COVID-19 increases extracorporeal coagulation during hemodialysis associated with upregulation of vWF/FBLN5 signaling in patients with severe/critical symptoms.

BACKGROUND: COVID-19 has been shown to increase the risk of extracorporeal coagulation during hemodialysis in patients, but the underlying mechanism remains unclear. This study aimed to investigate the effect and mechanism of COVID-19 on the risk of extracorporeal coagulation in patients with chronic kidney disease undergoing hemodialysis. METHODS: A retrospective analysis of the extracorporeal coagulation status of 339 hemodialysis patients at our center before and after COVID-19 infection was performed, including subgroup analyses. Post-infection blood composition was analyzed by protein spectrometry and ELISA. RESULTS: Compared to the pre-COVID-19 infection period, COVID-19-induced extracorporeal coagulation predominantly occurred in patients with severe/critical symptoms. Further proteomic analysis demonstrated that in patients with severe/critical symptoms, the coagulation cascade reaction, platelet activation, inflammation, and oxidative stress-related pathways were significantly amplified compared to those in patients with no/mild symptoms. Notably, the vWF/FBLN5 pathway, which is associated with inflammation, vascular injury, and coagulation, was significantly upregulated. CONCLUSIONS: Patients with severe/critical COVID-19 symptoms are at a higher risk of extracorporeal coagulation during hemodialysis, which is associated with the upregulation of the vWF/FBLN5 signaling pathway. These findings highlight the importance of early anticoagulant therapy initiation in COVID-19 patients with severe/critical symptoms, particularly those undergoing hemodialysis. Additionally, vWF/FBLN5 upregulation may be a novel mechanism for virus-associated thrombosis/coagulation.

Prevalence of Moderate to Severe Anxiety Symptoms among Patients with Myocardial Infarction: a Meta-Analysis.

This study attempted to synthesize the evidence on the prevalence of moderate to severe anxiety symptoms among myocardial infarction (MI) patients to offer a reliable and accurate estimate on the number of MI patients suffering from moderate to severe anxiety symptoms. Comprehensive electronic searches (PubMed, Embase and Web of Science) were performed from their inception to February 2021. Between-study heterogeneity was analyzed using the Cochran's Q test and [Formula: see text] statistic, and if it was high across the eligible studies, meta-regression and subgroup analyses were conducted to examine the source of heterogeneity. Publication bias and the robustness of the pooled results were also examined. A total of 18 eligible studies covering 8,532 MI patients were included, of which 3,443 were identified with moderate to severe anxiety symptoms. Between-study heterogeneity was high ([Formula: see text]=98.8%) with the reported prevalence ranging from 9.6% to 69.17%, and the pooled prevalence was 38.08% (95% confidence interval: 28.82-47.81%) by a random-effects model. Meta-regression analyses indicated that publication year (ß = -0.014) was significant moderators contributing 16.11% to the heterogeneity. Subgroup analyses indicated that studies using the anxiety subscale of Brief Symptom Inventory to assess anxiety were homogenous ([Formula: see text]=0.0). Furthermore, the pooled prevalence of moderate to severe anxiety symptoms varied significantly by geographic region, instrument used to assess anxiety, methodological quality, sex, education level, a history of previous MI and hypercholesterolemia. Additionally, the results of Egger's linear test (t = -0.630) and Begg's rank test (z = -0.190) indicated no evidence of publication bias, and the sensitivity of the pooled results was low. Nearly two fifth of MI patients suffered from moderate to severe anxiety symptoms, which emphasizes the importance of early identification of anxiety symptoms after MI, as well as the need of implementing psychological interventions for those with elevated anxiety symptoms.

Ultrasensitive Temperature Sensing Based on Ligand-Free Alloyed CsPbClx Br3-x Perovskite Nanocrystals Confined in Hollow Mesoporous Silica with High Density of Halide Vacancies.

Temperature sensing based on fluorescent semiconductor nanocrystals has recently received immense attention. Enhancing the trap-facilitated thermal quenching of the fluorescence should be an effective approach to achieve high sensitivity for temperature sensing. Compared with conventional semiconductor nanocrystals, the defect-tolerant feature of lead halide perovskite nanocrystals (LHP NCs) endows them with high density of defects. Here, hollow mesoporous silica (h-SiO2 ) template-assisted ligand-free synthesis and halogen manipulation (chloride-importing) are proposed to fabricate highly defective yet fluorescent CsPbCl1.2 Br1.8 NCs confined in h-SiO2 (CsPbCl1.2 Br1.8 NCs@h-SiO2 ) for ultrasensitive temperature sensing. The trap barrier heights, exciton-phonon scattering, and trap state filling process in the CsPbCl1.2 Br1.8 NCs@h-SiO2 and CsPbBr3 NCs@h-SiO2 are studied to illustrate the higher temperature sensitivity of CsPbCl1.2 Br1.8 NCs@h-SiO2 at physiological temperature range. By integrating the thermal-sensitive CsPbCl1.2 Br1.8 NCs@h-SiO2 and thermal-insensitive K2 SiF6 :Mn4+ phosphor into the flexible ethylene-vinyl acetate polymer matrix, ratiometric temperature sensing from 30.0 °C to 45.0 °C is demonstrated with a relative temperature sensitivity up to 13.44% °C-1 at 37.0 °C. The composite film shows high potential as a thermometer for monitoring the body temperature. This work demonstrates the unparalleled temperature sensing performance of LHP NCs and provides new inspiration on switching the defects into advantages in sensing applications.

Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.

BACKGROUND: Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. METHODS: We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. FINDINGS: Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p<0·001) and the mean total BILAG index score decreased from 28·4 (12·4) at enrolment to 17·4 (10·7) after 12 months of treatment (p<0·001). The mean daily dose of prednisone required to control disease activity decreased from 23·7 mg (SD 9·6) to 7·2 mg (2·3; p<0·001) after 12 months of treatment. Sirolimus expanded CD4+CD25+FoxP3+ regulatory T cells and CD8+ memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4+ and CD4-CD8- double-negative T cells after 12 months. CD8+ memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol (Z=-2·50, p=0·012), neutrophil counts (Z=-1·92, p=0·054), and haemoglobin (Z=-2·83, p=0·005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment (Z=2·06, p=0·0400). INTERPRETATION: These data show that a progressive improvement in disease activity is associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus. FUNDING: Pfizer, the National Institutes of Health, and the Central New York Community Foundation.

Fluorometric sensing of oxygen using manganese(II)-doped zinc sulfide nanocrystals.

Manganese(II)-doped zinc sulfide nanocrystals (Mn:ZnS NCs) with dual-emission fluorescence (peaks at 445 nm and 590 nm under 330 nm excitation), good water stability and low toxicity were synthesized by hot injection. The fluorescence intensity of both emission bands of the nanocrystals can change rapidly by the content of gaseous and dissolved oxygen. The process is fully reversible. Compared with the maximum intensity of Mn:ZnS sensing film in 100% nitrogen, the emission of the blue emission decreases by 72% in the presence of 100% oxygen, and the yellow emission by 32%. Response is linear in the presence of 3% to 12% of oxygen percentage in gas. For water-dissolved oxygen, the linear response occurs between 0.54 and 11.4 mg·L-1. Graphical abstractMn-doped ZnS NCs with dual-emission fluorescence were synthesized by hot-injection method. The reversible and rapid sensing characteristics of Mn-doped ZnS NCs to oxygen were studied, and the possible sensing mechanism was investigated.

Prevalence of acute stress disorder among road traffic accident survivors: a meta-analysis.

BACKGROUND: Road traffic accident (RTA), an unexpected traumatic event, may not only lead to death and serious physical injuries, but also could put survivors at an increased risk for a wide range of psychiatric disorders, particularly acute stress disorder (ASD). Early assessment of trauma-related psychological responses is important because acute trauma responses in the early post-traumatic period are among the robust predictors of long-term mental health problems. However, estimates of the prevalence of ASD among RTA survivors varied considerably across studies. Therefore, this meta-analysis aimed to identify the pooled prevalence of ASD among RTA survivors. METHODS: A systematic literature search in the databases of PubMed, PsycINFO, PsycARTICLES, Embase and Web of Science was performed from their inception dates to December 2017. Subject headings were used to identify relevant articles, and the search strategy was adjusted across databases. Heterogeneity across studies was evaluated by Cochran's χ2 test and quantified by the I2 statistic. Subgroup analyses were performed to identify the pooled prevalence in relation to the country of study, instrument used to identify ASD, age, gender and traumatic brain injury. When significant heterogeneity was observed, the influence of some potential moderators was explored using meta-regression analyses. RESULTS: Thirteen eligible studies conducted in 8 countries were included. A total of 2989 RTA survivors were assessed, of which 287 were identified with ASD. The overall heterogeneity was high across studies (I2=96.8%, P < 0.001), and the pooled prevalence of ASD among RTA survivors was 15.81% (95% confidence interval: 8.27-25.14%). Subgroup analyses indicated that the prevalence of ASD among RTA survivors differed significantly with regard to the country of study, instrument used to identify ASD, age and gender (P < 0.05). Meta-regression analyses showed that mean age of participants and quality assessment score were significant moderators for heterogeneity (P < 0.05). CONCLUSIONS: Nearly one-sixth of RTA survivors suffer from ASD, indicating the need for regular assessment of early trauma responses among RTA survivors, as well as the importance of implementing early psychological interventions.

Prevalence of Posttraumatic Stress Disorder among Children and Adolescents following Road Traffic Accidents: A Meta-Analysis.

OBJECTIVE: Children and adolescents are among the most vulnerable road users, and road traffic accidents (RTAs) can lead to not only physical injuries but also adverse psychological outcomes, particularly posttraumatic stress disorder (PTSD). However, estimates of the prevalence of PTSD among children and adolescents following RTAs varied considerably across studies. Therefore, this study aimed to estimate the pooled prevalence of PTSD among this population. METHODS: A systematic search for literature was performed in the electronic databases of PubMed, Web of Science, PsycINFO, and Embase. Heterogeneity was assessed using the Cochran's chi-square test and quantified by the I2 value. Meta-regression analyses were carried out to identify the effects of some potential moderators on the overall heterogeneity. Subgroup analyses were performed to estimate the pooled prevalence of PTSD according to some sample characteristics. RESULTS: Eleven eligible studies with a total of 1532 children and adolescents who were involved in RTAs were included. The overall heterogeneity (I2 = 89.7, P < 0.001) was high across the eligible studies, and the pooled prevalence of PTSD was 19.95% (95% confidence interval, 13.63% to 27.09%) by a random-effects model. No significant moderators of the overall heterogeneity were identified using meta-regression analyses. Subgroup analyses showed that the pooled prevalence of PTSD differed significantly according to the study location and gender (P < 0.05). CONCLUSIONS: One-fifth of children and adolescents developed PTSD in the aftermath of RTAs, indicating the need for regular assessment of PTSD and timely and effective psychological interventions among this population. Furthermore, more population-based studies with a large sample size are warranted. The protocol was registered in the PROSPERO database (No. CRD42018087941).

The incidence of post-traumatic stress disorder among survivors after earthquakes:a systematic review and meta-analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a common psychological disorder caused by unusual threats or catastrophic events. Little is known about the combined incidence of PTSD after earthquakes. This study aimed at evaluating the combined incidence of PTSD among survivors after earthquakes using systematic review and meta-analysis. METHODS: The electronic databases of PubMed, Embase, Web of Science and PsycARTICLES were searched for relevant articles in this study. Loney criteria were used to assess the quality of eligible articles. The combined incidence of PTSD was estimated by using the Freeman-Tukey double arcsine transformation method. Subgroup analyses were conducted using the following variables: the time of PTSD assessment, gender, educational level, marital status, damage to one's house, bereavement, injury of body and witnessing death. RESULTS: Forty-six eligible articles containing 76,101 earthquake survivors met the inclusion criteria, of which 17,706 were diagnosed as having PTSD. Using a random effects model, the combined incidence of PTSD after earthquakes was 23.66 %. Moreover, the combined incidence of PTSD among survivors who were diagnosed at not more than 9 months after earthquake was 28.76 %, while for survivors who were diagnosed at over nine months after earthquake the combined incidence was 19.48 %. A high degree of heterogeneity (I(2) = 99.5 %, p<0.001) was observed in the results, with incidence ranging from 1.20 to 82.64 %. The subgroup analyses showed that the incidence of PTSD after earthquake varied significantly across studies in relation to the time of PTSD assessment, gender, educational level, damage to one's house, bereavement, injury of body and witnessing death. However, stratified analyses could not entirely explain the heterogeneity in the results. CONCLUSIONS: Given the high heterogeneity observed in this study, future studies should aim at exploring more possible risk factors for PTSD after earthquakes, especially genetic factors. In spite of that, the results of this study suggest that nearly 1 in 4 earthquake survivors are diagnosed as having PTSD. Therefore, the local government should plan effective psychological interventions for earthquake survivors.

Predictors of recovery from post-traumatic stress disorder after the dongting lake flood in China: a 13-14 year follow-up study.

BACKGROUND: Floods are some of the most common and destructive natural disasters in the world, potentially leading to both physical injuries and psychological disorders, including post-traumatic stress disorder (PTSD). PTSD can damage functional capacity and interfere with social functioning. However, little is known about recovery from PTSD after floods. This study used 2013-2014 follow-up data on survivors of the 1998 Dongting Lake flood who were diagnosed with PTSD in 2000 to measure the prevalence rate of PTSD at follow-up and identify predictors of recovery from the PTSD diagnosis in 2000. METHODS: Participants included survivors who had been diagnosed as having PTSD in 2000 after the 1998 Dongting Lake flood. PTSD at follow-up was reassessed using the PTSD Checklist-Civilian version. Information on demographics, trauma-related stressors, post-trauma stressors, social support, and coping style were collected through face-to-face interviews. The association between the independent variables and PTSD at follow-up was analyzed using logistic regression analyses. RESULTS: A total of 201 participants with a PTSD diagnosis in 2000 were included in this study. A total of 19.4 % of the flood survivors with PTSD in 2000 continued to suffer from PTSD in 2013-2014. In the multivariable logistic regression model, individuals who had lost relatives (OR = 12.37, 95 % CI = 2.46-62.16), suffered from bodily injury (OR = 5.01, 95 % CI = 1.92-13.08), had a low level of social support (OR = 5.47, 95 % CI = 1.07-27.80), or had a negative coping style (OR = 4.92, 95 % CI = 1.89-12.81) were less likely to recover from PTSD. CONCLUSIONS: The prevalence rate of PTSD at follow-up indicates that natural disasters such as floods may have a negative influence on survivors' mental health for an extended period of time. Individuals who have lost relatives, suffered from bodily injury, had a low level of social support, or had a negative coping style were less likely to recover from PTSD. Therefore, effective psychological intervention measures are necessary for facilitating the recovery process from PTSD, especially for individuals with adverse prognostic factors.

Association between social support and recovery from post-traumatic stress disorder after flood: a 13-14 year follow-up study in Hunan, China.

BACKGROUND: Post-traumatic stress disorder (PTSD) is one of the most prevalent long-term psychiatric disorders among survivors of traumatic events. It is well established that social support has been related to the onset of PTSD after natural disasters. However, very little is known whether or not social support has had an influence on the recovery from the PTSD that was diagnosed after floods. This study, therefore, made a follow-up assessment of PTSD in flood victims 13-14 years after they were diagnosed with PTSD in 2000 to measure the prevalence rate of PTSD among them and identify the association between social support and their recovery from PTSD. METHODS: Victims who had experienced Dongting Lake flood in 1998 and had been diagnosed as having PTSD in 2000 were enrolled in this study. A follow-up survey was done between the years 2013 and 2014 to diagnose the victims again of PTSD using the DSM-IV criteria. Social support and its three dimensions were measured using the Chinese version of Social Support Rating Scale (SSRS), including objective support, subjective support and support utilization. Data were collected through face-to-face interviews using a structured questionnaire. Bivariate and multivariate logistic regression analyses were used to examine the relationship between social support and the recovery from PTSD after flood. RESULTS: Out of 321 subjects with prior PTSD, 51 (15.89%) were diagnosed as still having PTSD. Logistic regression analyses indicated that the recovery from prior PTSD was significantly associated with social support (odds ratio (OR) =0.202, 95% confidence interval (95% CI): 0.047-0.878), subjective support (OR = 0.236, 95% CI: 0.080-0.694) and support utilization (OR = 0.245, 95% CI: 0.071-0.844). CONCLUSIONS: The prevalence rate of current PTSD indicates that natural disasters, such as floods, may affect the mental health of victims for a long time. Social support was significantly associated with the recovery from prior PTSD, especially subjective support and support utilization.

Oxidative stress and Treg depletion in lupus patients with anti-phospholipid syndrome.

Anti-phospholipid antibodies (APLA) represent a diagnostic criterion of systemic lupus erythematosus (SLE) and cause morbidity, termed anti-phospholipid syndrome (APS). Activation of the mechanistic target of rapamycin (mTOR) has been recently associated with APS. mTOR is a sensor of oxidative stress. Therefore, we examined mitochondrial mass, superoxide production, mTOR activity and FoxP3 expression in 72 SLE patients, twelve of whom also had APS, and 54 healthy controls by flow cytometry. Mitochondrial mass was increased in CD4(-)CD8(-) double-negative (DN) T cells of SLE patients with APS (2.7-fold) in comparison to those without APS (1.7-fold; p = 0.014). Superoxide production was increased in all lymphocyte subsets of APS patients. FoxP3(+) cells were depleted within CD4(+)CD25(+) Tregs in patients with APS (28.4%) relative to those without APS (46.3%, p = 0.008). mTOR activity was similar between SLE patients with and without APS. Thus, oxidative stress and Treg depletion rather than mTOR activation underlie APS in patients with SLE.

Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus.

The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T cell lineage development; however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. In this study, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBLs relative to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p < 0.0005); increased mitochondrial mass of CD3(+)/CD4(-)/CD8(-) double-negative (DN) T cells (p = 1.1 × 10(-22)) and FOXP3 depletion in CD4(+)/CD25(+) T cells were top contributors (p = 6.7 × 10(-7)). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥ 4) relative to 61 visits of remission (SLEDAI decrease ≥ 4). mTOR activation in DN T cells was also noted at preflare visits of SLE patients relative to those with stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25(+)/CD19(+) B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FOXP3 in CD25(+)/CD4(+) T cells, and expanded CD25(+)/CD19(+) B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.

[Effect of underground work on cardiovascular system in coal miners].

OBJECTIVE: To study the effect of underground work on cardiovascular system health in coal miners.
 METHODS: Male coal miners, who received electrocardiographic examinations between June, 2013 and August, 2014 in Hunan Prevention and Treatment Institute for Occupational Diseases to exclude pneumoconiosis, were enrolled for this study (n=3 134). Miners with 2 years or more underground work experience were selected as the exposed group (n=2 370), while miners without underground work experience were selected as the control group (n=764). The prevalence of electrocardiographic abnormalities and the influential factors were compared between the 2 groups.
 RESULTS: The prevalences of electrocardiographic abnormalities, hypertension, heart rate abnormalities and cardiovascular system abnormalities in the exposed group vs the control group were 37.6% vs 25.4%, 20.5% vs 13.4%, 5.7% vs 6.0%, 49.8% vs 35.2%, respectively. The cardiovascular system abnormalities were correlated with the underground work (OR=3.128, 95% CI: 1.969-4.970), the underground work experience (OR=1.205, 95% CI: 1.070-1.358) and the type of works (mining worker OR=1.820, 95% CI: 1.527-2.169; auxiliary worker OR=1.937, 95% CI: 1.511-2.482; other worker OR=3.291, 95%CI: 2.120-5.109).
 CONCLUSION: Underground work may increase the prevalence of cardiovascular system abnormalities for coal miners. The longer the coal miners work in underground, the higher the risk of the cardiovascular system abnormalities they are.

[Analysis of pulmonary dysfunction of 1 953 coal miners in Hunan Province].

OBJECTIVE: To explore the effect of dust exposure, type of work, age, length of service and duration of dust exposure on pulmonary function in coal miners by pulmonary function tests.
 METHODS: A total of 1 953 coal miners, who received occupational healthy examination and pulmonary function tests during June, 2013 and August, 2014 in Hunan Prevention and Treatment Institute, were enrolled for this study.
 RESULTS: A total of 1 302 miners (66.7%) displayed pulmonary dysfunction, including 1 139 with mild dysfunction (58.3%) and 163 with moderate or more serious dysfunction (8.3%). The risk factors for pulmonary dysfunction were age (OR=1.329, 95% CI: 1.196-1.620), dust exposure duration (OR=1.267, 95% CI: 1.136-1.413) and type of works (mining workers OR=1.156, 95% CI: 1.033-1.293; all P<0.05).
 CONCLUSION: The incidence rate of pulmonary dysfunction in coal miners is relatively high in Hunan Province. Most of them are mild dysfunction. The incidence rate of pulmonary dysfunction in mining works is statistically higher than that in other work types. Older workers and long duration-exposed workers are more likely to have pulmonary dysfunction.

HRES-1/Rab4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE.

OBJECTIVE: Accumulation of mitochondria underlies T-cell dysfunction in systemic lupus erythematosus (SLE). Mitochondrial turnover involves endosomal traffic regulated by HRES-1/Rab4, a small GTPase that is overexpressed in lupus T cells. Therefore, we investigated whether (1) HRES-1/Rab4 impacts mitochondrial homeostasis and (2) Rab geranylgeranyl transferase inhibitor 3-PEHPC blocks mitochondrial accumulation in T cells, autoimmunity and disease development in lupus-prone mice. METHODS: Mitochondria were evaluated in peripheral blood lymphocytes (PBL) of 38 SLE patients and 21 healthy controls and mouse models by flow cytometry, microscopy and western blot. MRL/lpr mice were treated with 125 µg/kg 3-PEHPC or 1 mg/kg rapamycin for 10 weeks, from 4 weeks of age. Disease was monitored by antinuclear antibody (ANA) production, proteinuria, and renal histology. RESULTS: Overexpression of HRES-1/Rab4 increased the mitochondrial mass of PBL (1.4-fold; p=0.019) and Jurkat cells (2-fold; p=0.000016) and depleted the mitophagy initiator protein Drp1 both in human (-49%; p=0.01) and mouse lymphocytes (-41%; p=0.03). Drp1 protein levels were profoundly diminished in PBL of SLE patients (-86±3%; p=0.012). T cells of 4-week-old MRL/lpr mice exhibited 4.7-fold over-expression of Rab4A (p=0.0002), the murine homologue of HRES-1/Rab4, and depletion of Drp1 that preceded the accumulation of mitochondria, ANA production and nephritis. 3-PEHPC increased Drp1 (p=0.03) and reduced mitochondrial mass in T cells (p=0.02) and diminished ANA production (p=0.021), proteinuria (p=0.00004), and nephritis scores of lupus-prone mice (p<0.001). CONCLUSIONS: These data reveal a pathogenic role for HRES-1/Rab4-mediated Drp1 depletion and identify endocytic control of mitophagy as a treatment target in SLE.

Attention deficit and hyperactivity disorder scores are elevated and respond to N-acetylcysteine treatment in patients with systemic lupus erythematosus.

OBJECTIVE: To investigate whether attention deficit hyperactivity disorder (ADHD) may serve as a marker of neuropsychiatric disease and as a target for N-acetylcysteine (NAC) treatment in patients with systemic lupus erythematosus (SLE). METHODS: The ADHD Self-Report Scale (ASRS) was used to assess 49 patients with SLE and 46 matched healthy control subjects. Twenty-four of the patients with SLE were randomized to receive either placebo, NAC at a dosage of 2.4 gm/day, or NAC at a dosage of 4.8 gm/day. Disease activity was evaluated monthly using the British Isles Lupus Assessment Group (BILAG) index, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Fatigue Assessment Scale (FAS), and the ASRS, before and during the 3-month treatment period and after a 1-month washout period. RESULTS: The cognitive/inattentive (ASRS part A), hyperactivity/impulsive (ASRS part B), and combined (total) ASRS scores were increased in patients with SLE compared with control subjects (mean ± SEM 17.37 ± 1.03 [P = 3 × 10(-7) ], 14.51 ± 0.89 [P = 2 × 10(-4) ], and 31.92 ± 1.74 [P = 8 × 10(-7) ], respectively, versus 10.41 ± 1.02, 9.61 ± 1.21, and 20.02 ± 1.98, respectively. ASRS part A scores correlated with SLEDAI (r = 0.53, P < 0.0001) and BILAG scores (r = 0.36, P = 0.011). ASRS total scores also correlated with SLEDAI (r = 0.45, P = 0.0009) and BILAG scores (r = 0.31, P = 0.025). ASRS part A (r = 0.73, P < 0.0001), ASRS part B (r = 0.47, P = 0.0006), and ASRS total scores (r = 0.67, P < 0.0001) correlated with the FAS score. Relative to the scores in placebo-treated patients, ASRS total scores were reduced in SLE patients treated with NAC dosages of 2.4 gm/day and 4.8 gm/day combined (P = 0.037). ASRS part A scores were reduced by NAC dosages of 2.4 gm/day (P = 0.001) and 4.8 gm/day (P < 0.0001) as well as by NAC at dosages of 2.4 gm/day and 4.8 gm/day combined (P = 0.001). CONCLUSION: In patients with SLE, elevated ASRS scores reveal previously unrecognized and clinically significant symptoms of ADHD that respond to NAC treatment.

Diagnostic value of procalcitonin in patients with periprosthetic joint infection: a diagnostic meta-analysis.

Background: The success rate of periprosthetic joint infection (PJI) treatment is still low. Early diagnosis is the key to successful treatment. Therefore, it is necessary to find a biomarker with high sensitivity and specificity. The diagnostic value of serum procalcitonin (PCT) for PJI was systematically evaluated to provide the theoretical basis for clinical diagnosis and treatment in this study. Methods: We searched the Web of Science, Embase, Cochrane Library, and PubMed for studies that evaluated the diagnostic value of serum PCT for PJI (from the inception of each database until September 2020). Two authors independently screened the literature according to the inclusion and exclusion criteria. The quality of each selected literature was evaluated by using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) tool. RevMan 5.3 software was used for the quality evaluation. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were merged by using Meta-DiSc 1.4 software. The area under the curve (AUC) and Q index were calculated after the summary receiver operating characteristic (SROC) was generated. We also performed subgroup analysis. Results: A total of 621 patients were enrolled in the nine studies. The pooled sensitivity of serum PCT for PJI diagnosis was 0.441 [95% confidence interval (CI), 0.384-0.500], the pooled specificity was 0.852 (95% CI, 0.811-0.888), the pooled PLR was 2.271 (95% CI, 1.808-2.853), the pooled NLR was 0.713 (95% CI, 0.646-0.786), and the pooled DOR was 5.756 (95% CI, 3.673-9.026). The area under SROC (the pooled AUC) was 0.76 (0.72-0.79). Q index was 0.6948. Conclusion: This study showed that PCT detection of PJI had poor diagnostic accuracy. Hence, the serum PCT is not suitable as a serum marker for PJI diagnosis.

Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.

N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double-blind, placebo-controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N-acetylcysteine (NAC). METHODS: A total of 36 SLE patients received either daily placebo or 1.2 gm, 2.4 gm, or 4.8 gm of NAC. Disease activity was evaluated monthly by the British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index (SLEDAI), and the Fatigue Assessment Scale (FAS) before, during, and after a 3-month treatment period. Mitochondrial transmembrane potential and mTOR were assessed by flow cytometry. Forty-two healthy subjects matched to patients for age, sex, and ethnicity were studied as controls. RESULTS: NAC up to 2.4 gm/day was tolerated by all patients, while 33% of those receiving 4.8 gm/day had reversible nausea. Placebo or NAC 1.2 gm/day did not influence disease activity. Considered together, 2.4 gm and 4.8 gm NAC reduced the SLEDAI score after 1 month (P = 0.0007), 2 months (P = 0.0009), 3 months (P = 0.0030), and 4 months (P = 0.0046); the BILAG score after 1 month (P = 0.029) and 3 months (P = 0.009); and the FAS score after 2 months (P = 0.0006) and 3 months (P = 0.005). NAC increased Δψm (P = 0.0001) in all T cells, profoundly reduced mTOR activity (P = 0.0009), enhanced apoptosis (P = 0.0004), reversed expansion of CD4-CD8- T cells (mean ± SEM 1.35 ± 0.12-fold change; P = 0.008), stimulated FoxP3 expression in CD4+CD25+ T cells (P = 0.045), and reduced anti-DNA production (P = 0.049). CONCLUSION: This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.