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Abstract Background Institutions or clinicians (units) are often compared according to a performance indicator such as in-hospital mortality. Several approaches have been proposed for the detection of outlying units, whose performance deviates from the overall performance. Methods We provide an overview of three approaches commonly used to monitor institutional performances for outlier detection. These are the common-mean model, the ‘Normal-Poisson’ random effects model and the ‘Logistic’ random effects model. For the latter we also propose a visualisation technique. The common-mean model assumes that the underlying true performance of all units is equal and that any observed variation between units is due to chance. Even after applying case-mix adjustment, this assumption is often violated due to overdispersion and a post-hoc correction may need to be applied. The random effects models relax this assumption and explicitly allow the true performance to differ between units, thus offering a more flexible approach. We discuss the strengths and weaknesses of each approach and illustrate their application using audit data from England and Wales on Adult Cardiac Surgery (ACS) and Percutaneous Coronary Intervention (PCI). Results In general, the overdispersion-corrected common-mean model and the random effects approaches produced similar p-values for the detection of outliers. For the ACS dataset (41 hospitals) three outliers were identified in total but only one was identified by all methods above. For the PCI dataset (88 hospitals), seven outliers were identified in total but only two were identified by all methods. The common-mean model uncorrected for overdispersion produced several more outliers. The reason for observing similar p-values for all three approaches could be attributed to the fact that the between-hospital variance was relatively small in both datasets, resulting only in a mild violation of the common-mean assumption; in this situation, the overdispersion correction worked well. Conclusion If the common-mean assumption is likely to hold, all three methods are appropriate to use for outlier detection and their results should be similar. Random effect methods may be the preferred approach when the common-mean assumption is likely to be violated.

Abstract The importance of the global offset, the sum of femoral and acetabular offset, has been underlined in the literature as a key factor for the functional outcome of total hip arthroplasty (THA). However, the acetabular offset is not defined for bi-plane X-rays, a technology providing 3D measurements of the lower limb and commonly used for patients undergoing THA. The aim of this paper is to introduce a measurement method of the 3D acetabular offset with bi-plane X-rays. Our method combines the use of technical and anatomical coordinate systems. The most appropriate definition will be selected based on the best reliability and measurement error. The consequent reliability of the global offset was also assessed. Twenty-eight patients undergoing primary THA were selected retrospectively. Two operators performed three reconstructions for each patients before and after THA. Intraclass correlation (ICC) and smallest detectable change (SDC) were computed for intra-operator, inter-operator and test–retest conditions for all combinations of technical and anatomical coordinate systems. ICCs were good to excellent. One combination was more reliable than others with a moderate mean SDC of 6.3 mm (4.3–8.7 mm) for the acetabular offset and a moderate mean SDC of 6.2 mm (5.6–6.7 mm) for the global offset. This is similar to the reliability and mean SDC of the femoral offset (4.8 mm) approved for clinical use which indicates that this method of acetabular offset measurement is appropriate. This opens a research avenue to better understand the role of the acetabular offset on THA outcomes, which seems overlooked in the literature.

Abstract Background Zoledronic acid is an intravenous, highly potent aminobisphosphonate for use in patients with primary or secondary osteoporosis. Zoledronic acid-induced prolonged side-effects are well known and quite common. However, severe side-effects can be a threat to life. We report a case of severe side-effects induced by zoledronic acid infusion, and its positive effect on long-term back pain. Case presentation In 2012, a 62-year-old white native Finnish woman was operated on for an estrogen and progesterone receptor-positive breast cancer. After radiotherapy, an aromatase inhibitor (letrozole) was started. Nine months after the operation, the patient suffered a low-energy compression fracture of Th XII. She received denosumab to prevent fragility fractures and to improve bone mineral density. Letrozole was discontinued after 5.5 years, and the last denosumab injection was given after 7 years. Six months later, at the age of 71 years, the patient received a single intravenous zoledronic acid infusion. Suddenly, at 10 hours from the infusion, she complained of severe trismus, muscle twitching, spasms, and tingling, matching hypocalcemia and several other symptoms. Her serum 25-hydroxyvitamin D concentration was high (163 nmol/L), the concentration of serum calcium and calcium-ion was normal (2.32 mmol/L and 1.23 mmol/L, respectively). However, the neutrophil to lymphocyte ratio (NLR) was low (1.6). A complete recovery took 2 months. Zoledronic acid infusion also had a positive effect: for many years, the patient had suffered low back pain and strain, which came to an end after this single infusion. Conclusion It is important that the potential patients receive sufficient information about the possibility of side-effects following the administration of intravenous zoledronic acid. To ensure that a zoledronic acid infusion is given as safely as possible, the safety information should include that the patient should not be left without monitoring for a minimum 24 hours after the infusion. Being alone and experiencing serious side-effects may lead to acute cardiac problems. Furthermore, the chronic low back pain and strain that our patient suffered for many years has clearly reduced for 16 months after infusion, so far. We conclude that this is a positive effect of zoledronic acid.

Abstract Bi-plane X-ray provides 3D measurements of the lower limb based on the identification of anatomical landmarks in sagittal and frontal X-rays. In clinical practice, such measurements involve multiple operators and sessions. This study aimed at evaluating the reliability of anatomical landmarks identification and geometric parameters of the pelvis and femur measured with bi-plane X-rays before and after total hip arthroplasty (THA). Twenty-eight patients undergoing primary THA were selected retrospectively. Two operators performed three reconstructions for each patient before and after THA. Intraclass correlation (ICC) and smallest detectable change (SDC) were computed for intra-operator, inter-operator, and test–retest conditions. Most anatomical landmark positions had good to excellent SDC (

Abstract Background Hereditary transthyretin (ATTRv) amyloidosis is a rare, genetically heterogeneous and phenotypically variable systemic disease characterized by deposition of misfolded transthyretin fibrils in various tissues. ATTRv cardiomyopathy and progressive axonal polyneuropathy are the most common manifestations, leading to severe disability and ultimately death within approximately ten years. As disease-modifying treatment options evolve, timely diagnosis and treatment initiation are crucial to prevent rapid disease progression. Case presentation Here, we report on a 73-year old patient initially diagnosed with cardiac wild-type ATTR (ATTRwt) amyloidosis by endomyocardial biopsy. Molecular genetic analysis revealed a novel TTR sequence variant (p.Ala65Val) that is highly likely to be amyloidogenic in light of previously reported TTR mutations and the patient’s clinical presentation and family history. Conclusions Our findings expand the spectrum of known pathogenic TTR mutations and underline the importance of a thorough diagnostic workup in amyloidosis patients including careful genetic testing to avoid misdiagnosis and missing of treatment opportunities and to enable cascade testing and tracking of carriers.

Abstract Background About two-thirds of the in-hospital deaths after out-of-hospital cardiac arrests (OHCA) are a consequence of anoxic brain injuries, which are due to hypoperfusion of the brain during the cardiac arrests. Being able to monitor cerebral perfusion during cardiopulmonary resuscitation (CPR) is desirable to evaluate the effectiveness of the CPR and to guide further decision making and prognostication. Methods Two different devices were used to measure regional cerebral oxygen saturation (rSO2): INVOS™ 5100 (Medtronic, Minneapolis, MN, USA) and Root® O3 (Masimo Corporation, Irvine, CA, USA). At the scene of the OHCA, advanced life support (ALS) was immediately initiated by the Emergency Medical Services (EMS) personnel. Sensors for measuring rSO2 were applied at the scene or during transportation to the hospital. rSO2 values were documented manually together with ETCO2 (end tidal carbon dioxide) on a worksheet specially designed for this study. The study worksheet also included a questionnaire for the EMS personnel with one statement on usability regarding potential interference with ALS. Results Twenty-seven patients were included in the statistical analyses. In the INVOS™5100 group (n = 13), the mean rSO2 was 54% (95% CI 40.3–67.7) for patients achieving a return of spontaneous circulation (ROSC) and 28% (95% CI 12.3–43.7) for patients not achieving ROSC (p = 0.04). In the Root® O3 group (n = 14), the mean rSO2 was 50% (95% CI 46.5–53.5) and 41% (95% CI 36.3–45.7) (p = 0.02) for ROSC and no ROSC, respectively. ETCO2 values were not statistically different between the groups. The EMS personnel graded the statement of interference with ALS to a median of 2 (IQR 1–6) on a 10-point Numerical Rating Scale. Conclusion Our results suggest that both INVOS™5100 and ROOT® O3 can distinguish between ROSC and no ROSC in OHCA, and both could be used in the pre-hospital setting and during transport with minimal interference with ALS.

Background Patients with severe mental illness (SMI) or receiving treatment with antipsychotics (APs) have an increased risk of cardiovascular disease. Cardiovascular risk management (CVRM) increasingly depends on general practitioners (GPs) because of the shift of mental healthcare from secondary to primary care and the surge of off-label AP prescriptions. Nevertheless, the uptake of patients with SMI/APs in CVRM programmes in Dutch primary care is low.Objectives To explore which barriers and facilitators GPs foresee when including and treating patients with SMI or using APs in an existing CVRM programme.Methods In 2019, we conducted a qualitative study among 13 Dutch GPs. During individual in-depth, semi-structured interviews a computer-generated list of eligible patients who lacked annual cardiovascular risk (CVR) screening guided the interview. Data was analysed thematically.Results The main barriers identified were: (i) underestimation of patient CVR and ambivalence to apply risk-lowering strategies such as smoking cessation, (ii) disproportionate burden on GPs in deprived areas, (iii) poor information exchange between GPs and psychiatrists, and (iv) scepticism about patient compliance, especially those with more complex conditions. The main facilitators included: (i) support of GPs through a computer-generated list of eligible patients and (ii) involvement of family or carers.Conclusion This study displays a range of barriers and facilitators anticipated by GPs. These indicate the preconditions required to remove barriers and facilitate GPs, namely adequate recommendations in practice guidelines, improved consultation opportunities with psychiatrists, practical advice to support patient adherence and incentives for practices in deprived areas.

Abstract Monolithic integration of quantum dot (QD) gain materials onto Si photonic platforms via direct epitaxial growth is a promising solution for on-chip light sources. Recent developments have demonstrated superior device reliability in blanket hetero-epitaxy of III–V devices on Si at elevated temperatures. Yet, thick, defect management epi designs prevent vertical light coupling from the gain region to the Si-on-Insulator waveguides. Here, we demonstrate the first electrically pumped QD lasers grown by molecular beam epitaxy on a 300 mm patterned (001) Si wafer with a butt-coupled configuration. Unique growth and fabrication challenges imposed by the template architecture have been resolved, contributing to continuous wave lasing to 60 °C and a maximum double-side output power of 126.6 mW at 20 °C with a double-side wall-plug efficiency of 8.6%. The potential for robust on-chip laser operation and efficient low-loss light coupling to Si photonic circuits makes this heteroepitaxial integration platform on Si promising for scalable and low-cost mass production.

Abstract Background Previous studies have demonstrated that purinergic receptors could be therapeutic targets to modulate the inflammatory response in multiple models of brain diseases. However, tools for the selective and efficient targeting of these receptors are lacking. The development of new P2X7-specific nanobodies (nbs) has enabled us to effectively block the P2X7 channel. Methods Temporary middle cerebral artery occlusion (tMCAO) in wild-type (wt) and P2X7 transgenic (tg) mice was used to model ischemic stroke. Adenosine triphosphate (ATP) release was assessed in transgenic ATP sensor mice. Stroke size was measured after P2X7-specific nbs were injected intravenously (iv) and intracerebroventricularly (icv) directly before tMCAO surgery. In vitro cultured microglia were used to investigate calcium influx, pore formation via 4,6-diamidino-2-phenylindole (DAPI) uptake, caspase 1 activation and interleukin (IL)-1β release after incubation with the P2X7-specific nbs. Results Transgenic ATP sensor mice showed an increase in ATP release in the ischemic hemisphere compared to the contralateral hemisphere or the sham-treated mice up to 24 h after stroke. P2X7-overexpressing mice had a significantly greater stroke size 24 h after tMCAO surgery. In vitro experiments with primary microglial cells demonstrated that P2X7-specific nbs could inhibit ATP-triggered calcium influx and the formation of membrane pores, as measured by Fluo4 fluorescence or DAPI uptake. In microglia, we found lower caspase 1 activity and subsequently lower IL-1β release after P2X7-specific nb treatment. The intravenous injection of P2X7-specific nbs compared to isotype controls before tMCAO surgery did not result in a smaller stroke size. As demonstrated by fluorescence-activated cell sorting (FACS), after stroke, iv injected nbs bound to brain-infiltrated macrophages but not to brain resident microglia, indicating insufficient crossing of the blood–brain barrier of the nbs. Therefore, we directly icv injected the P2X7-specific nbs or the isotype nbs. After icv injection of 30 µg of P2X7 specific nbs, P2X7 specific nbs bound sufficiently to microglia and reduced stroke size. Conclusion Mechanistically, we can show that there is a substantial increase of ATP locally after stroke and that blockage of the ATP receptor P2X7 by icv injected P2X7-specific nbs can reduce ischemic tissue damage.

Abstract Extended cut-off filtration by medium cut-off membranes (MCO) has been shown to be safe in maintenance hemodialysis (HD). The notion of using them for the control of chronic low-grade inflammation and positively influencing cellular immune aberrations seems tempting. We conducted an open label, multicenter, randomized, 90 day 2-phase cross over clinical trial (MCO- vs. high flux-HD). 46 patients underwent randomization of which 34 completed the study. Dialysate- or pre- and post-dialysis serum inflammatory mediators were assayed for each study visit. Ex vivo T cell activation was assessed from cryopreserved leucocytes by flow cytometry. Linear mixed models were used to compare treatment modalities, with difference in pre-dialysis serum MCP-1 levels after 3 months as the predefined primary endpoint. Filtration/dialysate concentrations of most mediators, including MCP-1 (mean ± SD: 10.5 ± 5.9 vs. 5.1 ± 3.8 pg/ml, P

Introduction: Organ shortage, subsequent use of extended donor criteria organs and high-risk recipients needing redo-surgery are increasing the complexity of heart transplantation. Donor organ machine perfusion (MP) is an emerging technology allowing reduction of ischemia time as well as standardized evaluation of the organ. The aim of this study was to review the introduction of MP and analyze the results of heart transplantation after MP in our center. Methods: In a retrospective single-center study, data from a prospectively collected database were analysed. From July 2018 to August 2021, fourteen hearts were retrieved and perfused using the Organ Care System (OCS), 12 hearts were transplanted. Criteria to use the OCS were based on donor/recipient characteristics. Primary objective was 30-day survival, secondary objectives were major cardiac adverse events, graft function, rejection episodes as well as overall survival in the follow-up and assessment of MP technical reliability. Results: All patients survived the procedure and the postoperative 30-day interval. No MP related complications were noted. Graft ejection fraction beyond 14 days was ≥ 50% in all cases. Endomyocardial biopsy showed excellent results with no or mild rejection. Two donor hearts were rejected after OCS perfusion and evaluation. Conclusion: Ex vivo normothermic MP during organ procurement is a safe and promising technique to expand the donor pool. Reduction of cold ischemic time while providing additional donor heart assessment and reconditioning options increased the number of acceptable donor hearts. Additional clinical trials are necessary to develop guidelines regarding the application of MP.

Background: Extra Corporeal Life Support (ECLS) is an evolving therapy in therapy-resistant cardiogenic shock (CS). Vascular cannulation in emergency situations can be accomplished through puncture of the femoral vessels by specialised teams. Since lower limb ischemia constitutes one of the major complications following cannulation, a distal perfusion cannula (DPC) has emerged as standard of care. We here aimed to analyse the impact of the DPC on limb perfusion and 6-month survival rate. Methods: In a retrospective study from January 2012 to December 2018, 98 patients with cardiogenic shock and peripheral (v-a) ECLS implantation with documented limb perfusion status were identified and analysed. Demographic data, laboratory parameters, cause of CS, comorbidities, limb perfusion complications and complication management were analysed. Results: 53 patients (54%) received ECLS therapy in referral centers by our mobile ECLS team, while in 45 patients (46%) the cannulation occured in our center. 71 patients (72%) received a DPC (group A) at the time of ECLS implantation, whereas 27 (28%) (group B) did not or received later (14 patients owing to limb ischemia). 44 patients (45%) developed limb ischemia as a complication of ECLS therapy (31% in group A and 81% in group B- p

Background and purpose: A brain tumour, especially a glioma, is a rare disease; it is challenging to treat and the prognosis is often poor. Routine care includes surgery and concomitant chemoradiotherapy (CRT). Diagnostic work-up and treatment effects are typically evaluated using magnetic resonance imaging (MRI). Quantitative MRI (qMRI), unlike conventional MRI, has the advantage of providing tissue-specific relaxation rates and proton density. The purpose is to detect changes in normal appearing white matter (NAWM) in brain tumour patients after CRT using qMRI. Materials & methods: NAWM was analysed in 10 patients, in 83 MR examinations performed before and after surgery and after CRT. Relaxation rates R1 and R2, the proton density (PD) and the concentration of myelin (cMy) were calculated from the qMRI scans and analysed in correlation to radiation dose and time after treatment. Results: A significant decrease in cMy between pre-treatment imaging and first follow-up and an increase in PD were observed. For low doses (less than 30 Gy) PD and cMy returned to baseline (=pre-operative status), while for high doses (>30 Gy) the change increased during the full extent of the follow-up period. No difference could be established for R1. For R2 an increase was observed during the first year, which then gradually returned to baseline. For R2, stronger effects were seen as a consequence of higher absorbed doses. Conclusion: In the long-term follow-up for glioma patients, qMRI is a powerful tool for detecting small changes, such as a decrease of myelin concentration, in NAWM after CRT.

Abstract Non‐invasive technologies have become popular for the clinical evaluation of cardiac function. The present study evaluated hemodynamic response to cardiopulmonary exercise stress testing using bioreactance technology in patients with hypertrophic cardiomyopathy. The study included 29 patients with HCM (age 55 ± 15 years; 28% female) and 12 age (55 ± 14 years), and gender matched (25% female) healthy controls. All participants underwent maximal graded cardiopulmonary exercise stress testing with simultaneous non‐invasive hemodynamic bioreactance and gas exchange. At rest, patients with HCM demonstrated significantly lower cardiac output (4.1 ± 1.3 vs. 6.1 ± 1.2 L/min; p

Summary: Coat protein complex II (COPII) plays an integral role in the packaging of secretory cargoes within membrane-enclosed transport carriers that leave the endoplasmic reticulum (ER) from discrete subdomains. Lipid bilayer remodeling necessary for this process is driven initially by membrane penetration mediated by the Sar1 GTPase and further stabilized by assembly of a multilayered complex of several COPII proteins. However, the relative contributions of these distinct factors to transport carrier formation and protein trafficking remain unclear. Here, we demonstrate that anterograde cargo transport from the ER continues in the absence of Sar1, although the efficiency of this process is dramatically reduced. Specifically, secretory cargoes are retained nearly five times longer at ER subdomains when Sar1 is depleted, but they ultimately remain capable of being translocated to the perinuclear region of cells. Taken together, our findings highlight alternative mechanisms by which COPII promotes transport carrier biogenesis.

T cells play a critical role in antitumor immunity, where T cell activation is regulated by both inhibitory and costimulatory receptor signaling that fine-tune T cell activity during different stages of T cell immune responses. Currently, cancer immunotherapy by targeting inhibitory receptors such as CTLA-4 and PD-1/L1, and their combination by antagonist antibodies, has been well established. However, developing agonist antibodies that target costimulatory receptors such as CD28 and CD137/4-1BB has faced considerable challenges, including highly publicized adverse events. Intracellular costimulatory domains of CD28 and/or CD137/4-1BB are essential for the clinical benefits of FDA-approved chimeric antigen receptor T cell (CAR-T) therapies. The major challenge is how to decouple efficacy from toxicity by systemic immune activation. This review focuses on anti-CD137 agonist monoclonal antibodies with different IgG isotypes in clinical development. It discusses CD137 biology in the context of anti-CD137 agonist drug discovery, including the binding epitope selected for anti-CD137 agonist antibody in competition or not with CD137 ligand (CD137L), the IgG isotype of antibodies selected with an impact on crosslinking by Fc gamma receptors, and the conditional activation of anti-CD137 antibodies for safe and potent engagement with CD137 in the tumor microenvironment (TME). We discuss and compare the potential mechanisms/effects of different CD137 targeting strategies and agents under development and how rational combinations could enhance antitumor activities without amplifying the toxicity of these agonist antibodies.

Supernova (SN) 1987A offers a unique opportunity to study how a spatially resolved SN evolves into a young SN remnant. We present and analyze Hubble Space Telescope (HST) imaging observations of SN 1987A obtained in 2022 and compare them with HST observations from 2009 to 2021. These observations allow us to follow the evolution of the equatorial ring (ER), the rapidly expanding ejecta, and emission from the center over a wide range in wavelength from 2000 to 11,000 Å. The ER has continued to fade since it reached its maximum ∼8200 days after the explosion. In contrast, the ejecta brightened until day ∼11,000 before their emission levelled off; the west side brightened more than the east side, which we attribute to the stronger X-ray emission by the ER on that side. The asymmetric ejecta expand homologously in all filters, which are dominated by various emission lines from hydrogen, calcium, and iron. From this overall similarity, we infer the ejecta are chemically well mixed on large scales. The exception is the diffuse morphology observed in the UV filters dominated by emission from the Mg ii resonance lines that get scattered before escaping. The 2022 observations do not show any sign of the compact object that was inferred from highly ionized emission near the remnant’s center observed with JWST. We determine an upper limit on the flux from a compact central source in the [O iii ] HST image. The nondetection of this line indicates that the S and Ar lines observed with JWST originate from the O free inner Si–S–Ar-rich zone and/or that the observed [O iii ] flux is strongly affected by dust scattering.

Abstract Aims The study aimed to investigate the prevalence, phenotypic characteristics, and predictors of atrial fibrillation (AF) in patients presenting with cardiac amyloidosis (CA) of light‐chain (AL) or transthyretin (ATTR) type. Methods and results Clinical, biochemical, and echocardiographic data of patients presenting with CA between 2005 and 2020 were retrospectively collected. CA staging was based on established biomarker systems. Binomial logistic regression was run to analyse the effects of clinical variables on the likelihood of AF. The study included 133 patients [53% AL, 41% wild‐type (wt) ATTR‐CA, & 6% hereditary ATTR‐CA]. Mean age was 71 years, and 80% were male patients. AF was diagnosed in 64 (48%) patients (28% in AL‐CA, 80% in wtATTR, 13% in hATTR, P

Authors rely on a range of devices and techniques to attract and maintain the interest of readers, and to convince them of the merits of the author’s point of view. However, when writing a scientific article, authors must use these ‘persuasive communication devices’ carefully. In particular, they must be explicit about the limitations of their work, avoid obfuscation, and resist the temptation to oversell their results. Here we discuss a list of persuasive communication devices and we encourage authors, as well as reviewers and editors, to think carefully about their use.

IntroductionThe COVID-19 pandemic changed not only the working conditions but also the private conditions we live in. Health care professionals especially were confronted with multiple stressors, e.g., the risk of infection, lack of staff, and high workloads.MethodsTo estimate some of the pandemic-related impacts this anonymous personnel survey was conducted in two German military hospitals (Hamburg and Berlin). This study presents a comparative analysis of the hospital staff in general vs. the psychiatric personnel (N = 685) at two measurement time points (MTPs) in April 2021 (n = 399) and December 2021 (n = 286). The survey contains the German version of the Covid Stress Scale (CSS) to assess the perceived level of pandemic-related stress, the Patient Health Questionnaire (German Version: PHQ-D) to screen for three major mental disorders, and the adjustment disorder—New Module (ADNM) to estimate the problems of adaptation to change.ResultsThe results showed a process of adaptation over the two MTPs with significant stress reduction at MTP2 in the general staff. The psychiatric staff did not report significantly higher pandemic-related symptoms. Quite the contrary, not only did the CSS show significantly lower xenophobia, traumatic stress, and compulsive checking, but the PHQ also showed lower stress symptoms and somatic symptoms at both MTPs. Also, the ADNM scores delivered evidence for a more effective adaptation process in psychiatric personnel (e.g., depressive mood, avoidance, anxiety).DiscussionThe presented results must be interpreted while taking the unique situations of German military clinics into account. The supply of protective material was sufficient and there was no dramatic shortage of psychiatric staff during the pandemic. The inpatients were quite often (40%) elective treatments for trauma-related disorders, which could be discontinued in the case of a COVID-19 infection. The results of this study showed good adaptative skills among the psychiatric staff in military hospitals, which could be interpreted as a sign of good resilience. This might have led to lower stress-related symptoms during the COVID-19 pandemic.

IntroductionThe German Hodgkin Study Group (GHSG) HD17 trial established the omission of radiotherapy (RT) for patients with early-stage unfavorable Hodgkin lymphoma being PET-negative after 2 cycles of BEACOPP escalated plus 2 cycles of ABVD. This patient group reveals heterogeneity in characteristics and disease extent which prompted us to perform a decisive dosimetric analysis according to GHSG risk factors. This may help to tailor RT individually balancing risks and benefits.MethodsFor quality assurance, RT-plans were requested from the treating facilities (n= 141) and analyzed centrally. Dose-volume histograms were scanned either paper-based or digitally to obtain doses to mediastinal organs. These were registered and compared according to GHSG risk factors.ResultsOverall, RT plans of 176 patients were requested, 139 of which had dosimetric information on target volumes within the mediastinum. Most of these patients were stage II (92.8%), had no B-symptoms (79.1%) and were aged < 50 years (89.9%). Risk factors were present in 8.6% (extranodal involvement), 31.7% (bulky disease), 46.0% (elevated erythrocyte sedimentation rate) and 64.0% (three involved areas), respectively. The presence of bulky disease significantly affected the mean RT doses to the heart (p=0.005) and to the left lung (median: 11.3 Gy vs. 9.9 Gy; p=0.042) as well as V5 of the right and left lung, respectively (median right lung: 67.4% vs. 51.0%; p=0.011; median left lung: 65.9% vs. 54.2%; p=0.008). Significant differences in similar organs at risk parameters could be found between the sub-cohorts with the presence or absence of extranodal involvement, respectively. In contrast, an elevated erythrocyte sedimentation rate did not deteriorate dosimetry significantly. No association of any risk factor with radiation doses to the female breast was found.ConclusionPre-chemotherapy risk factors may help to predict potential RT exposure to normal organs and to critically review treatment indication. Individualized risk-benefit evaluations for patients with HL in early-stage unfavorable disease are mandatory.

Purpose: Radiation therapy (RT) is an integral part of treatment concepts for early-stage Hodgkin lymphoma. This analysis reports on RT quality in the recent HD16 and 17 trials of the German Hodgkin Study Group (GHSG). Methods and Materials: All RT plans of involved-node radiation therapy (INRT) in HD 17 were requested for analysis, along with 100 and 50 involved-field radiation therapy (IFRT) plans in HD 16 and 17, respectively. A structured assessment regarding field design and protocol adherence was performed by the reference radiation oncology panel of the GHSG. Results: Overall, 100 (HD 16) and 176 (HD 17) patients were eligible for analysis. In HD 16, 84% of RT series were evaluated as correct, with significant improvement compared with the predecessor studies (P < .001). In HD 17, 76.1% of INRT cases revealed a correct RT design compared with 69.0% of IFRT-cases, which was superior to previous studies (P < .001). Comparing INRT and IFRT, we found no significant differences in the percentage of any deviation (P = .418) or major deviations (P = .466). Regarding dosimetry, INRT was accompanied by an improvement in thyroid doses. Comparing different RT techniques, we found that intensity-modulated RT showed a reduction of high doses in the lung at the expense of an increased low-dose exposure in HD 17. Conclusions: The latest study generation of the GHSG demonstrates an improved quality in RT. A modern INRT design could be established without deterioration in quality. On a conceptual level, an individual consideration of the appropriate RT technique has to be performed.

BackgroundPercutaneous extracorporeal life support (pECLS) is increasingly applied in cardiogenic shock (CS) despite a lack of evidence from randomized trials. The in-hospital mortality rate of pECLS still reaches up to 60%, while vascular access site complications remain a shortcoming. Surgical approaches with central cannulation for ECLS (cELCS) have emerged as a bail-out option. To date, no systematic approach exists that allows a definition of inclusion or exclusion criteria for cECLS.Methods and resultsThis single-center, retrospective, case-control study includes all patients fulfilling criteria for CS at the West German Heart and Vascular Center Essen/Germany between 2015 and 2020 who underwent cECLS (n = 58), excluding post-cardiotomy patients. Seventeen patients received cECLS (29.3%) as a first-line treatment strategy and 41 patients as a second-line strategy (70.7%). The main complications leading to the use of cECLS as a second-line strategy were limb ischemia (32.8%) and ongoing insufficient hemodynamic support (27.6%). The first-line cECLS cohort showed a 30-day mortality rate of 53.3% that was constant during follow-up. The 30-day mortality rate of secondary cECLS candidates was 69.8% and the rate at 3 and 6 months was 79.1%. Younger patients (

BackgroundBreast density and exposure to sex steroids are major risk factors for breast cancer. The local microenvironment plays an essential role in progression of breast cancer. Metabolic adaption is a major hallmark of cancer. Whether proteins from the extracellular space regulating metabolism are affected in breast cancer, dense breasts or by estrogen exposure are not yet fully elucidated.MethodsWomen with breast cancer, postmenopausal women with normal breast tissue with varying breast density or premenopausal women with breasts exposed to high levels of estradiol were included in the study. Microdialysis was used to collect proteins from the extracellular space in vivo in 73 women; 12 with breast cancer, 42 healthy postmenopausal women with different breast densities, and 19 healthy premenopausal women. Breast density was determined as lean tissue fraction (LTF) using magnetic resonance imaging. Data were evaluated in a murine breast cancer model. We quantified a panel of 92 key proteins regulating metabolism using proximity extension assay.ResultsWe report that 29 proteins were upregulated in human breast cancer. In dense breasts 37 proteins were upregulated and 17 of these were similarly regulated as in breast cancer. 32 proteins correlated with LTF. In premenopausal breasts 19 proteins were up-regulated and 9 down-regulated. Of these, 27 correlated to estradiol, a result that was confirmed for most proteins in experimental breast cancer. Only two proteins, pro-cathepsin H and galanin peptide, were similarly regulated in breast cancer, dense- and estrogen exposed breasts.ConclusionsMetabolic proteins may be targetable for breast cancer prevention. Depending on risk factor, this may, however, require different approaches as breast density and estradiol induce distinct different expression patterns in the breast. Additionally, metabolic proteins from the extracellular space may indeed be further explored as therapeutic targets for breast cancer treatment.

Summary: Background: A prediction model that estimates survival and neurological outcome in out-of-hospital cardiac arrest patients has the potential to improve clinical management in emergency rooms. Methods: We used the Swedish Registry for Cardiopulmonary Resuscitation to study all out-of-hospital cardiac arrest (OHCA) cases in Sweden from 2010 to 2020. We had 393 candidate predictors describing the circumstances at cardiac arrest, critical time intervals, patient demographics, initial presentation, spatiotemporal data, socioeconomic status, medications, and comorbidities before arrest. To develop, evaluate and test an array of prediction models, we created stratified (on the outcome measure) random samples of our study population. We created a training set (60% of data), evaluation set (20% of data), and test set (20% of data).We assessed the 30-day survival and cerebral performance category (CPC) score at discharge using several machine learning frameworks with hyperparameter tuning. Parsimonious models with the top 1 to 20 strongest predictors were tested. We calibrated the decision threshold to assess the cut-off yielding 95% sensitivity for survival. The final model was deployed as a web application. Findings: We included 55,615 cases of OHCA. Initial presentation, prehospital interventions, and critical time intervals variables were the most important. At a sensitivity of 95%, specificity was 89%, positive predictive value 52%, and negative predictive value 99% in test data to predict 30-day survival. The area under the receiver characteristic curve was 0.97 in test data using all 393 predictors or only the ten most important predictors. The final model showed excellent calibration. The web application allowed for near-instantaneous survival calculations. Interpretation: Thirty-day survival and neurological outcome in OHCA can rapidly and reliably be estimated during ongoing cardiopulmonary resuscitation in the emergency room using a machine learning model incorporating widely available variables. Funding: Swedish Research Council (2019–02019); Swedish state under the agreement between the Swedish government, and the county councils (ALFGBG-971482); The Wallenberg Centre for Molecular and Translational Medicine.