The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 ...dissemination, understanding the in vivo characteristics of SARS-CoV-2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2-infected ferrets shed virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. At 2 days post-contact, SARS-CoV-2 was detected in all naive direct contact ferrets. Furthermore, a few naive indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.
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•SARS-CoV-2-infected ferrets exhibit elevated body temperature and virus replication•SARS-CoV-2 is shed in nasal washes, saliva, urine and feces•SARS-CoV-2 is effectively transmitted to naive ferrets by direct contact•SARS-CoV-2 infection leads acute bronchiolitis in infected ferrets
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spreads, leading to a pandemic infection. Kim et al. show that ferrets are highly susceptible to SARS-CoV-2 infection and effectively transmit the virus by direct or indirect contact, recapitulating human infection and transmission.
While the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger ...individuals. To further understand differing COVID-19 manifestations in patients of different ages, three age groups of ferrets are infected with SARS-CoV-2. Although SARS-CoV-2 is isolated from all ferrets regardless of age, aged ferrets (≥3 years old) show higher viral loads, longer nasal virus shedding, and more severe lung inflammatory cell infiltration, and clinical symptoms compared to juvenile (≤6 months) and young adult (1-2 years) groups. Furthermore, direct contact ferrets co-housed with the virus-infected aged group shed more virus than direct-contact ferrets co-housed with virus-infected juvenile or young adult ferrets. Transcriptome analysis of aged ferret lungs reveals strong enrichment of gene sets related to type I interferon, activated T cells, and M1 macrophage responses, mimicking the gene expression profile of severe COVID-19 patients. Thus, SARS-CoV-2-infected aged ferrets highly recapitulate COVID-19 patients with severe symptoms and are useful for understanding age-associated infection, transmission, and pathogenesis of SARS-CoV-2.
Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at ...clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect
virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.
The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.
This study proposed an optimization framework and methodologies to design edgeless lattice structures featuring fillet and multipipe functions. Conventional lattice structures typically experience ...stress concentration at the sharp edges of strut joints, resulting in reduced mechanical performance and premature failure. The proposed approach aimed to improve the compression behavior of lattice structures by introducing edgeless features. Through finite element analysis, the optimized fillet edgeless simple cubic unit cell with a fillet radius to strut radius ratio of 0.753 showed a 12.1% improvement in yield stress and a 144% reduction in stress concentration. To validate the finite element analysis, experimental compressive tests were conducted, confirming that the introduction of edgeless functions improved the compressive strength of lattice structures manufactured through additive manufacturing. The optimized fillet edgeless simple cubic lattice structure exhibited the most effective improvement. This approach has promising potential for lattice structure applications.
Underlying diseases might be risk factors for poor prognosis in patients with coronavirus disease (COVID-19); however, we still do not know whether these diseases are independent factors affecting ...prognosis, which type of underlying diseases are risk factors, and which type of clinical outcomes are affected. We retrospectively reviewed cohort data from 7,590 de-identified patients with COVID-19 who were diagnosed using severe acute respiratory syndrome-coronavirus-2 RNA polymerase chain reaction test up to May 15, 2020. We used linked-medical claims data provided by the Health Insurance Review and Assessment Service in South Korea. Underlying diseases were identified using the diagnostic codes in the patients' files from January 1, 2019 to December 31, 2019. The total mortality rate was 3.0% in patients with COVID-19. After adjusting for age, sex, and concomitant chronic conditions, we found that congestive heart failure, chronic pulmonary diseases, diabetes without chronic complications, renal diseases, and malignancy were factors that significantly increased the cost of treatment. Cerebrovascular disease, chronic pulmonary disease, and paralysis were found to be independent factors significant in prolonging hospital stay. Diabetes with chronic complications was independently associated with intensive care unit admission. In addition, underlying congestive heart failure (odds ratio OR, 1.724; P = 0.003), dementia (OR, 1.598; P = 0.012), diabetes with and without chronic complications (OR, 1.821; P = 0.002 and OR, 1.518; P = 0.022, respectively), renal disease (OR, 2.299; P = 0.002), and malignancy (OR, 1.529; P = 0.039) were significant factors associated with death, even after adjustments. Underlying diseases were significant independent factors of the poor prognosis in patients with COVID-19. The effects were variable according to the type of underlying disease and clinical outcome. Therefore, patients with COVID-19 with underlying diseases should be monitored more closely because they are more at risk of a poor prognosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
This study investigated survival differences following intra‐operative frozen‐section examination of bile duct resection margins and final longitudinal margin status (LMS) in distal bile ...duct cancer (BDC).
MethodsOne hundred and ninety‐three patients underwent Whipple's operation for curative resection of distal BDC from 2008 to 2016. Patients were sorted into two and three groups according to LMS of the frozen‐sections and the final pathological specimen results: R0 on first bile duct resection (primary R0), R0 after additional resection (secondary R0), and no evidence of residual carcinoma (FR0), carcinoma in situ or high‐grade dysplasia (FR1‐CIS/HGD), or invasive carcinoma (FR1‐INV). Survival and prognostic factors according to LMS were analyzed.
Results
The final R0 ratio increased from 82.3% to 90.1% through additional resection. The 5‐year overall survival (OS) of primary and secondary R0 were 60.8%, 46.1% (P = 0.969). And disease‐free survival of primary and secondary R0 were 54.6%, 54.9% (P = 0.903). The 5‐year OS after FR0, FR1‐CIS/HGD, FR1‐INV were 59.3%, 59.5%, 14.3% (P = 0.842). LMS of the bile duct was an independent prognostic factor by multivariable analyses.
Conclusions
If R0 of final LMS was achieved, it would help to improve survival regardless of R0 through additional resection. And, it should be avoided remaining invasive cancer at the longitudinal margin whenever possible.
Highlight
Comparing the longitudinal margin status in distal bile duct cancer confined to the intra‐pancreatic portion, the authors revealed that there were no significant differences in overall survival and disease‐free survival among cases with no residual tumor, high‐grade dysplasia and carcinoma in situ on both frozen‐section and final pathological examination.
Background Although laparoscopic surgery has many advantages, its application in pancreatic ductal adenocarcinoma has not been sufficiently studied. The objective of this study was to compare the ...surgical outcomes of laparoscopic distal pancreatectomy (LDP) to those of open distal pancreatectomy (ODP) for left-sided ductal adenocarcinoma. Study Design Among 167 consecutive patients between December 2006 and August 2013, 150 patients were included. Unmatched and propensity score-matched analyses were performed to compare the primary (oncologic adequacy) and secondary outcomes (hospital course and complications) between ODP and LDP groups. Results In unmatched patients, LDP was associated with an earlier return to diet and a shorter hospital stay compared with ODP. The 5-year survival rates were 27.6% in unmatched ODP (n = 80) and 32.5% in unmatched LDP (n = 70). Fifty-one patients from each group were selected by propensity score matching. In this matched patient comparison, LDP was again associated significantly with a shorter median postoperative time to restarting diet and a shorter hospital stay. The 2 groups did not differ significantly in terms of primary outcomes of operative time, number of harvested lymph nodes, resection margin status, and secondary outcomes of frequency of pancreatic fistula and complications. The 2 groups also had comparable patient survival (p = 0.91). Conclusions This large single-center study of laparoscopic surgery for left-sided pancreatic ductal adenocarcinoma indicated that LDP was safe and more efficacious than OPD after propensity score adjustment for presurgical variables of return to diet and length of stay.
Schematics showing Ce-O-Si bonding as well as the mechanisms of (a) physical (megasonic and brush scrubbing) and (b) chemical (SC1, DHF, and SPM) cleaning forces for ceria removal.
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...•Ceria particle removal using different forces were studied during oxide post-CMP cleaning.•Polishing with pH 4 ceria slurry resulted in only electrostatic attraction and easy to remove.•Polishing with pH 8 ceria slurry resulted in stronger Ce-O-Si bonding and difficult to remove.•Physical forces (megasonic and brush scrubbing) unable to break Ce-O-Si bonds.•DHF and SPM could effectively remove chemically bonded (Ce-O-Si) ceria particles.
Ceria removal during the STI post-CMP cleaning process has recently become a serious concern to the semiconductor industries. It is known that ceria forms a strong Ce-O-Si bonding with the oxide surface that causes the difficulty in ceria removal. In this study, the bond formation and their removal were studied by polishing the oxide surface at pH 4 and pH 8 conditions, i.e. the pH of commercially formulated slurries. Ceria removal mechanisms were investigated through the use of different physical cleaning methods (megasonic and brush scrubbing) and chemical cleaning solutions such as standard cleaning solution 1 (SC1, a mixture solution of NH4OH, H2O2 and H2O), sulfuric acid, and hydrogen peroxide mixture (SPM), and diluted HF (DHF). It was found that ceria particles were removed easily at pH 4 polishing conditions as the electrostatic attraction is dominant than Ce-O-Si bond formation. However, at pH 8 conditions, particles were not removed due to strong bond formation. Only DHF and SPM cleaning conditions were able to remove the ceria particles due to the strong undercutting of oxide and dissolution of ceria particles, respectively. SPM could be the better choice as DHF would cause the surface roughness issues.
The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a ...functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood-brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies. We observed that each type of stem cell showed unique neurorestorative effects, primarily by supporting endogenous recovery rather than through direct cell replacement, and that the recovery of synaptic activities is correlated with the recovery of the structural and functional integrity of the neurovascular unit rather than with the regeneration of neurons.
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