Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity.

The genome-wide perturbation of transcriptional networks with CRISPR-Cas technology has primarily involved systematic and targeted gene modulation. Here, we developed PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a screening platform that uses randomized CRISPR-Cas transcription factors (crisprTFs) to globally perturb transcriptional networks. By applying PRISM to a yeast model of Parkinson's disease (PD), we identified guide RNAs (gRNAs) that modulate transcriptional networks and protect cells from alpha-synuclein (αSyn) toxicity. One gRNA identified in this screen outperformed the most protective suppressors of αSyn toxicity reported previously, highlighting PRISM's ability to identify modulators of important phenotypes. Gene expression profiling revealed genes differentially modulated by this strong protective gRNA that rescued yeast from αSyn toxicity when overexpressed. Human homologs of top-ranked hits protected against αSyn-induced cell death in a human neuronal PD model. Thus, high-throughput and unbiased perturbation of transcriptional networks via randomized crisprTFs can reveal complex biological phenotypes and effective disease modulators.

Factors associated with subclinical inflammation of wrist joints in rheumatoid arthritis patients with low or no disease activity- a RA ultrasound registry study.

BACKGROUND: To evaluate the factors to predict subclinical inflammation of wrist joints in patients with RA who are in clinical remission or low disease activity. METHODS: Gray scale and power Doppler ultrasound were performed on the dorsal radio-lunate of both wrists. The presence of synovitis, comorbidities, and use of disease modifying anti-rheumatic drugs were recorded. A Multivariable forward logistical regression model was used to identify factors associated with subclinical inflammation. RESULTS: There were 1248 patients (1010 females, 238 males; mean age: 60.0 ± 10.5 years ). 57.4% of patients in complete remission and low disease activity had sonographic inflammation. Multivariable forward logistic regression analysis indicated that male sex, smoking are positively associated with inflammation and that age, alcohol consumption, and use of methotrexate, glucocorticoid, or a biological therapy are negatively associated with inflammation. Use of biological agents decreased the risk of inflammation by 40.9%. CONCLUSIONS: There was evidence of subclinical inflammation in most patients who were in low or no disease activity, those with biological therapy had lower risk of subclinical inflammation.

Recommendations for psoriatic arthritis management: A joint position paper of the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology.

In Taiwan, the incidence and prevalence of psoriatic arthritis (PsA) have risen significantly in recent years. Moreover, data from the Taiwan National Health Insurance Research Database (NHIRD) show that more than 85% of PsA patients are treated with just non-steroidal anti-inflammatory drugs (NSAIDs) and/or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Taiwanese clinicians have also expressed concerns regarding uncertainties in the diagnosis of PsA and the delayed, interrupted, and/or tapered use of biologics, as well as differences in therapeutic preferences between and within dermatologists and rheumatologists. To address these issues, the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology jointly convened a committee of 28 clinicians from the fields of rheumatology, dermatology, orthopedics, and rehabilitation, to develop evidence-based consensus recommendations for the practical management of PsA in Taiwan. A total of six overarching principles and 13 recommendations were developed and approved, as well as a treatment algorithm with four separate tracks for axial PsA, peripheral PsA, enthesitis, and dactylitis. Psoriasis (PsO) management was not discussed here, as the Taiwanese Dermatological Association has recently published a comprehensive consensus statement on the management of PsO. Together, these recommendations provide an up-to-date, evidence-based framework for PsA care in Taiwan.

Effects of Mean Artery Pressure and Blood pH on Survival Rate of Patients with Acute Kidney Injury Combined with Acute Hypoxic Respiratory Failure: A Retrospective Study.

Background and Objectives: In the intensive care unit (ICU), renal failure and respiratory failure are two of the most common organ failures in patients with systemic inflammatory response syndrome (SIRS). These clinical symptoms usually result from sepsis, trauma, hypermetabolism or shock. If this syndrome is caused by septic shock, the Surviving Sepsis Campaign Bundle suggests that vasopressin be given to maintain mean arterial pressure (MAP) > 65 mmHg if the patient is hypotensive after fluid resuscitation. Nevertheless, it is important to note that some studies found an effect of various mean arterial pressures on organ function; for example, a MAP of less than 75 mmHg was associated with the risk of acute kidney injury (AKI). However, no published study has evaluated the risk factors of mortality in the subgroup of acute kidney injury with respiratory failure, and little is known of the impact of general risk factors that may increase the mortality rate. Materials and Methods: The objective of this study was to determine the risk factors that might directly affect survival in critically ill patients with multiple organ failure in this subgroup. We retrospectively constructed a cohort study of patients who were admitted to the ICUs, including medical, surgical, and neurological, over 24 months (2015.1 to 2016.12) at Chiayi Chang Gung Memorial Hospital. We only considered patients who met the criteria of acute renal injury according to the Acute Kidney Injury Network (AKIN) and were undergoing mechanical ventilator support due to acute respiratory failure at admission. Results: Data showed that the overall ICU and hospital mortality rate was 63.5%. The most common cause of ICU admission in this cohort study was cardiovascular disease (31.7%) followed by respiratory disease (28.6%). Most patients (73%) suffered sepsis during their ICU admission and the mean length of hospital stay was 24.32 ± 25.73 days. In general, the factors independently associated with in-hospital mortality were lactate > 51.8 mg/dL, MAP ≤ 77.16 mmHg, and pH ≤ 7.22. The risk of in-patient mortality was analyzed using a multivariable Cox regression survival model. Adjusting for other covariates, MAP ≤ 77.16 mmHg was associated with higher probability of in-hospital death [OR = 3.06 (1.374-6.853), p = 0.006]. The other independent outcome predictor of mortality was pH ≤ 7.22 [OR = 2.40 (1.122-5.147), p = 0.024]. Kaplan-Meier survival curves were calculated and the log rank statistic was highly significant. Conclusions: Acute kidney injury combined with respiratory failure is associated with high mortality. High mean arterial pressure and normal blood pH might improve these outcomes. Therefore, the acid-base status and MAP should be considered when attempting to predict outcome. Moreover, the blood pressure targets for acute kidney injury in critical care should not be similar to those recommended for the general population and might prevent mortality.

The impact of long-term biologics/target therapy on bone mineral density in rheumatoid arthritis: a propensity score-matched analysis.

OBJECTIVES: To investigate changes in BMD in RA patients receiving 3-year biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) or conventional synthetic DMARD (csDMARD). METHODS: Patients with RA were recruited from September 2014 until March 2019. Clinical characteristics, BMD and evidence of fragility fractures at enrolment were documented. Participants were treated according to the National Institute for Health and Care Excellence (NICE) guidelines over a 3-year observation period. Repeated BMD was measured at the end of the study period. Participants were grouped into those receiving b/tsDMARD or csDMARD and by propensity score matching (1:2). RESULTS: A total of 388 participants completed the 3-year follow-up. After propensity score matching, 92 and 184 participants were allocated to the b/tsDMARD (Group I) and csDMARD (Group II), respectively. After 3 years, BMD remained stable at the femoral neck (FN), hip (total) (TH) and lumbar vertebra (L1-4) (P =0.09, 0.15, 0.87) in Group I. However, BMD decreased significantly in Group II (P=0.045, <0.001, 0.004) at corresponding sites. Participants receiving combined b/tsDMARD and anti-osteoporosis therapy experienced a greater BMD preserving effect than other subgroups. CONCLUSION: Long-term b/tsDMARDs therapy had protective effects on bone loss for patients with RA. Patients receiving concomitant anti-osteoporosis therapy and b/tsDMARDs therapy experienced the greatest BMD preserving effect.

Novel algorithm generating strategy to identify high fracture risk population using a hybrid intervention threshold.

INTRODUCTION: The aim of this study was to develop an algorithm to identify high-risk populations of fragility fractures in Taiwan. MATERIALS AND METHODS: A total of 16,539 postmenopausal women and men (age ≥ 50 years) were identified from the Taiwan Osteoporosis Survey database. Using the Taiwan FRAX® tool, the 10-year probability of major osteoporotic fracture (MOF) and hip fracture (HF) and the individual intervention threshold (IIT) of each participant were calculated. Subjects with either a probability above the IIT or those with MOF ≥ 20% or HF ≥ 9% were included as group A. Subjects with a bone mineral density (BMD) T-score at femoral neck based on healthy subjects of ≤ - 2.5 were included in group B. We tested several cutoff points for MOF and HF so that the number of patients in group A and group B were similar. A novel country-specific hybrid intervention threshold along with an algorithm was generated to identify high fracture risk individuals. RESULTS: 3173 (19.2%) and 3129 (18.9%) participants were categorized to groups A and B, respectively. Participants in group B had a significantly lower BMD (p < 0.001), but clinical characteristics, especially the 10-year probability of MOF (p < 0.001) or HF (p < 0.001), were significantly worse in group A. We found the algorithm generated from the hybrid intervention threshold is practical. CONCLUSION: The strategy of generating an algorithm for fracture prevention by novel hybrid intervention threshold is more efficient as it identifies patients with a higher risk of fragility fracture and could be a template for other country-specific policies.

Lower Central Fat Increase Risk of One-Year Muscle Mass Loss in Menopausal Women.

BACKGROUND: Hormonal changes had been found in menopausal women. Muscle and bone mass decline after menopause and with aging, increasing the risk for sarcopenia and osteoporosis in later life. Only a few studies suggest that menopausal hormonal changes have an effect on the decline in muscle mass. OBJECTIVES: This study aimed at evaluating the risk of muscle mass loss in menopausal women. MATERIALS AND METHODS: Menopausal women from routine physical health examination were eligible for this study. Muscle mass was determined using dual-energy X-ray absorptiometry at baseline and 1 year later. All of the patients underwent the assessments for liver and kidney function, diabetes, and hypertension, and associated comorbidities were recorded. RESULTS: A total of 172 patients were enrolled. 70 patients had muscle loss at 1 year, and the other 102 did not had loss. The mean age was 70.26 ± 9.93 years at the muscle loss group, while 69.25 ± 10.50 at the nonprogress group (p = 0.531). The mean body mass index was 22.96 ± 1.91 kg/m2 at the muscle loss group, while 23.33 ± 3.71 kg/m2 at the nonprogress group (p = 0.433). The baseline trunk limb fat mass ratio was 1.01 ± 0.20 in the muscle loss group and 1.12 ± 0.26 in the no muscle loss (p = 0.004). Using muscle mass loss as the outcome, logistical regression analysis showed that a baseline trunk limb mass ratio could predict muscle loss, and a higher baseline trunk limb mass ratio was associated with less muscle loss, while a lower trunk limb mass ratio was associated with increased muscle mass loss (p = 0.01). CONCLUSION: This is the first study to investigate the risk of muscle mass loss in menopausal women. Menopausal women with higher central fat had less muscle mass loss, while lower central fat was a risk factor for muscle mass loss. Chronic kidney disease was also a risk factor for muscle mass loss in menopausal women in this study.

Adherence to anti-osteoporosis medication associated with lower mortality following hip fracture in older adults: a nationwide propensity score-matched cohort study.

BACKGROUND: We investigated the association of anti-osteoporosis medication with mortality risk in older adults with hip fractures and evaluated the influence of medication adherence on mortality. METHODS: We conducted a population-based cohort study and identified a total of 13,123 patients aged 65 years or older with hip fracture from the Taiwan National Health Insurance Database during the period 2001-2010. Individuals with (n = 2092) and without (n = 2092) receiving anti-osteoporosis medication were matched using propensity score matching (1:1 ratio). The 1-, 3- and 5-year survival rates after the index fracture were compared between patients with and without treatment. In the treated group, survival rate was compared between those with good and non-adherence. Good adherence was defined as the medication possession ratio of ≥80% and non-adherence as a ratio < 80%. RESULTS: The 1-, 3- and 5-year mortality rates were significantly lower in the treated vs. the non-treated group (all p < 0.0001). In the treated group, the estimated 1-, 3- and 5-year survival rates were higher in those with good adherence than in those with non-adherence (all p < 0.0001). Regarding all-cause mortality, the adjusted hazard ratio in the treated vs. the non-treated group was 0.63 (95% confidence interval 0.58-0.68, p < 0.0001). The good adherence subgroup showed a significantly lower mortality risk than that in the non-adherence subgroup (hazard ratio 0.41, 95% confidence interval 0.32-0.51, p < 0.0001). CONCLUSIONS: The 1-, 3- and 5-year survival rates were significantly higher in patients receiving anti-osteoporosis medication than in the untreated group. All-cause mortality rates were lower in patients with good adherence to anti-osteoporosis medication.

Adherence to hydroxychloroquine improves long-term survival of patients with systemic lupus erythematosus.

Objectives: HCQ, which is known to decrease SLE activity, may have a protective effect on survival, but this has not been proven in Asia. This study aimed to determine whether HCQ treatment is associated with increased survival in patients with SLE. Methods: We designed this prospective SLE cohort study using data from the Taiwan National Health Insurance Research Database. The participants were divided into HCQ and control groups according to whether HCQ was prescribed during the first year after an SLE diagnosis. The primary outcome was mortality 1 year after inclusion. In the subgroup analysis, these participants were divided based on medication possession ratio (MPR) in the first year into non-users, MPR <40%, 40% ⩽ MPR < 80% and MPR ⩾80% subgroups to explore the relationship between survival and HCQ adherence. Results: A total of 12 443 patients were eligible for the analysis. After propensity score matching, we included 2287 patients in each group. During a mean follow-up of 7.6 years, there were 169 events in the HCQ group (7.4%) and 248 events in the control group (10.8%). The risk of mortality in the HCQ group was lower than that in the control group (hazard ratio = 0.68; 95% CI: 0.56, 0.82). The subgroup analysis revealed that the survival protective effect was associated with HCQ adherence. Conclusion: Patients with SLE who received HCQ had lower mortality rates due to any cause than those who did not. The survival benefit could be augmented by HCQ adherence.

Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study.

BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. TRIAL REGISTRATION NUMBER: NCT01721057; Results.

Cumulative immunosuppressant exposure is associated with diversified cancer risk among 14 832 patients with systemic lupus erythematosus: a nested case-control study.

Objectives: Immunosuppressive therapy is necessary to alter the natural course of SLE. However, immunosuppressant-related cancer risk is a major concern. The aim of this study was to determine whether immunosuppressant use is associated with cancer risk in SLE. Methods: We designed a retrospective nested case-control study within an SLE population based on the National Health Insurance Research Database in Taiwan. We screened 14 842 patients with SLE from 2001 to 2013 and compared patients with SLE complicated by later cancer with patients with SLE but without cancer. The cumulative dose of immunosuppressants was calculated from the SLE diagnosis date to the occurrence of cancer. The immunosuppressants of interest were AZA, CYC, MTX, HCQ and systemic glucocorticoids. Adjusted odds ratios (ORs) for cancer were calculated in conditional Cox regression models after propensity score matching. Results: The top five types of cancers were breast (16.9%), haematological (11.7%), colorectal (11.0%), lung (10.6%) and hepatobiliary (10.4%) cancers. After matching, this study included 330 cancer patients and 1320 matched cancer-free patients. The adjusted analyses showed an association of a higher cumulative CYC dose (OR = 1.09, 95% CI: 1.04, 1.13) and lower HCQ dose (OR = 0.93, 95% CI: 0.90, 0.97) with cancer risk in comparison with the controls. Conclusion: Diverse cancer risks are associated with different immunosuppressants in patients with SLE. CYC increases the risk of cancer, and HCQ decreases this risk in SLE patients, both in a dose-dependent manner.

Anti-TNF-Alpha-Adalimumab Therapy Had Time Lag of Improvement in Synovial Hypertrophy Compared to Rapid Response in Power Doppler Synovial Vascularity.

OBJECTIVES: The quantification of synovitis is of great significance for follow-up in patients with rheumatoid arthritis (RA). This study aimed to validate the use of power Doppler ultrasonography (PDUS) for evaluating synovial vascularity and synovial hypertrophy for synovitis in patients with rheumatoid arthritis treated with adalimumab. MATERIALS AND METHODS: The synovial disease activity and vascularity of RA on both wrists (radio-carpal joint) were assessed using GS and PDUS to derive the composite US scores based on abnormal counts and severity. The relationship between each measure was determined. RESULTS: The 71 patients who received adalimumab therapy had significantly decreased DAS28, ESR, and CRP. After one month, PD score decreased and then remained low for 12 months. Synovial hypertrophy did not change until 3-6 months after, when it started to improve (p = 0.017). By multivariate analysis, sex, age, BMI, and DAS28 did not lead to any difference between synovial hypertrophy and PDUS changes (p = 0.498). DISCUSSION: Composite US markers of synovial hypertrophy correlate significantly to the DAS28 score and ESR/CRP in adult RA. The time needed for synovial hypertrophy to decrease may be up to 3-6 months after adalimumab therapy. Switching to biological therapy before 3-6 months is inappropriate and ineffective.

Delayed anti-TNF therapy increases the risk of total knee replacement in patients with severe rheumatoid arthritis.

BACKGROUND: This study evaluated the effect of early anti-tumor necrosis factor (TNF) therapy in patients with severe rheumatoid arthritis (RA) on the subsequent risk of total knee replacement (TKR) surgery. METHODS: This retrospective observational study included a hospital-based cohort of 200 patients diagnosed with severe RA who received treatment with anti-TNF therapy between 2003 and 2014. Clinical parameters including age, sex, body mass index, and the time from the diagnosis of RA to the initiation of anti-TNF therapy were analyzed. RESULTS: Of the 200 enrolled patients, 84 underwent an early intervention (≤3 years from the diagnosis of RA to the initiation of anti-TNF therapy), and 116 underwent a late intervention(>3 years from the diagnosis of RA to the initiation of anti-TNF therapy). Five (6.0%) patients in the early intervention group underwent TKR compared to 31 (26.7%) in the late intervention group (p = 0.023). After adjusting for confounding factors, the late intervention group still had a significantly higher risk of TKR (p = 0.004; odds ratio, 5.572; 95% confidence interval, 1.933-16.062). Those receiving treatment including methotrexate had a lower risk of TKR (p = 0.004; odds ratio, 0.287; 95% confidence interval, 0.122-0.672). CONCLUSIONS: Delayed initiation of anti-TNF therapy in the treatment of severe RA was associated with an increased risk of TKR surgery. Adding methotrexate treatment decreased the risk of future TKR.

Predictor of Hand Radiological Progression in Patients With Rheumatoid Arthritis Receiving TNF Antagonist Therapy by Change in Grayscale Synovitis-A Preliminary Study.

OBJECTIVES: This prospective study aimed to compare synovial ultrasound scores to conventional measures (DAS28, CRP levels) in predicting radiographic progression in patients with rheumatoid arthritis under TNF antagonist therapy. METHODS: Patients with RA who received TNF antagonist therapy were enrolled, all of whom underwent clinical, laboratory, and ultrasonographic assessments with grayscale and power Doppler assessments of bilateral elbows (anterior and posterior recess), wrists (dorsal, palmar, and ulnar aspects), second and third MCP joints (dorsal and palmar recess), and PIP II and III (dorsal and palmar) at baseline and at 1, 3 months. Hand radiographic damage was evaluated using van der Heijde modified Total Sharp Score (TSS) at baseline and 12 months. RESULTS: Thirty-two patients (384 joints, 832 synovial sites) continued the same treatment regimen for 12 months and completed the study, 41.6% of whom showed radiographic progression during the study period. Baseline DAS28 (P = 0.123), CRP level (P = 0.177), grayscale synovitis (P = 0.092), and power Doppler synovitis (P = 0.120) could not predict radiological damage in the TNF antagonist therapy group. However, ΔTSS was significantly related to changes in grayscale synovitis between baseline and 1 month (P = 0.011), but not at 3 months (P = 0.591), and was not related to changes in the power Doppler score at 1 (P = 0.634) and 3 months (P = 0.298). CONCLUSIONS: Our data confirm that delayed improvement in grayscale synovitis between baseline and 1 month more accurately reflects 1-year radiological damage than conventional measures such as DAS28 score and CRP level. Therefore, we recommend serial ultrasound follow-up of patients with RA receiving TNF antagonist therapy.

Can antiosteoporotic therapy reduce mortality in MRI-proved acute osteoporotic vertebral fractures?

Patients with MRI-proved acute painful vertebral fractures in whom conservative pain management fails are frequently referred for vertebroplasty. This study investigated the effects of treating osteoporosis on the mortality rate of patients with MRI-proved acute osteoporosis-related vertebral fractures who had undergone vertebroplasty. We retrospectively reviewed the cases of osteoporosis patients with MRI-proved acute vertebral fractures who had been treated with vertebroplasty from January 2001 to December 2007. The long-term outcomes of the patients who received antiosteoporotic therapy were compared with those of patients who received no therapy. A total of 304 patients (247 female patients and 57 male patients; mean age, 74.1 ± 7.7 years) were enrolled in the study. The patients who received antiosteoporotic therapy had a significantly lower mortality rate than did patients who did not receive antiosteoporotic therapy (P = 0.001; hazard ratio, 0.396, 95 % confidence interval, 0.273-0.575). At the end of the study, 183 patients were alive, and 121 had died. Effective treatment for osteoporosis may improve survival in patients with osteoporosis-related vertebral fractures after vertebroplasty.

Can anti-osteoporotic therapy reduce adjacent fracture in magnetic resonance imaging-proven acute osteoporotic vertebral fractures?

BACKGROUND: Adjacent fracture of the cemented vertebrae result from crushed fragile trabeculae during follow-up, suggesting impaired bone marrow integrity. This study aimed to determine if anti-osteoporotic therapy can decrease the risk of adjacent fracture in patients after vertebroplasty. METHODS: This retrospective study reviewed of cases of osteoporotic patients with magnetic resonance imaging (MRI)-proven acute vertebral fractures between 2001 and 2007. Osteoporotic patients were investigated as determined by pre-operative MRI with subsequent adjacent fracture of the cemented vertebrae and for the possibility of anti-osteoporotic therapy decreasing the progression of collapse after a minimum of 6 months follow-up. All associated co-morbidities were recorded, as well as the use of anti-osteoporotic drugs (i.e., bisphosphonate, raloxifen, calcitonin, and teriparatide). Cox regression analysis was also performed. RESULTS: The 192 vertebral fractured patients who underwent vertebroplasty and anti-osteoporotic therapy had a mean age of 74.40 ± 6.41. The basic characteristics of patients with and without adjacent fracture differed in age, body mass index, rheumatoid arthritis, and use of glucocorticoids and anti-osteoporotic drugs (Table 1). Using the Kaplan-Meier curve, anti-osteoporotic therapy after vertebroplasty had a significant effect on adjacent fracture (p = 0.037, by log rank text). After adjusting for potential confounders, patients with anti-osteoporotic therapy still had a lower adjacent fracture rate than patients without anti-osteoporotic therapy (p = 0.006; HR: 2.137, 95 % CI: 1.1238-3.690). The adjacent fracture rate also increased in old age (p = 0.019; HR: 1.049; 95 % CI:1.008-1.039) and among smokers (p = 0.026; HR: 3.891; 95 % CI: 1.175-12.890). CONCLUSIONS: In this study, adjacent fracture of cemented vertebrae is inevitable after vertebroplasty but can be mitigated by anti-osteoporotic therapy to increase bone mass.

Is raloxifene associated with lower risk of mortality in postmenopausal women with vertebral fractures after vertebroplasty?: a hospital-based analysis.

BACKGROUND: Osteoporotic fractures are associated with mortality in postmenopausal woman. Whether raloxifen treatment after vertebroplasty can reduce mortality is unclear in this group. To compare the effect of raloxifene and no osteoporosis treatment on the risk of mortality after vertebroplasty, we designed this study. METHODS: This was a retrospective study (January 2001 to December 2007). Follow-up for each participant was calculated as the time from inclusion in the study to the time of death, or to December 31(st), 2013, whichever occurred first. All of the patients underwent baseline bone density studies, and age and body mass index (kg/m(2)) were recorded. All associated medical diseases such as diabetes, hypertension, and liver and renal disease were recorded. RESULTS: One hundred and forty-nine patients with vertebral fractures were enrolled, of whom 51 used raloxifene and 98 patients did not receive any anti-osteoporotic therapy. At the end of the follow-up period, 62 patients had died and 87 were still alive. The treated patients had a lower mortality rate than those who did not receive treatment (P = 0.001, HR = 3.845, 95% CI 1.884-7.845). The most common cause of mortality was sepsis, and those who received raloxifene had a lower rate of sepsis compared to those who did not receive treatment (P < 0.001). CONCLUSIONS: Effective treatment with raloxifene may had a lower mortality rate in patients with postmenopausal osteoporosis-related vertebral fractures after vertebroplasty.

Development of a Lipid-encapsulated TGFßRI-siRNA Drug for Liver Fibrosis Induced by Schistosoma mansoni.

Schistosoma mansoni infection leads to chronic schistosomiasis and severe hepatic fibrosis. We designed a liver-targeted lipid nanoparticle (LNP) carrying siRNA against type I TGF-ß receptor (TGFßRI) mRNA to treat schistosomiasis-induced liver fibrosis in BALB/c mice. Knockdown of TGFßRI by LNP-siTGFßRI reduced LX-2 cell activation in vitro and alleviated liver fibrosis in S. mansoni-infected mice. αSMA and Col1a1 fibrotic markers in the liver tissues of infected mice were significantly suppressed in the treatment groups. In the serum of the LNP-siTGFßRI-treated groups, cytokines IFNγ, IL-1α, IL-6, IL-12, RANTES (CCL5), and TNFα increased, while GM-CSF, IL-2, IL-4, IL-10, IL-13, and KC (CXCL1) decreased compared to the control. Cell proportions were significantly altered in S. mansoni-infected mice, with increased CD56d NK cells and decreased CD19+ B cells and CD4+ T cells compared to naïve mice. Following LNP-siTGFßRI treatment, CD56d NK cells were downregulated, while B and memory Th cell populations were upregulated. The density of fibrotic regions significantly decreased with LNP-siTGFßRI treatment in a dose-dependent manner, and no systemic toxicity was observed in the major organs. This targeted siRNA delivery strategy effectively reduced granulomatous lesions in schistosomiasis-induced liver fibrosis without detectable side effects.

Abatacept retention and clinical effectiveness in patients with rheumatoid arthritis in a real-world setting in Taiwan.

AIM: To evaluate real-world abatacept retention and clinical outcomes in patients with rheumatoid arthritis in Taiwan. METHODS: This prospective, observational study enrolled patients with rheumatoid arthritis aged ≥20 years who received abatacept in real-world practice. The primary endpoint was the abatacept retention rate at 24 months. Patients were categorized into subgroups based on abatacept treatment status and previous biological disease-modifying antirheumatic drug (bDMARD) therapy. Risk factors affecting abatacept retention were determined by regression analysis. RESULTS: A total of 212 patients were enrolled. The overall abatacept retention rate at 24 months among all patients was 59.9% (95% confidence interval 53.0%-66.6%). Patients who were ongoing users of abatacept and bDMARD-naïve had the highest retention rate (76.3%); of these, 31.6% achieved low disease activity or remission after 2 years. Previous treatment with bDMARDs was associated with an increased risk of abatacept discontinuation (hazard ratio 1.99; p = .002). The most common reasons for abatacept discontinuation were drug switch (11.3%) and loss to follow-up (6.1%). Abatacept was well-tolerated with no new safety signals. CONCLUSION: The 24-month retention rate of abatacept was 59.9%; abatacept was associated with improved clinical outcomes and was well-tolerated in the real-world setting in Taiwan.