Renal replacement therapy (RRT) is frequently used in critically ill patients with acute kidney injury (AKI). Here, we provide guidelines for the management of RRT in critically ill patients on the intensive care unit (ICU). We convened a systemic literature research and a Delphi process with a bi-national multidisciplinary consensus panel including 22 clinicians of 12 different German-speaking societies (Germany and Austria) with expertise in RRT. This structured guideline process was the basis for the evidence-based statements and recommendations. We identified seven clinical areas needing guidance: (1) start, (2) modality (diffusion and convection), (3) continuous/ intermittent, (4) anticoagulation, (5) dose (6) pharmacotherapy, (7) stopping criteria. The consensus produced 73 statements and recommendations regarding key clinical areas, the most important 47 statements and recommendations are summarized in this overview. This evidence-based bi-national guideline should provide physicians with guidance for delivering best practice to critically ill patients with a dialysis-dependent AKI.
Background Anti-programmed cell death protein 1 (PD-1) immunotherapy has revolutionized the treatment of stage III and IV melanoma. Real-world data on its resistance is needed to facilitate the development of combinatorial approaches to overcome anti-PD-1 resistance.Objectives To characterize anti-PD-1 resistance and assess whether progressive disease assigned by clinicians is concordant with scan data assessed by independent central reviewers (ICR).Methods A retrospective chart review was conducted in adult patients with stage III/IV melanoma who initiated anti-PD-1 therapy from January 2018 until 12 months before the start of data collection at 22 sites across six countries. Primary resistance and late relapse in the adjuvant setting, and primary, secondary resistance, and late progression in the advanced setting were assigned using Society for Immunotherapy of Cancer definitions. Demographic and clinical characteristics by type of resistance were compared with appropriate univariate tests. Time to resistance (TTR) and overall survival were analyzed using Kaplan-Meier. To compare the concordance of progression assigned by clinicians and ICR, the positive predictive value (PPV) was calculated in a subset of patients.Results Of 981 eligible patients, 738 were included. In the adjuvant setting (n=240), 53 (22.1%) patients developed primary resistance and 60 (25.0%) experienced late relapse. In the advanced setting (n=498), 222 (44.6%), 50 (10.0%), and 64 (12.9%) patients developed primary, secondary resistance, and late progression. Type of resistance significantly differed by country, race, type of BRAF mutation, and PD-L1 expression in both settings; and by sex, disease stage and tumor thickness in the adjuvant setting only (p<0.05). Mean (SD) TTR was 47.7 (1.3) and 24.2 (1.0) months in the adjuvant and advanced setting, respectively. Patients with primary resistance had the poorest overall survival. The PPV of progression assigned by clinicians was 87.2% (95% CI 72.6% to 95.7%).Conclusions This study showed that a substantial proportion of patients with melanoma receiving anti-PD-1 therapy in the adjuvant (47.1%) and advanced (67.5%) settings developed resistance or late relapse/progression, highlighting an unmet medical need. Real-world clinical practice provided a reliable assessment of progression. Factors associated with different types of resistance were identified. Further study is warranted to evaluate their impact on patient risk stratification. (Graphical abstract)
Ageing induces structural and functional changes in the neuromuscular systems that impair voluntary force production, compromising daily function and wellbeing. We examined whether older adults preserve the capacity for motor unit adaptations to a short-term strength training intervention previously shown to enhance neural drive to muscle in young adults. Twenty‑three older adults were assigned to a training group (INT, n = 13, 71 ± 4 years of age) or a control group (CON, n = 10, 69 ± 2 years of age) and completed pre- and postintervention assessments of ankle dorsiflexor maximal voluntary force (MVF). Motor unit behaviour was analysed from high‑density surface EMG recorded from tibialis anterior during submaximal trapezoidal contractions. The INT group performed a 4 week supervised isometric strength training programme, whereas the CON group maintained habitual activity. High‑density surface EMG signals were decomposed into individual motor units, tracked longitudinally across sessions. Training increased MVF by 17.6% and enhanced motor unit discharge rate at recruitment (+8.2%, P = 0.031) and constant force (+11.3%, P < 0.001), without changes in recruitment or derecruitment thresholds. Estimates of persistent inward currents (delta frequency) increased (+1.0 pulses per second) and were positively correlated with changes in discharge rate, which, in turn, were correlated with gains in MVF (rrm = 0.54-0.57, P < 0.05). This pattern suggests that enhanced intrinsic excitability and synaptic input to motor neurons contributed to improvements in strength. These results demonstrate that, despite age-related motor unit remodelling, the ageing nervous system remains responsive to targeted strength training, preserving the capacity for meaningful neural adaptations. KEY POINTS: We assessed whether a short-term intensive strength training intervention, previously shown to increase spinal motor output to the muscle significantly in young adults, would also be effective in older adults. High-density surface EMG was used to identify and longitudinally track the same motor units before and after a 4 week isometric strength training intervention. We found significant strength gains in older adults, with the increase in muscle force output being positively associated with higher motor unit discharge rate and persistent inward currents, indicating that neural drive enhancement was a key contributor to the observed improvements in force. Despite age-related motor neuron remodelling, the older nervous system remains highly responsive to strength training, exhibiting qualitatively similar but attenuated motor unit adaptations compared with young adults.
ABSTRACT:Ravulizumab, a humanized, long-acting monoclonal antibody against complement factor C5, is a widely used treatment for paroxysmal nocturnal hemoglobinuria (PNH). Given that pregnant women with PNH are at increased risk for complications and the safety and efficacy of ravulizumab in pregnancy is not known, we performed an international multicenter retrospective analysis of 16 patients with PNH with 19 pregnancies managed with ravulizumab and compared outcomes to 8 earlier pregnancies in the same patients treated with eculizumab. Of the 8 eculizumab-treated pregnancies, 3 resulted in miscarriages and 1 in early preterm delivery for threatened fetal demise and massive fetal growth retardation. All 19 pregnancies on ravulizumab resulted in the birth of live infants, with a median gestational age of 267 days (interquartile range [IQR], 259-275) and median birth weight of 3115 g (IQR, 2458-3349). Cord blood testing in 2 pregnancies receiving intensified ravulizumab dosing revealed detectable ravulizumab levels consistent with transplacental transfer. After a median follow-up of 16.2 months (IQR, 4.4-40.1), no developmental abnormalities or severe infectious complications were observed in the children. This retrospective analysis provides evidence for the safety and effectiveness of ravulizumab in managing PNH during pregnancy and breastfeeding with favorable maternal and fetal outcomes.
IntroductionManaging Mass Casualty Incidents (MCI) demands complex, cross-sectoral competencies. However, training these skills using traditional full-scale exercises is often limited by high resource requirements, low frequency, and a lack of patients (patho-)physiological dynamics. Against this backdrop, the research projects D2PuLs and D2PuLs PRO (Digital Dynamic Patient and Scene Simulation) developed a modular and adaptive digital simulation environment designed for interdisciplinary and cross-sectoral disaster response training.MethodsA core element of this system is a dynamic physiology model that simulates (patho-)physiological changes and therapeutic interventions in real time, replacing static vital signs with realistic, intervention-dependent progressions. The platform facilitates configurable scenarios ranging from individual training on mobile devices to distributed large-scale exercises incorporating external situation simulators and physical simulation manikins.ResultsPreliminary results of initial field tests and subsequent surveys of Emergency Medical Services (EMS) personnel and clinical teams showed the fundamental technical and didactic applicability of the system across the entire rescue chain—from initial care and triage to transport and trauma room management. The results provide solid, albeit preliminary, indications that the system can be successfully utilized to train decision-making, triage, and resource management across sector boundaries, while providing digital data foundation for debriefings. Although the complexity of the available medical interventions initially placed high demands on user operation, the modular architecture proved effective in adapting scenarios to specific learning objectives.DiscussionThe study concludes that dynamic digital simulations represent a scalable and valid supplement to practical exercises, serving to sustainably strengthen operational confidence in disaster medicine.
