[Severe cholecystitis during the COVID-19 pandemic : Influence of the COVID-19 pandemic on the frequency of surgery and outcome for elective and emergency cholecystectomy: a monocentric retrospective cohort analysis]. / Schwerere Cholezystitiden während der COVID-19-Pandemie : Einfluss der COVID-19-Pandemie auf OP-Frequenz und Outcome bei elektiven und notfälligen Cholezystektomien: eine monozentrische retrospektive Kohortenanalyse.

BACKGROUND: With the outbreak of the COVID-19 pandemic medical care focused on management of the infectious event. Elective interventions were cancelled and the general advice was to stay at home. How this impacted urgent and elective cholecystectomies is the subject of this work. METHOD: Urgent and elective cholecystectomy patients during the first year of the pandemic were compared with those of the previous year. The primary endpoint was the frequency of surgery. Furthermore, the American Society of Anesthesiologists (ASA) score, symptom duration until presentation as well as until surgery, preoperative inflammatory parameters, imaging, positive Murphy's sign, type and duration of surgery, intraoperative drain placement, intraoperative and histological severity, need for and duration of postoperative antibiotic therapy, intensive care stay, length of stay and occurrence of postoperative complications were recorded. RESULTS: During the pandemic patients were sicker (ASA 2.13 vs. 2.31; p = 0.039), the operating time was prolonged (64.4 min vs. 74.9 min; p = 0.001) and patients were more likely to have concomitant peritonitis (15.4% vs. 29.1%: p = 0.007). Furthermore, there was a trend in the presence of leukocytosis, a positive Murphy's sign, intraoperative drain placement, intraoperative severity of inflammation, duration of postoperative antibiotic therapy and complication rate. CONCLUSION: During the COVID-19 pandemic cholecystitis presented with more pronounced inflammation, the surgical conditions were more difficult and postoperative recovery was prolonged.

Survivors of infant atypical teratoid/rhabdoid tumors present with severely impaired cognitive functions especially for fluid intelligence and visual processing: data from the German brain tumor studies.

BACKGROUND: The contribution of tumor type, multimodal treatment, and other patient-related factors upon long-term cognitive sequelae in infant brain tumor survivors remains undefined. We add our retrospective analysis of neuropsychological and quality of survival (QoS) outcome data of survivors of atypical teratoid/rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors of the soft tissues (eMRT) and kidneys (RTK) treated within the same framework. Neuropsychological data from children with ATRT were compared to data from children with non-irradiated low-grade glioma (LGG). PATIENTS AND METHODS: Following surgery, patients (0-36 months at diagnosis) had received radio-chemotherapy (up to 54 Gy; ATRT: n = 13; eMRT/RTK: n = 7), chemotherapy only (LGG: n = 4; eMRT/RTK: n = 1) or had been observed (LGG: n = 11). Neuropsychological evaluation employing comparable tests was performed at median 6.8 years (ATRT), 6.6 years (eMRT/RTK), and 5.2 years (LGG) post diagnosis. RESULTS: We detected sequelae in various domains for all tumor types. Group comparison showed impairments, specifically in fluid intelligence (p = .041; d = 1.11) and visual processing (p = .001; d = 2.09) in ATRT patients when compared to LGG patients. Results for psychomotor speed and attention abilities were significantly below the norm for both groups (p < .001-.019; d = 0.79-1.90). Diagnosis predicted impairments of cognitive outcome, while sex- and age-related variables did not. QoS outcome for all rhabdoid patients displayed impairments mainly in social (p = .008; d = 0.74) and school functioning (p = .048; d = 0.67), as well as lower overall scores in psychosocial functioning (p = .023; d = 0.78) and quality of life (p = .006; d = 0.79) compared to healthy controls. CONCLUSION: Survivors of infant ATRT experience various late effects in cognition and QoS following multimodal treatment, while infant LGG patients without radiotherapy demonstrated comparable impairments in psychomotor and attention abilities. Early onset and multimodal treatment of rhabdoid tumors require close monitoring of neuropsychological and QoS sequelae.

Complications and Outcomes in 39,864 Patients Receiving Standard Care Plus Mechanical Circulatory Support or Standard Care Alone for Infarct-Associated Cardiogenic Shock.

BACKGROUND: Temporary mechanical circulatory support devices (tMCS) are increasingly being used in patients with infarct-associated cardiogenic shock (AMICS). Evidence on patient selection, complications and long-term outcomes is lacking. We aim to investigate differences in clinical characteristics, complications and outcomes between patients receiving no tMCS or either intra-aortic balloon pump (IABP), veno-arterial extracorporeal membrane oxygenation (V-A ECMO) or Impella® for AMICS, with a particular focus on long-term outcomes. METHODS: Using health claim data from AOK-Die Gesundheitskasse (local health care funds), we retrospectively analysed complications and outcomes of all insured patients with AMICS between 1 January 2010 and 31 December 2017. RESULTS: A total of 39,864 patients were included (IABP 5451; Impella 776; V-A ECMO 833; no tMCS 32,804). In-hospital complications, including renal failure requiring dialysis (50.3% V-A ECMO vs. 30.5% Impella vs. 29.2 IABP vs. 12.1% no tMCS), major bleeding (38.1% vs. 20.9% vs. 18.0% vs. 9.3%) and sepsis (22.5% vs. 15.9% vs. 13.9% vs. 9.3%) were more common in V-A ECMO patients. In a multivariate analysis, the use of both V-A ECMO (HR 1.57, p < 0.001) and Impella (HR 1.25, p < 0.001) were independently associated with long-term mortality, whereas use of IABP was not (HR 0.89, p < 0.001). Kaplan-Meier estimates showed better survival for patients on IABP compared with Impella, V-A ECMO and no-tMCS. Short- and long-term mortality was high across all groups. CONCLUSIONS: Our data show noticeably more in-hospital complications in patients on tMCS and higher mortality with V-A ECMO and Impella. The use of both devices is an independent risk factor for mortality, whereas the use of IABP is associated with a survival benefit.

Breast cancer screening with digital breast tomosynthesis: Is independent double reading still required? / Brustkrebs-Screening mit digitaler Brust-Tomosynthese: Ist weiterhin eine unabhängige Doppelbefundung erforderlich?

PURPOSE: The European guidelines recommend independent double reading in mammography screening programs. The prospective randomized controlled trial TOSYMA tested the superiority of digital breast tomosynthesis and synthetic mammography (DBT+SM) over digital mammography (DM) for invasive breast cancer detection. This sub-analysis compares the true-positive readings of screening-detected breast cancers resulting from independent double readings in the two trial arms. MATERIALS AND METHODS: The 1:1 randomized TOSYMA trial was executed in 17 screening units between 07/2018 and 12/2020. This sub-analysis included 49,762 women in the test arm (DBT+SM) and 49,796 women in the control arm (DM). The true-positive reading results (invasive breast cancers and ductal carcinoma in situ) from 83 readers were determined and merged in a double reading result. RESULTS: DBT+SM screening detected 416 women with breast cancer and DM screening detected 306. Double readings of DBT+SM examinations led to a single true-positive together with a single false-negative result in 26.9 % of cancer cases (112/416), and in 22.2 % of cases (68/306) in the DM examinations. The cancer detection rate with discordant reading results was 2.3 per 1,000 women screened with DBT+SM and 1.4 per 1,000 with DM. Discordant reading results occurred most often for invasive breast cancers [DBT+SM 75.9 % (85/112), DM 67.6 % (46/68)], category T1 [DBT+SM 67.9 % (76/112), DM 55.9 % (38/68)], and category 4a [DBT+SM: 67.6 % (73/112); DM: 84.6 % (55/68)]. CONCLUSION: The higher breast cancer detection rate with DBT screening includes a relevant percentage of breast cancers that were only detected by one reader in an independent double reading. As in digital mammography, independent double reading continues to be justified in screening with digital breast tomosynthesis. KEY POINTS: · The percentages of discordant cancer reading results were 26.9 % and 22.2 % for DBT+SM and DM, respectively.. · The single true-positive detection rate was 2.3 ‰ for DBT+ SM and 1.4 ‰ for DM.. · A relevant proportion of screening-detected cancers resulted from a single true-positive reading.. CITATION FORMAT: · Weigel S, Hense HW, Weyer-Elberich V et al. Breast cancer screening with digital breast tomosynthesis: Is independent double reading still required?. Fortschr Röntgenstr 2024; DOI: 10.1055/a-2216-1109.

Radiation Therapy Plays an Important Role in the Treatment of Atypical Teratoid/Rhabdoid Tumors: Analysis of the EU-RHAB Cohorts and Their Precursors.

PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignancy of the central nervous system in young children with a dismal prognosis. Prognostic markers have been extensively investigated but have not been validated. The role of radiation therapy (RT) remains controversial. We evaluated the impact of RT as part of multimodality treatment by analyzing data of a European AT/RT cohort. METHODS AND MATERIALS: We retrospectively analyzed data of the European Registry for Rhabdoid Tumors and its precursors. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Potential impact of prognostic factors was analyzed using univariable and multivariable Cox regression analyses with RT as a time-dependent factor. RESULTS: Data of 186 children (118 male, 68 female) treated from 1990 to 2016 were evaluable. The median age at diagnosis was 1.57 years (range, 0.01-26.70 years); 47% (87/186) of the patients were under the age of 18 months. Sixty-nine percent (128/186) received RT (focal RT, n = 93; craniospinal treatment with local boost, n = 34; spinal irradiation, n = 1). The median follow-up duration of the entire cohort was 1.73 years (range, 0.06-20.11 years). The estimated PFS and OS rates were 48% (95% CI, 41%-55%) and 72% (95% CI, 65%-78%) at 1 year and 33% (95% CI, 26%-40%) and 49% (95% CI, 41%-56%) at 2 years, respectively. On multivariable analysis, RT was an independent significant prognostic factor for PFS (hazard ratio, 0.45; 95% CI, 0.27-0.75; P = .002) and OS (hazard ratio, 0.54; 95% CI, 0.32-0.93; P = .025). CONCLUSIONS: This analysis confirms the relevance of local therapies. RT was an independent prognostic factor for outcomes in children experiencing AT/RT. However, long-term sequelae have to be carefully evaluated and considered given the young age at time of RT.

In-patient characteristics of peripheral artery disease in Germany.

Background: Peripheral artery disease (PAD) frequently leads to hospital admission. Sex related differences in in-patient care are a current matter of debate. Patients and methods: Data were provided from the German national in-patient sample provided by the Federal Bureau of Statistics (DESTATIS). Trends on risk profiles, therapeutic procedures, and outcomes were evaluated from 2014 until 2019 stratified by sex and PAD severity. Results: Two-thirds of an annual >191,000 PAD in-patient cases applied to male sex. Chronic limb-threatening ischemia (CLTI) was recorded in 49.6% of male and 55.2% of female cases (2019). CLTI was as a major risk factor of in-hospital amputation (OR 229) and death (OR 10.5), whereas endovascular revascularisation (EVR) with drug-coated devices were associated with decreased risk of in-hospital amputation (OR 0.52; all p<0.001). EVR applied in 47% of CLTI cases compared to 71% in intermittent claudication (IC) irrespective of sex. In-hospital mortality was 4.3% in male vs. 4.8% in female CLTI cases, minor amputations 18.4% vs. 10.9%, and major amputation 7.5% vs. 6.0%, respectively (data 2019; all p<0.001). After adjustment, female sex was associated with lower risk of amputation (OR 0.63) and death (OR 0.96) during in-patient stay. Conclusions: Male PAD patients were twice as likely to be admitted for in-patient treatment despite equal PAD prevalence in the general population. Among in-patient cases, supply with invasive therapy did not relevantly differ by sex, however is strongly reduced in CLTI. CLTI is a major risk factor of adverse short-term outcomes, whereas female sex was associated with lower risk of in-patient amputation and/or death.

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.

Contemporary secondary prevention in survivors of ST-elevation myocardial infarction with and without chronic kidney disease: a retrospective analysis.

Background: Survivors of myocardial infarction have an elevated risk of long-term mortality. We sought to evaluate guideline-directed medical treatment and its impact on long-term mortality in survivors of ST-elevation myocardial infarction (STEMI) according to their chronic kidney disease (CKD) stage. Methods: Using German health insurance claims data, 157 663 hospitalized survivors of STEMI were identified. Regarding different CKD stages, we retrospectively analysed the filled prescriptions of platelet inhibitors (PAI)/oral anticoagulation, statins, beta-blocker and angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor antagonists (ACE-I/AT1-A) and their association with long-term mortality. Results: Prescription rates for all four guideline-directed drugs were highest in patients without or with mild CKD and lowest in patients on dialysis. They dropped from 73.4% to 39.2% in patients without CKD and from 47.1% to 29% in patients on dialysis within the 5-year follow-up period. Mortality rates were dramatically increased in patients with CKD compared with patients without CKD (5-year mortality: no CKD, 16.7%; CKD stage 3, 47.1%; CKD stage 5d, 69.7%). Filled prescriptions of at least one drug class [one drug: hazard ratio (HR) 0.70, 95% confidence interval (95% CI) 0.66-0.74; four drugs: HR 0.28, 95% CI 0.27-0.30; P < .001 for both] as well as the distinct drug classes (statins: HR 0.55, 95% CI 0.54-0.56; ACE-I/AT1-A: HR 0.68, 95% CI 0.67-0.70; beta-blocker: HR 0.87, 95% CI 0.85-0.90; PAI/oral anticoagulation: HR 0.97, 95% CI 0.95-1.00; all P < .05) improved long-term mortality. Conclusions: An improved long-term guideline-recommended drug therapy after STEMI regardless of renal impairment might lead to beneficial effects on long-term mortality.

Survival of Patients with Acute Coronary Syndrome and Hematologic Malignancies-A Real-World Analysis.

BACKGROUND: The impact of the encounter between coronary heart disease (CHD) and cancer, and in particular hematologic malignancies (HM), remains poorly understood. OBJECTIVE: The aim of this analysis was to clarify how HM affects the prognosis of acute coronary syndrome (ACS). We analyzed German health insurance data from 11 regional Ortskrankenkassen (AOK) of patients hospitalized for ACS between January 2010 and December 2018, matched by age, sex and all comorbidities for short- and long-term survival and major adverse cardiac events (MACE). RESULTS: Of 439,716 patients with ACS, 2104 (0.5%) also had an HM. Myelodysplastic/myeloproliferative disorders (27.7%), lymphocytic leukemias (24.8%), and multiple myeloma (22.4%) predominated. These patients were about 6 years older (78 vs. 72 years *). They had an ST-segment elevation myocardial infarction (STEMI, 18.2 vs. 34.9% *) less often and more often had a non-STEMI (NSTEMI, 81.8 vs. 65.1% *). With the exception of dyslipidemia, these patients had more concomitant and previous cardiovascular disease and a worse NYHA stage. They were less likely to undergo coronary angiography (65.3 vs. 71.6% *) and percutaneous coronary intervention (PCI, 44.3 vs. 52.0% *), although the number of bleeding events was not relevantly increased (p = 0.22). After adjustment for the patients' risk profile, the HM was associated with reduced long-term survival. However, this was not true for short-term survival. Here, there was no difference in the STEMI patients, * p < 0.001. CONCLUSION: Survival in ACS and HM is significantly lower, possibly due to the avoidance of PCI because of a perceived increased risk of bleeding.

Rhabdoid tumors in patients conceived following ART: is there an association?

STUDY QUESTION: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY: Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT_ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE: The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION: RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS: This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Evaluation of Proenkephalin A 119-159 for liberation from renal replacement therapy: an external, multicenter pilot study in critically ill patients with acute kidney injury.

INTRODUCTION: Recent evidence suggests an association of plasma Proenkephalin A 119-159 (penKid) with early and successful liberation from continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury. However, these exploratory results are derived from a monocentric trial and therefore require external validation in a multicenter cohort. METHODS: Data and plasma samples from the "Effect of Regional Citrate Anticoagulation versus Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury-A Randomized Clinical Trial" (RICH Trial) were used for this validation study. PenKid was measured in all plasma samples available at CRRT initiation and at day 3 of CRRT. Patients were categorized into low and high penKid groups with a cutoff at 100 pmol/l. Competing-risk time-to-event analyses were performed. Competing risk endpoints were successful and unsuccessful liberation from CRRT, the latter meaning death or initiation of a new RRT within one week of discontinuation of primary CRRT. Then penKid was compared to urinary output. RESULTS: Low pre-CRRT penKid levels at CRRT initiation were not associated with early and successful liberation from CRRT compared to patients with high pre-CRRT penKid levels [subdistribution hazard ratio (sHR) 1.01, 95% CI 0.73-1.40, p = 0.945]. However, the landmark analysis on day 3 of ongoing CRRT demonstrated an association between low penKid levels and successful liberation from CRRT (sHR 2.35, 95% CI 1.45-3.81, p < 0.001) and an association between high penKid levels and unsuccessful liberation (sHR 0.46, 95% CI 0.26-0.80, p = 0.007). High daily urinary output (> 436 ml/d) was even stronger associated with successful liberation (sHR 2.91, 95% CI 1.80-4.73, p < 0.001) compared to penKid. DISCUSSION: This study suggests that penKid may be a competent biomarker to monitor the recovery of kidney function during CRRT. This is in line with previous findings and investigated this concept in a multicenter cohort. Again, low penKid was associated with early and successful CRRT liberation, but was outperformed by high daily urinary output. The findings of this study now warrant further evaluation in prospective studies or a randomized controlled trial. Trial registration The RICH Trial was registered at clinicaltrials.gov: NCT02669589. Registered 01 February 2016.

Contemporary Treatment and Outcome of Patients with Ischaemic Lower Limb Amputation: A Focus on Sex Differences.

OBJECTIVE: Chronic limb threatening ischaemia (CLTI) has a devastating prognosis with high rates of lower limb amputation (LLA) and deaths. This is an illustration of contemporary management and the long term fate of patients after ischaemic LLA, particularly with respect to sex, using real world data. METHODS: This was a multisectoral cross sectional and longitudinal analysis of health claims data from the largest German health insurance database (AOK). Data of 39 796 propensity score matched patients hospitalised for ischaemic LLA between 2010 and 2018 were analysed for cardiovascular comorbidities, treatment, and for subsequent cardiovascular and limb events, with a distinct focus on sex. Matching was performed, to ensure that the rate of major amputations and the age distribution were equal in both groups (in both sexes). An observation period of two years before index and a follow up (FU) period until 2019 were included. RESULTS: Before index amputation, 68% of patients had received any kind of peripheral revascularisation. The use of statins (37.0% vs. 42.6%) and antithrombotic substances (54.9% vs. 61.8%) was lower in women than in men (p < .001). During two year FU, cardiovascular and limb events occurred among women and men as follows: limb re-amputation (26.7% vs. 31.2%), myocardial infarction (10.9% vs. 14.5%), stroke (20.8% vs. 20.7%), and death from any cause (51.0% vs. 53.3%, p < .001 except for stroke). After adjustment for cardiovascular comorbidities and vascular procedures, female sex was associated with a higher probability of death (HR 1.04, 95% CI 1.04 - 1.04). CONCLUSION: Patients undergoing ischaemic LLA still have a poor prognosis marked by high rates of recurrent cardiovascular and limb events resulting in a > 50% mortality rate within two years. The continuous lack of guideline recommended therapies, particularly in women, may be associated with the persisting poor outcome, necessitating urgent further investigation.

Sex disparities in guideline-recommended therapies and outcomes after ST-elevation myocardial infarction in a contemporary nationwide cohort of patients over an eight-year period.

BACKGROUND AND AIMS: Acute myocardial infarction (AMI) is the leading cause of death worldwide. Outcome has improved during the last decades due to secondary prevention and widespread coronary interventions, but recent studies still show sex differences and insufficient drug adherence. We aimed to determine differences in the treatment strategies and outcomes between women and men with ST-elevation myocardial infarction (STEMI) in Germany. METHODS: From the Federal Association of the Local Health Insurance Funds (Allgemeine Ortskrankenkasse), 175,187 patients were identified who were hospitalized due to STEMI in Germany between January 1, 2010 and December 31, 2017. RESULTS: Compared to men, women were older (median 76 vs. 64 years) and had more often diabetes, hypertension, chronic heart failure, and chronic kidney disease (all p <0.001). Women suffered from higher rates of in-hospital complications such as bleeding (9.3 vs. 6.6%), longer hospitalizations (12.2 vs. 11.7 days) and were less likely to undergo percutaneous coronary intervention (75.5 vs. 85.2%). After adjustment for patient's risk profile, female sex was associated with decreased overall survival (HR 1.02, 95% confidence interval (CI) 1.00-1.04; p=0.036). Notably, more men received all four guideline-recommended drugs after STEMI (women 65.7% vs. men 69.8% after 90 days; p <0.001). With increasing number of prescribed drugs, patients benefit even more. This concerned both sexes, but was more pronounced in men (with 4 prescribed drugs: women HR 0.52, 95%CI 0.50-0.55; men HR 0.48, 95% CI 0.47-0.50, pint = 0.014). CONCLUSIONS: In a contemporary nationwide analysis, women with STEMI were older, had more comorbidities, underwent revascularization less often and had an increased risk for major complications as well as overall survival. Guideline-recommended drug therapy was applied less frequently in women although associated with an improved overall-survival.

Depression and Anxiety in Heart Transplant Recipients: Prevalence and Impact on Post-Transplant Outcomes.

BACKGROUND: Depression and anxiety (DA) are common mental disorders in patients with chronic diseases, but the research regarding their prevalence in heart transplantation (HTx) is still limited. METHODS: We performed an analysis of the prevalence and prognostic relevance of DA in patients who underwent HTx between 2010 and 2018 in Germany. Data were obtained from Allgemeine Ortskrankenkasse (AOK), which is the largest public health insurance provider. RESULTS: Overall, 694 patients were identified. More than a third of them were diagnosed with DA before undergoing HTx (n = 260, 37.5%). Patients with DA more often had an ischaemic cardiomyopathy (p < 0.001) and a history of previous myocardial infarction (p = 0.001) or stroke (p = 0.002). The prevalence of hypertension (p < 0.001), diabetes (p = 0.004), dyslipidaemia (p < 0.001) and chronic kidney disease (p = 0.003) was higher amongst transplant recipients with DA. Patients with DA were more likely to suffer an ischaemic stroke (p < 0.001) or haemorrhagic stroke (p = 0.032), or develop septicaemia (p = 0.050) during hospitalisation for HTx. Our analysis found no significant differences between the groups with respect to in-hospital mortality. The female sex and mechanical circulatory support were associated with an inferior prognosis. Pretransplant non-ischaemic cardiomyopathy was related to a favourable outcome. CONCLUSIONS: DA affect up to a third of the population undergoing HTx, with a greater prevalence in patients with comorbidities. DA are associated with a higher incidence of stroke and septicaemia after HTx.

Predicting the Development of Renal Replacement Therapy Indications by Combining the Furosemide Stress Test and Chemokine (C-C Motif) Ligand 14 in a Cohort of Postsurgical Patients.

OBJECTIVES: Optimal timing of renal replacement therapy (RRT) initiation in severe acute kidney injury (AKI) remains controversial. Initiation of treatment early in the course of AKI may lead to some patients undergoing unnecessary RRT, whereas delayed treatment is associated with increased mortality. This study aims to investigate whether the combination of the furosemide stress test (FST) and AKI-associated biomarkers can predict the development of indications for RRT. DESIGN: Single-center, prospective, observational study. SETTING: University Hospital of Muenster, Germany. PATIENTS: Critically ill, postoperative patients with moderate AKI (Kidney Disease: Improving Global Outcomes stage 2) and risk factors for further progression (vasopressors and/or mechanical ventilation) receiving an FST. INTERVENTIONS: Sample collection and measurement of different biomarkers (chemokine [C-C motif] ligand 14 [CCL14], neutrophil gelatinase-associated lipocalin, dipeptidyl peptidase 3). MEASUREMENT AND MAIN RESULTS: The primary endpoint was the development of greater than or equal to one predefined RRT indications (hyperkalemia [≥ 6 mmol/L], diuretic-resistant hypervolemia, high urea serum levels [≥ 150 mg/dL], severe metabolic acidosis [pH ≤ 7.15], oliguria [urinary output < 200 mL/12 hr], or anuria). Two hundred eight patients were available for the primary analysis with 108 having a negative FST (urine output < 200 mL in 2 hr following FST). Ninety-eight patients (47%) met the primary endpoint, 82% in the FST negative cohort. At the time of inclusion, the combination of a negative FST test and high urinary CCL14 levels had a significantly higher predictive value for the primary endpoint with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI, 0.82-0.92) compared with FST or CCL14 alone (AUC, 0.79; 95% CI, 0.74-0.85 and AUC, 0.83; 95% CI, 0.77-0.89; p < 0.001, respectively). Other biomarkers showed lower AUCs. CONCLUSIONS: The combination of the FST with the renal biomarker CCL14 predicts the development of indications for RRT.

The Role of Cell Cycle Arrest Biomarkers for Predicting Acute Kidney Injury in Critically Ill COVID-19 Patients: A Multicenter, Observational Study.

OBJECTIVES: Patients with COVID-19-associated acute respiratory distress syndrome (ARDS) have a high risk for developing acute kidney injury (AKI) which is associated with an increased risk of death and persistent renal failure. Early prediction of AKI is crucial in order to implement preventive strategies. The purpose of this study was to investigate the predictive performance of tissue inhibitor of metalloproteinases 2 and insulin like growth factor binding protein 7 (TIMP-2) × (IGFBP7) in critically ill patients with COVID-19-associated ARDS. DESIGN: Multicenter, prospective, observational study. SETTING: Twelve centers across Europe and United Kingdom. PATIENTS: Patients with moderate or severe COVID-19-associated ARDS were included and serial measurements of (TIMP-2) × (IGFBP7) were performed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the development of moderate or severe AKI according to the Kidney Disease: Improving Global Outcomes definition. Three hundred patients were available for the primary analysis, and 39 met the primary endpoint. At enrollment, urinary (TIMP-2) × (IGFBP7) had high predictive value for the primary endpoint with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.84-0.93). (TIMP-2) × (IGFBP7) was significantly higher in endpoint-positive patients at enrollment and at 12 hours. CONCLUSIONS: Urinary (TIMP-2) × (IGFBP7) predicts the occurrence of AKI in critically ill patients with COVID-19-associated ARDS.

Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial.

INTRODUCTION: Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation. METHODS AND ANALYSIS: The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage. ETHICS AND DISSEMINATION: The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research. TRIAL REGISTRATION NUMBER: NCT04647396.

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.

Contemporary in-hospital and long-term prognosis of patients with acute ST-elevation myocardial infarction depending on renal function: a retrospective analysis.

BACKGROUND: Cardiovascular disease is often associated with chronic kidney disease (CKD), resulting in an increased risk for poor outcome. We sought to determine short-term mortality and overall survival in ST-elevation myocardial infarction (STEMI) patients with different stages of CKD. METHODS: In our retrospective cohort study with health insurance claims data of the Allgemeine Ortskrankenkasse (AOK), anonymized data of all STEMI patients hospitalized between 2010 and 2017 were analyzed regarding presence and severity of concomitant CKD. RESULTS: A total of 175,187 patients had an index-hospitalisation for STEMI (without CKD: 78.6% patients, CKD stage 1: 0.8%, CKD stage 2: 4.8%, CKD stage 3: 11.7%, CKD stage 4: 2.8%, CKD stage 5: 0.7%, CKD stage 5d: 0.6%). Patients with CKD were older and had more co-morbidities than patients without CKD. With increasing CKD severity, patients received less revascularization therapies (91.2%, 85.9%, 87.0%, 81.8%, 71.7%, 76.9% and 78.6% respectively, p < 0.001). After 1 year, guideline-recommended medications were prescribed less frequently in advanced CKD (83.4%, 79.3%, 81.5%, 74.7%, 65.0%, 59.4% and 53.7%, respectively, p < 0.001). CKD stages 4, 5 and 5d as well as chronic limb threatening ischemia (CLTI) were associated with decreased overall survival [CKD stage 4: hazard ratio (HR) 1.72; 95% CI 1.66-1.78; CKD stage 5: HR 2.55; 95% CI 2.37-2.73; CKD stage 5d: 5.64; 95% CI 5.42-5.86; CLTI: 2.06; 95% CI 1.98-2.13; all p < 0.001]. CONCLUSIONS: CKD is a frequent co-morbidity in patients with STEMI and is associated with a worse prognosis especially in advanced stages. Guideline-recommended therapies in patients with STEMI and CKD are still underused.

A randomized phase 2 trial of nintedanib and low-dose cytarabine in elderly patients with acute myeloid leukemia ineligible for intensive chemotherapy.

We investigated the safety and efficacy of nintedanib added to low-dose cytarabine (LDAC) in a phase 1/2 study in patients 60 years or older with newly diagnosed or relapsed/refractory (r/r) AML ineligible for intensive chemotherapy. The results of the dose-finding phase 1 part have been previously published. Patients were randomized 1:1 to LDAC plus nintedanib or LDAC plus placebo stratified by AML status (newly diagnosed vs r/r). LDAC was applied subcutaneously at 20 mg twice daily on days 1 to 10. Nintedanib/placebo was orally administered twice daily on days 1 to 28 in 28-day cycles. The primary endpoint was overall survival (OS). Between 05/2017 and 09/2019, 31 patients were randomized and 30 were treated, before the study was terminated prematurely due to slow recruitment. Median (range) age of patients was 76 (60-84) years. Twenty-two patients (73%) had r/r AML. Median OS in patients treated with LDAC and nintedanib was 3.4 months, compared with 3.6 months in those treated in the placebo arm, with a HR adjusted for AML status of 1.19 (corresponding confirmatory adjusted 95% CI, 0.55-2.56; univariate log-rank P = 0.96). In the 22 patients with r/r AML, median OS was 3.0 months in the nintedanib and 3.6 months in the placebo arm (P = 0.36). One patient in the nintedanib and two patients in the placebo arm achieved a CR and entered maintenance treatment. Nintedanib showed no superior therapeutic activity over placebo when added to LDAC in elderly AML patients considered unfit for intensive chemotherapy. The trial was registered at clinicaltrials.gov NCT01488344.