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Simple and up-scalable synthesis method for human serum albumin nanoparticles with narrow size distribution, tunable size range, stable and reproducible.

Patient-related factors are of prognostic importance in acute myeloid leukemia (AML). Likewise, cardiac disorders may limit the tolerance of intensive therapy. Little is known about the prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP). We analyzed NT-proBNP levels at diagnosis in 312 AML patients (median age: 61 years; range 17-89 years) treated with 3 + 7-based induction-chemotherapy and consolidation with up to four cycles of intermediate or high-dose ARA-C. NT-proBNP levels were elevated in 199 patients (63.8%), normal (0-125 pg/ml) in 113 (36.2%), and highly elevated (2000 pg/ml) in 20 patients (6.4%). Median NT-proBNP levels differed significantly among patients with complete remission (153.3 pg/ml), no remission (225.9 pg/ml), or early death (735.5 pg/ml) (p = .002). In multivariate analysis, NT-proBNP, age, and the 2009 European LeukemiaNet (ELN-2009) classification were independent predictors of outcome after induction chemotherapy. Overall survival (OS) differed significantly between patients with normal, moderately elevated, and highly elevated NT-proBNP (p .001). These differences were observed in all patients and in patients60 years but not in those ≥60 years. In multivariate analysis, NT-proBNP, age, and ELN-2009 remained independent prognostic variables for OS (p .01). Together, NT-proBNP is an independent prognostic factor indicating the risk of induction failure, early death, and reduced OS in patients with AML.

Human monkeypox (MPX) cases are escalating worldwide. Smallpox vaccination, which was compulsory in Austria until 1981, was reported to confer 85% cross-protection against MPX.To assess the impact of smallpox vaccine-induced protection, the age-dependent vaccine-induced immunity against human MPX and the probability of infection according to age in the general population of Vienna, Austria, were determined using a modified susceptible-infected-removed model.Within the population born before 1981, the average vaccine-induced protective effect was calculated at 50.4%, whereas in the population born thereafter, protection was lacking. The overall probability of infection after exposure to an infected patient was calculated at 73.8%, which exceeds the threshold value of 46.9% for an index patient to infect at least one other person (R ≥1.0).Our model shows that if no additional interventions are taken, the collective immunization status of the population alone will not suffice to contain human MPX. Although the majority of cases have occurred in a subpopulation, given the steadily increasing incidence, dissemination into the general population remains possible, as observed before with HIV. Our model emphasizes the need for adequate containment measures and may aid in specific risk assessment because it can easily be adapted to other populations and cohorts worldwide.

Summary: Current standard technique for venous pressure measurement is still invasive, requiring insertion of a catheter. Additionally, clinical estimation of central venous pressure (CVP) has proven unreliable compared to invasive methods. Meanwhile, different non-invasive ultrasound guided modalities may provide a valid alternative to invasive venous pressure measurement. Particularly promising is a novel compression ultrasound (CUS) which combines ultrasound properties with a tissue pressure manometer enabling even further future applications. This review provides an overview using ultrasound guided non-invasive venous pressure measurement (UGPni) in clinical trials so far and focuses on three objectives: (1) To summarize the main methods using UGPni for central venous pressure measurement (2) To outline the key findings of previous clinical trials for UGPni regarding CVP measurement with primary focus on novel compression ultrasound of a forearm vein (3) To point out limitations and possible future clinical implications of these ultrasound modalities UGPni represents an easy-to-perform and safe alternative to invasive “gold standard” diagnostic tools for measuring central venous pressure. After a brief introduction, non-specialist personnel using a portable ultrasound device can apply this method in a feasible way. Of all mentioned methods in this review CUS is the method of choice underscoring its ability to assess a patient’s CVP categories correctly. Furthermore, detection of non-invasive central venous pressure in the emergency room represents an independent predictor for cardiac rehospitalization in patients with decompensated heart failure, thus helping in risk stratification as well as being an additive tool in general hemodynamic management of critically ill patients. This review concludes a significant role for ultrasound guided non-invasive venous pressure measurement suitable for a wide range of everyday clinical practice. However, further studies are warranted to proof a causal relationship in this regard.

To deal with increasingly severe periods of dehydration related to global climate change, it becomes increasingly important to understand the complex strategies many organisms have developed to cope with dehydration and desiccation. While it is undisputed that late embryogenesis abundant (LEA) proteins play a key role in the tolerance of plants and many anhydrobiotic organisms to water limitation, the molecular mechanisms are not well understood. In this review, we summarize current knowledge of the physiological roles of LEA proteins and discuss their potential molecular functions. As these are ultimately linked to conformational changes in the presence of binding partners, post-translational modifications, or water deprivation, we provide a detailed summary of current knowledge on the structure–function relationship of LEA proteins, including their disordered state in solution, coil to helix transitions, self-assembly, and their recently discovered ability to undergo liquid–liquid phase separation. We point out the promising potential of LEA proteins in biotechnological and agronomic applications, and summarize recent advances. We identify the most relevant open questions and discuss major challenges in establishing a solid understanding of how these intriguing molecules accomplish their tasks as cellular sentinels at the limits of surviving water scarcity.

Background This study aimed to compare functional outcomes of a volar plate osteosynthesis for distal radius fractures (DRF) performed with either a standard volar approach (SVA), which required detachment of the pronator quadratus muscle, or a pronator-sparing approach (PqSA). Materials and methods This prospective randomized controlled study included 106 patients scheduled for volar plate osteosyntheses. Patients were allocated to either the SVA group (n = 53) or the PqSA group (n = 53). Patients were blinded to treatment until completion of the study. The primary outcome measure was the Patient-Rated Wrist Evaluation (PRWE). Secondary outcome parameters were the Disabilities of the Arm, Shoulder, and Hand (DASH) score and the Modified Mayo Wrist Score (MMWS). Follow-up examinations were performed at 8 weeks and 3, 6, and 12 months postoperatively. Results Overall, 91 patients were included in the final analysis: 48 in the SVA group and 43 in the PqSA group. The two cohorts were not significantly different in demographic characteristics, including age, sex, injuries on the dominant side, type of injury, and fracture classification. We found significant differences between groups at 6 months in the mean PRWE (SVA: 12.3 ± 10.4, PqSA: 18.9 ± 14.11 points) and in the mean DASH score (SVA: 12.3 ± 11.9, PqSA: 19.3 ± 16.7 points), which favoured the SVA. We found no significant differences between groups in the MMWS or in the PRWE and DASH scores at any other time points. Conclusions This randomized comparative clinical trial failed to demonstrate that a volar plate osteosynthesis performed with a PqSA could improve the outcome, compared to the SVA, in patients with DRF. Level of evidence II Trial registration Comparison of Two Volar Plating Systems for Distal Radius Fractures, ClinicalTrials.gov (NCT03474445), registered 22 March 2018, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03474445?cond=radius&cntry=AT&draw=2&rank=1

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers.Significance:This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275

Summary Background The novel strain of severe acute respiratory syndrome coronavirus 2 is highly contagious; therefore, special emphasis must be given to personal protective equipment for healthcare workers. Reusable elastomeric respirators were previously used in intensive care units (ICU). These respirators include full or half masks and devices modified to accommodate a filter. Although the general comfort of masks used in the ICU has been studied, data comparing multiple types of masks during a pandemic are missing. Methods A prospective randomized trial was conducted in an ICU. After standardized training, participants were randomized to use one of three mask types (full, half or snorkelling mask), each fitted with a filter equivalent to a class 3 particle-filtering half mask (FFP3) during one shift. The main outcomes were characteristics of using the mask itself (donning/doffing, quality of seal, cleaning), working conditions with the mask (vision, comfort, perceived safety, communication) and a subjective comparison to single-use FFP2/3 masks. Results A total of 30 participants were included in the trial, randomized to 10 participants per group. The masks were worn 6.4 (4.5) times (mean SD) for a total duration of 132 (66) min per shift. The tested masks were rated 7 (2.6) (mean SD) in comparison to FFP2/3 on a Likert scale (0: worst, 10: best). Significant differences between the masks were found in respect to comfort (7/4/8), donning (8/7/9), overall rating (8/5/8) and comparison to single-use FFP2/3 masks (9/7/9; full-, half, snorkelling mask). Conclusion Using reusable elastomeric masks is feasible in clinical practice. Full face masks were significantly better in terms of comfort, donning, overall rating and in comparison to single-use FFP2/3 masks.

ZusammenfassungDas Feld der Alphabetisierung und Grundbildung Erwachsener nimmt einen zentralen Stellenwert in der Förderung gesellschaftlicher Partizipation von vulnerablen Gruppen ein. Die Covid-19 Pandemie bringt neue Transformationsprozesse mit sich, die sich auch auf die Risikofaktoren von Drop-out (Abbruch) in der Alphabetisierung und Grundbildung auswirken. Drop-out kann als Verstärker sozialer Ungleichheit beforscht werden, was insbesondere im Kontext pandemiebedingter Lernbedingungen an neuer Relevanz gewinnt. So werden in diesem Beitrag die pandemiebedingten Herausforderungen für das Feld mit besonderer Berücksichtigung von Drop-out herausgearbeitet. Anhand eines mehrstufigen Analyseverfahrens (Expert:inneninterviews & narratives Review) kann gezeigt werden, dass „Medienkompetenz und Medienzugang“, „Kontinuität und Kursstruktur“ sowie „Vertrauen und Kursbindung“ zwar als bereits bekannte Risikofaktoren für Drop-out gelten, jedoch vor dem Hintergrund pandemiebedingt veränderter Strukturen eine gestiegene Bedeutung bekommen. Pandemiebedingte Transformationsprozesse wirken wie ein Brennglas auf bereits bestehende Problemlagen im Feld der Alphabetisierung und Grundbildung. Somit kommt der pädagogischen Aufgabe der entsprechenden Gestaltung von unvorhersehbaren Veränderungen eine besondere Bedeutung zu, um der Verschärfung sozialer Ungleichheiten entgegenzuwirken.

We aimed to investigate whether (1) psychological and social indicators influence survival in patients diagnosed with cancer or haematologic malignancies when important biological aspects are controlled for, (2) psychological, social and biological indicators can be utilised to design one collated index for survival, usable in clinical practice to identify patients at risk of shorter survival and to improve personalised healthcare provision.In this cross-sectional study, 2263 patients with cancer or haematologic malignancies participated. We analysed 15 biological, psychological and social indicators as risk factors for survival with a Cox proportional hazards model. Indicators significantly associated with survival were combined to compute models for the identification of patient groups with different risks of death. The training sample contained 1122 patients. Validation samples included the remaining 1141 patients, the total sample, as well as groups with different cancer entities.Five indicators were found to significantly impact survival: Cancer site (HR: 3.56), metastatic disease (HR: 1.88), symptoms of depression (HR: 1.34), female sex (HR: 0.73) and anaemia (HR: 0.48). Combining these indicators to a model, we developed the Cancer Survival Index, identifying three distinct groups of patients with estimated survival times of 47.2 months, 141 months and 198.2 months (p 0.001). Post hoc analysis of the influence of depression on survival showed a mediating effect of the following four factors, related to both depression and survival: previous psychiatric conditions, employment status, metastatic disease and haemoglobin levels.Psychosocial and biological factors impact survival in various malignancies and can be utilised jointly to compute an index for estimating the survival of each patient individually-the Cancer Survival Index.

The mouse is a common and cost-effective animal model for basic research, and the number of genetically engineered mouse models with cardiac phenotype is increasing. In vivo electrophysiological study in mice is similar to that performed in humans. It is indispensable for acquiring intracardiac electrocardiogram recordings and determining baseline cardiac cycle intervals. Furthermore, the use of programmed electrical stimulation enables determination of parameters such as sinoatrial conduction time, sinus node recovery time, atrioventricular-nodal conduction properties, Wenckebach periodicity, refractory periods and arrhythmia vulnerability. This protocol describes specific procedures for determining these parameters that were adapted from analogous human protocols for use in mice. We include details of ex vivo electrophysiological study, which provides detailed insights into intrinsic cardiac electrophysiology without external influences from humoral and neural factors. In addition, we describe a heart preparation with intact innervation by the vagus nerve that can be used as an ex vivo model for vagal control of the cardiac conduction system. Data acquisition for in vivo and ex vivo electrophysiological study takes ~1 h per mouse, depending on the number of stimulation protocols applied during the procedure. The technique yields highly reliable results and can be used for phenotyping of cardiac disease models, elucidating disease mechanisms and confirming functional improvements in gene therapy approaches as well as for drug and toxicity testing.

Based on the current measures, it is unlikely that the targets of the Paris Agreement on climate change are to be achieved within the given time. Therefore, new solutions are needed to get climate change under control. Emerging technologies like blockchain allow for new ways to approach climate change. The blockchain serves only as an enabling technology for cryptocurrencies but is a stand-alone tool applicable for various purposes. This paper aims to shed light on the overlap between the areas of blockchain and climate change. Research in this area was examined for potential blockchain use cases to support climate action using a systematic literature review. The found applications can be grouped into the main categories of Emissions Trading and Green Certificates, Sustainable Energy, Sustainable Mobility, and Green Financing. Within these applications, blockchains are being used as supporting technology. Especially transparency, traceability, and immutability are particularly beneficial in blockchain-based applications against climate change. As a downside of the technology, controversial aspects of the blockchain are considered as the energy consumption of the technology.

Zusammenfassung Hintergrund In der ersten Pandemiewelle im Frühjahr 2020 sind in den stationären Langzeitpflegeeinrichtungen überproportional viele Bewohner*innen und Mitarbeiter*innen an COVID-19 erkrankt und hatten den höchsten Anteil im Ausbruchsgeschehen. Leitungspersonen stationärer Altenpflegeeinrichtungen mussten pandemiebedingt teilweise täglich neue eigene Entscheidungen treffen sowie Entscheidungen übergeordneter Stellen interpretieren und integrieren. Ziel der Arbeit Ziel war es zu beschreiben, welche Entscheidungen im Umgang mit der COVID-19-Pandemie von Leitungspersonen stationärer Altenpflegeeinrichtungen zu treffen waren, und welche Konsequenzen sich daraus ergaben. Material und Methoden Es wurde ein qualitatives multizentrisches Querschnittdesign gewählt. Die Datenerhebung fand mittels semistrukturierter Telefoninterviews statt. Die aufgezeichneten Audiodaten wurden transkribiert, mittels Framework Analysis analysiert und in „peer debriefings“ reflektiert. Ergebnisse Es konnten 78 Interviews in 43 Pflegeeinrichtungen geführt werden. Es wurden 3 Hauptthemen mit 10 Subthemen identifiziert: Entscheidungen zu sozialer Teilhabe; Entscheidungen zu Quarantäne und Isolation und Anpassen des Personaleinsatzes. Diskussion Gebraucht werden klarere Information und Anordnungen zur Umsetzung von Maßnahmen, z. B. durch bundesweit einheitliche Vorgaben. In der Informationspolitik werden auch die Gesundheitsämter in der Pflicht gesehen. Konsequenzen ihrer Entscheidungen waren für die Leitungspersonen kaum absehbar und von Unsicherheit geprägt. Verantwortlichkeiten für und Konsequenzen von Entscheidungen in der Pandemie sollten weiter evaluiert werden, um Leitungspersonen für Krisenzeiten zu stärken.

The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in patients with various neuroimmunologic disorders on anti-CD20 therapy. This included an analysis of the T cell vaccine response to the SARS-CoV-2 Delta variant.We investigated prospectively humoral and cellular responses to SARS-CoV-2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti-CD20 therapy and 82 age- and sex-matched healthy controls. For quantification of antibodies, the Elecsys anti-SARS-CoV-2 viral spike (S) immunoassay against the receptor-binding domain (RBD) was used. IFN-gamma enzyme-linked immunosorbent spot assays were performed to assess T cell responses against the SARS-CoV-2 Wuhan strain and the Delta variant.SARS-CoV-2-specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p 0.001). In patients without detectable B cells (1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti-CD20 treated patients. In contrast to the antibody response, the T-cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p 0.05) and magnitude (p 0.01) in B-cell depleted compared to nondepleted patients.Antibody responses to SARS-CoV-2 mRNA vaccinnation can be attained in patients on anti-CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID-19) in this high-risk population. ANN NEUROL 2022;91:342-352.

Supplemental Figures 1 to 6 from Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism

Supplementary Figure 1. Inhibitory effect of Cetuximab determined by western blot analysis of 12 HNSCC cell line lysates. Supplementary Figure 2. Time course of EGFR phosphorylation in HNSCC cell line UT-SCC 8. Supplementary Figure 3. Correlation of total and membrane exposed EGFR in HNSCC cell lines. Supplementary Figure 4. IL-3 dependent Ba/F3 cells can be transformed to EGF dependence by stable transduction with EGFR and EGFRK521 genes. Supplementary Figure 5. Far-UV CD spectra of Fc-EGFR and Fc-EGFRK521. Supplementary Figure 6. ADCC induction in EGFR-transduced Ba/F3 cells by Cetuximab and CetuGEX{trade mark, serif}.

Supplementary Table 1 Patient characteristics including EGFRK521 allele frequency. Supplementary Table 2 Characteristics and sequencing data of squamous cell carcinoma cell lines.

Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR-targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K521 (K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K521 was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K521 that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K521 expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform. Cancer Res; 77(5); 1188–99. ©2016 AACR.

Supplementary Table S3. PAX3-FOXO1 phospho-peptides identified by mass spectrometry.

Supplementary Table S2. Small-molecule library.

Pediatric tumors harbor very low numbers of somatic mutations and therefore offer few targets to improve therapeutic management with targeted drugs. In particular, outcomes remain dismal for patients with metastatic alveolar rhabdomyosarcoma (aRMS), where the chimeric transcription factor PAX3/7-FOXO1 has been implicated but problematic to target. In this report, we addressed this challenge by developing a two-armed screen for druggable upstream regulatory kinases in the PAX3/7-FOXO1 pathway. Screening libraries of kinome siRNA and small molecules, we defined PLK1 as an upstream-acting regulator. Mechanistically, PLK1 interacted with and phosphorylated PAX3-FOXO1 at the novel site S503, leading to protein stabilization. Notably, PLK1 inhibition led to elevated ubiquitination and rapid proteasomal degradation of the PAX3-FOXO1 chimeric oncoprotein. On this basis, we embarked on a preclinical validation of PLK1 as a target in a xenograft mouse model of aRMS, where the PLK1 inhibitor BI 2536 reduced PAX3-FOXO1–mediated gene expression and elicited tumor regression. Clinically, analysis of human aRMS tumor biopsies documented high PLK1 expression to offer prognostic significance for both event-free survival and overall survival. Taken together, these preclinical studies validate the PLK1–PAX3-FOXO1 axis as a rational target to treat aRMS. Cancer Res; 75(1); 98–110. ©2014 AACR.

Supplementary Table S1. PAX3-FOXO1 regulating kinases identified by siRNA screen.

Supplementary Figure Legends. Legend for Supplementary Figures S1-S7.

Supplementary Materials and Methods. Description of additional methods and procedures used in the study.

ZusammenfassungAusgehend von der theoretischen Perspektive der Educational Governance und des akteurszentrierten Institutionalismus, werden im folgenden Beitrag Akteure im Mehrebenensystem sowie ihr handelndes Zusammenwirken im Umgang mit Kursabbrüchen analysiert. Auf Basis der inhaltsanalytischen Auswertung von insgesamt 22 leitfadengestützten Interviews mit Dozierenden und Bildungsplanenden konnten drei wesentliche Umgangsstrategien mit Drop-out differenziert werden: Akzeptanz, Reduzierung und Verhinderung. Im Kern der Befunde steht die enge Zusammenarbeit zwischen Dozierenden und Bildungsplanenden. Deutlich werden die Eingebundenheit und Abhängigkeit ihrer Handlungskapazitäten, -optionen sowie ihrer wechselseitigen Erwartungen in und von umgangsstrategiespezifischen Akteurskonstellationen im Mehrebenensystem der Weiterbildung. Insgesamt verweist der Beitrag auf die Relevanz des handelnden Zusammenwirkens einer Vielzahl je unterschiedlicher Akteure im Umgang mit Kursabbrüchen, welche zukünftige Forschung berücksichtigen müsste.

Objectives: The objective of this work was to evaluate the incremental value of MR angiography over plain radiographs and MRI for the differentiation of aneurysmal bone cysts (ABCs) from unicameral bone cysts (UBCs). Methods: Thirty-six juvenile patients with histologically secured primary ABCs or UBCs were included in this retrospective study. Two radiologists assessed all obtained images in a blinded fashion using a catalog of previously suggested imaging findings. A second readout with supplementary MR angiography images was performed after 8 weeks to prevent observer recall bias. Diagnostic accuracy parameters were calculated for individual imaging findings, and overall diagnostic accuracy and diagnostic confidence were assessed for all readouts. Receiver operating characteristic (ROC) curve comparison was used to determine the incremental value of MR angiography. Results: Of 16 imaging features, only abnormal vascularization in MR angiography provided sufficient diagnostic accuracy for the identification of ABCs. Other imaging features such as fluid–fluid levels and internal septations were insufficient for the differentiation of UBCs from ABCs. Availability of MR angiography images significantly increased diagnostic accuracy (94.4 vs 75.0% and 83.3 vs 69.4%, respectively, p < 0.05) and diagnostic confidence (4.5 vs 3.7, p < 0.05) of reading radiologists. Conclusion: The presence of arterial feeders in MR angiography can accurately discriminate primary ABCs from UBCs and increases the diagnostic accuracy and diagnostic confidence of reporting radiologists. Advances in knowledge: Radiographic differentiation of cystic bone lesions such as ABCs and UBCs remains challenging. We demonstrate that MR angiography provides incremental value and suggest inclusion in standard examination protocols.

Object pose estimation is important for object manipulation and scene understanding. In order to improve the general applicability of pose estimators, recent research focuses on providing estimates for novel objects, that is objects unseen during training. Such works use deep template matching strategies to retrieve the closest template connected to a query image. This template retrieval implicitly provides object class and pose. Despite the recent success and improvements of Vision Transformers over CNNs for many vision tasks, the state of the art uses CNN-based approaches for novel object pose estimation. This work evaluates and demonstrates the differences between self-supervised CNNs and Vision Transformers for deep template matching. In detail, both types of approaches are trained using contrastive learning to match training images against rendered templates of isolated objects. At test time, such templates are matched against query images of known and novel objects under challenging settings, such as clutter, occlusion and object symmetries, using masked cosine similarity. The presented results not only demonstrate that Vision Transformers improve in matching accuracy over CNNs, but also that for some cases pre-trained Vision Transformers do not need fine-tuning to do so. Furthermore, we highlight the differences in optimization and network architecture when comparing these two types of network for deep template matching.

Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been associated with changes in blood coagulation resulting in increased incidence of venous thromboembolic events and coagulopathy. Moreover, single cases of ischemic priapism have been reported in adult patients with SARS-CoV-2 infection. In this report, we describe the case of ischemic priapism in a 12-year-old child with recent SARS- CoV-2 infection.

ZusammenfassungTrotz der Vielzahl seiner Erscheinungs- und Umgangsformen findet Drop-out in der erwachsenenpädagogischen Forschung vergleichsweise wenig Beachtung und theoretische Konzepte, welche die unterschiedlichen Lesarten des Phänomens in einem übergeordneten Rahmen systematisieren, gibt es bislang kaum. Im Beitrag werden daher bisherige theoretische Konzepte zu Weiterbildungsabbrüchen und Ansätze zur Einordnung von Weiterbildungsabbrüchen als Weiterbildungsverhalten zusammengetragen sowie die Forschungslücken in Bezug auf ein umfassendes Modell zur ursächlichen Erklärung von Drop-out in der Weiterbildung aufgezeigt. Anhand einer empirischen Studie – hier basierend auf der Auswertung von 40 problemzentrierten Interviews – werden eine Typologie sowie ein Modell zur Charakterisierung von Weiterbildungsabbrüchen vorgeschlagen und deren Potenzial für die weitere Theorieentwicklung in diesem Bereich herausgearbeitet. Als zentral kristallisiert sich dabei der Begriff „Passung“ heraus, mit dem sich die Vielfalt von Abbruchskonstellationen theoretisch anschlussfähig beschreiben lässt.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. Significance: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer. See related commentary by Letai, p. 290. This article is highlighted in the In This Issue feature, p. 275

A universal allometric scaling law has been proposed to describe cortical folding of the mammalian brain as a function of the product of cortical surface area and the square root of cortical thickness across different mammalian species, including humans. Since these cortical properties are vulnerable to developmental disturbances caused by preterm birth in humans and since these alterations are related to cognitive impairments, we tested (i) whether cortical folding in preterm-born adults follows this cortical scaling law and (ii) the functional relevance of potential scaling aberrances. We analysed the cortical scaling relationship in a large and prospectively collected cohort of 91 very premature-born adults (

Plant photosynthesis contains two functional modules, the light-driven reactions in the thylakoid membrane and the carbon-fixing reactions in the chloroplast stroma. In nature, light availability for photosynthesis often undergoes massive and rapid fluctuations. Efficient and productive use of such variable light supply requires an instant crosstalk and rapid synchronization of both functional modules. Here, we show that this communication involves the stromal exposed regulatory C-terminus (RCT) of the thylakoid K+-exchange antiporter KEA3. RCT-mediated control of KEA3 contributes to the balance between light capture and photoprotection. By combiningin silico, in vitro, andin vivoapproaches, we demonstrate that the RCT senses the energy state of the chloroplast in form of both, phosphorylation and redox potential, in a pH-dependent manner and regulates KEA3 activity in response. Together our data pinpoint a regulatory feedback loop by which the stromal energy state orchestrates light capture and photoprotection via KEA3.

In the life sciences, there has been growing awareness that the traditional 2D cell culture model has its limitations in advancing our understanding of the mechanisms that underlie cell behavior, as the behavior and response of cells depend on the 3D microenvironment. Studying models such as suspended cell clusters and organoids is a step toward closing the gap between in vitro and in vivo studies. The fact that sample confinement and contact with surfaces have an impact on cells creates a need for contact-less tools for the inspection of live biological samples. Recently, we developed an acoustofluidic chip to trap and manipulate sub-millimeter-sized biological samples, and here, we demonstrate that this device can be adapted to support high-resolution imaging and illumination scanning for multi-view image acquisition. After coupling acoustic bulk waves into a microfluidic chip, the sample is levitated by an optically transparent transducer in the vertical direction. Two orthogonal side-transducers give additional control over the sample. By tuning the relative strengths of the three transducers and thus inducing an acoustic torque, we can transiently rotate the sample into various orientations for image acquisition. Under different operating conditions, exciting other modes, we can also induce sustained rotation of samples by means of other torque contributions and around axes perpendicular to the imaging axis, which is important to avoid “missing cone” artifacts in the tomographic reconstruction of the sample. We will discuss the modifications to our previously established device that were necessary to comply with the requirements for high-NA imaging and high-NA illumination. We provide a characterization of the performance and show examples of rotation and reorientation of biological samples, such as large pollen grains and cancer spheroids.

Background Ceftolozane/tazobactam (C/T) has demonstrated efficacy to treat complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI) and hospital acquired bacterial and ventilator-associated bacterial pneumonia. However, physicians, providers, and other stakeholders including payers want broader real-world evidence to inform clinical decisions and optimize healthcare resource use. Methods SPECTRA is a multi-national, multicenter, retrospective, inpatient, observational study of patients treated with C/T in Australia, Austria, Germany, Italy, Mexico, Spain and The United Kingdom. Adult inpatients treated with ≥48 hours of C/T were included. Demographics, clinical characteristics, treatment management patterns, and outcomes were analyzed. Results There were 687 patients from 38 participating hospitals in 7 countries. The average age was 57.6 years (±17.3 [SD]) and most were male 456 (66.4%). The majority had at least one comorbidity 563 (82.0%), with the most common being heart disease 208 (30.3%), immunocompromised state 207 (30.1%) and chronic pulmonary disease 195 (28.4%). The most common indications were pneumonia 204 (29.7%), sepsis 147 (21.4%), and cIAI 106 (15.4%); 162 (23.6%) had multiple sites of infection and 245 (35.7%) were polymicrobial infections. Median C/T treatment was 12.0 days (11.0 [IQR]). Half of the patients were admitted to the ICU 343 (49.9%), 43.4% of which was related to the infection. Clinical success was 66.1%. All-cause in-hospital mortality was 22.0% with 8.7% being infection related. 30-day all-cause readmission was 9.8% and 4.7% were infection related. Conclusion C/T was used to treat infections among critically ill patients and for multi-source, polymicrobial infections. Despite the complexity of the patients in this real-world analysis, most C/T patients had beneficial outcomes that are similar to results of controlled clinical trials. Disclosures Alex Soriano, MD, MSD, Pfizer, Shionogi, Angelini, Menarini, Gilead: Honoraria Laura A. Puzniak, MPH, PhD, Merck & Co., Inc.: former employee and stockholder David Paterson, MBBS, Accelerate: Honoraria|bioMerieux: Honoraria|Entasis: Advisor/Consultant|Janssen-Cilag: Grant/Research Support|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Grant/Research Support|Pfizer: Honoraria|PPD: Grant/Research Support|Shionogi: Grant/Research Support|VenatoRx: Advisor/Consultant Stefan Kluge, MD, Astrazeneca: Lecture fees|Biotest: Lecture fees|Cytosorbents: Grant/Research Support|Cytosorbents: Lecture fees|Daiichi Sankyo: Grant/Research Support|Daiichi Sankyo: Lecture fees|Fresenius Medical Care: Advisor/Consultant|Fresenius Medical Care: Lecture fees|Gilead: Advisor/Consultant|Gilead: Lecture fees|Mitsubishi Tanabe Pharma: Lecture fees|MSD: Advisor/Consultant|MSD: Lecture fees|Pfizer: Advisor/Consultant|Pfizer: Lecture fees|Phillips: Lecture fees|Zoll: Lecture fees Alexandre H. Watanabe, PharmD, Merck & Co., Inc.: Employee Engels N. Obi, PhD, Merck & Co., Inc.: Employee|Merck & Co., Inc.: Stocks/Bonds Sunny Kaul, BSc, MBChB, PHD, FRCP, FFICM, Chiesi: Speaker fees|Gilead: Speaker fees|GlaxoSmithKline: Speaker fees|MSD: Grant/Research Support|MSD: Speaker fees|Shionogi: Speaker fees|Vifor Pharma: Grant/Research Support.

Summary: The use of vascular ultrasound, especially with the increasing prevalence of percutaneous arteriovenous fistulas, has taken a central role as a diagnostic and therapeutic imaging procedure in vascular access creation. The current review article stresses the importance of vascular ultrasound in arteriovenous fistula, from planning to creation to maintenance. It summarises and gives practical guidance regarding sonographic criteria for vascular access procedure planning, the application of vascular ultrasound intraoperatively and during follow-up. Ultrasound education and training modalities to meet high standards of patient care in hemodialysis are presented.

This prospective study sought to evaluate potential savings of radiation dose to medical staff using real-time dosimetry coupled with visual radiation dose feedback during angiographic interventions. For this purpose, we analyzed a total of 214 angiographic examinations that consisted of chemoembolizations and several other types of therapeutic interventions. The Unfors RaySafe i2 dosimeter was worn by the interventionalist at chest height over the lead protection. A total of 110 interventions were performed with real-time radiation dosimetry allowing the interventionalist to react upon higher x-ray exposure and 104 examinations served as the comparative group without real-time radiation monitoring. By using the real-time display during interventions, the overall mean operator radiation dose decreased from 3.67 (IQR, 0.95-23.01) to 2.36 μSv (IQR, 0.52-12.66) (-36%; p = 0.032) at simultaneously reduced operator exposure time by 4.5 min (p = 0.071). Dividing interventions into chemoembolizations and other types of therapeutic interventions, radiation dose decreased from 1.31 (IQR, 0.46-3.62) to 0.95 μSv (IQR, 0.53-3.11) and from 24.39 (IQR, 12.14-63.0) to 10.37 μSv (IQR, 0.85-36.84), respectively, using live-screen dosimetry (p ≤ 0.005). Radiation dose reductions were also observed for the participating assistants, indicating that they could also benefit from real-time visual feedback dosimetry during interventions (-30%; p = 0.039). Integration of real-time dosimetry into clinical processes might be useful in reducing occupational radiation exposure time during angiographic interventions. The real-time visual feedback raised the awareness of interventionalists and their assistants to the potential danger of prolonged radiation exposure leading to the adoption of radiation-sparing practices. Therefore, it might create a safer environment for the medical staff by keeping the applied radiation exposure as low as possible.