Cryptococcus neoformans, a global threat to human health.

BACKGROUND: Emerging fungal pathogens pose important threats to global public health. The World Health Organization has responded to the rising threat of traditionally neglected fungal infections by developing a Fungal Priority Pathogens List (FPPL). Taking the highest-ranked fungal pathogen in the FPPL, Cryptococcus neoformans, as a paradigm, we review progress made over the past two decades on its global burden, its clinical manifestation and management of cryptococcal infection, and its antifungal resistance. The purpose of this review is to drive research efforts to improve future diagnoses, therapies, and interventions associated with fungal infections. METHODS: We first reviewed trends in the global burden of HIV-associated cryptococcal infection, mainly based on a series of systematic studies. We next conducted scoping reviews in accordance with the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews using PubMed and ScienceDirect with the keyword Cryptococcus neoformans to identify case reports of cryptococcal infections published since 2000. We then reviewed recent updates on the diagnosis and antifungal treatment of cryptococcal infections. Finally, we summarized knowledge regarding the resistance and tolerance of C. neoformans to approved antifungal drugs. RESULTS: There has been a general reduction in the estimated global burden of HIV-associated cryptococcal meningitis since 2009, probably due to improvements in highly active antiretroviral therapies. However, cryptococcal meningitis still accounts for 19% of AIDS-related deaths annually. The incidences of CM in Europe and North America and the Latin America region have increased by approximately two-fold since 2009, while other regions showed either reduced or stable numbers of cases. Unfortunately, diagnostic and treatment options for cryptococcal infections are limited, and emerging antifungal resistance exacerbates the public health burden. CONCLUSION: The rising threat of C. neoformans is compounded by accumulating evidence for its ability to infect immunocompetent individuals and the emergence of antifungal-resistant variants. Emphasis should be placed on further understanding the mechanisms of pathogenicity and of antifungal resistance and tolerance. The development of novel management strategies through the identification of new drug targets and the discovery and optimization of new and existing diagnostics and therapeutics are key to reducing the health burden.

The Effects of COVID-19 Lockdown on Air Pollutant Concentrations across China: A Google Earth Engine-Based Analysis.

To overcome the spread of the severe COVID-19 outbreak, various lockdown measures have been taken worldwide. China imposed the strictest home-quarantine measures during the COVID-19 outbreak in the year 2020. This provides a valuable opportunity to study the impact of anthropogenic emission reductions on air quality. Based on the GEE platform and satellite imagery, this study analyzed the changes in the concentrations of NO2, O3, CO, and SO2 in the same season (1 February-1 May) before and after the epidemic control (2019-2021) for 16 typical representative cities of China. The results showed that NO2 concentrations significantly decreased by around 20-24% for different types of metropolises, whereas O3 increased for most of the studied metropolises, including approximately 7% in megacities and other major cities. Additionally, the concentrations of CO and SO2 showed no statistically significant changes during the study intervals. The study also indicated strong variations in air pollutants among different geographic regions. In addition to the methods in this study, it is essential to include the differences in meteorological impact factors in the study to identify future references for air pollution reduction measures.

Development of a UVC-based disinfection robot

Purpose>The disinfection robot developed by the authors and team focuses on achieving fast and precise disinfection under a given or specific disinfection zone. This looks to solve problems with traditional robots that pay less attention to the level, efficiency and zones of disinfection. To effectively support and guarantee normal running for the whole system, a digital twin system is applied to the disinfection robot. This study aims to achieve fast, precise and thorough disinfection via the developed mobile robot.Design/methodology/approach>The designed robot is composed primarily of the following three parts: a mobile platform, a six-axis robotic arm and a ultraviolet-C (UVC) LED array. The UVC LED array is installed on the end-effector to achieve large-scale, precise manipulation. The adoption of all types of advanced sensors and the development of an intuitive and user-friendly client interface are helpful in achieving remote control, path planning, data monitoring and custom disinfection functions.Findings>Disinfection of three different locations in the laboratory was performed;the dosage distribution of the surface as radiated by the UVC robot was detected;and feasibility of development was validated.Originality/value>The developed disinfection robot achieved fast, precise and thorough disinfection for a given or specific disinfection zone.

Biologics for Psoriasis During the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19), a new form of acute infectious respiratory syndrome first reported in 2019, has rapidly spread worldwide and has been recognized as a pandemic by the WHO. It raised widespread concern about the treatment of psoriasis in this COVID-19 pandemic era, especially on the biologics use for patients with psoriasis. This review will summarize key information that is currently known about the relationship between psoriasis, biological treatments, and COVID-19, and vaccination-related issues. We also provide references for dermatologists and patients when they need to make clinical decisions. Currently, there is no consensus on whether biological agents increase the risk of coronavirus infection; however, current research shows that biological agents have no adverse effects on the prognosis of patients with COVID-19 with psoriasis. In short, it is not recommended to stop biological treatment in patients with psoriasis to prevent the infection risk, and for those patients who tested positive for SARS-CoV-2, the decision to pause biologic therapy should be considered on a case-by-case basis, and individual risk and benefit should be taken into account. Vaccine immunization against SARS-CoV-2 is strictly recommendable in patients with psoriasis without discontinuation of their biologics but evaluating the risk-benefit ratio of maintaining biologics before vaccination is mandatory at the moment.

Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. METHODS: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). FINDINGS: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. INTERPRETATION: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. FUNDING: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.

Characterization of fungal communities on shared bicycles in Southwest China.

BACKGROUND: The widespread use of shared bicycles has increased the demand and sanitary requirements for shared bicycles. Previous studies have identified potentially pathogenic bacteria on the surfaces of shared bicycles, but fungal communities have not been investigated. METHODS: We sampled shared-bicycle handles and saddles from five selected locations in a metropolis (Chengdu, China, n = 98) and used surrounding air deposition samples as controls (n = 12). Full-length ITS sequencing and multiple bioinformatic analyses were utilized to reveal fungal community structures and differences. RESULTS: Aspergillus was dominant on both the handles and saddles of shared bicycles, and Alternaria and Cladosporium were the most abundant families in the air samples. Significant differences in fungal community structures were found among the three groups. The handle samples contained higher abundances of Aureobasidium melanogenum and Filobasidium magnum than the saddle and air samples. The saddle samples had a higher abundance of Cladosporium tenuissimum than the other two sample types (P < 0·05). A higher abundance of fungal animal pathogens on shared-bicycle surfaces than in air by FUNGuild (P < 0·05). Moreover, the co-occurrence network of fungi on handles was more stable than that on saddles. CONCLUSION: There were more potential pathogens, including Aspergillus pseudoglaucus, Aureobasidium melanogenum, Kazachstania pintolopesii, Filobasidium magnum, Candida tropicalis, and Malassezia globose were found on shared bicycles than in air, suggesting that hands should not contact mucous membrane after cycling, especially in susceptible individuals, and hygiene management of shared bicycles should be given more attention by relevant organizations worldwide.

Comprehensive Insights Into O3 Changes During the COVID-19 From O3 Formation Regime and Atmospheric Oxidation Capacity.

Economic activities and the associated emissions have significantly declined during the 2019 novel coronavirus (COVID-19) pandemic, which has created a natural experiment to assess the impact of the emitted precursor control policy on ozone (O3) pollution. In this study, we utilized comprehensive satellite, ground-level observations, and source-oriented chemical transport modeling to investigate the O3 variations during the COVID-19 pandemic in China. Here, we found that the significant elevated O3 in the North China Plain (40%) and Yangtze River Delta (35%) were mainly attributed to the enhanced atmospheric oxidation capacity (AOC) in these regions, associated with the meteorology and emission reduction during lockdown. Besides, O3 formation regimes shifted from VOC-limited regimes to NOx-limited and transition regimes with the decline of NOx during lockdown. We suggest that future O3 control policies should comprehensively consider the effects of AOC on the O3 elevation and coordinated regulations of the O3 precursor emissions.

The breadth of concomitant virological features in a family cluster outbreak of COVID-19 pneumonia.

An outbreak of a novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had emerged in 2019 and rapidly posed a global epidemic. Here, we report the breadth of concomitant virological features of a family cluster with COVID-19. The period of virus shedding is significantly different between upper respiratory and feces samples. Even the SARS-CoV-2 virus titers were undetectable in feces, it could be positive again soon and likely related to fluctuated inflammation levels (interleukin-6, etc.) and lowered immune responses (CD4 + T lymphocyte, etc.). Our findings expand the novel understanding of the breadth of concomitant virological features during a non-severe family cluster of COVID-19.

Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial.

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.

Responses of decline in air pollution and recovery associated with COVID-19 lockdown in the Pearl River Delta.

The Guangdong government implemented lockdown measures on January 23, 2020, to ease the spread of the coronavirus disease 2019 (COVID-19). These measures prohibit a series of human activities and lead to a great reduction in anthropogenic emissions. Starting on February 20, all companies resumed work and production, and emissions gradually recovered. To investigate the response of air pollutants in the Pearl River Delta (PRD) to the emission reduction and recovery related to COVID-19 lockdown, we used the Community Multi-scale Air Quality (CMAQ) model to estimate the changes in air pollutants, including three periods: Period I (January 10 to January 22, 2020), Period II (January 23 to February 19, 2020), Period III (February 20 to March 9, 2020). During Period II, under the concurrent influence of emissions and meteorology, air quality improved significantly with PM2.5, NO2, and SO2 decreased by 52%, 67%, and 25%, respectively. O3 had no obvious changes in most cities, which mainly due to the synergetic effects of emissions and meteorology. In Period III, with the recovery of emissions and the changes in meteorology, the increase of secondary components was faster than that of primary PM2.5 (PPM), which indicated that changes in PPM concentration were more sensitive to emissions reduction. O3 concentration increased as emission and temperature rising. Our findings elucidate that more effective emission control strategies should be implemented in PRD to alleviate the increasingly serious pollution situation.

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial.

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.

Single-cell landscape of immunological responses in patients with COVID-19.

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.

Immunological and inflammatory profiles in mild and severe cases of COVID-19.

COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.

Omics-Driven Systems Interrogation of Metabolic Dysregulation in COVID-19 Pathogenesis.

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.