Immunogenicity of the mRNA-1273 and ChAdOx1 nCoV-19 vaccines in Asian patients with autoimmune rheumatic diseases under biologic and/or conventional immunosuppressant treatments.

OBJECTIVE: Nucleic acid-based vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are effective in the general population. However, it is unknown whether this is true in Asian patients with autoimmune rheumatic diseases (ARDs) who have received various combinations of disease-modifying anti-rheumatic drugs (DMARDs). METHOD: We designed a large prospective observational study recruiting 228 patients with ARDs in a tertiary rheumatology centre in Taiwan. Altogether, 142 received biological or targeted synthetic DMARDs and 86 received only conventional synthetic (cs) DMARDs. Serum levels of immunoglobulin G antibody against SARS-CoV-2 spike proteins were measured 2-6 weeks after COVID-19 vaccination with mRNA-1273 (Moderna®) or ChAdOx1 nCoV-19 (Oxford/AstraZeneca®). The immunomodulatory therapies were not modified before or after vaccination. RESULTS: Overall, 194 patients (85.09%) exhibited antibodies (758.33 ± 808.43 ng/mL) but 34 patients did not (103.24 ± 41.08 ng/mL). Patients with systemic lupus erythematosus or rheumatoid arthritis had significantly lower humoral responses to COVID-19 vaccination than those with other ARDs (p < 0.05). There was no significant difference in immunogenicity among patients on different csDMARD treatments. Compared to patients treated with only csDMARDs, those on rituximab or abatacept therapy had significantly lower immune response to the vaccination (p = 0.008 and p = 0.035, respectively). Patients who were treated with anti-tumour necrosis factor-α or interleukin-6 inhibitor exhibited higher titres of vaccination antibodies than those treated with direct lymphocyte inhibitors. CONCLUSIONS: mRNA-1273 and ChAdOx1 nCoV-19 vaccines were immunogenic in the majority of ARD patients. Rituximab and abatacept were associated with significantly diminished COVID-19 vaccination immunogenicity.

Seasonal variation of chemical characteristics of fine particulate matter at a high-elevation subtropical forest in East Asia.

The aim of this study was to chemically characterize the fine particulate matter (PM2.5) at a subtropical forest in East Asia under the influences of anthropogenic and biogenic sources and a complex topographic setting. Four seasonal campaigns were conducted at the Xitou Experimental Forest in central Taiwan from the winter of 2013 to the autumn of 2014. The results indicated that the ambient levels and chemical features of PM2.5 exhibited pronounced seasonal variations. Non-sea-salt sulfate (nss-SO42-) constituted the major component of PM2.5, followed by ammonium (NH4+) and nitrate (NO3-) during winter, summer and autumn. However, it was revealed that the mass fraction of NO3- increased to be comparable with that of nss-SO42- in springtime. The mass contribution of secondary organic carbon (SOC) to PM2.5 peaked in summer (13.2%), inferring the importance of enhanced photo-oxidation reactions in SOC formation. Diurnal variations of O3 and SO2 coincided with each other, suggesting the transport of aged pollutants from distant sources, whereas CO and NOx were shown to be under the influences of both local and regional sources. Notably high sulfur oxidation ratio (SOR) and nitrogen oxidation ratio (NOR) were observed, which were 0.93 ±â€¯0.05 and 0.39 ±â€¯0.20, respectively. Precursor gases (i.e. SO2 and NOx) could be converted to sulfate and nitrate during the transport by the uphill winds. Furthermore, due to the high relative humidity at Xitou, enhanced aqueous-phase and/or heterogeneous reactions could further contribute to the formation of sulfate and nitrate at the site. This study demonstrated the significant transport of urban pollutants to a subtropical forest by the mountain-valley circulations as well as the long-range transport from regional sources, whereas the implications of which for regional climate change necessitated further investigation.

Incidence and risk factors of osteomyelitis in adult and pediatric systemic lupus erythematosus: a nationwide, population-based cohort study.

OBJECTIVE: The objective of this paper is to investigate the incidence rate, risk factors and outcome of osteomyelitis among patients with systemic lupus erythematosus (SLE). MATERIALS AND METHODS: We conducted a cohort study using data for patients enrolled in the Taiwan National Health Insurance Database from 2000 to 2012. Patients with SLE and age- and sex-matched controls without SLE were enrolled. Primary endpoint was the first occurrence of osteomyelitis. Risks of osteomyelitis in SLE patients were analyzed with Cox proportional hazards regression models, including age, sex, comorbidities and medications. RESULTS: Among 24,705 SLE patients (88.4% women, mean age 35.8 years) with a median follow-up of 9.1 years, 386 patients had osteomyelitis. The incidence rate ratio (IRR) of osteomyelitis in the SLE group vs the control group was 8.52 (95% confidence interval (CI) 7.24-10.05). The SLE group had higher incidence rates of osteomyelitis than the control group, especially in pediatric subgroups (IRR 41.1 95% CI 18.57-107.35). Compared to controls, SLE patients experienced osteomyelitis at a younger age (42.3 vs 58.1 years) but did not have an increased risk of mortality (hazard ratio 0.7; 95% CI 0.21-2.38). Age >60 years, male gender, malignancy within five years, prior bone fracture and higher daily prednisolone dose (>7.5 mg) cumulatively for >180 days increased risk for osteomyelitis. CONCLUSIONS: SLE patients have a higher IRR of osteomyelitis than controls. Pediatric and elder SLE patients, patients with a history of bone fracture, malignancy within five years and higher-dose glucocorticoid use have a higher risk of osteomyelitis and should be carefully monitored.

Invasive aspergillosis in patients with systemic lupus erythematosus: a retrospective study on clinical characteristics and risk factors for mortality.

Objective The objective of this paper is to analyze the clinical features, outcomes, mortality risk factors, and all-cause mortalities of invasive aspergillosis (IA) in patients with systemic lupus erythematosus (SLE). Methods Medical records were reviewed to identify SLE patients with IA from January 2006 to June 2017, at Taipei Veterans General Hospital, Taiwan. A total of 6714 SLE patients were included. Clinical/laboratory parameters and treatment outcomes were analyzed. Results Four patients (19.0%) had definite and 17 had probable (81.0%) IA. Seven patients (33.3%) survived and 14 died (66.7%). Concurrently, there were 19 pneumonias (90.5%), 17 cases of other infections (81.0%), eight bacteremia (38.1%), nine cytomegalovirus (CMV, 42.7%) and six Candida (28.6%) infections. In all 55 blood cultures, 38 (69.1%) yielded gram-negative bacilli, of which carbapenem-resistant A. baumannii accounted for eight (21.1%); 17 (30.9%) yielded gram-positive cocci, of which methicillin-resistant S. aureus accounted for six (35.3%); and vancomycin-resistant Enterococcus accounted for four (23.5%). Daily steroid dose ≥ 20 mg (hazard ratio (HR) 2.00), recent pulse steroid therapy (HR 2.80), azathioprine (HR 2.00), rituximab (HR 2.00), plasmapheresis (HR 2.00), acute respiratory distress syndrome (HR 2.00), concurrent infections (HR 5.667) and CMV viremia (HR 1.75) were higher in the fatality group. All p values were less than 0.05. Septic shock ( n = 7, 50% in the fatality group) is the most common cause of mortality. Conclusions High daily steroid dosing, recent pulse steroid therapy, azathioprine, rituximab, concurrent infections, and CMV viremia were mortality risk factors for IA in SLE.

Bone morphogenetic proteins and Dickkopf-1 in ankylosing spondylitis.

OBJECTIVES: To determine bone morphogenetic proteins (BMPs) and Dickkopf homologue-1 (Dkk-1) levels in ankylosing spondylitis (AS). METHOD: Serum BMPs and Dkk-1 were measured in 72 AS patients and 30 healthy controls. For AS patients, we recorded the demographic data, disease activity, functional index, and global assessment with questionnaires, and image changes with roentgenography. We also measured human leucocyte antigen-B27 and systemic inflammatory reactants. RESULTS: BMPs were higher but Dkk-1 was significantly lower in AS patients than in controls. Dkk-1 was higher in AS patients who received non-steroidal anti-inflammatory drugs (NSAIDs) regularly in the past year (p = 0.001). Serum BMP-7 level and the BMP-7/Dkk-1 ratio correlated significantly with sacroiliitis severity, Bath Ankylosing Spondylitis Radiology Index (BASRI)-total, modified Stoke Ankylosing Spondylitis Spinal Score, and disease duration. There were also significant positive correlations among serum levels of BMP-2, -4, and -6, BASRI-total, and disease duration (p < 0.05). However, BMP-2/Dkk-1 was only significantly correlated with disease duration. The calculated area under the standard receiver operating characteristics curve suggested that BMP-2/Dkk-1 and serum BMP-2 are good indicators to predict disease activity, functional index, and patient global assessment in AS patients. CONCLUSION: BMPs and BMPs/Dkk-1 were significantly correlated with disease activity, and radiological and functional indices in AS patients. Dkk-1 was lower in AS patients than in controls. Among AS patients, Dkk-1 was higher in those taking NSAIDs regularly. BMP or Dkk-1 may be taken as a biomarker for disease severity or a treatment outcome predictor in AS, but this needs further study.

Ledipasvir + Sofosbuvir for Liver Transplant Recipients With Recurrent Hepatitis C: A Systematic Review and Meta-analysis.

INTRODUCTION: Studies focusing on the efficacy and safety of ledipasvir (LDV) + sofosbuvir (SOF) therapy in liver transplant (LT) recipients with hepatitis C virus (HCV) recurrence are still limited. Therefore, the aim of our work was to perform a systematic review and meta-analysis to evaluate outcome data of LDV + SOF therapy in LT recipients. METHODS: Multiple databases were systematically searched for eligible studies. We included studies reporting sustained virological response 12 weeks after treatment (SVR12) and treatment-related adverse events (AEs) in LT recipients treated with LDV + SOF ± ribavirin (RBV) for HCV recurrence. All statistical analyses were conducted by using R version 3.3.1 (The R Foundation for Statistical Computing, Vienna, Austria). RESULTS: Twelve studies with a total of 994 LT recipients were included, most of which were diagnosed with HCV genotype 1 infection. The overall SVR12 reached 96.3% (95% confidence interval [CI]: 94.9%-97.5%) and no significant heterogeneity was observed (Q statistic = 10.63, P = .47; I2 = 0%). No difference was found in SVR12 between treatments for 12 weeks and 24 weeks (P = .18). Patients treated with LDV + SOF + RBV (n = 525) exhibited an SVR12 rate of 95.1% (95% CI 92.8%-96.6%), which showed no difference from the findings in the LDV + SOF treatment group (n = 314) with an SVR12 reaching 94.9% (95% CI 91.5%-97.0%; P = .92). There was a tendency for a higher SVR12 in patients without cirrhosis than those with cirrhosis (P < .05). The most common AEs were listed as following: anemia 41.9% (n = 203 of 484), fatigue 39.1% (n = 207 of 530), headache 24.2% (n = 128 of 530), nausea 21.9% (n = 106 of 484), and diarrhea 19.0% (n = 92 of 484). CONCLUSION: LDV + SOF-based treatment is highly effective and well tolerated in LT recipients with HCV reinfection.

Association of CHADS2 and CHA2DS2-VASc Scores with Left Atrial Thrombus with Nonvalvular Atrial Fibrillation: A Single Center Based Retrospective Study in a Cohort of 2695 Chinese Subjects.

The main mechanism of the CHADS2 and CHA2DS2-VASc scores to predict stroke in nonvalvular atrial fibrillation (NVAF) is still controversial. We evaluated the association of the CHADS2 and CHA2DS2-VASc scores with left atrial thrombus (LAT) as detected by transesophageal echocardiographic (TEE) and compared the predictive ability of these risk stratification schemes with nonvalvular atrial fibrillation (NVAF). Data from 2,695 consecutive NVAF patients in whom TEE was performed for screening LAT from July 2007 to February 2014 were analyzed. Only 3% of the subjects had LAT. Presence of LAT was not significantly associated with either CHADS2 (P = 0.07) or CHA2DS2-VASc score (P = 0.12). The area under the curve (AUC) concerning LAT prediction using CHADS2 and CHA2DS2-VASc was 0.574 and 0.569, respectively. A composition model includes previous stroke or transient ischemic attack, nonparoxysmal AF, moderate to severe left ventricular systolic dysfunction, left atrial enlargement, and cardiomyopathy which improved the discrimination significantly (AUC = 0.743). In our cohort, both CHADS2 and CHA2DS2-VASc scores were of limited value for predicting LAT in patients with NVAF. This questions the CHADS2/CHA2DS2-VASc score predicting stroke mainly through the mechanism of cardiogenic embolism. A scoring scheme combining clinical and echocardiographic parameters may better predict LAT as a surrogate for cardioembolic risk in NVAF patients.

Determination of a threshold compromise value for the perfusion index by laser Doppler imaging after digital revascularization.

We have used laser Doppler imaging to monitor the microcirculation of replanted digits during the post-operative period in 103 patients who underwent either replantation after traumatic amputation or toe-to-finger reconstruction. The blood flow (perfusion unit) in each revascularized digit was compared with that of an unaffected digit. The perfusion index was defined as the perfusion value of a revascularized digit divided by the perfusion value of the neighbouring normal digit. The ideal threshold value of the perfusion index (0.397) was calculated by determining the receiver operating characteristic curve with optimal sensitivity and specificity. The corresponding Youden's index was 0.828. We believe that by establishing a threshold, that laser Doppler imaging should provide a reliable and objective assessment for the development of perfusion compromise in revascularized digits. LEVEL OF EVIDENCE: III.

Ethylene Oxide Sterilization Preserves Bioactivity and Attenuates Burst Release of Encapsulated Glial Cell Line Derived Neurotrophic Factor from Tissue Engineered Nerve Guides For Long Gap Peripheral Nerve Repair.

Synthetic nerve guides are widely utilized to reconstruct peripheral nerve defects that are less than three centimeters. However, there are no clinically available nerve guides that are approved to promote repair over long gaps (>3 cm). Many currently available guides are unable to sustain large defect regeneration either because of limitations in fabrication or short degradation times in vivo. Furthermore, current clinically available nerve guides do not contain neurotrophic factor delivery systems to promote nerve tissue regeneration over long gaps. The purpose of this paper is to describe the manufacturing parameters and sterilization procedures of a 5.2 cm poly(caprolactone) nerve conduit with embedded polymeric microspheres that encapsulate glial cell line-derived neurotrophic factor (GDNF) for implantation into a preclinical rhesus macaque 5 cm median nerve defect model. Nerve conduits were sterilized with room temperature ethylene oxide (RT EtO) and assessed for morphology as well as maintenance of porosity. Release kinetics and bioactivity of GDNF were also assessed in RT EtO sterilized guides. Scanning electron microscopy indicated that RT EtO treatment did not affect morphology and porosity percentage of nerve guides. Furthermore, RT EtO had no effect on GDNF bioactivity based on Schwannoma cell migration studies. RT EtO guides exhibited significantly slowed GDNF release compared to GDNF release from nonsterile guides indicating that EtO treatment may enhance the long-term delivery kinetics of GDNF from polymeric microspheres within the nerve guide.

Inverted-T lip reduction for lower lip repair in Van der Woude syndrome: a review and comparison of aesthetic results.

Elimination of cosmetic deformity of lower lip pits and lower lip protrusion is the most common indication for lower lip repair in Van der Woude syndrome. 34 patients with lower lip pits that were operated on between 1982 and 2006 were reviewed. Surgical correction was performed with one of three different techniques: simple excision, vertical wedge resection, or inverted-T lip reduction. The aesthetic results were evaluated by two groups of raters. One group consisted of 10 medical professionals, and the other 10 lay people. A rating scheme was utilized, with a score of 3 for good, 2 for fair, and 1 for poor results. The final results were compared based on the mean score for each patient and inter-rater reliability was assessed using a weighted kappa coefficient. There was a fair agreement on the ratings between raters within groups. Inverted-T lip reduction received the best aesthetic result score from both groups of evaluators, with a mean score of 2.38±0.30 in the professional group, and 2.43±0.29 in the lay group. The results conclude that inverted-T lip reduction is a simple, safe and effective technique that achieves a better aesthetic result in lower lip repair of Van der Woude syndrome.

Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition.

BACKGROUND AND PURPOSE: Capsaicin, an agonist of transient receptor potential vanilloid 1 (TRPV1) channels, is pro-nociceptive in the periphery but is anti-nociceptive when administered into the ventrolateral periaqueductal gray (vlPAG), a midbrain region for initiating descending pain inhibition. Here, we investigated how activation of TRPV1 channels in the vlPAG leads to anti-nociception. EXPERIMENTAL APPROACH: We examined synaptic transmission and neuronal activity using whole-cell recordings in vlPAG slices in vitro and hot-plate nociceptive responses in rats after drug microinjection into the vlPAG in vivo. KEY RESULTS: Capsaicin (1-10 µM) depressed evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in vlPAG slices presynaptically, while increasing miniature excitatory PSC frequency. Capsaicin-induced eIPSC depression was antagonized by cannabinoid CB1 and metabotropic glutamate (mGlu5) receptor antagonists, and prevented by inhibiting diacylglycerol lipase (DAGL), which converts DAG into 2-arachidonoylglycerol (2-AG), an endocannabinoid. Capsaicin induced membrane depolarization in 2/3 neurons recorded but, overall, increased neuronal firings by increasing evoked postsynaptic potentials. Intra-vlPAG capsaicin reduced hot-plate responses in rats, effects blocked by CB1 and mGlu receptor antagonists. Effects of capsaicin were antagonized by SB 366791, a TRPV1 channel antagonist. CONCLUSIONS AND IMPLICATIONS: Capsaicin activated TRPV1s on glutamatergic terminals to release glutamate which activated postsynaptic mGlu5 receptors, yielding 2-AG from DAG by DAGL hydrolysis. 2-AG induces retrograde inhibition (disinhibition) of GABA release via presynaptic CB1 receptors. This disinhibition in the vlPAG leads to anti-nociception by activating the descending pain inhibitory pathway. This is a novel TRPV1 channel-mediated anti-nociceptive mechanism in the brain and a new interaction between vanilloid and endocannabinoid systems.

Prevalence of spondyloarthritis in 504 Chinese patients with HLA-B27-associated acute anterior uveitis.

OBJECTIVES: To estimate the prevalence of spondyloarthritis (SpA) and the clinical features of human leucocyte antigen (HLA)-B27-associated acute anterior uveitis (HLA-B27 uveitis) in Chinese patients. METHODS: We conducted a retrospective cohort study using a structured chart review to record the complete ocular history, including the onset of uveitis, month of uveitis attack, specific eye involvement, the time of first attack, and rheumatic manifestations from 1987 to 2004. A total of 504 patients with HLA-B27 uveitis were consequently enrolled consecutively from the uveitis clinic of Taipei Veterans General Hospital. RESULTS: In total, 1719 attacks of uveitis in 504 patients were recorded. Females tended to have a higher frequency of attack than males, and those with a disease course of less than 5 years showed more uveitis recurrence. The same eye attacks were observed in 156 of 332 patients (47%), more than the expected percentage compared with attacks with random-eye occurrence (p < 0.001). A significantly higher number of uveitis attacks occurred in winter. SpA-related acute anterior uveitis (AAU) was found in 387 patients (76.8%). Ankylosing spondylitis (AS) occurred in 214 patients (42.5%), with a significantly higher prevalence in males than in females (p < 0.001). Undifferentiated SpA (USpA)-related AAU occurred in 150 patients (29.8%), with a significantly higher prevalence in females than in males (p < 0.001). Patients with SpA had an earlier onset of uveitis (p = 0.01) and a greater number (> or = 6) of attacks (p = 0.03). CONCLUSIONS: The prevalence of SpA was high in the Chinese population with HLA-B27-associated uveitis. The association with SpA indicated an earlier age of uveitis onset and a greater likelihood of having a higher number of uveitis attacks.

Alveolar bone grafting in the treatment of midline alveolar cleft and diastema in incomplete median cleft lip.

Median cleft lip is a rare congenital anomaly. The wide diastema with mesial tipping observed in these patients has been largely overlooked. A midline submucosal alveolar cleft prevents adequate treatment. The purpose of this article is to describe an alveolar bone grafting (ABG) technique used in the combined surgical-orthodontic approach to diastema treatment in patients presenting with incomplete median cleft lip. Patients treated for incomplete median cleft lip and diastema were identified in the clinic registry from 1981 to 2007. Six patients were identified; 4 underwent ABG before permanent maxillary incisor eruption, the other 2 were seen later when they were 11 years old. All 6 ABGs were successful. The incisors erupted through the graft or were successfully moved into it with lasting results. Follow-up ranged from 8 to 21 years. The existence of a midline submucosal alveolar cleft and subsequent diastema should be recognized and addressed in all patients who present with incomplete median cleft lip repair. This includes taking maxillary occlusal view X-rays before the age of 5 years to detect the cleft, and proceed to ABG if necessary, generally before permanent maxillary incisor eruption.

The effect of etanercept on anti-cyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the changes in anti-cyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor (RF) following etanercept treatment in patients with rheumatoid arthritis. METHODS: The study included 90 patients with rheumatoid arthritis who failed treatment with disease modifying antirheumatic drugs (DMARDs). All patients were allowed to continue treatment with DMARDs; 52 of them received etanercept as a twice weekly 25 mg subcutaneous injection for three months, and the others did not. Serum samples were collected at baseline and one month intervals during the treatment course. The serum levels of anti-CCP and RF were tested by enzyme linked immunosorbent assay and nephelometry, respectively. RESULTS: At baseline, 45 of the 52 etanercept treated patients (86.5%) and 32 of the 38 controls (84.2%) were positive for anti-CCP. Tests for RF were positive in 78.9% and 84.2% of patients with or without etanercept treatment, respectively. The serum levels of anti-CCP and RF decreased significantly after a three month etanercept treatment (p = 0.007 and p = 0.006, respectively). The average decrease from baseline calculated for each individual patient in the etanercept treated group was 31.3% for anti-CCP and 36% for RF. The variation in anti-CCP was positively correlated with the variation in disease activity, swollen and tender joint counts, RF, and C reactive protein. CONCLUSIONS: Etanercept combined with DMARDs leads to a much greater decrease than DMARDs alone in the serum levels of anti-CCP and RF in rheumatoid arthritis, compatible with a reduction in clinical disease activity.

Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in ankylosing spondylitis: MMP-3 is a reproducibly sensitive and specific biomarker of disease activity.

OBJECTIVE: To submit serum levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) to statistical analyses to test their exact degrees of clinical usefulness as biomarkers for detecting high disease activity in ankylosing spondylitis (AS), comparing them with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). METHODS: Serum levels of MMP-1, -3, -9 and TIMP-1 and -2 were measured in 42 AS patients and 20 healthy controls. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) provided the gold standard for measuring disease activity. Patients with BASDAI > or =4 were regarded as having high disease activity. The results were compared with results for a separate cohort of 41 AS patients. RESULTS: Only MMP-3 levels were significantly higher in AS patients than in healthy controls (P<0.001). Within AS patients, MMP-3 levels were also higher in patients with high disease activity compared with those with low disease activity, and correlated significantly with BASDAI (r = 0.366, P = 0.017) and functional indices (r = 0.344, P = 0.026). The correlation with BASDAI was stable in a 1-yr follow-up (r = 0.464, P = 0.095) and reproducible with two different enzyme-linked immunosorbent assays. For detecting high disease activity, the sensitivity and specificity of MMP-3 level was 69.2 and 68.8% respectively. Most importantly, using receiver operating characteristic plots to analyse the two cohorts, MMP-3 was more accurate than ESR and CRP in detecting AS patients with high disease activity (P = 0.01 and P = 0.009, respectively). CONCLUSION: Using several analytical approaches that have never been reported previously, we showed that MMP-3 is a more useful biomarker than ESR and CRP to detect high disease activity in AS.