Corrigendum: Associations between omega-3 fatty acids and insulin resistance and body composition in women with polycystic ovary syndrome.

[This corrects the article DOI: 10.3389/fnut.2022.1016943.].

Effect of Corticosteroids on Long-term Humoral and Memory T-Cell Responses in Follow-up Visit of Hospitalized Patients With COVID-19.

BACKGROUND: Corticosteroids have beneficial effects in improving outcomes in hospitalized patients with severe COVID-19 by suppressing excessive immune responses. However, the effect of corticosteroids on the humoral and T-cell responses of survivors of COVID-19 1 year after infection remains uncertain because it relates to the extent of immediate, antigen-specific defense provided by protective memory. RESEARCH QUESTION: What is the effect of corticosteroids on long-term humoral and T-cell immune responses? STUDY DESIGN AND METHODS: In this retrospective cohort study conducted at a single center, we analyzed data from a cohort who had survived COVID-19 to compare the 1-year seropositivity and titer changes in neutralizing antibodies (NAbs) and SARS-CoV-2-specific antibodies. Additionally, we evaluated the magnitude and rate of SARS-CoV-2-specific T-cell response in individuals who received corticosteroids during hospitalization and those who did not. RESULTS: Our findings indicated that corticosteroids do not statistically influence the kinetics or seropositive rate of NAbs against the Wuhan strain of SARS-CoV-2 from 6 months to 1 year. However, subgroup analysis revealed a numerical increase of absolute NAbs titers, from 20.0 to 28.2, in categories where long-term (> 15 days) and high-dose (> 560 mg) corticosteroids are administered. Similarly, corticosteroids showed no significant effect on nucleoprotein and receptor-binding domain IgG at 1 year, except for spike protein IgG (ß, 0.08; 95% CI, 0.04-0.12), which demonstrated a delayed decline of titers. Regarding T-cell immunity, corticosteroids did not affect the rate or magnitude of T-cell responses significantly. However, functional assessment of memory T cells revealed higher interferon-γ responses in CD4 (ß, 0.61; 95% CI, 0.10-1.12) and CD8 (ß, 0.63; 95% CI, 0.11-1.15) memory T cells in the corticosteroids group at 1 year. INTERPRETATION: Based on our findings, short-term and low-dose corticosteroid therapy during hospitalization does not have a significant effect on long-term humoral kinetics or the magnitude and rate of memory T-cell responses to SARS-CoV-2 antigens. However, the potential harmful effects of long-term and high-dose corticosteroid use on memory immune responses require further investigation.

Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial.

Background: Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. Findings: Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. Interpretation: Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. Funding: This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.

Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19.

BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

3-year outcomes of discharged survivors of COVID-19 following the SARS-CoV-2 omicron (B.1.1.529) wave in 2022 in China: a longitudinal cohort study.

BACKGROUND: There is a paucity of data on the natural trajectory of outcomes in survivors of COVID-19 beyond 2 years after symptom onset, and no evidence exists on the effect of re-infection in people with long COVID symptoms. We aimed to investigate the 3-year health outcomes of COVID-19 survivors and the effect of omicron re-infection. METHODS: In this single-centre, longitudinal cohort study, we recruited participants with confirmed COVID-19 who were discharged from the Jin Yin-tan hospital in Wuhan, China, between Jan 7 and May 29, 2020. Participants completed three follow-up visits at 6 months (June 16 to Sept 13, 2020), 1 year (Dec 16, 2020, to Feb 7, 2021), and 2 years (Nov 16, 2021, to Jan 10, 2022) since symptom onset (reported previously). At 1-year follow-up, community controls without a history of SARS-CoV-2 infection were recruited from two communities in Wuhan and at 2 years were matched (1:1) with survivors of COVID-19 who underwent pulmonary function tests. We did a 3-year follow-up from Feb 23, 2023, to April 20, 2023, after the omicron (B.1.1.529) wave in winter, 2022. All eligible survivors of COVID-19 and community controls matched at 2-year follow-up were invited to the outpatient clinic at the hospital to complete several face-to-face questionnaires, a 6-min walking test (6MWT), and laboratory tests. A subgroup of survivors of COVID-19 identified by stratified sampling on the basis of disease severity scale score during hospitalisation and community controls underwent pulmonary function tests. Survivors of COVID-19 who received high-resolution CT and showed abnormal lung images at 2-year follow-up were invited for another assessment. We identified participants with and without long COVID at 2 years. The primary outcomes were sequelae symptoms, omicron infection, lung function, and chest imaging at the 3-year follow-up. FINDINGS: Of 1359 COVID-19 survivors who completed 2-year and 3-year follow-up, 728 (54%) had at least one sequelae symptom at 3 years after symptom onset and before omicron infection, mainly mild to moderate severity. During the omicron wave, participants with long COVID at 2 years had a significantly higher proportion of re-infection (573 [76%] of 753 vs 409 [67%] of 606 without long COVID; p=0·0004), pneumonia (27 [5%] of 568 vs seven [2%] of 403; p=0·012). 3 months after omicron infection, 126 (62%) of 204 survivors with long COVID at 2 years had newly occurring or worse symptoms, which was significantly higher than the proportion in the non-long COVID group (85 [41%] of 205; p<0·0001) and community controls (81 [40%] of 205; p<0·0001), and not significantly different between COVID-19 survivors without long COVID and matched community controls (85 [41%] of 205 vs 81 [39%] of 206; p=0·66). Re-infection was a risk factor for dyspnoea (odds ratio 1·36 [95% CI 1·04 to 1·77]; p=0·023), anxiety or depression (OR 1·65 [1·24 to 2·20]; p=0·0007), EuroQol visual analogue scale score (ß -4·51 [-6·08 to -2·95]; p<0·0001), but not for reduced daily activity (0·72 [0·38 to 1·37]; p=0·32) at 3 years. Lung function of survivors at 3 years was similar to that of matched community controls. We found irregular line, traction bronchiectasis, subpleural lines and ground glass opacity at 3 years, but the volume ratio of lung lesion to total lung was only 0·2-0·3%. INTERPRETATION: Most long COVID symptoms at 3 years were mild to moderate, with lung function recovering to levels of matched controls. Survivors with long COVID had a higher proportion of participants with re-infection and newly occurring or worse symptoms 3 months after omicron infection than those without long COVID. Re-infection had increased symptom occurrence but not increased reduced daily activity. Although the organ function of survivors of COVID-19 recovered over time, those with severe long COVID symptoms, abnormal organ function, or limited mobility require urgent attention in future clinical practice and research. FUNDING: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China.

Oral VV116 versus placebo in patients with mild-to-moderate COVID-19 in China: a multicentre, double-blind, phase 3, randomised controlled study.

BACKGROUND: Spread of SARS-CoV-2 led to a global pandemic, and there remains unmet medical needs in the treatment of Omicron infections. VV116, an oral antiviral agent that has potent activity against SARS-CoV-2, was compared with a placebo in this phase 3 study to investigate its efficacy and safety in patients with mild-to-moderate COVID-19. METHODS: This multicentre, double-blind, phase 3, randomised controlled study enrolled adults in hospitals for infectious diseases and tertiary general hospitals in China. Eligible patients were randomly assigned in a 1:1 ratio using permuted block randomisation to receive oral VV116 (0·6 g every 12 h on day 1 and 0·3 g every 12 h on days 2-5) or oral placebo (on the same schedule as VV116) for 5 days. Randomisation stratification factors included SARS-CoV-2 vaccination status and the presence of high-risk factors for progression to severe COVID-19. Inclusion criteria were a positive SARS-CoV-2 test, an initial onset of COVID-19 symptoms 3 days or less before the first study dose, and a score of 2 or more for any target COVID-19-related symptoms in the 24 h before the first dose. Patients who had severe or critical COVID-19 or who had taken any antiviral drugs were excluded from the study. The primary endpoint was the time to clinical symptom resolution for 2 consecutive days. Efficacy analyses were performed on a modified intention-to-treat population, comprising all patients who received at least one dose of VV116 or placebo, tested positive for SARS-CoV-2 nucleic acid, and did not test positive for influenza virus before the first dose. Safety analyses were done on all participants who received at least one dose of VV116 or placebo. This study was registered with ClinicalTrials.gov, NCT05582629, and has been completed. FINDINGS: A total of 1369 patients were randomly assigned to treatment groups and 1347 received either VV116 (n=674) or placebo (n=673). At the interim analysis, VV116 was superior to placebo in reducing the time to sustained clinical symptom resolution among 1229 patients (hazard ratio [HR] 1·21, 95% CI 1·04-1·40; p=0·0023). At the final analysis, a substantial reduction in time to sustained clinical symptom resolution was observed for VV116 compared with placebo among 1296 patients (HR 1·17, 95% CI 1·04-1·33; p=0·0009), consistent with the interim analysis. The incidence of adverse events was similar between groups (242 [35·9%] of 674 patients vs 283 [42·1%] of 673 patients). INTERPRETATION: Among patients with mild-to-moderate COVID-19, VV116 significantly reduced the time to sustained clinical symptom resolution compared with placebo, with no observed safety concerns. FUNDING: Shanghai Vinnerna Biosciences, Shanghai Science and Technology Commission, and the National Key Research and Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Human monoclonal antibody F61 nasal spray effectively protected high-risk populations from SARS-CoV-2 variants during the COVID-19 pandemic from late 2022 to early 2023 in China.

Following the national dynamic zero-COVID strategy adjustment, the utilization of broad-spectrum nasal neutralizing antibodies may offer alternative approach to controlling the outbreak of Omicron variants between late 2022 and early 2023 in China. This study involved an investigator-initiated trial (IIT) to assess the pharmacokinetic, safety and efficacy of the F61 nasal spray. A total of 2,008 participants were randomly assigned to receive F61 nasal spray (24 mg/0.8 mL/dose) or normal saline (0.8 mL/dose) and 1,336 completed the follow-up in the IIT. Minimal absorption of F61 antibody into the bloodstream was detected in individuals receiving F61 nasal spray for seven consecutive days. No treatment-emergent adverse reactions of grade 3 severity or higher were reported. In the one-dose cohort, the 7-day cumulative SARS-CoV-2 infection rate was 79.0% in the F61 group and 82.6% in the placebo group, whereas, in the multiple-dose (once daily for 7 consecutive days) cohort, the rates were 6.55% in the F61 group and 23.83% in the placebo group. The laboratory-confirmed efficacy of F61 was 3.78% (-3.74%-10.75%) in the one-dose cohort and 72.19% (57.33%-81.87%) in the multiple-dose cohort. In the real-world study, 60,225 volunteers in four different regions were administered the F61 nasal spray based on subject's wishes, over 90% efficacy rate was observed against different Omicron variants. The F61 nasal spray, with its favorable safety profile, could be a promising prophylactic monoclonal antibody against SARS-CoV-2 VOCs.

Early age at menarche is associated with an increased risk of preeclampsia and adverse neonatal outcomes: a 6­year retrospective study.

PURPOSE: Preeclampsia affects between 2 to 8% of pregnancies worldwide and is associated with significant adverse outcomes for both mothers and their offspring. The present study aims to investigate whether there is a correlation between early age at menarche and an increased risk of developing preeclampsia and experiencing adverse neonatal outcomes. METHODS: The study involved a review of medical records of 4227 pregnant women who gave birth at The First Affiliated Hospital of Chengdu Medical College between January 2017 and December 2022. The collected data included demographic characteristics, clinical manifestations of preeclampsia, laboratory indicators, gestational complications, and neonatal outcomes. Pregnant women were categorized into four groups based on their age at menarche (≤ 12, 13, 14, and ≥ 15 years). Logistic regression analysis was conducted to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between different menarche age groups and the risk of preeclampsia and adverse neonatal outcomes. RESULTS: Pregnant women who had an age at menarche of ≤ 12 years had a higher risk of preeclampsia than women who had their menarche at 13, 14, and ≥ 15 years of age, with adjusted ORs (95% CIs) for preeclampsia of 1.00 (reference), 0.78 (0.45-0.91), 0.76 (0.59-0.88), and 0.73 (0.56-0.94), respectively. The predictive efficacy of age at menarche for preeclampsia was assessed with a sensitivity and specificity of 85.2% and 76.4%, respectively, and an AUC of 0.82. Moreover, infants born to women with an age at menarche of ≤ 12 years had a higher risk of adverse neonatal outcomes, including small for gestational age, preterm birth, low birth weight, neonatal respiratory distress syndrome, and neonatal intensive care unit admission. CONCLUSION: Our findings suggest that an early age at menarche is associated with an increased risk of preeclampsia and adverse neonatal outcomes. This information could be useful for obstetricians to identify women at risk for preeclampsia early on and implement timely interventions to reduce the incidence of preeclampsia and associated adverse neonatal outcomes.

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.

BACKGROUND: The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity. METHODS: We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. Patients who died before follow-up; patients for whom follow-up would be difficult because of psychotic disorders, dementia, or readmission to hospital; those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism; those who declined to participate; those who could not be contacted; and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5-6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received SARS-CoV-2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences. FINDINGS: In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 years (IQR 47·0-65·0) and 897 (52%) were male and 836 (48%) were female. The follow-up study was done from June 16 to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 days (175·0-199·0). Fatigue or muscle weakness (52%, 855 of 1654) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1616) of patients. The proportions of 6-min walking distance less than the lower limit of the normal range were 17% for those at severity scale 3, 13% for severity scale 4, and 28% for severity scale 5-6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5-6, and median CT scores were 3·0 (IQR 2·0-5·0) for severity scale 3, 4·0 (3·0-5·0) for scale 4, and 5·0 (4·0-6·0) for scale 5-6. After multivariable adjustment, patients showed an odds ratio (OR) of 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·76 (1·05-2·96) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·87 (0·68-1·11) for scale 4 versus scale 3 and 2·75 (1·61-4·69) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with an estimated glomerular filtration rate (eGFR) of 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up. INTERPRETATION: At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery. FUNDING: National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.

Integrative proteomic profiling of lung tissues and blood in acute respiratory distress syndrome.

Introduction: Acute respiratory distress syndrome and acute lung injury (ARDS/ALI) still lack a recognized diagnostic test and pharmacologic treatments that target the underlying pathology. Methods: To explore the sensitive non-invasive biomarkers associated with pathological changes in the lung of direct ARDS/ALI, we performed an integrative proteomic analysis of lung and blood samples from lipopolysaccharide (LPS)-induced ARDS mice and COVID-19-related ARDS patients. The common differentially expressed proteins (DEPs) were identified based on combined proteomic analysis of serum and lung samples in direct ARDS mice model. The clinical value of the common DEPs was validated in lung and plasma proteomics in cases of COVID-19-related ARDS. Results: We identified 368 DEPs in serum and 504 in lung samples from LPS-induced ARDS mice. Gene ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEPs in lung tissues were primarily enriched in pathways, including IL-17 and B cell receptor signaling pathways, and the response to stimuli. In contrast, DEPs in the serum were mostly involved in metabolic pathways and cellular processes. Through network analysis of protein-protein interactions (PPI), we identified diverse clusters of DEPs in the lung and serum samples. We further identified 50 commonly upregulated and 10 commonly downregulated DEPs in the lung and serum samples. Internal validation with a parallel-reacted monitor (PRM) and external validation in the Gene Expression Omnibus (GEO) datasets further showed these confirmed DEPs. We then validated these proteins in the proteomics of patients with ARDS and identified six proteins (HP, LTA4H, S100A9, SAA1, SAA2, and SERPINA3) with good clinical diagnostic and prognostic value. Discussion: These proteins can be viewed as sensitive and non-invasive biomarkers associated with lung pathological changes in the blood and could potentially serve as targets for the early detection and treatment of direct ARDS especially in hyperinflammatory subphenotype.

Polycystic ovary syndrome is associated with a higher risk of premalignant and malignant endometrial polyps in premenopausal women: a retrospective study in a tertiary teaching hospital.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by anovulation, insufficient progesterone, hyperandrogenism, and insulin resistance. These factors can disrupt the endometrium of PCOS patients and can lead to chronic low-grade inflammation in the endometrium, endometrial hyperplasia, or even endometrial cancer. OBJECTIVE: The aim of this study was to investigate the prevalence of premalignant and malignant endometrial polyps in premenopausal women and to further explore whether PCOS is associated with premalignant and malignant changes in endometrial polyps. METHODS: This study was conducted by retrieving the medical data of 4236 premenopausal women who underwent hysteroscopic polypectomies between January 2015 and December 2021. Demographic and clinical data regarding age, height, weight, parity, hormone replacement therapy, oral contraceptives, abnormal uterine bleeding, hypertension, diabetes mellitus, PCOS, number of polyps, and size of polyps were collected, and their associations with premalignant and malignant changes in endometrial polyps were analysed. RESULT: Among the endometrial polyps removed by hysteroscopic polypectomy in premenopausal women, the prevalence of premalignant and malignant polyps was 2.15%, which comprised hyperplasia with atypia at 1.13% and endometrial carcinoma at 1.02%. PCOS was associated with a higher risk of premalignant and malignant endometrial polyps in premenopausal women after adjustment for potential confounding factors. CONCLUSION: PCOS is associated with a higher risk of premalignant and malignant endometrial polyps in premenopausal women. Therefore, it is important to evaluate the endometrium in PCOS patients with ultrasonography or hysteroscopy, and active management involving hysteroscopic polypectomy should be offered to PCOS patients diagnosed with endometrial polyps regardless of symptoms.

Antiviral activity of the HSP90 inhibitor VER-50589 against enterovirus 71.

Enterovirus 71 (EV71) is the major pathogen responsible for hand, foot, and mouth disease (HFMD) outbreaks; to date, there is no specific anti-EV71 agent. HSP90 is a crucial host factor for the viral life cycle and an ideal therapeutic target for limiting viral proliferation. However, the specific role of HSP90 in EV71-related signaling pathways and anti-EV71 agents targeting HSP90 remains unclear. This study aimed to verify the role of HSP90 in signaling pathways involved in EV71 replication and investigate the antiviral effects of a small molecule of VER-50589, a potent HSP90 inhibitor, against EV71 both in vitro and in vivo. Viral plaque assay, western blotting, and qPCR results showed that VER-50589 diminished the plaque formation induced by EV71 and inhibited EV71 mRNA and protein synthesis. A single daily dose of VER-50589 treatment significantly improved the survival rate of EV71-infected mice (p < 0.005). Interestingly, VER-50589 also exhibits activities against a series of human enteroviruses, including Coxsackievirus B3 (CVB3), Coxsackievirus B4-5 (CVB4-5), Coxsackievirus B4-7 (CVB4-7), and Echovirus 11 (Echo11). EV71 infection activated the AKT and ERK signaling pathways, and phosphorylation of AKT and RAF/MEK/ERK was weakened by VER-50589 administration. Thus, VER-50589 exhibits robust antiviral activity by inhibiting HSP90 and mediating the AKT and RAF/MEK/ERK signaling pathways. Considering that there are no effective antivirals or vaccines for the prevention and cure of HFMD in a clinical setting, the development of an anti-EV71 agent would be a straightforward and feasible therapeutic approach.

PLX8394, a RAF inhibitor, inhibits enterovirus 71 replication by blocking RAF/MEK/ERK signaling.

Enterovirus 71 (EV71) poses a serious threat to human health, with scattered outbreaks worldwide. There are several vaccines against a few EV71 strains but no efficient drug for the treatment of EV71 infection. Therefore, it is urgent and of significance to develop anti-EV71 drugs. Here, we found that PLX8394, a RAF inhibitor, possesses high antiviral activity against EV71 in vitro, being superior to the traditional clinical drug ribavirin. Moreover, PLX8394 exhibits broad-spectrum antiviral activity against enteroviruses. Notably, in a suckling mouse model, PLX8394 provided a 70% protection rate for EV71-infected mice, reduced the viral load in liver and heart tissues, and relieved the inflammatory response. A mechanistic study showed that PLX8394 inhibited EV71 by suppressing the RAF/MEK/ERK signaling pathway. Thus, PLX8394 lays a foundation for the development of new drugs against EV71.

ML390 inhibits enterovirus 71 replication by targeting de novo pyrimidine biosynthesis pathway.

Enterovirus 71 (EV71), a small, single-stranded, positive-sense RNA virus belonging to the enterovirus genus in the family Picornaviridae, causes hand, foot, and mouth disease. Although EV71 seriously threatens to public health, no effective antiviral drugs are available for treating this disease. In this study, we found that ML390, a dihydroorotate dehydrogenase inhibitor, has potential anti-EV71 activity. ML390 dose-dependently inhibited EV71 replication with IC50 and selectivity index values of 0.06601 µM and 156.5, respectively. Supplementation with the downstream product orotate significantly suppressed the ability of ML390 to inhibit EV71 replication. Moreover, an adequate supply of exogenous uridine and cytosine suppressed the anti-EV71 activity of ML390. Thus, the antiviral activity of ML390 is mediated by the inhibition of the pyrimidine synthesis pathway. In an EV71-infected mouse model, ML390 reduced the load of EV71 in the brain, liver, heart, spleen, front legs, and hind legs, and significantly increased the survival rate of the mice infected by EV71. ML390 shows potential for the treatment of hand, foot, and mouth disease caused by EV71 infection.

Maternal serum NGAL in the first trimester of pregnancy is a potential biomarker for the prediction of gestational diabetes mellitus.

Objective: Gestational diabetes mellitus (GDM) has adverse effects on the health of mothers and their offspring. Currently, no known biomarker has been proven to have sufficient validity for the prediction of GDM in the first trimester of pregnancy. The aim of this study was to investigate the potential relationship between serum neutrophil gelatinase-associated lipocalin (NGAL) levels in the first trimester of pregnancy and later GDM risk and to evaluate the performance of serum NGAL as a biomarker for the prediction of GDM. Methods: The study was conducted by recruiting participants at 8-13 weeks of gestation from The First Affiliated Hospital of Chengdu Medical College between January and June 2021; participants were followed up for oral glucose tolerance test (OGTT) screening at 24-28 gestational weeks. We examined the serum NGAL levels of all subjects in the first trimester who met the inclusion and exclusion criteria. Anthropometric, clinical, and laboratory parameters of the study subjects were obtained during the same study period. A logistic regression model was carried out to investigate the potential relationship between serum NGAL levels in the first trimester of pregnancy and later GDM risk. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to assess the discrimination and calibration of serum NGAL as a biomarker for the prediction of GDM in the first trimester of pregnancy. Results: Serum NGAL levels in the first trimester of pregnancy were significantly higher in women who later developed GDM than in those who did not develop GDM. Serum NGAL levels in the first trimester of pregnancy were positively associated with an increased risk of GDM after adjustment for potential confounding factors. The risk prediction model for GDM constructed by using serum NGAL levels in the first trimester of pregnancy achieved excellent performance. Conclusions: Maternal serum NGAL in the first trimester of pregnancy is a potential biomarker for the prediction of GDM, which could help guide the clinical practice of antenatal care.

Comparison of clinical characteristics between COVID-19 and H7N9 fatal cases: An observational study.

Objective: The outbreak of COVID-19 in 2020 is reminiscent of the H7N9 outbreak in 2013, which poses a huge threat to human health. We aim to compare clinical features and survival factors in fatal cases of COVID-19 and H7N9. Methods: Data on confirmed COVID-19 and H7N9 fatal cases identified in mainland China were analyzed to compare demographic characteristics and clinical severity. Survival curves were estimated by the Kaplan-Meier method and compared using log-rank tests and a restricted mean survival time model. A Cox regression model was used to identify survival factors in fatal cases of COVID-19 and H7N9. Results: Similar demographic characteristics were observed in fatal cases of COVID-19 and H7N9. The proportion of fatal cases of H7N9 receiving antibiotics, antiviral drugs, and oxygen treatment was higher than that of COVID-19. The potential protective factors for fatal COVID-19 cases were receiving antibiotics (HR: 0.37, 95% CI: 0.22-0.61), oxygen treatment (HR: 0.66, 95% CI: 0.44-0.99), and corticosteroids (HR: 0.46, 95% CI: 0.35-0.62). In contrast, antiviral drugs (HR: 0.21, 95% CI: 0.08-0.56) and corticosteroids (HR: 0.45, 95% CI: 0.29-0.69) were the protective factors for H7N9 fatal cases. Conclusion: The proportion of males, those having one or more underlying medical condition, and older age was high in COVID-19 and H7N9 fatal cases. Offering antibiotics, oxygen treatment, and corticosteroids to COVID-19 cases extended the survival time. Continued global surveillance remains an essential component of pandemic preparedness.

Associations between omega-3 fatty acids and insulin resistance and body composition in women with polycystic ovary syndrome.

Background: Polycystic ovary syndrome (PCOS) is strongly associated with abdominal obesity and insulin resistance and effective approaches to nutrition (e.g., omega-3 fatty acids intake) might improve the cardiometabolic risk profile. This study aimed to examine the associations of dietary and serum omega-3 fatty acids with insulin resistance (IR) and body composition among PCOS patients. Methods: A total of 185 patients with PCOS were included in our analysis. Dietary information was collected through face-to-face interviews using a 102-item food frequency questionnaire (FFQ). Serum omega-3 fatty acid levels were measured with the gas chromatography method. Body composition was measured by both dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance (BIA) methods. The multivariable linear regression model was applied to analyze the associations of dietary and serum omega-3 fatty acids with the levels of Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and body composition parameters among PCOS patients. Results: Our results indicated that the dietary long-chain omega-3 polyunsaturated fatty acids (PUFA) intakes were negatively associated with HOMA-IR (ß = -0.089, P = 0.040), fat mass (ß = -0.022, P = 0.047), and body fat percentage (ß = -0.026, P = 0.032). For serum biomarkers, higher total omega-3 PUFAs levels (ß = -0.158, P = 0.021) and long-chain omega-3 PUFAs levels (ß = -0.187, P < 0.001), particularly eicosapentaenoic acid (EPA) (ß = -164, P = 0.011) and docosahexaenoic acid (DHA) (ß = -0.158, P = 0.001) were also associated with decreased HOMA-IR. In addition, generally, dietary and serum long-chain omega-3 PUFA levels, DPA, and DHA levels were both positively associated with muscle mass measured by DXA; whereas serum total, long-chain and individual omega-3 PUFA levels (e.g., DPA, EPA, and DHA) were all negatively associated with fat mass and body fat percentage. These findings were further confirmed by the findings for body composition measured by the BIA method. Conclusion: Higher levels of dietary and serum omega-3 PUFAs, particularly long-chain omega PUFAs (DPA and DHA), might have beneficial effects on metabolic parameters and body composition among PCOS patients.

Lung-function trajectories in COVID-19 survivors after discharge: A two-year longitudinal cohort study.

Background: Data on the long-term trajectories of lung function are scarce in COVID-19 survivors. Methods: We re-analyzed the data from a prospective longitudinal cohort follow-up study of COVID-19 survivors over 2 years after infection. All participants were divided into scale 3, scale 4 and scale 5-6 groups according to seven-category ordinal scale. The changes of pulmonary function tests (PFTs), the Modified Medical Research Council (mMRC) Dyspnea Scale, 6-min walking test health-related quality of life (HRQoL) across the three serial follow-up visits were evaluated, and compared among three groups. We performed liner regression to determine potential factors that were associated with changes of PFTs and distance walked in 6 minutes (6MWD). Findings: In this study, 288 participants generally presented an improvement of PFTs parameters from 6 months to 1 year after infection. The scale 5-6 group displayed a significantly higher increase of PFTs compared with scale 3 and scale 4 groups (all p<0.0167), and corticosteroids therapy was identified as a protective factor for the PFTs improvement with a correlation coefficient of 2.730 (0.215-5.246) for forced vital capacity (FVC), 2.909 (0.383-5.436) for total lung capacity (TLC), and 3.299 (0.211-6.387) for diffusion capacity for carbon monoxide (DLco), respectively. From 1-year to 2-year follow-up, the PFTs parameters generally decreased, which was not observed to be associated with changes of 6MWD and HRQoL. Dyspnea (mMRC≥1) generally decreased over time (23.3% [61/262] for 6-month, 27.9% [67/240] for 1-year, 13.4% [35/261] for 2-year), and 6MWD increased continuously (500.0 m vs 505.0 m vs 525.0 m). Interpretation: Corticosteroids therapy during hospitalization was a protective factor for PFTs improvement from 6 months to 1 year. The relatively fast decline trend of PFTs from 1 year to 2 years needs to be paid attention and further validated in the future follow-up study. Fundings: This work was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS 2021-I2M-1-048) and the National Key Research and Development Program of China (2021YFC0864700).