Digital Breast Tomosynthesis versus Digital Mammography for Detection of Early-Stage Cancers Stratified by Grade: A TOSYMA Subanalysis.

Background Breast cancer screening with digital breast tomosynthesis (DBT) plus synthesized mammography (SM) increases invasive tumor detection compared with digital mammography (DM). However, it is not known how the prognostic characteristics of the cancers detected with the two screening approaches differ. Purpose To compare invasive breast cancers detected with DBT plus SM (test arm) versus DM (control arm) screening with regard to tumor stage, histologic grade, patient age, and breast density. Materials and Methods This exploratory subanalysis of the Tomosynthesis plus Synthesized Mammography (TOSYMA) study, which is a multicenter randomized controlled trial embedded in the German mammography screening program, recruited women aged 50-70 years from July 2018 to December 2020. It compared invasive cancer detection rates (iCDRs), rate differences, and odds ratios (ORs) between the arms stratified by Union for International Cancer Control (UICC) stage (I vs II-IV), histologic grade (1 vs 2 or 3), age group (50-59 vs 60-70 years), and Breast Imaging Reporting and Data System categories of breast density (A or B vs C or D). Results In total, 49 462 (median age, 57 years [IQR, 53-62 years]) and 49 669 (median age, 57 years [IQR, 53-62 years]) participants were allocated to DBT plus SM and DM screening, respectively. The iCDR of stage I tumors with DBT plus SM was 51.6 per 10 000 women (255 of 49 462) and with DM it was 30.0 per 10 000 women (149 of 49 669). DBT plus SM depicted more stage I tumors with grade 2 or 3 (166 of 49 462, 33.7 per 10 000 women) than DM (106 of 49 669, 21.3 per 10 000 women; rate difference, +12.3 per 10 000 women [95% CI: 0.3, 24.9]; OR, 1.6 [95% CI: 0.9, 2.7]). DBT plus SM achieved the highest iCDR of stage I tumors with grade 2 or 3 among women aged 60-70 years with dense breasts (41 of 7364, 55.4 per 10 000 women; rate difference, +21.6 per 10 000 women [95% CI: -21.1, 64.3]; OR, 1.6 [95% CI: 0.6, 4.5]). Conclusion DBT plus SM screening appears to lead to higher detection of early-stage invasive breast cancers of grade 2 or 3 than DM screening, with the highest rate among women aged 60-70 years with dense breasts. Clinical trial registration no. NCT03377036 © RSNA, 2023 See also the editorial by Ha and Chang in this issue.

Artificial Intelligence for Indication of Invasive Assessment of Calcifications in Mammography Screening. / Künstliche Intelligenz zur Indikationsstellung einer invasiven Mikrokalkabklärung im Mammografie-Screening.

PURPOSE: Lesion-related evaluation of the diagnostic performance of an individual artificial intelligence (AI) system to assess mamographically detected and histologically proven calcifications. MATERIALS AND METHODS: This retrospective study included 634 women of one screening unit (July 2012 - June 2018) who completed the invasive assessment of calcifications. For each leasion, the AI-system calculated a score between 0 and 98. Lesions scored > 0 were classified as AI-positive. The performance of the system was evaluated based on its positive predictive value of invasive assessment (PPV3), the false-negative rate and the true-negative rate. RESULTS: The PPV3 increased across the categories (readers: 4a: 21.2 %, 4b: 57.7 %, 5: 100 %, overall 30.3 %; AI: 4a: 20.8 %, 4b: 57.8 %, 5: 100 %, overall: 30.7 %). The AI system yielded a false-negative rate of 7.2 % (95 %-CI: 4.3 %: 11.4 %) and a true-negative rate of 9.1 % (95 %-CI: 6.6 %; 11.9 %). These rates were highest in category 4a, 12.5 % and 10.4 % retrospectively. The lowest median AI score was observed for benign lesions (61, interquartile range (IQR): 45-74). Invasive cancers yielded the highest median AI score (81, IQR: 64-86). Median AI scores for ductal carcinoma in situ were: 74 (IQR: 63-84) for low grade, 70 (IQR: 52-79) for intermediate grade and 74 (IQR: 66-83) for high grade. CONCLUSION: At the lowest threshold, the AI system yielded calcification-related PPV3 values that increased across categories, similar as seen in human evaluation. The strongest loss in AI-based breast cancer detection was observed for invasively assessed calcifications with the lowest suspicion of malignancy, yet with a comparable decrease in the false-positive rate. An AI-score based stratification of malignant lesions could not be determined. KEY POINTS: · The AI-based PPV3 for calcifications is comparable to human assessment.. · AI showed a lower detection performance of screen-positive and screen-negative lesions in category 4a.. · Histological subgroups could not be discriminated by AI scores.. CITATION FORMAT: · Weigel S, Brehl AK, Heindel W et al. Artificial Intelligence for Indication of Invasive Assessment of Calcifications in Mammography Screening. Fortschr Röntgenstr 2023; 195: 38 - 46.

Breast Density and Breast Cancer Screening with Digital Breast Tomosynthesis: A TOSYMA Trial Subanalysis.

Background Digital breast tomosynthesis (DBT) plus synthesized mammography (SM) reduces the diagnostic pitfalls of tissue superimposition, which is a limitation of digital mammography (DM). Purpose To compare the invasive breast cancer detection rate (iCDR) of DBT plus SM versus DM screening for different breast density categories. Materials and Methods An exploratory subanalysis of the TOmosynthesis plus SYnthesized MAmmography (TOSYMA) study, a randomized, controlled, multicenter, parallel-group trial recruited within the German mammography screening program from July 2018 to December 2020. Women aged 50-69 years were randomly assigned (1:1) to DBT plus SM or DM screening examination. Breast density categories A-D were visually assessed according to the Breast Imaging Reporting and Data System Atlas. Exploratory analyses were performed of the iCDR in both study arms and stratified by breast density, and odds ratios and 95% CIs were determined. Results A total of 49 762 women allocated to DBT plus SM and 49 796 allocated to DM (median age, 57 years [IQR, 53-62 years]) were included. In the DM arm, the iCDR was 3.6 per 1000 screening examinations in category A (almost entirely fatty) (16 of 4475 screenings), 4.3 in category B (102 of 23 534 screenings), 6.1 in category C (116 of 19 051 screenings), and 2.3 in category D (extremely dense breasts) (six of 2629 screenings). The iCDR in the DBT plus SM arm was 2.7 per 1000 screening examinations in category A (12 of 4439 screenings), 6.9 in category B (154 of 22 328 screenings), 8.3 in category C (156 of 18 772 screenings), and 8.1 in category D (32 of 3940 screenings). The odds ratio for DM versus DBT plus SM in category D was 3.8 (95% CI: 1.5, 11.1). The invasive cancers detected with DBT plus SM were most often grade 2 tumors; in category C, it was 58% (91 of 156 invasive cancers), and in category D, it was 47% (15 of 32 invasive cancers). Conclusion The TOmosynthesis plus SYnthesized MAmmography trial revealed higher invasive cancer detection rates with digital breast tomosynthesis plus synthesized mammography than digital mammography in dense breasts, relatively and absolutely most marked among women with extremely dense breasts. ClinicalTrials.gov registration no.: NCT03377036 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Moy in this issue.

Respiratory motion correction in F-18-FDG PET/CT impacts lymph node assessment in lung cancer patients.

BACKGROUNDS: Elastic motion correction in PET has been shown to increase image quality and quantitative measurements of PET datasets affected by respiratory motion. However, little is known on the impact of respiratory motion correction on clinical image evaluation in oncologic PET. This study evaluated the impact of motion correction on expert readers' lymph node assessment of lung cancer patients. METHODS: Forty-three patients undergoing F-18-FDG PET/CT for the staging of suspected lung cancer were included. Three different PET reconstructions were investigated: non-motion-corrected ("static"), belt gating-based motion-corrected ("BG-MC") and data-driven gating-based motion-corrected ("DDG-MC"). Assessment was conducted independently by two nuclear medicine specialists blinded to the reconstruction method on a six-point scale [Formula: see text] ranging from "certainly negative" (1) to "certainly positive" (6). Differences in [Formula: see text] between reconstruction methods, accounting for variation caused by readers, were assessed by nonparametric regression analysis of longitudinal data. From [Formula: see text], a dichotomous score for N1, N2, and N3 ("negative," "positive") and a subjective certainty score were derived. SUV and metabolic tumor volumes (MTV) were compared between reconstruction methods. RESULTS: BG-MC resulted in higher scores for N1 compared to static (p = 0.001), whereas DDG-MC resulted in higher scores for N2 compared to static (p = 0.016). Motion correction resulted in the migration of N1 from tumor free to metastatic on the dichotomized score, consensually for both readers, in 3/43 cases and in 2 cases for N2. SUV was significantly higher for motion-corrected PET, while MTV was significantly lower (all p < 0.003). No significant differences in the certainty scores were noted. CONCLUSIONS: PET motion correction resulted in significantly higher lymph node assessment scores of expert readers. Significant effects on quantitative PET parameters were seen; however, subjective reader certainty was not improved.

Termination of pregnancy in the second trimester - the course of different therapy regimens.

OBJECTIVES: To compare two prostaglandin analogs and two application intervals between mifepristone and the prostaglandin analog administration on the time to abortion in second trimester termination of pregnancy. Other endpoints were live birth rate and fetal lifetime after expulsion. METHODS: Retrospective data of 373 abortions performed were evaluated. Four medical induction subgroups and two feticide subgroups were considered. The definition criteria of the subgroups were the choice of administered prostaglandin analog (misoprostol vs. sulprostone) and the time interval between mifepristone and prostaglandin analog administration (48 vs. 24 h). The outcome parameters were the time to complete uterine evacuation (TCUE), the live birth rate and duration of fetal life. RESULTS: In the misoprostol subgroups, the median TCUE was 1.6 h longer in the 24-h group than in the 48-h group (p=0.950). In the sulprostone subgroups, the median TCUE was 1.9 h shorter in the 24-h group than in the 48-h group (p=0.950). The median TCUE was shorter for sulprostone than for misoprostol in all six subgroups (p<0.001). The rate of fetal live births ranged between 13.6 and 15.9% within the medical induction subgroups (p=0.969). The median fetal lifetime was slightly shorter in the sulprostone groups than in the misoprostol groups (p=0.563). CONCLUSIONS: Both application intervals and prostaglandin analogs are similarly effective. The therapy regime should be adapted to the personal preferences of the woman, the situational and clinical conditions.

Digital breast tomosynthesis plus synthesised mammography versus digital screening mammography for the detection of invasive breast cancer (TOSYMA): a multicentre, open-label, randomised, controlled, superiority trial.

BACKGROUND: Two dimensional (2D) full-field digital mammography is the current standard of breast cancer screening. Digital breast tomosynthesis generates pseudo-three dimensional datasets of the breast from which synthesised 2D (s2D) mammograms can be reconstructed. This innovative approach reduces the likelihood of overlapping breast tissues that can conceal features of malignancy. We aimed to compare digital breast tomosynthesis plus s2D mammography with digital screening mammography for the detection of invasive breast cancer. METHODS: TOSYMA was a randomised, open-label, superiority trial done at 17 screening units in two federal states of Germany. Eligible participants were women aged 50-69 years who had been invited to participate in a population-wide, quality-controlled mammography screening programme. Women were randomly assigned (1:1) to digital breast tomosynthesis plus s2D mammography or digital mammography alone using block randomisation (block size of 32), stratified by site. The primary endpoints were the detection rate of invasive breast cancer and invasive interval cancer rate at 24 months, analysed in the modified full analysis set, which included all randomly assigned participants who underwent either type of screening examination. Ten examinations, corresponding to a second study participation, were excluded. Analyses were done according to the intention-to-treat principle. Interval cancer rates will be reported in the follow-up study. Safety was assessed in the as-treated population, which included all participants who were randomly assigned. This trial is registered with ClinicalTrials.gov, NCT03377036, and is closed to accrual. FINDINGS: Between July 5, 2018, and Dec 30, 2020, 99 689 women were randomly assigned to digital breast tomosynthesis plus s2D mammography (n=49 804) or digital mammography (n=49 830). Invasive breast cancers were detected in 354 of 49 715 women with evaluable primary endpoint data in the digital breast tomosynthesis plus s2D group (detection rate 7·1 cases per 1000 women screened) and in 240 of 49 762 women in the digital mammography group (4·8 cases per 1000 women screened; odds ratio 1·48 [95% CI 1·25-1·75]; p<0·0001). Adverse events and device deficiencies were rare (six adverse events in each group; 23 device deficiencies in the digital breast tomosynthesis plus s2D group vs five device deficiencies in the digital mammography group) and no serious adverse events were reported. INTERPRETATION: The results from this study indicate that the detection rate for invasive breast cancer was significantly higher with digital breast tomosynthesis plus s2D mammography than digital mammography alone. Evaluation of interval cancer rates in the follow-up study will further help to investigate incremental long-term benefits of digital breast tomosynthesis screening. FUNDING: Deutsche Forschungsgemeinschaft (German Research Foundation).

Using deep learning to assist readers during the arbitration process: a lesion-based retrospective evaluation of breast cancer screening performance.

OBJECTIVES: To evaluate if artificial intelligence (AI) can discriminate recalled benign from recalled malignant mammographic screening abnormalities to improve screening performance. METHODS: A total of 2257 full-field digital mammography screening examinations, obtained 2011-2013, of women aged 50-69 years which were recalled for further assessment of 295 malignant out of 305 truly malignant lesions and 2289 benign lesions after independent double-reading with arbitration, were included in this retrospective study. A deep learning AI system was used to obtain a score (0-95) for each recalled lesion, representing the likelihood of breast cancer. The sensitivity on the lesion level and the proportion of women without false-positive ratings (non-FPR) resulting under AI were estimated as a function of the classification cutoff and compared to that of human readers. RESULTS: Using a cutoff of 1, AI decreased the proportion of women with false-positives from 89.9 to 62.0%, non-FPR 11.1% vs. 38.0% (difference 26.9%, 95% confidence interval 25.1-28.8%; p < .001), preventing 30.1% of reader-induced false-positive recalls, while reducing sensitivity from 96.7 to 91.1% (5.6%, 3.1-8.0%) as compared to human reading. The positive predictive value of recall (PPV-1) increased from 12.8 to 16.5% (3.7%, 3.5-4.0%). In women with mass-related lesions (n = 900), the non-FPR was 14.2% for humans vs. 36.7% for AI (22.4%, 19.8-25.3%) at a sensitivity of 98.5% vs. 97.1% (1.5%, 0-3.5%). CONCLUSION: The application of AI during consensus conference might especially help readers to reduce false-positive recalls of masses at the expense of a small sensitivity reduction. Prospective studies are needed to further evaluate the screening benefit of AI in practice. KEY POINTS: • Integrating the use of artificial intelligence in the arbitration process reduces benign recalls and increases the positive predictive value of recall at the expense of some sensitivity loss. • Application of the artificial intelligence system to aid the decision to recall a woman seems particularly beneficial for masses, where the system reaches comparable sensitivity to that of the readers, but with considerably reduced false-positives. • About one-fourth of all recalled malignant lesions are not automatically marked by the system such that their evaluation (AI score) must be retrieved manually by the reader. A thorough reading of screening mammograms by readers to identify suspicious lesions therefore remains mandatory.

Improvement of patient stratification in human papilloma virus-associated oropharyngeal squamous cell carcinoma by defining a multivariable risk score.

BACKGROUND: Precise risk stratification models are necessary to determine patient selection for deintensifying treatment trials in human papilloma virus (HPV)-associated oropharyngeal squamous cell cancer (HPV+ OPSCC). METHODS: We examined 526 cases with OPSCC treated at our department between 2002 and 2017. Every patient was classified after the 7th and 8th edition UICC staging manual. For HPV+ OPSCC, we calculated a simple risk score with four risk groups based on multivariable Cox regression analysis of clinical and lifestyle parameters (UICC 8th edition stage, tobacco/alcohol abuse, age, gender). RESULTS: Two hundred and thirty-nine patients with OPSCC (45.4%) showed a positive histological HPV status. In comparison to UICC 8th edition stages, our proposed risk model showed a tendency for better stratification between risk strata I/III, I/IV, and II/IV (each p < 0.002) and I/II, II/III, and III/IV (each p < 0.09). CONCLUSION: Age, gender, tobacco, and alcohol abuse should be added to the current UICC staging system in order to improve risk stratification in HPV+ OPSCC.

Vitamin D Status in Distinct Types of Ichthyosis: Importance of Genetic Type and Severity of Scaling.

Data on vitamin D status of patients with inherited ichthyosis in Europe is scarce and unspecific concerning the genetic subtype. This study determined serum levels of 25-hydroxyvitamin D3 (25(OH)D3) in 87 patients with ichthyosis; 69 patients were additionally analysed for parathyroid hormone. Vitamin D deficiency was pronounced in keratinopathic ichthyosis (n = 17; median 25(OH)D3: 10.5 ng/ml), harlequin ichthyosis (n = 2;7.0 ng/ml) and rare syndromic subtypes (n = 3; 7.0 ng/ml). Vitamin D levels were reduced in TG1-proficient lamellar ichthyosis (n = 15; 8.9 ng/ml), TG1-deficient lamellar ichthyosis (n = 12; 11.7 ng/ml), congenital ichthyosiform erythroderma (n = 13; 12.4 ng/ml), Netherton syndrome (n = 7; 10.7 ng/ml) and X-linked ichthyosis (n = 8; 13.9 ng/ml). In ichthyosis vulgaris 25(OH)D3 levels were higher (n = 10; 19.7 ng/ml). Parathyroid hormone was elevated in 12 patients. Low 25(OH)D3 levels were associated with high severity of scaling (p = 0.03) implicating scaling as a risk factor for vitamin D deficiency. Thus, this study supports our recent guidelines for ichthyoses, which recommend screening for and substituting of vitamin D deficiency.

Postoperative pancreatic fistula affects recurrence-free survival of pancreatic cancer patients.

PURPOSE: Postoperative pancreatic fistula (POPF) with reported incidence rates up to 45% contributes substantially to overall morbidity. In this study, we conducted a retrospective evaluation of POPF along with its potential perioperative clinical risk factors and its effect on tumor recurrence. METHODS: Clinical data on patients who had received pancreatoduodenectomy (PD), distal pancreatectomy (DP), or duodenum-preserving pancreatic head resection (DPPHR) were prospectively collected between 2007 and 2016. A Picrosirius red staining score was developed to enable morphological classification of the resection margin of the pancreatic stump. The primary end point was the development of major complications. The secondary end points were overall and recurrence-free survival. RESULTS: 340 patients underwent pancreatic resection including 222 (65.3%) PD, 87 (25.6%) DP, and 31 (9.1%) DPPHR. Postoperative major complications were observed in 74 patients (21.8%). In multivariable logistic regression analysis, POPF correlated with body mass index (BMI) (p = 0.025), prolonged stay in hospital (p<0.001), high Picrosirius red staining score (p = 0.049), and elevated postoperative levels of amylase or lipase in drain fluid (p≤0.001). Multivariable Cox regression analysis identified UICC stage (p<0.001), tumor differentiation (p<0.001), depth of invasion (p = 0.001), nodal invasion (p = 0.001), and the incidence of POPF grades B and C (p = 0.006) as independent prognostic markers of recurrence-free survival. CONCLUSION: Besides the known clinicopathological risk factors BMI and amylase in the drain fluid, the incidence of POPF correlates with high Picrosirius red staining score in the resection margins of the pancreatic stumps of curatively resected pancreatic ductal adenocarcinoma (PDAC). Furthermore, clinically relevant POPF seems to be a prognostic factor for tumor recurrence in PDAC.

Symptom Diary-Based Analysis of Disease Course among Patients with Mild Coronavirus Disease, Germany, 2020.

Limited information is available on the clinical course of outpatients with mild coronavirus disease (COVID-19). This information is critically important to inform public health prevention strategies and to provide anticipatory guidance to patients, primary care providers, and employers. We retrospectively assessed the daily prevalence of symptoms in 313 COVID-19 outpatients for the first 20 days of illness. Generalized estimating equations were used to assess the probability of symptom occurrence over time. Fatigue (91%), cough (85%), and headache (78%) were the most common symptoms and occurred a median of 1 day from symptom onset. Neurologic symptoms, such as loss of taste (66%) and anosmia (62%), and dyspnea (51%) occurred considerably later (median 3-4 days after symptom onset). Symptoms of COVID-19 are similar to those of other respiratory pathogens, so symptomatic patients should be tested more frequently for severe acute respiratory syndrome coronavirus 2 during influenza season to prevent further spread of COVID-19.

Teriflunomide treatment is associated with optic nerve recovery in early multiple sclerosis.

BACKGROUND AND AIMS: Various attempts have been made to support recovery following optic neuritis (ON), but the respective trials have mostly been negative. The aim of this study was to determine whether disease-modifying treatment (DMT) following ON as first manifestation of relapsing-remitting multiple sclerosis influences long-term outcomes. METHODS: A total of 79 patients with ON were identified and evaluated at relapse, DMT induction, and 12 months following treatment induction with either glatiramer acetate (GLAT), interferon-beta (IFN), or teriflunomide (TRF). Low-contrast letter acuity (LCLA) and full-field visual-evoked potentials (FF-VEP) were compared between treatment groups using multivariable regression models. The impact of TRF treatment induction compared with IFN or GLAT following relapses outside the optic nerves was evaluated in an independent cohort of 122 patients. Magnetic resonance imaging (MRI) outcomes and rates of confirmed improvement of relapse-related disability were evaluated. RESULTS: TRF-treated patients exhibited higher LCLA and lower relative P100 latencies normalized to the fellow-eye. Findings were significant following covariate-adjustment by multivariable analyses. Cranial MRI lesion load as well as disability progression rates were not significantly different between groups. The cohort of patients following relapses other than ON showed no differences in confirmed improvement of disability. CONCLUSION: TRF treatment is associated with favorable outcomes regarding functional optic nerve recovery following ON in early multiple sclerosis.

Minimal extrathyroid extension in papillary micro carcinoma of the thyroid is an independent risk factor for relapse through lymph node and distant metastases.

Aims: Minimal extrathyroid extension (mETE) is no longer considered in the new 8th edition of the AJCC/UICC staging system. Therefore, papillary thyroid microcarcinoma with mETE previously staged as pT3 will now be staged as pT1a and most likely not receive adjuvant radioiodine therapy. However, it remains unclear if mETE is associated with higher aggressiveness in papillary thyroid microcarcinoma. Therefore, the aim of this study was to investigate if mETE is associated with higher risk of lymph node or distant metastases. Methods: 721 patients with thyroid papillary microcarcinoma presenting at our department for postoperative counseling from 05/1983 to 8/2012 were included in this retrospective analysis (median follow-up time 9.30 years). The impact of mETE on the presence of lymph node metastases at thyroidectomy and relapse through lymph node and distant metastases was assessed by logistic regression and Fine-Gray model analyses. Results: 10.7% (n = 77) of patients had mETE. mETE was an independent risk factor for lymph node metastases at thyroidectomy with an adjusted odds ratio of 4.33 (95%CI: 2.02-9.60, p<0.001) in multivariable analysis. Patients with mETE had significantly more relapses through lymph node (over 5 years: 13.1% vs. 1.25%; P < 0.001) and distant metastases (over 5 years: 7.8% vs. 1.1%; P < 0.001) compared to patients without mETE. mETE was an independent risk factor for relapse through lymph node and distant metastases in multivariable analysis (hazard ratio: 7.78, 95%CI: 2.87-21.16, p< 0.001 and 4.09, 95%CI: 1.25-13.36, P = 0.020). Conclusion: mETE is a statistically significant and independent risk factor for relapse through lymph node and distant metastases in papillary microcarcinoma. Therefore, future studies should evaluate, if patients with mETE and microcarcinoma might benefit from intensified surveillance and therapy.

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI): study protocol for a multicentre, observational trial.

INTRODUCTION: More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. METHODS AND ANALYSIS: EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. ETHICS AND DISSEMINATION: EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. TRIAL REGISTRATION NUMBER: NCT04165369.

Effects of Different Doses of Remote Ischemic Preconditioning on Kidney Damage Among Patients Undergoing Cardiac Surgery: A Single-Center Mechanistic Randomized Controlled Trial.

OBJECTIVES: We have previously shown that remote ischemic preconditioning reduces acute kidney injury (acute kidney injury) in high-risk patients undergoing cardiopulmonary bypass and that the protective effect is confined to patients who exhibit an increased urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 in response to remote ischemic preconditioning. The purpose of this study was to determine the optimal intensity of remote ischemic preconditioning to induce required [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] changes and further explore mechanisms of remote ischemic preconditioning. DESIGN: Observational and randomized controlled, double-blind clinical trial. SETTING: University Hospital of Muenster, Germany. PATIENTS: High-risk patients undergoing cardiac surgery as defined by the Cleveland Clinic Foundation Score. INTERVENTIONS: In the interventional part, patients were randomized to receive either one of four different remote ischemic preconditioning doses (3 × 5 min, 3 × 7 min, 3 × 10 min remote ischemic preconditioning, or 3 × 5 min remote ischemic preconditioning + 2 × 10 min remote ischemic preconditioning in nonresponders) or sham-remote ischemic preconditioning (control). MEASUREMENTS AND MAIN RESULTS: The primary endpoint of the interventional part was change in urinary [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] between pre- and postintervention. To examine secondary objectives including acute kidney injury incidence, we included an observational cohort. A total of 180 patients were included in the trial (n = 80 observational and n = 100 randomized controlled part [20 patients/group]). The mean age was 69.3 years (10.5 yr), 119 were men (66.1%). Absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] were significantly higher in all remote ischemic preconditioning groups when compared with controls (p < 0.01). Although we did not observe a dose-response relationship on absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] across the four different remote ischemic preconditioning groups, in the 15 patients failing to respond to the lowest dose, nine (60%) responded to a subsequent treatment at a higher intensity. Compared with controls, fewer patients receiving remote ischemic preconditioning developed acute kidney injury within 72 hours after surgery as defined by both Kidney Disease: Improving Global Outcomes criteria (30/80 [37.5%] vs 61/100 [61.0%]; p = 0.003). CONCLUSIONS: All doses of remote ischemic preconditioning significantly increased [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] and significantly decreased acute kidney injury compared with controls. High-dose remote ischemic preconditioning could stimulate [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] increases in patients refractory to low-dose remote ischemic preconditioning.

An improved one-sample log-rank test.

The one-sample log-rank test allows to compare the survival of a single sample with a prefixed reference survival curve. It naturally applies in single-arm phase IIa trials with time-to-event endpoint. Several authors have described that the original one-sample log-rank test is conservative when sample size is small and have proposed strategies to correct the conservativeness. Here, we propose an alternative approach to improve the one-sample log-rank test. Our new one-sample log-rank statistic is based on the unique transformation of the underlying counting process martingale such that the moments of the limiting normal distribution have no shared parameters. Simulation results show that the new one-sample log-rank test gives type I error rate and power close to the nominal levels also when sample size is small, while relevantly reducing the required sample size to achieve the desired power as compared to current approaches to design studies to compare the survival outcome of a sample with a reference.

Influence of mydriasis on optical coherence tomography angiography imaging in patients with age-related macular degeneration.

PURPOSE: To evaluate the effect of topical mydriatic eye drops on optical coherence tomography angiography (OCTA) parameters in patients with age-related macular degeneration (AMD). METHODS: 27 eyes of 27 patients suffering from AMD were included in this cross-sectional study. Patients with ≥-4.5 diopters spherical equivalent, corneal opacities or dense cataract preventing high-quality imaging were excluded. Whole-en-face scans of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in the central 3x3mm foveal region as well as whole-en-face and peripapillary scans of the radial peripapillary capillaries (RPC) were generated using OCTA (AngioVue®, Optovue). Imaging was first conducted with patients' eyes in miosis, then in mydriasis after instillation of a dilating eye drop (0.5% tropicamide, 2.5% phenylephrine-HCl). Main outcome measures were flow density (FD), foveal avascular zone (FAZ), signal strength index (SSI) and motion artifact score (MAS). RESULTS: Our results reveal that in AMD patients there is no significant difference between FD measurements taken in miosis and those taken in mydriasis around the SCP (p = 0.198), DCP (p = 0.458), RPC whole-en-face (p = 0.275) and RPC peripapillary (p = 0.503). Measurements taken in these two states appear to be equivalent for assessment of FD (90%CI within ± 0.05). No significant difference was found either in the area of the FAZ (p = 0.338) or in the SSI (p = 0.371) before and after the instillation of tropicamide/phenylephrine. MAS was significantly lower after the application of mydriatic eye drops (p = 0.003). CONCLUSIONS: Our findings reveal that neither measurements of FD nor measurements of the FAZ area changed significantly in AMD patients after the application of tropicamide/phenylephrine. Since MAS improved significantly in dilation, mydriatic examination is recommended. Nevertheless, a comparison of OCTA metrics from images taken with different pupil states (miosis versus mydriasis) is valid for clinical trials.

Acinetobacter baumannii Is a Risk Factor for Lower Respiratory Tract Infections in Children and Adolescents With a Tracheostomy.

BACKGROUND: Lower respiratory tract infections (LRIs) are a major cause of hospitalization for children and adolescents with a tracheostomy. The aim of this study was to identify risk factors for LRI. METHODS: In this retrospective study, we assessed the number of LRI and hospitalizations for LRI from 2004 to 2014 at the University Hospital Muenster Pediatric Department. We analyzed associations between LRI and clinical findings, and we cultured pathogens in tracheal aspirates (TAs) during noninfection periods. Univariable and multivariable negative, binomial regression analyses were applied to identify associations between possible risk factors and LRI. RESULTS: Seventy-eight patients had 148 LRI, of which 99 were treated in hospital. The median number of LRI per year was 0.4. Six-hundred thirteen pathogens were detected in 315 specimens; Staphylococcus aureus (22.5%), Pseudomonas aeruginosa (14.8%) and Haemophilus influenzae (6.2%) were most frequently detected. Acinetobacter baumannii is an independent risk factor for LRI (rate ratio, 1.792; P = 0.030) and hospital admissions for LRI (rate ratio, 1.917; P = 0.011). CONCLUSIONS: Children with a tracheostomy have frequent LRI. A. baumannii but not P. aeruginosa or S. aureus in TA is a risk factor for LRI in children with a long-term tracheostomy. This supports repetitive culture of TA for microbiologic workup to identify children and adolescents with an increased risk for LRI.

Fetal adrenal gland size in gestational diabetes mellitus.

Background The aim of this study was to compare the adrenal gland size of fetuses of women with gestational diabetes mellitus (GDM) with that of healthy control fetuses. Methods This prospective cross-sectional study included measurements of the adrenal gland size of 62 GDM fetuses (GDM group) and 370 normal controls (control group) between the 19th and 41st week of gestation. A standardized transversal plane was used to measure the total width and the medulla width. The cortex width and an adrenal gland ratio (total width/medulla width) were calculated from these data. Adrenal gland size measurements were adjusted to the week of gestation and compared between the two groups in a multivariable linear regression analysis. A variance decomposition metric was used to compare the relative importance of predictors of the different adrenal gland size measurements. Results For all the investigated parameters of the adrenal gland size, increased values were found in the case of GDM (P < 0.05), while adjusting for the week of gestation. GDM seems to have a greater impact on the size of the cortex than on the size of the medulla. Conclusion The fetal adrenal gland is enlarged in pregnancy complicated by GDM. The width of the cortex seems to be particularly affected.

Diurnal variations in flow density measured using optical coherence tomography angiography and the impact of heart rate, mean arterial pressure and intraocular pressure on flow density in primary open-angle glaucoma patients.

PURPOSE: To determine the diurnal variations in peripapillary and macular flow density (FD), as measured using optical coherence tomography angiography (OCTA) and to elaborate on the relationship between diurnal FD, circulatory parameters and intraocular pressure (IOP) variations in primary open-angle glaucoma (POAG). METHODS: Forty eyes of 40 POAG patients were drawn into this cross-sectional study. The retinal microvasculature of the macula (superficial and deep layers) and optic nerve [radial peripapillary capillary (RPC)] was examined by OCTA (AngioVue® , Optovue). Optical coherence tomography angiography (OCTA) measurements were conducted at 08:00, 11:00, 15:00 and 20:00 over the course of two consecutive days. Intraocular pressure (IOP) and circulatory parameters were assessed accordingly. Diurnal variations in FD were analysed using linear mixed models. RESULTS: While superficial macular FD and RPC FD revealed not to be affected by diurnal variations (p = 0.492, p = 0.319), FD in the deep layer of the macula increased throughout the day (p < 0.001). Superficial macular FD was influenced significantly by mean arterial pressure (MAP) (p = 0.006) and heart rate (HR) (p = 0.033), whereas FD in the RPC layer was significantly affected by HR (p = 0.010). No statistically significant effect of IOP fluctuations on FD was observed. CONCLUSION: This study shows diurnal fluctuations of deep macular FD measured by OCTA and outlines the relationship between FD and hemodynamic parameters (MAP/HR) in POAG patients.