraoperative Handovers of Anesthesia Care on Mortality, Readmission, or Postoperative Complications Among Adults: The HandiCAP Randomized Clinical Trial.

Importance: Intraoperative handovers of anesthesia care are common. Handovers might improve care by reducing physician fatigue, but there is also an inherent risk of losing critical information. Large observational analyses report associations between handover of anesthesia care and adverse events, including higher mortality. Objective: To determine the effect of handovers of anesthesia care on postoperative morbidity and mortality. Design, Setting, and Participants: This was a parallel-group, randomized clinical trial conducted in 12 German centers with patients enrolled between June 2019 and June 2021 (final follow-up, July 31, 2021). Eligible participants had an American Society of Anesthesiologists physical status 3 or 4 and were scheduled for major inpatient surgery expected to last at least 2 hours. Interventions: A total of 1817 participants were randomized to receive either a complete handover to receive anesthesia care by another clinician (n = 908) or no handover of anesthesia care (n = 909). None of the participating institutions used a standardized handover protocol. Main Outcomes and Measures: The primary outcome was a 30-day composite of all-cause mortality, hospital readmission, or serious postoperative complications. There were 19 secondary outcomes, including the components of the primary composite, along with intensive care unit and hospital lengths of stay. Results: Among 1817 randomized patients, 1772 (98%; mean age, 66 [SD, 12] years; 997 men [56%]; and 1717 [97%] with an American Society of Anesthesiologists physical status of 3) completed the trial. The median total duration of anesthesia was 267 minutes (IQR, 206-351 minutes), and the median time from start of anesthesia to first handover was 144 minutes in the handover group (IQR, 105-213 minutes). The composite primary outcome occurred in 268 of 891 patients (30%) in the handover group and in 284 of 881 (33%) in the no handover group (absolute risk difference [RD], -2.5%; 95% CI, -6.8% to 1.9%; odds ratio [OR], 0.89; 95% CI, 0.72 to 1.10; P = .27). Nineteen of 889 patients (2.1%) in the handover group and 30 of 873 (3.4%) in the no handover group experienced all-cause 30-day mortality (absolute RD, -1.3%; 95% CI, -2.8% to 0.2%; OR, 0.61; 95% CI, 0.34 to 1.10; P = .11); 115 of 888 (13%) vs 136 of 872 (16%) were readmitted to the hospital (absolute RD, -2.7%; 95% CI, -5.9% to 0.6%; OR, 0.80; 95% CI, 0.61 to 1.05; P = .12); and 195 of 890 (22%) vs 189 of 874 (22%) experienced serious postoperative complications (absolute RD, 0.3%; 95% CI, -3.6% to 4.1%; odds ratio, 1.02; 95% CI, 0.81 to 1.28; P = .91). None of the 19 prespecified secondary end points differed significantly. Conclusions and Relevance: Among adults undergoing extended surgical procedures, there was no significant difference between the patients randomized to receive handover of anesthesia care from one clinician to another, compared with the no handover group, in the composite primary outcome of mortality, readmission, or serious postoperative complications within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04016454.

Results of the prospective multicenter SoLKiD cohort study indicate bio-psycho-social outcome risks to kidney donors 12 months after donation.

The outcome after living kidney donation was assumed to be comparable to that of the general population. However, recent register studies reveal negative changes in kidney function, quality of life and fatigue. Avoiding methodological issues of previous studies, the Safety of the Living Kidney Donor (SoLKiD) cohort study analyzed the outcome of donors in a multicenter and interdisciplinary fashion. Donor data were collected pre-donation and two-, six- and 12-months post-donation in 20 German transplantation centers. Primary parameters were kidney function, quality of life, and fatigue. Secondary endpoints were blood pressure, hemoglobin, hemoglobin A1c, body mass index, depression and somatization. Parameters were analyzed with non-parametric statistical tests and a mixed model regression for changes in time, their clinical relevance and interaction encompassing 336 donors with mean age of 52 years. Most of the physical secondary parameters, depression, and quality of life showed little or no changes and regained their pre-donation level. Kidney function decreased significantly with a 37% loss of glomerular filtration rate and an increase of donors with chronic kidney disease stage 3 from 1.5% pre-donation to about 50%. Donors consistently showed increased fatigue and somatization. Mental fatigue increased from 10.6% to 28.1%. The main influencing factors for decreased kidney function and increased fatigue were their respective pre-donation levels, and donor age for kidney function and subject stress level in fatigue. Thus, our study showed that a significant number of donors developed clinically relevant changes in physical and mental health and emphasizes the urgent need to inform potential donors about these risks.

Simplifying Diagnosis of Fetal Alcohol Syndrome Using Machine Learning Methods.

INTRODUCTION: The fetal alcohol spectrum disorder (FASD) is a complex and heterogeneous disorder, caused by gestational exposure to alcohol. Patients with fetal alcohol syndrome (FAS-most severe form of FASD) show abnormal facial features. The aim of our study was to use 3D- metric facial data of patients with FAS and identify machine learning methods, which could improve and objectify the diagnostic process. MATERIAL AND METHODS: Facial 3D scans of 30 children with FAS and 30 controls were analyzed. Skeletal, facial, dental and orthodontic parameters as collected in previous studies were used to evaluate their value for machine learning based diagnosis. Three machine learning methods, decision trees, support vector machine and k-nearest neighbors were tested with respect to their accuracy and clinical practicability. RESULTS: All three of the above machine learning methods showed a high accuracy of 89.5%. The three predictors with the highest scores were: Midfacial length, palpebral fissure length of the right eye and nose breadth at sulcus nasi. CONCLUSIONS: With the parameters right palpebral fissure length, midfacial length and nose breadth at sulcus nasi, machine learning was an efficient method for the objective and reliable detection of patients with FAS within our patient group. Of the three tested methods, decision trees would be the most helpful and easiest to apply method for everyday clinical and private practice.

The Simpson grading: defining the optimal threshold for gross total resection in meningioma surgery.

Classification of the extent of resection into gross and subtotal resection (GTR and STR) after meningioma surgery is derived from the Simpson grading. Although utilized to indicate adjuvant treatment or study inclusion, conflicting definitions of STR in terms of designation of Simpson grade III resections exist. Correlations of Simpson grading and dichotomized scales (Simpson grades I-II vs ≥ III and grade I-III vs ≥ IV) with postoperative recurrence/progression were compared using Cox regression models. Predictive values were further compared by time-dependent receiver operating curve (tdROC) analyses. In 939 patients (28% males, 72% females) harboring WHO grade I (88%) and II/III (12%) meningiomas, Simpson grade I, II, III, IV, and V resections were achieved in 29%, 48%, 11%, 11%, and < .5%, respectively. Recurrence/progression was observed in 112 individuals (12%) and correlated with Simpson grading (p = .003). The risk of recurrence/progression was increased after STR in both dichotomized scales but higher when subsuming Simpson grade ≥ IV than grade ≥ III resections (HR: 2.49, 95%CI 1.50-4.12; p < .001 vs HR: 1.67, 95%CI 1.12-2.50; p = .012). tdROC analyses showed moderate predictive values for the Simpson grading and significantly (p < .05) lower values for both dichotomized scales. AUC values differed less between the Simpson grading and the dichotomization into grade I-III vs ≥ IV than grade I-II vs ≥ III resections. Dichotomization of the extent of resection is associated with a loss of the prognostic value. The value for the prediction of progression/recurrence is higher when dichotomizing into Simpson grade I-III vs ≥ IV than into grade I-II vs ≥ III resections.

Risk of tumor recurrence in intracranial meningiomas: comparative analyses of the predictive value of the postoperative tumor volume and the Simpson classification.

OBJECTIVE: In meningiomas, the Simpson grading system is applied to estimate the risk of postoperative recurrence, but might suffer from bias and limited overview of the resection cavity. In contrast, the value of the postoperative tumor volume as an objective predictor of recurrence is largely unexplored. The objective of this study was to compare the predictive value of residual tumor volume with the intraoperatively assessed extent of resection (EOR). METHODS: The Simpson grade was determined in 939 patients after surgery for initially diagnosed intracranial meningioma. Tumor volume was measured on initial postoperative MRI within 6 months after surgery. Correlation between both variables and recurrence was compared using a tree-structured Cox regression model. RESULTS: Recurrence correlated with Simpson grading (p = 0.003). In 423 patients (45%) with available imaging, residual tumor volume covered a broad range (0-78.5 cm3). MRI revealed tumor remnants in 8% after gross-total resection (Simpson grade I-III, range 0.12-33.5 cm3) with a Cohen's kappa coefficient of 0.7153. Postoperative tumor volume was correlated with recurrence in univariate analysis (HR 1.05 per cm3, 95% CI 1.02-1.08 per cm3, p < 0.001). A tree-structured Cox regression model revealed any postoperative tumor volume > 0 cm3 as a critical cutoff value for the prediction of relapse. Multivariate analysis confirmed the postoperative tumor volume (HR 1.05, p < 0.001) but not the Simpson grading (p = 0.398) as a predictor for recurrence. CONCLUSIONS: EOR according to Simpson grading was overrated in 8% of tumors compared to postoperative imaging. Because the predictive value of postoperative imaging is superior to the Simpson grade, any residual tumor should be carefully considered during postoperative care of meningioma patients.

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study.

BACKGROUND: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction. METHODS: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts. RESULTS: MTD was 3 mg/m2 tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t1/2(terminal) of 8 to 9 h without accumulation in daily administrations. CONCLUSION: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.

Evaluation of Cervical Elastography Strain Pattern to Predict Preterm Birth.

PURPOSE: To evaluate cervical elastography strain pattern as a predictive marker for spontaneous preterm delivery (SPTD). MATERIALS AND METHODS: In this case-control study cervical length (CL) and elastographic data (strain ratio, elastography index, strain pattern score) were acquired from 335 pregnant women (20th - 34th week of gestation) by transvaginal ultrasound. Data of 50 preterm deliveries were compared with 285 normal controls. Strain ratio and elastography index were calculated by placing two regions of interest (ROIs) in parallel on the anterior cervical lip. The strain ratio was determined by dividing the higher strain value by the lower one. The elastography index was defined as the maximum of the strain ratio curve. Elastographic images were assigned a new established strain pattern (SP) score between 0 and 2 according to the distribution of strain induced by compression. RESULTS: Elastography index, SP score and CL differed between preterm and normal pregnancies (1.61 vs. 1.27, p < 0.001; SP score value of "2": n = 31 (62 %) vs. n = 36 (12.6 %), p < 0.001; CL 30.7 vs. 41.0 mm, p < 0.001; respectively). The elastography index and SP score were associated with a higher predictive potential than CL measurement alone (AUC 0.8059 (area under the curve); AUC 0.7716; AUC 0.7631; respectively). A combination of all parameters proved more predictive than any single parameter (AUC 0.8987; respectively). CONCLUSION: Higher elastography index and SP scores were correlated with an elevated risk of SPTD and are superior to CL measurement as a predictive marker. A combination of these parameters could be used as a "Cervical Index" for the prediction of SPTD.

Comparing Plasma Exchange to Escalated Methyl Prednisolone in Refractory Multiple Sclerosis Relapses.

Intravenous methyl prednisolone (IVMPS) represents the standard of care for multiple sclerosis (MS) relapses, but fail to improve symptoms in one quarter of patients. In this regard, apart from extending steroid treatment to a higher dose, therapeutic plasma exchange (TPE) has been recognized as a treatment option. The aim of this retrospective, monocentric study was to investigate the efficacy of TPE versus escalated dosages of IVMPS in refractory MS relapses. An in-depth medical chart review was performed to identify patients from local databases. Relapse recovery was stratified as "good/full", "average" and "worst/no" according to function score development. In total, 145 patients were analyzed. Good/average/worst recovery at discharge was observed in 60.9%/32.6%/6.5% of TPE versus 15.2%/14.1%/70.7% of IVMPS patients, respectively. A total of 53.5% of IVMPS patients received TPE as rescue treatment and 54.8% then responded satisfactorily. The multivariable odds ratio (OR) for worst/no recovery was 39.01 (95%-CI: 10.41-146.18; p ≤ 0.001), favoring administration of TPE as first escalation treatment. The effects were sustained at three-month follow-ups, as OR for further deterioration was 6.48 (95%-CI: 2.48-16.89; p ≤ 0.001), favoring TPE. In conclusion, TPE was superior over IVMPS in the amelioration of relapse symptoms at discharge and follow-up. This study provides class IV evidence supporting the administration of TPE as the first escalation treatment to steroid-refractory MS relapses.

Vascular Adhesion Protein-1 Is Associated With Acute Kidney Injury in High-Risk Patients After Cardiac Surgery.

BACKGROUND: Acute kidney injury is a common complication after cardiac surgery, with a high impact on morbidity and mortality. Vascular adhesion protein-1 is involved in inflammation, which, in turn, is part of the development of acute kidney injury after cardiac surgery. METHODS: In this ancillary study to the RENal effects of Remote Ischemic Preconditioning in cardiac surgery trial, we investigated whether vascular adhesion protein-1 might be associated with the development of acute kidney injury in high-risk patients after cardiac surgery. In total, 114 patients were included in this data set. Acute kidney injury was defined by the Kidney Disease: Improving Global Outcomes criteria serum creatinine and/or urine output. Vascular adhesion protein-1 concentrations were measured at baseline (before surgery), 4 hours, and 12 hours after cardiopulmonary bypass. RESULTS: Vascular adhesion protein-1 levels at 12 hours were significantly higher in patients with acute kidney injury (no acute kidney injury, 271 ng/mL [Q1, Q3, 179, 364 ng/mL] versus acute kidney injury, 384 ng/mL [Q1, Q3, 311, 478 ng/mL]; P < .001). Moreover, patients developing acute kidney injury had higher differences in vascular adhesion protein-1 levels between 12 hours and baseline (P < .001) and between 12 and 4 hours (P < .001) after cardiopulmonary bypass. At a cut point difference value of 99 ng/mL (95% CI, 63-133) between 12 hours and baseline, patients with differences >99 ng/mL showed a higher occurrence rate of acute kidney injury (acute kidney injury, 78.6% versus no acute kidney injury, 31.5%; P < .001). Receiver-operating characteristic curve analyses demonstrated best performance for vascular adhesion protein-1 levels at 12 hours for acute kidney injury within 72 hours after surgery, especially in the subgroup of patients with chronic kidney disease (area under the receiver-operating characteristic curve, 0.78; P < .001). CONCLUSIONS: Vascular adhesion protein-1 is elevated in patients developing acute kidney injury assuming that vascular adhesion protein-1 plays a crucial role in the development of acute kidney injury in high-risk patients after cardiac surgery.

Impact of nighttime procedures on outcomes after liver transplantation.

BACKGROUND: Sleep deprivation is a well-known risk factor for the performance of medical professionals. Solid organ transplantation (especially orthotopic liver transplantation (oLT)) appears to be vulnerable since it combines technically challenging operative procedures with an often unpredictable start time, frequently during the night. Aim of this study was to analyze whether night time oLT has an impact on one-year graft and patient survival. MATERIAL AND METHODS: Deceased donor oLTs between 2006 and 2017 were retrospectively analyzed and stratified for recipients with a start time at day (8 a.m. and 6 p.m.) or at night (6 p.m. to 8 a.m.). We examined donor as well as recipient demographics and primary outcome measure was one-year patient and graft survival. RESULTS: 350 oLTs were conducted in the study period, 154 (44%) during daytime and 196 (56%) during nighttime. Donor and recipient variables were comparable. One-year patient survival (daytime 75.3% vs nighttime 76.5%, p = 0.85) as well as graft survival (daytime 69.5% vs nighttime 73.5%, p = 0.46) were similar between the two groups. Frequencies of reoperation (daytime 53.2% vs nighttime 55.1%, p = 0.74) were also not significantly different. CONCLUSION: Our retrospective single center data derived from a German transplant center within the Eurotransplant region provides evidence that oLT is a safe procedure irrespective of the starting time. Our data demonstrate that compared to daytime surgery nighttime liver transplantation is not associated with a greater risk of surgical complications. In addition, one-year graft and patient survival do not display inferior results in patients undergoing nighttime transplantation.

The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia.

Calcitonin receptor-like (CALCRL) is a G-protein-coupled neuropeptide receptor involved in the regulation of blood pressure, angiogenesis, cell proliferation, and apoptosis, and is currently emerging as a novel target for the treatment of migraine. This study characterizes the role of CALCRL in acute myeloid leukemia (AML). We analyzed CALCRL expression in collectively more than 1500 well-characterized AML patients from five international cohorts (AMLCG, HOVON, TCGA, Leucegene, and UKM) and evaluated associations with survival. In the AMLCG analytic cohort, increasing transcript levels of CALCRL were associated with decreasing complete remission rates (71.5%, 53.7%, 49.6% for low, intermediate, high CALCRL expression), 5-year overall (43.1%, 26.2%, 7.1%), and event-free survival (29.9%, 15.8%, 4.7%) (all P < 0.001). CALCRL levels remained associated with all endpoints on multivariable regression analyses. The prognostic impact was confirmed in all validation sets. Genes highly expressed in CALCRLhigh AML were significantly enriched in leukemic stem cell signatures and CALCRL levels were positively linked to the engraftment capacity of primary patient samples in immunocompromised mice. CRISPR-Cas9-mediated knockout of CALCRL significantly impaired colony formation in human myeloid leukemia cell lines. Overall, our study demonstrates that CALCRL predicts outcome beyond existing risk factors and is a potential therapeutic target in AML.