A New Orthonairovirus Associated with Human Febrile Illness.

BACKGROUND: In June 2019, a patient presented with persistent fever and multiple organ dysfunction after a tick bite at a wetland park in Inner Mongolia. Next-generation sequencing in this patient revealed an infection with a previously unknown orthonairovirus, which we designated Wetland virus (WELV). METHODS: We conducted active hospital-based surveillance to determine the prevalence of WELV infection among febrile patients with a history of tick bites. Epidemiologic investigation was performed. The virus was isolated, and its infectivity and pathogenicity were investigated in animal models. RESULTS: WELV is a member of the orthonairovirus genus in the Nairoviridae family and is most closely related to the tickborne Hazara orthonairovirus genogroup. Acute WELV infection was identified in 17 patients from Inner Mongolia, Heilongjiang, Jilin, and Liaoning, China, by means of reverse-transcriptase-polymerase-chain-reaction assay. These patients presented with nonspecific symptoms, including fever, dizziness, headache, malaise, myalgia, arthritis, and back pain and less frequently with petechiae and localized lymphadenopathy. One patient had neurologic symptoms. Common laboratory findings were leukopenia, thrombocytopenia, and elevated d-dimer and lactate dehydrogenase levels. Serologic assessment of convalescent-stage samples obtained from 8 patients showed WELV-specific antibody titers that were 4 times as high as those in acute-phase samples. WELV RNA was detected in five tick species and in sheep, horses, pigs, and Transbaikal zokors (Myospalax psilurus) sampled in northeastern China. The virus that was isolated from the index patient and ticks showed cytopathic effects in human umbilical-vein endothelial cells. Intraperitoneal injection of the virus resulted in lethal infections in BALB/c, C57BL/6, and Kunming mice. The Haemaphysalis concinna tick is a possible vector that can transovarially transmit WELV. CONCLUSIONS: A newly discovered orthonairovirus was identified and shown to be associated with human febrile illnesses in northeastern China. (Funded by the National Natural Science Foundation of China and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.).

Projecting spatiotemporal dynamics of severe fever with thrombocytopenia syndrome in the mainland of China.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with increasing incidence and geographic extent. The extent to which global climate change affects the incidence of SFTS disease remains obscure. We use an integrated multi-model, multi-scenario framework to assess the impact of global climate change on SFTS disease in China. The spatial distribution of habitat suitability for the tick Haemaphysalis longicornis was predicted by applying a boosted regression tree model under four alternative climate change scenarios (RCP2.6, RCP4.5, RCP6.0, and RCP8.5) for the periods 2030-2039, 2050-2059, and 2080-2089. We incorporate the SFTS cases in the mainland of China from 2010 to 2019 with environmental variables and the projected distribution of H. longicornis into a generalized additive model to explore the current and future spatiotemporal dynamics of SFTS. Our results demonstrate an expanded geographic distribution of H. longicornis toward Northern and Northwestern China, showing a more pronounced change under the RCP8.5 scenario. In contrast, the environmental suitability of H. longicornis is predicted to be reduced in Central and Eastern China. The SFTS incidence in three time periods (2030-2039, 2050-2059, and 2080-2089) is predicted to be increased as compared to the 2010s in the context of various RCPs. A heterogeneous trend across provinces, however, was observed, when an increased incidence in Liaoning and Shandong provinces, while decreased incidence in Henan province is predicted. Notably, we predict possible outbreaks in Xinjiang and Yunnan in the future, where only sporadic cases have been reported previously. These findings highlight the need for tick control and population awareness of SFTS in endemic regions, and enhanced monitoring in potential risk areas.

Coinfections in hospitalized patients with severe fever with thrombocytopenia syndrome: A retrospective study.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with a high case fatality rate. Few studies have been performed on bacterial or fungal coinfections or the effect of antibiotic therapy. A retrospective, observational study was performed to assess the prevalence of bacterial and fungal coinfections in patients hospitalized for SFTSV infection. The most commonly involved microorganisms and the effect of antimicrobial therapy were determined by the site and source of infection. A total of 1201 patients hospitalized with SFTSV infection were included; 359 (29.9%) had microbiologically confirmed infections, comprised of 292 with community-acquired infections (CAIs) and 67 with healthcare-associated infections (HAIs). Death was independently associated with HAIs, with a more significant effect than that observed for CAIs. For bacterial infections, only those acquired in hospitals were associated with fatal outcomes, while fungal infection, whether acquired in hospital or community, was related to an increased risk of fatal outcomes. The infections in the respiratory tract and bloodstream were associated with a higher risk of death than that in the urinary tract. Both antibiotic and antifungal treatments were associated with improved survival for CAIs, while for HAIs, only antibiotic therapy was related to improved survival, and no effect from antifungal therapy was observed. Early administration of glucocorticoids was associated with an increased risk of HAIs. The study provided novel clinical and epidemiological data and revealed risk factors, such as bacterial coinfections, fungal coinfections, infection sources, and treatment strategies associated with SFTS deaths/survival. This report might be helpful in curing SFTS and reducing fatal SFTS.

Plasma glucose levels and diabetes are independent predictors for mortality in patients with COVID-19.

This study is performed to figure out how the presence of diabetes affects the infection, progression and prognosis of 2019 novel coronavirus disease (COVID-19), and the effective therapy that can treat the diabetes-complicated patients with COVID-19. A multicentre study was performed in four hospitals. COVID-19 patients with diabetes mellitus (DM) or hyperglycaemia were compared with those without these conditions and matched by propensity score matching for their clinical progress and outcome. Totally, 2444 confirmed COVID-19 patients were recruited, from whom 336 had DM. Compared to 1344 non-DM patients with age and sex matched, DM-COVID-19 patients had significantly higher rates of intensive care unit entrance (12.43% vs. 6.58%, P = 0.014), kidney failure (9.20% vs. 4.05%, P = 0.027) and mortality (25.00% vs. 18.15%, P < 0.001). Age and sex-stratified comparison revealed increased susceptibility to COVID-19 only from females with DM. For either non-DM or DM group, hyperglycaemia was associated with adverse outcomes, featured by higher rates of severe pneumonia and mortality, in comparison with non-hyperglycaemia. This was accompanied by significantly altered laboratory indicators including lymphocyte and neutrophil percentage, C-reactive protein and urea nitrogen level, all with correlation coefficients >0.35. Both diabetes and hyperglycaemia were independently associated with adverse prognosis of COVID-19, with hazard ratios of 10.41 and 3.58, respectively.

Effect of tocilizumab plus corticosteroid on clinical outcome in patients hospitalized with severe fever with thrombocytopenia syndrome: A randomized clinical trial.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with high fatality rates. The blockade of pro-inflammatory cytokines presents a promising therapeutic strategy. METHODS: We conducted a randomized clinical trial at the 154th hospital, Xinyang, Henan Province. Eligible patients with severe SFTS disease were randomly assigned in a 1:2 ratio to receive either a single intravenous infusion of tocilizumab plus usual care; or usual care only. The primary outcome was the clinical status of death/survival at day 14, while secondary outcomes included improvement from baseline in liver and kidney damage and time required for hospital discharge. The efficacy of tocilizumab plus corticosteroid was compared to those receiving corticosteroid alone. The trial is registered with the Chinese Clinical Trial Registry website (ChiCTR2300076317). RESULTS: 63 eligible patients were assigned to the tocilizumab group and 126 to the control group. The addition of tocilizumab to usual care was associated with a reduced death rate (9.5%) compared to those received only usual care (23.0%), with an adjusted hazard ratio (aHR) of 0.37 (95% confidence interval [CI], 0.15 to 0.91, P = 0.029). Combination therapy of tocilizumab and corticosteroids was associated with a significantly reduced fatality (aHR, 0.21; 95% CI, 0.08 to 0.56; P = 0.002) compared to those receiving corticosteroids alone. CONCLUSIONS: A significant benefit of reducing fatality in severe SFTS patients was observed by using tocilizumab. A combined therapy of tocilizumab plus corticosteroids was recommended for the therapy of severe SFTS.

Clinical efficacy of low-dose glucocorticoid therapy for critically ill patients with severe fever with thrombocytopenia syndrome: A retrospective cohort study.

OBJECTIVES: To determine whether glucocorticoids can improve clinical outcomes of severe fever with thrombocytopenia syndrome (SFTS) patients, and how to identify patients who may benefit from the treatment. METHODS: A retrospective study was performed to include patients with confirmed SFTS from designated hospitals. The effect of glucocorticoids in reducing case fatality rate (CFR) and improving clinical recovery was evaluated by multivariate logistic regression models. RESULTS: A total of 2478 eligible patients were analyzed, of whom 331 received glucocorticoids. An integrated parameter (L-index) based on Log10(lactate dehydrogenase*blood urea nitrogen/lymphocyte count) was constructed to discriminate disease severity. In patients with L-index >3.823 indicating severe SFTS, significantly reduced CFR was observed in patients receiving low-moderate glucocorticoid doses with ≤60 mg daily methylprednisolone or equivalent (odds ratio [OR] 0.46, 95% confidence interval [CI], 0.23-0.88), but not in patients receiving high doses. In patients with L-index ≤3.823 indicating mild SFTS, glucocorticoid treatment was significantly associated with increased CFR (OR 3.34, 95% CI, 1.35-9.51), and mainly attributable to high-dose glucocorticoids (OR 2.83, 95% CI, 1.72-4.96). Disaggregated data analysis revealed a significant effect only in patients ≤65 years old, male, and early admission within 7 days after onset, but not in their counterparts. CONCLUSION: Glucocorticoids are not recommended for mild patients defined by L-index <3.823; however, patients with severe SFTS may benefit from low-moderate doses of glucocorticoids.

Relationships between urinary antimony concentrations and depressive symptoms in adults.

BACKGROUND: Antimony is widely used in industrial production. The general population may be exposed to long-term low-dose antimony, and there are no studies on antimony and depression symptoms. This study aims to explore the relationships between urinary antimony concentrations and depressive symptoms in adults. METHODS: We conducted a cross-sectional study using data from U.S. National Health and Nutrition Examination Survey (NHANES) 2007-2016 for urinary antimony (N = 8538). Depressive symptoms were assessed through Patient's Health Questionnaire (PHQ-9). In order to determine the relationships between urinary antimony concentrations and depressive symptoms, binary logistic regression model and restricted cubic spline were used. Dominance analysis was used to explore the relative importance between variables associated with depressive symptoms. RESULTS: There was a significant positive relationship between urinary antimony concentrations and depressive symptoms in the general population, and OR with 95% CI was 1.72 (1.15, 2.60). This relationship also occurred in participants without disease status, and OR with 95% CI was 2.05 (1.10, 3.82). After stratified gender, the urinary antimony concentrations were positively correlated with depressive symptoms in the highest tertiles of female participants, and OR with 95% CI was 1.74 (1.06, 2.86). After adjusted urinary lead, arsenic, cadmium, and mercury as covariates, the result was still statistically significant, and OR with 95% CI was 1.83 (1.23, 2.72). Restricted cubic spline showed a nonlinear positive relationship between urinary antimony and depressive symptoms. Based on the result of dominance analysis, the relative importance of urinary antimony concentration accounted for 3.58%. CONCLUSION: This study indicated that urinary antimony was positively related to depressive symptoms, especially in female.

Mast Cell-Derived Proteases Induce Endothelial Permeability and Vascular Damage in Severe Fever with Thrombocytopenia Syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever acquired by tick bites. Whether mast cells (MCs), the body's first line of defense against pathogens, might influence immunity or pathogenesis during SFTS virus (SFTSV) infection remained unknown. Here, we found that SFTSV can cause MC infection and degranulation, resulting in the release of the vasoactive mediators, chymase, and tryptase, which can directly act on endothelial cells, break the tight junctions of endothelial cells and threaten the integrity of the microvascular barrier, leading to microvascular hyperpermeability in human microvascular endothelial cells. Local activation of MCs (degranulation) and MC-specific proteases-facilitated endothelial damage were observed in mouse models. When MC-specific proteases were injected subcutaneously into the back skin of mice, signs of capillary leakage were observed in a dose-dependent manner. MC-specific proteases, chymase, and tryptase were tested in the serum collected at the acute phase of SFTS patients, with the higher level significantly correlated with fatal outcomes. By performing receiver operator characteristic curve (ROC) analysis, chymase was determined as a biomarker with the area under the curve value of 0.830 (95% CI = 0.745 to 0.915) for predicting fatal outcomes in SFTS. Our findings highlight the importance of MCs in SFTSV-induced disease progression and outcome. An emerging role for MCs in the clinical prognosis and blocking MC activation as a potential drug target during SFTSV infection was proposed. IMPORTANCE We revealed a pathogenic role for MCs in response to SFTSV infection. The study also identifies potential biomarkers that could differentiate patients at risk of a fatal outcome for SFTS, as well as novel therapeutic targets for the clinical management of SFTS. These findings might shed light on an emerging role for MCs as a potential drug target during infection of other viral hemorrhagic fever diseases with similar host pathology as SFTS.

Impact of glycemia and insulin treatment in fatal outcome of severe fever with thrombocytopenia syndrome.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with a high fatality rate. How the glucose level might affect the clinical outcome remains obscure. METHODS: A multicenter study was performed in 2 hospitals from 2011 to 2021. Patients with SFTS and acute hyperglycemia (admission fasting plasma glucose [FPG] ≥7 mmol/L), postadmission hyperglycemia (admission FPG <7 mmol/L but FPG ≥7 mmol/L after admission), and euglycemia (FPG <7 mmol/L throughout hospitalization) were compared for their clinical progress and outcomes. RESULTS: A total of 3225 patients were included in this study, 37.9% of whom developed acute hyperglycemia and 7.6% postadmission hyperglycemia. The presence of acute hyperglycemia, with or without known diabetes, was associated with increased risk of death (odds ratio [OR]: 1.63; 95% confidence interval [CI]: 1.29-2.05) compared with euglycemia. This effect, however, was only determined in female patients (OR: 2.15; 95% CI: 1.54-2.93). Insulin treatment of patients with SFTS and acute hyperglycemia without previous diabetes was associated with significantly increased mortality (OR: 1.58; 95% CI: 1.16-2.16). CONCLUSION: Acute hyperglycemia can act as a strong predictor of SFTS-related death in female patients. Insulin treatment of hyperglycemia in patients with SFTS without pre-existing diabetes has adverse effects.

Fatal patients with severe fever with thrombocytopenia syndrome in China.

OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with a high case fatality rate. Key gaps remained as to the assessment of the clinical picture in fatal cases. METHODS: A retrospective study was performed on 496 patients with fatal SFTS. The dynamic pattern of clinical manifestations and laboratory indicators were delineated. RESULTS: The mean age of the fatal cases was 69.0 years (standard deviation: 9.3), and 52.8% were male. The median clinical course from disease onset to death was 11 (interquartile range: 10-13) days. A total of 11 laboratory indicators (neutrophil %, platelet, aspartate aminotransferase, aspartate aminotransferase/alanine transaminase, lactate dehydrogenase, creatine kinase, cystatin C, D-dimer, activated partial thromboplastin time, thrombin time, glucose) persistently deviated from normality across hospitalization. The critical time points when the rapid worsening of the indicators was at 6-9 days after disease onset. Alanine transaminase, AST, lactate dehydrogenase, total bile acid, gamma-glutamyl transpeptidase, and glucose were all elevated to a more pronounced level in fatal cases of those aged ≤70 years. CONCLUSION: The fatal outcome was developed in rather a short course after the disease onset of SFTS. High vigilance should be put on the key time points when the severe worsening and severe complications occur.

Human infection with a reassortment avian influenza A H3N8 virus: an epidemiological investigation study.

A four-year-old boy developed recurrent fever and severe pneumonia in April, 2022. High-throughput sequencing revealed a reassortant avian influenza A-H3N8 virus (A/Henan/ZMD-22-2/2022(H3N8) with avian-origin HA and NA genes. The six internal genes were acquired from Eurasian lineage H9N2 viruses. Molecular substitutions analysis revealed the haemagglutin retained avian-like receptor binding specificity but that PB2 genes possessed sequence changes (E627K) associated with increased virulence and transmissibility in mammalian animal models. The patient developed respiratory failure, liver, renal, coagulation dysfunction and sepsis. Endotracheal intubation and extracorporeal membrane oxygenation were administered. H3N8 RNA was detected from nasopharyngeal swab of a dog, anal swab of a cat, and environmental samples collected in the patient's house. The full-length HA sequences from the dog and cat were identical to the sequence from the patient. No influenza-like illness was developed and no H3N8 RNA was identified in family members. Serological testing revealed neutralizing antibody response against ZMD-22-2 virus in the patient and three family members. Our results suggest that a triple reassortant H3N8 caused severe human disease. There is some evidence of mammalian adaptation, possible via an intermediary mammalian species, but no evidence of person-to-person transmission. The potential threat from avian influenza viruses warrants continuous evaluation and mitigation.

Exploring the bidirectional associations between handgrip strength and depression in middle and older Americans.

OBJECTIVE: Current evidence on the relationship between decreased handgrip strength and depression risk is controversial, and there is limited study focus on the potential bidirectional associations between them. We aim to explore their bidirectional relationships. METHODS: This study used panel data from the Health and Retirement Study involving 17,713 aging Americans (≥50 years old) who participated in at least 2 waves. Smedley spring-type hand-held dynamometer was used to assess the handgrip strength. Depression was evaluated by the 8-item Center for Epidemiologic Studies-Depression (CESD) scale. Time-lagged general estimating equations (GEE) were used to assess the bidirectional association between handgrip strength and the depression risk. RESULTS: In the fully adjusted model, every 5 kg decreased handgrip strength was associated with a 6% (95%CI: 3%-9%) increased risk of depression. Compared with non-weakness participants, those with weakness had a higher depression risk (OR = 1.22, 95%CI: 1.09-1.36). Conversely, depression might associate with a 0.33 kg (95% CI: 0.09-0.56) decrease in handgrip strength and increased the risk of weakness by 18% (95% CI: 6%-33%). In addition, the results remained stable in the stratified analyses by gender and sex. Interestingly, the above-mentioned associations were also observed in overweight and obese participants. CONCLUSIONS: The present study found bidirectional associations between handgrip strength and depression risk. Our results indicated early interventions for depression and handgrip strength might achieve reciprocal benefits over time.

Associations of urinary bisphenol A and its alternatives bisphenol S and F concentrations with depressive symptoms among adults.

BACKGROUND: Bisphenol S (BPS) and bisphenol F (BPF), as substitutes for bisphenol A (BPA), are synthetic compounds detected increasingly frequently in plastics and resins. BPA, BPS, and BPF are endocrine disruptors with unclear effects on depressive symptoms. This study aims to evaluate the effects of these compounds on depressive symptoms in adults. METHODS: We used data from the U.S. National Health and Nutrition Examination Survey (NHANES) 2007-2016 for BPA (N = 7,085) and NHANES 2013-2016 for BPS and BPF (N = 2,707). BPA, BPS and BPF were detected in urine samples. Depressive symptoms were assessed with a nine-item patient health questionnaire (PHQ-9). Logistic regression models were used to investigate the effects of urinary BPA, BPS, and BPF concentrations on depressive symptoms. RESULTS: In the general population, no significant association was observed between urinary BPA, BPS, and BPF and depressive symptoms. However, in stratified analyses, urinary BPS was positively associated with depressive symptoms in men (odds ratio [OR], 2.90; 95% confidence interval [CI], 1.13-7.47). In elderly men (≥60 years old), urinary BPA and BPS were positively correlated with depressive symptoms with ORs (95% CIs) of 5.53 (1.55-19.70) and 28.89 (4.23-192.75), respectively. In addition, urinary BPS was negatively associated with depressive symptoms (OR, 0.16; 95% CI, 0.04-0.59) in elderly women (≥60 years old). CONCLUSIONS: This study indicated that exposure to BPA and BPS was positively associated with depressive symptoms, especially in men. However, BPS was negatively associated with depressive symptoms in elderly women.

Associations of Dietary ω-3, ω-6 Fatty Acids Consumption with Sleep Disorders and Sleep Duration among Adults.

The relationship between ω-3 and ω-6 fatty acids consumption and sleep disorders or duration are controversial. Therefore, we used the data of the National Health and Nutrition Examination Survey 2007-2016 in this cross-sectional study to explore their relationships. ω-3 and ω-6 fatty acids consumption was assessed using two 24 h dietary recall interviews. Sleep disorders and sleep duration were based on self-reported data. Logistic regression models and restricted cubic spline analyses were used. Compared with tertile one, the odds ratios (ORs) and 95% confidence intervals (CIs) of sleep disorders for the second tertile of ω-6 fatty acid intake and the highest tertile of ω-6:ω-3 ratio were 1.30 (1.04-1.62) and 1.36 (1.08-1.70), respectively. Inverse U-shaped and linear dose-response relationships were observed between dietary ω-6 fatty acid intake and ω-6:ω-3 ratio and sleep disorders, respectively. In addition, ω-3 fatty acid consumption was adversely related to sleep disorders in men and the OR (95% CI) was 0.68 (0.49-0.95). Compared with normal sleep duration, ω-3 fatty acid consumption was negatively related to very short, short, and long sleep duration risk. The relative risk ratios (RRRs) were 0.53 (0.35-0.81), 0.79 (0.67-0.93), and 0.81 (068-0.98), respectively. The RRR of very short sleep for ω-6 fatty acid consumption was 0.57 (0.45-0.73). Our study indicates that ω-6 fatty acid consumption and the ω-6:ω-3 ratio are positively associated with the risk of sleep disorders, while the negative association between ω-3 fatty acids and sleep disorders may exist only in men. Furthermore, ω-3 and ω-6 fatty acid consumption are negatively related to the risk of non-normal sleep duration.

Associations between dietary carotenoid intakes and the risk of depressive symptoms.

BACKGROUND: Dietary factors play an important role in the development of depressive symptoms. Carotenoids have effective antioxidant and anti-inflammatory effects, but few studies have explored the associations between dietary carotenoid intake and depressive symptoms. OBJECTIVE: To evaluate the association between dietary carotenoid intake and the risk of depressive symptoms in adults from the United States. DESIGN: This cross-sectional study included adult participants from the National Health and Nutrition Examination Survey 2009-2016. Depressive symptoms were assessed using the Patients' Health Questionnaire-9. Intake of carotenoids was obtained through two 24-h dietary recall interviews. We applied logistic regression models and restricted cubic spline models to evaluate the associations of dietary alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein with zeaxanthin, and total carotenoid intake with the risk of depressive symptoms. RESULTS: Overall, a total of 17,401 adults aged 18-80 years were included in this study. After adjustment for potential confounders, the odds ratios (95% confidence intervals) of depressive symptoms in the highest versus lowest quartiles were 0.71 (0.56-0.92) for alpha-carotene, 0.59 (0.47-0.75) for beta-carotene, 0.71 (0.55-0.92) for beta-cryptoxanthin, 0.66 (0.49-0.89) for lycopene, 0.50 (0.39-0.64) for lutein with zeaxanthin, and 0.59 (0.45-0.78) for total carotenoid intake. U-shaped dose-response relationships were found between both beta-carotene and lutein with zeaxanthin intake and the risk of depressive symptoms. CONCLUSION: Results suggest that alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein with zeaxanthin, and total carotenoid intake may be inversely associated with the risk of depressive symptoms in the U.S. adults.