Varenicline solution nasal spray for dry eye disease in Chinese patients: a randomized phase 3 trial.

Background: Dry eye disease has a high prevalence and exerts a significant negative effect on quality of life. In China, there are currently no available nasal sprays to promote natural tear production in patients with dry eye disease. We therefore evaluated the efficacy and safety of OC-01 (varenicline solution) nasal spray versus vehicle in Chinese patients with dry eye disease. Methods: This was a randomized, multicenter, double-masked, vehicle-controlled, phase 3 clinical trial conducted at ophthalmology departments in 20 hospitals across China (NCT05378945). Eligible patients had a diagnosis of dry eye disease based on patient symptoms, Eye Dryness Score (EDS), Schirmer's Test (with topical anesthesia) Score (STS), and corneal fluorescein staining (CFS) score. Participants were randomly assigned 1:1 using an Interactive Web Response System (IWRS) to receive OC-01 0.6 mg/mL twice daily (BID) or vehicle nasal spray. Participants, investigators, and sponsor were all masked to treatment assignment. The primary endpoint was the percentage of subjects in the intention-to-treat population achieving ≥10 mm improvement in STS from baseline at week 4. Findings: In total, 340 patients were randomized from 21 July 2022 to 04 April 2023, 78.8% were female. Patients in the OC-01 group (n = 176) had significantly higher achievement of ≥10 mm improvement in STS (35.8% [n = 63] versus 17.7% [n = 29], stratified odds ratio: 2.67, 95% CI: 1.570-4.533, p = 0.0002) and a significantly greater increase from baseline STS (least-squares mean difference [SE]: 3.87 [0.794], p < 0.0001) at week 4 versus the vehicle group (n = 164). In addition, OC-01 led to a numerically greater reduction in mean EDS from baseline at week 4 compared to the vehicle group (LS mean [SE] difference: -1.3 [2.20]; 95% CI: -5.64 to 2.99, p = 0.5467). The most common adverse event was mild, transient sneezing (78% of OC-01 administrations). No serious adverse events related to nasal administration occurred. Interpretation: OC-01 (varenicline solution) nasal spray BID has clinically meaningful efficacy for reducing the signs (as measured by STS) and may improve the symptoms (as measured by EDS) of dry eye disease, with an excellent safety and tolerability profile, in the Chinese population. Funding: Jixing Pharmaceutical Co. Ltd.

Semi-PBPK Modeling and Simulation to Evaluate the Local and Systemic Pharmacokinetics of OC-01(Varenicline) Nasal Spray.

This study aimed to build a nasal semi-physiologically based pharmacokinetic (PBPK) model to predict the intranasal pharmacokinetic (PK) of the OC-01(varenicline) nasal spray and accelerate the development of this drug. Based on the physiology of the human upper respiratory system, the semi-PBPK model was established and validated using systemic plasma PK data of varenicline previously observed in Americans and Chinese. Drug concentrations, both in respiratory tissue and plasma circulation system, were well simulated, and it was indicated that local concentration at the target site (nasal cavity) was significantly higher than that of plasma when OC-01 nasal spray was administered. The nasal semi-PBPK model successfully depicted the absorption and distribution of intranasal varenicline in the respiratory tissues and provided an alternative to clinical PK study of OC-01 nasal spray in Chinese. Meanwhile the current study presented a viable framework for predicting respiratory concentrations for other novel nasal spray drugs by semi-PBPK modeling.

Atypical de Winter ECG pattern may be the mirror image of ST elevation.

BACKGROUND: The de Winter ECG pattern of ST-segment depression and tall symmetrical T waves, known as an ST elevation equivalent, accounts for approximately 2% of patients with occlusion of the proximal left anterior descending (LAD) coronary artery. The classic de Winter pattern is restricted to cases without ST elevation. However, mixed cases with different types of ST deviation have been described. Here, we describe an interesting case as an example of an ST elevation myocardial infarction (STEMI) equivalent, showing transient transmural ischemia of the inferolateral myocardium, with ECG changes that mimic the de Winter pattern.

Reduction in SLEDAI is associated with improved arterial stiffness in systemic lupus erythematosus.

Lipid abnormalities are an important cause of premature atherosclerosis in patients with systemic lupus erythematosus (SLE). This longitudinal study investigates the changes in lipid profile and arterial stiffness with SLE disease activity index (SLEDAI) reduction.Fifty one female SLE patients with baseline SLEDAI ≥ 6 and SLEDAI reduction >3 at 1-year follow-up were included. Neutrophil-to-lymphocyte ratio (NLR), erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hsCRP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and mean brachial-ankle pulse wave velocity (baPWV) were measured and compared between baseline and 1-year follow-up. Correlations between inflammation biomarkers, SLEDAI, mean baPWV and lipid profile were assessed.We observed significant decreases in ESR, mean baPWV, TG and TC to HDL-C ratio compared with baseline at 1-year follow up, while HDL-C, hsCRP, and NLR were not significantly changed. Significant correlations were found between the reductions in ESR and TG, and SLEDAI and mean baPWV, with adjustment to age, disease duration, blood pressure, and medications (prednisone, immunosuppressants and ARB/ACEI).SLE patients experiencing SLEDAI reductions showed improvements in arterial stiffness. This finding may provide insight into the beneficial effects of reducing SLEDAI on atherosclerosis risk in SLE.

Risk factors for progression of carotid intima-media thickness in patients with systemic lupus erythematosus: protocol for an observational cohort study in China.

INTRODUCTION: Accelerated atherosclerosis is a major complication of systemic lupus erythematosus (SLE), and it leads to increased cardiovascular morbidity and mortality in patients with SLE. This study aimed to investigate the natural progression of carotid intima-media thickness (CIMT), and to examine the risk factors for progression of CIMT and atherosclerotic plaques based on a Chinese SLE cohort. METHODS AND ANALYSIS: Participants were continuously enrolled as outpatients of the Department of Rheumatology in Peking Union Medical College Hospital (PUMCH) from October 2013 to December 2016. Inclusion criteria were as follows: (1) age ≥18 years, (2) fulfilment of clinical classification criteria of SLE and (3) provision of signed written informed consent. Patients with clinically overt coronary artery disease, a history of cardiovascular disease (previous stroke, heart failure, myocardial infarction, angina or symptomatic peripheral artery disease) and malignancy, and pregnant/lactating women were excluded. The primary outcome is progression of CIMT from baseline. A total of 440 patients with SLE will be enrolled. Participants will receive follow-up surveys ~5 years after their baseline visit. A standard structural survey form, including demographic data, medical history, clinical and laboratory assessments and CIMT measurement, is planned for data collection at baseline and follow-up. The risk prediction model for progression of CIMT will be created by using a mixed effect model. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board of PUMCH (S-599). Informed consent was obtained from all participants according to the Declaration of Helsinki on Biomedical Research Involving Human Studies. All data will be managed confidentially according to guidelines and legislation. Dissemination will include publication of scientific papers and/or presentations of the study findings at international conferences.

Arterial Stiffness and Cerebral Small Vessel Disease.

Background and Objective: Studies on relations between arterial stiffness and full spectrum of radiological features of cerebral small vessel disease (CSVD) are scarce. We aim to investigate the association of arterial stiffness with lacunes, white matter hyperintensities (WMH), microbleeds (CMBs), dilated perivascular spaces (PVS), and brain atrophy in a community-based sample. Methods: A total of 953 participants (55.7 ± 9.4 years) who underwent brachial-ankle pulse wave velocity (baPWV) and brain magnetic resonance imaging were included. Lacunes, CMBs, and PVS were visually rated. Brain structure and WMH were automatically segmented. Brain parenchyma fraction (BPF), a surrogate index of brain atrophy, was calculated as a ratio of brain parenchyma volume to total intracranial volume. Multivariable logistic and linear regressions were used to investigate the associations between baPWV and CSVD. Subsequently, we explored these associations in strata of age. Results: Increased baPWV was associated with severe PVS in white matter (OR, 1.09; 95%CI, 1.01-1.17; p = 0.022), larger WMH volume (ß, 0.08; 95%CI, 0.04-0.12; p < 0.001), lower BPF (ß, -0.09; 95%CI, -0.15- -0.03; p = 0.007), and marginally associated with strictly lobar CMBs (OR, 1.11; 95%CI, 1.00-1.23; p = 0.055), but not with lacunes. WMH volume mediated the relation between baPWV and BPF. In age subgroup analysis, the association of baPWV with PVS in white matter was stronger among those aged <55 years, whereas the association with brain atrophy was more prominent among those aged ≥55 years. Increased baPWV was associated with larger WMH volume in both younger and older individuals. Conclusions: Increased arterial stiffness was associated with most of imaging markers of CSVD, including PVS in white matter, larger WMH volume, strictly lobar CMBs, and brain atrophy, but not lacunes. The mechanisms underlying these associations and their potential clinical significances warrant further investigations.

MicroRNA-210 aggravates hypoxia-induced injury in cardiomyocyte H9c2 cells by targeting CXCR4.

BACKGROUND: Myocardial infarction (MI), a leading cause of mortality, is identified as the myocardial necrosis due to prolonged ischemia. Hypoxia, resulting from ischemia, induces cell apoptosis during MI. Since miR-210 is a hypoxia inducible factor, we aimed to explore the functional role of miR-210 in hypoxic H9c2 cells. METHODS: Hypoxia-induced cell injury was evaluated according to cell viability, apoptosis and expression of apoptosis-associated proteins. miR-210 expression after hypoxia was tested. Then, miR-210 was overexpressed or silenced, and its effects on viability and apoptosis of H9c2 cells under normoxia and hypoxia were measured. Utilizing bioinformatics method, possible target genes of miR-210 were screened, and the interaction between miR-210 and target gene was investigated. Moreover, the effect of co-transfections with microRNAs and small interfering RNAs on hypoxia-induced cell injury as well as the possible involved signaling pathways was also determined. RESULTS: Hypoxia induced cell injury and up-regulation of miR-210 in H9c2 cells. Hypoxia-induced cell injury was aggravated by miR-210 overexpression but was attenuated by miR-210 suppression. CXC chemokine receptor 4 (CXCR4) was a target gene of miR-210, and CXCR4 inhibition could reverse the effects of miR-210 inhibition on H9c2 cells. Furthermore, the key kinases involved in the SMAD and mTOR signaling pathways were down-regulated by hypoxia, and the down-regulations were reversed by miR-210 suppression through modulating CXCR4. CONCLUSION: miR-210 was up-regulated in hypoxic H9c2 cells. Suppression of miR-210 attenuated hypoxia-induced cell injury in H9c2 cells by targeting CXCR4, along with activations of the SMAD and mTOR signaling pathways.

Relationship between Neutrophil-to-Lymphocyte Ratio and Pulse Wave Velocity in Young Patients with Systemic Lupus Erythematosus.

BACKGROUND: The incidence of atherosclerosis-related myocardial infarction can be as much as 50-fold greater in young patients with systemic lupus erythematosus (SLE) than in age-matched controls. There are several explanations for this phenomenon, all of which result in a chronic state of low-grade inflammation. Recently, the neutrophil-to-lymphocyte ratio (NLR) has been proposed as a useful biomarker of inflammation. Pulse wave velocity (PWV) is a reliable indicator of vascular damage and atherosclerosis. There is a paucity of data concerning the relationship between NLR and atherosclerosis as measured by PWV in patients with SLE. This study aimed to verify whether there is a positive correlation between NLR and PWV and to explore factors that influence PWV in young SLE patients. METHODS: A total of 90 female patients with SLE were enrolled in this cross-sectional investigation. Traditional and nontraditional cardiovascular risk factors were assessed on the same day that brachial-ankle PWV (baPWV) was examined. The patients were divided into three groups according to their mean baPWV values: patients whose mean baPWV value was lower than the first tertile were placed in Group 1; patients whose mean baPWV value was between the first tertile and the second tertile were placed in Group 2; and patients whose mean baPWV value was higher than the second tertile were placed in Group 3. SPSS 20.0 was used to perform all statistical analyses in this study. Both univariate linear regression and multivariate regression models were utilized to analyze the association between NLR and arterial stiffness. RESULTS: Systolic blood pressure, diastolic blood pressure (DBP), and triglycerides were all significantly different among Groups 1, 2, and 3 (111.90 ± 12.85 mmHg vs. 114.60 ± 12.88 mmHg vs. 129.43 ± 16.21 mmHg, P < 0.001; 68.77 ± 8.63 mmHg vs. 71.87 ± 9.77 mmHg vs. 82.57 ± 14.89 mmHg, P < 0.001; and 1.44 [0.91-2.47] mmol/L vs. 0.98 [0.78-1.26] mmol/L vs. 2.20 [0.94-3.66] mmol/L, P = 0.030; respectively), as were creatinine (57.50 [52.00-69.00] µmol/L vs. 55.50 [49.00-64.00] µmol/L vs. 64.00 [56.00-86.00] µmol/L, P = 0.045) and blood urea nitrogen (4.27 [3.79-6.22] mmol/L vs. 4.16 [3.47-4.84] mmol/L vs. 5.88 [4.04-8.19] mmol/L, P = 0.011). NLRs were significantly different among Groups 1, 2, and 3 (2.16 [1.56-3.42] vs. 3.12 [1.91-4.19] vs. 5.29 [2.63-7.25], P = 0.001). NLR, together with DBP and the SLE disease activity index, independently predicts PWV. CONCLUSIONS: This study demonstrated that there was a positive correlation between NLR and PWV. Moreover, we found that disease activity and DBP were also positively correlated with PWV.

Interarm Blood Pressure Difference in Patients With Systemic Lupus Erythematosus.

OBJECTIVES: This study was performed to determine the relationship between systemic lupus erythematosus (SLE) and the interarm blood pressure difference (IAD) and to elucidate the role of the IAD as a surrogate marker for early detection of peripheral artery disease (PAD) in patients with SLE. METHODS: In total, 135 patients with SLE and 135 age- and gender-matched subjects were enrolled. The IAD and risk of an abnormal IAD were compared between the SLE and control groups, and logistic regression analysis was performed to determine the relationship between SLE and an abnormal IAD. The specificity and sensitivity of an IAD of 10 mm Hg or greater for diagnosis of PAD (ankle brachial index of <0.90) were calculated. RESULTS: Both the systolic and diastolic IADs were significantly higher in the SLE group than in the control group (P < 0.001). After adjustment for confounding factors, SLE remained significantly associated with an abnormal IAD (P = 0.039). Both the systolic and diastolic IADs were negatively associated with the ankle brachial index. Using a systolic IAD of 10 mm Hg or greater as the cutoff point, the specificity and sensitivity for PAD were 90% and 41%, respectively. A diastolic IAD of 10 mm Hg or greater exhibited higher specificity (92%), but lower sensitivity (30%). CONCLUSIONS: Systemic lupus erythematosus is independently associated with an abnormal IAD, and an IAD of 10 mm Hg or greater predicts PAD with high specificity but low sensitivity. Blood pressure should be measured at least once in both arms in patients with SLE for early detection of asymptomatic PAD.

[Incidence and associated risk factors of arterial stiffness in patients with systemic lupus erythematosus].

OBJECTIVE: To observe the prevalence and related risk factors of arterial stiffness measured by brachial-ankle pulse wave velocity (baPWV) in patients with systemic lupus erythematosus (SLE). METHODS: The study population included 135 patients currently enrolled in the Chinese SLE Treatment and Research group registry (CSTAR). All traditional cardiovascular risk factors and SLE-related disease factors were collected on the day of the baPWV examination. RESULTS: (1)Significant differences were observed in age (P < 0.000) , family history of cardiovascular disease (P = 0.003), mean blood pressure (P = 0.000) and hemoglobin A1c (P = 0.023) between SLE patients with normal and abnormal arterial stiffness. In addition, SLE patients with abnormal arterial stiffness had lower creatinine clearance rates [85.9 (65.5-108.8) ml/min vs. 106.4 (86.8-124.6) ml/min, P = 0.011], longer disease and hydroxychloroquine duration (P = 0.002 and P = 0.022, respectively), and higher proportion of intravenous cyclophosphamide use (OR = 3.04, 95%CI:1.230-7.514, P = 0.013) as compared to patients with normal arterial stiffness. (2)After adjustment of all confounding factors, age (OR = 4.56, 95%CI: 1.863-11.133, P = 0.001), mean blood pressure (OR = 1.12, 95%CI: 1.055-1.196, P = 0.000) , disease duration (OR = 1.12, 95%CI: 1.050-1.367, P = 0.007) and the proportion of intravenous cyclophosphamide use (OR = 2.86, 95%CI: 1.364-5.979, P = 0.005) remained as independent risk factors for abnormal arterial stiffness in SLE patients. CONCLUSION: Both traditional cardiovascular risk factors and SLE-related factors are associated with the risk of increased arterial stiffness.

Computed tomography for detecting left atrial thrombus: a meta-analysis.

INTRODUCTION: Thromboembolism, usually originating from the left atrium (LA) and left atrial appendage (LAA), is a major complication of atrial fibrillation and may result in transient ischemic attack and stroke. Computed tomography (CT) is a noninvasive test for detection of LA and LAA thrombus. We sought to conduct a meta-analysis to evaluate the accuracy of CT in detecting LA/LAA thrombus. MATERIAL AND METHODS: The PubMed, Medline, ISI Web of Knowledge and Cochrane Library databases up to June 2012 were searched for studies comparing CT and transesophageal echocardiography as the reference standard in detecting LA/LAA thrombus. Meta-analysis methods were used to pool sensitivity and specificity and to construct summary receiver operating characteristic (SROC) curves. RESULTS: A total of 9 studies with 1646 patients were included in this meta-analysis. The publication years spanned from 2007 to 2012. For CT diagnosis of LA/LAA thrombus, the mean sensitivity and specificity were 81% (95% CI: 70-90%) and 90% (95% CI: 88-91%), respectively. The SROC analysis showed an area under the curve of 0.93. CONCLUSIONS: Computed tomography shows a good diagnostic accuracy in detecting LA/LAA thrombus with high sensitivity and specificity. Thus CT should be considered the foremost noninvasive alternative to transesophageal echocardiography for detecting LA/LAA thrombus. Randomized studies at the patient level are needed to address the potential use of CT in detecting LA/LAA thrombus.

[The sural medial gastrocnemius island muscle flap to cover wound of infection on upper region of the tibial].

OBJECTIVE: To summarize clinical application of the sural medial gastrocnemius island muscle flap to cover wound of infection on upper region of the tibial. METHODS: Nine patients (7 men, 2 women) with soft tissue defects on the upper region of the tibial underwent reconstruction with the sural medial gastrocnemius island muscle flap. The age ranged from 21 to 60 years old (mean, 34 years). The immediate coverage of the muscle flaps were performed by a meshed split-thickness skin graft. The donor site was closed directly. The donor leg was ipsilateral in all cases. RESULTS: Only one case sustained superficial infection postoperative and the gradual wound healed by daily wound dressings. All the muscle flaps and skin graft had survived completely without major complication with satisfactory clinical results. All patients were followed-up for 13 months to 4 years (mean 21 months), the donor site was healing, there was no remarkable donor site morbidity. CONCLUSION: The sural medial gastrocnemius island muscle flap is nourished by the medial sural artery. The muscle flaps seem to have highly vascularize, a constant vascular anatomy and a long vascular pedicle. The muscle flap is thin and suitable for repairing soft tissue defect on the upper region of the tibial.

[Treatment of occluded iliofemoral veins with great saphenous vein cross-over bypasses].

OBJECTIVE: To summarize clinical application experience of treatment of occluded iliofemoral veins with great saphenous vein cross-over bypasses. METHODS: From September 1998 to December 2005,6 patients(5 men, 1 woman) with occluded iliofemoral veins underwent great saphenous vein cross-over bypasses. They ranged in age from 36 to 52 years (mean, 41 years old). All patients had unilateral thigh and leg edema and swelling with accompanying pain. The normal contralateral great saphenous vein was dissected and it was tunneled across the super-pubic fat pad and anastomosed to the femoral vein or the proximal portion of great saphenous vein in distal to occluded iliofemoral veins. RESULTS: The postoperative course was uneventful. One case sustained superficial infection postoperatively at donor site and the gradual wound healed by daily wound dressings. At 1 to 3.5 years (mean 1.8 years) followed up, all patients had pain disappearance and obvious relief of the edema but some swelling. CONCLUSION: Great saphenous vein cross-over bypasses is effective operative method of treatment of occluded iliofemoral veins. The operation is relatively simple and safe.

[High tibial osteotomy for the treatment of osteoarthritis of the knee].

OBJECTIVE: To summarize clinical application of the high tibial osteatomy (HTO) with lateral closing-wedge for the treatment of pain of unicompartmental osteoarthritis of the knee. METHODS: From February 2000 to February 2004,9 patients (3 males and 6 females, ranging in age from 52 to 58 years, with an average of 56 years) with unicompartmental osteoarthritis of the knee treated by HTO with lateral closing-wedge. The proximal tibiofibular joint was exposed, the anterior part of the capsule was incised, and to remove a laterally based wedge with saw cuts and osteotomes. Stepped staples were used for the fixation of tibial osteotomies after closing the defect of osteotomy. RESULTS: The operative course was uneventful. There were no complications after operation. The postoperative follow-up period ranged from 2 to 5.5 years (mean, 3.5 years). The results were evaluated with functional assessment criterion of the osteoarthritis of the knee, among the 9 cases, excellent was in 5 cases, good in 3 cases, fair in 1 case. CONCLUSION: HTO with lateral closing-wedge is an effective operative method for the treatment of pain of unicompartmental osteoarthritis of the knee, but except for older patients over 60 years.

[Repair of soft-tissue defect of amputation stumps of the forearm with free flap from the traumatic amputated extremity].

OBJECTIVE: To report the clinical results of the repair of soft-tissue defect of amputation stumps of the forearm with free flap from the traumatic amputated extremity. METHODS: Five patients, 4 males and 1 female, aged 32 (22 - 43), with soft-tissue defect of the remaining stump of the traumatic amputation of the forearm, 3 cases in the right forearm and 2 cases in the left forearm, underwent repair of the defect by free flap from the traumatic amputated extremity with the size of the flaps ranging from 8 cm x 9 cm to 9 cm x 12 cm. The patients were followed up for 2.6 years (1.5 - 3.5 years). RESULTS: Superficial infection occurred in one patient postoperatively and the wound was gradually healed by daily wound dressings. All the flaps survived completely with satisfactory clinical results. The cosmetic appearance on the recipient area was good and the function of the elbow recovered satisfactorily. CONCLUSION: The flap from the traumatic amputated extremity has a constant vascular anatomy and a long vascular pedicle, so that dissection of the flap can be accomplished easily. The surgery allows to preserve the functional length or the elbow function of the remaining stump of the traumatic amputation.