Factors Associated with Attrition in a Longitudinal Cohort of Older Adults in the Community.

Introduction: Retaining participants in longitudinal studies increases their power. We undertook this study in a population-based longitudinal cohort of adults with COPD to determine the factors associated with increased cohort attrition. Methods: In the longitudinal population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study, 1561 adults > 40 years old were randomly recruited from 9 urban sites. Participants completed in-person visits at 18-month intervals and also were followed up every 3 months over the phone or by email. The cohort retention for the study and the reasons for attrition were analyzed. Hazard ratios and robust standard errors were calculated using Cox regression methods to explore the associations between participants who remained in the study and those who did not. Results: The median follow-up (years) of the study is 9.0 years. The overall mean retention was 77%. Reasons for attrition (23%) were: dropout by participant (39%), loss of contact (27%), investigator-initiated withdrawal (15%), deaths (9%), serious disease (9%), and relocation (2%). Factors independently associated with attrition were lower educational attainment, higher pack-year tobacco consumption, diagnosed cardiovascular disease, and a higher Hospital Anxiety and Depression Scale score: adjusted hazard ratios (95% confidence interval) were 1.43(1.11, 1.85); 1.01(1.00, 1.01); 1.44(1.13, 1.83); 1.06(1.02, 1.10) respectively. Conclusions: Identification and awareness of risk factors for attrition could direct targeted retention strategies in longitudinal studies. Moreover, the identification of patient characteristics associated with study dropout could address any potential bias introduced by differential dropouts.

[Demographic characteristics and associated influencing factors in treated patients with chronic hepatitis B with hypoviremia : a single-center retrospective cross-sectional study].

Objective: To investigate the demographic characteristics and clinical influencing factors which associates with the occurrence probability of persistent or intermittent hypoviremia (LLV) in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs). Methods: A single-center retrospective analysis was performed on patients with CHB who received outpatient NAs therapy for≥48 ± 2 weeks. According to the serum hepatitis B virus (HBV) DNA load at 48±2 weeks treatment, the study groups were divided into LLV (HBV DNA < 20 IU/ml and < 2 000 IU/ml) and MVR group (sustained virological response, HBV DNA < 20 IU/ml). Demographic characteristics and clinical data at the start of NAs treatment (considered as baseline) were retrospectively collected for both patient groups. The differences in the reduction of HBV DNA load during treatment was compared between the two groups. Correlation and multivariate analysis were further conducted to analyze the associated factors influencing the LLV occurrence. Statistical analysis was performed using the independent samples t-test, c2 test, Spearman analysis, multivariate logistic regression analysis, or area under the receiver operating characteristic curve. Results: A total of 509 cases were enrolled, with 189 and 320 in the LLV and MVR groups, respectively. Compared to patients with MVR group at baseline: (1) the demographics characteristics of patients showed that LLV group was younger in age (39.1 years, P = 0.027), had a stronger family history (60.3%, P = 0.001), 61.9% received ETV treatment, and higher proportion of compensated cirrhosis (20.6%, P = 0.025) at baseline; (2) the serum virological characteristics of patients showed that LLV group had higher HBV DNA load, qHBsAg level, qHBeAg level, HBeAg positive rate, and the proportion of genotype C HBV infection but decreased HBV DNA during treatment (P < 0.001) at baseline; (3) the biochemical characteristics of patients showed that LLV group had lower serum ALT levels (P = 0.007) at baseline; (4) the noninvasive fibrosis markers of patients showed that LLV group were characterized by high aspartate aminotransferase platelet ratio index (APRI) (P = 0.02) and FIB-4 (P = 0.027) at baseline. HBV DNA, qHBsAg and qHBeAg were positively correlated with LLV occurrence (r = 0.559, 0.344, 0.435, respectively), while age and HBV DNA reduction were negatively correlated (r = -0.098, -0.876, respectively). Logistic regression analysis showed that ETV treatment history, high HBV DNA load at baseline, high qHBsAg level, high qHBeAg level, HBeAg positive, low ALT and HBV DNA level were independent risk factors for patients with CHB who developed LLV with NAs treatment. Multivariate prediction model had a good predictive value for LLV occurrence [AUC 0.922 (95%CI: 0.897 ~ 0.946)]. Conclusion: In this study, 37.1% of CHB patients treated with first-line NAs has LLV. The formation of LLV is influenced by various factors. HBeAg positivity, genotype C HBV infection, high baseline HBV DNA load, high qHBsAg level, high qHBeAg level, high APRI or FIB-4 value, low baseline ALT level, reduced HBV DNA during treatment, concomitant family history, metabolic liver disease history, and age < 40 years old are potential risk factors for developing LLV in patients with CHB during the therapeutic process.

Andrographolide Liquisolid using Porous-Starch as the Adsorbent with Enhanced Oral Bioavailability in Rats.

Andrographolide (AGL) is the major component of Andrographispaniculata. The poor water solubility and low dissolution strongly affect its oral absorption. Liquisolid technology has been used to improve its dissolution and oral bioavailability. Liquisolid powders of AGL (AGL-LS-PSG) were obtained by firstly dissolving AGL in the mixture of NMP, PEG 6000 and Soluplus®, and solidified by absorption of the blend in porous starch. Angle of repose, Carr index and Hauser ratio presented good powder fluidity and compressibility characteristics of AGL-LS-PSG. The results of optical microscopic observation, PXRD and DSC analysis indicated that AGL has been completely adsorbed in porous starch granules and existed in an amorphous or molecularly dispersing state. AGL-LS-PSG can obviously increase the drug dissolution rate compared to commercial guttate pills and raw drug. In vivo pharmacokinetic behavior of AGL-LS-PSG was investigated following a single oral administration to rats. The Cmax (0.37 ± 0.06 µg mL-1) and AUC0-2h (13.55 ± 2.67 µg h mL-1) of AGL-LS-PSG were evidently increased compared to commercial guttate pills (Cmax = 0.30 ± 0.21 µg mL-1, AUC0-2h = 9.88 ± 3.57 µg h mL-1). This study indicated great potential of liquisolid technology in effectively improving the dissolution and bioavailability of AGL.

[A case of spontaneous remission of acute myeloid leukemia with MLL-AF9 rearrangement and abnormal liver function].

Objective: To explore the clinical features and possible pathogenesis of spontaneous remission of acute myeloid leukemia (AML) . Methods: We retrospectively analyzed the clinical data of a patient with spontaneous remission of AML, MLL-AF9 rearrangement, and abnormal liver function in the First Affiliated Hospital of Zhengzhou University, and the relevant pieces of literature were summarized. Results: The patient experienced lung infection, fever, and liver dysfunction and was treated with anti-infection and blood transfusion. After complete response (CR) , the patient remained in CR with mild, indirect bilirubin elevation at 35 months of follow-up. Additionally, 56 cases of adult AML (non-acute promyelocytic leukemia) were reported in the literature from 1990 to June 2021. The cases were checked by bone marrow aspiration, and our patients were summarized and analyzed. Furthermore, 57 patients, including 37 males and 20 females, with a median age of 51 (20-83) years and a median remission time of five months; 52 patients achieved complete remission. In addition, there were five cases with long-term remission and a chromosomal record, with no recurrence so far, three with normal karyotype and two with t (9;11) (q21;q23) . Conclusion: The spontaneous remission of leukemia is rare and may be related to immunosuppression and genes.

[Clinical features of 123 patients with hyperinsulinemic hypoglycemia auxiliarily diagnosed by 18F-DOPA-PET CT scanning].

Objective: To summarize the clinical features and therapeutic outcomes of patients with hyperinsulinemic hypoglycemia (HH) auxiliarily diagnosed by 18F-DOPA positron emission tomography (PET) CT scanning. Methods: The clinical data of 123 patients who were diagnosed with hyperinsulinemic hypoglycemia by comprehensive clinical diagnostic procedures in the Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University between January 2016 and December 2020 were retrospectively analyzed. Clinical data such as gender, age of onset, province, concurrent serum insulin level measured during hypoglycemia, lesion type of pancreas by 18F-DOPA-PET CT scanning, genetic test results, and treatment were collected successively. The clinical features and therapeutic outcomes were compared between patients with focal and diffuse pancreatic lesions. T test, Rank sum test, and χ² test were used for comparison between groups. Results: A total of 123 patients with hyperinsulinemic hypoglycemia (72 males and 51 females), whose average age of onset was 3 days (ranging from 1 day to 4 860 days), were recruited from 24 provinces. The concurrent serum insulin level was 7.1 (0.4-303.0) mU/L during hypoglycemia. 18F-DOPA-PET CT scanning identified focal lesions in 25.2% (31/123) and diffuse lesions in 74.8% (92/123) of the patients; 64.2% (79/123) of the HH cases were found to have pathogenic gene variants, in which 88.6% (70/79) were found to have KATP channel related genes (61 in ABCC8 and 9 in KCNJ11 mutations). Thirty-seven patients (17 focal and 20 diffuse) received surgical treatment with a success rate of 67.6% (25/37). The effective rate of diazoxide for children with diffuse type was significantly higher than that of children with focal group (28.3% (26/92) vs. 9.7% (3/31), χ²=10.31, P=0.001). Conclusions: 18F-DOPA-PET CT scan can improve the success rate of surgery. Comprehensive diagnosis of the etiology of hyperinsulinemic hypoglycemia by genetic analysis and 18F-DOPA-PET CT scanning can result in better treatment and prognosis.

[Clinical observation of surgical resection combined radiofrequency in patients with CNLC â ¡a~â ¢a stage multiple hepatocellular carcinoma].

Objective: To investigate the effects of four therapeutic methods in the comprehensive treatment of China liver cancer staging (CNLC)Ⅱa~Ⅲa stage multiple hepatocellular carcinoma. Method: A retrospective study was conducted to collect clinical data of patients with multiple hepatocellular carcinoma (CNLC stage Ⅱa-Ⅲa), who received transhepatic arterial chemoembolization (TACE group, 73 cases), radiofrequency ablation (RFA group, 70 cases), TACE combined RFA (TACE combined RFA group, 69 cases) and surgical resection combined RFA (surgical resection combined RFA group, 57 cases) in the First Hospital of Lanzhou University from January 11, 2010 to January 31, 2017. The general data of age, gender, primary tumor, and laboratory examination were collected. The differences in overall survival rates and the survival rates among stratified subgrouping with different clinical factors between the four groups of patients were compared by the Kaplan-Meier method. Cox proportional hazards regression model analyzed the prognostic factors. Result: A total of 269 patients were enrolled and there were 194 males and 59 females with a median age of 58 years ranging from 23 to 84. The TACE group's 1, 3, and 5-year survival rates were 43.5%, 10.2%, and 0, respectively. The RFA group were 46.3%, 17.7%, and 0, respectively. The TACE combined RFA group were 56.8%, 21.5%, and 2.3%, respectively. The surgical resection combined RFA group was 76.5%, 38.7%, and 3.8%, respectively. The surgical resection combined RFA group has the best outcome(P<0.05). Univariate analysis showed that surgery combined RFA, tumor diameter<5 cm, no vascular invasion, preoperative AFP≤400 µg/L and TB<34 µmol/L are protective factors to improve the survival prognosis of patients with CNLCⅡa~Ⅲa stage multiple hepatocellular carcinoma(HR=0.784,0.718,0.633,0.846,0.617;all P<0.05). Multivariate Cox analysis showed that surgery combined RFA, tumor diameter<5 cm, preoperative AFP≤400 µg/L were independent risk prognostic factors for CNLCⅡa-Ⅲa stage multiple hepatocellular carcinoma (HR=0.702,0.743,0.647;all P<0.05). Conclusions: Surgical resection combined RFA is an effective method for the treatment of stage Ⅱa-Ⅲa hepatocellular carcinoma. Surgical resection combined RFA has more advantages in treatment patients with complicated hepatocellular carcinoma whose diameter<5 cm, tumor number<3, and preoperative AFP≤400 µg/L. Surgical resection combined RFA, tumor diameter<5 cm, preoperative AFP≤400 µg/L are independent influencing factors for the survival prognosis of patients with complicated hepatocellular carcinoma.

[Correlation analysis between ICG-R15 and modified Scheuer score in liver tissues of patients with hepatitis B e antigen-positive/negative chronic hepatitis B].

Objective: To analyze the correlation between indocyanine green retention rate at 15 minutes (ICG-R15) and modified Scheuer score in liver tissues of patients with hepatitis B e antigen-positive/negative chronic hepatitis B (CHB), and further explore the indocyanine green clearance test (ICGCT) applied value in judging the progress of CHB-related liver disease. Methods: 407 HBeAg (+) / HBeAg (-) CHB inpatients with normal or slightly elevated serum alanine aminotransferase (ALT) [< 2 times the upper limit of normal (ULN)] and modified Scheuer score were collected, and divided into mild liver disease group (M group, 131 cases, modified Scheuer score < G2S2) and progressive liver disease group (A group, 276 cases, modified Scheuer score≥G2 and / or S2). Furthermore, the groups were sub-divided into HBeAg (+) - M group, HBeAg (-) - M group, HBeAg (+) - A group and HBeAg (-) - A group. The correlation between ICG-R15 and modified Scheuer score was analyzed retrospectively. The data were analyzed by SPSS 24.0 software. Results: Basic clinical characteristics: Among the 407 CHB cases with normal or mildly elevated serum ALT, 171 were HBeAg(+) CHB and 236 were HBeAg(-) CHB. The baseline mean serum HBV DNA was higher in HBeAg(+) CHB patients [(6.06 ± 1.95) log10IU/ml] than HBeAg(-) CHB patients [(3.60±1.37)log10IU/ml (P = 0.000)]. Included patients ICG-R15 detection characteristics: (1) The baseline mean value of ICG-R15 was not statistically significant between the two groups of HBeAg(+) CHB and HBeAg(-) CHB, and was basically within the normal range (< 10%); (2) Comparison of ICG-R15 baseline mean value among the subgroups showed that the patients in the HBeAg(+)-A group/HBeAg(-)-A group were higher than the HBeAg(+)-M group/HBeAg(-)-M group patients, and the difference was statistically significant (P = 0.013/P = 0.000). Included patients' correlation analysis between ICG-R15 and modified Scheuer score: (1) ICG-R15 and modified Scheuer score had shown weak positive correlation with inflammatory activity grade (g) in HBeAg (+) / HBeAg (-) CHB (r = 0.237, P = 0.002); r = 0.244, P = 0.000); (2) There was a weak positive correlation between ICG-R15 and fibrosis stage (s) in HBeAg (+) / HBeAg (-) CHB (r = 0. 254, P = 0; r = 0.225, P = 0.001). Included patients ICG-R15 predictive value for the severity of liver histological progression: when the cut-off value of ICG-R15 was 5.1%, the area under the receiver operating characteristic curve from M group to A group was 0.601 (P = 0.001) for predicting HBeAg (+) / HBeAg (-) CHB patients. Conclusion: ICG-R15 is positively correlated with the modified Scheuer score of liver tissue in HBeAg (+)/HBeAg (-) CHB patients with normal or slightly elevated ALT. In addition, when the cut-off value of ICG-R15 was 10%, it could not accurately reflect the effective hepatocyte reserve function of HBeAg (+) / HBeAg (-) CHB patients with normal or slightly elevated ALT. Importantly, when the cut-off value of ICG-R15 is 4.0% ~ 5.0%, it may have predictive value for liver disease progression to modified Scheuer score ≥ G2 and / or ≥S2 in HBeAg (+) / HBeAg (-) CHB patients with normal or slightly elevated ALT.

Technical note: Understanding the effect of COVID-19 on particle pollution using a low-cost sensor network.

The 2020 coronavirus pandemic and the following quarantine measures have led to significant changes in daily life worldwide. Preliminary research indicates that air quality has improved in many urban areas as a result of these measures. This study takes a neighborhood-scale approach to quantifying this change in pollution. Using data from a network of citizen-hosted, low-cost particulate matter (PM) sensors, called Air Quality & yoU (AQ&U), we obtained high-spatial resolution measurements compared to the relatively sparse state monitoring stations. We compared monthly average estimated PM2.5 concentrations from February 11 to May 11, 2019 at 71 unique locations in Salt Lake County, UT, USA with the same (71) sensors' measurements during the same timeframe in 2020. A paired t-test showed significant reductions (71.1% and 21.3%) in estimated monthly PM2.5 concentrations from 2019 to 2020 for the periods from March 11-April 10 and April 11-May 10, respectively. The March time period corresponded to the most stringent COVID-19 related restrictions in this region. Significant decreases in PM2.5 were also reported by state monitoring sites during March (p < 0.001 compared to the previous 5-year average). While we observed decreases in PM2.5 concentrations across the valley in 2020, it is important to note that the PM2.5 concentrations did not improve equally in all locations. We observed the greatest reductions at lower elevation, more urbanized areas, likely because of the already low levels of PM2.5 at the higher elevation, more residential areas, which were generally below 2 µg/m3 in both 2019 and 2020. Although many of measurements during March and April were near or below the estimated detection limit of the low-cost PM sensors and the federal equivalent measurements, every low-cost sensor (51) showed a reduction in PM2.5 concentration in March of 2020 compared to 2019. These results suggest that the air quality improvement seen after March 11, 2020 is due to quarantine measures reducing traffic and decreasing pollutant emissions in the region.

Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms.

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease.

The clinical value of serum sirtuin-1 in the diagnosis of rheumatoid arthritis: a pilot study.

Introduction: Cell biology studies, animal models and other data suggest a role for sirtuin-1 in the pathogenesis of rheumatoid arthritis (RA). We hypothesized the clinical significance of serum sirtuin-1 in this disease.Methods: Serum was obtained from 141 RA patients, 144 non-RA patients and 88 healthy controls. Sirtuin-1, anti-mutant citrulline vimentin antibody (anti-MCV), anti-cyclic citrulline polypeptide antibody (anti-CCP), rheumatoid factor and C-reactive protein were measured by immunological methods, and erythrocyte sedimentation rate was determined by the Westergren method.Results: All markers were higher in the RA group than in the non-RA group and the healthy control group (P < 0.01). The specificity of sirtuin-1 for the diagnosis of RA was 97% (the highest among all markers), sensitivity was 71%. In ROC curve analysis, the AUCs (95% CI) of sirtuin-1, anti-CCP and anti-MCV were 0.87 (0.82-0.91), 0.91 (0.88-0.94) and 0.92 (0.89-0.95) respectively (all p < 0.01). The combination of sirtuin-1and anti-MCV gave the highest Youden index of 0.79, whilst Cox regression showed sirtuin-1 and rheumatoid factor were the strongest independent predictors of RA.Conclusions: Serum sirtuin-1 is increased in RA, and may have a place is the diagnosis of this disease when combined with other markers.

Value of serum collagen triple helix repeat containing-1(CTHRC1) and 14-3-3η protein compared to anti-CCP antibodies and anti-MCV antibodies in the diagnosis of rheumatoid arthritis.

INTRODUCTION: Serological markers are important in the diagnosis of rheumatoid arthritis (RA) and other connective tissues diseases This study explored the clinical value of collagen triple helix repeat containing-1 (CTHRC1) and 14-3-3η protein, compared to routine markers, in the diagnosis of RA. METHODS: We recruited 103 RA patients, 105 non-RA patients (osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus) and 59 healthy controls. CTHRC1, 14-3-3η, anti-cyclic citrullinated peptide antibody (anti-CCP), anti-mutated citrullinated vimentin antibody (anti-MCV), rheumatoid factor and erythrocyte sedimentation rate (ESR) levels were measured, and their diagnostic value for RA evaluated and compared. RESULTS: All laboratory indices were elevated in RA (P < 0.05). Of these, anti-MCV had the highest sensitivity (86.4%) and anti-CCP the highest specificity (94.5%). The areas under the curve (AUC) of CTHRC1, 14-3-3η, anti-CCP, anti-MCV, rheumatoid factor and ESR were 0.84, 0.81, 0.89, 0.91, 0.85 and 0.77 respectively (all P < 0.01). Anti-CCP and anti-MCV were the most valuable in the diagnosis of RA. The combination of anti-CCP and anti-MCV had the maximum Youden index, followed by the combination of anti-CCP and 14-3-3η. Binary logistic regression analysis showed that 14-3-3η had the largest odds ratio value (95% CI) at 5.1 (2.1-12.5) for RA. CONCLUSION: CTHRC1 and 14-3-3η are promising serological indicators of RA, and when combined with anti-CCP, anti-MCV and ESR, can improve the diagnosis of this disease.

iTRAQ-based quantitative proteomics analysis reveals inhibitory mechanismsof the antimicrobial peptide MDAP-2 against Salmonella gallinarum.

MDAP-2 is a new AMP with high inhibitory activity on Salmonella gallinarum, which may be developed as an antimicrobial agent in the agricultural industry and food preservation. To investigate the underlying the action mechanism of MDAP-2 on Salmonella gallinarum, impacts of MDAP-2 on the growth curve and bacterial morphology of Salmonella gallinarum were studied. iTRAQ-based proteomics analysis was also performed on proteins extracted from treated and untreated Salmonella gallinarum cells. The differentially expressed proteins were then analyzed using the KEGG and GO databases. Finally, the function of some differentially expressed proteins was verified. The results showed that 150 proteins (41 up-regulated and 109 down-regulated) were found differentially expressed (fold > 1.8, p⟨0.05). The results indi- cate that MDAP-2 kills Salmonella gallinarum mainly through two mechanisms: (i) direct inhibi- tion of cell wall/ membrane/ envelope biogenesis, energy production/ conversion, carbohydrate transport/ metabolism, and DNA transcription/ translation through regulation of special protein levels; (ii) indirect effects on the same pathway through the accumulation of Reactive oxygen species (O2 ▪-, H2O2 and OH▪-).

PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients.

BACKGROUND: The most common dementia worldwide, Alzheimer's disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aß1-42, and increases in total tau and phosphorylated tau-181. Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer's disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer's disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aß42's toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aß-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A's linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aß42's activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer's disease brain. OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A's altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aß42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4. DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study. SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application. PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer's disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aß42 ratio ≥0.30. INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days. MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer's disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aß42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1ß and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aß42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition. RESULTS: Consistent with the drug's mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer's disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125. Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aß42's signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aß42 increased slightly - a desirable result because low Aß42 indicates Alzheimer's disease. This increase is consistent with PTI-125's 1,000-fold reduction of Aß42's femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A's conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aß42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1. CONCLUSIONS: PTI-125 significantly reduced biomarkers of Alzheimer's disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.

[Comparison of the early efficacy of unicompartmental and total knee arthroplasty in patients with medial compartmental osteoarthritis of the knee: a propensity score matching study].

Objective: To compare the short-term efficacy of unicompartmental knee arthroplasty (UKA) and total knee arthroplasty(TKA) in the treatment of medial compartmental knee osteoarthritis. Methods: A retrospective analysis was performed on 197 patients with medial compartment osteoarthritis of the knee treated by the same group of doctors from January 2015 to December 2018.There were 86 males and 111 females, aged (67.7±10.5) years (range: 46 to 92 years), among which 101 cases received UKA and 96 cases received TKA.The UKA and TKA patients were matched by the propensity score matching method, and a total of 41 pairs of patients were successfully matched.The difference of short-term outcomes between the two groups were compared by t test, χ(2) test or Fisher exact probability methods. Results: Compared with TKA group, the postoperative reduction of hemogloblin in the UKA group was lower ((15.3±6.4) g/L vs. (20.1±7.5) g/L, t=-3.117, P<0.01), opioid dosage was lower ((160.5±29.3) mg vs. (186.1±46.8) mg, t=-2.969, P<0.01), and the length of hospital stay was shorter ((7.0±2.0)d vs. (10.0±2.5)d, t=-6.000, P<0.01). Forgotten joint score of UKA group was higher ( (65.1±7.6) vs. (58.3±13.9) , t=2.732, P<0.01), the incidence of knee clunk or crepitus was lower (P=0.03) . There was no significant difference in the time of surgical tourniquet, range of motion, American knee society clinical score and incidence of deep vein thrombosis in lower extremities between the two groups.No complications such as surgical site infection, prosthesis loosening and dislocation occurred in the two groups. Conclusion: The early effect of UKA is similar to that of TKA, and it is better than TKA in the aspects of knee clunk or crepitus, forgotten joint score, blood loss, opioid dosage and postoperative hospital stay.

Clinical and genetic features of patients with amyotrophic lateral sclerosis in southern China.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS)-related genes and mutations have been increasingly discovered recently and an improved understanding of genotype-phenotype relationships may help to predict the disease course and refine genetic diagnosis. METHODS: We collected clinical data and blood samples from 268 patients and used next-generation sequencing to comprehensively assay genetic variations in a panel of known ALS genes from 2015 to 2019. RESULTS: Among these patients, the mean age of onset was 52.30 ± 10.42 years with a mean diagnosis delay of 15.90 ± 11.88 months. Patients with SOD1, TARDBP and FUS variants were more likely to suffer from familial ALS. Additionally, carriers of FUS variants displayed the earliest onset, followed by those with SOD1 variants. Patients with NEFH variants showed a closer link to pesticide exposure. Patients with SETX variants were prone to bulbar onset with moderate anxiety problems. No genotype-phenotype relations were found in SPG11 and ERBB4 mutants. CONCLUSION: Our findings uncovered some genotype-phenotype relationships and may help to predict the disease course of patients with ALS in southern China.

Identification and definition of asthma-COPD overlap: The CanCOLD study.

BACKGROUND AND OBJECTIVE: Lack of consensus on diagnosis of ACO limits our understanding of the impact, management and outcomes of ACO. The present observational study aims to describe the prevalence, clinical characteristics and course of individuals with ACO based on various definitions used in clinical practice. METHODS: We included individuals with COPD from the prospective, multisite CanCOLD study and defined subjects with ACO using seven definitions commonly used in the literature. RESULTS: Data including questionnaires, lung function and CT scans were analysed from 522 individuals with COPD who were randomly recruited from the population. Among them, 264 fulfilled at least one of the seven definitions of ACO. Prevalence of ACO varied from 3.8% to 31%. Regardless of the definition, individuals with ACO had worse outcomes (lung function and higher percentage of fast decliners, symptoms and exacerbations, health-related quality of life and comorbidities) than the remaining patients with COPD. Conversely, patients with non-ACO had higher emphysema and bronchiolitis scores. The three definitions that included atopy and/or physician diagnosis of asthma identified subjects who differed significantly from patients with COPD. The two ACO definitions with post-bronchodilator reversibility were concordant with COPD and were the least stable, with less than 50% of the patients from each group maintaining reversibility over visits. CONCLUSION: Atopy and physician-diagnosed asthma are more distinguishing characteristics to identify ACO. This finding needs to be validated using measures of airway inflammation and other specific biomarkers.

Clinical diagnostic significance of 14-3-3η protein, high-mobility group box-1, anti-cyclic citrullinated peptide antibodies, anti-mutated citrullinated vimentin antibodies and rheumatoid factor in rheumatoid arthritis.

Introduction: Circulating markers of rheumatoid arthritis (RA) include the 14-3-3η protein, high-mobility group box-1 (HMGB1), anti-cyclic citrullinated peptide (anti-CCP) antibodies, anti-mutated citrullinated vimentin (anti-MCV) antibodies and rheumatoid factor (RF). We set out to determine which two markers in combination provided best discriminatory power for this disease.Methods: We recruited 108 RA patients, 102 non-RA patients (SLE, AS, Sjogren's syndrome, MCTD) and 90 healthy controls. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and the Youden index of each analyte were calculated and binary logistic regression analysis and receiver operating characteristic (ROC) curve were performed to evaluate their diagnostic value for RA alone and in paired combination.Results: As expected, all markers were elevated in RA patients (P < 0.05). Binary logistic regression analysis showed that 14-3-3η had the highest odds ratio (95% CI) at 2.4 (1.9-2.8). Anti-CCP and anti-MCV had the highest areas under the curves [AUC (95% CI)] at 0.85 (0.78-0.90) and 0.85 (0.78-0.91) respectively (both P < 0.001). In serial detection (one marker followed by another), no combination had a Youden index >0.6. In parallel analysis (both considered together) several combinations had a Youden index >0.7, of which the highest (0.78) was anti-CCP with anti-MCV, with a sensitivity of 93.3% and specificity of 84.7%.Conclusions: Despite individual increases in serum 14-3-3η, HMGB1, anti-CCP, anti-MCV and RF, the combination of anti-CCP and anti-MCV might be of great help for diagnostic in RA, and so should be considered as routine tests for this disease.