Clinical application of intrapulmonary percussive ventilation: A scoping review.

Impaired respiratory function secondary to acute or chronic respiratory disease poses a significant clinical and healthcare burden. Intrapulmonary percussive ventilation (IPV) is used in various clinical settings to treat excessive airway secretions, pulmonary atelectasis, and impaired gas exchange. Despite IPV's wide use, there is a lack of clinical guidance on IPV application which may lead to inconsistency in clinical practice. This scoping review aimed to summarise the clinical application methods and dosage of IPV used by clinicians and researchers to provide guidance. A two-staged systematic search was conducted to retrieve studies that used IPV in inpatient and outpatient settings. MEDLINE, EMBASE, CINAHL, Scopus, and Google scholar were searched from January 1979 till 2022. Studies with patients aged ≥16 years and published in any language were included. Two reviewers independently screened the title and abstract, reviewed full text articles, and extracted data. Search yielded 514 studies. After removing duplicates and irrelevant studies, 25 studies with 905 participants met the inclusion criteria. This is the first scoping review to summarise IPV application methods and dosages from the available studies in intensive care unit (ICU), acute inpatient (non-ICU), and outpatient settings. Some variations in clinical applications and prescribed dosages of IPV were noted. Despite variations, common trends in clinical application and prescription of IPV dosages were observed and summarised to assist clinicians with IPV intervention. Although an evidence-based clinical guideline could not be provided, this review provides detailed information on IPV application and dosages in order to provide clinical guidance and lays a foundation towards developing a clinical practice guideline in the future.

The value of right ventricular to pulmonary arterial coupling in the critically ill: a National Echocardiography Database of Australia (NEDA) substudy.

BACKGROUND: Right ventricular (RV) function is tightly coupled to afterload, yet echocardiographic indices of RV function are frequently assessed in isolation. Normalizing RV function for afterload (RV-PA coupling) using a simplified ratio of tricuspid annular plane systolic excursion (TAPSE)/ tricuspid regurgitant velocity (TRV) could help to identify RV decompensation and improve risk stratification in critically ill patients. This is the first study to explore the distribution of TAPSE/TRV ratio and its prognostic relevance in a large general critical care cohort. METHODS: We undertook retrospective analysis of echocardiographic, clinical, and mortality data of intensive care unit (ICU) patients between January 2012 and May 2017. A total of 1077 patients were included and stratified into tertile groups based on TAPSE/TRV ratio: low (< 5.9 mm.(m/s)-1), middle (≥ 5.9-8.02 mm.(m/s)-1), and high (≥ 8.03 mm.(m/s)-1). The distribution of the TAPSE/TRV ratio across ventricular function subtypes of normal, isolated left ventricular (LV), isolated RV, and biventricular dysfunction was explored. The overall prognostic relevance of the TAPSE/TRV ratio was tested, including distribution across septic, cardiovascular, respiratory, and neurological subgroups. RESULTS: Higher proportions of ventricular dysfunctions were seen in low TAPSE/TRV tertiles. TAPSE/TRV ratio is impacted by LV systolic function but to a lesser extent than RV dysfunction or biventricular dysfunction. There was a strong inverse relationship between TAPSE/TRV ratio and survival. After multivariate analysis, higher TAPSE/TRV ratios (indicating better RV-PA coupling) were independently associated with lower risk of death in ICU (HR 0.927 [0.872-0.985], p < 0.05). Kaplan-Meier analysis demonstrated higher overall survival in middle and high tertiles compared to low tertiles (log rank p < 0.0001). The prognostic relevance of TAPSE/TRV ratio was strongest in respiratory and sepsis subgroups. Patients with TAPSE/TRV < 5.9 mm (m/s)-1 had a significantly worse prognosis than those with higher TAPSE/TRV ratios. CONCLUSION: The TAPSE/TRV ratio has prognostic relevance in critically ill patients. The prognostic power may be stronger in respiratory and septic subgroups. Larger prospective studies are needed to investigate the role of TAPSE/TRV in pre-specified subgroups including its role in clinical decision-making.

Risk factors for mortality in severe COVID-19: Exploring the interplay of immunomodulatory therapy and coinfection.

Patients with severe clinical manifestations of coronavirus disease 2019 (COVID-19) present particular diagnostic and management challenges to critical care physicians, including identifying and responding to concurrent bacterial and fungal coinfections. This study evaluates risk factors for in-hospital mortality in patients admitted to the intensive care unit with severe COVID-19 during circulation of the B.1.617.2 (Delta) variant, including the impact of immunomodulators and bacterial and/or fungal coinfection. This retrospective cohort study enrolled patients with severe COVID-19. A Cox proportional hazard ratio analysis identified risk factors for in-hospital mortality. Outcomes were also compared between patients receiving and not receiving immunomodulatory therapy alongside standard care. Ninety patients admitted to the intensive care unit were enrolled. On multivariate analysis, the greatest risk factors for in-hospital mortality were invasive mechanical ventilation (hazard ratio (HR) = 15.27; 95% confidence interval (CI) 3.29-71.0; P < 0.001), elevated body mass index (HR = 1.07 per unit; 95% CI 1.02-1.13; P = 0.007) and older age (HR = 1.53 per decade; 95% CI 1.05-2.24; P = 0.028). Bacterial and/or fungal coinfection occurred at equal frequency in patients receiving and not receiving immunomodulatory therapy. However, in patients receiving immunomodulators, coinfection carried a significantly higher mortality risk (63.0%) compared with those without coinfection (15.4%; P = 0.038). Mortality from severe COVID-19 is significantly higher in older patients and those with elevated body mass index and requiring mechanical ventilation. Immunomodulatory therapy necessitates vigilance towards evolving coinfection in the intensive care setting.

Genetic and Immunohistochemistry Tools to Visualize Rat Macrophages In Situ.

Macrophages contribute to many aspects of development and homeostasis, innate and acquired immunity, immunopathology, and tissue repair. Every tissue contains an abundant resident macrophage population. Inflammatory stimuli promote the recruitment of monocytes from the blood and their adaptation promotes the removal of the stimulus and subsequent restoration of normal tissue architecture. Dysregulation of this response leads to chronic inflammation and tissue injury. In many tissues, their differentiation and survival are dependent on the colony stimulating factor 1 receptor (CSF1R) signalling axis, which is highly conserved across all vertebrates. Complete loss of either CSF1R or its cognate ligands, colony stimulating factor 1 (CSF1), and interleukin 34 (IL-34), results in the loss of many tissue-resident macrophage populations. This provides a useful paradigm to study macrophages.There are many tools used to visualize tissue-resident macrophages and their precursors, monocytes, in mice and humans. Particularly in mice there are genetic tools available to delete, enhance and manipulate monocytes and macrophages and their gene products to gain insight into phenotype and function. The laboratory rat has many advantages as an experimental model for the understanding of human disease, but the analytical resources are currently more limited than in mice. Here, we describe available genetic models, antibodies, and immunohistochemistry (IHC) methods that may be used to visualize tissue-resident macrophages in rats.

Echocardiography phenotypes of right ventricular involvement in COVID-19 ARDS patients and ICU mortality: post-hoc (exploratory) analysis of repeated data from the ECHO-COVID study.

PURPOSE: Exploratory study to evaluate the association of different phenotypes of right ventricular (RV) involvement and mortality in the intensive care unit (ICU) in patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). METHODS: Post-hoc analysis of longitudinal data from the multicenter ECHO-COVID observational study in ICU patients who underwent at least two echocardiography examinations. Echocardiography phenotypes were acute cor pulmonale (ACP, RV cavity dilatation with paradoxical septal motion), RV failure (RVF, RV cavity dilatation and systemic venous congestion), and RV dysfunction (tricuspid annular plane systolic excursion ≤ 16 mm). Accelerated failure time model and multistate model were used for analysis. RESULTS: Of 281 patients who underwent 948 echocardiography studies during ICU stay, 189 (67%) were found to have at least 1 type of RV involvements during one or several examinations: ACP (105/281, 37.4%), RVF (140/256, 54.7%) and/or RV dysfunction (74/255, 29%). Patients with all examinations displaying ACP had survival time shortened by 0.479 [0.284-0.803] times when compared to patients with all examinations depicting no ACP (P = 0.005). RVF showed a trend towards shortened survival time by a factor of 0.642 [0.405-1.018] (P = 0.059), whereas the impact of RV dysfunction on survival time was inconclusive (P = 0.451). Multistate analysis showed that patients might transit in and out of RV involvement, and those who exhibited ACP in their last critical care echocardiography (CCE) examination had the highest risk of mortality (hazard ratio (HR) 3.25 [2.38-4.45], P < 0.001). CONCLUSION: RV involvement is prevalent in patients ventilated for COVID-19 ARDS. Different phenotypes of RV involvement might lead to different ICU mortality, with ACP having the worst outcome.

Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension.

BACKGROUND: Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis. METHODS: In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring. RESULTS: Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r = -0.56 at week 8; 95% confidence interval, -0.69 to -0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively. CONCLUSIONS: Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.).

Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: Results from randomized clinical trials.

BACKGROUND & AIMS: Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that target all major HBV transcripts. METHODS: We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n = 24 and n = 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200 mg of VIR-2218 (total n = 24) vs. placebo (n = 8), given 4 weeks apart, in participants with cHBV infection. RESULTS: In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200 mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion. CONCLUSIONS: VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188. IMPACT AND IMPLICATIONS: A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians.

Intraperitoneal transfer of wild-type bone marrow repopulates tissue macrophages in the Csf1r knockout rat without contributing to monocytopoiesis.

Homozygous null mutation of the Csf1r gene (Csf1rko) in rats leads to the loss of most tissue macrophage populations and pleiotropic impacts on postnatal growth and organ maturation, leading to early mortality. The phenotype can be reversed by intraperitoneal transfer of WT BM cells (BMT) at weaning. Here, we used a Csf1r-mApple transgenic reporter to track the fate of donor-derived cells. Following BMT into Csf1rko recipients, mApple+ve cells restored IBA1+ tissue macrophage populations in every tissue. However, monocytes, neutrophils, and B cells in the BM, blood, and lymphoid tissues remained of recipient (mApple-ve ) origin. An mApple+ve cell population expanded in the peritoneal cavity and invaded locally in the mesentery, fat pads, omentum, and diaphragm. One week after BMT, distal organs contained foci of mApple+ve , IBA1-ve immature progenitors that appeared to proliferate, migrate, and differentiate locally. We conclude that rat BM contains progenitor cells that are able to restore, replace, and maintain all tissue macrophage populations in a Csf1rko rat directly without contributing to the BM progenitor or blood monocyte populations.

Remi-fent 1-A pragmatic randomised controlled study to evaluate the feasibility of using remifentanil or fentanyl as sedation adjuncts in mechanically ventilated patients.

Objective: To evaluate the feasibility of conducting a prospective randomised controlled trial (pRCT) comparing remifentanil and fentanyl as adjuncts to sedate mechanically ventilated patients. Design: Single-center, open-labelled, pRCT with blinded analysis. Setting: Australian tertiary intensive care unit (ICU). Participants: Consecutive adults between June 2020 and August 2021 expected to receive invasive ventilation beyond the next day and requiring opioid infusion were included. Exclusion criteria were pregnant/lactating women, intubation >12 h, or study-drug hypersensitivity. Interventions: Open-label fentanyl and remifentanil infusions per existing ICU protocols. Outcomes: Primary outcomes were feasibility of recruiting ≥1 patient/week and >90 % compliance, namely no other opioid infusion used during the study period. Secondary outcomes included complications, ICU-, ventilator- and hospital-free days, and mortality (ICU, hospital). Blinded intention-to-treat analysis was performed concealing the allocation group. Results: 208 patients were enrolled (mean 3.7 patients/week). Compliance was 80.6 %. More patients developed complications with fentanyl than remifentanil: bradycardia (n = 44 versus n = 21; p < 0.001); hypotension (n = 78 versus n = 53; p < 0.01); delirium (n = 28 versus n = 15; p = 0.001). No differences were seen in ICU (24.3 % versus 27.6 %,p = 0.60) and hospital mortalities (26.2 % versus 30.5 %; p = 0.50). Ventilator-free days were higher with remifentanil (p = 0.01). Conclusions: We demonstrated the feasibility of enrolling patients for a pRCT comparing remifentanil and fentanyl as sedation adjuncts in mechanically ventilated patients. We failed to attain the study-opioid compliance target, likely because of patients with complex sedative/analgesic requirements. Secondary outcomes suggest that remifentanil may reduce mechanical ventilation duration and decrease the incidence of complications. An adequately powered multicentric phase 2 study is required to evaluate these results.

Right ventricular outflow tract Doppler flow analysis and pulmonary arterial coupling by transthoracic echocardiography in sepsis: a retrospective exploratory study.

INTRODUCTION: Right ventricular (RV) and pulmonary vascular dysfunction appear to be common in sepsis. RV performance is frequently assessed in isolation, yet its close relationship to afterload means combined analysis with right ventricular outflow tract (RVOT) Doppler and RV-pulmonary arterial (RV-PA) coupling may be more informative than standard assessment techniques. Data on feasibility and utility of these parameters in sepsis are lacking and were explored in this study. METHODS: This is a retrospective study over a 3-year period of one-hundred and thirty-one patients admitted to ICU with sepsis who underwent transthoracic echocardiography (TTE) with RVOT pulsed wave Doppler. RVOT Doppler flow and RV-PA coupling was evaluated alongside standard measurements of RV systolic function and pulmonary pressures. RVOT Doppler analysis included assessment of pulmonary artery acceleration time (PAAT), velocity time integral and presence of notching. RV-PA coupling was assessed using tricuspid annular planar systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio. RESULTS: PAAT was measurable in 106 (81%) patients, and TAPSE/PASP was measurable in 77 (73%). Seventy-three (69%) patients had a PAAT of ≤ 100 ms suggesting raised pulmonary vascular resistance (PVR) is common. RVOT flow notching occurred in 15 (14%) of patients. TRV was unable to be assessed in 24 (23%) patients where measurement of PAAT was possible. RV dysfunction (RVD) was present in 28 (26%), 26 (25%) and 36 (34%) patients if subjective assessment, TAPSE < 17 mm and RV dilatation definitions were used, respectively. There was a trend towards shorter PAAT with increasing severity of RVD. RV-PA uncoupling defined as a TAPSE/PASP < 0.31 mm/mmHg was present in 15 (19%) patients. As RV dilatation increased the RV-PA coupling ratio decreased independent of LV systolic function, whereas TAPSE appeared to be more susceptible to changes in LV systolic function. CONCLUSION: Raised PVR and RV-PA uncoupling is seen in a significant proportion of patients with sepsis. Non-invasive assessment with TTE is feasible. The role of these parameters in assisting improved definitions of RVD, as well as their therapeutic and prognostic utility against standard parameters, deserves further investigation.

Full and simplified assessment of left ventricular diastolic function in covid-19 patients admitted to ICU: Feasibility, incidence, and association with mortality.

PURPOSE: Left ventricular diastolic dysfunction (LVDD) is associated with poor outcomes in the intensive care unit (ICU). Nonetheless, precise reporting of LVDD in COVID-19 patients is currently lacking and assessment could be challenging. METHODS: We performed an echocardiography study in COVID-19 patients admitted to ICU with the aim to describe the feasibility of full or simplified LVDD assessment and its incidence. We also evaluated the association of LVDD or of single echocardiographic parameters with hospital mortality. RESULTS: Between 06.10.2020 and 18.02.2021, full diastolic assessment was feasible in 74% (n = 26/35) of patients receiving a full echocardiogram study. LVDD incidence was 46% (n = 12/26), while the simplified assessment produced different results (incidence 81%, n = 21/26). Nine patients with normal function on full assessment had LVDD with simplified criteria (grade I = 2; grade II = 3; grade III = 4). Nine patients were hospital-survivors (39%); the incidence of LVDD (full assessment) was not different between survivors (n = 2/9, 22%) and non-survivors (n = 10/17, 59%; p = .11). The E/e' ratio lateral was lower in survivors (7.4 [3.6] vs. non-survivors 10.5 [6.3], p = .03). We also found that s' wave was higher in survivors (average, p = .01). CONCLUSION: In a small single-center study, assessment of LVDD according to the latest guidelines was feasible in three quarters of COVID-19 patients. Non-survivors showed a trend toward greater LVDD incidence; moreover, they had significantly worse s' values (all) and higher E/e' ratio (lateral).

Echocardiography findings in COVID-19 patients admitted to intensive care units: a multi-national observational study (the ECHO-COVID study).

PURPOSE: Severely ill patients affected by coronavirus disease 2019 (COVID-19) develop circulatory failure. We aimed to report patterns of left and right ventricular dysfunction in the first echocardiography following admission to intensive care unit (ICU). METHODS: Retrospective, descriptive study that collected echocardiographic and clinical information from severely ill COVID-19 patients admitted to 14 ICUs in 8 countries. Patients admitted to ICU who received at least one echocardiography between 1st February 2020 and 30th June 2021 were included. Clinical and echocardiographic data were uploaded using a secured web-based electronic database (REDCap). RESULTS: Six hundred and seventy-seven patients were included and the first echo was performed 2 [1, 4] days after ICU admission. The median age was 65 [56, 73] years, and 71% were male. Left ventricle (LV) and/or right ventricle (RV) systolic dysfunction were found in 234 (34.5%) patients. 149 (22%) patients had LV systolic dysfunction (with or without RV dysfunction) without LV dilatation and no elevation in filling pressure. 152 (22.5%) had RV systolic dysfunction. In 517 patients with information on both paradoxical septal motion and quantitative RV size, 90 (17.4%) had acute cor pulmonale (ACP). ACP was associated with mechanical ventilation (OR > 4), pulmonary embolism (OR > 5) and increased PaCO2. Exploratory analyses showed that patients with ACP and older age were more likely to die in hospital (including ICU). CONCLUSION: Almost one-third of this cohort of critically ill COVID-19 patients exhibited abnormal LV and/or RV systolic function in their first echocardiography assessment. While LV systolic dysfunction appears similar to septic cardiomyopathy, RV systolic dysfunction was related to pressure overload due to positive pressure ventilation, hypercapnia and pulmonary embolism. ACP and age seemed to be associated with mortality in this cohort.

Criteria, Processes, and Determination of Competence in Basic Critical Care Echocardiography Training: A Delphi Process Consensus Statement by the Learning Ultrasound in Critical Care (LUCC) Initiative.

BACKGROUND: With the paucity of high-quality studies on longitudinal basic critical care echocardiography (BCCE) training, expert opinion guidelines have guided BCCE competence educational standards and processes. However, existing guidelines lack precise detail due to methodological flaws during guideline development. RESEARCH QUESTIONS: To formulate methodologically robust guidelines on BCCE training using evidence and expert opinion, detailing specific criteria for every step, we conducted a modified Delphi process using the principles of the validated AGREE-II tool. Based on systematic reviews, the following domains were chosen: components of a longitudinal BCCE curriculum; pass-grade criteria for image-acquisition and image-interpretation; and formative/summative assessment and final competence processes. STUDY DESIGN AND METHODS: Between April 2020 and May 2021, a total of 21 BCCE experts participated in four rounds. Rounds 1 and 2 used five web-based questionnaires, including branching-logic software for directed questions to individual panelists. In round 3 (videoconference), the panel finalized the recommendations by vote. During the journal peer-review process, Round 4 was conducted as Web-based questionnaires. Following each round, the agreement threshold for each item was determined as ≥ 80% for item inclusion and ≤ 30% for item exclusion. RESULTS: Following rounds 1 and 2, agreement was reached on 62 of 114 items. To the 49 unresolved items, 12 additional items were added in round 3, with 56 reaching agreement and five items remaining unresolved. There was agreement that longitudinal BCCE training must include introductory training, mentored formative training, summative assessment for competence, and final cognitive assessment. Items requiring multiple rounds included two-dimensional views, Doppler, cardiac output, M-mode measurement, minimum scan numbers, and pass-grade criteria. Regarding objective criteria for image-acquisition and image-interpretation quality, the panel agreed on maintaining the same criteria for formative and summative assessment, to categorize BCCE findings as major vs minor and a standardized approach to errors, criteria for readiness for summative assessment, and supervisory options. INTERPRETATION: In conclusion, this expert consensus statement presents comprehensive evidence-based recommendations on longitudinal BCCE training. However, these recommendations require prospective validation.

Criteria, Processes and Determination of Competence in Basic Critical Care Echocardiography Training - a Delphi Process Consensus Statement by the Learning Ultrasound in Critical Care (LUCC) Initiative

With the paucity of high-quality studies on longitudinal basic critical care echocardiography (BCCE) training, expert-opinion guidelines have guided BCCE training. However, existing guidelines lack precise detail due to methodological flaws during guideline-development. To formulate methodologically robust guidelines on BCCE training using evidence and expert opinion, detailing specific criteria for every step, we conducted a modified Delphi process using the principles of the validated AGREE-II tool. Based on systematic reviews, the following domains were chosen ­ components of a longitudinal BCCE curriculum; pass-grade criteria for image-acquisition and image-interpretation; formative/summative assessment and final competence processes. Between April 2020 and May 2021, 21 BCCE experts participated in four rounds. Rounds 1 and 2 used five web-based questionnaires, including branching-logic software for directed questions to individual panelists. In round 3 (videoconference), the panel finalized the recommendations by vote. During the journal peer-review process, Round 4 was conducted as web-based questionnaires. After each round, the agreement threshold for each item was determined >80% for item-inclusion and <30% for item-exclusion. After rounds 1 and 2, agreement was reached on 62/114 item. To the 49 unresolved items, 12 additional items were added in round 3, with 56 reaching agreement and five items remaining unresolved. There was agreement that longitudinal BCCE training must include introductory training, mentored formative training, summative assessment for competence and final cognitive assessment. Items requiring multiple rounds included 2D views, Doppler, cardiac output, M-mode measurement, minimum scan numbers, pass-grade criteria. Regarding objective criteria for image-acquisition and image-interpretation quality, the panel agreed on maintaining the same criteria for formative and summative assessment, to categorize BCCE findings as major versus minor and a standardized approach to errors, criteria for readiness for summative assessment and supervisory options. In conclusion, this expert consensus statement presents comprehensive evidence-based recommendations on longitudinal BCCE training. However, they require prospective validation.

Cell-Extrinsic Differentiation Block Mediated by EphA3 in Pre-Leukaemic Thymus Contributes to Disease Progression.

We recently characterised the NUP98-HOXD13 (NHD13) mouse as a model of T-cell pre-leukaemia, featuring thymocytes that can engraft in recipient animals and progress to T-cell acute lymphoblastic leukaemia (T-ALL). However, loss of this engraftment ability by deletion of Lyl1 did not result in any loss of leukemogenesis activity. In the present study, we observe that NHD13 thymocytes overexpress EPHA3, and we characterise thymocyte behaviour in NHD13 mice with deletion of EphA3, which show a markedly reduced incidence of T-ALL. Deletion of EphA3 from the NHD13 mice does not prevent the abnormal accumulation or transplantation ability of these thymocytes. However, upon transplantation, these cells are unable to block the normal progression of recipient wild type (WT) progenitor cells through the normal developmental pathway. This is in contrast to the EphA3+/+ NHD13 thymocytes, which block the progression of incoming WT progenitors past the DN1 stage. Therefore, EphA3 is not critical for classical self-renewal, but is essential for mediating an interaction between the abnormally self-renewing cells and healthy progenitors-an interaction that results in a failure of the healthy cells to differentiate normally. We speculate that this may orchestrate a loss of healthy cell competition, which in itself has been demonstrated to be oncogenic, and that this may explain the decrease in T-ALL incidence in the absence of EphA3. We suggest that pre-leukaemic self-renewal in this model is a complex interplay of cell-intrinsic and -extrinsic factors, and that multiple redundant pathways to leukaemogenesis are active.

Effect of intrapulmonary percussive ventilation on intensive care unit length of stay, the incidence of pneumonia and gas exchange in critically ill patients: A systematic review.

BACKGROUND: Pulmonary complications such as pneumonia, pulmonary atelectasis, and subsequent respiratory failure leading to ventilatory support are a common occurrence in critically ill patients. Intrapulmonary percussive ventilation (IPV) is used to improve gas exchange and promote airway clearance in these patients. The current evidence regarding the effectiveness of intrapulmonary percussive ventilation in critical care settings remains unclear. This systematic review aims to summarise the evidence of the effectiveness of intrapulmonary percussive ventilation on intensive care unit length of stay (ICU-LOS) and respiratory outcomes in critically ill patients. RESEARCH QUESTION: In critically ill patients, is intrapulmonary percussive ventilation effective in improving respiratory outcomes and reducing intensive care unit length of stay. METHODS: A systematic search of intrapulmonary percussive ventilation in intensive care unit (ICU) was performed on five databases from 1979 to 2021. Studies were considered for inclusion if they evaluated the effectiveness of IPV in patients aged ≥16 years receiving invasive or non-invasive ventilation or breathing spontaneously in critical care or high dependency units. Study titles and abstracts were screened, followed by data extraction by a full-text review. Due to a small number of studies and observed heterogeneities in the study methodology and patient population, a meta-analysis could not be included in this review. Outcomes of interest were summarised narratively. RESULTS: Out of 306 identified abstracts, seven studies (630 patients) met the eligibility criteria. Results of the included studies provide weak evidence to support the effectiveness of intrapulmonary percussive ventilation in reducing ICU-LOS, improving gas exchange, and reducing respiratory rate. INTERPRETATION: Based on the findings of this review, the evidence to support the role of IPV in reducing ICU-LOS, improving gas exchange, and reducing respiratory rate is weak. The therapeutic value of IPV in airway clearance, preventing pneumonia, and treating pulmonary atelectasis requires further investigation.

Feasibility and safety of intrapulmonary percussive ventilation in spontaneously breathing, non-ventilated patients in critical care: A retrospective pilot study.

BACKGROUND: Intrapulmonary percussive ventilation is used in various clinical settings to promote secretion clearance, reverse or treat atelectasis and improve gas exchange. Despite a few studies reporting the use of intrapulmonary percussive ventilation in critical care, the available data remain insufficient, contributing to weaker evidence toward its effectiveness. Also, there is a paucity of studies evaluating the safety and feasibility of intrapulmonary percussive ventilation application in critical care. This retrospective pilot study has evaluated the safety and feasibility of intrapulmonary percussive ventilation intervention in non-intubated patients admitted to an intensive care unit. METHODS: The medical records of 35 subjects were reviewed, including 22 subjects who received intrapulmonary percussive ventilation intervention and 13 subjects matched for age, sex, and primary diagnosis who received chest physiotherapy. The records were audited for feasibility, safety, changes in oxygen saturation, chest X-ray changes, and intensive care unit length of stay. RESULTS: A total of 104 treatment sessions (IPV 65 and CPT 39) were delivered to subjects admitted with a range of respiratory conditions in critical care. Subjects completed 97% of IPV sessions. No major adverse events were reported with intrapulmonary percussive ventilation intervention. Intensive care unit length of stay in the intrapulmonary percussive ventilation group was 9.6 ± 6 days, and in the CPT group, it was 11 ± 9 days (p = 0.59). Peripheral oxygen saturation pre to post intervention was 92% ± 4 to 96% ± 4 in IPV group and 95% ± 4 to 95% ± 3 in the CPT group. CONCLUSION: Application of intrapulmonary percussive ventilation intervention was feasible and safe in non-ventilated adult patients in critical care.

Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease.

[Figure: see text].