Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become an unprecedented global health emergency. At present, SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research. Here, we showed that northern pig-tailed macaques (
namely 10% and 34%, respectively in 1988, compared with 5% and 28% (if seborrhoea is included) or 18% (for eczema excluding seborrhoea). 8The differences might indicate a lower threshold for referral or an actual increase in disease prevalence.The apparent surge in impetigo and tinea in the first quarter of the twentieth century, as judged by Radcliffe Crocker's hospital data and the 1921-22 Edinburgh figures, in comparison with McCall Anderson's 1873 observations, is possibly from close contact of school children. 5,6 It is notable that Radcliffe Crocker's 1903 private patients had lower prevalences of infections and infestations, suggesting a social class difference. 6 By the mid-twentieth century, effective treatments had largely conquered such contagions irrespectively of social class.The biggest surprise for the present-day dermatologist must be the very low rate of skin cancers of any description in the 1920s, something that was still apparent in 1950s Northern Ireland. 7 Accepting the evidence that skin cancer incidence increased in the last quarter of the twentieth century, an additional explanation for the low prevalence of skin cancers may be that in the 1920s presentations were delayed and, because life expectancies, as mentioned, were lower, those affected may have died from other causes before their cutaneous malignancies precipitated referral.An additional possibility, impossible to quantify, is that some or indeed most skin cancers, such as basal cell carcinoma, were referred directly to surgeons.A major criticism of this and other clinic-based case mix studies is one of selection referral, something that can only be overcome by true population studies, of which there are very few for skin disease.A recent such study by Svensson et al. of 12 377 participants aged 18-74 years, drawn from Germany, Italy, the Netherlands, Portugal and Sweden, showed that, for 'active manifestation' (rather than lifetime prevalence), eczema was the most common diagnosis, at a point prevalence of 16% (most frequently, contact dermatitis), with psoriasis at 3%, acne 5%, vitiligo 1Á4% and skin cancer 0Á5%. 9he study by Svensson et al. suffers from the drawback that it excludes children and those older than 74 years, thus skewing the findings away from atopic dermatitis and skin cancers.No similar population study exists for the early part of the twentieth century to indicate whether the 1921-22 data are applicable to the populace at large.However, some inference might be drawn by looking at the ranking of diseases.In 1921-22 data, tinea, impetigo and scabies were the second, third and fourth most common diagnoses (accounting for 39% of referrals), implying significant prevalence in the public at large, whereas for Svensson et al. these conditions did not merit their own diagnostic categories. 9he dermatological case mix of a century ago at the founding of the British Association of Dermatologists shows both similarities and differences from that of the present day.A wide range of factors, including environmental, social, medical referral practice and demographic, seem to be involved in the observed shifting pattern of case mix.
Safe, efficacious, and deployable vaccines are urgently needed to control COVID-19 in the large-scale vaccination campaigns. We report here the preclinical studies of an approved protein subunit vaccine against COVID-19, ZF2001, which contains tandem-repeat dimeric receptor-binding domain (RBD) protein with alum-based adjuvant. We assessed vaccine immunogenicity and efficacy in both mice and non-human primates (NHPs). ZF2001 induced high levels of RBD-binding and SARS-CoV-2 neutralizing antibody in both mice and non-human primates, and elicited balanced TH1/TH2 cellular responses in NHPs. Two doses of ZF2001 protected Ad-hACE2-transduced mice against SARS-CoV-2 infection, as detected by reduced viral RNA and relieved lung injuries. In NHPs, vaccination of either 25 μg or 50 μg ZF2001 prevented infection with SARS-CoV-2 in lung, trachea, and bronchi, with milder lung lesions. No evidence of disease enhancement was observed in both animal models. ZF2001 has been approved for emergency use in China, Uzbekistan, Indonesia, and Columbia. The high safety, immunogenicity, and protection efficacy in both mice and NHPs found in this preclinical study was consistent with the results in human clinical trials.
Background Ureteral stents, such as double-J stents, have become indispensable in urologic procedures but are associated with complications like hematuria and pain. While the advancement of artificial intelligence (AI) technology has led to its increasing application in the health sector, AI has not been used to provide information on potential complications and to facilitate subsequent measures in the event of such complications. Objective This study aimed to assess the effectiveness of an AI-based prediction tool in providing patients with information about potential complications from ureteroscopy and ureteric stent placement and indicating the need for early additional therapy. Methods Overall, 28 patients (aged 20-70 years) who underwent ureteral stent insertion for the first time without a history of psychological illness were consecutively included. A “reassurance-call” service was set up to equip patients with details about the procedure and postprocedure care, to monitor for complications and their severity. Patients were randomly allocated into 2 groups, reassurance-call by AI (group 1) and reassurance-call by humans (group 2). The primary outcome was the level of satisfaction with the reassurance-call service itself, measured using a Likert scale. Secondary outcomes included satisfaction with the AI-assisted reassurance-call service, also measured using a Likert scale, and the level of satisfaction (Likert scale and Visual Analogue Scale [VAS]) and anxiety (State-Trait Anxiety Inventory and VAS) related to managing complications for both groups. Results Of the 28 recruited patients (14 in each group), 1 patient in group 2 dropped out. Baseline characteristics of patients showed no significant differences (all P>.05). Satisfaction with reassurance-call averaged 4.14 (SD 0.66; group 1) and 4.54 (SD 0.52; group 2), with no significant difference between AI and humans (P=.11). AI-assisted reassurance-call satisfaction averaged 3.43 (SD 0.94). Satisfaction about the management of complications using the Likert scale averaged 3.79 (SD 0.70) and 4.23 (SD 0.83), respectively, showing no significant difference (P=.14), but a significant difference was observed when using the VAS (P=.01), with 6.64 (SD 2.13) in group 1 and 8.69 (SD 1.80) in group 2. Anxiety about complications using the State-Trait Anxiety Inventory averaged 36.43 (SD 9.17) and 39.23 (SD 8.51; P=.33), while anxiety assessed with VAS averaged 4.86 (SD 2.28) and 3.46 (SD 3.38; P=.18), respectively, showing no significant differences. Multiple regression analysis was performed on all outcomes, and humans showed superior satisfaction than AI in the management of complications. Otherwise, most of the other variables showed no significant differences (P.>05). Conclusions This is the first study to use AI for patient reassurance regarding complications after ureteric stent placement. The study found that patients were similarly satisfied for reassurance calls conducted by AI or humans. Further research in larger populations is warranted to confirm these findings. Trial Registration Clinical Research Information System KCT0008062; https://tinyurl.com/4s8725w2
ABSTRACT COVID-19 is a multi-system disease affecting many organs outside of the lungs, and patients generally develop varying degrees of neurological symptoms. Whereas, the pathogenesis underlying these neurological manifestations remains elusive. Although in vitro models and animal models are widely used in studies of SARS-CoV-2 infection, human organ models that can reflect the pathological alterations in a multi-organ context are still lacking. In this study, we propose a new strategy to probe the effects of SARS-CoV-2 on human brains in a linked alveolus-BBB organ chip platform. The new multi-organ platform allows to recapitulate the essential features of human alveolar-capillary barrier and blood-brain barrier in a microfluidic condition by co-culturing the organ-specific cells. The results reveal direct SARS-CoV-2 exposure has no obvious effects on BBB chip alone. While, infusion of endothelial medium from infected alveolus chips can cause BBB dysfunction and neuroinflammation on the linked chip platform, including brain endothelium disruption, glial cell activation and inflammatory cytokines release. These new findings suggest that SARS-CoV-2 could induce neuropathological alterations, which might not result from direct viral infection through hematogenous route, but rather likely from systemic inflammation following lung infection. This work provides a new strategy to study the virus-host interaction and neuropathology at an organ-organ context, which is not easily obtained by other in vitro models. This will facilitate to understand the neurological pathogenesis in SARS-CoV-2 and accelerate the development of new therapeutics. SUMMARY A linked human alveolus-BBB chip platform is established to explore the influences of SARS-CoV-2 on human brains in an organ-organ context. SARS-CoV-2 infection could induce BBB injury and neuroinflammation. The neuropathological changes are caused by SARS-CoV-2 indirectly, which might be mediated by systemic inflammation following lung infection, but probably not by direct viral neuroinvasion.
As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques ( Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b + and CD8 + cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b + cells, and persistent infiltration of CD8 + cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs. However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000 single-nucleus transcriptomes of the lung, liver, kidney, and cerebral cortex in rhesus macaques ( Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multi-organ dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019 (COVID-19). Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway, which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy (an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection, which may facilitate the development of therapeutic interventions for COVID-19.新型冠状病毒（SARS-CoV-2）感染可以造成多种临床表现和多种器官的组织损伤。但是对于新冠病毒感染相关的病理和免疫防御特征的细胞和分子水平的理解还不完善。该研究中，我们对感染新冠病毒的猕猴及健康对照个体的肺脏、肝脏、肾脏、大脑皮层进行单细胞核转录组测序和分析，共获得了约77 000个单细胞核的转录组数据。多器官数据集整合分析结果表明肝脏具有最强的全局转录改变。我们发现肺脏中的上皮细胞，尤其是AT2细胞和纤毛细胞，存在突出的损伤特征，在成纤维细胞中纤维化迹象明显。肺部的这些损伤特征与新冠肺炎（COVID-19）病人中报道的结果很相似。此外，我们发现肺中的主要组织相容性复合体（MHC）I/II类分子活性下调，肝脏中存在炎症反应和犬尿氨酸通路的激活，它会诱导免疫抑制性微环境的发展。对肾脏数据集的分析发现肾小管上皮细胞对新冠病毒具有更强的趋向性，同时发现了感染猕猴出现了由足细胞失调引起的膜性肾病(一种自身免疫疾病)。另外，我们还识别到了大脑皮层中星形胶质细胞和少突胶质细胞的病理状态，为新冠肺炎相关的神经学影响提供了分子洞察。总之，此项对新冠病毒感染的猕猴模型多器官进行单细胞核转录组研究的工作拓宽了我们对新冠病毒感染造成的疾病特征和机体抗病毒免疫缺陷的理解，这可能促进新冠肺炎治疗干预手段的开发。.
Abstract Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2. Here we report that nelfinavir, an FDA approved drug for the treatment of HIV infection, is effective against SARS-CoV-2 and COVID-19. Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2 (IC 50 = 8.26 μM), while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93 μM (EC 50 ). In comparison with vehicle-treated animals, rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals. At necropsy, nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude. A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center, which were randomized (1:1) to nelfinavir and control groups, showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days (9.0 vs. 14.5 days, P = 0.055) and the duration of fever time by 3.8 days (2.8 vs. 6.6 days, P = 0.014) in mild/moderate COVID-19 patients. The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients, together with its well-established good safety profile in almost all ages and during pregnancy, indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.
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