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Lymphangiomyomatosis is a member of the PEComa family, and usually involves the pulmonary parenchyma of middle-aged females. Infrequently, it may involve abdominal and retroperitoneal lymph nodes, and rarely it has been described to be associated with fallopian tube-type ciliated epithelium co-existing in one neoplasm. To increase our understanding of this unusual tumor, we describe the morphology and genetics of one case and review the literature. We present the case of a 50-year-old female found to have 12.5 and 7.7 cm cystic retroperitoneal masses, describe its unique pathological features and review the literature on the previously reported cases. Based on its unique morphological, immunohistochemical, and molecular features we propose the term adenoPEComa to represent this entity. This case represents a rare example of adenoPEComa with lymphangiomyomatosis of the lymph nodes. It is the first example that has undergone next-generation sequencing revealing a mutation in TSC2 making it a confirmed member of the PEComa family of tumors.

PDF file - 107K, Figure S1: (A) Experimental setup. (B) Beam steering pattern used during volumetric sonication. The order of the nine "subsonications" is indicated. (C) Pulsing scheme used during volumetric sonication. Three 50 s sonications were delivered with a 25 s pause between sonications. During each sonication, 10 ms bursts were delivered to the nine locations in sequence, typically every 200 ms

PDF file - 130K, Figure S3: MRI and histological effects of sonication delivered at an exposure level that produced tissue damage in addition to BBB disruption. (A) T2*-weighted imaging after volumetric sonication (nine locations in a 3�3 grid) in the thalamus at 249 kPa. At three of the nine sonicated locations, severe hypointense spots were observed in T2*-weighted imaging, and they were persistent for the next six months (B) Microphotograph of an H&E stained section showing parenchymal damage (box) evident six months after sonication. Macrophage accumulation and scattered brownish granules (hemosiderin deposits, arrows) are also evident. (C-D) High-magnification view of hemosiderin deposits from another part of this sonicated region. Prussian blue staining (D) was used to verify that the light brown clusters evident in H&E were hemosiderin (B-C: H&E; D: Prussian blue; scale bars: B: 100 Mum; C-D: 20 Mum)

Figure S1 EAC has ligand dependent activation of Notch. Figure S2 Activations of Notch were elevated in esophageal adenocarcinoma cell lines. Figure S3 Activation of Notch signaling promotes proliferation of EAC cells. Figure S4 EAC derived tumor spheres display characteristics of cancer stem cells. Table S1 Active NOTCH signaling is associated with poor prognosis in EAC.

Supplementary Figures 1-9 - Germline mutation of Brca1 transforms p18-deficient luminal tumors into basal-like tumors with induction of EMT (Suppl. Fig. 1); Germline mutation of Brca1 activates EMT-TFs in mammary and tumor development (Suppl. Fig. 2); Specific deletion of Brca1 in mammary epithelia impairs luminal differentiation (Suppl. Fig. 3); Haploid loss of Brca1 in mammary epithelium inhibits the expression of luminal genes but stimulates the expression of basal genes and EMT-TFs in p18 deficient LSCs (Suppl. Fig. 4); Ck5 and Ck8 double positive epithelial cells are frequently detected in p18-/-;Brca1f/-;MC mammary glands (Suppl. Fig. 5); Characterization of human breast cancer cell lines (Suppl. Fig. 6); BRCA1 inhibits the expression of TWIST and FOXC2 in 293T cells (Suppl. Fig. 7); Knockdown of BRCA1 in T47D cells activates EMT (Suppl. Fig. 8); BRCA1 and TWIST mRNA levels are inversely correlated in human claudin-low type breast cancers (Suppl. Fig. 9).

PDF file - 349K, Figure S2: Histology after volumetric sonication in the hippocampus/LGN in monkey 4. This target was sonicated ~2h before the animal was sacrificed and in seven prior sessions over several months. (A) Contrast-enhanced T1-weighted MRI showing BBB disruption. The region with contrast enhancement is indicated (red dotted line). Inset: Low-magnification microphotograph showing histology in the hippocampus/LGN. The approximate location of this section is indicated in the MR image by the white rectangle. (B) Low- and (C) high-magnification views of the LGN showing normal cell layers and undamaged nerve fibers, respectively. (D) Low and (E) high-magnification views showing normal-appearing granular cell layer of hippocampus. (F): Small capillaries in the LGN found with a few extravasated red blood cells, presumably from the last sonication session. Only a very small number of such extravasations were found. (B, F: H&E; C: H&E-LFB D, E: Nissl; scale bars: A: 1 cm, B, D: 1 mm, C,E-F: 200 Mum)

Legends for Supplementary Figures 1-9.

PDF file - 75K, Supplementary Methods including focused ultrasound system calibration, USCA infusion protocol and MRI sequences

During natural vision, primates shift their gaze several times per second with large, ballistic eye movements known as saccades. Open questions remain as to whether visual neurons retain their classical retinotopic response properties during natural vision or whether neurons integrate information across fixations and predict the consequences of impending saccades. Answers are especially wanting for vision in complex scenes relevant to natural behavior. We let 13 monkeys freely view thousands of large natural images, recorded over 883 hours of neuronal responses throughout the ventral visual pathway across 4.7 million fixations, and designed flexible analyses to reveal the spatial, temporal, and feature selectivity of the responses. Ventral visual responses followed each fixation and did not become gaze-invariant as monkeys examined an image over seconds. Computational models revealed that neuronal responses corresponded to eye-centered receptive fields. The results suggest that ventral visual cortex remains predominantly retinotopic during natural vision and does not establish a gaze-independent representation of the world.

Previous studies showed that baby monkeys separated from their mothers develop strong and lasting attachments to inanimate surrogate mothers, but only if the surrogate has a soft texture; soft texture is more important for the infant’s attachment than is the provision of milk. Here I report that postpartum female monkeys also form strong and persistent attachments to inanimate surrogate infants, that the template for triggering maternal attachment is also tactile, and that even a brief period of attachment formation can dominate visual and auditory cues indicating a more appropriate target.

How does the brain encode information about the environment? Decades of research have led to the pervasive notion that the object-processing pathway in primate cortex consists of multiple areas that are each specialized to process different object categories (such as faces, bodies, hands, non-face objects and scenes). The anatomical consistency and modularity of these regions have been interpreted as evidence that these regions are innately specialized. Here, we propose that ventral-stream modules do not represent clusters of circuits that each evolved to process some specific object category particularly important for survival, but instead reflect the effects of experience on a domain-general architecture that evolved to be able to adapt, within a lifetime, to its particular environment. Furthermore, we propose that the mechanisms underlying the development of domains are both evolutionarily old and universal across cortex. Topographic maps are fundamental, governing the development of specializations across systems, providing a framework for brain organization.

To prospectively assess intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL) using single voxel spectroscopy (SVS) and multi voxel magnetic resonance spectroscopy (MVS) in soleus muscle and correlate results with metabolic variables in non-obese (BMI

Systemic inflammation is a hallmark of severe coronavirus disease-19 (COVID-19). Anti-inflammatory therapy is considered crucial to modulate the hyperinflammatory response (cytokine storm) in hospitalized COVID-19 patients. There is currently no specific, conclusively proven, cost-efficient, and worldwide available anti-inflammatory therapy available to treat COVID-19 patients with cytokine storm. The present study aimed to investigate the treatment benefit of oral colchicine for hospitalized COVID-19 patients with suspected cytokine storm. Colchicine is an approved drug and possesses multiple anti-inflammatory mechanisms. This was a pilot, open-label randomized controlled clinical trial comparing standard of care (SOC) plus oral colchicine (colchicine arm) vs. SOC alone (control arm) in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. Colchicine treatment was initiated within first 48 hours of admission delivered at 1.5 mg loading dose, followed by 0.5 mg b.i.d. for next 6 days and 0.5 mg q.d. for the second week. A total of 96 patients were randomly allocated to the colchicine (n=48) and control groups (n=48). Both colchicine and control group patients experienced similar clinical outcomes by day 14 of hospitalization. Treatment outcome by day 14 in colchicine vs control arm: recovered and discharged alive: 36 (75.0%) vs. 37 (77.1%), remain admitted after 14-days: 4 (8.3%) vs. 5 (10.4%), ICU transferred: 4 (8.3%) vs. 3 (6.3%), and mortality: 4 (8.3%) vs. 3 (6.3%). The speed of improvement of COVID-19 acute symptoms including shortness of breath, fever, cough, the need of supplementary oxygen, and oxygen saturation level, was almost identical in the two groups. Length of hospitalization was on average 1.5 day shorter in the colchicine group. There was no evidence for a difference between the two groups in the follow-up serum levels of inflammatory biomarkers including C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), ferritin, interleukin-6 (IL-6), high-sensitivity troponin T (hs-TnT) and N-terminal pro b-type natriuretic peptide (NT pro-BNP). According to the results of our study, oral colchicine does not appear to show clinical benefits in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. It is possible that the anti-inflammatory pathways of colchicine are not crucially involved in the pathogenesis of COVID-19.

Unfolded protein response (UPR) protects malignant cells from endoplasmic reticulum stress-induced apoptosis. We report that Aurora kinase A (AURKA) promotes cancer cell survival by activating UPR in esophageal adenocarcinoma (EAC). A strong positive correlation between AURKA and binding immunoglobulin protein (BIP) mRNA expression levels was found in EACs. The in vitro assays indicated that AURKA promoted IRE1α protein phosphorylation, activating prosurvival UPR in FLO-1 and OE33 cells. The use of acidic bile salts to mimic reflux conditions in patients induced high AURKA and IRE1α levels. This induction was abrogated by AURKA knockdown in EAC cells. AURKA and p-IRE1α protein colocalization was observed in neoplastic gastroesophageal lesions of the L2-IL1b mouse model of Barrett’s esophageal neoplasia. The combined treatment using AURKA inhibitor and tunicamycin synergistically induced cancer cell death. The use of alisertib for AURKA inhibition in the EAC xenograft model led to a decrease in IRE1α phosphorylation with a significant reduction in tumor growth. These results indicate that AURKA activates UPR, promoting cancer cell survival during ER stress in EAC. Targeting AURKA can significantly reverse prosurvival UPR signaling mechanisms and decrease cancer cell survival, providing a promising approach for the treatment of EAC patients.

The evolution and development of anatomical–functional relationships in the cerebral cortex is of major interest in neuroscience. Here, we leveraged the fact that a functional region selective for visual scenes is located within a sulcus in the medial ventral temporal cortex (VTC) in both humans and macaques to examine the relationship between sulcal depth and place selectivity in the medial VTC across species and age groups. To do so, we acquired anatomical and functional magnetic resonance imaging scans in 9 macaques, 26 human children, and 28 human adults. Our results revealed a strong structural–functional coupling between sulcal depth and place selectivity across age groups and species in which selectivity was strongest near the deepest sulcal point (the sulcal pit). Interestingly, this coupling between sulcal depth and place selectivity strengthens from childhood to adulthood in humans. Morphological analyses suggest that the stabilization of sulcal–functional coupling in adulthood may be due to sulcal deepening and areal expansion with age as well as developmental differences in cortical curvature at the pial, but not the white matter surfaces. Our results implicate sulcal features as functional landmarks in high-level visual cortex and highlight that sulcal–functional relationships in the medial VTC are preserved between macaques and humans despite differences in cortical folding.

Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8+ T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM., Uveal melanoma is highly metastatic and unresponsive to checkpoint immunotherapy. Here, the authors present single-cell transcriptomics of 59,915 cells in 8 primary and 3 metastatic samples, highlighting the diversity of the tumour microenvironment.

Corpus callosum (CC) is the largest commissural white matter bundle in the brain, responsible for the integration of information between hemispheres. Reduction in the size of the CC structure has been predominantly reported in children with autism spectrum disorder (ASD) compared to typically developing children (TD). However, most of these studies are based on high-functioning individuals with ASD but not on an inclusive sample of individuals with ASD with varying abilities. Our current study aimed to examine the CC morphometry between children with ASD and TD in the Indian population. We also compared CC morphometry in autistic children with autism severity, verbal IQ (VIQ) and full-scale IQ (FSIQ). T1-weighted structural images were acquired using a 3T MRI scanner to examine the CC measures in 62 ASD and 17 TD children. The length and height of the CC and the width of genu were decreased in children with ASD compared to TD. There was no significant difference in CC measures based on autism severity, VIQ or FSIQ among children with ASD. To our knowledge, this is the first neuroimaging study to include a significant number (n = 56) of low-functioning ASD children. Our findings suggest the atypical interhemispheric connectivity of CC in ASD.

Neoadjuvant chemotherapy (NAC) ± radiation (NRT) is the “gold standard” approach for locally advanced esophageal cancer (EC). However, the benefits of RT on overall survival (OS) in patients with resectable EC undergoing neoadjuvant therapy followed by esophagectomy remain controversial. The National Cancer Data Base was queried for patients with nonmetastatic EC between 2004 and 2014. Kaplan–Meier, log-rank, and Cox multivariable regression analysis were performed to analyze OS. Logistic regression analyzed factors associated with 90-day mortality, lymph node involvement, and complete pathological response (pCR). A total of 12,238 EC patients who underwent neoadjuvant therapy [neoadjuvant chemoradiation (NACR), 92.1% and NAC, 7.9%] followed by esophagectomy were included. OS was similar in patients undergoing NAC ± RT (35.9 vs. 37.6 mo, respectively, p = 0.393). pCR rate was 18.1% (19.2%, NACR vs. 6.3%, NAC, p

OBJECTIVE: To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy. BACKGROUND: Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown. METHODS: Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19–9 decrease ≥50% vs

Esophageal gastrointestinal stromal tumors (E-GIST) and leiomyosarcoma (E-LMS) are rare tumors. Previous studies are limited to small number of patients. We sought to study these two tumors using a large national database.The National Cancer Data Base 2004-2014 was queried for patients with E-GIST and E-LMS. The primary outcome was overall survival (OS). Univariate and multivariable Cox regression models were used to investigate OS predictors.We found 141 E-GIST and 38 E-LMS patients, with esophagectomy and systemic treatment rate of 55% and 49% for E-GIST and 50% and 26% for E-LMS. The 5-year OS of E-GIST and E-LMS were 62% and 23%, respectively, p 0.001. In multivariable analysis, young age, tumor10 cm, esophagectomy, and E-GIST were associated with superior OS. There was a higher median and mean OS with neoadjuvant vs. upfront surgery for E-GIST group (98 and 111 vs 79 and 80 months).E E-GIST has superior OS compared to E-LMS. Esophagectomy is the cornerstone treatment modality. Further studies are needed to evaluate the role of neoadjuvant therapy in E-GIST patients.

Background: Fluoroscopy-guided interventions can potentially increase radiation risk to patients, if awareness on angiographic imaging technique and radiation dose is neglected. Aim: To develop patient radiation dose reference card from standardized imaging techniques for various radiology interventions performed using flat detector based angiography system. Materials and Methods: Real-time monitoring of angiographic exposure parameters and radiation dose were performed for 16 types of radiological interventions. Effective dose (ED) was estimated from dose area product (DAP) using PCXMC Monte Carlo simulation software. Radiation risk levels were estimated based on Biological Effects of Ionising radiation (BEIR) report VII predictive models for an Asian population. Results: Pulse rates of 7.5 pps and 0.6 mm Copper filtration during fluoroscopy and 4 frames per second (fps) and 0.1-0.3 mm Cu filtration during image acquisitions were found to reduce radiation dose. Owing to increased number of image acquisitions, DAP was highest during diagnostic spinal angiography 186.7 Gycm2 (44.0–377.5). This resulted in highest ED of 59.4 mSv with moderate risk levels (1 in 1000 to 1 in 500). Most of the radiological interventions had low radiation risk levels (1 in 10,000 to 1 in 1000). Conclusion: The patient radiation dose reference card is valuable to the medical community and can aid in patient counselling on radiation induced risk from radiological interventions.

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

With improved responses to chemotherapy and targeted treatments, the role of surgery in metastatic gastric cancer (MGC) to the liver needs to be revisited. We sought to examine whether surgical resection is associated with improvement of long-term survival.The National Cancer Database was queried for MGC to the liver (2010-2014). Survival analysis was performed to compare the effect of gastrectomy and perioperative chemotherapy (G-CT) to palliative chemotherapy (PCT) alone.We identified 3175 patients with MGC to the liver. Most patients (94%, n = 2979) were treated with PCT, whereas 6% (n = 196 patients) underwent G-CT. Overall survival improved in patients treated with G-CT compared to PCT alone (16 versus 9.7 mo, P 0.001). In patients undergoing G-CT, neoadjuvant chemotherapy was associated with increased overall survival compared to adjuvant chemotherapy (18.9 versus 14.8 mo, P = 0.011). Hazards of death significantly decreased with gastrectomy (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.44-0.63, P 0.001). Negative prognostic factors included advanced age (HR: 1.10, 95% CI: 1.06-1.14, P 0.001), treatment at nonacademic institution (HR: 1.23, 95% CI: 1.13-1.33, P 0.001), and poorly differentiated grade (HR: 1.54, 95% CI: 1.17-2.03, P 0.001).G-CT is associated with improved survival in patients with gastric cancer and synchronous liver metastasis. Further experience with well-designed prospective trials may be warranted to confirm these findings.

Primate cerebral cortex is highly convoluted with much of the cortical surface buried in sulcal folds. The origins of cortical folding and its functional relevance has been a major focus of systems and cognitive neuroscience. Stereotyped patterns of cortical folding across individuals and multiple primate species indicate common evolutionary pressures in their development. However, foundational questions regarding organizing principles shared across species remain unanswered. Taking a cross-species comparative approach with a careful consideration of historical observations, we investigate cortical folding within the calcarine sulcus, a primary fold in primates. We identify two macroanatomical structures – the retrocalcarine and external calcarine sulci – in 24 humans and 6 macaque monkeys. We show that within species, these sulci are identifiable in all individuals, fall on a similar part of the V1 retinotopic map, and thus, serve as anatomical landmarks predictive of functional organization. Yet, across species, the actual underlying visual field representations differ strikingly across humans and macaques. Thus, the structure-function correspondence for an evolutionarily old structure like V1 is species-specific and suggests intriguing differences in developmental constraints across primates.

Primate cerebral cortex is highly convoluted with much of the cortical surface buried in sulcal folds. The origins of cortical folding and its functional relevance have been a major focus of systems and cognitive neuroscience, especially when considering stereotyped patterns of cortical folding that are shared across individuals within a primate species and across multiple species. However, foundational questions regarding organizing principles shared across species remain unanswered. Taking a cross-species comparative approach with a careful consideration of historical observations, we investigate cortical folding relative to primary visual cortex (area V1). We identify two macroanatomical structures—the retrocalcarine and external calcarine sulci—in 24 humans and 6 macaque monkeys. We show that within species, these sulci are identifiable in all individuals, fall on a similar part of the V1 retinotopic map, and thus, serve as anatomical landmarks predictive of functional organization. Yet, across species, the underlying eccentricity representations corresponding to these macroanatomical structures differ strikingly across humans and macaques. Thus, the correspondence between retinotopic representation and cortical folding for an evolutionarily old structure like V1 is species-specific and suggests potential differences in developmental and experiential constraints across primates.

Yttrium-90 (Y-90) trans-arterial radioembolization (TARE) is used in the management of unresectable hepatocellular carcinoma (HCC). During the last 5 years, dosimetry software has been developed to allow for a more rigorous approach of dose prescription in Y-90 TARE. We present here a case study of a 77-year-old woman diagnosed with HCC, who underwent a Y-90 TARE as a bridge procedure to liver resection. This clinical scenario represents a unique opportunity to illustrate the predictive value of dosimetric findings correlating dosimetry with pathological findings. In this case, Y-90 TARE dosimetry was predictive of treatment response in which the tumor received a mean dose of 156 Gy and demonstrated a complete pathologic response.

Background Refractory cardiogenic shock (CS), frequently complicated by pulmonary failure, often requires veno-arterial extracorporeal membrane oxygenation (VA-ECMO) to sustain end-organ perfusion. Currently available animal models, such as the coronary ligation model, result in highly variable injury profiles and unacceptably high levels of subsequent ventricular fibrillation, cardiac arrest, and death. As the use of ECMO increases, there is a growing need for a clinically relevant, robust, and titratable model of severe cardiopulmonary failure supported by VA-ECMO. Methods Six sheep (60 ± 6 kg) were anaesthetized, intubated and mechanically ventilated. VA-ECMO was initially carried out at a flow rate of 1 L/min. CS was induced through 1-mL left ventricle myocardial injections of 96% ethanol and confirmed when systolic blood pressure (SBP) was 4 mmol/L. Then, pulmonary failure was confirmed when PaO2 was

The acute respiratory distress syndrome (ARDS) is a severe lung disorder with a high morbidity and mortality which affects all age groups. Despite active research with intense, ongoing attempts in developing pharmacological agents to treat ARDS, its mortality rate remains unaltered high and treatment is still only supportive. Over the years, there have been many attempts to identify meaningful subgroups likely to react differently to treatment among the heterogenous ARDS population, most of them unsuccessful. Only recently, analysis of large ARDS cohorts from randomized controlled trials have identified the presence of distinct biological subphenotypes among ARDS patients: a hypoinflammatory (or uninflamed; named P1) and a hyperinflammatory (or reactive; named P2) subphenotype have been proposed and corroborated with existing retrospective data. The hyperinflammatory subphenotyope was clearly associated with shock state, metabolic acidosis, and worse clinical outcomes. Core features of the respective subphenotypes were identified consistently in all assessed cohorts, independently of the studied population, the geographical location, the study design, or the analysis method. Additionally and clinically even more relevant treatment efficacies, as assessed retrospectively, appeared to be highly dependent on the respective subphenotype. This discovery launches a promising new approach to targeted medicine in ARDS. Even though it is now widely accepted that each ARDS subphenotype has distinct functional, biological, and mechanistic differences, there are crucial gaps in our knowledge, hindering the translation to bedside application. First of all, the underlying driving biological factors are still largely unknown, and secondly, there is currently no option for fast and easy identification of ARDS subphenotypes. This narrative review aims to summarize the evidence in biological subphenotyping in ARDS and tries to point out the current issues that will need addressing before translation of biological subohenotypes into clinical practice will be possible.

OBJECTIVES Early detection of bleeding into a joint is crucial in patients with haemophilia. This study was designed to evaluate the sensitivity of ultrasonography (USG) and magnetic resonance imaging (MRI) to detect the presence of blood in small concentrations in a simulated model to mimic joint bleeding. MATERIALS AND METHODS Different concentrations of blood in plasma, varying from 0.1% to 45%, were collected in 10-ml plastic syringes and imaged using 12 and 18 MHz USG transducers and with 1.5T and 3T MRI scanners, at different intervals of time following dilution. The images were scored for the presence of blood by four experienced radiologists who were blinded to the concentration of blood. RESULTS Within the first 2 h, the 18 MHz transducer was able to detect blood consistently up to 0.5%, whereas the 12 MHz transducer could consistently identify blood up to 1.4%. After the first 12 h, both transducers were able to detect blood up to 0.5% concentration. However, at concentrations below 0.5%, there was discordance in the ability to detect blood, with both transducers. There was no correlation between the signal intensities of MRI images and concentration of blood, at different time intervals, irrespective of the magnetic field strength. CONCLUSIONS Detection of blood using the USG is dependent on variables such as the concentration of blood, frequency of the transducer used and timing of the imaging. As the concentration of blood decreases below 0.5%, the discordance between the observers increases, implying that the detection limit of USG affects its reliability at lower concentrations of blood. Caution is urged while interpreting USG imaging studies for the detection of blood in symptomatic joints.

The acute respiratory distress syndrome (ARDS) is a severe lung disorder with a high morbidity and mortality which affects all age groups. Despite active research with intense, ongoing attempts in developing pharmacological agents to treat ARDS, its mortality rate remains unaltered high and treatment is still only supportive. Over the years, there have been many attempts to identify meaningful subgroups likely to react differently to treatment among the heterogenous ARDS population, most of them unsuccessful. Only recently, analysis of large ARDS cohorts from randomized controlled trials have identified the presence of distinct biological subphenotypes among ARDS patients: a hypoinflammatory (or uninflamed; named P1) and a hyperinflammatory (or reactive; named P2) subphenotype have been proposed and corroborated with existing retrospective data. The hyperinflammatory subphenotyope was clearly associated with shock state, metabolic acidosis, and worse clinical outcomes. Core features of the respective subphenotypes were identified consistently in all assessed cohorts, independently of the studied population, the geographical location, the study design, or the analysis method. Additionally and clinically even more relevant treatment efficacies, as assessed retrospectively, appeared to be highly dependent on the respective subphenotype. This discovery launches a promising new approach to targeted medicine in ARDS. Even though it is now widely accepted that each ARDS subphenotype has distinct functional, biological, and mechanistic differences, there are crucial gaps in our knowledge, hindering the translation to bedside application. First of all, the underlying driving biological factors are still largely unknown, and secondly, there is currently no option for fast and easy identification of ARDS subphenotypes. This narrative review aims to summarize the evidence in biological subphenotyping in ARDS and tries to point out the current issues that will need addressing before translation of biological subohenotypes into clinical practice will be possible.

IntroductionThere is a paucity of data that can be used to guide the management of critically ill patients with COVID-19. In response, a research and data-sharing collaborative—The COVID-19 Critical Care Consortium—has been assembled to harness the cumulative experience of intensive care units (ICUs) worldwide. The resulting observational study provides a platform to rapidly disseminate detailed data and insights crucial to improving outcomes.Methods and analysisThis is an international, multicentre, observational study of patients with confirmed or suspected SARS-CoV-2 infection admitted to ICUs. This is an evolving, open-ended study that commenced on 1 January 2020 and currently includes >350 sites in over 48 countries. The study enrols patients at the time of ICU admission and follows them to the time of death, hospital discharge or 28 days post-ICU admission, whichever occurs last. Key data, collected via an electronic case report form devised in collaboration with the International Severe Acute Respiratory and Emerging Infection Consortium/Short Period Incidence Study of Severe Acute Respiratory Illness networks, include: patient demographic data and risk factors, clinical features, severity of illness and respiratory failure, need for non-invasive and/or mechanical ventilation and/or extracorporeal membrane oxygenation and associated complications, as well as data on adjunctive therapies.Ethics and disseminationLocal principal investigators will ensure that the study adheres to all relevant national regulations, and that the necessary approvals are in place before a site may contribute data. In jurisdictions where a waiver of consent is deemed insufficient, prospective, representative or retrospective consent will be obtained, as appropriate. A web-based dashboard has been developed to provide relevant data and descriptive statistics to international collaborators in real-time. It is anticipated that, following study completion, all de-identified data will be made open access.Trial registration numberACTRN12620000421932 (http://anzctr.org.au/ACTRN12620000421932.aspx).

Simple Summary Traditional therapeutic approaches to esophageal adenocarcinoma involve a combination of surgery, chemotherapy, and radiation. Despite innovations in treatment, outcomes remain poor. Targeted molecular therapies and immunotherapies have been used to great effect in various other solid tumors. Several targeted agents show promise in treating esophageal adenocarcinoma. In this review, we aim to highlight recent developments in the arena of targeted therapeutics and suggest topics of future investigations. Abstract Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor. Current treatment approaches involve a combination of surgery, chemotherapy, and radiotherapy. Unfortunately, standard first-line approaches are met with high rates of recurrence and metastasis. More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression. These discoveries have driven the development of targeted therapeutic agents in esophageal adenocarcinoma. While many agents have been studied, therapeutics targeting the human epidermal growth factor receptor (HER2) and vascular endothelial growth factor (VEGF) pathways have demonstrated improved survival. More recent advances in immunotherapies have also demonstrated survival advantages with monoclonal antibodies targeting the programmed death ligand 1 (PD-L1). In this review we highlight recent advances of targeted therapies, specifically agents targeting receptor tyrosine kinases, small molecule kinase inhibitors, and immune checkpoint inhibitors. While targeted therapeutics and immunotherapies have significantly improved survival, the benefits are limited to patients whose tumors express biomarkers such as PD-L1 and HER2. Survival remains poor for the remainder of patients with esophageal adenocarcinoma, underscoring the critical need for development of novel treatment strategies.