Search

Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences. Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes. Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1e6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO2

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.

Fire safety considerations have an impact on the design of almost all structures, ranging from small residential structures to high‐rise buildings. One important aspect of building fire safety is structural‐fire safety, with the goal of preventing or delaying collapse of structures during severe fires. Structural‐fire safety is of particular importance for steel structures, because of the high thermal conductivity of steel. Structural‐fire safety design is most often accomplished using non‐engineered prescriptive approaches. However, there is increasing interest in engineered structural‐fire safety design for potential advantages in safety, economy and design flexibility. This paper provides an overview of engineered structural‐fire safety design for steel buildings, and discusses some of the challenges in this field.

In No. 11-12 of the Kazan medical journal for 1931, in the editorial article that opens the issue, a rather significant place is devoted to an assessment of two of my works that appeared in the same journal (1,2). Completely and completely in solidarity with the guidelines of the Editors developed at the beginning of the article, which, as the very title of the article indicates, takes as the basis of all its work the practical implementation of the instructions of Comrade Stalin on the fight against alien theories and on vigilance on the ideological front, I cannot agree with the assessment of my works given in the article, as allegedly imbued with theories alien to dialectical materialism, and revealing mechanistic attitudes.

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.

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

In the meantime, it’s well known that post-weld fatigue strength improvement techniques for welded structures like high-frequency mechanical impact (HFMI) treatment increase the fatigue live of welded joints. Although the current design recommendations for HFMI-treated welded joints give first design proposals for the HFMI-treated welds, in practice the application of HFMI treatment and the associated increase in fatigue resistance are still being discussed. There are, for example, reservations regarding the efficiency of HFMI-treated welded joints under variable amplitude loading (VAL). This paper analyses first results for the sequence effect of VAL of a p (1/3) spectrum on the service fatigue strength of HFMI-treated transverse stiffeners (TS) of mild steel (S355). Fatigue test results with random and high-low loading for the two states as-welded (AW) and HFMI-treated joints will be presented. The modified linear damage accumulation and the failure locations will be discussed. The experimental results show a clear change in the slope of the S-N curve from the as-welded (AW) state to the HFMI state and additionally in the HFMI state from constant amplitude loading (CAL) to variable amplitude loading (VAL). It was particularly noticeable in the experimental results of all tested HFMI series that the specimens failed exclusively in the base material 2–4mm before the HFMI-treated welds. The presented results of the investigations show that with application of the nominal stress concept, no sequence effect was recognizable.

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.

The aim of this randomized controlled laboratory study was to evaluate the role of standardized protection, rest, ice (cryotherapy), compression and elevation (PRICE) therapy on microvascular blood flow in human skeletal muscle. Quantifiable contrast-enhanced ultrasound was used to analyze intramuscular tissue perfusion (ITP) of the rectus femoris (RF) and vastus intermedius (VI) muscles in 20 healthy athletes who were randomly assigned to PRICE or control groups. Baseline perfusion measurements (resting conditions, T0) were compared with cycling exercise (T1), intervention (PRICE or control, T2) and follow-up at 60 min post-intervention (T3). The 20 min PRICE intervention included rest, cryotherapy (3°C), compression (35 mm Hg) and elevation. After intervention, PRICE demonstrated a decrease of ITP in VI (–47%, p = 0.01) and RF (–50%, p = 0.037) muscles. At T3, an ongoing decreased ITP for the RF (p = 0.003) and no significant changes for the VI were observed. In contrast, the control group showed an increased ITP at T2 and no significant differences at T3. PRICE applied after exercise led to a down-regulation of ITP, and the termination of PRICE does not appear to be associated with a reactive hyperemia for at least 60 min after treatment.

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.

The complexity and variability of cancer progression necessitate a quantitative paradigm for therapeutic decision-making that is dynamic, personalized, and capable of identifying optimal treatment strategies for individual patients under substantial uncertainty. Here, we discuss the core components and challenges of such an approach and highlight the need for comprehensive longitudinal clinical and molecular data integration in its development. We describe the complementary and varied roles of mathematical modeling and machine learning in constructing dynamic optimal cancer treatment strategies and highlight the potential of reinforcement learning approaches in this endeavor.

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.

1,4 1 Conti , Thomas Picht . Charite - Universita€tsmedizin Berlin, Germany; 3 University of Bologna, Italy; 4 Humboldt Low frequency repetitive transcranial magnetic stimulation (rTMS) is capable of inducing changes in functional organization of underlying brain regions, however often at the cost of long stimulation protocols over several weeks. As these protocols can be difficult to implement in clinical settings, the aim of the present study was to show the feasibility and safety of an accelerated low-frequency rTMS protocol applying multiple sessions daily. To this purpose, nine healthy subjects (mean age 25.4 years; 1 female) received 14 sessions of rTMS (1 Hz, 30 minutes, 110% RMT) to the hand motor hotspot. Subjects received stimulation for either 14 days once daily (classical rTMS; c-rTMS), 7 days twice-daily (accelerated rTMS; a-rTMS) or sham stimulation for 14 days once-daily (s-rTMS). Daily stimulation ses- sions in the a-rTMS group were delivered with a 90-minute break in between. In total, 74% of rTMS sessions in the c-rTMS group, 89% in the a-rTMS group and 98% in the s-rTMS group were free of any side effects. Subjects re- ported occurrence of brief headaches in 14% of sessions in the c-rTMS group, 2% in the a-rTMS group and 0% in the s-rTMS group. Dizziness during stimulation was reported in 5% of sessions in the c-rTMS group, 2% in the a-rTMS group and 0% in the s-rTMS. Subjects reported a feeling of fatigue in the stimulated hand muscles in 2% of all sessions in the c-rTMS group, 7% in the a-rTMS group and 0% in the s-rTMS group. All side effects were reported to be at maximum mild and of short duration. Thus, accelerated low-frequency rTMS of the motor cortex is a safe and feasible method, previously shown to induce a functional reorganisation of the motor system. By shortening treatment duration in days, this approach can potentially make rTMS protocols more accessible to a wider range of patients.

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

The proteasome inhibitors, carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these proteasome inhibitors in combination with cyclophosphamide and dexamethasone (KCd vs. VCd) in second-line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomized patients (2:1) to KCd (n=201) or VCd (n=99); responding patients on carfilzomib were randomized to maintenance carfilzomib (n=69) or no further treatment (n=72). Primary endpoints were: (i) very good partial response (non-inferiority, odds ratio [OR] 0.8) at 24 weeks, and (ii) progression-free survival. More participants achieved a very good partial response or better with carfilzomib than with bortezomib (40.2% vs. 31.9%, OR=1.48, 90% confidence interval [CI]: 0.95, 2.31; non-inferior), with a trend for particular benefit in patients with adverse-risk disease. KCd was associated with higher overall response (partial response or better, 84.0% vs. 68.1%, OR=2.72, 90% CI: 1.62, 4.55, P=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, P0.0001), while grade ≥3 cardiac events and hypertension were only reported in the KCd arm (3.6% each). The median progression-free survival in the KCd arm was 11.7 months vs. 10.2 months in the VCd arm (hazard ratio [HR]=0.95, 80% CI: 0.77, 1.18). Carfilzomib maintenance was associated with longer progression-free survival, median 11.9 months vs. 5.6 months for no maintenance (HR 0.59, 80% CI: 0.46-0.77, P=0.0086). When used as fixed duration therapy in first relapase, KCd is at least as effective as VCd, and carfilzomib is an effective maintenance agent. This trial was registered with International Standard Randomised Controlled Trial Number (ISRCTN) identifier: ISRCTN17354232.

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.

The modulation of the endocannabinoid system (ECS) has shown positive results in animal models of multiple sclerosis (MS) and immune and inflammatory disorders. However, chronic administration of CB1 receptor agonists and degrading enzyme inhibitors can lead to CB1 receptor desensitization and sedation. WOBE437 is the prototype of a new class of ECS modulators named selective endocannabinoid reuptake inhibitors (SERIs), which mildly and selectively increase central endocannabinoid levels with a self-limiting mode of action. In previous studies, WOBE437 demonstrated analgesic, anxiolytic, and anti-inflammatory effects. Here, we tested the therapeutic potential of WOBE437 in a clinically relevant mouse model of MS (experimental autoimmune encephalomyelitis). C57BL/6 mice were administered WOBE437 (10 mg/kg, 20 days) or vehicle using two therapeutic options: (1) starting the treatment at the disease onset or (2) before reaching the peak of the disease. In both strategies, WOBE437 significantly reduced disease severity and accelerated recovery through CB1 and CB2 receptor-dependent mechanisms. At the peak of the disease, WOBE437 increased endocannabinoid levels in the cerebellum, concurring with a reduction of central nervous system (CNS)-infiltrating immune cells and lower microglial proliferation. At the end of treatment, endocannabinoid levels were mildly increased in brain, cerebellum, and plasma of WOBE437-treated mice, without desensitization of CB1 receptor in the brain and cerebellum. In a mouse model of spasticity (Straub test), WOBE437 (10 mg/kg) induced significant muscle relaxation without eliciting the typical sedative effects associated with muscle relaxants or CB1 receptor agonists. Collectively, our results show that WOBE437 (and SERIs) may represent a novel therapeutic strategy for slowing MS progression and control major symptoms.

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.

Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man(5)GlcNAc(2) consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.

Background Renal ischemia-reperfusion (I/R) injury is a major cause of AKI. Noncoding RNAs are intricately involved in the pathophysiology of this form of AKI. Transcription of hypoxia-induced, long noncoding RNA H19, which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R injury. Methods Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated H19 in vitro. In vivo analyses used constitutive H19 knockout mice. In addition, renal vein injection of adeno-associated virus 2 (AAV2) carrying H19 caused overexpression in the kidney. Expression of H19 in kidney transplant patients with I/R injury was investigated. Results H19 is upregulated in kidney biopsies of patients with AKI, in murine ischemic kidney tissue, and in cultured and ex vivo sorted hypoxic endothelial cells (ECs) and tubular epithelial cells (TECs). Transcription factors hypoxia-inducible factor 1-α, LHX8, and SPI1 activate H19 in ECs and TECs. H19 overexpression promotes angiogenesis in vitro and in vivo. In vivo, transient AAV2-mediated H19 overexpression significantly improved kidney function, reduced apoptosis, and reduced inflammation, as well as preserving capillary density and tubular epithelial integrity. Sponging of miR-30a-5p mediated the effects, which, in turn, led to target regulation of Dll4, ATG5, and Snai1. Conclusions H19 overexpression confers protection against renal injury by stimulating proangiogenic signaling. H19 overexpression may be a promising future therapeutic option in the treatment of patients with ischemic AKI.

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 (

Structural heart disease (SHD) is a new field within cardiovascular medicine. Traditional imaging modalities fall short in supporting the needs of SHD interventions, as they have been constructed around the concept of disease diagnosis. SHD interventions disrupt traditional concepts of imaging in requiring imaging to plan, simulate, and predict intraprocedural outcomes. In transcatheter SHD interventions, the absence of a gold-standard open cavity surgical field deprives physicians of the opportunity for tactile feedback and visual confirmation of cardiac anatomy. Hence, dependency on imaging in periprocedural guidance has led to evolution of a new generation of procedural skillsets, concept of a visual field, and technologies in the periprocedural planning period to accelerate preclinical device development, physician, and patient education. Adaptation of 3-dimensional (3D) printing in clinical care and procedural planning has demonstrated a reduction in early-operator learning curve for transcatheter interventions. Integration of computation modeling to 3D printing has accelerated research and development understanding of fluid mechanics within device testing. Application of 3D printing, computational modeling, and ultimately incorporation of artificial intelligence is changing the landscape of physician training and delivery of patient-centric care. Transcatheter structural heart interventions are requiring in-depth periprocedural understanding of cardiac pathophysiology and device interactions not afforded by traditional imaging metrics.

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.

To talk about how, over the past two to three decades, interest in blood research has been rapidly increasing in various physiological and pathological conditions, it would mean repeating what has already become a commonplace. The figures below can serve as an illustration of the current state of affairs.

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.

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.

Within the framework of the research and restoration project “Jean-Pierre Latz” of the Museum of Decorative Arts (Staatliche Kunstsammlungen Dresden), three clocks and their corresponding pedestals, all of the same model – the so-called pendules aux biches – were extensively analyzed in terms of construction, marquetry and mounts. The analyses showed that the three ensembles, all of which are traceable in Saxony without a gap since 1768, exhibit significant differences with respect to their construction, the design of the marquetry and its execution, as well as to the processing of the mounts. These varied features enable the distinction of two production types that may suggest their manufacturing in two different workshops.

Objective To provide an overview of ML models and data streams utilized for automated surgical phase recognition. Background Phase recognition identifies different steps and phases of an operation. ML is an evolving technology that allows analysis and interpretation of huge data sets. Automation of phase recognition based on data inputs is essential for optimization of workflow, surgical training, intraoperative assistance, patient safety, and efficiency. Methods A systematic review was performed according to the Cochrane recommendations and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Web of Science, IEEExplore, GoogleScholar, and CiteSeerX were searched. Literature describing phase recognition based on ML models and the capture of intraoperative signals during general surgery procedures was included. Results A total of 2254 titles/abstracts were screened, and 35 full-texts were included. Most commonly used ML models were Hidden Markov Models and Artificial Neural Networks with a trend towards higher complexity over time. Most frequently used data types were feature learning from surgical videos and manual annotation of instrument use. Laparoscopic cholecystectomy was used most commonly, often achieving accuracy rates over 90%, though there was no consistent standardization of defined phases. Conclusions ML for surgical phase recognition can be performed with high accuracy, depending on the model, data type, and complexity of surgery. Different intraoperative data inputs such as video and instrument type can successfully be used. Most ML models still require significant amounts of manual expert annotations for training. The ML models may drive surgical workflow towards standardization, efficiency, and objectiveness to improve patient outcome in the future. Registration prospero CRD42018108907.

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.

In endoscopy, depth estimation is a task that potentially helps in quantifying visual information for better scene understanding. A plethora of depth estimation algorithms have been proposed in the computer vision community. The endoscopic domain however, differs from the typical depth estimation scenario due to differences in the setup and nature of the scene. Furthermore, it is unfeasible to obtain ground truth depth information owing to an unsuitable detection range of off-the-shelf depth sensors and difficulties in setting up a depth-sensor in a surgical environment. In this paper, an existing self-supervised approach, called Monodepth [1], from the field of autonomous driving is applied to a novel dataset of stereo-endoscopic images from reconstructive mitral valve surgery. While it is already known that endoscopic scenes are more challenging than outdoor driving scenes, the paper performs experiments to quantify the comparison, and describe the domain gap and challenges involved in the transfer of these methods.