Multiple RONS-Loaded Plasma-Activated Ice Microneedle Patches for Transdermal Treatment of Psoriasis.

Cold atmospheric plasma (CAP) is a fledgling therapeutic technique for psoriasis treatment with noninvasiveness, but clinical adoption has been stifled by the insufficient production and delivery of plasma-generated reactive oxygen and nitrogen species (RONS). Herein, patches of air-discharge plasma-activated ice microneedles (PA-IMNs) loaded with multiple RONS are designed for local transdermal delivery to treat psoriasis as an alternative to direct CAP irradiation treatment. By mixing two RONS generated by the air-discharge plasma in the NOx mode and O3 mode, abundant high-valence RONS are produced and incorporated into PA-IMNs via complex gas-gas and gas-liquid reactions. The PA-IMNs abrogate keratinocyte overproliferation by inducing reactive oxygen species (ROS)-mediated loss of the mitochondrial membrane potential and apoptosis of keratinocytes. The in vivo transdermal treatment confirms that PA-IMNs produce significant anti-inflammatory and therapeutic actions for imiquimod (IMQ)-induced psoriasis-like dermatitis in mice by inhibiting the release of associated inflammatory factors while showing no evident systemic toxicity. Therefore, PA-IMNs have a large potential in transdermal delivery platforms as they overcome the limitations of using CAP directly in the clinical treatment of psoriasis.

Plasma-generated RONS in liquid transferred into cryo-microneedles patch for skin treatment of melanoma.

Malignant melanoma is the most lethal form of skin cancer. As a promising anti-cancer agent, plasma-activated water (PAW) rich in reactive oxygen and nitrogen species (RONS) has shown significant potential for melanoma treatment. However, rapid decay of RONS and inefficient delivery of PAW in conventional injection methods limit its practical applications. To address this issue, here we report a new approach for the production of plasma-activated cryo-microneedles (PA-CMNs) patches using custom-designed plasma devices and processes. Our innovation is to incorporate PAW into the PA-CMNs that are fabricated using a fast cryogenic micro-molding method. It is demonstrated that PA-CMNs can be easily inserted into skin to release RONS and slow the decay of RONS thereby prolonging their bioactivity and effectiveness. The new insights into the effective melanoma treatment suggest that the rich mixture of RONS within PA-CMNs prepared by custom-developed hybrid plasma-assisted configuration induces both ferroptosis and apoptosis to selectively kill tumor cells. A significant inhibition of subcutaneous A375 melanoma growth was observed in PA-CMNs-treated tumor-bearing nude mice without any signs of systemic toxicity. The new approach based on PA-CMNs may potentially open new avenues for a broader range of disease treatments.

Association between inflammatory cytokines and anti-SARS-CoV-2 antibodies in hospitalized patients with COVID-19.

BACKGROUND: COVID-19 patients may experience "cytokine storm" when human immune system produces excessive cytokines/chemokines. However, it remains unclear whether early responses of inflammatory cytokines would lead to high or low titers of anti-SARS-CoV-2 antibodies. METHODS: This retrospective study enrolled a cohort of 272 hospitalized patients with laboratory-confirmed SARS-CoV-2. Laboratory assessments of serum cytokines (IL-2R, IL-6, IL-8, IL-10, TNF-α), anti-SARS-CoV-2 IgG/IgM antibodies, and peripheral blood biomarkers were conducted during hospitalization. RESULTS: At hospital admission, 36.4% patients were severely ill, 51.5% patients were ≥ 65 years, and 60.3% patients had comorbidities. Higher levels of IL-2R and IL-6 were observed in older patients (≥65 years). Significant differences of IL-2R (week 2 to week ≥5 from symptom onset), IL-6 (week 1 to week ≥5), IL-8 (week 2 to week ≥5), and IL-10 (week 1 to week 3) were observed between moderately-ill and severely ill patients. Anti-SARS-CoV-2 IgG titers were significantly higher in severely ill patients than in moderately ill patients, but such difference was not observed for IgM. High titers of early-stage IL-6, IL-8, and TNF-α (≤2 weeks after symptom onset) were positively correlated with high titers of late-stage IgG (≥5 weeks after symptom onset). Deaths were mostly observed in severely ill older patients (45.9%). Survival analyses revealed risk factors of patient age, baseline COVID-19 severity, and baseline IL-6 that affected survival time, especially in severely ill older patients. CONCLUSION: Early responses of elevated cytokines such as IL-6 reflect the active immune responses, leading to high titers of IgG antibodies against COVID-19.

Danoprevir for the Treatment of Hepatitis C Virus Infection: Design, Development, and Place in Therapy.

On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b - the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.

Mortality risk of COVID-19 in elderly males with comorbidities: a multi-country study.

The COVID-19 pandemic causes severe morbidity and mortality. This multi-country study aimed to explore risk factors that drive mortality in COVID-19 patients who received neither dexamethasone nor remdesivir. We analyzed a cohort of 568 survivors and 507 non-survivors from China, European regions, and North America. Elderly males ≥70 years accounted for only 25% of survivors, but this rate was significantly higher in non-survivors from China (55%), European regions (63%), and North America (47%). Compared with survivors, non-survivors had more incidences of comorbidities such as cerebrovascular disease and chronic obstructive pulmonary disease (COPD, p-values<0.05). Survival analyses revealed age, male gender, shortness of breath, cerebrovascular disease, and COPD as mortality-associated factors. Survival time from symptom onset was significantly shorter in elderly versus young patients (median: 29 versus 62 days), males versus females (median: 46 versus 59 days), and patients with versus without comorbidities (mean: 41 versus 61 days). Mortality risk was higher in elderly males with comorbidities than in young females without comorbidities (p-value<0.01). Elderly male survivors with comorbidities also had longer hospital stays than other survivors (25 versus 18.5 days, p-value<0.01). Overall, the high mortality risk in elderly males with COVID-19-associated comorbidities supports early prevention and critical care for elderly populations.