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Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both [CD8.sup.+] and [CD4.sup.+] CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1[beta] and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights., Introduction Chimeric antigen receptor T cells (CAR T cells) are highly effective against B cell malignancies (1-8) but are frequently associated with cytokine-mediated toxicities or hyperinflammatory conditions (9, 10). The [...]

The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial cochaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in RBC hemoglobinization, and the development of siderocytes and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene., Introduction The congenital sideroblastic anemias (CSAs) are a group of uncommon inherited blood disorders characterized by abnormal iron accumulation in the mitochondria of erythroid cells. As the normal location of [...]

Introduction: Empyema secondary to pneumonia is a common condition. A significant number of patients will require surgical intervention for drainage and decortication. The aim of this study was to identify predictive factors for surgical intervention. Materials and Methods: The medical records of patients who were diagnosed with empyema secondary to pneumonia between the years 2010 and 2019 in a university hospital were included in the study. Patients who underwent surgical intervention were defined as group A and nonoperative treatment as group B. Clinical and laboratory data were collected from medical records and patients' chest computerized tomography (CT) scans were reviewed. Results: A total of 194 patients were included in the study—86 patients were included in group A and 108 patients in group B. Several parameters on admission were found to have a statistically significant correlation with surgical intervention: younger age, higher systolic blood pressure, and elevated white blood count. Multivariant analysis showed that younger age was found to have a statistically significant correlation with operative intervention (adjusted odds ratio = 0.971, P = .023). A statistically significant correlation between surgical intervention and survival (adjusted hazard ratio [HR] = 1.762, P = .046) and an inverse correlation between age and survival (adjusted HR = 0.050, P < .001) were found. Surgical intervention was associated with increased survival irrespective of age. A total of 42 CT scans were available for review. The mean density of the empyema fluid in group A was higher by 4.3 hounsfield units compared to group B (P < .067). Conclusions: Younger age was found to be associated with surgical intervention among patients suffering from empyema secondary to pneumonia. Surgical intervention was associated with increased long-term survival, irrespective of patients' age. Several radiologic characteristics were associated with the need for surgery in this study: empyema fluid density, pleural thickening, and fluid loculations. Additional prospective studies are required to ascertain these results. [ABSTRACT FROM AUTHOR]

Rationale Detecting weaning-induced pulmonary oedema (WIPO) is important because its treatment might prompt extubation. For this purpose, lung ultrasound might be an attractive tool, since it demonstrates pulmonary oedema through the appearance of B-lines. Objectives To test the ideal profile (increase in the number of B-lines) for diagnosing WIPO. Methods Before and at the end of 62 spontaneous breathing trials (SBT) performed in 42 patients, we prospectively assessed lung ultrasound on four anterior chest wall points. B-lines were counted before and at the end of SBT. We looked for the threshold of B-line increase (Delta-B-lines) that provided the best diagnostic accuracy, compared to the reference diagnosis of WIPO established by experts blinded to lung ultrasound. Results SBT failed in 33 cases. WIPO occurred in 17 cases and all failed. The best diagnostic accuracy was reached with a Delta-B-lines [greater than or equal to] 6. Among WIPO, the number of B-lines increased by [greater than or equal to] 6 in 15 cases (including 13 cases with an increase of [greater than or equal to] 8 B-lines). Among the 16 cases with SBT failure but without WIPO, the Delta-B-lines was [greater than or equal to] 6 in two cases. Among the 33 cases with SBT failure, this profile diagnosed WIPO with a sensitivity of 88% (64-98) and a specificity of 88% (62-98) [area under the receiver operating characteristic curve 0.91 (0.75-0.98)]. Among the 29 cases with SBT success, a Delta-B-lines [greater than or equal to] 6 occurred in two cases. Conclusions This study suggests that a Delta-B-lines [greater than or equal to] 6 on four anterior points allows the diagnosis of WIPO with the best accuracy. This should be confirmed in larger populations., Author(s): Alexis Ferré [sup.1] [sup.2], Max Guillot [sup.1] [sup.2], Daniel Lichtenstein [sup.3], Gilbert Mezière [sup.4], Christian Richard [sup.1] [sup.2], Jean-Louis Teboul [sup.1] [sup.2], Xavier Monnet [sup.1] [sup.2] Author Affiliations: (1) [...]

Purpose Imaging has become increasingly important across medical specialties for diagnostic, monitoring, and investigative purposes in acute respiratory distress syndrome (ARDS). Methods This review addresses the use of imaging techniques for the diagnosis and management of ARDS as well as gaining knowledge about its pathogenesis and pathophysiology. The techniques described in this article are computed tomography, positron emission tomography, and two easily accessible imaging techniques available at the bedside-ultrasound and electrical impedance tomography (EIT). Results The use of computed tomography has provided new insights into ARDS pathophysiology, demonstrating that ARDS does not homogeneously affect the lung parenchyma and that lung injury severity is widely distributed in the ARDS population. Positron emission tomography is a functional imaging technique whose value resides in adding incremental insights to morphological imaging. It can quantify regional perfusion, ventilation, aeration, lung vascular permeability, edema, and inflammation. Lung ultrasound and EIT are radiation-free, noninvasive tools available at the bedside. Lung ultrasound can provide useful information on ARDS diagnosis when x-rays or CT scan are not available. EIT is a useful tool to monitor lung ventilation and to assess the regional distribution of perfusion. Conclusions The future of imaging in critical care will probably develop in two main directions: easily accessible imaging techniques that can be used at the bedside and sophisticated imaging methods that will be used to aid in difficult diagnostic cases or to advance our understanding of the pathogenesis and pathophysiology of an array of critical illnesses., Author(s): Antonio Pesenti [sup.1] [sup.2], Guido Musch [sup.3], Daniel Lichtenstein [sup.4], Francesco Mojoli [sup.5] [sup.6], Marcelo B. P. Amato [sup.7], Gilda Cinnella [sup.8], Luciano Gattinoni [sup.9], Michael Quintel [sup.9] Author [...]

Author(s): Joao Santos-Silva [sup.1] , Daniel Lichtenstein [sup.2] , Pieter R. Tuinman [sup.3] , Paul W. G. Elbers [sup.3] Author Affiliations: (1) Intensive Care Unit, Hospital Santa Maria, Centro Hospitalar [...]

Author(s): Daniel Lichtenstein [sup.1], Gemma Rialp [sup.2] Author Affiliations: (1) 0000 0000 9982 5352, grid.413756.2, Intensive Care Unit, Hôpital Ambroise-Paré, , Boulogne (Paris-Ouest), France (2) grid.413457.0, Intensive Care Department, Hospital [...]

Objectives: Lung ultrasound has shown increasing diagnostic value in many lung diseases and has become an efficient tool in the management of dyspnea. In the present case report, we describe a new ultrasound feature of potential interest.Data Sources: Clinical observation of a patient.Study Selection: Case report.Data Extraction: Data were extracted from medical records, after obtaining consent from the patient's family. Illustrations were extracted from the imaging software and a video device.Data Synthesis: A 56-year-old man was admitted with pneumonia of adverse outcome. Lung ultrasound, a method increasingly considered as a bedside gold standard in critically ill patients due to its overwhelming advantages, was the only tool able to specify the lung injuries. We describe herein a distinctive sign unequivocally evoking a destructive process suggestive of pulmonary gangrene, a variant of the fractal sign combining a lung consolidation with an underlying heterogeneous free fluid.Conclusions: Lung ultrasound may help highlight pulmonary gangrene, a poorly-known disease, with this new ultrasonographic description. The next step will be to ascertain the relation between this new ultrasound feature and pulmonary gangrene and to assess how this bedside diagnosis could impact the prognosis of the disease. [ABSTRACT FROM AUTHOR]

Background: Dengue, chikungunya, and Zika are arboviruses of major global health concern. Decisions regarding the clinical management of suspected arboviral infection are challenging in resource-limited settings, particularly when deciding on patient hospitalization. The objective of this study was to determine if hospitalization of individuals with suspected arboviral infections could be predicted using subject intake data. Methodology/Principal findings: Two prediction models were developed using data from a surveillance study in Machala, a city in southern coastal Ecuador with a high burden of arboviral infections. Data were obtained from subjects who presented at sentinel medical centers with suspected arboviral infection (November 2013 to September 2017). The first prediction model—called the Severity Index for Suspected Arbovirus (SISA)—used only demographic and symptom data. The second prediction model—called the Severity Index for Suspected Arbovirus with Laboratory (SISAL)—incorporated laboratory data. These models were selected by comparing the prediction ability of seven machine learning algorithms; the area under the receiver operating characteristic curve from the prediction of a test dataset was used to select the final algorithm for each model. After eliminating those with missing data, the SISA dataset had 534 subjects, and the SISAL dataset had 98 subjects. For SISA, the best prediction algorithm was the generalized boosting model, with an AUC of 0.91. For SISAL, the best prediction algorithm was the elastic net with an AUC of 0.94. A sensitivity analysis revealed that SISA and SISAL are not directly comparable to one another. Conclusions/Significance: Both SISA and SISAL were able to predict arbovirus hospitalization with a high degree of accuracy in our dataset. These algorithms will need to be tested and validated on new data from future patients. Machine learning is a powerful prediction tool and provides an excellent option for new management tools and clinical assessment of arboviral infection. Author summary: Patient triage is a critical decision for clinicians. Patients with suspected arbovirus infection are difficult to diagnose as symptoms can be vague and molecular testing can be expensive or unavailable. Determining whether these patients should be hospitalized or not can be challenging, especially in resource-limited settings. Our study included data from 543 subjects with a diagnosis of suspected dengue, chikungunya, or Zika infection. Using a machine learning approach, we tested the ability of seven algorithms to predict hospitalization status based on the signs, symptoms, and laboratory data that would be available to a clinician at patient intake. Using only signs and symptoms, we were able to predict hospitalization with high accuracy (94%). Including laboratory data also resulted in highly accurate prediction of hospitalization (92%). This tool should be tested in future studies with new subject data. Upon further development, we envision a simple mobile application to aid in the decision-making process for clinicians in areas with limited resources. [ABSTRACT FROM AUTHOR]

The article analyzes misconceptions associated with ultrasound of lung. It is stated that lung ultrasound can diagnose almost everything and bedside lung ultrasound in an emergency (BLUE) protocol helps refine its cause. We noted that some authors define interstitial syndrome as comet-tail artifact through using standardized criteria. It also discusses correlation between lung rockets and radiologic alveolar-interstitial syndrome.

Point-of-care ultrasound is increasingly used at the bedside to integrate the clinical assessment of the critically ill; in particular, lung ultrasound has greatly developed in the last decade. This review describes basic lung ultrasound signs and focuses on their applications in critical care. Lung semiotics are composed of artifacts (derived by air/tissue interface) and real images (i.e., effusions and consolidations), both providing significant information to identify the main acute respiratory disorders. Lung ultrasound signs, either alone or combined with other point-of-care ultrasound techniques, are helpful in the diagnostic approach to patients with acute respiratory failure, circulatory shock, or cardiac arrest. Moreover, a semiquantification of lung aeration can be performed at the bedside and used in mechanically ventilated patients to guide positive end-expiratory pressure setting, assess the efficacy of treatments, monitor the evolution of the respiratory disorder, and help the weaning process. Finally, lung ultrasound can be used for early detection and management of respiratory complications under mechanical ventilation, such as pneumothorax, ventilator-associated pneumonia, atelectasis, and pleural effusions. Lung ultrasound is a useful diagnostic and monitoring tool that might in the near future become part of the basic knowledge of physicians caring for the critically ill patient. [ABSTRACT FROM AUTHOR]

This review article shows the potential of lung ultrasound in the critically ill (LUCI) to study lung sliding and describes the optimal equipment for its assessment. Then, it analyses the integration of lung sliding within lung ultrasound then whole body critical ultrasound. It describes the place of lung sliding in the BLUE-protocol (bedside lung ultrasound in emergency) (lung and venous ultrasound for diagnosing acute respiratory failure), the FALLS-protocol (fluid administration limited by lung sonography) (the role of lung sliding in circulatory failure), and the SESAME-protocol (sequential assessment of sonography assessing mechanism or origin of severe shock of indistinct cause) (whole body ultrasound in cardiac arrest). In the LUCIFLR project (LUCI favoring limitation of radiations), the consideration of lung sliding allows drastic reduction in irradiation and costs. In conclusion, lung sliding is proposed as a gold standard for indicating the presence of the lung at the chest wall and its correct expansion. [ABSTRACT FROM AUTHOR]

The most critical application of critical ultrasound - cardiac arrest - is the opportunity for technical considerations. The necessity to immediately detect reversible causes is integrated in the concept of holistic ultrasound. Holistic ultrasound is defined as a discipline where each element interacts with the others, and where the understanding of each of them allows understanding the whole. A narrow machine (not necessarily a laptop), a fast start-on time, a simple keyboard highlighting three useful buttons, a universal microconvex probe able to immediately detect pneumothorax, then deep venous thrombosis, then abdominal bleeding, then pericardial tamponade, then cardiac anomalies will allow a fast protocol. The concept of holistic ultrasound is particularly on focus in the first step done at the lung (search for pneumothorax and clearance for fluid therapy), since the best image is obtained with the simplest equipment devoid of traditional facilities (image filtering, harmonics, time lag, Doppler...). The same simple gray-scale equipment is used for the other steps, all what is needed is to see the real-time image of what is facing the probe: the very principle of visual medicine. The same approach can be used with no change, just more quietly, for many less urgent settings. [ABSTRACT FROM AUTHOR]

Lung ultrasound is a bedside noninvasive method allowing immediate assessment of most disorders impairing the function of this vital organ. Although little used for decades, lung ultrasound provides standardized and reproducible information, using a simple small grayscale hybrid unit (such as the one we have used since 1992, but 1982 machines have also proved excellent for this task). All of our work has described and assessed signs using computed tomography (CT) as a reference, demonstrating a high correlation between both tests. Considering the normal pattern and the main diagnoses, i.e., inter- stitial syndrome, pneumothorax, alveolar consolidation and pleural effusion, the control of no more than 10 signs provides a multitude of combinations allowing critical applications: accurate diagnosis of acute respiratory failure (a cyanotic patient, sometimes said to be undergoing the ‘blue protocol''), assessing thoracic pain from pleural or lung cause, safe management of chest tube insertion or thoracentesis, assessment of acute respiratory distress syndrome or trauma patients without need for transportation to CT, management of critically ill neonates, implementation of this discipline from sophisticated intensive care units to austere areas of the world, or hyper-sophisticated but remote areas (i.e., spacecraft). The combination of lung ultrasound with other critical targets like the venous system (the blue protocol) makes ultrasound a tool for visual medicine. Lung ultrasound can, with the same very simple material, be combined with other areas (heart, abdomen, etc.), providing a transparent overview of the critically ill. A new discipline can originate from the integration of lung and whole body ultrasound into traditional critical care. The training, if done in authorized training centers, is a minor problem, since lung ultrasound is far more accessible than fields such as cardiology or obstetrics. Our material makes lung ultrasound easy to perform with short training. Lung ultrasound has a role in nearly one half of clinical disciplines in medicine (pediatrics, pulmonology, family medicine, etc.), resulting in cost savings, relief from irradiation, and major simplification of the daily problems encountered when managing extreme health emergencies. [Copyright &y& Elsevier]

The article focuses on the statement from the Critical Network of the American College of Chest Physicians (ACCP) with its partner, defining the competence in critical care ultrasonography (CCUS). Accordingly, CCUS may be divided into thoracic, vascular, abdominal and echocardiography, and intensivists should have special skills in each component for them to be competent. It states that the statement will guide intensivists in achieving proficiency on the minimum standard for CCUS.

The lung is a vital organ. Although often deemed of limited value at this area, ultrasound proves its ability in detecting the main disorders that affect the critically ill. Pleural effusion, alveolar consolidation, interstitial syndrome, pneumothorax and other are assessed. The clinical relevance of these findings, especially detecting interstitial syndrome in a dyspneic patient or the use of interventional ultrasound are then envisaged. Outcomes like the possibility of decreasing medical radiation doses or cost-savings are viewed. Used like a visual stethoscope, ultrasound highlights the lungs together with the heart, making the thorax a whole for the intensivist. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Striae are a common cosmetic problem with no effective treatment options. A recent study has shown improvement in the appearance of mature striae following a single 585-nm pulsed dye laser (PDL) treatment at low fluence. OBJECTIVE: To evaluate the effectiveness of treating mature striae with the 585-nm PDL. METHODS: Five patients with mature striae on the abdomen were prospectively treated with the 585-nm PDL at 2-month intervals for 1-2 years. The response of the striae to laser treatment was evaluated in each patient through sequential clinical, photographic, textural, and histologic assessment. RESULTS: All five patients reported a slight overall improvement in the appearance of the striae following multiple PDL treatments. Comparison of pre- and post-treatment photographs, however, failed to reveal improvement in any patients. Optical profilometry performed on striae impressions showed mild improvement in the surface texture of striae in three patients. Histologic comparison of pre- and post-treatment biopsy specimens failed to reveal normalization of skin architecture. CONCLUSIONS: Serial treatment of mature striae with the PDL results in mild, subjective, clinical improvement but no significant photographic, textural or histologic improvement. [ABSTRACT FROM AUTHOR]