A systematic review and meta-analysis was conducted in an attempt to systematically collect and evaluate the associations of epidemiological, comorbidity factors with the severity and prognosis of coronavirus disease 2019 (COVID-19). The systematic review and meta-analysis was conducted according to the guidelines proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Sixty nine publications met our study criteria, and 61 studies with more than 10,000 COVID-19 cases were eligible for the quantitative synthesis. We found that the males had significantly higher disease severity (RR: 1.20, 95% CI: 1.13-1.27, P <0.001) and more prognostic endpoints. Older age was found to be significantly associated with the disease severity and six prognostic endpoints. Chronic kidney disease contributed mostly for death (RR: 7.10, 95% CI: 3.14-16.02), chronic obstructive pulmonary disease (COPD) for disease severity (RR: 4.20, 95% CI: 2.82-6.25), admission to intensive care unit (ICU) (RR: 5.61, 95% CI: 2.68-11.76), the composite endpoint (RR: 8.52, 95% CI: 4.36-16.65,), invasive ventilation (RR: 6.53, 95% CI: 2.70-15.84), and disease progression (RR: 7.48, 95% CI: 1.60-35.05), cerebrovascular disease for acute respiratory distress syndrome (ARDS) (RR: 3.15, 95% CI: 1.23-8.04), coronary heart disease for cardiac abnormality (RR: 5.37, 95% CI: 1.74-16.54). Our study highlighted that the male gender, older age and comorbidities owned strong epidemiological evidence of associations with the severity and prognosis of COVID-19.

The long-term (4-month) responses to treatment of stroke in the older adult rat, using rat bone marrow stromal cells (MSCs), have not been investigated. Retired breeder rats were subjected to middle cerebral artery occlusion (MCAo) alone, or injected intravenously with 3 x 10(6) MSCs, at 7 days after MCAo. Functional recovery was measured using an adhesive-removal patch test and a modified neurological severity score. Bromodeoxyuridine, a cell proliferation marker, was injected daily for 14 before sacrifice. Animals were sacrificed 4 months after stroke. Double immunostaining was used to identify cell proliferation and cell types for axons, astrocytes, microglia, and oligodendrocytes. MSC treatment induced significant improvement in neurological outcome after MCAo compared with control rats. MSC treatment reduced the thickness of the scar wall (P < 0.05) and reduced the numbers of microglia/macrophages within the scar wall (P < 0.01). Double staining showed increased expression of an axonal marker (GAP-43), among reactive astrocytes in the scar boundary zone and in the subventricular zone in the treated rats. Bromodeoxyuridine in cells preferentially colocalized with markers of astrocytes (GFAP) and oligodendrocytes (RIP) in the ipsilateral hemisphere, and gliogenesis was enhanced in the subventricular zone of the rats treated with MSCs. This is the first report to show that MSCs injected at 7 days after stroke improve long-term neurological outcome in older animals. Brain tissue repair is an ongoing process with reactive gliosis, which persists for at least 4 months after stroke. Reactive astrocytes responding to MSC treatment of ischemia may also promote axonal regeneration during long-term recovery.

Bone marrow stromal cells (BMSCs) facilitate functional recovery in rats after stroke when administered acutely (1 day) or subacutely (7 days). In this study, we postponed the time of cell transplantation to 1 month after stroke. Female retired breeder rats were subjected to 2 h of middle cerebral artery occlusion (MCAo). Male BMSCs (3¾10 6 ) or phosphate-buffered saline were administered intravenously, and the animals were killed 3 months later. An additional population of nontreated rats was killed at 1 month after MCAo. Significant recovery of behavior was found in BMSC-treated rats beginning at 1 month after cell injection in the modified neurologic severity score test and the adhesive-removal test compared with control animals (P < 0.05). In situ hybridization showed that BMSCs survived and preferentially localized to the ipsilateral hemisphere. Double staining revealed that approximately 13% and 6% Y-chromosome-positive cells expressed the astrocyte marker, glial fibrillary acidic protein, and the neuronal marker, microtubule-associated protein-2, respectively. In addition, BMSC treatment reduced scar thickness, and increased the number of proliferating cells and oligodendrocyte precursor cells along the subventricular zone in the ipsilateral hemisphere. Expression of the chemokine stromal-cell-derived factor-1 (SDF-1) was significantly increased along the ischemic boundary zone compared with the corresponding areas in the contralateral hemisphere at 1 month and 4 months (P < 0.01) after stroke. The SDF-1 receptor, CXC-chemokine receptor-4 (CXCR4), was expressed in BMSCs both in vitro and in vivo. Our data show that the time window of BMSC therapy is at least 1 month after stroke; the interaction of SDF-1/ CXCR4 may contribute to the trafficking of transplanted BMSCs.

Background and Purpose-We sought to evaluate the long-term effects of bone marrow stromal cell (BMSC) treatment on retired breeder rats with stroke. Methods-Female retired breeder rats were subjected to 2-hour middle cerebral artery occlusion (MCAO) followed by an injection of 2ϫ10 6 male BMSCs (nϭ8) or phosphate-buffered saline (nϭ11) into the ipsilateral internal carotid artery at 1 day after stroke. The rats were humanely killed 1 year later. Functional tests, in situ hybridization, and histochemical and immunohistochemical staining were performed. Results-Significant recovery of neurological deficits was found in BMSC-treated rats beginning 2 weeks after cell injection compared with control animals. The beneficial effects of cell transplantation persisted for at least 1 year (PϽ0.01). In situ hybridization for the Y chromosome showed that donor cells survived in the brains of recipient rats, among which 22.3Ϯ1.95% of cells expressed the astrocyte marker glial fibrillary acidic protein, 16.8Ϯ2.13% expressed the neuronal marker microtubule-associated protein 2, and 5.5Ϯ0.42% and Ͻ1% of cells colocalized with the microglial marker IB4 and the endothelial cell marker von Willebrand factor, respectively. Only very few BMSCs, however, were found in peripheral organs such as the heart, lung, liver, spleen, and kidney in recipient rats. BMSCs significantly reduced axonal loss (PϽ0.01), the thickness of the lesion scar wall (PϽ0.01), and the number of Nogo-A-positive cells (PϽ0.05) along the scar border; meanwhile, synaptophysin expression (PϽ0.05) was significantly increased in BMSC-treated ischemic brains compared with control untreated brains. Conclusions-The beneficial effects of BMSCs on ischemic brain tissue persisted for at least 1 year. Most surviving BMSCs were present in the ischemic brain, but very few were found in other organs. The long-term improvement in functional outcome may be related to the structural and molecular changes induced by BMSCs.