Pulmonary Rehabilitation Outcomes of Post-Acute COVID-19 Patients during Different Waves of the Pandemic.

(1) Background: Between the beginning of the coronavirus pandemic and summer 2022, we distinguished four pandemic waves, with different characteristics of the affected patients. This study investigated the impact of patient characteristics on the outcome of inpatient pulmonary rehabilitation (PR). (2) Methods: Using a prospective approach, the characteristics of post-acute COVID-19 patients of the different waves who participated in inpatient PR were compared based on their assessments and results collected as part of PR (Cumulative Illness Rating Scale (CIRS), six-minute walk test (6-MWT), Pulmonary Function Testing (PFT), and Functional Independent Measurement (FIM).

Effects of Sprint Interval and Endurance Respiratory Muscle Training on Postcycling Inspiratory and Quadriceps Fatigue.

Purpose: We investigated whether a 4-wk period of respiratory muscle endurance training (RMET) or respiratory muscle sprint interval training (RMSIT) would lead to an attenuation of inspiratory muscle and quadriceps fatigue after a bout of high-intensity cycling compared with a placebo intervention (PLAT), as predicted by the respiratory metaboreflex model.

Methods: Thirty-three active, young healthy adults performed RMET, RMSIT, or PLAT. Changes in inspiratory muscle and quadriceps twitches in response to a cycling test at 90% of peak work capacity were assessed before and after training.

Sex differences in quadriceps and inspiratory muscle fatigability following high-intensity cycling.

Objectives: As females have been hypothesized to have more fatigue resistant inspiratory muscles, this study aimed to compare the development of inspiratory and leg muscle fatigue between males and females following high-intensity cycling.

Design: Cross-sectional comparison.

Methods: 17 healthy young males (27 ± 6 years, V̇O 55 ± 10 ml･min･kg) and females (25 ± 4 years, V̇O 45 ± 7 ml･min･kg) cycled until exhaustion at 90% of the peak power output achieved during an incremental test.

Single-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial.

Background: Standard treatment options for patients with stage IIA or stage IIB seminoma include either para-aortic and pelvic radiotherapy or three to four cycles of cisplatin-based combination chemotherapy. These options result in 3-year progression free survival rates of at least 90%, but bear risks for acute and late toxic effects, including secondary malignancies. We tested a novel approach combining de-escalated chemotherapy with de-escalated involved node radiotherapy, with the aim of reducing toxicity while preserving efficacy.

Differences in spinal posture and mobility between children/adolescents with obesity and age-matched normal-weight individuals.

The aim of this study was to cross-sectionally explore the association of obesity with spinal posture and mobility, commonly associated with musculoskeletal problems, by comparing the spinal parameters between 90 obese and 109 normal-weight children and adolescents. A non-invasive electromechanical device, the Idiag M360 (Idiag, Fehraltorf, Switzerland), was used to measure the spinal parameters. An age-and-sex-adjusted two-way analysis of variance (ANOVA) was used to determine postural and mobility differences between the two groups.

Heme-stress activated NRF2 skews fate trajectories of bone marrow cells from dendritic cells towards red pulp-like macrophages in hemolytic anemia.

Heme is an erythrocyte-derived toxin that drives disease progression in hemolytic anemias, such as sickle cell disease. During hemolysis, specialized bone marrow-derived macrophages with a high heme-metabolism capacity orchestrate disease adaptation by removing damaged erythrocytes and heme-protein complexes from the blood and supporting iron recycling for erythropoiesis. Since chronic heme-stress is noxious for macrophages, erythrophagocytes in the spleen are continuously replenished from bone marrow-derived progenitors.

Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury.

Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI.

Acute Hemolysis and Heme Suppress Anti-CD40 Antibody-Induced Necro-Inflammatory Liver Disease.

Clearance of red blood cells and hemoproteins is a key metabolic function of macrophages during hemolytic disorders and following tissue injury. Through this archetypical phagocytic function, heme is detoxified and iron is recycled to support erythropoiesis. Reciprocal interaction of heme metabolism and inflammatory macrophage functions may modify disease outcomes in a broad range of clinical conditions.

[The role of thoracic CT scan, a triage tool for suspected COVID-19 cases].

The SARS-Cov-2 pandemic took health care players across the world by surprise, including caregivers, managers and logisticians. In the absence of a vaccine or a specific therapy, detecting the disease at an early stage and isolating confirmed cases from the rest of the healthy population was soon considered to be essential. The RT-PCR technique was the gold standard method for testing for infection with the virus.

Hemolysis transforms liver macrophages into antiinflammatory erythrophagocytes.

During hemolysis, macrophages in the liver phagocytose damaged erythrocytes to prevent the toxic effects of cell-free hemoglobin and heme. It remains unclear how this homeostatic process modulates phagocyte functions in inflammatory diseases. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we found that erythrophagocytosis skewed liver macrophages into an antiinflammatory phenotype that we defined as MarcohiHmoxhiMHC class IIlo erythrophagocytes.

Line-selective macrophage activation with an anti-CD40 antibody drives a hemophagocytic syndrome in mice.

Hemophagocytic syndromes comprise a cluster of hyperinflammatory disorders, including hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Overwhelming macrophage activation has long been considered a final common pathway in the pathophysiology of hemophagocytic syndromes leading to the characteristic cytokine storm, laboratory abnormalities, and organ injuries that define the clinical spectrum of the disease. So far, it is unknown whether primary macrophage activation alone can induce the disease phenotype.

Determining the Optimal Normalization Factor of Different Target Arteries for ex vivo Vascular Function Experiments: A New Standardized Procedure.

The standardization of resistance vessel preparation is crucial to compare physiologic vascular reactivity under different experimental conditions. Here, we describe a generalizable experimental setup for ex vivo vascular function experiments and their mathematical basis. Porcine basilar arteries and chicken common carotid arteries were isolated post mortem via standardized surgical approaches.

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm.

Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction.

Effects of Sprint-Interval and Endurance Respiratory Muscle Training Regimens.

Introduction: Recently a novel, time-saving respiratory muscle sprint-interval training (RMSIT) was developed. To test the extent to which RMSIT improves respiratory muscle performance compared with a conventional respiratory muscle endurance training (RMET), a novel incremental respiratory muscle test (IncRMT), loading inspiratory and expiratory muscles, was designed to assess performance changes associated with respiratory muscle training (RMT).

Methods: Healthy, moderately trained males and females (age: 26 ± 5 yr, V˙O2peak: 47 ± 12 mL·min·kg) were randomized and balanced to three groups (RMSIT 5m/5f; RMET 6m/6f; PLAT 5m/6f).

Revisiting the putative role of heme as a trigger of inflammation.

Activation of the innate immune system by free heme has been proposed as one of the principal consequences of cell-free hemoglobin (Hb) exposure. Nonetheless, in the absence of infection, heme exposures within a hematoma, during hemolysis, or upon systemic administration of Hb (eg, as a Hb-based oxygen carrier) are typically not accompanied by uncontrolled inflammation, challenging the assumption that heme is a major proinflammatory mediator in vivo. Because of its hydrophobic nature, heme liberated from oxidized hemoglobin is rapidly transferred to alternative protein-binding sites (eg, albumin) or to hydrophobic lipid compartments minimizing protein-free heme under in vivo equilibrium conditions.

Phenotype-specific recombinant haptoglobin polymers co-expressed with C1r-like protein as optimized hemoglobin-binding therapeutics.

Background: Preclinical studies have evaluated haptoglobin (Hp) polymers from pooled human plasma as a therapeutic protein to attenuate toxic effects of cell-free hemoglobin (Hb). Proof of concept studies have demonstrated efficacy of Hp in hemolysis associated with transfusion and sickle cell anemia. However, phenotype-specific Hp products might be desirable to exploit phenotype specific activities of Hp 1-1 versus Hp 2-2, offering opportunities for recombinant therapeutics.

Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response.

Intravascular hemolysis can result in hemoglobinuria with acute kidney injury. In this study we systematically explored two in vivo animal models and a related cell culture system to identify hemoglobinuria-triggered damage pathways. In models of stored blood transfusion and hemoglobin (Hb) exposure in guinea pigs and beagle dogs we found that hemoglobinuria led to intrarenal conversion of ferrous Hb(Fe(2+)) to ferric Hb(Fe(3+)), accumulation of free heme and Hb-cross-linking products, enhanced 4-hydroxynonenal reactivity in renal tissue, and acute tubule injury.

Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis.

Rationale: Hemolysis occurs not only in conditions such as sickle cell disease and malaria but also during transfusion of stored blood, extracorporeal circulation, and sepsis. Cell-free Hb depletes nitric oxide (NO) in the vasculature, causing vasoconstriction and eventually cardiovascular complications. We hypothesize that Hb-binding proteins may preserve vascular NO signaling during hemolysis.

Different target specificities of haptoglobin and hemopexin define a sequential protection system against vascular hemoglobin toxicity.

Free hemoglobin (Hb) triggered vascular damage occurs in many hemolytic diseases, such as sickle cell disease, with an unmet need for specific therapeutic interventions. Based on clinical observations the Hb and heme scavenger proteins haptoglobin (Hp) and hemopexin (Hx) have been characterized as a sequential defense system with Hp as the primary protector and Hx as a backup when all Hp is depleted during more severe intravascular hemolysis. In this study we present a mechanistic rationale for this paradigm based on a combined biochemical and cell biological approach directed at understanding the unique roles of Hp and Hx in Hb detoxification.

Integrative proteome and transcriptome analysis of extramedullary erythropoiesis and its reversal by transferrin treatment in a mouse model of beta-thalassemia.

Beta-thalassemia results from mutations of the β-hemoglobin (Hbb) gene and reduced functional Hbb synthesis. Excess α-Hb causes globin chain aggregation, oxidation, cytoskeletal damage, and increased red blood cell clearance. These events result in anemia, altered iron homeostasis, and expansion of extramedullary erythropoiesis.

Proteasome inhibition and oxidative reactions disrupt cellular homeostasis during heme stress.

Dual control of cellular heme levels by extracellular scavenger proteins and degradation by heme oxygenases is essential in diseases associated with increased heme release. During severe hemolysis or rhabdomyolysis, uncontrolled heme exposure can cause acute kidney injury and endothelial cell damage. The toxicity of heme was primarily attributed to its pro-oxidant effects; however additional mechanisms of heme toxicity have not been studied systematically.