STAT3 activation of SCAP-SREBP-1 signaling upregulates fatty acid synthesis to promote tumor growth.

SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression.

Dynamic changes of functional fitness, antibodies to SARS-CoV-2 and immunological indicators within 1 year after discharge in Chinese health care workers with severe COVID-19: a cohort study.

BACKGROUND: Few studies had described the health consequences of patients with coronavirus disease 2019 (COVID-19) especially in those with severe infections after discharge from hospital. Moreover, no research had reported the health consequences in health care workers (HCWs) with COVID-19 after discharge. We aimed to investigate the health consequences in HCWs with severe COVID-19 after discharge from hospital in Hubei Province, China. METHODS: We conducted an ambidirectional cohort study in "Rehabilitation Care Project for Medical Staff Infected with COVID-19" in China. The participants were asked to complete three physical examinations (including the tests of functional fitness, antibodies to SARS-CoV-2 and immunological indicators) at 153.4 (143.3, 164.8), 244.3 (232.4, 259.1), and 329.4 (319.4, 339.3) days after discharge, respectively. Mann-Whitney U test, Kruskal-Wallis test, t test, one-way ANOVA, χ2, and Fisher's exact test were used to assess the variance between two or more groups where appropriate. RESULTS: Of 333 HCWs with severe COVID-19, the HCWs' median age was 36.0 (31.0, 43.0) years, 257 (77%) were female, and 191 (57%) were nurses. Our research found that 70.4% (114/162), 48.9% (67/137), and 29.6% (37/125) of the HCWs with severe COVID-19 were considered to have not recovered their functional fitness in the first, second, and third functional fitness tests, respectively. The HCWs showed improvement in muscle strength, flexibility, and agility/dynamic balance after discharge in follow-up visits. The seropositivity of IgM (17.0% vs. 6.6%) and median titres of IgM (3.0 vs. 1.4) and IgG (60.3 vs. 45.3) in the third physical examination was higher than that in the first physical examination. In the third physical examination, there still were 42.1% and 45.9% of the HCWs had elevated levels of IL-6 and TNF-α, and 11.9% and 6.3% of the HCWs had decreased relative numbers of CD3+ T cells and CD4+ T cells. CONCLUSION: The HCWs with severe COVID-19 showed improvement in functional fitness within 1 year after discharge, active intervention should be applied to help their recovery if necessary. It is of vital significance to continue monitoring the functional fitness, antibodies to SARS-CoV-2 and immunological indicators after 1 year of discharge from hospital in HCWs with severe COVID-19.

Proteasome Inhibitors Bortezomib and Carfilzomib Stimulate the Transport Activity of Human Organic Anion Transporter 1.

Organic anion transporter 1 (OAT1), expressed at the basolateral membrane of renal proximal tubule epithelial cells, mediates the renal excretion of many clinically important drugs. Previous study in our laboratory demonstrated that ubiquitin conjugation to OAT1 leads to OAT1 internalization from the cell surface and subsequent degradation. The current study showed that the ubiquitinated OAT1 accumulated in the presence of the proteasomal inhibitors MG132 and ALLN rather than the lysosomal inhibitors leupeptin and pepstatin A, suggesting that ubiquitinated OAT1 degrades through proteasomes. Anticancer drugs bortezomib and carfilzomib target the ubiquitin-proteasome pathway. We therefore investigate the roles of bortezomib and carfilzomib in reversing the ubiquitination-induced downregulation of OAT1 expression and transport activity. We showed that bortezomib and carfilzomib extremely increased the ubiquitinated OAT1, which correlated well with an enhanced OAT1-mediated transport of p-aminohippuric acid and an enhanced OAT1 surface expression. The augmented OAT1 expression and transport activity after the treatment with bortezomib and carfilzomib resulted from a reduced rate of OAT1 degradation. Consistent with this, we found decreased 20S proteasomal activity in cells that were exposed to bortezomib and carfilzomib. In conclusion, this study identified the pathway in which ubiquitinated OAT1 degrades and unveiled a novel role of anticancer drugs bortezomib and carfilzomib in their regulation of OAT1 expression and transport activity. SIGNIFICANCE STATEMENT: Bortezomib and carfilzomib are two Food and Drug Administration-approved anticancer drugs, and proteasome is the drug target. In this study, we unveiled a new role of bortezomib and carfilzomib in enhancing OAT1 expression and transport activity by preventing the degradation of ubiquitinated OAT1 in proteasomes. This finding provides a new strategy in regulating OAT1 function that can be used to accelerate the clearance of drugs, metabolites, or toxins and reverse the decreased expression under disease conditions.

PKC/Nedd4-2 Signaling Pathway Regulates the Cell Surface Expression of Drug Transporter hOAT1.

Human organic anion transporter-1 (hOAT1) regulates the absorption, distribution, and excretion of a wide range of clinically important drugs. Our previous work demonstrated that hOAT1 is a dynamic membrane transporter, constitutively internalizing from and recycling back to the cell plasma membrane. Short-term activation (<30 minutes) of protein kinase C (PKC) promotes the attachment of a lysine 48-linked polyubiquitin chain to hOAT1, a process catalyzed by ubiquitin ligase neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2). The ubiquitination of hOAT1 then triggers an accelerated endocytosis of the transporter from plasma membrane, which results in reduced hOAT1 expression at the cell surface and decreased hOAT1 transport activity. In the present study, we investigated the long-term effect of PKC on hOAT1. We showed that long-term activation (>2 hours) of PKC significantly enhanced hOAT1 degradation, and such action was partially blocked by ubiquitin mutant Ub-K48R, which has its lysine (K) 48 mutated to arginine (R) and is incapable of forming a K48-linked polyubiquitin chain. The ubiquitin ligase Nedd4-2 was also found to augment hOAT1 degradation. These results suggest that PKC-regulated and Nedd4-2-catalyzed attachment of a lysine 48-linked polyubiquitin chain to hOAT1 is important for hOAT1 stability. We further showed through coimmunoprecipitation experiments that there was a direct association between hOAT1 and Nedd4-2, and such interaction was weakened when the WW3 and WW4 domains of the ligase were mutated. Mutating WW3 and WW4 domains of the ligase also impaired its ability to ubiquitinate hOAT1. Therefore, WW3 and WW4 domains of Nedd4-2 are critical for its association with and modulation of the transporter.

Does ventilator-associated event surveillance detect ventilator-associated pneumonia in intensive care units? A systematic review and meta-analysis.

BACKGROUND: Ventilator-associated event (VAE) is a new surveillance paradigm for monitoring complications in mechanically ventilated patients in intensive care units (ICUs). The National Healthcare Safety Network replaced traditional ventilator-associated pneumonia (VAP) surveillance with VAE surveillance in 2013. The objective of this study was to assess the consistency between VAE surveillance and traditional VAP surveillance. METHODS: We systematically searched electronic reference databases for articles describing VAE and VAP in ICUs. Pooled VAE prevalence, pooled estimates (sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)) of VAE for the detection of VAP, and pooled estimates (weighted mean difference (WMD) and odds ratio ([OR)) of risk factors for VAE compared to VAP were calculated. RESULTS: From 2191 screened titles, 18 articles met our inclusion criteria, representing 61,489 patients receiving mechanical ventilation at ICUs in eight countries. The pooled prevalence rates of ventilator-associated conditions (VAC), infection-related VAC (IVAC), possible VAP, probable VAP, and traditional VAP were 13.8 %, 6.4 %, 1.1 %, 0.9 %, and 11.9 %, respectively. Pooled sensitivity and PPV of each VAE type for VAP detection did not exceed 50 %, while pooled specificity and NPV exceeded 80 %. Compared with VAP, pooled ORs of in-hospital death were 1.49 for VAC and 1.76 for IVAC; pooled WMDs of hospital length of stay were -4.27 days for VAC and -5.86 days for IVAC; and pooled WMDs of ventilation duration were -2.79 days for VAC and -2.89 days for IVAC. CONCLUSIONS: VAE surveillance missed many cases of VAP, and the population characteristics identified by the two surveillance paradigms differed. VAE surveillance does not accurately detect cases of traditional VAP in ICUs.

Awareness and knowledge about human papillomavirus vaccination and its acceptance in China: a meta-analysis of 58 observational studies.

BACKGROUND: The human papillomavirus (HPV) vaccines have been widely introduced in immunization programs worldwide, however, it is not accepted in mainland China. We aimed to investigate the awareness and knowledge about HPV vaccines and explore the acceptability of vaccination among the Chinese population. METHODS: A meta-analysis was conducted across two English (PubMed, EMBASE) and three Chinese (China National Knowledge Infrastructure, Wan Fang Database and VIP Database for Chinese Technical Periodicals) electronic databases in order to identify HPV vaccination studies conducted in mainland China. We conducted and reported the analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Fifty-eight unique studies representing 19 provinces and municipalities in mainland China were assessed. The pooled awareness and knowledge rates about HPV vaccination were 15.95 % (95 % CI: 12.87-19.29, I (2) = 98.9 %) and 17.55 % (95 % CI: 12.38-24.88, I (2) = 99.8 %), respectively. The female population (17.39 %; 95 % CI: 13.06-22.20, I (2) = 98.8 %) and mixed population (18.55 %; 95 % CI: 14.14-23.42, I (2) = 98.8 %) exhibited higher HPV vaccine awareness than the male population (1.82 %; 95 % CI: 0.50-11.20, I (2) = 98.5 %). Populations of mixed ethnicity had lower HPV vaccine awareness (9.61 %; 95 % CI: 5.95-14.03, I (2) = 99.0 %) than the Han population (20.17 %; 95 % CI: 16.42-24.20, I (2) = 98.3 %). Among different regions, the HPV vaccine awareness was higher in EDA (17.57 %; 95 % CI: 13.36-22.21, I (2) = 98.0 %) and CLDA (17.78 %; 95 % CI: 12.18-24.19, I (2) = 97.6 %) than in WUDA (1.80 %; 95 % CI: 0.02-6.33, I (2) = 98.9 %). Furthermore, 67.25 % (95 % CI: 58.75-75.21, I (2) = 99.8 %) of participants were willing to be vaccinated, while this number was lower for their daughters (60.32 %; 95 % CI: 51.25-69.04, I (2) = 99.2 %). The general adult population (64.72 %; 95 % CI: 55.57-73.36, I (2) = 99.2 %) was more willing to vaccinate their daughters than the parent population (33.78 %; 95 % CI: 26.26-41.74, I (2) = 88.3 %). Safety (50.46 %; 95 % CI: 40.00-60.89, I (2) = 96.6 %) was the main concern about vaccination among the adult population whereas the safety and efficacy (68.19 %; 95 % CI: 53.13-81.52, I (2) = 98.6 %) were the main concerns for unwillingness to vaccinate their daughters. CONCLUSIONS: Low HPV vaccine awareness and knowledge was observed among the Chinese population. HPV vaccine awareness differed across sexes, ethnicities, and regions. Given the limited quality and number of studies included, further research with improved study designis necessary.

Spatial, temporal, and spatiotemporal analysis of malaria in Hubei Province, China from 2004-2011.

BACKGROUND: Malaria remains a public health concern in Hubei Province despite the significant decrease in malaria incidence over the past decades. Furthermore, history reveals that malaria transmission is unstable and prone to local outbreaks in Hubei Province. Thus, understanding spatial, temporal, and spatiotemporal distribution of malaria is needed for the effective control and elimination of this disease in Hubei Province. METHODS: Annual malaria incidence at the county level was calculated using the malaria cases reported from 2004 to 2011 in Hubei Province. Geographical information system (GIS) and spatial scan statistic method were used to identify spatial clusters of malaria cases at the county level. Pure retrospective temporal analysis scanning was performed to detect the temporal clusters of malaria cases with high rates using the discrete Poisson model. The space-time cluster was detected with high rates through the retrospective space-time analysis scanning using the discrete Poisson model. RESULTS: The overall malaria incidence decreased to a low level from 2004 to 2011. The purely spatial cluster of malaria cases from 2004 to 2011 showed that the disease was not randomly distributed in the study area. A total of 11 high-risk counties were determined through Local Moran's I analysis from 2004 to 2011. The method of spatial scan statistics identified different 11 significant spatial clusters between 2004 and 2011. The space-time clustering analysis determined that the most likely cluster included 13 counties, and the time frame was from April 2004 to November 2007. CONCLUSIONS: The GIS application and scan statistical technique can provide means to detect spatial, temporal, and spatiotemporal distribution of malaria, as well as to identify malaria high-risk areas. This study could be helpful in prioritizing resource assignment in high-risk areas for future malaria control and elimination.

Preformulation characterization and in vivo absorption in beagle dogs of JFD, a novel anti-obesity drug for oral delivery.

JFD (N-isoleucyl-4-methyl-1,1-cyclopropyl-1-(4-chlorine)phenyl-2-amylamine·HCl) is a novel investigational anti-obesity drug without obvious cardiotoxicity. The objective of this study was to characterize the key physicochemical properties of JFD, including solution-state characterization (ionization constant, partition coefficient, aqueous and pH-solubility profile), solid-state characterization (particle size, thermal analysis, crystallinity and hygroscopicity) and drug-excipient chemical compatibility. A supporting in vivo absorption study was also carried out in beagle dogs. JFD bulk powders are prismatic crystals with a low degree of crystallinity, particle sizes of which are within 2-10 µm. JFD is highly hygroscopic, easily deliquesces to an amorphous glass solid and changes subsequently to another crystal form under an elevated moisture/temperature condition. Similar physical instability was also observed in real-time CheqSol solubility assay. pK(a) (7.49 ± 0.01), log P (5.10 ± 0.02) and intrinsic solubility (S0) (1.75 µg/ml) at 37 °C of JFD were obtained using potentiometric titration method. Based on these solution-state properties, JFD was estimated to be classified as BCS II, thus its dissolution rate may be an absorption-limiting step. Moreover, JFD was more chemically compatible with dibasic calcium phosphate, mannitol, hypromellose and colloidal silicon dioxide than with lactose and magnesium stearate. Further, JFD exhibited an acceptable pharmacokinetic profiling in beagle dogs and the pharmacokinetic parameters T(max), C(max), AUC(0-t) and absolute bioavailability were 1.60 ± 0.81 h, 0.78 ± 0.47 µg/ml, 3.77 ± 1.85 µg·h/ml and 52.30 ± 19.39%, respectively. The preformulation characterization provides valuable information for further development of oral administration of JFD.

[Analysis on absentees due to injury during 2012-2013 school year from 32 primary schools in Hubei province].

OBJECTIVE: To analyze absentees due to injury among primary school pupils in Hubei, 2012-2013; and to provide theoretical basis for the prevention and control of injuries. METHODS: A total of 32 primary schools in Qianjiang city and Shayang county were sampled to conduct injury absenteeism surveillance, and the total number of students was 21 493. The surveillance contents included absent dates, genders, grades, initial or return absent, and the detailed absent reasons. The classification of injury was based on the 10th Revision of the international classification of diseases developed by WHO. Data from 2012-2013 school-year were extracted from the surveillance system for analysis. The total surveillance period was 182 days, of which the fall semester was 98 days and the spring semester was 84 days. The absenteeism rate and injury rate in different characteristics of primary school students were compared by χ² test, and the possible risk factors of injury were preliminary explored by calculating the RR (95% CI) value. RESULTS: The total daily injury absenteeism rate was 8.26/100 100 during 2012-2013 school-year in 32 primary schools in Hubei province, which was higher in fall semester (9.16/100 000), Qianjiang area (9.63/100 000), rural primary schools (13.44/100 000), boys (9.57/100 000), 1-2 grades (10.41/100 000), and the differences were significant (P < 0.05). The total injury rate was 0.46%. Rural primary schools (RR = 2.32, 95% CI: 1.46-3.70), boys (RR = 1.88, 95% CI: 1.23-2.87), and 3-4 grades (RR = 1.85, 95% CI: 1.10-3.09) were identified as high-risk factors, while using city primary schools, girls, and 5-6 grades as references, respectively. CONCLUSION: The injury absenteeism rate and injury rate were more higher in rural primary schools, boys and low or middle grades in Hubei province during 2012 to 2013 school year, so monitoring and preventive measures should be focused on those students.

Comparing the Effects of Two Culture Methods to Determine the Total Heterotrophic Bacterial Colony Count in Hospital Purified Water.

BACKGROUND: Accurately detecting the quantity of microorganisms in hospital purified water is of significant importance for early identification of microbial contamination and reducing the occurrence of water-borne hospital infections. The choice of detection method is a prerequisite for ensuring accurate results. Traditional Plate Count Agar (PCA) belongs to a high-nutrient medium, and there may be limitations in terms of accuracy or sensitivity in detecting microorganisms in hospital purified water. On the other hand, Reasoner's 2A agar (R2A) has characteristics, such as low-nutrient levels, low cultivation temperature, and extended incubation time, providing advantages in promoting the growth of aquatic microorganisms. This study, through comparing the differences in total colony counts between two detection methods, aims to select the method more suitable for the growth of aquatic microorganisms, offering new practical insights for accurately detecting the total count of heterotrophic bacteria in hospital purified water. METHODS: The most commonly used plate count agar (PCA) method, and the R2A agar culture were adopted to detect microorganisms and determine the total number of bacterial colonies in the water for oral diagnosis and treatment water and terminal rinse water for endoscopes in medical institutions. The two water samples were inoculated by pour plate and membrane filtration methods, respectively. Using statistical methods including Spearman and Pearson correlation, Wilcoxon signed-rank sum test, paired-Chi-square test, and linear regression, we analyze the differences and associations in the bacterial counts cultivated through two different methods. RESULTS: In 142 specimens of the water, the median and interquartile range of the heterotrophic bacterial colony number under the R2A culture method and under the PCA culture method were 200 (Q1-Q3: 25-18,000) and 6 (Q1-Q3: 0-3700). The total number of heterotrophic bacteria colonies cultured in R2A medium for 7 days was more than that cultured in PCA medium for 2 days (P < 0.05). The linear regression results showed a relatively strong linear correlation between the number of colonies cultured by the R2A method and that cultured by the PCA method (R2 = 0.7264). The number of bacterial species detected on R2A agar medium is greater than that on PCA agar medium. CONCLUSION: The R2A culture method can better reflect the actual number of heterotrophic bacterial colonies in hospital purified water. After logarithmic transformation, the number of colonies cultured by the two methods showed a linear correlation.

[The application of integrated surveillance system for symptoms in surveillance of influenza among children].

OBJECTIVE: To explore the integrated application of sales of child-specific over-the-counter (OTC) cold related medications in retail pharmacies and healthcare visits of children for influenza-like illness (ILI) in surveillance and early warning of influenza among children. METHODS: An integrated surveillance system (ISS) was implemented since 2012 in Qianjiang County, a rural area in Hubei Province of China. The daily information from August 1, 2012 to February 28, 2013 of health care visits of children for ILI reported by 80 health facilities and sales of 14 child-specific over-the-counter (OTC) cold related medications reported by 11 pharmacies were extracted from ISS database. Cumulative sums (CUSUM) model was conducted to analyze the degree of fitting and the early warning signal generated; the correlationship was then analyzed further. RESULTS: In 212 days, 983 visits of children for ILI and 12 819 sales by person of child-specific OTC were reported. Conducting CUSUM model, the fitting degree was in the acceptable range, 31 warning signals were generated from ILI data series with 3 peak periods and 14 from OTC data series with 2 peak periods. A similar time trend of two data series was observed with a correlation(r = 0.497, P < 0.05), but without any spatial clustering. And the optimal correlation(r = 0.505, P < 0.05) appeared at a time offset of 4 days preceded by OTC sales. CONCLUSION: The availability of integrated surveillance system for symptoms could be applied for surveillance of influenza among children; while it could explore the possibility of real epidemic in the very early stage.

Inhibition of proteasome, but not lysosome, upregulates organic anion transporter 3 in vitro and in vivo.

Organic anion transporter 3 (OAT3), an indispensable basolateral membrane transporter predominantly distributed in the kidney proximal tubules, mediated the systemic clearance of substrates including clinical drugs, nutrients, endogenous and exogenous metabolites, toxins, and critically sustains body homeostasis. Preliminary data in this study showed that classical proteasome inhibitors (e.g., MG132), but not lysosome inhibitors, significantly increased the OAT3 ubiquitination and OAT3-mediated transport of estrone sulfate (ES) in OAT3 stable expressing cells, indicating that proteasome rather than lysosome is involved in the intracellular fate of OAT3. Next, bortezomib and carfilzomib, two FDA-approved and widely applied anticancer agents through selective targeting proteasome, were further used to define the role of inhibiting proteasome in OAT3 regulation and related molecular mechanisms. The results showed that 20S proteasome activity in cell lysates was suppressed with bortezomib and carfilzomib treatment, leading to the increased OAT3 ubiquitination, stimulated transport activity of ES, enhanced OAT3 surface and total expression. The upregulated OAT3 function by proteasome inhibition was attributed to the augment in maximum transport velocity and stability of membrane OAT3. Lastly, in vivo study using Sprague Dawley rats validated that proteasome inhibition using bortezomib induced enhancement of OAT3 ubiquitination and membrane expression in kidney. These data suggest that activity of proteasome but not lysosome could have an impact on the physiological function of OAT3, and proteasome displayed a promising target for OAT3 regulation in vitro and in vivo, and could be used in restoring OAT3 impairment under pathological conditions, avoiding OAT3-associated toxicity and diseases, ensuring drug efficacy and safety.

Age at SARS-CoV-2 infection and psychological and physical recovery among Chinese health care workers with severe COVID-19 at 28 months after discharge: A cohort study.

Background: No prior study had reported the psychological and physical recovery of patients with COVID-19 2~3 years after discharge from the hospital. Moreover, it is not clear whether there is any difference in the health status of the patients with COVID-19 of different ages after discharge from the hospital. Methods: Embedding in the "Rehabilitation Care Project for Medical Staff Infected with COVID-19" in China, this study included 271 health care workers (HCWs) with severe COVID-19. Their status of health-related quality of life, persistent symptoms, functional fitness and immune function at 28 months after discharge were followed, and compared according to tertiles of age at SARS-CoV-2 infection (group of younger (≤ 33 years); medium (34-42 years); and older (≥43 years)). Multivariate linear regression and multivariable adjusted logistic regression models were applied in investigating the associations of age at SARS-CoV-2 infection and outcomes. Results: At 28 months after discharge, 76% of the HCWs with severe COVID-19 had symptom of fatigue/weakness; 18.7% of the HCWs with severe COVID-19 did not fully recover their functional fitness; the decrease of CD3+ T cells, CD8+ T cells and the increase of natural killer cells accounted for 6.6, 6.6, and 5.5%, respectively. Compared with the HCWs with severe COVID-19 in younger group, HCWs with severe COVID-19 in older group had lower scores regarding physical functioning, role physical, bodily pain and role emotional; HCWs with severe COVID-19 in older group had higher risk of cough, joint pain, hearing loss and sleep disorder; HCWs with severe COVID-19 in older group scored lower on flexibility test. The variance of relative numbers of CD3+ T cells, CD8+ T cells and natural killer cells among HCWs with severe COVID-19 of different age groups were significant. Conclusions: This study demonstrated that older HCWs with severe COVID-19 recovered slower than those with younger age regarding health-related quality of life, persistent symptoms, functional fitness and immune function at 28 months after discharge. Effective exercise interventions regarding flexibility should be performed timely to speed their rehabilitation, especially among those with older age.

Nitrate in drinking water and bladder cancer: a meta-analysis.

This study examined whether exposure to nitrate in drinking water is associated with increased risk for bladder cancer by conducting a comprehensive literature research. A meta-analysis was performed with and without adjustment for confounding factors. Three groups (reference, intermediate and high groups) were established in terms of different nitrate concentrations in each included study. Separate relative risk measures were calculated for intermediate and high groups. Heterogeneity was assessed by using the Q statistics. Publication bias was evaluated by Egger's and Begg's test. Quality assessment for studies was performed by using the Newcastle-Ottawa scale. Two cohorts, two case-controls, and one ecological study were included in this study. The adjusted data showed that the combined risk ratios (RRs) were 1.13 (95% CI: 0.81 to 1.57) and 1.27 (95% CI: 0.75 to 2.15) for intermediate and high groups respectively. For unadjusted data, the corresponding RRs were 1.18 (95% CI: 0.89 to 1.57) and 1.29 (95% CI: 0.81 to 2.07). Sensitivity test indicated that results were significantly underestimated when Ward's study was included. No significant publication bias was found. There was heterogeneity among studies. The results suggested that there was no sufficient evidence that nitrate in drinking water is associated with increased risks for bladder cancer.

Recovery of functional fitness, lung function, and immune function in healthcare workers with nonsevere and severe COVID-19 at 13 months after discharge from the hospital: a prospective cohort study.

OBJECTIVES: This study aimed to evaluate the recovery of functional fitness, lung function, and immune function in healthcare workers (HCWs) with nonsevere and severe COVID-19 at 13 months after discharge from the hospital. METHODS: The participants of "Rehabilitation Care Project for Medical Staff Infected with COVID-19" underwent a functional fitness test (muscle strength, flexibility, and agility/dynamic balance), lung function test, and immune function test (including cytokines and lymphocyte subsets) at 13 months after discharge. RESULTS: The project included 779 HCWs (316 nonsevere COVID-19 and 463 severe COVID-19). This study found that 29.1% (130/446) of the HCWs have not yet recovered their functional fitness. The most affected lung function indicator was lung perfusion capacity (34% with diffusion capacity for carbon monoxide-single breath <80%). The increase of interleukin-6 (64/534, 12.0%) and natural killer cells (44/534, 8.2%) and the decrease of CD3+ T cells (58/534, 10.9%) and CD4+ T cells (26/534, 4.9%) still existed at 13 months after discharge. No significant difference was found in the HCWs with nonsevere and severe COVID-19 regarding recovery of functional fitness, lung function, and immune function at 13 months after discharge. CONCLUSION: The majority of Chinese HCWs with COVID-19 had recovered their functional fitness, lung function, and immune function, and the recovery status in HCWs with severe COVID-19 is no worse than that in HCWs with nonsevere COVID-19 at 13 months after discharge from the hospital.

Long-Term Effects of COVID-19 on Health Care Workers 1-Year Post-Discharge in Wuhan.

INTRODUCTION: To assess the long-term consequences of coronavirus disease (COVID-19) among health care workers (HCWs) in China (hereafter surviving HCWs). METHODS: A total of 303 surviving HCWs were included. Lung (pulmonary function test, 6-min walk test [6MWT], chest CT), physical (St. George's Respiratory Questionnaire [SGRQ], Modified Medical Research Council dyspnea scale [mMRC], and Borg scale), and psychiatric functions (Essen Trauma Inventory) were evaluated during the 1-year follow-up. RESULTS: Surviving HCWs had an abnormal diffusion capacity 1 year post-discharge. Participants with a reduced carbon monoxide diffusing capacity (DLCO) comprised 43.48%. The proportion of HCWs with a median 6MWT distance below the lower limit of the normal was 19.4%. An abnormal CT pattern was observed in 37.5% of the HCWs. The SGRQ, mMRC, and Borg scores of surviving HCWs, especially those with critical/severe disease, were significantly higher than those in the normal population. Probable post-traumatic stress disorder (PTSD) was reported in 21.9% of the surviving HCWs. Diffusion capacity impairment was associated with women. Critical/severe illness and nurses were associated with impaired physical function. CONCLUSIONS: Most surviving HCWs, especially female HCWs, still had an abnormal diffusion capacity at 1 year. The physical and psychiatric functions of surviving HCWs were significantly worse than those of the healthy population. Long-term follow-up of pulmonary, physical, and psychiatric functions for surviving HCWs is required.

Oral Proteasomal Inhibitors Ixazomib, Oprozomib, and Delanzomib Upregulate the Function of Organic Anion Transporter 3 (OAT3): Implications in OAT3-Mediated Drug-Drug Interactions.

Organic anion transporter 3 (OAT3) is mainly expressed at the basolateral membrane of kidney proximal tubules, and is involved in the renal elimination of various kinds of important drugs, potentially affecting drug efficacy or toxicity. Our laboratory previously reported that ubiquitin modification of OAT3 triggers the endocytosis of OAT3 from the plasma membrane to intracellular endosomes, followed by degradation. Oral anticancer drugs ixazomib, oprozomib, and delanzomib, as proteasomal inhibitors, target the ubiquitin-proteasome system in clinics. Therefore, this study investigated the effects of ixazomib, oprozomib, and delanzomib on the expression and transport activity of OAT3 and elucidated the underlying mechanisms. We showed that all three drugs significantly increased the accumulation of ubiquitinated OAT3, which was consistent with decreased intracellular 20S proteasomal activity; stimulated OAT3-mediated transport of estrone sulfate and p-aminohippuric acid; and increased OAT3 surface expression. The enhanced transport activity and OAT3 expression following drug treatment resulted from an increase in maximum transport velocity of OAT3 without altering the substrate binding affinity, and from a decreased OAT3 degradation. Together, our study discovered a novel role of anticancer agents ixazomib, oprozomib, and delanzomib in upregulating OAT3 function, unveiled the proteasome as a promising target for OAT3 regulation, and provided implication of OAT3-mediated drug-drug interactions, which should be warned against during combination therapies with proteasome inhibitor drugs.

Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination.

The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intestine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signaling molecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for maintaining systemic homeostasis. Alterations in the expression and function of OATs contribute to the intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs, and to many pathophysiological conditions. Consequently, the activity of these transporters must be highly regulated to carry out their normal functions. This review will present an update on the recent advance in understanding the cellular and molecular mechanisms underlying the regulation of renal OATs, emphasizing on the post-translational modification (PTM), the crosstalk among these PTMs, and the remote sensing and signaling network of OATs. Such knowledge will provide significant insights into the roles of these transporters in health and disease.

Automated Cluster Detection of Health Care-Associated Infection Based on the Multisource Surveillance of Process Data in the Area Network: Retrospective Study of Algorithm Development and Validation.

BACKGROUND: The cluster detection of health care-associated infections (HAIs) is crucial for identifying HAI outbreaks in the early stages. OBJECTIVE: We aimed to verify whether multisource surveillance based on the process data in an area network can be effective in detecting HAI clusters. METHODS: We retrospectively analyzed the incidence of HAIs and 3 indicators of process data relative to infection, namely, antibiotic utilization rate in combination, inspection rate of bacterial specimens, and positive rate of bacterial specimens, from 4 independent high-risk units in a tertiary hospital in China. We utilized the Shewhart warning model to detect the peaks of the time-series data. Subsequently, we designed 5 surveillance strategies based on the process data for the HAI cluster detection: (1) antibiotic utilization rate in combination only, (2) inspection rate of bacterial specimens only, (3) positive rate of bacterial specimens only, (4) antibiotic utilization rate in combination + inspection rate of bacterial specimens + positive rate of bacterial specimens in parallel, and (5) antibiotic utilization rate in combination + inspection rate of bacterial specimens + positive rate of bacterial specimens in series. We used the receiver operating characteristic (ROC) curve and Youden index to evaluate the warning performance of these surveillance strategies for the detection of HAI clusters. RESULTS: The ROC curves of the 5 surveillance strategies were located above the standard line, and the area under the curve of the ROC was larger in the parallel strategy than in the series strategy and the single-indicator strategies. The optimal Youden indexes were 0.48 (95% CI 0.29-0.67) at a threshold of 1.5 in the antibiotic utilization rate in combination-only strategy, 0.49 (95% CI 0.45-0.53) at a threshold of 0.5 in the inspection rate of bacterial specimens-only strategy, 0.50 (95% CI 0.28-0.71) at a threshold of 1.1 in the positive rate of bacterial specimens-only strategy, 0.63 (95% CI 0.49-0.77) at a threshold of 2.6 in the parallel strategy, and 0.32 (95% CI 0.00-0.65) at a threshold of 0.0 in the series strategy. The warning performance of the parallel strategy was greater than that of the single-indicator strategies when the threshold exceeded 1.5. CONCLUSIONS: The multisource surveillance of process data in the area network is an effective method for the early detection of HAI clusters. The combination of multisource data and the threshold of the warning model are 2 important factors that influence the performance of the model.

Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.

Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.