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Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT‐PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure‐response relationships for efficacy and safety endpoints using data from the SELECT‐PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure‐response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure‐response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure‐response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure‐response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.

Congenital interstitial lung diseases can affect both adults and children. Pediatric congenital interstitial lung diseases generally carry high risk for morbidly and mortality and include congenital alveolar capillary dysplasia with misalignment of pulmonary veins, congenital alveolar dysplasia, acinar dysplasia, congenital pulmonary lymphangiectasis, diffuse pulmonary lymphangiomatosis, neuroendocrine cell hyperplasia of infancy, pulmonary hemosiderosis, pulmonary alveolar proteinosis, and pulmonary interstitial glycogenosis. Given their usual non-specific clinical presentation, they are frequently misdiagnosed and recognized late, particularly in children who have been apparently healthy for several years (eg, diffuse pulmonary lymphangiomatosis). Some diseases have a very poor prognosis, whereas others have a benign course with appropriate treatment. The current manuscript reviews congenital interstitial lung diseases that typically affect neonates and young children and may be encountered by the pediatric anesthesiologist.

High-dose chemotherapy, followed by autologous hematopoietic stem cell transplantation (auto-HSCT), is an established therapy for patients with hematological malignancies. The age of patients undergoing auto-HSCT and, therefore, the comorbidities, has increased over the last decades. However, the assessment of organ dysfunction prior to auto-HSCT has not been well studied. Therefore, we retrospectively analyzed the association of clinical factors and lung and cardiac function with outcome and complications after conditioning with BEAM (BCNU/carmustine, etoposide, cytarabine, melphalan) or high-dose melphalan in patients undergoing auto-HSCT. This study included 629 patients treated at our institution between 2007 and 2017; 334 and 295 were conditioned with BEAM or high-dose melphalan, respectively. The median follow-up was 52 months (range, 0.2-152) and 50 months (range, 0.5-149), respectively. In the multivariate analysis, we identified that progressive disease, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, Karnofsky Performance Status (KPS) ≤ 80%, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score ≥ 4, and age > 70 years were associated with decreased overall survival (OS) in patients treated with BEAM. Similarly, DLCOcSB ≤ 60% of predicted, HCT-CI score ≥ 4, and age > 60 years were identified in patients treated with high-dose melphalan. Abnormalities in DLCOcSB ≤ 60% of predicted were associated with chemotherapy with lung-toxic substances, mediastinal radiotherapy, KPS ≤ 80%, current/previous smoking, and treatment in the intensive care unit. More often, patients with DLCOcSB ≤ 60% of predicted experienced nonrelapse mortality, including pulmonary causes of death. In summary, we identified DLCOcSB ≤ 60% of predicted as an independent risk factor for decreased OS in patients conditioned with BEAM or high-dose melphalan prior to auto-HSCT.

Purpose of review Multiple myeloma is a disease of elderly adults. Improvement in survival has occurred because of biological insights and novel agents. Therapeutic options involve choices today, thus have become more complex. Demographics have led to an increased number of elderly patients and age may be associated with a poorer outcome but is not the only prognostic predictor today. Recent findings To evaluate patients’ health status rather than their chronological age alone, frailty scores and functional geriatric assessments are used to identify prognostic groups, avoid adverse events, compare clinical trials and tailor treatment. As most clinical trials exclude frail elderly patients, those enrolled therein are often younger and healthier than the typical multiple myeloma patient. This represents a challenge for frail cohorts because of their increased risk of adverse events, overtreatment and undertreatment and/or therapy discontinuation, which may lead to poorer survival and quality of life (QoL). Reassessing patients’ status via geriatric assessments is also relevant during treatment to adjust interventions appropriately. Summary Integrating geriatric assessments may lead to individual treatment decisions, dose adjustments, better clinical outcome and QoL. Prospective clinical trials that enroll elderly multiple myeloma patients with comorbidities, incorporate frailty scores/geriatric assessments and help with prognostication, adverse event avoidance and QoL maintenance, remain warranted.

OBJECTIVES The Pediatric Emergency Ruler (PaedER) is a height-based drug dose recommendation tool that was reported to reduce life-threatening medication errors by 90%. The PaedER was introduced into the Cologne Emergency Medical Service (EMS) in 2008 along with educational measures, publications, and lectures for pediatric drug safety. We reviewed the impact of these continuously ongoing measures on medication errors after 10 years. METHODS The PaedER was introduced and distributed to all 14 emergency ambulances and 2 helicopters staffed with emergency physicians in the city of Cologne in November 2008. Electronic records and medical protocols of the Cologne EMS over two 20-month periods from March 2007 to October 2008 and March 2018 to October 2019 data sets were retrieved. The administered doses of either intravenous, intraosseous, intranasal, or buccal fentanyl, midazolam, ketamine, or epinephrine were recorded. Primary outcome measure was the rate of severe drug dosing errors with a deviation from the recommended dose of greater than 300%. RESULTS A total of 59 and 443 drug administrations were analyzed for 2007/08 and 2018/19, respectively. The overall rate of drug dosing errors decreased from 22.0% to 9.9% (P = 0.014; relative risk reduction, 55%). Four of 5 severe dosing errors for epinephrine were avoided (P < 0.021; relative risk reduction, 78%). Documentation of patient's weight increased from 3.2% in 2007/08 to 30.5% in 2018/19 (P < 0.001). CONCLUSIONS The distribution of the PaedER combined by educational measures significantly reduced the rates of life-threatening medication errors in a large EMS. Those results should motivate further initiatives on pediatric drug safety in prehospital emergency care.

Our objective was to assess the relationship between overall survival (OS) and distance travelled to the treating facility for patients undergoing liver resection for hepatocellular carcinoma and to determine whether this relationship was dependent upon the structural factors of the treating facility.Using National Cancer Database, we focused on extremes of travel: Local (12.5 miles to treating facility) and Travel (≥50 miles). We analyzed OS with Cox models; we estimated stratified models to assess interaction between distance and facility characteristics (volume, academic status).We included 6860 patients. After correction for confounding, distance travelled was not associated with OS (p = 0.444). However, Travel patients treated at high-volume, academic centers had worse OS compared to Local patients (HR 1.54, 95%CI 1.07-2.21); this association was not seen for patients treated at low volume, academic centers (p = 0.708) high volume non-academic centers (p = 0.174) or low volume non-academic centers (p = 515).For those patients treated at high-volume, academic centers, living far from the facility was associated with worse OS. The reasons for this association should be investigated further.

Summary Introduction The aim of the present observational study was to evaluate the effects of the first lockdown 2020 on the patients of our Movement Disorders clinic. Methods We included 65 patients with Parkinson`s disease and 40 patients with post stroke spasticity in our observational study. Medical examinations were performed prior to the lockdown, after the end of the first lockdown in June and at the end of October 2020. Participation in physiotherapy, occupational therapy, sports activities and general physical activity were recorded. In addition data regarding pain, falls, neurological functioning and access to medication were collected. Ambulatory patients performed a walking test. Results The discontinuation of physiotherapy and occupational therapy and the marked reduction of sports activities correlated with a decrease of general physical activities/week. We observed an increase of pain and spasticity. About 20% of patients with post stroke spasticity lost their independence in some aspects of self-care activities. Both groups of patients needed more time for the walking test after the lockdown. The effects of the lockdown continued until October 2020. Conclusion Discontinuation of physiotherapy, occupational therapy and reduction of sports activities had severe and long lasting consequences for the physical and mental condition of our patients.

Changes in discharge disposition and delays in discharge negatively impact the patient and hospital system. Our objectives wereDischarge dispositions and barriers to discharge for 200 TEGS patients were predicted individually by members of the multidisciplinary TEGS team within 24 h of patient admission. Univariate analyses and multivariable logistic least absolute shrinkage and selection operator regressions determined the associations between patient characteristics and correct predictions.A total of 1,498 predictions of discharge disposition were made by the multidisciplinary TEGS team for 200 TEGS patients. Providers correctly predicted 74% of discharge dispositions. Prediction accuracy was not associated with clinical experience or job title. Incorrect predictions were independently associated with older age (OR 0.98; P0.001), trauma admission as compared to emergency general surgery (OR 0.33; P0.001), higher Injury Severity Scores (OR 0.96; P0.001), longer lengths of stay (OR 0.90; P0.001), frailty (OR 0.43; P = 0.001), ICU admission (OR 0.54; P0.001), and higher Acute Physiology and Chronic Health Evaluation II scores (OR 0.94; P = 0.006).The TEGS team can accurately predict the majority of discharge dispositions. Patients with risk factors for unpredictable dispositions should be flagged to better allocate appropriate resources and more intensively plan their discharges.

Geschwister von kranken/behinderten Kindern haben ein erhohtes Risiko fur die Entwicklung von psychischen Auffalligkeiten. Durch Befragung von Kursleitenden, Teilnehmenden am GeschwisterTREFF und ihren Eltern wurde untersucht, ob die Geschwisterkinder in Abhangigkeit von Geschlecht, Alter und Geburtenfolge in den Bereichen (1) Psychoedukation (Krankheitswissen), (2) Emotionsregulation (emotionale Probleme), (3) Selbst- und Fremdwahrnehmung (Selbstwert) sowie (4) soziale Unterstutzung (soziale Integration) unterschiedlich stark profitieren. Der GeschwisterTREFF ist ein standardisiertes und evaluiertes Praventionsprogramm zur Forderung der Resilienz von Geschwisterkindern. Zunachst wurden 12 Kursleitende befragt, welche Geschwisterkinder (Jungen vs. Madchen, jungere vs. altere Kinder, fruher vs. spater geborene Geschwister) in den resilienzfordernden Bereichen des GeschwisterTREFFs starker profitieren. Weiterhin wurde anhand von Daten aus einer Multicenterstudie mit 97 Geschwisterkindern und ihren Eltern varianzanalytisch untersucht, ob Veranderungen in diesen Bereichen durch das Geschlecht, das Alter und die Geburtenfolge moderiert werden. Kursleitende haben die Erfahrung gemacht, dass Jungen sich starker im Bereich Emotionsregulation und Madchen sich starker in der Selbst- und Fremdwahrnehmung verbessern und dass jungere Teilnehmende starker von der Psychoedukation und altere Teilnehmende mehr im Bereich Selbst- und Fremdwahrnehmung profitieren. In der Evaluationsstudie zeigte sich, dass die Veranderungen im Bereich emotionale Probleme durch das Geschlecht (starkere Pra-Post-Unterschiede bei Jungen) und im Bereich Krankheitswissen durch das Alter (Altere gewannen mehr Krankheitswissen hinzu) moderiert wurden. Weiterhin zeigten fruher geborene (vs. spater geborene) Geschwisterkinder tendenziell eine starkere Selbstwertsteigerung. Durch Berucksichtigung dieser Eigenschaften konnen Geschwisterkinder zukunftig noch besser unterstutzt werden. Beispielsweise konnte die Durchfuhrung des Kurses in homogenen (vs. heterogenen) Gruppen vorteilhaft sein, sofern dies praktikabel ist.

Die Qualitat der Behandlung unterliegt im Gesamtkontext des Gesundheitswesens multifaktoriellen Einflussen. In dem Bestreben die Qualitat der handchirurgischen Versorgung zu verbessern, haben die in der Deutschen Gesellschaft fur Handchirurgie (DGH) vertretenen Handchirurgen eine Vielzahl von Projekten initiiert. Hierzu zahlen die von der DGH mit entwickelten S3-Leitlinien, das HandTraumaRegister der DGH, die Definition von Kriterien zur Durchfuhrung handchirurgischer Operationen im ambulanten Bereich im Rahmen einer Konsensusempfehlung sowie die Beteiligung an einer grosen epidemiologischen Studie mit der speziellen Erfassung pathologischer Veranderungen der Hand zur Bestimmung von Pravalenzen (Study of Health in Pomerania, SHIP). Die Qualitat der Behandlung selbst wird im Rahmen dieser Studien allerdings nicht erfasst. Die aktuell in der Handchirurgie verfugbaren Qualitatsindikatoren evaluieren bei dem Versuch der Erfassung der Qualitat wahrscheinlich nur bedingt die fur die Patienten wirklich relevanten Aspekte. Daher beteiligte sich die DGH bereits fruhzeitig an der Entwicklung von Assessments im Rahmen einer von der WHO zum Leuchtturmprojekt ernannten internationalen Studie. Die dabei entwickelten und validierten Assessments sollen alle Aspekte der Ergebnisse unter Einbeziehung der individuellen Patientensicht erfassen und diese Ergebnisqualitat exakt definierten Verletzungsmustern zuordenbar machen. Die Verwendung dieser Assessments soll es auf Dauer ermoglichen, fur jeden Patienten eine individuelle Ergebnisqualitat zu prognostizieren. All diese Projekte leben von einer moglichst grosen Beteiligung mit Erfassung moglichst vieler Daten. In diesem Bestreben koordiniert und entwickelt die DGH diese Projekte in den Kommissionen des erweiterten Vorstands weiter und versucht, moglichst viele Chirurgen zu einer Beteiligung zu motivieren.

Aim: To evaluate the efficacy and safety of ceftobiprole in patients from East Asia. Materials & methods: A post hoc analysis was conducted of two randomized, double-blind, Phase III studies in patients with community- or hospital-acquired pneumonia. Results: Findings for East Asian patients were consistent with the overall study populations. A trend toward higher microbiological eradication rates and numerically lower rates of all-cause mortality were reported for ceftobiprole versus comparators (all-cause mortality [intent-to-treat]: community-acquired pneumonia, 1.5 vs 2.8%; hospital-acquired pneumonia excluding ventilator-associated pneumonia, 5.9 vs 11.4%). The incidence of adverse events was similar between treatment groups. Conclusion: This post hoc analysis supports the efficacy and tolerability of ceftobiprole in East Asian patients. ClinicalTrials.gov trial identifiers: NCT00326287 , NCT00210964 , NCT00229008 .

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P P

Lay abstractInfections are a common cause of severe disease and death in older patients. Antibiotic treatment may also be complicated by age-related changes within the body. The present study analyzed results from three large clinical trials that assessed the benefits of the novel antibiotic ceftobiprole in the older population. In patients aged over 65 years with skin infections or with pneumonia acquired either in the community or in a hospital setting, ceftobiprole offered similar benefits to established antibiotics. There was also some preliminary evidence that older patients may respond more quickly to ceftobiprole compared with the other antibiotics used in these studies. Overall, ceftobiprole was well tolerated and will be a useful treatment option for infections in older patients.Aim: To evaluate the efficacy and safety of ceftobiprole in patients aged >= 65 years. Materials & methods: We conducted a post hoc analysis of three randomized, double-blind, Phase III studies in patients with acute bacterial skin and skin structure infections, community-acquired pneumonia and hospital-acquired pneumonia. Results: Findings for patients aged >= 65 years (n = 633) were consistent with those for the overall study populations, although a trend toward improved outcomes was reported in some subgroups, for example, patients aged >= 75 years with community-acquired pneumonia were more likely to achieve an early clinical response with ceftobiprole than comparator (treatment difference 16.3% [95% CI:1.8-30.8]). The safety profile was similar between treatment groups in all studies. Conclusion: This analysis further supports the efficacy and safety of ceftobiprole in older patients with acute bacterial skin and skin structure infections or pneumonia.Clinicaltrials.gov trial identifiers: , ,

Pediatric anesthesia is large part of anesthesia clinical practice. Children, parents and anesthesiologists fear anesthesia because of the risk of acute morbidity and mortality. Modern anesthesia in otherwise healthy children above 1 year of age in developed countries has become very safe due to recent advance in pharmacology, intensive education, and training as well as centralization of care. In contrast, anesthesia in these children in low-income countries is associated with a high risk of mortality due to lack of basic resources and adequate training of health care providers. Anesthesia for neonates and toddlers is associated with significant morbidity and mortality. Anesthesia-related (near) critical incidents occur in 5% of anesthetic procedures and are largely dependent on the skills and up-to-date knowledge of the whole perioperative team in the specific needs for children. An investment in continuous medical education of the perioperative staff is required and international standard operating protocols for common procedures and critical situations should be defined.

Purpose of review Children are at risk of severe hypoxemia in the perioperative period owing to their unique anatomy and physiology. Safe and effective airway management strategies are therefore key to the practice of pediatric anesthesia. The goal of this review is to highlight recent publications (2019-2021) aimed to advance pediatric airway safety and to highlight a proposed simple, pediatric-specific, universal framework to guide clinical practice. Recent findings Recent investigations demonstrate that infants with normal and difficult airways experience high incidences of multiple laryngoscopy attempts and resulting hypoxemia. Video laryngoscopy may improve tracheal intubation first attempt success rate in infants with normal airways. In infants with difficult airways, standard blade video laryngoscopy is associated with higher first attempt success rates over non-standard blade video laryngoscopy. Recent studies in children with Pierre Robin sequence and mucopolysaccharidoses help guide airway equipment and technique selection. Department airway leads and hospital difficult airway services are necessary to disseminate knowledge, lead quality improvement initiatives, and promote evidence-based practice guidelines. Summary Pediatric airway management morbidity is a common problem in pediatric anesthesia. Improvements in individual practitioner preparation and management strategies as well as systems-based policies are required. A simple, pediatric-specific, universal airway management framework can be adopted for safe pediatric anesthesia practice.

Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19, This study has been funded by the Austrian Forum against Cancer, which covered in part expenses for interaction between authors and for secretarial support.

According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and

International audience; PURPOSE: Meningiomas represent the most frequent tumor of the central nervous system in adults. While most meningiomas are efficiently treated by surgery and radiotherapy/radiosurgery, there is a small portion of radiation- and surgery-refractory tumors for which there is no clear recommendation for optimal management. The French National Tumor Board Meeting on Meningiomas (NTBM) offers a glimpse on the current management of such patients. METHODS: We retrospectively reviewed the charts of patients presented to the multidisciplinary Meeting between 2016 and 2019. We selected patients with a progressive disease after at least two treatments, including surgery and radiotherapy. RESULTS: In this multicentric cohort of 86 cases, patients harbored 17 (19.8%) WHO Grade I, 48 (55.8%) WHO Grade II and 21 (24.4%) WHO Grade III tumors. The median number of treatments received before inclusion was 3 (range: 2 - 11). Following the Board Meeting, 32 patients (37.2%) received chemotherapy, 11 (12.8%) surgery, 17 (19.8%) radiotherapy, 14 (16.3%) watchful observation and 12 (13.9%) palliative care. After a mean follow-up of 13 months post-inclusion, 32 patients (37.2%) had died from their disease. The mean progression free survival was 27 months after radiotherapy, 10 months after surgery, 8.5 months after chemotherapy (Bevacizumab: 9 months - Octreotide/Everolimus: 8 months). CONCLUSIONS: Surgery- and radiation-refractory meningiomas represent a heterogeneous group of tumors with a majority of WHO Grade II cases. If re-irradiation and redo-surgery are not possible, bevacizumab and octreotide-everolimus appear as a valuable option in heavily pre-treated patients considering the current EANO guidelines.

Objective To examine the role and benefits of transcervical fibroid ablation (TFA) in the treatment of submucous and large uterine fibroids. Methods A subgroup of patients with submucous or large fibroids were analyzed from two prospective clinical trials (FAST‐EU and SONATA) of sonography‐guided TFA with the Sonata® system. Key outcomes were changes in menstrual blood loss, symptom severity and health‐related quality of life on the Uterine Fibroid Symptom and Quality‐of‐Life Questionnaire, health‐related quality of life on the EQ‐5D questionnaire, and surgical reinterventions for heavy menstrual bleeding. Results Among 197 women (534 treated fibroids), 86% of women with only submucous fibroids and 81% of women with large fibroids (>5 cm) experienced bleeding reduction within 3 months post‐ablation. Overall symptom severity and health‐related quality of life showed sustained, significant improvements over 12 months. Additional fibroid mapping of large fibroids with magnetic resonance imaging in the FAST‐EU trial showed an average volume reduction of 68%. Among women with only submucous fibroids, the rate of surgical reintervention through 1 year of follow up was 3.7% in FAST‐EU and 0.0% in SONATA. Conclusion With the Sonata system, TFA is an effective single‐stage treatment option for non‐pedunculated submucous myomata, and larger or deeper uterine fibroids (including fibroid clusters) for which hysteroscopic treatment is not suitable. ClinicalTrials.gov: FAST‐EU, NCT01226290; SONATA, NCT02228174., Synopsis Transcervical fibroid ablation with the Sonata™ system is an effective single‐stage treatment option for non‐pedunculated submucous and large myomata.

Shooting precision as well as dribbling and agility are crucial components of performance in basketball. We examined the effects of anodal tDCS over the dominant primary motor cortex in supporting these basketball specific abilities. Fifty-two sports students were enrolled in a double-blind, randomized, placebo-controlled, crossover trial with two interventions. Twenty minutes of anodal 1 mA tDCS/sham tDCS were applied over the primary motor cortex of the dominant hemisphere. Basketball shooting precision (basketball shooting accuracy test) and basketball specific dribbling and agility (Illinois ball-dribbling test) were tested prior and after each intervention. Basketball shooting precision and basketball specific dribbling and agility improved after real tDCS but not after sham tDCS. ANOVAs show significant intervention*time effects on both the shooting accuracy test (

Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD‐1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body‐weight‐based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune‐related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD‐1 targeting agents. No treatment‐related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD‐1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure‐safety analyses did not indicate any trends. Observed PK and PD‐1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.

Background: Acute peptic ulcer bleeding is still a major reason for hospital admission. Especially the management of bleeding duodenal ulcers needs a structured therapeutic approach due to the higher morbidity and mortality compared to gastric ulcers. Patient with these bleeding ulcers are often in a high-risk situation, which requires multidisciplinary treatment. Summary: This review provides a structured approach to modern management of bleeding duodenal ulcers and elucidates therapeutic practice in high-risk situations. Initial management including pharmacologic therapy, risk stratification, endoscopy, surgery, and transcatheter arterial embolization are reviewed and their role in the management of bleeding duodenal ulcers is critically discussed. Additionally, a future perspective regarding prophylactic therapeutic approaches is outlined. Key Messages: Beside pharmacotherapeutic and endoscopic advances, bleeding management of high-risk duodenal ulcers is still a challenge. When bleeding persists or rebleeding occurs and the gold standard endoscopy fails, surgical and radiological procedures are indicated to manage ulcer bleeding. Surgical procedures are performed to control hemorrhage, but they are still associated with a higher morbidity and a longer hospital stay. In the meantime, transcatheter arterial embolization is recommended as an alternative to surgery and more often replaces surgery in the management of failed endoscopic hemostasis. Future studies are needed to improve risk stratification and therefore enable a better selection of high-risk ulcers and optimal treatment. Additionally, the promising approach of prophylactic embolization in high-risk duodenal ulcers has to be further investigated to reduce rebleeding and improve outcomes in these patients.

With advancements in whole slide imaging technology and improved understanding of the features of pathologist workstations required for digital slide evaluation, many institutions are investigating broad digital pathology adoption. The benefits of digital pathology evaluation include remote access to study or diagnostic case materials and integration of analysis and reporting tools. Diagnosis based on whole slide images is established in human medical pathology, and the use of digital pathology in toxicologic pathology is increasing. However, there has not been broad adoption in toxicologic pathology, particularly in the context of regulatory studies, due to lack of precedence. To address this topic, as well as practical aspects, the European Society of Toxicologic Pathology coordinated an expert international workshop to assess current applications and challenges and outline a set of minimal requirements needed to gain future regulatory acceptance for the use of digital toxicologic pathology workflows in research and development, so that toxicologic pathologists can benefit from digital slide technology.

To investigate the impact of atrial fibrillation/flutter (AF) on adverse in-hospital outcomes in hospitalized surgical patients.The nationwide German inpatient sample of the years 2005-2018 was used for this analysis. Surgical patients were stratified by AF and compared. Logistic regression models were used to investigate the impact of AF on in-hospital outcomes.In total, 96,589,627 hospitalizations with surgery were included in the present analysis in Germany (2005-2018). Among these, 6,680,261 were additionally coded with AF (6.9%). In-hospital death rate was substantially higher in surgical patients with AF (6.3%) than without (1.1%). Proportion of surgical patients with AF increased from 4.8% in 2005 to 8.9% in 2018, whereas in-hospital mortality decreased from 7.6% to 5.6%. For further analysis of the year 2014, 7,043,514 hospitalized surgical patients (54.5% females, 31.6% aged ≥0 years) were included in the analysis. Of these, 546,019 patients (7.8%) were diagnosed with AF. Overall, 1.4% of the surgical patients and 5.8% of the surgical patients with AF died in-hospital. Surgical patients with coded AF were in median 20 years older (57.0 [37.0-72.0] vs. 77.0 [72.0-83.0] years, P 0.001), had more often comorbidities such as heart failure (31.3% vs. 3.8%, P 0.001). All-cause death (RR 6.14 (95%CI 6.05-6.22), P 0.001) occurred more often in patients with AF than without. AF was an important predictor for in-hospital death (OR 1.58 [95%CI 1.56-1.61], P 0.001) independent of age, sex and comorbidities.The proportion of AF increased from 2005 to 2018 in surgical patients. AF was an independent risk factor for in-hospital death in these patients.

Allogeneic stem cell transplantation (allo-SCT) offers a curative option in adult patients with acute lymphoblastic leukemia (ALL). Prognostic factors for survival after allo-SCT have not been sufficiently defined: pheno-/genotype, patients´ age, conditioning regimens and remission at allo-SCT are under discussion. We analyzed the outcome of 180 consecutive adult ALL-patients undergoing allo-SCT at our center between 1995 and 2018 to identify specific prognostic factors. In our cohort 19% were older than 55 years, 28% had Philadelphia-positive B-ALL, 24% T-ALL. 54% were transplanted in first complete remission (CR1), 13% in CR2 after salvage therapy, 31% reached no remission (8% within first-line, 23% within salvage therapy). In 66% conditioning contained total body irradiation (TBI). With a median follow-up of 10 years, we observed an overall survival of 33% at 10 years, and a progression free survival of 31%. The cumulative incidence of relapse was 41% at 10 years, the cumulative incidence of non-relapse mortality 28%. Acute graft-versus-host disease (GvHD) II°–IV° occurred in 31%, moderate/severe chronic GvHD in 27%. Survival was better in patients reaching CR before allo-SCT and in those receiving TBI. No difference between patients younger/older than 55 years and between different phenotypes was observed. Survival after allo-SCT improved considerably over the last decades.

Trans-1233zd was developed as a refrigerant and propellant in consumer products; its toxicity has been studied extensively. The scope of this assessment is to apply the confirmed NOAEC to conduct Benchmark Dose Modeling (BMD) and determine the Point of Departure (POD). In a previously published 13-week inhalation study, a NOAEC was identified at 4000 ppm. Due to uncertainty concerning the cardiac lesion, an external pathology peer review of heart tissues was undertaken using published best practices and consistent nomenclature and diagnostic criteria. The cardiac lesion observed at 4000 ppm was considered to be spontaneous based on lesion location and microscopic features. BMD was applied to derive the BMDL05 and BMDL10; the more conservative BMDL05 was used as the POD for risk assessment to calculate the Reference Exposure Levels (RELs). The 2-Box Air Dispersion Model was used to calculate the exposure to consumer products. Both the acute and chronic exposure concentrations calculated were compared to the acute and chronic RELs. The acute and chronic exposure to trans-1233zd in the assessed consumer products are below the RELs and deemed safe for their intended uses.

Summary For many years, strength training has been an integral part of rehabilitation after knee trauma. In the first part of the paper, new research results on muscle contraction, especially eccentric muscle action, are presented in rehabilitative accentuated strength training after knee trauma. It is pointed out that the strength training methodology, which has mostly been validated with young and athletic persons, cannot be transferred to persons with knee traumas. Biomechanical stress during rehabilitative, every day, and sports activities will be discussed as well as the additional joint stress caused by activated muscles and various co-factors. In the second part of the paper, the theoretical considerations are illustrated using selected examples of strength training after knee trauma, and an outlook on future strategies is given.

Context: Foam rolling (FR) has been developed into a popular intervention and has been established in various sports disciplines. However, its effects on target tissue, including changes in stiffness properties, are still poorly understood. Objective: To investigate muscle-specific and connective tissue-specific responses after FR in recreational athletes with different FR experience. Design: Case series. Setting: Laboratory environment. Participants: The study was conducted with 40 participants, consisting of 20 experienced (EA) and 20 nonexperienced athletes (NEA). Intervention: The FR intervention included 5 trials per 45 seconds of FR of the lateral thigh in the sagittal plane with 20 seconds of rest between each trial. Main Outcome Measures: Acoustic radiation force impulse elastosonography values, represented as shear wave velocity, were obtained under resting conditions (t0) and several times after FR exercise (0 min [t1], 30 min [t2], 6 h [t3], and 24 h [t4]). Data were assessed in superficial and deep muscle (vastus lateralis muscle; vastus intermedius muscle) and in connective tissue (iliotibial band). Results: In EA, tissue stiffness of the iliotibial band revealed a significant decrease of 13.2% at t1 (P ≤ .01) and 12.1% at t3 (P = .02). In NEA, a 6.2% increase of stiffness was found at t1, which was not significantly different to baseline (P = .16). For both groups, no significant iliotibial band stiffness changes were found at further time points. Also, regarding muscle stiffness, no significant changes were detected at any time for EA and NEA (P > .05). Conclusions: This study demonstrates a significant short-term decrease of connective tissue stiffness in EA, which may have an impact on the biomechanical output of the connective tissue. Thus, FR effects on tissue stiffness depend on the athletes’ experience in FR, and existing studies have to be interpreted cautiously in the context of the enrolled participants.

Summary CrossFit is a form of high-intensity interval training and comparable to other high-intensity exercises. CrossFit exercises increase VO2max, strength, endurance, and improves the body composition (e. g. lean body mass). The injury risk in CrossFit is similar to that of other, comparable sports such as Olympic weightlifting, powerlifting and gymnastics and lower than that of competitive contact sports such as rugby union and rugby league. Shoulder joint, shoulder girdle and spine injuries are predominating in CrossFit and require special attention from physicians and coaches. In particular, this includes expert instruction for CrossFit beginners as well as an initial orthopedic examination before starting CrossFit training. The involvement of well-educated coaches correlates with a decreased injury rate. For this reason, it is recommended that beginners complete a special program with slow load increase and instructions of the fundamental CrossFit techniques. In CrossFit, previous injuries also increase the risk of re-injury, which is consistent with the findings of other sport-related injury studies, and should also be taken into account. Evidence Level III

Objective To review the incidence, risk factors, prevention, and management of genital mycotic infections (GMIs) associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors. Data Sources A literature search of PubMed and Reactions Weekly was performed in February 2020 with updated searches monthly through July 2020 to identify relevant data regarding SGLT2 inhibitors and GMIs. Manufacturers of each agent were contacted, and clinical practice guidelines were consulted. Study Selection and Data Extraction All available literature was evaluated for inclusion based on relevance to the research question, timeliness of the publication, validity, and impact on current practice. A date limit was not set; however, publications from 2010 to July 2020 were prioritized. Data Synthesis The 3- to 4-fold increased incidence of GMIs is considered a classwide effect of SGLT2 inhibitors. Female sex and a prior history of GMIs are factors associated with the highest risk, whereas circumcised males are at the lowest risk of SGLT2 inhibitor–induced GMI. Personal hygiene advice can reduce the infection risk. When candidiasis occurs, it is often mild and responsive to treatment and often does not require discontinuation of the medication. Relevance to Patient Care and Clinical Practice This narrative review can assist in shared decision-making discussions with patients who may benefit from SGLT2 inhibitors and provides guidance for health care professionals managing SGLT2 inhibitor–associated GMIs. Conclusions SGLT2 inhibitors predispose patients to developing mild GMIs. Strong consideration should be given to avoid SGLT2 inhibitors in female patients with a history of severe, recurrent infections. Preventive strategies are optimized diabetes management and personal hygiene advice.

ZusammenfassungDieser Fallbericht zeigt die interdisziplinäre Behandlung einer 28-jährigen Patientin mit ausgeprägtem frontalen Volumendefekt nach schwerem Schädelhirntrauma. Durch die Kombination aus Schädeldachplastik mittels Polymethylmethacrylat (PMMA), freier M. gracilis-Lappenplastik und serieller Eigenfett-Transplantation in das transplantierte Muskelgewebe, konnte der Weichteildefekt ausgeglichen und eine ästhetische Rekonstruktion erzielt werden. Dieses Beispiel unterstreicht die Erweiterung des Behandlungsspektrums an interdisziplinären Exzellenzzentren durch Plastische Chirurgen, wodurch die Versorgung immer komplexerer Knochen-Weichteilläsionen möglich wird.

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting.

Zusammenfassung Hintergrund Eine validierte telefonische Fassung der deutschen Version des Fragebogens „Informant Questionnaire on Cognitive Decline in the Elderly“ (IQCODE) zur Erfassung kognitiver Veränderungen von Schlaganfall-Patienten über einen Zeitraum von 10 Jahren vor Schlaganfall durch Befragung Angehöriger liegt bislang nicht vor. Eine deutsche telefonische Kurzversion existiert ebenfalls nicht. Methoden 60 Angehörige von 60 Patientinnen und Patienten mit ischämischem Schlaganfall wurden mit der persönlichen und der telefonischen 26-Item-Version des IQCODE in randomisierter Reihenfolge befragt. Als Maß zur Quantifizierung der Reliabilität beider IQCODE-Versionen wurde ein gewichtetes Kappa berechnet (Fleiss-Cohen Gewichte). Mithilfe von Varianzinflationsfaktoren wurde eine telefonische Kurzversion des IQCODE entwickelt und diese Version mit der 26-Item-Telefonversion mittels Spearman‘s Korrelationskoeffizienten verglichen. Ergebnisse Das gewichtete Kappa der telefonischen Befragung gegenüber der persönlichen betrug 0,84 (95 % Konfidenzintervall 0,72–0,97). Die neu entwickelte Kurzversion des telefonbasierten IQCODE umfasste 10 Items. Der Korrelationskoeffizient zwischen der Kurz- und der Langversion betrug 0,97 (95 % Konfidenzintervall 0,96–0,99). Schlussfolgerung Die telefonische Version des deutschsprachigen 26-Item IQCODE zeigte im Vergleich zur persönlichen Befragung exzellente Übereinstimmungswerte. Die telefonische 10-Item-Kurzversion zeigte eine exzellente Übereinstimmung mit der telefonischen Langversion. Somit stehen nun auch für den deutschen Sprachraum vereinfachte Werkzeuge für die effiziente Befragung großer Kollektive zur Verfügung.

The novel coronavirus (SARS-CoV-2, COVID-19) was first identified in the province of Wuhan, China in December 2019 [1], following the emergence of new cases of pneumonia of unknown etiology. Since then, the manifestations of COVID-19 infections have ranged from asymptomatic to severe respiratory infections, with increased morbidity in older adults including those with co-morbidities and cancer [2,3]. Presently, global mortality is reported at 4.7%, but this varies widely by location, from 0.7% in Germany to 10.8% in Italy [4]. As of April 13, 2020, the number of infections continues to rise well beyond the 1.9 million cases, and approximately 120,000 COVID-19-related deaths that have already occurred globally [5]. Multiple myeloma (MM) is a malignant plasma cell dyscrasia which predominantly affects older and often frail adults. Although tremendous gains have been made for older adults with MM, infections, including respiratory infections, significantly impact the rate of early mortality in these patients [6,7]. Furthermore, older adults with MM have age-associated vulnerabilities leading to heterogeneity in outcomes [8]. The complexity of caring for older patients have increased substantially during this pandemic, due to concern about their risk of severe morbidity of COVID19 infection. Optimal strategies for these patients will involve staging the malignancy/aging, while simultaneously considering the local prevalence of COVID-19 infection. Herein, we discuss strategies for the risk reduction of COVID-19 transmission, treatment stratification of anti-myeloma therapy and discussion regarding goals of care for older adults with MM during the COVID-19 pandemic.

Summary Background Treatment of multiple myeloma is not curative, but targeting CD38 improves patient survival. To further explore this therapeutic approach, we investigated the safety and activity of MOR202, a novel monoclonal antibody targeting CD38, in patients with multiple myeloma. Methods This is a multicentre, open-label, phase 1–2a trial done at ten hospitals in Germany and Austria. Enrolled patients were aged 18 years or older with relapsed or refractory multiple myeloma and Karnofsky performance status of 60% or higher. Patients were assigned to the different treatment regimens with MOR202 ranging between 0·01 mg/kg and 16 mg/kg in a 3 + 3 design. Dose-escalation and expansion was done either with MOR202 intravenous infusions alone (MOR202 q2w [twice a week] and q1w [weekly] groups) or in combination with dexamethasone (MOR202 with dexamethasone group), with dexamethasone plus pomalidomide (MOR202 with dexamethasone plus pomalidomide group) or plus lenalidomide (MOR202 with dexamethasone plus lenalidomide group). Primary endpoints were safety, MOR202 maximum tolerated dose (or recommended dose) and regimen, and immunogenicity. The primary analysis was assessed in the safety population, which included patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov , NCT01421186 . Findings Between Aug 24, 2011, and Aug 1, 2017, 91 patients were treated, 35 with MOR202 monotherapy, and 56 with MOR202 combination regimens (18 in the MOR202 with dexamethasone group, 21 in the MOR202 with dexamethasone plus pomalidomide group, and 17 in the MOR202 with dexamethasone plus lenalidomide group). MOR202 intravenous infusions were safely administered within 30 min. Infusion-related reactions occurred in 14 (40%) of 35 patients receiving MOR202 monotherapy without steroids, and in four (7%) of 56 patients receiving MOR202 combination treatment. MOR202 maximum tolerated dose was not reached and the recommended regimens were MOR202 administered as an intravenous infusion for 30 min at doses up to 16 mg/kg with dexamethasone (40 mg), or in combination with dexamethasone plus lenalidomide (25 mg) or pomalidomide (4 mg). 35 (38%) of 91 patients developed lymphopenia, 30 (33%) developed neutropenia, and 27 (30%) developed leukopenia; these were the most common grade 3 or higher treatment-emergent adverse events. Serious adverse events were reported in 51 (56%) of 91 patients. None of the deaths were associated with MOR202. One pomalidomide-associated death occurred in the MOR202 with dexamethasone plus pomalidomide group. No anti-MOR202 antibodies were detected in patients. Interpretation MOR202 is safe and its clinical activity in patients with relapsed or refractory multiple myeloma is promising. Further clinical investigations of combinations with an immunomodulatory drug and dexamethasone are recommended. Funding MorphoSys AG.

Background Snowboarding is a very common sport especially among young adults. Common injuries are hand, wrist, shoulder and ankle injuries. Purpose of this study was to analyze different injury pattern in children and young adults comparing with adults. Methods Patients who were admitted for ambulant or stationary treatment as a result of injury practicing snowboard received a questionnaire and were divided into three groups (children, young adults and adults) according to their age. Between october 2002 and may 2007 1929 injured snowboard sportsmen were included in the study. Data such as location, date and time of accident as well as information about the slope were carried out. In addition snowboard skills were classified and patients were questioned whether they wore special protectors. Results 32.5% of injured patients were female (n = 626) and 67.5% male (n = 1303) with a mean age of patients of 21.9 (7–66) years. 13% of all patients were in group I (children), 19.2% in group II (young adults) and 67.8% in group III (adults). Most common injuries with 60% of all accidents were injuries of the hand wrist especially in children beginning with snowboard sports. Injuries on the regular track were most common followed by jumps in the kicker park and rails in the fun-park. 20.6% in group I, 13.6% in group II and 12.8% group III did not wear any protectors. Conclusion Children and adolescents presented different injury patterns than adults. Young participants of up to 14 years of age are endangered especially during the first days of learning this sport. Further development of protectors with regard to biomechanical characteristics is important to achieve an optimal protective effect. Level of evidence 2b

The severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) pandemic has challenged medical systems and clinicians globally to unforeseen levels. Rapid spread of COVID-19 has forced clinicians to care for patients with a highly contagious disease without evidence-based guidelines. Using a virtual modified nominal group technique, the Pediatric Difficult Intubation Collaborative (PeDI-C), which currently includes 35 hospitals from 6 countries, generated consensus guidelines on airway management in pediatric anesthesia based on expert opinion and early data about the disease. PeDI-C identified overarching goals during care, including minimizing aerosolized respiratory secretions, minimizing the number of clinicians in contact with a patient, and recognizing that undiagnosed asymptomatic patients may shed the virus and infect health care workers. Recommendations include administering anxiolytic medications, intravenous anesthetic inductions, tracheal intubation using video laryngoscopes and cuffed tracheal tubes, use of in-line suction catheters, and modifying workflow to recover patients from anesthesia in the operating room. Importantly, PeDI-C recommends that anesthesiologists consider using appropriate personal protective equipment when performing aerosol-generating medical procedures in asymptomatic children, in addition to known or suspected children with COVID-19. Airway procedures should be done in negative pressure rooms when available. Adequate time should be allowed for operating room cleaning and air filtration between surgical cases. Research using rigorous study designs is urgently needed to inform safe practices during the COVID-19 pandemic. Until further information is available, PeDI-C advises that clinicians consider these guidelines to enhance the safety of health care workers during airway management when performing aerosol-generating medical procedures. These guidelines have been endorsed by the Society for Pediatric Anesthesia and the Canadian Pediatric Anesthesia Society.

BACKGROUND miR-21 is a central regulator of cardiac fibrosis, and its inhibition in small-animal models has been shown to be an effective antifibrotic strategy in various organs, including the heart. Effective delivery of therapeutic antisense micro-ribonucleic acid (antimiR) molecules to the myocardium in larger organisms is challenging, though, and remains to be established for models of chronic heart failure.OBJECTIVES The aims of this study were to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a pig model of heart failure and determine its effect on the cardiac transcriptomic signature and cellular composition.METHODS Pigs underwent transient percutaneous occlusion of the left coronary artery and were followed up for 33 days. AntimiR-21 (10 mg) was applied by intracoronary infusion at days 5 and 19 after the injury. Cardiac function was assessed in vivo, followed by histological analyses and deep ribonucleic acid sequencing (RNA-seq) of the myocardium and genetic deconvolution analysis.RESULTS AntimiR-21 effectively suppressed the remodeling-associated increase of miR-21. At 33 days after ischemia/reperfusion injury, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy and improved cardiac function. Deep RNA-seq revealed a significant derepression of the miR-21 targetome in antimiR-21-treated myocardium and a suppression of the inflammatory response and mitogen-activated protein kinase signaling. A genetic deconvolution approach built on deep RNA-seq and single-cell RNA-seq data identified reductions in macrophage and fibroblast numbers as the key cell types affected by antimiR-21 treatment.CONCLUSIONS This study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of heart failure. (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Treatment decision-making for patients with incurable non-small cell lung cancer (NSCLC) is complex due to the rapidly increasing number of treatments and discovery of new biomarkers. Decision support systems (DSS) could assist thoracic oncologists (TO) weighing of the pros and cons of treatments in order to arrive at an evidence-based and personalized treatment advice. Our aim is to inventory (1) TO’s needs with regard to DSS in the treatment of incurable (stage IIIB/IV) NSCLC patients, and (2) preferences regarding the development of future tools in this field. We disseminated an online inventory questionnaire among all members of the Section of Oncology within the Society of Physicians in Chest Medicine and Tuberculosis. Telephone interviews were conducted to better contextualize the findings from the questionnaire. In total, 58 TO completed the questionnaire and expressed a need for new DSS. They reported that it is important for tools to include genetic and immune markers, to be sufficiently validated, regularly updated, and time-efficient. Also, future DSS should incorporate multiple treatment options, integrate estimates of toxicity, quality of life and cost-effectiveness of treatments, enhance communication between caregivers and patients, and use IT solutions for a clear interface and continuous updating of tools. With this inventory among Dutch TO, we summarized the need for new DSS to aid treatment decision-making for patients with incurable NSCLC. To meet the expressed needs, substantial additional efforts will be required by DSS developers, above already existing tools.

Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.

A significant number of chronic venous ulcers (CVUs) fail to heal despite guideline-conform standards of care. Skin-derived ABCB5+ mesenchymal stem cells can dampen the sustained IL-1β‒driven inflammation present in chronic wounds. On the basis of their wound healing‒facilitating effects in a mouse CVU model and an autologous first-in-human study, ABCB5+ mesenchymal stem cells have emerged as a potential candidate for cell-based advanced therapy of nonhealing CVUs. In this interventional, multicenter, single-arm, phase I/IIa clinical trial, subjects whose CVUs had emerged as standard therapy resistant received one or two topical applications of 1 × 106 allogeneic ABCB5+ mesenchymal stem cells per cm2 wound area, in addition to standard treatment. Of 83 treatment-emergent adverse events, only three were judged related to the cell product; they were mild or moderate and recovered without sequelae. Wound size markedly decreased from baseline to week 12, resulting in a median wound size reduction of 76% (full analysis set, n = 31), 78% (per-protocol set, n = 27), and 87% (subset of responders, n = 21). In conclusion, the study treatment was well-tolerated and safe. The treatment elicited a profound wound size reduction within 12 weeks, identifying ABCB5+ mesenchymal stem cells as a potential candidate for adjunctive therapy of otherwise incurable CVUs. These results justify the conduct of a larger, randomized, controlled trial to confirm clinical efficacy.

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0–2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1–21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60–72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4–20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3–19·3] vs 6·9 months [5·5–9·3]; hazard ratio 0·63 [95% CI 0·47–0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. Funding: European Myeloma Network and Janssen Research and Development., European Myeloma Network and Janssen Research and Development.

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.

In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population.