Objectives: To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard–of–care (SOC) compared with SOC alone in adult patients with COVID–19. Design: Multicenter, open–label, randomized controlled trial. Setting: 16 government–designated COVID–19 treatment centers in China through 11 to 29 in February 2020. Participants: 150 patients hospitalized with laboratory confirmed COVID–19 were included in the intention to treat analysis. 75 patients were assigned to HCQ plus SOC and 75 to SOC alone. Interventions: HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). Main outcome measures: The primary outcome was whether participants had a negative conversion of SARS–CoV–2 by 28 days, and was analyzed according to the intention–to–treat principle. Adverse events were analyzed in the safety population in which HCQ recipients were participants who actually received at least one dose of HCQ and HCQ non–recipients were those actually managed with SOC alone. Results: Among 150 patients, 148 were with mild to moderate disease and 2 were with severe disease. The mean days (± standard deviation, min to max) from symptoms onset to randomization was 16.6 (±10.5 days, 3 to 41 days). The negative conversion probability by 28 days in SOC plus HCQ group was 85.4% (95% confidence interval (CI) 73.8% to 93.8%), similar to that in the SOC group 81.3% (95%CI 71.2% to 89.6%). Between–group difference was 4.1% (95%CI –10.3% to 18.5%). In the safety population, adverse events were recorded in 7 (8.8%) HCQ non–recipients (N=80) and in 21 (30%) HCQ recipients (N=70). The most common adverse event in the HCQ recipients was diarrhea, reported in 7 (10%) patients. Two HCQ recipients reported serious adverse events. Conclusions: The administration of HCQ did not result in a significantly higher negative conversion probability than SOC alone in patients mainly hospitalized with persistent mild to moderate COVID–19. Adverse events were higher in HCQ recipients than in HCQ non–recipients. Trial registration: ChiCTR2000029868 What is already known on this topic: — The pandemic of coronavirus disease 2019 (COVID–19) imposes substantial burdens on individuals, communities, health–care facilities, markets, governments, etc. globally. — There is no specific treatment approved for COVID–19 or vaccine to prevent infection with the novel coronavirus. — During the urgent pandemic, media headlines the utility of drugs without solid evidence but buries the side–effects of these drugs. What this study adds: — In this randomized clinical trial of patients mainly with persistent mild to moderate COVID–19, exposure to hydroxychloroquine led to a similar probability of virus elimination comparing to the current standard–of–care. — Adverse events, mostly gastrointestinal related, were significantly increased in patients who received hydroxychloroquine. — Overall, the results from our trial do not support the use of hydroxychloroquine in patients with persistent mild to moderate COVID–19. Print Study question: To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard–of–care (SOC) compared with SOC alone in adult patients with COVID–19. Methods: This is a multicenter, open–label, randomized controlled trial conducted in 16 government–designated COVID–19 treatment centers in China through 11 to 29 in February 2020. A total of 150 patients hospitalized with laboratory confirmed COVID–19 were included in the intention to treat analysis. Among them, 75 patients were assigned to HCQ plus SOC and 75 to SOC alone. HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). The primary outcome was whether participants had a negative conversion of SARS–CoV–2 by 28 days, and was analyzed according to the intention to treat principle. Adverse events were analyzed in the safety population in which HCQ recipients were participants who actually received at least one dose of HCQ and HCQ non–recipients were those actually managed with SOC alone. Study answer and limitations: Among 150 patients, 148 were with mild to moderate disease and 2 were with severe disease. The mean days (± standard deviation, min to max) from symptoms onset to randomization was 16.6 (±10.5 days, 3 to 41 days). The negative conversion probability by 28 days in SOC plus HCQ group was 85.4% (95% confidence interval (CI) 73.8% to 93.8%), similar to that in the SOC group 81.3% (95%CI 71.2% to 89.6%). Between–group difference was 4.1% (95%CI –10.3% to 18.5%). In the safety population, adverse events were recorded in 7 (8.8%) HCQ non–recipients (N=80) and in 21 (30%) HCQ recipients (N=70) with two serious adverse events. The most common adverse event in the HCQ recipients was diarrhea, reported in 7 (10%) patients. Two HCQ recipients reported serious adverse events. What this study adds: Our trial does not support the use of hydroxychloroquine in patients with persistent mild to moderate COVID–19 due to limited effects on virus eliminating and significantly increased adverse events. Funding, competing interests, data sharing: This work was supported by the Emergent Projects of National Science and Technology (2020YFC0844500), National Natural Science Foundation of China (81970020, 81770025), National Key Research and Development Program of China (2016YFC0901104), Shanghai Municipal Key Clinical Specialty...

Graphene-based nanomaterials (GBNs) consist of a single or few layers of graphene sheets or modified graphene including pristine graphene, graphene nanosheets (GNS), graphene oxide (GO), reduced graphene oxide (rGO), as well as graphene modified with various functional groups or chemicals (e.g., hydroxyl, carboxyl, and polyethylene glycol), which are frequently used in industrial and biomedical applications owing to their exceptional physicochemical properties. Given the widespread production and extensive application of GBNs, they can be disseminated in a wide range of environmental mediums, such as air, water, food, and soil. GBNs can enter the human body through various routes such as inhalation, ingestion, dermal penetration, injection, and implantation in biomedical applications, and the majority of GBNs tend to accumulate in the respiratory system. GBNs inhaled and substantially deposited in the human respiratory tract may impair lung defenses and clearance, resulting in the formation of granulomas and pulmonary fibrosis. However, the specific toxicity of the respiratory system caused by different GBNs, their influencing factors, and the underlying mechanisms remain relatively scarce. This review summarizes recent advances in the exposure, metabolism, toxicity and potential mechanisms, current limitations, and future perspectives of various GBNs in the respiratory system.

Chronic sleep deprivation (SD) from shift work and a high-fat diet (HFD) disrupt circadian rhythms and affect physiological systems, yet their impact on lu