Comparison of 6-Month Outcomes of Survivors of COVID-19 versus Non-COVID-19 Critical Illness.

Rationale: The outcomes of survivors of critical illness due to coronavirus disease (COVID-19) compared with non-COVID-19 are yet to be established. Objectives: We aimed to investigate new disability at 6 months in mechanically ventilated patients admitted to Australian ICUs with COVID-19 compared with non-COVID-19. Methods: We included critically ill patients with COVID-19 and non-COVID-19 from two prospective observational studies. Patients were eligible if they were adult (age ⩾ 8 yr) and received ⩾24 hours of mechanical ventilation. In addition, patients with COVID-19 were eligible with a positive laboratory PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Measurements and Main Results: Demographic, intervention, and hospital outcome data were obtained from electronic medical records. Survivors were contacted by telephone for functional outcomes with trained outcome assessors using the World Health Organization Disability Assessment Schedule 2.0. Between March 6, 2020, and April 21, 2021, 120 critically ill patients with COVID-19, and between August 2017 and January 2019, 199 critically ill patients without COVID-19, fulfilled the inclusion criteria. Patients with COVID-19 were older (median [interquartile range], 62 [55-71] vs. 58 [44-69] yr; P = 0.019) with a lower Acute Physiology and Chronic Health Evaluation II score (17 [13-20] vs. 19 [15-23]; P = 0.011). Although duration of ventilation was longer in patients with COVID-19 than in those without COVID-19 (12 [5-19] vs. 4.8 [2.3-8.8] d; P < 0.001), 180-day mortality was similar between the groups (39/120 [32.5%] vs. 70/199 [35.2%]; P = 0.715). The incidence of death or new disability at 180 days was similar (58/93 [62.4%] vs. 99/150 [66/0%]; P = 0.583). Conclusions: At 6 months, there was no difference in new disability for patients requiring mechanical ventilation for acute respiratory failure due to COVID-19 compared with non-COVID-19. Clinical trial registered with www.clinicaltrials.gov (NCT04401254).

The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study.

BACKGROUND: There are few reports of new functional impairment following critical illness from COVID-19. We aimed to describe the incidence of death or new disability, functional impairment and changes in health-related quality of life of patients after COVID-19 critical illness at 6 months. METHODS: In a nationally representative, multicenter, prospective cohort study of COVID-19 critical illness, we determined the prevalence of death or new disability at 6 months, the primary outcome. We measured mortality, new disability and return to work with changes in the World Health Organization Disability Assessment Schedule 2.0 12L (WHODAS) and health status with the EQ5D-5LTM. RESULTS: Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51-70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06-13.77]; p < 0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, - 0.19 [- 0.28 to - 0.10]; p < 0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty. CONCLUSIONS: At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning. Clinical trial registration NCT04401254 May 26, 2020.

PRELP secreted from mural cells protects the function of blood brain barrier through regulation of endothelial cell-cell integrity.

Introduction: Proline/arginine-rich end leucine-rich repeat protein (PRELP), is a small secreted proteoglycan expressed by pericytes and vascular smooth muscle cells surrounding the brain vasculature of adult mouse. Methods: We utilised a Prelp knockout (Prelp -/-) mouse model to interrogate vasculature integrity in the brain alongside performing in vitro assays to characterise PRELP application to endothelial cells lines. Our findings were supplemented with RNA expression profiling to elucidate the mechanism of how PRELP maintains neurovasculature function. Results: Prelp -/- mice presented with neuroinflammation and reducedneurovasculature integrity, resulting in IgG and dextran leakage in the cerebellum and cortex. Histological analysis of Prelp -/- mice revealed reducedcell-cell integrity of the blood brain barrier, capillary attachment of pericytes andastrocyte end-feet. RNA-sequencing analysis found that cell-cell adhesion andinflammation are affected in Prelp -/- mice and gene ontology analysis as well as gene set enrichment analysis demonstrated that inflammation related processes and adhesion related processes such as epithelial-mesenchymal transition and apical junctions were significantly affected, suggesting PRELP is a regulator of cell-cell adhesion. Immunofluorescence analysis showed that adhesion junction protein expression levels of cadherin, claudin-5, and ZO-1, was suppressed in Prelp -/- mice neurovasculature. Additionally, in vitro studies revealed that PRELP application to endothelial cells enhances cell-cell integrity, induces mesenchymal-endothelial transition and inhibits TGF-ß mediated damage to cell-cell adhesion. Discussion: Our study indicates that PRELP is a novel endogenous secreted regulator of neurovasculature integrity and that PRELP application may be a potential treatment for diseases associated with neurovascular damage.

PRELP Regulates Cell-Cell Adhesion and EMT and Inhibits Retinoblastoma Progression.

Retinoblastoma (RB) is the most common intraocular pediatric cancer. Nearly all cases of RB are associated with mutations compromising the function of the RB1 tumor suppressor gene. We previously demonstrated that PRELP is widely downregulated in various cancers and our in vivo and in vitro analysis revealed PRELP as a novel tumor suppressor and regulator of EMT. In addition, PRELP is located at chromosome 1q31.1, around a region hypothesized to be associated with the initiation of malignancy in RB. Therefore, in this study, we investigated the role of PRELP in RB through in vitro analysis and next-generation sequencing. Immunostaining revealed that PRELP is expressed in Müller glial cells in the retina. mRNA expression profiling of PRELP-/- mouse retina and PRELP-treated RB cells found that PRELP contributes to RB progression via regulation of the cancer microenvironment, in which loss of PRELP reduces cell-cell adhesion and facilitates EMT. Our observations suggest that PRELP may have potential as a new strategy for RB treatment.

Two Secreted Proteoglycans, Activators of Urothelial Cell-Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression.

Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-ß and EGF pathways, which reversed epithelial-mesenchymal transition (EMT), activated cell-cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer.

Use of conivaptan for the treatment of symptomatic hyponatremia in a patient with acute decompensated heart failure.

PURPOSE: The successful use of conivaptan for the treatment of symptomatic hypervolemic hyponatremia in a patient with acute decompensated heart failure is reported. SUMMARY: A 67-year-old woman with severe ischemic dilated cardiomyopathy was admitted to the hospital due to a heart failure exacerbation. She was initially managed with furosemide and milrinone, but her condition continued to worsen. By hospital day 10, her serum sodium concentration had decreased to 114 meq/L. A 96-hour trial of conivaptan was initiated, and the patient's serum sodium concentration increased to 125 meq/L, blood urea nitrogen level decreased from 34 to 15 g/dL, serum creatinine concentration decreased from 1.1 to 0.9 g/dL, and fluid balance was -9800 mL. After completion of the 96-hour trial of conivaptan, the patient quickly decompensated. Conivaptan was restarted three days later; again, the patient's sodium level quickly increased, and aquaresis occurred. By hospital day 24, the patient was stable enough to undergo a cardiac catheterization, and a stent was placed. On day 26, the patient died while being prepared for an upgrade to a biventricular implantable cardioverter defibrillator. Multiple trials have evaluated conivaptan for the treatment of heart failure. Conivaptan improves hyponatremia and hemodynamic parameters acutely and increases urine output but has failed to show improvement in heart failure symptoms in the published literature. No adverse cardiac effects resulted from the use of conivaptan in this patient. CONCLUSION: Treatment with i.v. conivaptan in a patient with symptomatic hyponatremia and acute decompensated heart failure resulted in marked diuresis and improvement of hyponatremia.