Quantitative CT scan and response to pronation in COVID-19 ARDS.

Background: The use of the prone position (PP) has been widespread during the COVID-19 pandemic. While it has demonstrated benefits, including improved oxygenation and lung aeration, the factors influencing the response in terms of gas exchange to PP remain unclear. In particular, the association between baseline quantitative Computed Tomography (qCT) scan results and gas exchange response to PP in intubated, mechanically ventilated subjects with COVID-19 ARDS is unknown. The present study aimed to compare baseline qCT results between subjects responding to PP in terms of oxygenation or carbon dioxide (CO2) clearance and those who did not.Methods: This was a single-center, retrospective observational study, including critically ill, intubated, mechanically ventilated subjects with COVID-19 related acute respiratory distress syndrome admitted to the ICUs of Niguarda Hospital between March 2020 and November 2021. Blood-gas samples were collected before and after PP. Subjects in whom the PaO2/FiO2 increase was ≥ 20 mmHg after PP were defined as Oxygen responders (Oxy-R). CO2-responders (CO2R) were defined when the ventilatory ratio (VR) decreased during PP. Automated qCT analyses were performed to obtain tissue mass and density of the lungs.Results: One hundred twenty-five subjects were enrolled, of which 116 (93%) were Oxy-R and 51 (41%) CO2R. No difference in qCT characteristics and oxygen were observed between Oxy-R and Oxygen Non Responders (Tissue mass 1532 ±396 vs. 1654 ±304 g, p= .28; density -544±109 vs. -562±58 HU, p= .42). Similar findings were observed when dividing the population according to CO2 response (Tissue mass 1551±412 vs. 1534±377 g, p= .89; density -545±123 vs. -546±94 HU, p= .99).Conclusions: Most COVID-19 related ARDS subjects improve their oxygenation at the first pronation cycle. The study suggests that baseline qCT scan data are not associated with the response to PP in oxygenation or CO2 in mechanically ventilated COVID-19 related ARDS subjects.

Use, applicability, and dissemination of patient versions of clinical practice guidelines in oncology in Germany: a qualitative interview study with healthcare providers.

BACKGROUND: People with cancer have high information needs; however, they are often inadequately met. Patient versions of clinical practice guidelines (PVGs), a special form of evidence-based information, translate patient-relevant recommendations from clinical practice guidelines into lay language. To date, little is known about the experience of PVGs from healthcare providers' perspective in healthcare. This study aims to investigate the use, applicability, and dissemination of PVGs in oncology from the healthcare providers' perspective in Germany. METHODS: Twenty semi-structured telephone interviews were conducted with oncological healthcare providers in Germany between October and December 2021. Interviews were recorded and transcribed verbatim. Mayring's qualitative content analysis with MAXQDA software was utilised to analyse the data. RESULTS: A total of 20 healthcare providers (14 female, 6 male), mainly working as psychotherapists/psycho-oncologists and physicians, participated. Most participants (75%) were aware of the existence of PVGs. The content was predominantly perceived as comprehensible and relevant, whereas opinions on the design and format were mixed. The perceived lack of up-to-date information limited participants' trust in the content. Most felt that PVGs positively impact healthcare owing to the fact that they improve patients' knowledge about their disease. Additionally, PVGs served as a guide and helped healthcare providers structure physician-patient talks. Healthcare provider's unawareness of the existence of PVGs was cited as an obstructive factor to its dissemination to patients. CONCLUSION: Limited knowledge of the existence of PVGs among healthcare providers, coupled with alternative patient information, hinders the use and dissemination of PVGs in healthcare. However, the applicability of PVGs seemed to be acceptable owing to their content and good comprehensibility, especially with respect to physician-patient communication.

Successful Versus Failed Transition From Controlled Ventilation to Pressure Support Ventilation in COVID-19 Patients: A Retrospective Cohort Study.

OBJECTIVES: In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes. DESIGN: Retrospective observational cohort study. SETTING: Twenty-four Italian ICUs from February 2020 to May 2020. PATIENTS: Mechanically ventilated ICU patients with COVID-19-induced respiratory failure. INTERVENTION: The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours. MEASUREMENTS AND MAIN RESULTS: Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao2/Fio2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00; p = 0.003). Patients in the success group displayed a better trend in Pao2/Fio2, Paco2, plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04). CONCLUSIONS: Our study emphasizes that the Pao2/Fio2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes.

Quantifying pH-induced changes in plasma strong ion difference during experimental acidosis: clinical implications for base excess interpretation.

It is commonly assumed that changes in plasma strong ion difference (SID) result in equal changes in whole blood base excess (BE). However, at varying pH, albumin ionic-binding and transerythrocyte shifts alter the SID of plasma without affecting that of whole blood (SIDwb), i.e., the BE. We hypothesize that, during acidosis, 1) an expected plasma SID (SIDexp) reflecting electrolytes redistribution can be predicted from albumin and hemoglobin's charges, and 2) only deviations in SID from SIDexp reflect changes in SIDwb, and therefore, BE. We equilibrated whole blood of 18 healthy subjects (albumin = 4.8 ± 0.2 g/dL, hemoglobin = 14.2 ± 0.9 g/dL), 18 septic patients with hypoalbuminemia and anemia (albumin = 3.1 ± 0.5 g/dL, hemoglobin = 10.4 ± 0.8 g/dL), and 10 healthy subjects after in vitro-induced isolated anemia (albumin = 5.0 ± 0.2 g/dL, hemoglobin = 7.0 ± 0.9 g/dL) with varying CO2 concentrations (2-20%). Plasma SID increased by 12.7 ± 2.1, 9.3 ± 1.7, and 7.8 ± 1.6 mEq/L, respectively (P < 0.01) and its agreement (bias[limits of agreement]) with SIDexp was strong: 0.5[-1.9; 2.8], 0.9[-0.9; 2.6], and 0.3[-1.4; 2.1] mEq/L, respectively. Separately, we added 7.5 or 15 mEq/L of lactic or hydrochloric acid to whole blood of 10 healthy subjects obtaining BE of -6.6 ± 1.7, -13.4 ± 2.2, -6.8 ± 1.8, and -13.6 ± 2.1 mEq/L, respectively. The agreement between ΔBE and ΔSID was weak (2.6[-1.1; 6.3] mEq/L), worsening with varying CO2 (2-20%): 6.3[-2.7; 15.2] mEq/L. Conversely, ΔSIDwb (the deviation of SID from SIDexp) agreed strongly with ΔBE at both constant and varying CO2: -0.1[-2.0; 1.7], and -0.5[-2.4; 1.5] mEq/L, respectively. We conclude that BE reflects only changes in plasma SID that are not expected from electrolytes redistribution, the latter being predictable from albumin and hemoglobin's charges.NEW & NOTEWORTHY This paper challenges the assumed equivalence between changes in plasma strong ion difference (SID) and whole blood base excess (BE) during in vitro acidosis. We highlight that redistribution of strong ions, in the form of albumin ionic-binding and transerythrocyte shifts, alters SID without affecting BE. We demonstrate that these expected SID alterations are predictable from albumin and hemoglobin's charges, or from the noncarbonic whole blood buffer value, allowing a better interpretation of SID and BE during in vitro acidosis.

Functional studies with IgM and IgA immunoglobulins: binding to pIgR, FcαµR, FcµR, and CDC activities.

IgMs are the first antibodies produced by the immune system upon encounter of a possible pathogen and are one of five antibody subclasses in humans. For IgG, the most intensively studied antibody class, the N-linked glycosylation site located in the Fc-domain is directly involved in high affinity binding to the respective receptors and initiation of corresponding immune response. IgM molecules have five N-glycosylation sites and one N-glycosylation site in the J-chain, which can be incorporated in IgM or IgA molecules. There is only limited knowledge available concerning the function of these N-glycosylations in IgMs. To address this question, we produced IgM molecules lacking a particular N-glycosylation site and tested these variants as well as IgA molecules for binding to the known receptors: the polymeric immunoglobulin receptor (pIgR), the dual receptor for IgA and IgM, FcαµR, and the specific receptor for IgM, FcµR. The single glycosylation sites did not show an impact on expression and multimerization, except for variant N402Q, which could not be expressed. In SPR measurements, no major impact on the binding to the receptors by particular glycosylation sites could be detected. In cellular assays, deglycosylated variants showed some alterations in induction of CDC activity. Most strikingly, we observed also binding of IgA to the FcµR in the same affinity range as IgM, suggesting that this might have a physiological role. To further substantiate the binding of IgA to FcµR we used IgA from different origins and were able to confirm binding of IgA preparations to the FcµR.

Barriers and facilitators in developing patient versions of clinical practice guidelines - qualitative interviews on experiences of international guideline producers.

BACKGROUND: Several guideline organizations produce patient versions of clinical practice guidelines (PVGs) which translate recommendations into simple language. A former study of our working group revealed that few guideline organizations publish their methods used to develop PVGs. Clear definitions of PVGs do not prevail and their purposes often remain unclear. We aimed to explore experts' perspectives on developing, disseminating and implementing PVGs to discuss and incorporate these experiences when consenting on methodological guidance and further improving PVGs. METHODS: We conducted 17 semi-structured telephone interviews with international experts working with PVGs from September 2021 through January 2022. We conducted the interviews in English or German, they were recorded and transcribed verbatim. We utilized Mayring's qualitative content analysis with MAXQDA software to analyze the data. RESULTS: In two interviews two participants were interviewed at the same time. This resulted in a total of 19 participants from 16 different organizations and eight different countries participated. Most were female (16/19) and their experience in working with PVGs ranged from 1 to 20 years. All follow methodological standards when developing PVGs, but the extent of these standards and their public accessibility differs. Aims and target groups of PVGs vary between organizations. Facilitators for developing PVGs are working with a multidisciplinary team, financial resources, consultation processes and a high-quality underlying CPG. Facilitators for disseminating and implementing PVGs are using various strategies. Barriers, on the other hand, are the lack of these factors. All participants mentioned patient involvement as a key aspect in PVG development. CONCLUSION: The steps in the PVG development process are largely similar across the countries. Focus is placed on the involvement of patients in the development process, although the extent of participation varies. The experts collectively attribute great importance to PVGs overall, but in order to constantly adapt to medical progress and changing conditions, the focus in the future may be more on formats like living guidelines. Although there are different views on the mandatory development of PVGs, there is a consistent call for more transparency regarding the methodology used for PVGs.

Validation of Indirect Calorimetry in Children Undergoing Single-Limb Non-Invasive Ventilation: A Proof of Concept, Cross-Over Study.

BACKGROUND: The accurate assessment of resting energy expenditure (REE) is essential for personalized nutrition, particularly in critically ill children. Indirect calorimetry (IC) is the gold standard for measuring REE. This methodology is based on the measurement of oxygen consumption (VO2) and carbon dioxide production (VCO2). These parameters are integrated into the Weir equation to calculate REE. Additionally, IC facilitates the determination of the respiratory quotient (RQ), offering valuable insights into a patient's carbohydrate and lipid consumption. IC validation is limited to spontaneously breathing and mechanically ventilated patients, but it is not validated in patients undergoing non-invasive ventilation (NIV). This study investigates the application of IC during NIV-CPAP (continuous positive airway pressure) and NIV-PS (pressure support). METHODS: This study was conducted in the Pediatric Intensive Care Unit of IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, between 2019 and 2021. Children < 6 years weaning from NIV were enrolled. IC was performed during spontaneous breathing (SB), NIV-CPAP, and NIV-PS in each patient. A Bland-Altman analysis was employed to compare REE, VO2, VCO2, and RQ measured by IC. RESULTS: Fourteen patients (median age 7 (4; 18) months, median weight 7.7 (5.5; 9.7) kg) were enrolled. The REE, VO2, VCO2, and RQ did not differ significantly between the groups. The Limits of Agreement (LoA) and bias of REE indicated good agreement between SB and NIV-CPAP (LoA +28.2, -19.4 kcal/kg/day; bias +4.4 kcal/kg/day), and between SB and NIV-PS (LoA -22.2, +23.1 kcal/kg/day; bias 0.4 kcal/kg/day). CONCLUSIONS: These preliminary findings support the accuracy of IC in children undergoing NIV. Further validation in a larger cohort is warranted.

CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.

CLPB is a mitochondrial intermembrane space AAA+ domain-containing disaggregase. CLPB mutations are associated with 3-methylglutaconic aciduria and neutropenia; however, the molecular mechanism underscoring disease and the contribution of CLPB substrates to disease pathology remains unknown. Interactions between CLPB and mitochondrial quality control (QC) factors, including PARL and OPA1, have been reported, hinting at dysregulation of organelle QC in disease. Utilizing proteomic and biochemical approaches, we show a stress-specific aggregation phenotype in a CLPB-null environment and define the CLPB substrate profile. We illustrate an interplay between intermembrane space proteins including CLPB, HAX1, HTRA2, and the inner membrane quality control proteins (STOML2, PARL, YME1L1; SPY complex), with CLPB deficiency impeding SPY complex function by virtue of protein aggregation in the intermembrane space. We conclude that there is an interdependency of mitochondrial QC components at the intermembrane space/inner membrane interface, and perturbations to this network may underscore CLPB disease pathology.

Ferroptosis in mitochondrial cardiomyopathy.

Ferroptosis is a form of necrotic cell death characterized by iron-dependent lipid peroxidation culminating in membrane rupture. Accumulating evidence links ferroptosis to multiple cardiac diseases and identifies mitochondria as important regulators of ferroptosis. Mitochondria are not only a major source of reactive oxygen species (ROS) but also counteract ferroptosis by preserving cellular redox balance and oxidative defense. Recent evidence has revealed that the mitochondrial integrated stress response limits oxidative stress and ferroptosis in oxidative phosphorylation (OXPHOS)-deficient cardiomyocytes and protects against mitochondrial cardiomyopathy. We summarize the multiple ways in which mitochondria modulate the susceptibility of cells to ferroptosis, and discuss the implications of ferroptosis for cardiomyopathies in mitochondrial disease.

Combining the Physical-Chemical Approach with Standard Base Excess to Understand the Compensation of Respiratory Acid-Base Derangements: An Individual Participant Meta-analysis Approach to Data from Multiple Canine and Human Experiments.

BACKGROUND: Several studies explored the interdependence between Paco2 and bicarbonate during respiratory acid-base derangements. The authors aimed to reframe the bicarbonate adaptation to respiratory disorders according to the physical-chemical approach, hypothesizing that (1) bicarbonate concentration during respiratory derangements is associated with strong ion difference; and (2) during acute respiratory disorders, strong ion difference changes are not associated with standard base excess. METHODS: This is an individual participant data meta-analysis from multiple canine and human experiments published up to April 29, 2021. Studies testing the effect of acute or chronic respiratory derangements and reporting the variations of Paco2, bicarbonate, and electrolytes were analyzed. Strong ion difference and standard base excess were calculated. RESULTS: Eleven studies were included. Paco2 ranged between 21 and 142 mmHg, while bicarbonate and strong ion difference ranged between 12.3 and 43.8 mM, and 32.6 and 60.0 mEq/l, respectively. Bicarbonate changes were linearly associated with the strong ion difference variation in acute and chronic respiratory derangement (ß-coefficient, 1.2; 95% CI, 1.2 to 1.3; P < 0.001). In the acute setting, sodium variations justified approximately 80% of strong ion difference change, while a similar percentage of chloride variation was responsible for chronic adaptations. In the acute setting, strong ion difference variation was not associated with standard base excess changes (ß-coefficient, -0.02; 95% CI, -0.11 to 0.07; P = 0.719), while a positive linear association was present in chronic studies (ß-coefficient, 1.04; 95% CI, 0.84 to 1.24; P < 0.001). CONCLUSIONS: The bicarbonate adaptation that follows primary respiratory alterations is associated with variations of strong ion difference. In the acute phase, the variation in strong ion difference is mainly due to sodium variations and is not paralleled by modifications of standard base excess. In the chronic setting, strong ion difference changes are due to chloride variations and are mirrored by standard base excess.