Survival and Long-Term Functional Status of COVID-19 Patients Requiring Prolonged Extracorporeal Membrane Oxygenation Support.

Rationale: Severe cases of acute respiratory distress syndrome (ARDS) may require prolonged (>28 d) extracorporeal membrane oxygenation (ECMO). In nonresolving disease, recovery is uncertain, and lung transplant may be proposed. Objectives: This study aims to identify the variables influencing survival and to describe the functional status of these patients at 6 months. Methods: This was a retrospective, multicenter, observational cohort study including patients requiring ECMO support for coronavirus disease (COVID-19)-related ARDS for >28 days. Multivariate analysis was performed using Cox regression in preselected variables and in least absolute shrinkage and selection operator selected variables. In a post hoc analysis to account for confounders and differences in awake strategy use by centers, treatment effects of the awake strategy were estimated using an augmented inverse probability weighting estimator with robust standard errors clustered by center. Results: Between March 15, 2020 and March 15, 2021, 120 patients required ECMO for >28 days. Sixty-four patients (53.3%) survived decannulation, 62 (51.7%) were alive at hospital discharge, and 61 (50.8%) were alive at 6-month follow-up. In the multivariate analysis, age (1.09; 95% confidence interval [CI], 1.03-1.15; P = 0.002) and an awake ECMO strategy (defined as the patient being awake, cooperative, and performing rehabilitation and physiotherapy with or without invasive mechanical ventilation at any time during the extracorporeal support) (0.14; 95% CI, 0.03-0.47; P = 0.003) were found to be predictors of hospital survival. At 6 months, 51 (42.5%) patients were at home, 42 (84.3%) of them without oxygen therapy. A cutoff point of 47 ECMO days had a 100% (95% CI, 76.8-100%) sensitivity and 60% (95% CI, 44.3-73.6%) specificity for oxygen therapy at 6 months, with 100% specificity being found in 97 days. Conclusions: Patients with COVID-19 who require ECMO for >28 days can survive with nonlimiting lung impairment. Age and an awake ECMO strategy may be associated with survival. Longer duration of support correlates with need for oxygen therapy at 6 months.

Palytoxin-Related Keratoconjunctivitis Assessed by High-Resolution Anterior Segment Optical Coherence Tomography.

Palytoxin (PTX) is produced by corals such as zoanthid corals. Here we present a case of bilateral PTX-induced keratoconjunctivitis. A 63-year-old man presented to the emergency department with symptoms of red eye, purulent discharge, and foreign body sensation in both eyes. On slit lamp examination, epithelial defects in both eyes with a ring-shaped corneal stromal infiltrate in the right eye and a marginal stromal infiltrate in the left eye were noted. High-resolution anterior segment optical coherence tomography (HR-AS-OCT) showed stromal hyperreflectivity and Descemet folds. Bacterial, fungal, and amoebic cultures were taken. Empirical treatment with topical dexamethasone as well as antibiotics and systemic doxycycline was started. The next day the patient stated that he had been handling zoanthid coral without gloves and had rubbed his eyes afterward. Bilateral PTX-induced keratoconjunctivitis was diagnosed. His eyes were irrigated abundantly with saline solution, and umbilical cord serum eye drops were added to the treatment. Treatment was tapered according to improvement of the corneal infiltrates and epithelial defects. After four months, the stromal infiltrates were resolved but corneal scars persisted in both eyes. HR-AS-OCT showed anterior stromal hyperreflectivity corresponding to corneal leucomas. PTX can cause ocular adverse effects such as keratolysis and corneal inflammation, and in some cases can lead to corneal perforation. It can also produce systemic adverse effects, hence the importance of the preventive measures when handling corals that can produce this toxin.

Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.

PURPOSE: Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach. METHODS: Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays. RESULTS: We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70. CONCLUSION: This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching.

Mental Health in the Workplace: A Call to Action Proceedings From the Mental Health in the Workplace-Public Health Summit.

OBJECTIVE: The aim of the study was to declare a call to action to improve mental health in the workplace. METHODS: We convened a public health summit and assembled an Advisory Council consisting of experts in the field of occupational health and safety, workplace wellness, and public policy to offer recommendations for action steps to improve health and well-being of workers. RESULTS: The Advisory Council narrowed the list of ideas to four priority projects. CONCLUSIONS: The recommendations for action include developing a mental health in the workplace (1) "how to" guide, (2) scorecard, (3) recognition program, and (4) executive training.

Increased visceral to subcutaneous fat ratio is associated with decreased overall survival in patients with metastatic melanoma receiving anti-angiogenic therapy.

BACKGROUND: Body fat distribution is an emerging prognostic indicator in patients treated with anti-angiogenic (AA) therapy. We sought to evaluate the association of visceral and subcutaneous fat with progression free survival (PFS) and overall survival (OS) in patients with metastatic melanoma treated with AA therapy. METHODS: Stage IV melanoma patients received bevacizumab ± interferon-alpha. Total abdominal fat, visceral fat area (VFA) and subcutaneous fat area (SFA) were measured at L3-L4 on CT images (cm(2)). PFS and OS were estimated by the Kaplan-Meier method. Cox proportional hazards model was used to assess the association of fat and clinical variables with PFS and OS. Prediction accuracy was evaluated using receiver operating characteristic curve with area under the curve (AUC). RESULTS: Forty-two patients were evaluated. Median VFA/SFA and body mass index (BMI) were used to group patients into high and low cohorts. PFS and OS were significantly decreased in patients with high VFA/SFA versus low (PFS, p=0.009; OS, p = 0.007), but not for BMI (PFS, p=0.774; OS, p=0.881). VFA/SFA, LDH and liver metastasis (LM) were predictors of PFS and OS on multivariate analysis. A prognostic score combining VFA/SFA, LDH, and presence or absence of LM had a higher accuracy for predicting PFS at 3 months (AUC 0.759) and OS at 24 months (AUC 0.846) than LDH and LM alone (PFS, AUC 0.705; OS, AUC 0.786). CONCLUSION: Increased VFA/SFA is associated with decreased PFS and OS in patients with metastatic melanoma treated with AA therapy, indicating body fat distribution is an important prognostic factor.

Predicting Overall Survival in Patients With Metastatic Melanoma on Antiangiogenic Therapy and RECIST Stable Disease on Initial Posttherapy Images Using CT Texture Analysis.

OBJECTIVE: The purpose of this study was to use CT texture analysis to predict overall survival (OS) in patients with metastatic melanoma and stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) on initial posttherapy CT images. MATERIALS AND METHODS: This retrospective study included 42 patients with metastatic melanoma who received bevacizumab therapy in the context of a randomized prospective phase II clinical trial. Target lesions on the baseline and initial posttherapy contrast-enhanced CT examinations were evaluated by CT texture analysis using TexRAD software before and after image filtering in patients with RECIST SD on initial posttherapy images. Cox proportional hazards models were used to assess the associations of CT texture analysis measurements and of other patient factors with OS. The AUC was used to evaluate predictive accuracy. RESULTS: In multivariate analysis (in 23 patients with RECIST SD; median OS, 1.51 years), absolute change in mean positive pixels at spatial scaling filter of 4 mm, change in tumor size, and baseline serum lactate dehydrogenase (LDH) level were predictors of OS (hazard ratio [HR] = 5.05 for decrease in mean positive pixels at spatial scaling filter of 4 mm vs increase, p = 0.007; HR = 4.14 for > 5% increase in tumor size vs otherwise, p = 0.025; and HR = 1.29 for every 100 IU/L increase in baseline LDH level, p = 0.068). A prognostic index containing these three factors was highly accurate for predicting OS at 18 months (AUC = 0.917). CONCLUSION: In patients with metastatic melanoma and RECIST SD on initial post-therapy CT images, a model incorporating CT texture analysis of target lesions, tumor size changes, and baseline LDH levels was highly accurate in predicting OS.

Differential accumulation of retroelements and diversification of NB-LRR disease resistance genes in duplicated regions following polyploidy in the ancestor of soybean.

The genomes of most, if not all, flowering plants have undergone whole genome duplication events during their evolution. The impact of such polyploidy events is poorly understood, as is the fate of most duplicated genes. We sequenced an approximately 1 million-bp region in soybean (Glycine max) centered on the Rpg1-b disease resistance gene and compared this region with a region duplicated 10 to 14 million years ago. These two regions were also compared with homologous regions in several related legume species (a second soybean genotype, Glycine tomentella, Phaseolus vulgaris, and Medicago truncatula), which enabled us to determine how each of the duplicated regions (homoeologues) in soybean has changed following polyploidy. The biggest change was in retroelement content, with homoeologue 2 having expanded to 3-fold the size of homoeologue 1. Despite this accumulation of retroelements, over 77% of the duplicated low-copy genes have been retained in the same order and appear to be functional. This finding contrasts with recent analyses of the maize (Zea mays) genome, in which only about one-third of duplicated genes appear to have been retained over a similar time period. Fluorescent in situ hybridization revealed that the homoeologue 2 region is located very near a centromere. Thus, pericentromeric localization, per se, does not result in a high rate of gene inactivation, despite greatly accelerated retrotransposon accumulation. In contrast to low-copy genes, nucleotide-binding-leucine-rich repeat disease resistance gene clusters have undergone dramatic species/homoeologue-specific duplications and losses, with some evidence for partitioning of subfamilies between homoeologues.

Replication of nonautonomous retroelements in soybean appears to be both recent and common.

Retrotransposons and their remnants often constitute more than 50% of higher plant genomes. Although extensively studied in monocot crops such as maize (Zea mays) and rice (Oryza sativa), the impact of retrotransposons on dicot crop genomes is not well documented. Here, we present an analysis of retrotransposons in soybean (Glycine max). Analysis of approximately 3.7 megabases (Mb) of genomic sequence, including 0.87 Mb of pericentromeric sequence, uncovered 45 intact long terminal repeat (LTR)-retrotransposons. The ratio of intact elements to solo LTRs was 8:1, one of the highest reported to date in plants, suggesting that removal of retrotransposons by homologous recombination between LTRs is occurring more slowly in soybean than in previously characterized plant species. Analysis of paired LTR sequences uncovered a low frequency of deletions relative to base substitutions, indicating that removal of retrotransposon sequences by illegitimate recombination is also operating more slowly. Significantly, we identified three subfamilies of nonautonomous elements that have replicated in the recent past, suggesting that retrotransposition can be catalyzed in trans by autonomous elements elsewhere in the genome. Analysis of 1.6 Mb of sequence from Glycine tomentella, a wild perennial relative of soybean, uncovered 23 intact retroelements, two of which had accumulated no mutations in their LTRs, indicating very recent insertion. A similar pattern was found in 0.94 Mb of sequence from Phaseolus vulgaris (common bean). Thus, autonomous and nonautonomous retrotransposons appear to be both abundant and active in Glycine and Phaseolus. The impact of nonautonomous retrotransposon replication on genome size appears to be much greater than previously appreciated.

The aerobic electron transport system of Eikenella corrodens.

The respiratory system of the fastidious beta-proteobacterium Eikenella corrodens grown with limited oxygen was studied. Membranes showed the highest oxidase activity with ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) or succinate and the lowest activity with NADH and formate. The presence of a bc1-type complex was suggested by the inhibition exerted by 2-heptyl-4-hydroxyquinoline-N-oxide (HOQNO), myxothiazol, and antimycin A on respiration with succinate and by the effect of the latter two inhibitors on the succinate-reduced difference spectra. Respiration with succinate or ascorbate-TMPD was abolished by low KCN concentrations, suggesting the presence of a KCN-sensitive terminal oxidase. Cytochromes b and c were spectroscopically detected after reduction with physiological or artificial electron donors, whereas type a and d cytochromes were not detected. The CO difference spectrum of membranes reduced by dithionite and its photodissociation spectrum (77 K) suggested the presence of a single CO compound that had the spectral features of a cytochrome o-like pigment. High-pressure liquid chromatography analysis of membrane haems confirmed the presence of haem B; in contrast, haems A and O were not detected. Peroxidase staining of membrane type c cytochromes using SDS-PAGE revealed the presence of five bands with apparent molecular masses of 44, 33, 30, 26, and 14 kDa. Based on our results, a tentative scheme of the respiratory chain in E. corrodens, comprising (i) dehydrogenases for succinate, NADH, and formate, (ii) a ubiquinone, (iii) a cytochrome bc1, and (iv) a type-cbb' cytochrome c oxidase, is proposed.