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PURPOSE: To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. METHODS: Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (< 2 h), 'urgent' (2-6 h), and 'delayed' (> 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). RESULTS: The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value ≤ 4-55.4% for a value > 12, p < 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (< 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). CONCLUSION: 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT03270345.

To examine the effects of implementing a dedicated orthopaedic trauma room (DOTR) on hip and femur fracture care.A retrospective cohort study. Setting: Level 1 trauma center. Patients: 2928 patients with femoral neck, pertrochanteric, and femoral shaft and distal femur (FSDF) fractures.Implementation of a DOTR.Hospital length of stay (LOS), emergency department (ED) LOS, intensive care unit (ICU) LOS, and time to operating room (TTOR).Implementation of a DOTR resulted in significant improvement in TTOR for all patient groups ( P0.05). We found shorter TTOR for pertrochanteric ( P0.001), femoral neck ( P = 0.039), and FSDF groups ( P = 0.046). Total hospital LOS was shorter for patients with pertrochanteric ( P0.001) and femoral neck fractures ( P = 0.044). Patients with pertrochanteric hip fractures demonstrated shorter ICU LOS ( P0.001). No LOS improvements were observed among patients in the FSDF group. ED LOS was significantly longer in all patient groups ( P0.001).Implementation of a DOTR was associated with shorter TTOR, shorter hospital and ICU LOS, and longer ED LOS. There was a greater number of patients transferred into the investigating institution and fewer patients transferred out. These data support the utility of a DOTR as it relates to an improvement in hospital stay-related outcomes in patients with fractures of the hip and femur. Our results suggest that a DOTR in a Level I trauma hospital is associated with improvement in patient care.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

With the increasing need for minimally invasive procedures based on lower complication rates, higher patient acceptance, and technical developments, there is a growing focus on the sound interventional training of young radiologists. This survey aimed to analyze the current situation in interventional radiology (IR) training in Germany to detect shortcomings and identify areas for improvement.From November 1-30, 2020, an online questionnaire was distributed to representative radiological associations and societies with the request to forward it to radiology residents and radiologists 40 years. The 44 questions covered six distinct areas from personal working conditions to the characterization of the IR department, training conditions, role of women in IR, and attendance at congresses/external training.A total of 330 participants completed the questionnaire. 77 % of participants expressed a high interest in IR, and 47 % could even imagine subspecializing in interventional radiology. Most institutions provided the necessary learning conditions and infrastructure. The rate of overall satisfaction with IR training conditions was 45 % (vs. a dissatisfaction rate of 39 %). However, females showed a lower satisfaction rate with their training environment than male participants (28 % vs. 51 %; P = 0.06). Positive correlations with work satisfaction were found for the presence and duration of the IR rotation, the number of partly independently/mentored performed interventions, and structured feedback. Moreover, the need for a structured training curriculum was expressed by 67 % of participants.Radiological residents and young radiologists expressed a high interest in interventional radiology, and they rate the infrastructure of German hospitals regarding IR as sufficient. However, they expressed the need for consistent IR rotations and better-structured resident and postgraduate education (curriculainterviews).Interest in interventional radiology among radiological residents and young radiologists in Germany is high, but satisfaction with interventional radiology training leaves room for improvement. The most frequently mentioned aspects that can improve IR training were · organized rotations of at least 6 months. · structured curriculums with face-to-face feedback. · structured guidance by senior interventionists during procedures. CITATION FORMAT: · Sieren M, Katoh M, Mahnken AH et al. Work and Training Conditions of German Residents and Young Radiologists in Interventional Radiology - A Nationwide Survey. Fortschr Röntgenstr 2022; 194: 1346 - 1357.Die fundierte interventionelle Ausbildung junger RadiologInnen gerät durch den zunehmenden Bedarf an minimal-invasiven Prozeduren immer mehr in den Fokus. Ziel dieser Umfrage war es, die aktuelle Situation der Ausbildung in der Interventionellen Radiologie (IR) in Deutschland zu analysieren, um Defizite aufzudecken und Verbesserungsmöglichkeiten zu identifizieren.Vom 1. bis 30. November 2020 wurde ein Online-Fragebogen an repräsentative radiologische Verbände und Gesellschaften versandt mit der Bitte, ihn an AssistenzärztInnen und RadiologInnen 40 Jahre weiterzuleiten. Die 44 Fragen deckten 6 verschiedene Bereiche ab, von den persönlichen Arbeitsbedingungen bis zur Charakterisierung der IR-Abteilung, den Ausbildungsbedingungen, der Rolle der Frauen in der IR und der Teilnahme an Kongressen/externen Fortbildungen.Insgesamt haben 330 TeilnehmerInnen den Fragebogen ausgefüllt. 77 % der TeilnehmerInnen bekundeten ein hohes Interesse an der IR und 47 % konnten sich sogar eine Subspezialisierung in der interventionellen Radiologie vorstellen. Die Mehrheit der Institutionen stellten die notwendigen Rahmenbedingungen und Infrastruktur bereit. Insgesamt lag die Zufriedenheit über die interventionsradiologische Weiterbildung bei 45 % (vs. 39 % Unzufriedenheit), wobei die Zufriedenheit mit den Ausbildungsbedingungen bei Teilnehmerinnen geringer ausfiel als bei den Teilnehmern (28 % vs. 51 %; P = 0,06). Positive Korrelationen mit der Arbeitszufriedenheit wurden für das Vorhandensein und die Dauer der IR-Rotation, die Anzahl der teilweise selbstständig/supervidiert durchgeführten Eingriffe und ein institutionalisiertes, strukturiertes Feedback festgestellt. Darüber hinaus äußerten 67 % der Teilnehmer den Wunsch nach einem strukturierten Ausbildungscurriculum.AssistenzärztInnen und junge RadiologInnen zeigen ein hohes Interesse an der Interventionellen Radiologie und bewerten die Infrastruktur deutscher Krankenhäuser im Bereich der IR als ausreichend. Sie äußerten jedoch den Bedarf an konsistenten IR-Rotationen und einer besser strukturierten grundlegenden und weiterführenden Ausbildung (CurriculaInterviews).Das Interesse an der Interventionellen Radiologie ist bei Assistenzärzten und jungen Radiologen in Deutschland hoch, die Zufriedenheit mit der Ausbildung in der Interventionellen Radiologie ist geringer. Die am häufigsten genannten Aspekte, die die IR-Ausbildung verbessern können, waren · organisierte Rotationen von mindestens 6 Monaten Dauer. · strukturierte Curricula mit persönlichem Feedback. · strukturierte Anleitung durch erfahrene Interventionisten während der Eingriffe.

Charge nurses (CNs) are shift leaders who manage resources and facilitate patient care, yet CNs in EDs receive minimal training, with implications for patient safety and emergency nursing practice. The purpose of the study was to describe the experiences of emergency nurses related to training, preparation, and function of the CN role.An explanatory sequential mixed methods design using survey data (n = 2579) and focus group data (n = 49) from both CN and staff nurse perspectives.Participants reported minimal training for the CN role, with divergent understandings of role, required education and experience, the need for situational awareness, and the acceptability of the CN taking on other duties.The ED CN is critical to the safety of both nursing environment and patient care. Nurses in this pivotal role do not receive adequate leadership orientation or formal training in the key areas of nurse patient assignment, communication, and situational awareness. Formal training in nurse-patient assignment, communication, and situational awareness are critical to appropriate patient care and maintenance of interprofessional trust necessary for successful execution of the CN role. ED nurse managers should advocate for this training.

Aims The value of additional ablation beyond pulmonary vein isolation for atrial fibrillation (AF) ablation is unclear, especially for persistent AF. The optimal target for substrate modification to improve outcomes is uncertain. We investigate the utility of low-voltage area (LVA) substrate modification in patients undergoing catheter ablation for AF. Methods and results This meta-analysis was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Medline, Scopus and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. Risk of bias was assessed using the Cochrane risk of bias tool. Only randomized studies were included. AF patients who underwent catheter ablation with voltage-guided substrate modification targeting LVA (LVA group) vs. conventional ablation approaches not targeting LVA (non-LVA group) were compared. Four studies comprising 539 patients were included (36% female). Freedom from arrhythmia (FFA) in patients with persistent AF was greater in the LVA group [risk ratio (RR) 1.30; 95% confidence interval (CI) 1.03–1.64]. There was no difference in FFA in patients with paroxysmal AF between groups (RR 1.30; 95% CI 0.89–1.91). There was no difference in total procedural time (mean difference −17.54 min; 95% CI −64.37 to 29.28 min) or total ablation time (mean difference −36.17 min; 95% CI −93.69 to 21.35 min) in all included patients regardless of AF type between groups. There was no difference in periprocedural complications between groups in all included patients regardless of AF type (RR 0.93; 95% CI 0.22–3.82). Conclusion This meta-analysis demonstrates improved FFA in persistent AF patients who underwent voltage-guided substrate modification targeting LVA.

BACKGROUND & AIMS: Wilson disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using positron emission tomography (PET) with copper-64 (64 Cu) as tracer. Furthermore, we assessed the diagnostic potential of the method.METHODS: Nine patients with WD, five healthy heterozygote subjects, and eight healthy controls were injected with an intravenous bolus of 64 Cu followed by a 90-min dynamic PET scan of the liver and static whole-body PET/CT scans after 1.5, 6, and 20 hours. Blood 64 Cu concentrations were measured in parallel. The hepatic copper retention and redistribution were evaluated by standardized uptake values (SUV).RESULTS: At 90 min, the hepatic SUVs were similar in the three groups. In contrast, at 20 hours post injection, the SUV in WD patient (Mean±SEM 31±4) was higher than in heterozygotes (24±3) or controls (21±4), (p < 0.001). An SUV-ratio of the hepatic 64 Cu concentration at 20 and 1.5 hours completely discriminated between the WD patients and control groups (p < 0.0001; ANOVA). By Patlak-analysis of the initial 90 min of the PET scan, the steady-state hepatic clearance of 64 Cu was estimated to be slightly lower in the patients with WD than in controls, (p = 0.04).CONCLUSIONS: 64 Cu PET imaging enables visualisation and quantification of the hepatic copper retention characteristic for WD patients. This method represents a valuable tool for future studies of WD pathophysiology, which may assist the development of novel therapies, and accurate diagnosis.

Purpose The aim of this study was to analyze the impact of minimally invasive intermittent Pringle maneuver (IPM) on postoperative outcomes in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Methods In this retrospective cohort study, we evaluated the safety of IPM in patients with HCC who underwent minimally invasive liver resection during five years at our center. Factors influencing the use of IPM were examined in univariate and multivariate regression analysis. Cases with use of IPM (IPM) and those without use of IPM (no IPM) were then compared regarding intraoperative and postoperative outcomes after propensity score matching (PSM) for surgical difficulty. Results One hundred fifty-one patients underwent liver resection for HCC at our center and met inclusion criteria. Of these, 73 patients (48%) received IPM with a median duration of 18 min (5–78). One hundred patients (66%) had confirmed liver cirrhosis. In multivariate analysis, patients with large tumors (≥ 3 cm) and difficult tumor locations (segments VII or VIII) were more likely to undergo IPM (OR 1.176, p = 0.043, and OR 3.243, p = 0.001, respectively). After PSM, there were no differences in intraoperative blood transfusion or postoperative complication rates between the IPM and no IPM groups. Neither did we observe any differences in the subgroup analysis for cirrhotic patients. Postoperative serum liver function tests were not affected by the use of IPM. Conclusions Based on our findings, we conclude that the use of IPM in minimally invasive liver resection is safe and feasible for patients with HCC, including those with compensated liver cirrhosis.

Sexual dysfunctions are common experiences that often impact negatively on the health and well-being of affected individuals. We used baseline questionnaire data from 62,675 Danes aged 15-89 years, who participated in the cohort study Project SEXUS 2017-2018, to yield nationally representative estimates of the prevalence of sexual inactivity and dysfunction and to identify their sociodemographic correlates. Overall, we found that 23.0% of sexually experienced men and 28.8% of sexually experienced women had not been sexually active with another person within the last year. Sexual inactivity with another person was associated with both young and old age, single status, less favorable socioeconomic conditions, underweight and obesity, indicators of poor health, no use of alcohol, and physical inactivity. Among sexually active respondents, 18.0% of men had experienced any dysfunction within the last year, including erectile dysfunction (7.4%), premature ejaculation dysfunction (10.0%), orgasmic dysfunction (4.0%), and/or genital pain dysfunction (0.7%). Among women, 20.4% had experienced any dysfunction within the last year, including lubrication dysfunction (9.1%), orgasmic dysfunction (12.2%), genital pain dysfunction (5.0%), and/or vaginal cramp dysfunction (vaginismus) (0.8%). Additionally, 3.4% of men and 9.9% of women with a spouse/partner had experienced hypoactive sexual desire disorder within the last four weeks. Using the 5-item International Index of Erectile Function (IIEF-5) and the 6-item Female Sexual Function Index (FSFI-6) among respondents with a spouse/partner who had attempted sexual intercourse within the last four weeks, we found that 3.8% of men had experienced moderate or severe erectile dysfunction (IIEF-5 score ≤ 11) and 20.8% of women had experienced any sexual dysfunction (FSFI-6 score ≤ 19) during that period. Single status, difficulties paying bills and, among men, unemployment were positively associated with sexual dysfunction. In conclusion, we document several sociodemographic disparities in the prevalence of sexual inactivity and dysfunction in Denmark. In particular, both sexual inactivity and dysfunction were more common among singles and those reporting financial difficulties.

The modeling of chimeric antigen receptor (CAR) T cell therapies has been mostly focused on immunodeficient models. However, there are many advantages in studying CAR-T cell biology in an immunocompetent setting. We generated a fully murine CAR targeting CD105 (endoglin), a component of the TGFβ receptor expressed on the surface of certain solid tumors and acute leukemias. CD105-targeted CAR-T cells can be grown from various murine backgrounds, tracked

Intraoperative medial collateral ligament (MCL) injury during total knee arthroplasty (TKA) is a serious complication. External bracing and/or conversion to a constrained implant has previously been studied. The technique of using an internal high-strength suture brace to augment an MCL repair has been evaluated in the nonarthroplasty patient and could provide an alternate solution. The goal of this study was to determine whether MCL repair with internal suture bracing restores stability of the implanted knee joint. A robotic simulator completed laxity testing on 5 cadaveric knee specimens in 4 sequential phases: (1) intact knee, (2) after implantation with TKA, (3) after sectioning of the MCL, and (4) after MCL repair with suture brace augmentation. Laxity was compared between the different test phases throughout range of motion. Subsequently, the internal brace was tested to failure under valgus load. The MCL repair with internal bracing was effective at restoring laxity in varus-valgus, internal-external, and medial-lateral degrees of freedom through midflexion, with limited support at deeper flexion angles and in anterior-posterior laxity. Rotational laxity was not significantly different than intact knee laxity. Generally, medial-lateral translations were less and anterior-posterior translations were greater and were significantly different at 30° to 45° and 90°, respectively. The mean failure moment was 46.4±9.1 Nm, with the primary mode of failure being MCL repair. Primary MCL repair with internal bracing using a high-strength suture augment showed the potential to provide adequate stability and strength to correct MCL incompetence in TKA without the use of an external knee brace or constrained implants. [ Orthopedics . 2022;45(5):e269–e275.]

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Neurologist and psychiatrist Kurt Goldstein (1878-1965) made substantial contributions to neuropsychology in general and to the development of tests for the assessment of brain damage sequelae in particular. Unlike present-day neuropsychology’s psychometric orientation, Goldstein kept a critical distance to a mere quantitative evaluation. Eighty years ago, he impressively demonstrated his own, qualitatively oriented diagnostic approach both in a remarkable monograph and in a didactic film, in collaboration with psychologist Martin Scheerer (1900-1961). By modifying a classical paradigm for the assessment of deficits in visuospatial construction, the Block Design Test, the two authors developed the Goldstein-Scheerer Cube Test. This version characterizes itself by offering the patient different types of cues in order to reveal the nature of the deficit at stake. The test remains an impressive illustration of Goldstein’s most famous neuropsychological concept, viz. the human ability to abstract from a concrete situation: the abstract (or categorial) attitude.

Mobile electrocardiogram (mECG) devices are being used increasingly, supplying recordings to providers and providing automatic rhythm interpretation. Given the intermittent nature of certain cardiac arrhythmias, mECGs allow instant access to a recording device. In the current COVID-19 pandemic, efforts to limit in-person patient interactions and avoid overwhelming emergency and inpatient services would add value. Our goal was to evaluate whether a mECG device would reduce healthcare utilization overall, particularly those of urgent nature. We identified a cohort of KardiaMobile (AliveCor, USA) mECG users and compared their healthcare utilization 1 year prior to obtaining the device and 1 year after. One hundred and twenty-eight patients were studied (mean age 64, 47% female). Mean duration of follow-up pre-intervention was 9.8 months. One hundred and twenty-three of 128 individuals completed post-intervention follow-up. Patients were less likely to have cardiac monitors ordered (30 vs 6; p

Aims Proton beam therapy (PBT) has increasingly been applied for the treatment of young children when radiotherapy is needed. The treatment requires intensive multimodality care and is logistically demanding. In this analysis, we evaluated our experiences in treating infants with tumours of the central nervous system with PBT. Materials and methods Children younger than 2 years of age treated with PBT for central nervous system tumours enrolled in the prospective registry study KiProReg were retrospectively analysed. Information on patient characteristics, treatment, toxicities and outcome were evaluated. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE V4.0) before, during and after PBT. Results Between September 2013 and June 2018, 51 infants were eligible. The median age was 19 months (range 11–23 months) at the time of PBT. Tumour entities were ependymoma (51.0%), atypical teratoid rhabdoid tumour (39.0%), high-grade glioma (6.0%), pineoblastoma (2.0%) and medulloblastoma (2.0%). The prescribed median total dose was 54.0 Gy (range 45.0–59.4 Gy). Most received local radiotherapy. In four patients, craniospinal irradiation followed by a boost to the local tumour bed was applied. The median follow-up time was 42.0 months (range 7.3–86.2 months). The estimated 3-year local control, progression-free survival and overall survival rates for all patients were 62.7, 47.1 and 76.5%, respectively. During radiotherapy, 24 events of higher-grade (CTCAE ≥ °III) toxicities were reported. Interruption of radiotherapy for more than 2 days was due to infection (n = 3) or shunt complication (n = 2). Unexpected hospitalisation during radiotherapy affected 12 patients. Late adverse events attributable to radiotherapy included endocrinopathy (CTCAE °II; 7.8%), new onset of hearing loss (CTCAE °III; 5.8%) and visual impairment (CTCAE °IV; 1.9%). Transient radiation-induced imaging changes occurred in five patients (9.8%). Conclusions Our study indicates that PBT is feasible for very young children with central nervous system tumours, at least in the short term. However, it requires challenging interdisciplinary medical care and high logistical effort. For evaluation of late effects, longer follow-up and evaluation of neurocognitive outcome are desirable. More data have to be gathered to further define the role of radiotherapy in infants over time.

Mobile electrocardiographic (mECG) devices that record ECG lead I have been used to detect atrial fibrillation. Other arrhythmias may not be readily diagnosed with one lead. Obtaining multi‑lead tracings from an mECG (MLmECG) to simulate a 12‑lead ECG may lead to more accurate diagnoses.We developed a method to generate multi‑lead ECGs using a mECG device by attaching it with alligator clips connected to an insulated copper wire to adhesive electrodes on the patient's limbs and torso according to standard lead configurations. Different rhythm and conduction abnormalities from a sample of inpatients were collected. Arrhythmias were recorded in three ways (single lead, MLmECG, and standard 12‑lead) and grouped by category. Recordings were sent to cardiology fellows in the form of a multiple choice survey. Participants were asked for their diagnosis and confidence in their decision.Survey response rate was 100%. Single‑lead, MLmECG, and 12‑lead yielded 48.2%, 81.6%, and 88.6% of agreement with the correct diagnosis, respectively (single‑lead vs. MLmECG or 12‑lead; p0.01). Overall mean confidence scores were 3.34, 4.35, and 4.53 out of 5, for single‑lead, MLmECG, and 12‑lead ECG, respectively (single‑lead vs. MLmECG or 12‑lead; p0.01, MLmECG vs. 12‑lead; p = 0.09).The diagnostic accuracy of MLmECGs were similar to that of a standard 12‑lead ECG. Fellows' confidence in their diagnosis were similar between MLmECG or 12‑lead ECG, and higher with both modalities compared to a single‑lead tracing. The ability to recreate, as fully as possible, a standard 12‑lead ECG is a reasonable goal for mobile technology.

Here, we describe a protocol for a microcarrier (MC)-based, large-scale generation and cryopreservation of human-induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes. We also detail steps to isolate these populations with a high degree of purity. Finally, we describe how to cryopreserve these cell types while maintaining high levels of viability and preserving cellular function post-thaw. For complete details on the use and execution of this protocol, please refer to Brookhouser et al. (2021).

Response rates to immunotherapy in solid tumors remain low due in part to the elevated prevalence of terminally exhausted T cells, a hypofunctional differentiation state induced through persistent antigen and stress signaling. However, the mechanisms promoting progression to terminal exhaustion in the tumor remain undefined. Using the low-input chromatin immunoprecipitation sequencing method CUT&RUN, we profiled the histone modification landscape of tumor-infiltrating CD8 + T cells throughout differentiation. We found that terminally exhausted T cells had unexpected chromatin features that limit their transcriptional potential. Terminally exhausted T cells had a substantial fraction of active chromatin, including active enhancers enriched for bZIP/AP-1 transcription factor motifs that lacked correlated gene expression, which was restored by immunotherapeutic costimulatory signaling. Reduced transcriptional potential was also driven by an increase in histone bivalency, which we linked directly to hypoxia exposure. Enforced expression of the hypoxia-insensitive histone demethylase Kdm6b was sufficient to overcome hypoxia, increase function, and promote antitumor immunity. Our study reveals the specific epigenetic changes mediated by histone modifications during T cell differentiation that support exhaustion in cancer, highlighting that their altered function is driven by improper costimulatory signals and environmental factors. These data suggest that even terminally exhausted T cells may remain competent for transcription in settings of increased costimulatory signaling and reduced hypoxia.

Excessive lean tissue uptake of fatty acids (FA) is important in the development of insulin resistance and may be caused by impaired dietary FA (DFA) storage and/or increased non-esterified FA (NEFA) flux from adipose tissue intracellular lipolysis. Cardiac and hepatic total postprandial FA uptake of NEFA+DFA has, however, never been reported in prediabetes with overweight. Twenty individuals with impaired glucose tolerance (IGT) and 19 participants with normal glucose tolerance (NGT) and normal fasting glucose underwent postprandial studies with whole-body positron emission tomography/computed tomography (PET/CT) with oral [18F]-fluoro-thia-heptadecanoic acid and dynamic PET/CT with intravenous [11C]-palmitate. Hepatic (97[range 36-215]mmol/6h vs. 68[23-132]mmol/6h, P=0.03), but not cardiac (11[range 4-24]mmol/6h vs. 8[3-20]mmol/6h, P=0.09) uptake of most sources of postprandial FA (NEFA+DFA uptake) integrated over 6 hours was higher in IGT vs. NGT. DFA accounted for lower fractions of total cardiac (21[5-47]% vs. 25[9-39]%, P=0.08) and hepatic (19[6-52]% vs. 28[14-50]%, P=0.04) uptake in IGT vs. NGT. Increased adipose tissue DFA trapping predicted lower hepatic DFA uptake, and was associated with higher total cardiac fatty acid uptake. Hence, enhanced adipose tissue DFA trapping in the face of increased postprandial NEFA flux is insufficient to fully curb increased postprandial lean organ FA uptake in prediabetes with overweight (ClinicalTrials.gov; NCT02808182).

BACKGROUND Effective concepts are required to overcome the negative impact of daily stressful overwhelming. We investigated the effectiveness of a 1-week multimodal program for stress reduction. METHODS We performed a randomized controlled trial including adults with above-average stress level. The intervention consisted of health coaching, relaxation, physical activity, and balneotherapeutic elements. Individuals were randomized either to the intervention group (IG) or to one of the two control groups B and C. The main outcome was change in stress (Perceived Stress Questionnaire PSQ, Screening Scale of Chronic Stress of the Trier Inventory for Chronic Stress TICS-SSCS) at 6 months post intervention; further outcomes were well-being (World Health Organization 5-Item Well-Being Index WHO-5) and health status (EuroQol visual analog scale EQ-5D VAS). Data were collected pre/post intervention as well as after 1, 3, and 6 months. RESULTS Data of 96 individuals (mean age 48.0 years, 74{\%} female) were available for analyses. The IG improved overtime with -13.45 points for the PSQ and -6.44 points for the TICS-SSCS after 6 months. At 6-month follow-up the IG did not significantly differ from group B (PSQ: p = 0.2332; TICS-SSCS: p = 0.0805) or group C (PSQ: p = 0.0950; TICS-SSCS: p = 0.0607) when controlling for baseline (ANCOVA). Compared to group C, ANCOVA revealed significant differences in WHO-5 (p = 0.0292) and EQ-5D VAS (p = 0.0177) post intervention. At the 3- and 6-month follow-up and compared to group B, no substantial differences could be found for WHO-5 and EQ-5D VAS. CONCLUSION The results indicate that even a short-term multimodal program for stress reduction appears to set a positive trend towards less perceived and chronic stress. Hintergrund: Es bedarf effektiver Ans{\"a}tze, um den negativen Einfl{\"u}ssen t{\"a}glicher stressreicher Belastungen zu begegnen. Wir untersuchten die Wirksamkeit eines einw{\"o}chigen multimodalen Programms zur Stressreduzie­rung. Methoden: Wir f{\"u}hrten eine randomisierte kontrollierte Studie mit Erwachsenen durch, die ein erh{\"o}htes Stresslevel aufwiesen. Die Intervention beinhaltete ein Gesundheitscoaching, Entspannungs- und Bewegungs­einheiten sowie balneotherapeutische Elemente. Die Teilnehmenden wurden entweder in die Interventionsgruppe (IG) oder in eine von zwei Kontrollgruppen B oder C randomisiert. Die prim{\"a}re Zielgr{\"o}{\ss}e war die Ver{\"a}nde­rung im Stressniveau (Perceived Stress Questionnaire PSQ, Screening Scale of Chronic Stress of the Trier Inventory for Chronic Stress TICS-SSCS) 6 Monate nach der Intervention; weitere Zielgr{\"o}{\ss}en waren das Wohlbefinden (World Health Organization 5-Item Well-Being Index WHO-5) und der aktuelle Gesundheitsstatus (EuroQol visuelle Analogskala EQ-5D VAS). Daten wurden vor und nach der Intervention erfasst sowie nach 1, 3 und 6 Mona­ten. Ergebnisse: Daten von 96 Teilnehmenden (mittleres Alter 48.0 Jahre, 74{\%} weiblich) standen f{\"u}r die Analyse zur Verf{\"u}gung. Die IG verbesserte sich im Zeitverlauf, mit --13.45 Punkten im PSQ sowie --6.44 Punkten im TICS-SSCS nach 6 Monaten. Zum 6-Monats-Follow-up unterschied sich die IG nicht signifikant von Gruppe B (PSQ: p = 0.2332; TICS-SSCS: p = 0.0805) oder Gruppe C (PSQ: p = 0.0950; TICS-SSCS: p = 0.0607), kontrolliert f{\"u}r den Ausgangswert (ANCOVA). Verglichen mit Gruppe C zeigte die ANCOVA nach der Intervention signifikante Unterschiede im WHO-5 (p = 0.0292) und der EQ-5D VAS (p = 0.0177). Zum 3- und 6-Monats-Follow-up sowie verglichen mit Gruppe B konnten keine substanziellen Unterschiede im WHO-5 und der EQ-5D VAS gefunden werden. Schlussfolgerung: Die Ergebnisse weisen darauf hin, dass selbst ein kurzes multimodales Programm zur Stressreduzierung einen positiven Trend hin zu weniger subjektiv wahrgenommenem und chronischem Stress setzen kann.

The bony otic capsule is comprised of highly mineralized and dense compact bone. It is rarely remodelled and degenerative changes, therefore, accumulate around the inner ear. It is also a predilection site for the pathological remodelling seen in otosclerosis. Morphometric studies have documented increased numbers of dead osteocytes and microcracks in the human otic capsule. Microcracks may disrupt the lacuno-canalicular network and cause osteocyte apoptosis ultimately breaking up the perilabyrinthine bone signalling pathways and dynamics. This may be important to understand the pathogenesis of remodelling diseases like otosclerosis.This study describes the spatial and regional distribution of microcrack surface density in relation to the inner ear and compares it to that previously recorded for otosclerosis.Forty-two temporal bones and five ribs were used. All samples were undecalcified, bulk stained in basic fuchsin and plastic embedded. Unbiased stereology was used to estimate the true surface density of microcracks (mmThe surface density of microcracks accumulates around the inner ear spaces, particularly in the lateral window regions, and increases with age.This study documents the spatial and temporal association between microfractures and otosclerosis in the otic capsule.

Introduction:The year 2020 was defined by the 29,903 base pairs of RNA that codes for the SARS-CoV-2 genome. SARS-CoV-2 infects humans to cause COVID-19, spreading from patient-to-patient yet impacts patients very divergently. Areas covered: Within this review, we address the known molecular mechanisms and supporting data for COVID-19 clinical course and pathology, clinical risk factors and molecular signatures, therapeutics of severe COVID-19, and reinfection/vaccination. Literature and published datasets were reviewed using PubMed, Google Scholar, and NCBI SRA tools. The combination of exaggerated cytokine signaling, pneumonia, NETosis, pyroptosis, thrombocytopathy, endotheliopathy, multiple organ dysfunction syndrome (MODS), and acute respiratory distress syndrome (ARDS) create a positive feedback loop of severe damage in patients with COVID-19 that impacts the entire body and may persist for months following infection. Understanding the molecular pathways of severe COVID-19 opens the door for novel therapeutic design. We summarize the current insights into pathology, risk factors, secondary infections, genetics, omics, and drugs being tested to treat severe COVID-19. Expert opinion: A growing level of support suggests the need for stronger integration of biomarkers and precision medicine to guide treatment strategies of severe COVID-19, where each patient has unique outcomes and thus require guided treatment.

Multiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute inflammation and relapse biology. These results paved the way for further research on the implication of B cells in the pathogenesis of MS. Besides controlling relapse development in RMS, ocrelizumab (OCR) also showed clinical benefits in patients with PPMS and became the first approved drug for this disease course. In this review, we provide an overview of the current anti-CD20 mabs used or tested for the treatment of MS—namely rituximab (RTX), OCR, ofatumumab (OFA), and ublituximab (UB). Besides their effectiveness, we also discuss possible limitations and safety concerns especially in regard to long-term treatment, both for this class of drugs overall as well as for each anti-CD20 mab individually. Additionally, we elucidate to what extent anti-CD20 therapy may alter the function of other immune cells, both directly or indirectly. Finally, we cover the current knowledge on repopulation of CD20+ cells after cessation of anti-CD20 treatment and discuss future aspirations towards alternative, further developed B cell silencing therapies. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01048-z.

Genome-wide association studies (GWAS) have identified polymorphism in the Apolipoprotein E gene (APOE) to be the most prominent risk factor for Alzheimer’s disease (AD). Compared to individuals homozygous for the APOE3 variant, individuals with the APOE4 variant have a significantly elevated risk of AD. On the other hand, longitudinal studies have shown that the presence of the APOE2 variant reduces the lifetime risk of developing AD by 40 percent. While there has been significant research that has identified the risk-inducing effects of APOE4, the underlying mechanisms by which APOE2 influences AD onset and progression have not been extensively explored. In this study, we utilize an isogenic human induced pluripotent stem cell (hiPSC)-based system to demonstrate that conversion of APOE3 to APOE2 greatly reduced the production of amyloid-beta (Aβ) peptides in hiPSC-derived neural cultures. Mechanistically, analysis of pure populations of neurons and astrocytes derived from these neural cultures revealed that mitigating effects of APOE2 are mediated by cell autonomous and non-autonomous effects. In particular, we demonstrated the reduction in Aβ is potentially driven by a mechanism related to non-amyloidogenic processing of amyloid precursor protein (APP), suggesting a gain of the protective function of the APOE2 variant. Together, this study provides insights into the risk-modifying effects associated with the APOE2 allele and establishes a platform to probe the mechanisms by which APOE2 enhances neuroprotection against AD.

Background Recent clinical advances in cancer immuno-therapeutics underscore the need for improved understanding of the complex relationship between cancer and the multiple, multi-functional, inter-dependent, cellular and humoral mediators/regulators of the human immune system. This interdisciplinary effort exploits engineering analysis methods utilized to investigate anomalous physical system behaviors to explore immune system behaviors. Cancer Immune Control Dynamics (CICD), a systems analysis approach, attempts to identify differences between systemic immune homeostasis of 27 healthy volunteers versus 14 patients with metastatic malignant melanoma based on daily serial measurements of conventional peripheral blood biomarkers (15 cell subsets, 35 cytokines). The modeling strategy applies engineering control theory to analyze an individual’s immune system based on the biomarkers’ dynamic non-linear oscillatory behaviors. The reverse engineering analysis uses a Singular Value Decomposition (SVD) algorithm to solve the inverse problem and identify a solution profile of the active biomarker relationships. Herein, 28,605 biologically possible biomarker interactions are modeled by a set of matrix equations creating a system interaction model. CICD quantifies the model with a participant’s biomarker data then computationally solves it to measure each relationship’s activity allowing a visualization of the individual’s current state of immunity. Results CICD results provide initial evidence that this model-based analysis is consistent with identified roles of biomarkers in systemic immunity of cancer patients versus that of healthy volunteers. The mathematical computations alone identified a plausible network of immune cells, including T cells, natural killer (NK) cells, monocytes, and dendritic cells (DC) with cytokines MCP-1 [CXCL2], IP-10 [CXCL10], and IL-8 that play a role in sustaining the state of immunity in advanced cancer. Conclusions With CICD modeling capabilities, the complexity of the immune system is mathematically quantified through thousands of possible interactions between multiple biomarkers. Therefore, the overall state of an individual’s immune system regardless of clinical status, is modeled as reflected in their blood samples. It is anticipated that CICD-based capabilities will provide tools to specifically address cancer and treatment modulated (immune checkpoint inhibitors) parameters of human immunity, revealing clinically relevant biological interactions.

Background Pulmonary infections associated with Pseudomonas aeruginosa can be life-threatening for patients suffering from chronic lung diseases such as cystic fibrosis. In this scenario, the formation of biofilms embedded in a mucus layer can limit the permeation and the activity of anti-infectives. Objectives Native human pulmonary mucus can be isolated from endotracheal tubes, but this source is limited for large-scale testing. This study, therefore, aimed to evaluate a modified artificial sputum medium (ASMmod) with mucus-like viscoelastic properties as a surrogate for testing anti-infectives against P. aeruginosa biofilms. Methods Bacterial growth in conventional broth cultures was compared with that in ASMmod, and PAO1-GFP biofilms were imaged by confocal microscopy. Transport kinetics of three antibiotics, tobramycin, colistin, and ciprofloxacin, through native mucus and ASMmod were studied, and their activity against PAO1 biofilms grown in different media was assessed by determination of metabolic activity and cfu. Results PAO1(-GFP) cultured in human pulmonary mucus or ASMmod showed similarities in bacterial growth and biofilm morphology. A limited permeation of antibiotics through ASMmod was observed, indicating its strong barrier properties, which are comparable to those of native human mucus. Reduced susceptibility of PAO1 biofilms was observed in ASMmod compared with LB medium for tobramycin and colistin, but less for ciprofloxacin. Conclusions These findings underline the importance of mucus as a biological barrier to antibiotics. ASMmod appears to be a valuable surrogate for studying mucus permeation of anti-infectives and their efficacy against PAO1 biofilms.

Escalating commitment describes the phenomenon that decision makers may become stuck in losing courses of action, throwing good money after bad. In a seminal study, testing interventions against escalating commitment, Simonson and Staw (1992) found that holding decision makers accountable for the decision process (i.e., the decision strategies they use) decreases escalating commitment, whereas accountability for the decision outcomes tends to increase it. The initial aim of our study was to extend the original findings by testing for interactive effects of both types of accountability. However, as we did not replicate the original effects in a first experiment, in spite of the fact that our materials and our procedure resembled the original study as closely as possible, we conducted a second experiment with an even stronger accountability manipulation as compared to the original study, and with an increased sample size. Once again, no effects of accountability were found. Taken together, the results of these two experiments question the robustness of the original findings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background A growing body of evidence supports the safety of the human papillomavirus (HPV) vaccines. However, concerns about autonomic dysfunction syndromes and non-specific symptoms continue to linger. These conditions are not easily captured by traditional diagnostic classification schemes and call for innovative approaches to the study of vaccine safety which take more general measures of all-cause morbidity into account. Methods Taking advantage of the unique Danish registers, including regional registration of absence from school, we conducted a cohort study of 14 068 adolescent Danish girls attending 5th through 9th grade in public schools in the municipality of Copenhagen during 1 August 2013–23 January 2018. We obtained time-varying HPV vaccination status and demographic information from nationwide registers. Using Poisson regression with random effects, we estimated rate ratios (RRs) of absence due to illness, comparing HPV-vaccinated girls with unvaccinated girls with adjustment for grade, season, calendar period, demographic factors and random effects at the individual, class and school levels. Results Our study included 6 206 188 school days with 213 221 days of absence from school due to illness (absence rate, 3.4%). Comparing absence rates due to illness in HPV-vaccinated and unvaccinated girls yielded an adjusted RR of 1.00 (95% confidence interval [CI], 0.98–1.03). Conclusions Our study provides an important and novel contribution to HPV vaccine safety. Using absence from school records, we were able to address important safety concerns without relying on medical diagnoses. We conclude that HPV vaccination does not increase the risk of morbidity in any manner that manifests as absence from school due to illness.

OBJECTIVES: The curative effect of allogeneic haematopoietic stem cell transplantation (HSCT) for acute leukaemia is due in part to the donor T cell-mediated graft-versus-leukaemia immune reaction (GvL). Several studies have suggested that donor CD25+CD4+Foxp3+ regulator T cells (Tregs) may decrease graft-versus-host disease (GvHD) without abrogating GVL. This notion may need modification in acute lymphoblastic leukaemia (ALL).METHODS: Foxp3 mRNA level was measured by qPCR in pre-harvest donor blood CD4+ T cells. The study comprised 45 patients with ALL in 1st or 2nd CR who received myeloablative HSCT using T-replete bone marrow grafts.RESULTS: Relapse occurred in 17 patients median 363 days after HSCT. The relapse risk was estimated by Cox univariate and multivariate proportional hazard regression. The proportionality assumption was met by analysing the pre-harvest donor Foxp3 mRNA level as a time-dependent covariate. Early relapse was not modified by the Foxp3 mRNA level. However, a higher Foxp3 mRNA level was associated with a significantly increased relapse risk after day 363 after transplantation, compatible with inhibition of GvL. In contrast, a higher pre-harvest donor CD4+ T cell concentration was associated with reduced relapse risk.CONCLUSION: A higher pre-harvest donor Foxp3 mRNA level may be predictive of late ALL relapse after HSCT.

Background & Aims: Obeticholic acid (OCA) is an agonist of the nuclear bile acid receptor farnesoid X receptor, which regulates hepatic bile acid metabolism. We tested whether OCA treatment would influence hepatic transport of conjugated bile acids in patients with primary biliary cholangitis (PBC) who responded inadequately to treatment with ursodeoxycholic acid (UDCA). Methods: Eight UDCA-treated patients with PBC with alkaline phosphatase ≥1.5 times the upper limit of normal range participated in a double-blind, placebo-controlled study. While continuing on UDCA, the patients were randomised to two 3-month crossover treatment periods with placebo and OCA, in random order, separated by a 1-month washout period without study treatment. After each of the two treatment periods, we determined rate constants for transport of conjugated bile acids between blood, hepatocytes, biliary canaliculi, and bile ducts by positron emission tomography of the liver using the conjugated bile acid tracer [N-methyl- 11C]cholylsarcosine ( 11C-CSar). The hepatic blood perfusion was measured using infusion of indocyanine green and Fick's principle. Results: Compared with placebo, OCA increased hepatic blood perfusion by a median of 11% (p = 0.045), the unidirectional uptake clearance of 11C-CSar from blood into hepatocytes by a median of 11% (p = 0.01), and the rate constant for secretion of 11C-CSar from hepatocytes into biliary canaliculi by a median of 73% (p = 0.03). This resulted in an OCA-induced decrease in the hepatocyte residence time of 11C-CSar by a median of 30% (p = 0.01), from group median 11 min to 8 min. Conclusions: This study of UDCA-treated patients with PBC showed that, compared with placebo, OCA increased the hepatic transport of the conjugated bile acid tracer 11C-CSar, and thus endogenous conjugated bile acids, from hepatocytes into biliary canaliculi. As a result, OCA reduced the time hepatocytes are exposed to potentially cytotoxic bile acids. Lay summary: Primary biliary cholangitis is a chronic liver disease in which the small bile ducts are progressively destroyed. We tested whether the treatment with obeticholic acid (OCA) would improve liver excretion of bile acids compared with placebo in 8 patients with primary biliary cholangitis. A special scanning technique (PET scan) showed that OCA increased the transport of bile acids from blood to bile. OCA thereby reduced the time that potentially toxic bile acids reside in the liver by approximately one-third.

Background: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM). Objectives: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers. Methods: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring. Results: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35–3.75, n = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49–2.16), n = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78–2.54), n = 11). Conclusion: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.

BACKGROUND Prior knee surgery before total knee arthroplasty (TKA) puts patients at higher risk of inferior outcomes and increased care cost. This study compares intraoperative and postoperative variables including procedure duration, components, length of stay, readmission, complications, and reoperations among patients undergoing conversion TKA. METHODS Primary TKA from a single-surgeon database identified 130 patients with prior knee surgery to form a "conversion" cohort. One-to-one matching identified 130 patients of similar age, American Society of Anesthesiologists score, body mass index, and gender without prior knee surgery for comparison. Perioperative and 90-day postoperative variables were compared between patients with and without prior surgery, within the conversion group based on the type of prior surgery, and whether the prior surgery was bony or soft tissue. RESULTS The conversion group had longer mean operative time (96.1 vs 90.0 minutes, P = .01), higher revision component utilization (8.5% vs 0.8%, P = .005), and higher calculated blood loss (1440 vs 1249 mL, P = .004). Thirty-eight patients with prior fracture or osteotomy were compared to the remaining 92 patients in the conversion group and showed longer operative time (107.1 vs 91.3 minutes, P < .001), higher 90-day readmissions (18.4% vs 3.3%, P = .003), more complications (23.7% vs 8.7%, P = .021), and greater utilization of revision components (26.3% vs 1.1%, P < .001). CONCLUSION Patients undergoing conversion TKA required increased resource utilization, particularly patients with a prior osteotomy or fracture. Policymakers should consider these variables, as they did in conversion THA, in adding a code to account for increased case complexity and resource utilization.

Remission assessment in acute myeloid leukemia has evolved over the recent years with the advent of molecular and flow-based minimal residual disease determination. Nonetheless, early time point such as day 5 and day 14 (D14), still have prognostic and therapeutic implications. D14 refractory disease is regarded as a poor prognostic factor, however the therapeutic intervention is still under debate, with evidence suggesting a successful re-induction might offer similar long-term outcome as D14 aplasia. Others advocate the use of more intensive salvage protocols as a mean to overcome the negative prognostic effect. In the current study, we compare outcome of D14 refractory AML patients treated with either re-induction or salvage protocol. More importantly, we identify response characteristics that might suggest which patients will benefit from re-induction approach. Accurate identification of chemotherapy refractory patients might allow the early incorporation of non-chemotherapy based protocols in the future.

AimsTest for an association between prehospital delay for symptoms suggestive of acute coronary syndrome (ACS), persistent symptoms, and healthcare utilization (HCU) 30-days and 6-months post hospital discharge.BackgroundDelayed treatment for ACS increases patient morbidity and mortality. Prehospital delay is the largest factor in delayed treatment for ACS.MethodsSecondary analysis of data collected from a multi-center prospective study. Included were 722 patients presenting to the Emergency Department (ED) with symptoms that triggered a cardiac evaluation. Symptoms and HCU were measured using the 13-item ACS Symptom Checklist and the Froelicher's Health Services Utilization Questionnaire-Revised instrument. Logistic regression models were used to examine hypothesized associations.ResultsFor patients with ACS (n=325), longer prehospital delay was associated with fewer MD/NP visits (OR, 0.986) at 30days. Longer prehospital delay was associated with higher odds of calling 911 for any reason (OR, 1.015), and calling 911 for chest related symptoms (OR, 1.016) 6months following discharge. For non-ACS patients (n=397), longer prehospital delay was associated with higher odds of experiencing chest pressure (OR, 1.009) and chest discomfort (OR, 1.008) at 30days. At 6months, longer prehospital delay was associated with higher odds of upper back pain (OR, 1.013), palpitations (OR 1.014), indigestion (OR, 1.010), and calls to the MD/NP for chest symptoms (OR, 1.014).ConclusionsThere were few associations between prehospital delay and HCU for patients evaluated for ACS in the ED. Associations between prolonged delay and persistent symptoms may lead to increased HCU for those without ACS.

During the SARS-CoV-2 pandemic, higher education worldwide had to switch to digital formats. The purpose of this study was to evaluate CoRad-19, a digital teaching tool created by the German Radiological Society for medical students during the COVID-19 pandemic.A total of 13 German-speaking universities implemented CoRad-19 in their curriculum and partially or completely replaced their classes with the online courses. Previous experience and contact with radiology and the participants' opinions regarding the medium of e-learning were surveyed using a custom questionnaire. The subjective level of knowledge regarding the individual modules was also surveyed before and after participation to measure learning effects. The data of 994 medical students from the participating sites were analyzed and compared intraindividually using the Friedman test.From 4/1/2020-10/1/2020, 451 complete data sets from a total of 994 surveys were included. E-learning was rated "very useful" both before and after course participation (4 [IQR 3-4], p = 0.527, r = 0.16). E-learning as a method was also rated as a "very good" medium both before and after participation (4 [IQR 3-4], p = 0.414, r = 0.17). After participation, participants rated radiology as particularly suitable for digital teaching (before: 3 [IQR 3-4] vs. after 4 [IQR 3-4], p = 0.005, r = 0.6). Significant learning gains were measurable in all course modules (p ≤ 0.009). Post-hoc analysis showed interest in radiology to increase significantly after course participation (p = 0.02).In the representative survey, significant learning effects were observed in all course modules. In addition, it should be particularly emphasized that the students' interest in radiology was increased by course participation. Thus, the German Radiological Society provided significant support to German-speaking medical faculties with respect to maintaining excellent education using CoRad-19.· Co-Rad-19 course participation results in measurable subjective learning effects and increases student interest in radiology..· Brendlin AS, Molwitz I, Oechtering TH et al. CoRad-19 - Modular Digital Teaching during the SARS-CoV-2 Pandemic. Fortschr Röntgenstr 2022; 194: 644 - 651.ZIEL: Während der SARS-CoV-2-Pandemie musste die Hochschullehre weltweit auf digitale Formate umstellen. In dieser Studie sollte CoRad-19, ein im Rahmen der COVID-19-Pandemie erstelltes digitales Lehrangebot der Deutschen Röntgengesellschaft (DRG) für Medizinstudierende, evaluiert werden.Insgesamt 13 deutschsprachige Hochschulstandorte haben CoRad-19 in ihr Curriculum implementiert sowie ihre Lehrangebote teilweise oder sogar vollständig durch die Online-Kurse ersetzt. Mithilfe eines eigens entworfenen Fragebogens wurden Vorerfahrungen in und bisherige Kontakte zur Radiologie erfragt sowie die Meinung der Teilnehmenden gegenüber dem Medium E-Learning erhoben. Als Maßstab für den Lernerfolg wurde der subjektive Kenntnisstand bezüglich der einzelnen Module jeweils vor und nach der Teilnahme erhoben. Die Angaben 994 Medizinstudierender aus den beteiligten Standorten wurden analysiert und mittels Friedman-Test intraindividuell verglichen.Vom 01.04.2020–01.10.2020 wurden aus insgesamt 994 Erhebungen 451 vollständige Datensätze inkludiert. E-Learning wurde sowohl vor als auch nach der Teilnahme an den Kursen als „sehr sinnvoll“ eingeschätzt (4 [IQR 3–4], p = 0,527, r = 0,16). Auch E-Learning als Methode wurde sowohl vor als auch nach der Teilnahme als „sehr gutes“ Medium bewertet (4 [IQR 3–4], p = 0,414, r = 0,17). Nach Teilnahme an den Kursen schätzten die Teilnehmenden die Radiologie als besonders geeignet für digitale Lehre ein (vorher: 3 [IQR 3–4] vs. nachher 4 [IQR 3–4], p = 0,005, r = 0,6). In allen Kursmodulen waren signifikante Lernerfolge messbar (p ≤ 0,009). Eine Post-hoc-Analyse zeigte, dass das Interesse an der Radiologie nach Teilnahme an den Kursen signifikant zunahm (p = 0,02).In der repräsentativen Umfrage wurden signifikante Lerneffekte in allen Kursmodulen beobachtet. Zudem ist besonders hervorzuheben, dass das Interesse der Studierenden an der Radiologie durch die Kursteilnahme gesteigert werden konnte. Die DRG konnte den deutschsprachigen medizinischen Fakultäten durch CoRad-19 also wichtige Unterstützung bei der Aufrechterhaltung exzellenter Lehre bieten.· Die Kursteilnahme an CoRad-19 führt zu messbaren subjektiven Lerneffekten und steigert das Interesse Studierender an der Radiologie..· Brendlin AS, Molwitz I, Oechtering TH et al. CoRad-19 – Modular Digital Teaching during the SARS-CoV-2 Pandemic. Fortschr Röntgenstr 2022; 194: 644 – 651.

Mobile electrocardiogram (ECG) devices are valuable tools for teaching ECG interpretation. The primary purpose of this follow-up study was to determine if an ECG active learning session could be safely and effectively performed during the coronavirus disease 2019 (COVID-19) pandemic using a newly developed mobile 6-lead ECG device. Additionally, we examined the educational impact of these active learning sessions on student knowledge of cardiovascular physiology and the utility of the mobile 6-lead ECG device in a classroom setting. In this study, first-year medical students (MS1) performed four active learning activities using the new mobile 6-lead ECG device. Data were collected from 42 MS1s through a quantitative survey administered in September 2020. Overall, students felt the activity enhanced their understanding of the course material and that the activity was performed safely and in compliance with local COVID-19 guidelines. These results emphasize student preference for hands-on, small group learning activities in spite of the pandemic.

Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. Eighty percent were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. Twelve patients (48%) achieved complete response (CR) with gilteritinib. The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3 months, CI 95% 0-36.2 vs. 2.6 months, CI 95% 1.47-3.7; p value = 0.046). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p = 0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p = 0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6 months (CI 95% 2.3-16.8) vs. 7 months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869). In conclusion, in the real-world setting, gilteritinib is effective, including in heavily pre-treated, TKI exposed patients.

Venetoclax in combination with intensive therapies is explored in both the upfront and relapse/refractory (R/R) setting, and available data suggest that such regimens are effective albeit with added hematological and infectious toxicity. We conducted a multicenter retrospective cohort study of patients with acute myeloid leukemia (AML) treated with venetoclax in combination with FLAG-IDA protocol. Twenty-five patients were included in this analysis (median age 53.4 years). Most patients were treated for R/R AML (n = 24, 96%) with a median of one (range 0-3) previous lines of therapy and 44% of patients (n = 11) having prior allogeneic hematopoietic cell transplantation (HCT). Median follow-up was 10 (range, 4-26) months. Platelet and neutrophil recovery were observed at a median of 31 (95% CI 17.6-38.3) and 23 (95% CI 20-28) days, respectively. The most common adverse events were infectious (blood stream infections, 48% and invasive fungal infections, 32%). Thirty-day mortality was 12%. Composite complete remission (CRc) was 72% for the entire cohort and 91% in patients treated for post-HCT relapse. Incidences of relapse-free and overall survival at 12 months were 67% (95% CI 58-76%) and 50% (95% CI 31-69%), respectively. Real-world data show that the addition of venetoclax to FLAG-IDA protocol is effective in patients with high-risk AML, most notably in the post-HCT relapse setting. Prophylaxis and surveillance for infections are crucial.

Whether male circumcision in infancy or childhood provides protection against the acquisition of human immunodeficiency virus (HIV) or other sexually transmitted infections (STIs) in adulthood remains to be established. In the first national cohort study to address this issue, we identified 810,719 non-Muslim males born in Denmark between 1977 and 2003 and followed them over the age span 0–36 years between 1977 and 2013. We obtained information about cohort members’ non-therapeutic circumcisions, HIV diagnoses and other STI outcomes from national health registers and used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) associated with foreskin status (i.e., circumcised v. genitally intact). During a mean of 22 years of follow-up, amounting to a total observation period of 17.7 million person-years, 3375 cohort members (0.42%) underwent non-therapeutic circumcision, and 8531 (1.05%) received hospital care for HIV or other STIs. Compared with genitally intact males, rates among circumcised males were not statistically significantly reduced for any specific STI. Indeed, circumcised males had a 53% higher rate of STIs overall (HR = 1.53, 95% CI: 1.24–1.89), and rates were statistically significantly increased for anogenital warts (74 cases in circumcised males v. 7151 cases in intact males, HR = 1.51; 95% CI: 1.20–1.90) and syphilis (four cases in circumcised males v. 197 cases in intact males, HR = 3.32; 95% CI: 1.23–8.95). In this national cohort study spanning more than three decades of observation, non-therapeutic circumcision in infancy or childhood did not appear to provide protection against HIV or other STIs in males up to the age of 36 years. Rather, non-therapeutic circumcision was associated with higher STI rates overall, particularly for anogenital warts and syphilis.

Acute stress may impair cognitive performance and multitasking, both vital in the practice of emergency medicine (EM). Previous research has demonstrated that board-certified emergency physicians experience physiologic stress while working clinically. We sought to determine whether EM residents have a similar stress response, and hypothesized that residents experience acute stress while working clinically.We performed a prospective observational study of physiologic stress including heart rate (HR), heart rate variability (HRV), and subjective stress in EM residents during clinical shifts in the emergency department. HR and HRV were measured via 3-lead Holter monitors and compared to baseline data obtained during weekly educational didactics. Subjective stress was assessed before and after clinical shifts via a Likert-scale questionnaire and written comments.We enrolled 21 residents and acquired data from 40 shifts. Residents experienced an increase in mean HR of eight beats per minute (P0.001) and decrease in HRV of 53.9 milliseconds (P = 0.005) while working clinically. Subjective stress increased during clinical work (P0.001). HRV was negatively correlated with subjective stress, but this did not reach statistical significance (P = 0.09).EM residents experience acute subjective and physiologic stress while working clinically. HR, HRV, and self-reported stress are feasible indicators to assess the acute stress response during residency training. These findings should be studied in a larger, more diverse cohort of residents and efforts made to identify characteristics that contribute to acute stress and to elicit targeted educational interventions to mitigate the acute stress response.

Background: Visual impairment, specifically anterior segment pathology, presents a significant burden of disease in the world. Introduction: Inexpensive tools are necessary to improve eye health of residents in developing countries where care is difficult to access. Our study aimed at determining whether a $5 macro lens attached to a smartphone camera is an effective anterior segment imaging method for screening diseases. Materials and Methods: Fifty four (n = 54) patients had anterior segment imaging performed by using an Easy Macro lens and an iPhone. Imaging was performed at the Floating Doctors' mobile clinic sites in Panama. Images were sent back and graded by two board-certified ophthalmologists using a modified version of the FOTO-ED scale. Statistical analysis was performed by using a Wilcoxon signed-rank test to compare grades between the two imaging modalities. Results: There was no significant difference in overall clinical utility of images obtained by the iPhone versus Easy Macro lens. The iPhone was significantly superior in imaging of the lens and conjunctiva, whereas the Easy Macro lens was superior in regards to the anterior chamber, iris, and lens. Discussion: The imaging modality that best captures pathology is dependent on what part of the anterior segment is being examined. An imaging protocol with a pair of images, one from a smartphone and one from a macro lens, would have significant clinical utility. Conclusion: Our study demonstrates how minimally trained users can deliver effective eye screening via a telemedicine-based approach in a resource-deprived setting. Future directions would be to develop a telemedicine protocol and determine whether it improves clinically measurable outcomes in patients.

Einleitung: Ziel dieser systematischen Übersicht war die Bewertung der verfügbaren Evidenz zur Wirkung der Kneipp-Therapie. Methoden: MEDLINE, Embase, Web of Science, Cochrane-Library und CAMbase wurden nach relevanten Artikeln, veröffentlicht zwischen 2000 und 2019, durchsucht. Graue Literatur wurde über Google Scholar und andere Tools bezogen. Studien mit jeglicher Art von Studiendesign, die die Effekte der Kneipp-Therapie untersuchten, wurden eingeschlossen. Die Qualitätsbewertung erfolgte mittels EPHPP-QAT. Ergebnisse: 25 Quellen, darunter 14 kontrol-lierte Studien, wurden eingeschlossen. Gemäß EPHPP-QAT wurden 3 Studien "stark", 13 "moderat" und 9 "schwach" bewertet. Neun (64%) der kontrollierten Studien berichteten signifikante Verbesserungen nach Kneipp-Therapie im Gruppenvergleich bei chronisch-venöser Insuffizienz, Hypertonie, leichter Herzinsuffizienz, menopausalen Be-schwerden und Schlafstörungen in verschiedenen Patientenkollektiven sowie verbesserte Immunparameter bei gesunden Probanden. Im Hinblick auf Depression und Angst bei Mammakarzinom-Patientinnen mit klimakterischen Beschwerden, Lebensqualität bei Post-Polio-Syndrom, krankheitsbedingten polyneuropathischen Beschwerden und Inzidenz von Erkältungsepisoden bei Kindern konnten keine signifikanten Gruppenunterschiede festgestellt werden. Elf unkontrollierte Studien berichteten Verbesse-rungen bei allergischen Symptomen, Dyspepsie, Lebens-qualität, Herzratenvariabilität, Infekten, Hypertonie, Wohlbefinden, Schmerz und polyneuropathischen Beschwerden. Diskussion/Schlussfolgerung: Die Kneipp-Therapie scheint bei zahlreichen Beschwerdebildern in verschiedenen Patientenkollektiven positive Effekte zu bewirken. Zukünftige Studien sollten noch stärker auf eine methodisch sorgfältige Studienplanung achten (Kontrollgruppen, Randomisierung, adäquate Fallzahlen, Verblindung), um Verzerrungen entgegenzuwirken.The aim of this systematic review was to evaluate the available evidence on the effect of Kneipp therapy.MEDLINE, Embase, Web of Science, Cochrane Library and CAMbase were searched for relevant articles published between 2000 and 2019. Grey literature was obtained through Google Scholar and other tools. Studies with any kind of study design that examined the effects of Kneipp therapy were included. The quality assessment was carried out using EPHPP-QAT.25 sources, including 14 controlled studies, were included. According to EPHPP-QAT, 3 studies were rated as “strong,” 13 as “moderate” and 9 as “weak.” Nine (64%) of the controlled studies reported significant improvements after Kneipp therapy in a between-group comparison in chronic venous insufficiency, hypertension, mild heart failure, menopausal complaints, and sleep disorders in different patient collectives as well as improved immune parameters in healthy subjects. Regarding depression and anxiety in breast cancer patients with climacteric complaints, quality of life in post-polio syndrome, disease-related polyneuropathic complaints and incidence of cold episodes in children, no significant group differences were found. Eleven uncontrolled studies reported improvements in allergic symptoms, dyspepsia, quality of life, heart rate variability, infections, hypertension, well-being, pain and polyneuropathic complaints.Kneipp therapy seems to be beneficial for numerous symptoms in different patient groups. Future studies should pay even more attention to methodologically careful study planning (control groups, randomisation, adequate case numbers, blinding) to counteract bias.

ObjectiveOur objective was to estimate the relative risk of IBD among first-generation and second-generation immigrants in Denmark compared with native Danes.DesignUsing national registries, we established a cohort of Danish residents between 1977 and 2018. Cohort members with known country of birth were followed for Crohn’s disease (CD) and ulcerative colitis (UC) diagnoses. Incidence rate ratios (IRRs) served as measures of relative risk and were calculated by log-linear Poisson regression, using rates among native Danes as reference, stratified by IBD risk in parental country of birth, and among first-generation immigrants by age at immigration and duration of stay in Denmark.ResultsAmong 8.7 million Danes, 4156 first-generation and 898 second-generation immigrants were diagnosed with CD or UC. Overall, comparing first-generation immigrants with native Danes, the IRR was 0.80 (95% CI 0.76 to 0.84) for CD and 0.74 (95% CI 0.71 to 0.77) for UC. The IRR of IBD increased with ≥20 years stay in Denmark. The IRR of CD increased with immigration at ≥40 years of age. Comparing second-generation immigrants with native Danes, the IRR of IBD was 0.97 (95% CI 0.91 to 1.04). There was significant interaction with sex, with higher IRR of IBD in male than in female immigrants.ConclusionRelative to native Danish men and women, IBD risk among first-generation immigrants was lower, reflected the risk in their parental country of birth and increased with ≥20 years stay in Denmark. For second-generation immigrants, relative risk of IBD was lower only among women. These complex patterns suggest the role of environmental IBD risk factors.

ObjectiveThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic challenges national health systems and the global economy. Monitoring of infection rates and seroprevalence can guide public health measures to combat the pandemic. This depends on reliable tests on active and former infections. Here, we set out to develop and validate a specific and sensitive enzyme linked immunosorbent assay (ELISA) for detection of anti-SARS-CoV-2 antibody levels.MethodsIn our ELISA, we used SARS-CoV-2 receptor-binding domain (RBD) and a stabilized version of the spike (S) ectodomain as antigens. We assessed sera from patients infected with seasonal coronaviruses, SARS-CoV-2 and controls. We determined and monitored IgM-, IgA- and IgG-antibody responses towards these antigens. In addition, for a panel of 22 sera, virus neutralization and ELISA parameters were measured and correlated.ResultsThe RBD-based ELISA detected SARS-CoV-2-directed antibodies, did not cross-react with seasonal coronavirus antibodies and correlated with virus neutralization (R2 = 0.89). Seroconversion started at 5 days after symptom onset and led to robust antibody levels at 10 days after symptom onset. We demonstrate high specificity (99.3%;N = 1000) and sensitivity (92% for IgA, 96% for IgG and 98% for IgM; > 10 days after PCR-proven infection;N = 53) in serum.ConclusionsWith the described RBD-based ELISA protocol, we provide a reliable test for seroepidemiological surveys. Due to high specificity and strong correlation with virus neutralization, the RBD ELISA holds great potential to become a preferred tool to assess thresholds of protective immunity after infection and vaccination.

Background: Reusable elastomeric respirator use in health care may represent one solution to address N95 respirator shortages experienced during infectious disease outbreaks, but cleaning and disinfection requirements may limit their utility. Evidence of respirator cleaning and disinfection behaviors and practices by health care workers may inform guidance on reusable respirator use. Methods: Medical system elastomeric respirator users were surveyed about respirator cleaning and disinfection practices and perceptions via an electronic survey. Respondents were subsequently classified based on reported compliance with their assigned respirator use. To explore whether respirator cleaning and disinfection issues affected compliance with assigned device use, responses were compared between user groups and adjusted for covariates. Results: A total of 432 of 2,024 (21%) eligible elastomeric respirator users completed the survey. Most (>90%) reported that their respirator was clean, but only 52% reported that they always disinfect their respirators after use according to the hospital’s expected practice. Only 40 respondents (9%) reported regularly cleaning the respirator with soap and water, in accordance with manufacturer recommendations. Reporting of suboptimal decontamination practice was not associated with assigned device compliance, however, except among providers and respiratory therapists. Conclusion/Application to Practice: Although perceptions of cleanliness and adherence to expected decontamination practices during routine use did not appear to influence compliance with assigned respirator use overall, this did predict compliance among providers and respiratory therapists, both of whom have nonfixed workstations. Practical and effective strategies to assure easy access to and availability of clean reusable respiratory protective devices are needed to facilitate their use in health care respiratory protection programs.

Objective This study evaluated the risk of subclinical atrial fibrillation (AF) in patients with central retinal artery occlusion (CRAO) compared to those with cryptogenic stroke using implantable loop recorders (ILR). Methods We conducted a retrospective analysis of 273 consecutive patients who had ILRs inserted at our institution for either cryptogenic stroke (n = 227) or CRAO (n = 46). Our primary endpoint was a time to event analysis for the new diagnosis of AF by ILR. Univariable and multivariable Cox proportional hazard models were used to determine the predictors of time-to-AF. Results A total of 64 patients were found to have newly diagnosed AF by remote monitoring of the ILR. AF was detected in 57 of 227 (25%) cryptogenic stroke patients by the end of a maximum 5.1 years follow-up and in 7 of 46 (15%) CRAO patients by the end of a maximum 3.6year follow-up (p = .215, log-rank test). The Kaplan-Meier estimates for freedom from AF was 59.4% for CRAO and 66.6% for cryptogenic stroke (p = NS, log-rank test). Baseline variables predicting AF included older patients, higher CHADS2 VASC score, longer PR interval on initial EKG evaluation and mitral annular calcification (MAC) on transthoracic echocardiogram. Conclusions Patients with CRAO are at risk for subclinical AF, similar to those with cryptogenic stroke. Long term monitoring to detect AF may lead to changes in pharmacotherapy to reduce the risk for subsequent stroke. This article is protected by copyright. All rights reserved.