Use of cardiac contractility modulation combined with left bundle branch pacing CRT-P in a female with a 22-year history of non-ischemic dilated cardiomyopathy: A case report.

Cardiac contractility modulation (CCM) is a novel device-based therapy used to treat patients with heart failure with reduced ejection fraction (HFrEF). In both randomized clinical trials and real-life studies, CCM has been shown to improve exercise tolerance and quality of life, reverse left ventricular remodeling, and reduce hospitalization in patients with HFrEF. In this case report, we describe for the first time the use of CCM combined with left bundle branch pacing (LBBP) cardiac resynchronization therapy pacemaker (CRT-P) implantation therapy in a female with a 22-year history of non-ischemic dilated cardiomyopathy. With the optimal medical therapy and cardiac resynchronization therapy (CRT) strategies, the patient's quality of life initially recovered to some extent, but began to deteriorate in the past year. Additionally, heart transplantation was not considered due to economic reasons and late stage systolic heart failure. This is the first case of CCM implantation in Fujian Province and the first report of a combined CCM and left bundle branch pacing CRT-P implantation strategy in a patient with non-ischemic etiology dilated cardiomyopathy in China.

Analysis of factors with low positive predictive value in the diagnosis of urinary tract infection by flow cytometry.

PURPOSE: Culture-negative urine specimens can be rapidly screened by urine flow cytometry (UFC), while low positive predictive value (PPV) limits the clinical application. We explored the factors associated with a low PPV. METHODS: A total of 5095 urine specimens were analyzed with UFC and culture. Diagnostic performance of leukocytes, bacteria, and BACT-info flags was evaluated by sensitivity, specificity, PPV, and negative predictive value (NPV). The association of contaminated culture and squamous epithelial cell count and BACT-info flag was performed by logistic regression analysis. RESULTS: The NPVs of parallel combination of bacteria and leucocytes were 98.9% in males and 97.9% in females, and PPVs of serial combination were 86.6% and 77.8% in men and women, respectively. The PPV of Gram-negative flag was higher than that of Gram-positive flag. The proportions of contamination in the urine culture results of false positive specimens were 86.9% in males and 98.5% in females at the cutoff points of the serial combination, and these parameters were 53.2% in males and 85.6% in females for the Gram-positive flag. There was a statistically significant association between contaminated cultures and squamous epithelial cells count in females, but not in males. Associations between contaminated cultures and Gram-positive flags or Gram-pos/-neg flags were statistically significant, but there was no association between contaminated cultures and Gram-negative flags. CONCLUSIONS: A serial combination of leukocytes and bacteria may maximize PPV in the diagnosis of bacterial urinary tract infection by urine flow cytometry, and contamination is the main reason for a low PPV.

Combined strategy of knowledge-based rule selection and historical data percentile-based range determination to improve an autoverification system for clinical chemistry test results.

BACKGROUND: Current autoverification, which is only knowledge-based, has low efficiency. Regular historical data analysis may improve autoverification range determination. We attempted to enhance autoverification by selecting autoverification rules by knowledge and ranges from historical data. This new system was compared with the original knowledge-based system. METHODS: New types of rules, extreme values, and consistency checks were added and the autoverification workflow was rearranged to construct a framework. Criteria for creating rules for extreme value ranges, limit checks, consistency checks, and delta checks were determined by analyzing historical Zhongshan laboratory data. The new system's effectiveness was evaluated using pooled data from 20 centers. Efficiency improvement was assessed by a multicenter process. RESULTS: Effectiveness was evaluated by the true positive rate, true negative rate, and overall consistency rate, as compared to manual verification, which were 77.55%, 78.53%, and 78.3%, respectively for the new system. The original overall consistency rate was 56.2%. The new pass rates, indicating efficiency, were increased by 19%-51% among hospitals. Further customization using individualized data increased this rate. CONCLUSIONS: The improved system showed a comparable effectiveness and markedly increased efficiency. This transferable system could be further improved and popularized by utilizing historical data from each hospital.

ProGRP AS A NOVEL BIOMARKER FOR THE DIFFERENTIAL DIAGNOSIS OF MEDULLARY THYROID CARCINOMA IN PATIENTS WITH THYROID NODULES.

Objective: To investigate the release of progastrin-releasing peptide (ProGRP) in patients with thyroid nodules and the value of ProGRP in fine-needle aspirate washout fluid (FNA-ProGRP) in the differential diagnosis between medullary thyroid carcinoma (MTC) and non-MTC thyroid nodules. Methods: We investigated 2,446 healthy persons and 212 patients with 235 thyroid nodules. They were classified into healthy, nodular goiter, chronic thyroiditis, thyroid follicular neoplasm, papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma. The serum ProGRP and FNA-ProGRP were measured. Results: The serum ProGRP median concentration in MTC was 124.40 pg/mL, significantly higher than in other groups. The cutoff value of serum ProGRP was 68.30 pg/mL, leading to 53.85% sensitivity, 96.98% specificity, and 0.51 kappa value in MTC. The FNA-ProGRP median concentration in MTC nodules was 2,096.00 pg/mL, significantly higher than in other groups. A receiver operating characteristic analysis of MTC nodules and non-MTC nodules indicated that the cutoff value was 22.77 pg/mL, leading to 94.12% sensitivity, 98.27% specificity, and 0.85 kappa value. Conclusion: FNA-ProGRP measurement could be served as an ancillary method for the differential diagnosis between MTC and non-MTC thyroid nodules. Abbreviations: CEA = carcinoembryonic antigen; CT = calcitonin; FNAC = fine-needle aspiration cytology; FNA-CT = calcitonin in fine-needle aspirate washout fluid; FNA-ProGRP = ProGRP in fine-needle aspirate washout fluid; MTC = medullary thyroid carcinoma; ProGRP = progastrin-releasing peptide; SCLC = small-cell lung cancer; TM = tumor marker.

Expression and clinical value of gastrin-releasing peptide precursor in nephropathy and chronic kidney disease.

AIM: To explore whether serum pro-gastric releasing peptide (proGRP) is elevated in nephropathy patients and evaluate the diagnostic value of proGRP in chronic kidney disease (CKD) patients. METHODS: A total of 498 nephropathy patients and 170 healthy were selected in Zhongshan Hospital, Medical College of Xiamen University, from February 2016 to September 2017. The clinical data of the different groups including serum proGRP, CKD grading, and other serum and urine renal function biomarkers were analyzed by group comparison, correlation analysis and receiver operating characteristic curve. RESULTS: Serum proGRP levels were significantly higher in the acute kidney injury and CKD groups compared with the other groups of kidney disease patients (P < 0.01), and increased with CKD grading (P < 0.01). Serum proGRP was substantially correlated with serum creatinine (r = 0.637, P < 0.01) and cystain C (0.837, P < 0.01). Serum proGRP had moderate correlations with urine ß2-macroglobulin (ß2-m; r = 0.587, P < 0.01) and α1-macroglobulin (α1-m; r = 0.557, P < 0.01). There were fair associations of serum proGRP with albumin (r = 0.10, P = 0.067), 24 h proteinuria (24 h-TPU; r = 0.092, P = 0.099), urinary albumin/urocreatinine (uAlb/Cr; r = 0.29, P < 0.01) and urinary N-acetyl-ß-D-glucosidase (r = -0.142, P < 0.01). The sensitivity of proGRP was superior to that of simplified modification of diet in renal disease (MDRD) formula in diagnosing CKD I + II (81.25% vs 66.67%), CKD III (86.42% vs 74.36%) and CKD IV (71.19% vs 69.64%), while its specificity was inferior to that of simplified MDRD formula in diagnosing CKD I + II (37.65% vs 66.97%), CKD III (56.25% vs 86.67%) and CKD IV (75.31% vs 88.46%). CONCLUSION: Serum proGRP is elevated in acute renal injury and CKD patients and increases with CKD grading. Serum proGRP is mainly affected by glomerular filtration rate and could be used for CKD staging, although the overall diagnostic sufficiency is inferior to simplified MDRD formula.

Origin of Nontreponemal Antibodies During Treponema pallidum Infection: Evidence From a Rabbit Model.

The origin of nontreponemal antibodies during syphilis infection is hotly debated. Here, we analyzed the immune response in rabbits immunized with various antigens. Inactivated treponemes elicited the production of low-titer nontreponemal antibodies in some rabbits. Cardiolipin combined with bovine serum albumin also induced anticardiolipin antibody production. These findings indicate that Treponema pallidum contained a cardiolipin antigen with weak immunogenicity. However, active T. pallidum induced higher nontreponemal antibody production with strong immunogenicity at an earlier time point, and the antibody titer was consecutive, suggesting the high nontreponemal antibody titer resulted from the combined effects of both the T. pallidum cardiolipin antigen and the damaged host-cell cardiolipin antigen during syphilis infection, the latter of which plays a major role in the induction of nontreponemal antibody production. Our study provides direct animal evidence of the origin of nontreponemal antibodies during T. pallidum infection.

Development of tissue inflammation accompanied by NLRP3 inflammasome activation in rabbits infected with Treponema pallidum strain Nichols.

BACKGROUND: The inflammasome responses in Treponema pallidum infection have been poorly understood to date. This study aimed to investigate the expression of the nucleotide-binding leucine-rich receptor protein 3 (NLRP3) inflammasome in the development of tissue inflammation in rabbits infected with T. pallidum. METHODS: Forty-five rabbits were randomly assigned to a blank group or an infection group, and the latter was divided into no benzathine penicillin G (BPG) and BPG treatment subgroups. Rabbits in the infection group were injected intradermally with 0.1 mL of a 107/mL T. pallidum suspension at 10 marked sites along the back, and the blank group was treated with normal saline. The BPG treatment subgroup received 200,000 U of BPG administered intramuscularly twice, at 14 d and 21 d post-infection. The development of lesions was observed, and biopsies of the injection site and various organs, including the kidney, liver, spleen, lung, and testis, were obtained for NLRP3, caspase-1, and interleukin-1ß (IL-1ß) mRNA analysis during infection. Blood was also collected for the determination of IL-1ß concentration. RESULTS: Rabbits infected with T. pallidum (both the BPG treatment and no BPG treatment subgroups), exhibited NLRP3 inflammasome activation and IL-1ß secretion in cutaneous lesions, showing a trend in elevation to decline; NLRP3 mRNA expression reached a peak at 18 d in the BPG treatment subgroup and 21 d in the no BPG treatment subgroup and returned to "normal" levels [vs. the blank group (P > 0.05)] at 42 d post-infection. The trend was similar to the change in cutaneous lesions in the infected rabbits, which reached a peak at 16 d in the BPG treatment subgroup and 18 d in the no BPG treatment subgroup. NLRP3, caspase-1, and IL-1ß mRNA expression levels were slightly different in different organs. NLRP3 inflammasome activation was also observed in the kidney, liver, lung, spleen and testis. IL-1ß expression was observed in the kidney, liver, lung and spleen; however, there was no detectable level of IL-1ß in the testes of the infected rabbits. CONCLUSIONS: This study established a clear link between NLRP3 inflammasome activation and the development of tissue inflammation in rabbits infected with T. pallidum. BPG therapy imperceptibly adjusted syphilitic inflammation.

Clinical Application of Pro-Gastrin-Releasing Peptide.

BACKGROUND: The diagnostic sensitivity and specificity of serum Pro-gastrin-releasing peptide (ProGRP) in benign or malignant diseases remains controversial. METHODS: The clinical data of 6,948 patients who were examined for ProGRP from February 2015 to January 2017 in the Zhongshan Hospital of the XiaMen University, were collected. The clinical data of the different groups were analyzed by statistical methods. RESULTS: The ProGRP reference levels were 68.50 pg/mL. The percentages of abnormal ProGRP levels were 23.87%, 26.14%, 22.87%, 84.56%, 16.1%, 15.59% and 43.75% for the pneumonia, cardiovascular disease, cerebral vascular disease, renal failure, small cell lung cancer (SCLC), colorectal cancer, and prostate cancer groups, respectively. The 95th percentile of the serum ProGRP concentration levels in the renal failure group was 364.22 pg/mL. The ProGRP cutoff levels for SCLC group were 162.90 pg/mL and the area under the receiver-operating characteristic curve (AUC) was 0.940 (95% CI, 0.892 to 0.987). The parameters sensitivity, specificity, PLR (positive likelihood ratio), NLR (negative likelihood) and Kappa value for the SCLC group with the exclusion of the renal failure group were 81.10% (95% CI: 38.19% - 89.71%), 99.51% (95% CI: 99.31% - 99.66%), 167.59 (95% CI: 116.06 - 241.99), 0.19 (95% CI: 0.11 - 0.32), and 0.6830 (Sig: 0.000), respectively. In the SCLC group, significantly higher concentrations of serum ProGRP of M1 were observed compared with M0. All esophageal neoplasms with high-level ProGRP were identified as small cell neoplasms. CONCLUSIONS: The ProGRP levels were increased in a variety of benign and malignant diseases and were considered a putative marker for SCLC with the exception of the renal failure group. It may be suggested that the high ProGRP levels originated from patients with neuroendocrine tumor.

Isotetrandrine protects against lipopolysaccharide-induced acute lung injury by suppression of mitogen-activated protein kinase and nuclear factor-kappa B.

BACKGROUND: Mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) signaling pathways are pleiotropic regulator of many genes involved in lipopolysaccharide (LPS)-induced acute lung injury (ALI). The present study aimed to reveal the protective effect of isotetrandrine (ITD), a small molecule inhibitor, on various aspects of LPS-induced inflammation in vitro and in vivo. METHODS: In vitro, RAW 264.7 cells were pretreated with different dose of ITD 1 h before treatment with 1 mg/L of LPS. In vivo, to induce ALI, male BALB/c mice were injected intranasally with LPS and treated with ITD (20 and 40 mg/kg) 1 h before LPS. RESULTS: In vitro, the cytokine levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in supernatant were reduced by ITD. Meanwhile, in vivo, pulmonary inflammatory cell infiltration, myeloperoxidase activity, total cells, neutrophils, macrophages, along with the levels of tumor necrosis factor-α, IL-1ß, and IL-6 in bronchoalveolar lavage fluid were dose-dependently attenuated by ITD. Furthermore, our data showed that ITD significantly inhibited the activation of MAPK and NF-κB, which are induced by LPS in ALI model. CONCLUSIONS: These results suggested that ITD dose-dependently suppressed the severity of LPS-induced ALI by inactivation of MAPK and NF-κB, which may involve the inhibition of tissue oxidative injury and pulmonary inflammatory process.

Automated cell analysis of cerebrospinal fluid with XE-5000.

BACKGROUND: Hematology analyzers have been able to make automated counts of cells present in CSF samples in recent years. Most of them cannot provide reliable counts of the low cell levels usually present in CSF. METHODS: Functional sensitivity, precision, analytical measurement range, and method comparisons were deter- mined according to Clinical Laboratory Standards Institute (CLSI) guidelines. RESULTS: The functional sensitivity for white blood cells (WBC) and red blood cells (RBC) was 18/µL and 725/µL (minimum reported concentration), respectively. The total precision ranged from 6.1% to 16.3% for WBC counts within the concentration of 33-183/µL and from 4.1% to 19.4% for RBC counts within the concentration of 745-11,350/µL. The within-run precision for WBC was 3.1% at 7,592/µL. The analytical measurement range was 18-10,078/µL for WBC and 725-5,222,550/µL for RBC. There was good correlation between WBC and RBC counts determined by the XE5000 and microscopic examination, according to slopes and R2 method comparisons. The correlation of the two methods for mononuclear cell (MN) counts was 0.907 with the WBC count of 50-5,000/µL. The reliability of WBC counts produced by the XE-5000 was 0.7. CONCLUSIONS: The XE-5000 performed satisfactorily in the CSF assay, but it is still necessary to manually confirm the WBC count when it is less than 18/µL.

Clinical significance of combined testing of YKL-40 with CEA in Chinese colorectal cancer patients.

BACKGROUND: To investigate the practical value of individual and combined testing of plasma levels of YKL-40, CEA, and CA199 for auxiliary diagnosis and detection of recurrence of colorectal cancer. METHODS: ELISA and ECLIA were used to evaluate levels of YKL-40, CEA, and CA199 in 120 colorectal cancer patients (56 initial-diagnosis, 42 post-operative, and 22 recurrent cases). Forty-three patients with benign colorectal disease and 36 healthy patients were enrolled as controls. The relationship between YKL-40 and clinical indicators of tumor pathology was analyzed. The positive rate and diagnostic efficacy of single and combined YKL-40, CEA, and CA199 testing were assessed in patients with colorectal cancer. RESULTS: Plasma YKL-40 in the cancer group was significantly higher than in the benign control and healthy control group, and the mean values were 145.4 ng/mL, 107.7 ng/mL, and 51.3 ng/mL (p < 0.05), respectively. With 72 ng/mL as the diagnostic threshold, the sensitivity and specificity of YKL-40 in colorectal cancer diagnosis were found to be 73.2% and 66.7%, respectively. Early-stage colorectal cancer patients showed a YKL-40 positive rate (73%) significantly higher than those of CEA and CA199 (50% and 32%, respectively; p < 0.05). When YKL-40 testing was combined with CEA or CA199, the positive rate increased to 82.1% and 80.3%, respectively. Through ROC curve analysis of the post-operative recurrent group against the non-recurrent group, the areas under the curve for YKL-40, CEA, and CA199 were found to be 0.907, 0.714, and 0.759, respectively. Based on the Dukes classification, the mean YKL-40 value for stages A/B, C, and D were 120.1 ng/mL, 131.7 ng/mL, and 226.8 ng/mL (p = 0.008), respectively. The plasma YKL-40 level gradually increased as the disease progressed. Lower degrees of tumor differentiation were correlated with higher YKL-40 levels. The mean YKL-40 values of high, medium, and low tumor differentiation groups were 96.8 ng/mL, 127.5 ng/mL, and 225.7 ng/mL (p = 0.004), respectively. CONCLUSIONS: The benefits of using YKL-40 testing are higher than CEA and CA199 for the monitoring of colorectal cancer recurrence. Combined testing of both YKL-40 and CEA was found to be optimal for auxiliary diagnosis of colorectal cancer. Plasma YKL-40 was found to be suitable for auxiliary diagnosis of colorectal cancer.

SGLT2i relieve proteinuria in diabetic nephropathy patients potentially by inhibiting renal oxidative stress rather than through AGEs pathway.

AIMS: To estimate the effects of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) on proteinuria and oxidative stress expression in type 2 diabetes patients. MATERIALS AND METHODS: 68 patients with type 2 diabetes mellitus (T2DM) were divided into three groups according urinary albumin-to-creatinine ratio (UACR), including T2DM with non-albuminuria group (UACR < 30 mg/g), T2DM with microalbuminuria group (30 ≤ UACR ≤ 300 mg/g), T2DM with macroalbuminuria group (UACR>300 mg/g). They all received SGLT2 inhibitors (SGLT2i) treatment for 12 weeks. The expression of advanced glycation end products (AGEs) in plasma and 8-hydroxy-2-deoxyguanosine (8-OHdG) in urine were measured as indications of oxidative stress. The 24-hour urine samples were collected to measure the concentration of proteinuria and 8-OHdG before and after 12 weeks SGLT2i treatment. Plasma renin activity (PRA), angiotensin II (Ang II) and Aldosterone (ALD) were measured to evaluate renin angiotensin aldosterone system (RASS) levels. RESULTS: After 12 weeks SGLT2 inhibitors treatment, the median values of 24-hour proteinuria decreased in macroalbuminuria compared to baseline (970 vs. 821 mg/d, P = 0.006). The median values of AGEs and 8-OHdG decreased in microalbuminuria and macroalbuminuria groups when compared to baseline, AGEs (777 vs. 136 ug/ml, P = 0.003) and (755 vs. 210 ug/ml, P = 0.001), 8-OHdG (8.00 vs. 1.88 ng/ml, P = 0.001) and (11.18 vs. 1.90 ng/ml, P < 0.001), respectively. Partial correlations showed that 8-OHdG were relevant to the baseline 24-h proteinuria (r = 0.389, p = 0.001), the reduction of OHdG (Δ8-OHdG) were positively correlated with the decrease of 24-h proteinuria (Δ24-h proteinuria) after 12 weeks of SGLT2i treatment (r = 0.283, P = 0.031). There was no significant correlation between 24-h proteinuria and AGEs in baseline (r = -0.059, p = 0.640) as well as between ΔAGEs and Δ24-h proteinuria (r = 0.022, p = 0.872) after12 weeks of SGLT2i treatment in T2DM patients. CONCLUSIONS: SGLT2i may reduce proteinuria in diabetic nephropathy patients, potentially by inhibiting renal oxidative stress, but not through the AGEs pathway and does not induce RAAS activation. TRIAL REGISTRATION: This clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.

Clinical characteristics of bloodstream infections in adult patients with solid tumours and a nomogram for mortality prediction: a 5-year case-controlled retrospective study in a tertiary-level hospital.

Background: Bloodstream infections (BSIs) are one of the leading causes of death in cancer patients. Nevertheless, the risk factors of BSIs in solid tumors have rarely been ascertained adequately. Methods: We conducted a single-center case-controlled retrospective study from 2017 to 2021 among adults with solid tumors in a tertiary-level hospital. The BSIs and control group were matched by the propensity score matching method. We found independent risk factors of occurrence and death of BSIs using univariate and multivariate regression analysis. Additionally, a nomogram was constructed to predict the risk of mortality in BSIs. Results: Of 602 patients with solid tumors in the study period, 186 had BSIs and 416 had non-BSIs. The incidence of BSIs was 2.0/1,000 admissions (206/102,704), and the 30-day mortality rate was 18.8% (35/186). Compared to the control group, the BSIs had longer hospital stays (24.5 days vs. 20.0 days), and higher frequency complicating with organ failure (10.5% vs. 2.4%), nephropathy (19.6% vs. 3.8%), comorbidities≥3 (35.5% vs. 20.0%), and liver-biliary-pancreatic infections (15.6% vs. 5.3%) (all P<0.001). Among the 186 patients with BSIs, 35 died within 30 days after BSIs. Gram-negative bacteria were the most frequent microorganisms (124/192, 64.6%). Liver cancer, organ failure, a high level of lactate dehydrogenase and septic shock were the independent hazardous factors for death of BSIs. What's more, a nomogram was constructed to predict the 30-day survival rate of BSIs, which was proved to have good accuracy (AUC: 0.854; 95% confidence interval: 0.785~0923) and consistency. Conclusion: Being aware of the risk factors of BSIs redounds to take preventive measures to reduce the incidence and death of BSIs.

PCR combined with serologic testing improves the yield and efficiency of SARS-CoV-2 infection hunting: A study in 40,689 consecutive overseas arrivals.

Background: The global epidemiological situation of COVID-19 remains serious. The rapid hunting of SARS-CoV-2 infection is the key means for preventing transmission. Methods: A total of 40,689 consecutive overseas arrivals were screened for SARS-CoV-2 infection based on PCR and serologic testing. The yield and efficiency of different screening algorithms were evaluated. Result: Among the 40,689 consecutive overseas arrivals, 56 (0.14%) subjects were confirmed to have SARS-CoV-2 infection. The asymptomatic rate was 76.8%. When the algorithm based on PCR alone was used, the identification yield of a single round of PCR (PCR1) was only 39.3% (95% CI: 26.1-52.5%). It took at least four rounds of PCR to achieve a yield of 92.9% (95% CI: 85.9-99.8%). Fortunately, an algorithm based on a single round of PCR combined with a single round of serologic testing (PCR1+ Ab1) greatly improved the screening yield to 98.2% (95% CI: 94.6-100.0%) and required 42,299 PCR and 40,689 serologic tests that cost 6,052,855 yuan. By achieving a similar yield, the cost of PCR1+ Ab1 was 39.2% of that of four rounds of PCR. For hunting one case in PCR1+ Ab1, 769 PCR and 740 serologic tests were required, costing 110,052 yuan, which was 63.0% of that of the PCR1 algorithm. Conclusion: Comparing an algorithm based on PCR alone, PCR combined with a serologic testing algorithm greatly improved the yield and efficiency of the identification of SARS-CoV-2 infection.

Anti-SARS-CoV-2 IgM Secondary Response Was Suppressed by Preexisting Immunity in Vaccinees: A Prospective, Longitudinal Cohort Study over 456 Days.

To obtain more insight into IgM in anti-SARS-CoV-2 immunity a prospective cohort study was carried out in 32 volunteers to longitudinally profile the kinetics of the anti-SARS-CoV-2 IgM response induced by administration of a three-dose inactivated SARS-CoV-2 vaccine regimen at 19 serial time points over 456 days. The first and second doses were considered primary immunization, while the third dose was considered secondary immunization. IgM antibodies showed a low secondary response that was different from the other three antibodies (neutralizing, total, and IgG antibodies). There were 31.25% (10/32) (95% CI, 14.30-48.20%) of participants who never achieved a positive IgM antibody conversion over 456 days after vaccination. The seropositivity rate of IgM antibodies was 68.75% (22/32) (95% CI, 51.80-85.70%) after primary immunization. Unexpectedly, after secondary immunization the seropositivity response rate was only 9.38% (3/32) (95% CI, 1.30-20.10%), which was much lower than that after primary immunization (p = 0.000). Spearman's correlation analysis indicated a poor correlation of IgM antibodies with the other three antibodies. IgM response in vaccinees was completely different from the response patterns of neutralizing, total, and IgG antibodies following both the primary immunization and the secondary immunization and was suppressed by pre-existing immunity induced by primary immunization.

A Review of Bioactive Compounds against Porcine Enteric Coronaviruses.

Pig diarrhea is a universal problem in the process of pig breeding, which seriously affects the development of the pig industry. Porcine enteric coronaviruses (PECoVs) are common pathogens causing diarrhea in pigs, currently including transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus (PDCoV) and swine acute diarrhea syndrome coronavirus (SADS-CoV). With the prosperity of world transportation and trade, the spread of viruses is becoming wider and faster, making it even more necessary to prevent PECoVs. In this paper, the host factors required for the efficient replication of these CoVs and the compounds that exhibit inhibitory effects on them were summarized to promote the development of drugs against PECoVs. This study will be also helpful in discovering general host factors that affect the replication of CoVs and provide references for the prevention and treatment of other CoVs.

Unspecific reactivity must be excluded in COVID-19 epidemiological analyses or virus tracing based on serologic testing: Analysis of 46,777 post-pandemic samples and 1,114 pre-pandemic samples.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Serologic testing is complementary to nucleic acid screening to identify SARS-CoV-2. This study aimed to evaluate unspecific reactivity in SARS-CoV-2 serologic tests. Materials and methods: Total anti-SARS-CoV-2 antibodies from 46,777 subjects who were screened for SARS-CoV-2 were retrospectively studied to evaluate the incidence and characteristics of the unspecific reactivity. A total of 1,114 pre-pandemic samples were also analysed to compare unspecific reactivity. Results: The incidence of unspecific reactivity in anti-SARS-CoV-2 total antibody testing was 0.361% in 46,777 post-pandemic samples, similar to the incidence of 0.359% (4/1,114) in 1,114 pre-pandemic samples (p = 0.990). Subjects ≥ 19 years old had a 2.753-fold [95% confidence interval (CI), 1.130-6.706] higher probability of unspecific reactivity than subjects < 19 years old (p = 0.026). There was no significant difference between the sexes. The unspecific reactivity was associated with 14 categories within the disease spectrum, with three tops being the skin and subcutaneous tissue diseases (0.93%), respiratory system diseases (0.78%) and neoplasms diseases (0.76%). The percentage of patients with a titer ≥ 13.87 cut-off index (COI) in the unspecific reactivity was 7.69%. Conclusion: Our results suggest a unspecific reactivity incidence rate of 0.361% involving 14 categories on the disease spectrum. Unspecific reactivity needs to be excluded when performing serologic antibody testing in COVID-19 epidemiological analyses or virus tracing.

SGLT2 inhibitors attenuate nephrin loss and enhance TGF-ß1 secretion in type 2 diabetes patients with albuminuria: a randomized clinical trial.

To evaluate the effect of SGLT2 inhibitor (SGLT2i) on albuminuria, nephrin (NPH) and transforming-growth-factor-beta1 (TGF-ß1) levels in urine and low-grade inflammation in type 2 diabetes (T2D) patients. A randomized, blank-controlled clinical trial included 68 T2D patients and 10 controls. Based on the urinary albumin-to-creatinine ratio (UACR), 68 diabetic patients were stratified into three levels, UACR < 30 mg/g, UACR ≧ 30 mg/g to ≦ 300 mg/g and UACR ˃ 300 mg/g, who were randomized (1:1:1) to receive SGLT2i treatment for 12 weeks. The concentrations of NPH and TGF-ß1 in urine were measured as indications of podocyte injury and renal fibrosis. Low-grade inflammation was assessed by the levels of IL-6, TNFα and hsCRP. After 12 weeks of SGLT2i treatment, the levels of UACR and NPH decreased, UTGF-ß1 increased in the T2D with microalbuminuria and macroalbuminuria groups, NPH (1.12 [0.59, 1.29] vs. 0.71 [0.41, 1.07] µg/ml, P = 0.022) and (1.29 [0.99, 1.96] vs. 0.93 [0.57, 1.31] µg/ml, P = 0.002), UTGF-ß1 (4.88 ± 1.31 vs. 7.27 ± 1.21 pg/ml, P  < 0.001) and (4.30 ± 1.34 vs. 6.78 ± 2.59 pg/ml, P  < 0.001), respectively. The changes in NPH were positively correlated with the UACR and negatively correlated with UTGF-ß1 in T2D with albuminuria. SGLT2i alleviate nephrin loss and enhance TGF-ß1 excretion in urine in T2DM with albuminuria. The anti-albuminuric effect of SGLT2i could be attributed to mitigating podocyte apoptosis and attenuating renal fibrosis.Trial registration This clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.

A Third Dose of an Inactivated Vaccine Dramatically Increased the Levels and Decay Times of Anti-SARS-CoV-2 Antibodies, but Disappointingly Declined Again: A Prospective, Longitudinal, Cohort Study at 18 Serial Time Points Over 368 Days.

Background: Due to anti-SARS-CoV-2 antibody decay and SARS-CoV-2 variants, vaccine booster doses are a constant concern. It was focused on whether the third dose can quickly evoke and activate immunity and produce a sufficient and durable immune protection. Objectives: To evaluate the responses and durations of five subsets of anti-SARS-CoV-2 antibodies and their predictive values for protection after the administration of a three-dose inactivated SARS-CoV-2 vaccines regimens. Methods: A prospective cohort study of five subsets of anti-SARS-CoV-2 antibodies (neutralizing antibody, anti-RBD total antibody, anti-Spike IgG, anti-Spike IgM, and anti-Spike IgA) was carried out to evaluate the efficacies and immune characteristics of a three-dose inactivated SARS-CoV-2 vaccines regimen in 32 volunteers. The dynamic response and immune decay were longitudinally profiled at 18 serial time points over 368 days. Results: The neutralizing antibody, anti-RBD total antibody, anti-Spike IgG and anti-Spike IgA levels rapidly increased to 773.60 (380.90-1273.00) IU/mL, 639.30 (399.60-878.60) AU/mL, 34.48 (16.83-44.68) S/CO and 0.91 (0.35-1.14) S/CO, respectively, after the administration of the third dose. Compared to the peak value after the second dose, these values were increased by 4.22-fold, 3.71-fold, 1.01-fold and 0.92-fold. On the other hand, the half-lives of the neutralizing antibody, anti-RBD total antibody, and anti-Spike IgG were 56.26 (95% CI, 46.81 to 70.49) days, 66.37 (95% CI, 54.90 to 83.88) days, and 82.91 (95% CI, 63.65 to 118.89) days, respectively. Compared to the half-lives after the second dose, these values were increased by 1.71-fold, 2.00-fold, and 2.93-fold, respectively. Nevertheless, the positive conversion rate of anti-Spike IgM was decreased to 9.38% (3/32), which was much lower than that after the second dose (65.63% (21/32)). Conclusions: Compared to the second dose, the third dose dramatically increased the antibody levels and decay times. However, the half-life of neutralizing antibody remained unsatisfactory. Due to decay, a fourth dose, and even annual revaccination, might be considered in the SARS-CoV-2 vaccination management strategy.

Comparing the diagnostic value of bronchoalveolar lavage fluid galactomannan, serum galactomannanan, and serum 1,3-ß-d-glucan in non-neutropenic respiratory disease patients with invasive pulmonary aspergillosis.

ABSTRACT: The incidence of invasive pulmonary aspergillosis (IPA) is increasing higher in non-neutropenic patients. This study aimed to assess the diagnostic performance of bronchoalveolar lavage fluid (BALF). Galactomannan (GM), serum GM, and 1,3-ß-d-glucan (BDG) in non-neutropenic respiratory disease patients with IPA.A total of 333 non-neutropenic patients suspected IPA were recruited from Xiamen University Zhong Shan hospital between January 2016 and February 2019. One, 33, and 92 cases were diagnosed with proven, and possible IPA.BALF and serum GM were both elevated in the possible IPA group and the probable/proven IPA group (p < 0.001). BALF and serum GM showed a fair correlation in the possible IPA group (r = 0.286, p = 0.008), and moderate correlation in the probable/proven IPA group (r = 0.466, p = 0.005). When the cutoff value was 0.5, the sensitivity and negative likelihood ratio of BALF GM were superior to serum GM (78.3% vs 47.8%, 96.7% vs 91.6%). The specificity and positive likelihood ratio of BALF GM were slightly weaker than serum GM (91.8% vs 95.4%, 56.7% vs 85.0%). When the cutoff value was 1.0, the sensitivity and negative predictive value of BALF GM were better than serum GM (73.9% vs 26.1%, 94.5% vs 88.8%), and the specificity of were equivalent (99.2%). The optimal cutoff value of BALF GM was 0.6, wherein the sensitivity reached 78.3% and the specificity reached 95.4%. Given the extremely low sensitivity of serum BDG at different cutoff values (≥10 µg/mL = 5.3%, ≥20 µg/mL = 2.1%), it cannot be used as a preferred biomarker.The diagnostic performance of BALF GM was superior to other biomarkers and the optimal cutoff value was 0.6.